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Pharmacists Council of Nigeria

1 FPGOP Lecture Note on Applied Pharmacology and Toxicology

APPLIED PHARMACOLOGY AND TOXICOLOGY

A. GENETIC AND NUTRITIONAL FACTORS IN DRUG ACTION

Course outline

(1). Nutritional factors in drug action

(i). Malnutrition

(ii). Some features of protein-energy malnutrition and drug action

(iii). Miscellaneous dietary factors and drug action

(iv). Food-derived intoxicants

(2). Pharmacogenetics

Learning Objectives

At the end of the course participants should

(a). Explain how malnutrition, particularly protein-energy malnutrition, can influence drug

absorption, distribution, metabolism, excretion, and therapeutic effect.

(b). Mention poisons/intoxicants from food.

(c). State some constituents of our diet that may affect drug action, and how?

(d). Mention genetic factors involved in drug action, and the mechanisms involved.

(e). Understand the roles of pharmacogenetics, including its possible applications.

(f). Mention some drugs whose actions are affected by genetic polymorphisms, and the

mechanism(s) involved.

(g). Mention drugs and other substances to be avoided by G6PD deficient individuals.

A1. NUTRITIONAL FACTORS IN DRUG ACTION

Human nutrition deals with the provision of essential nutrients in food, that are necessary to

support life and health. Nutrition as a science, involves the interaction of nutrients and other

substances in food relative to maintenance, growth, reproduction, health and disease of

humans. It encompasses food intake, absorption, catabolism and excretion. Nutrition is

dependent on the diet. A good nutrition provides essential nutrients needed for good health and

sustenance, while poor nutrition or malnutrition results in morbidity and mortality.

(i). Malnutrition



Malnutrition is one of the major public health problems of the Third World and several million

people are underfed and suffer from deficiencies of essential nutrients.

Definition of Malnutrition

Malnutrition is a condition due to consumption of diet in which one or more nutrients are either

inadequate or in excess, resulting in ill health. Lack of adequate nutrients is called

undernutrition or undernourishment while too much is called overnutrition. Overnutrition may

result in being overweight, obesity and other disorders. Undernutrition may lead to starvation,

physical and mental underdevelopment, infections, and other diseases.

Generally, malnutrition is often used to specifically refer to undernutrition where an individual is

not getting enough calories, protein, or micronutrients. There are two main types of

undernutrition; protein-energy malnutrition and dietary deficiencies.

Protein-energy malnutrition (PEM) results when the body is lacking the calories it needs from

protein, carbohydrates and fats. In addition to macronutrient deficiency, there is clinical and/or

subclinical deficiency of micronutrients. Three forms of PEM are marasmus, kwashiorkor and

marasmic-kwashiorkor.

Kwashiokor

Kwashiorkor, also called protein malnutrition, is due to severe protein deficiency. Kwashiokor

was first described in children in 1932. The term kwashiorkor is derived from the Ga language

of coastal Ghana, translated as ‘the sickness the baby gets when the new baby comes’ or ‘the

disease of the deposed child’; this refers to the development of the disorder in an older child

who has been weaned from the breast when a younger sibling comes. In another dialect, it

connotes ‘red boy’, referring to the reddish orange discoloration of the hair that is characteristic

of the disease.

Kwashiorkor occurs in areas of famine or poor food supply, e.g. during the Nigerian civil war. It

is most often encountered in areas where the diet is high in starch and low in proteins, cases

are rare in the developed countries. In at-risk populations, kwashiorkor may develop after a

mother weans her child from breast milk (contains proteins and amino acids vital to a child's

growth), replacing it with a diet high in carbohydrates and low in proteins. It is common in

young children weaned to a diet consisting mainly of cereal grains, cassava, yam, sweet potato

or other foods high in carbohydrates. Ignorance of nutrition could also be a cause of

https://en.wikipedia.org/wiki/Diet_(nutrition)

https://en.wikipedia.org/wiki/Nutrient

https://en.wikipedia.org/wiki/Overnutrition

https://en.wikipedia.org/wiki/Overweight

https://en.wikipedia.org/wiki/Micronutrients

https://en.wikipedia.org/wiki/Protein-energy_malnutrition

https://en.wikipedia.org/wiki/Protein-energy_malnutrition

https://www.britannica.com/science/protein

https://en.wikipedia.org/wiki/Ga_language

https://en.wikipedia.org/wiki/Ghana

https://en.wikipedia.org/wiki/Breastfeeding#Weaning

https://www.merriam-webster.com/dictionary/dialect

https://www.britannica.com/science/disease

https://en.wikipedia.org/wiki/Amino_acid

https://en.wikipedia.org/wiki/Carbohydrate

https://www.britannica.com/plant/cassava

https://en.wikipedia.org/wiki/Carbohydrate



kwashiorkor. In addition to protein-deficient diet, other causes of kwashiorkor include poor

intestinal absorption, chronic alcoholism, kidney disease, infection, and burns or other trauma

resulting in the abnormal loss of body protein.

Symptoms of kwashiorkor include distended abdomen with ascites, edema (including pitting

edema), thinning of hair reddish orange discoloration of the hair, dry skin, skin rash, skin

depigmentation, dermatitis, wide spread dermatosis, shock due to bacterial infection, weakness,

nervous irritability, anemia, digestive disturbances such as diarrhea, anorexia, enlarged liver

with fatty infiltrates, and delayed growth. Generally, the disease can be treated by adding

protein to the diet; however, it can have a long-term impact on a child's physical and mental

development, and in severe cases may lead to death.

Marasmus

Marasmus is a form of severe malnutrition characterized by energy deficiency. It can be

distinguished from kwashiorkor in that kwashiorkor is protein deficiency with adequate energy

intake whereas marasmus is inadequate energy intake in all forms, including protein (some

body protein is metabolized to supply the body’s energy needs, in cases of inadequate

carbohydrate intake).

It can occur in anyone with severe malnutrition but usually occurs in children. The incidence of

marasmus increases prior to 1 year of age, whereas kwashiorkor increases after 18 months. A

child with marasmus looks emaciated, body weight is reduced to less than 62% of the normal

(expected) body weight for the age. Protein wasting in kwashiorkor generally leads to edema

and ascites, while muscule wasting and loss of subcutaneous fat are the main clinical signs of

marasmus.

Precise separation of marasmus and kwashiorkor is however not always clinically evident and a

mixed clinical picture, called marasmic-kwashiorkor occurs.

(ii). Some features of protein-energy malnutrition and drug action

Nutritional status is one of the major factors that modify the pharmacological effect of drugs.

Macro- and micro-nutrient deficiencies cause pathological changes that interfere with

pharmacokinetic and pharmacodynamic processes in the body, resulting in altered drug

response. Studies in laboratory animals and in malnourished human subjects indicate that

dietary factors and nutritional status considerably influence absorption, distribution, plasma

https://www.britannica.com/science/alcoholism

https://www.britannica.com/science/edema

https://www.britannica.com/science/anemia

https://en.wikipedia.org/wiki/Malnutrition

https://en.wikipedia.org/wiki/Protein%E2%80%93energy_malnutrition

https://en.wikipedia.org/wiki/Kwashiorkor

https://en.wikipedia.org/wiki/Emaciation

https://en.wikipedia.org/wiki/Edema

https://en.wikipedia.org/wiki/Ascites



protein binding, metabolism and excretion of drugs; hence therapeutic response and toxicity are

likely to be altered.

In malnutrition, changes in nutrient transport, morphology of body tissues (e.g mucosal and

villous atrophy), permeability of the intestinal mucosa and activity of enzymes could contribute

to modifications in drug absorption. Drug distribution could be altered by changes in body

composition (such as changes in fat/lean body mass ratio secondary to malnutrition), and

decreased protein-binding capacity. Numerous studies have demonstrated that drug metabolism

may be affected by acute starvation, undernutrition, and deficiencies of macro- and

micronutrients. Liver dysfunction in malnutrition contributes to the altered metabolism of

drugs; also impaired renal function, especially in dehydration, significantly influences drug

excretion.

Definitely, kwashiorkor, marasmus, and other types of malnutrition may lead to many

pathophysiological changes which may subsequently influence pharmacokinetics and

pharmacodynamics of drugs. For instance, infections such as measles, malaria, acute

respiratory tract infection, intestinal parasitosis, tuberculosis and HIV/AIDS may complicate PEM

with two or more infections co-existing. Thus, numerous drugs may be required to treat the

patients. The treatment of malnourished patients is very difficult; and impaired nutritional status

may contribute to ineffective treatment of patients, especially those with severe concomitant

diseases. A good knowledge of pathophysiology of PEM and pharmacology of drugs frequently

used is essential for safe and rational treatment. The following features and pathophysiological

changes in PEM may affect drug disposition:

(a). Body fluid distribution: The total body water (TBW) is increased in proportion to the

degree of malnutrition. The increased TBW is associated with a proportional rise in extracellular

fliud, particularly in malnourished children with edema. Children with marasmus have the

highest TBW, while there is a significant reduction in adipose mass as well as lean body mass in

marasmus and marasmic- kwashiorkor which can alter the apparent volume of distribution of

drugs. The distribution of lipid soluble drugs into adipose tissues is reduced in PEM;

consequently, the concentration of a lipid soluble drug would increase at the target tissues,

prolonging the actions with possible increased toxicity.

Children with severe PEM may have edema, wide spread dermatosis and shock due to bacterial

infection. Infection is a major complication of PEM and may occur without the classical signs



and symptoms. Consequently, the WHO has recommended that all children admitted with PEM

should routinely receive parenteral antibiotics. The clinical efficacy and toxicity potentials of

antibiotics are determined by their volume of distribution, penetration into superficial and deep

tissues, and other pharmacokinetic parameters. The volume of distribution of some drugs,

including antibiotics may be affected by the edematous state, and other pathophysiologic

features of PEM with consequent modification of drug action.

(b). Plasma protein concentration: Plasma protein concentration is low in edema, especially

in children. Hypoproteinemia is a common feature of PEM. Plasma albumin and fractions of the

glycoproteins responsible for binding drugs are decreased, leading to decreased protein binding.

This decreased protein binding may theoretically lead to an increase in the plasma free-drug

fractions of highly protein-bound drugs, variations in response to the drug, and risk of increased

drug toxicity. However, in clinical practice, decreased plasma protein has not been reported to

signficantly increase plasma free-drug fractions in PEM patients.

(c). Changes in the gastrointestinal system: Symptoms of PEM include diarrhea and

vomiting. With diarrhea and vomiting, orally administered drugs may not be retained;

nevertheless if retained, the intestinal transit time may be decreased. PEM is associated with

various degrees of intestinal malabsorption, e.g. villous atrophy of the jejunal mucosa resulting

in impaired drug absorption. The oral absorption of chloroquine, chloramphenicol, sulfadiazine

and carbamazepine have been demonstrated to decrease significantly, attributable to the

morphological changes in the jejunum, in children with PEM compared with healthy normal

children.

(d). Changes in hepatic function: Hepatic drug metabolism may be impaired in PEM,

leading to decreased clearance of some drugs.

(e). Changes in renal function: There may be renal dysfunction in PEM, as shown by

decreased glomerular filtration rate and renal blood flow in children with PEM, particularly in the

presence of dehydration. Also the edema observed in kwashiorkor and marasmic-kwashiokor

has been attributed to the inability of the kidneys to adequately excrete excess fluid and

sodium, as well as the presence of hypoproteinaemia and aflatoxins. The renal clearance of

penicillin, cefoxitin, gentamicin, ethambutol, and other drugs were shown to be decreased in

children with PEM. In malnourished patients, adjustment of doses of drugs primarily excreted



by the kidneys using their relative weight and other specific features such as glomerular

filtration rate may be necessary.

(f). Deficiency in immune system: Malnutrition is one of the causes of secondary

immunodeficiency. Lack of proteins and immune mediators causes deficiency in humoral and

cellular immunity, with consequent increased infections in individuals with PEM.

(g). Changes in cardiovascular system: Heart failure occurs in severe PEM; also children

with severe PEM have a smaller and thinner heart, and a lower stroke volume. The inability of

the kidneys to adequately excrete excess fluid and sodium in kwashiorkor and marasmic-

kwashiokor, and the resultant edema adversely affects the heart. Consequently, there is volume

overload in the circulation, increased permeability of the cardiac cell membranes, and

ultimately, reduced cardiac contractility, pumping efficiency and stroke volume. Circulatory

insufficiency, as occurs in PEM, is associated with a prolonged circulation time and ineffective

transport of substances in the circulation; consequently there is inadequate absorption and

distribution of drugs and nutrients.

Furthermore, fluid retention would cause expansion of the extracellular fluid (ECF) volume and

may increase the volume of distribution of water soluble drugs.

(h). Changes in endocrine function: Insulin levels are decreased while growth hormone is

elevated in children with PEM. Serum triiodothyronine (T3) was found to be decreased with

normal thyroxine (T4) level in children with PEM, possibly due to a reversible defect in extra-

thyroidal conversion of T4 to T3. Though thyroid hormones are associated with the action of

some drugs, the implications of these findings in PEM are yet to be explored.

(iii). Miscellaneous dietary factors and drug action

An individual’s nutrition is dependent on the diet, which is what one eats as determined by the

availability and palatability of foods.

A healthy diet ensures balanced availability of nutrients in the food, and consists of micro- and

macronutrients needed for well-being, good health and sustenance. It also encompasses the

care and preparation of food, storage methods that prevent deterioration of nutrients and

reduce the risk of foodborne illness. Diet contributes to individual variations in drug response.



(a). Diet may affect the metabolism of drugs: Grapefruit and grapefruit juice inhibit

CYP3A4, and hence interact with several drugs; e.g. grapefruit juice inhibits the metabolism of

co-administered drugs such as halofantrine, erythromycin, quinine, alprazolam, cisapride,

cyclosporine, midazolam and triazolam atorvastatin, lovastatin, simvastatin nifedipine, etc.

Cruciferous vegetables (e.g. cabbage, broccoli, cauliflower) induce CYP1A2; consequently,

consumption of cruciferous vegetables may decrease bioavailability and half-life of some drugs

metabolized by CYP1A2 such as haloperidol and theophylline.

(b). Diet counteracts the effect of some drugs: Nutrient or food ingredient may oppose

the desired action of a drug. High fat diet counteracts the effect of antihyperlipidemic drugs

such as lovastatin or gemfibrozil. Vitamin K aids the production of clotting factors in direct

opposition to the action of warfarin. Caffeine (present in coffee, some teas) is a stimulant which

may counteract the effect of central nervous system depressants.

(c). Diet may enhance the effects or toxicity of drug: Foods or additives that have effects

similar to those of a drug, may enhance its effects or toxicity. High caffeine intake may increase

the central nervous system stimulant and other adverse effects of theophylline (such as

nervousness, tremor and insomnia). Tyramine (in e.g., strong or aged cheese, yeast extracts,

tofu and some red wines), dopamine or other vasoconstrictors in food enhance the toxic effects

of monoamine oxidase inhibitors, such as tranylcypromine; this effect may cause a hypertensive

crisis, which can be fatal. Diet rich in fat increases the absorption, bioavailability and toxicity of

halofantrine.

(iv). Food-derived intoxicants

Food-derived intoxicant is a toxin arising from food; it could be due to consumption of

contaminated food or improperly processed food. The intake of food derived intoxicants gives

rise to foodborne illness.

Foodborne illness (foodborne disease, food poisoning) results from consumption of food

contaminated with chemicals (from e.g. pesticides, storage cans, etc); pathogenic bacteria,

viruses, or parasites; and toxins (e.g. poisonous mushrooms). Foodborne illness may also result

from consumption of spoiled food, improperly processed food such as inadequately processed

cassava, and improperly cooked food e.g meat, beans, etc. The contamination of food may

occur at any stage in the process from food production to consumption (‘farm to fork’).

https://en.wikipedia.org/wiki/Bioavailability

https://en.wikipedia.org/wiki/Biological_half-life

https://en.wikipedia.org/wiki/Haloperidol

https://en.wikipedia.org/wiki/Theophylline

https://en.wikipedia.org/wiki/Pathogen

https://en.wikipedia.org/wiki/Bacteria

https://en.wikipedia.org/wiki/Virus

https://en.wikipedia.org/wiki/Parasite

https://en.wikipedia.org/wiki/Toxin

https://en.wikipedia.org/wiki/Poisonous_mushrooms



The process of monitoring food to prevent foodborne illness is known as food safety. Good

safety and hygienic practices before, during, and after food preparation can reduce the chances

of introducing toxins to food. Regular hand-washing is one of the most effective ways to

prevent food contamination and spread of foodborne illness.

Sources of food-derived intoxicants

Food-derived intoxicants could arise from improper handling, preparation, or storage (e.g.

botulinum toxin) of food. Food-derived intoxicants could be from a large variety of

environmental toxins, pesticides, other chemicals (used during cultivation, preservation of

produce or ready-to-eat food), and natural toxic substances such as poisonous mushrooms,

plants or animals.

Toxins that may contaminate food include:

(a). Bacteria – For example, Staphyloccocus, Campylobacter jejuni, Salmonella, Escherichia

coli, Clostridium botulinum, Clostridium perfringens, Bacillus cereus, etc. Botulism occurs when

the anaerobic bacterium Clostridium botulinum grows in improperly canned low-acid foods and

produces botulinum toxin a neurotoxic protein, which causes flaccid paralysis. Tetrodotoxin, a

lethal toxin, is produced by Pseudoalteromonas tetraodonis, certain species of Pseudomonas

and Vibrio, and some other bacteria.

(b). Enterotoxins – In addition to disease caused by direct bacterial infection, some

foodborne illnesses are caused by enterotoxins (i.e. bacterial exotoxins targeting the intestines).

Enterotoxins are chromosomally encoded or plasmid encoded exotoxins that are produced and

secreted from several bacteria. Enterotoxins can produce illness even when the microbes that

produced them have been killed. Examples are staphylococcal enterotoxins A and B which occur

mainly in cooked and processed foods.

(c). Mycotoxins - Mycotoxins are produced by fungi that readily colonize crops. Mycotoxins

include aflatoxins (found in groundnuts, maize, etc.) and ochratoxins (found in dried fruit,

maize, wheat, oats and other cereals, etc.).

(d). Viruses – e.g. enteroviruses, hepatitis A

(e). Parasites – Parasites such as nematodes, platyhelminthes, and other helminths; protozoa

(e.g. Entamoeba histolytica, Giardia lamblia) also contaminate food and cause foodborne illness.

https://en.wikipedia.org/wiki/Food_safety

https://en.wikipedia.org/wiki/Pesticide

https://en.wikipedia.org/wiki/Mushroom_poisoning

https://en.wikipedia.org/wiki/Clostridium_perfringens

https://en.wikipedia.org/wiki/Bacillus_cereus

https://en.wikipedia.org/wiki/Anaerobic_organism

https://en.wikipedia.org/wiki/Clostridium_botulinum

https://en.wikipedia.org/wiki/Tetrodotoxin

https://en.wikipedia.org/wiki/Pseudomonas

https://en.wikipedia.org/wiki/Vibrio

https://en.wikipedia.org/wiki/Enterotoxin

https://en.wikipedia.org/wiki/Exotoxin

https://en.wikipedia.org/wiki/Exotoxin



(f). Natural toxins - Some animals and plants used as food naturally contain toxins: e.g.

cyanide in cassava, phytohaemaagglutinin in red kidney beans; toxins in some fish, tetrodotoxin

is also found in moon snails, certain species of fish and octopus.

A2. PHARMACOGENETICS

Pharmacogenetics is the study of the genetic basis for individual variation in drug response.

Although individual differences in drug response can result from the effects of age, sex,

disease, or drug interactions, genetic factors also influence both the efficacy of a drug and the

likelihood of an adverse reaction. The potential of pharmacogenetics lies in identification of the

right drug and dose for each patient.

The term pharmacogenomics is often used interchangeably with pharmacogenetics.

Pharmacogenomics (pharmaco- + genomics; reflects combination of pharmacology and

genomics) is the study of the role of the genome in drug response. Although both terms relate

to drug response based on genetic influences, pharmacogenetics focuses on single drug-gene

interactions, while pharmacogenomics encompasses a more genome-wide approach,

incorporating genomics and epigenetics while dealing with the effects of multiple genes on drug

response.

(i). Genetic factors affecting drug action

Genetic Polymorphisms

Genetic polymorphisms are naturally occurring variations (or variants) in the DNA sequence

(gene structure) that occur in more than 1 percent of the population, i.e. it is present at an

allele frequency of 1% or greater in a population. A true genetic polymorphism is defined as the

occurrence of a variant allele of a gene at a population frequency of ≥ 1%, resulting in altered

expression or functional activity of the gene product, or both.

Genetic polymorphisms (genetic variations, genetic alterations) may influence a drug's action by

changing its pharmacokinetics or its pharmacodynamics.

Types of polymorphisms

https://en.wikipedia.org/wiki/Toxins

https://en.wikipedia.org/wiki/Tetrodotoxin

https://en.wikipedia.org/wiki/Pharmacogenetics

https://en.wiktionary.org/wiki/pharmaco-#Prefix

https://en.wikipedia.org/wiki/Genomics

https://en.wikipedia.org/wiki/Pharmacology

https://en.wikipedia.org/wiki/Genomics

https://en.wikipedia.org/wiki/Genome

https://en.wikipedia.org/wiki/Drug

https://en.wikipedia.org/wiki/Gene

https://en.wikipedia.org/wiki/Epigenetics



The most common type of polymorphism involves variation at a single base pair, however

polymorphisms may be much larger in size and involve long stretches of DNA. Types of genetic

variations include single nucleotide polymorphism (SNP), insertion deletion mutations (indel)

and copy number variations. Single nucleotide polymorphism and indel are majorly associated

with variations in human phenotype.

There are over 1 million SNPs in the human genome that occur at a frequency of 1% or greater

in the general population. A SNP is a variation/change in a single (1) nucleotide or base-pair

within a codon in the DNA. Depending on its location, a SNP may alter how a gene is

transcribed or the amino acid sequence for the protein being made, ultimately causing a change

in activity of that protein. SNPs can occur with many proteins involved in drug transport,

metabolism and receptors that ultimately influence both the pharmacokinetic and

pharmacodynamic properties of drugs. The SNP is one of the most common and studied genetic

polymorphisms increasingly being recognized in clinical practice.

Genetic polymorphisms for many drug-metabolizing enzymes and drug targets (e.g., receptors)

have been identified, thereby making it increasingly important in drug development, and routine

drug prescription and dosing. Pharmacogenetic testing may enable physicians to understand

why patients react differently to various drugs and to make better decisions about therapy.

Currently, some drugs (e.g. clopidogrel and mercaptopurine) contain labels stating that

genotyping before prescription is recommended or mandatory. Ultimately, application of

pharmacogenetics may provide highly individualized, safer and more effective therapeutic

regimens.

Pharmacogenetic Phenotypes

Genes known to exhibit polymorphisms, with consequent modification of therapeutic and other

actions of a drug, can be divided into three categories: pharmacokinetics, drug target, and

disease-modifying genes polymorphisms.

(a). Pharmacokinetics genes

Pharmacokinetics is the study of the nature, rate and extent of drug absorption, distribution,

metabolism and excretion. These processes determine the fate of a drug in the body.

Furthermore, multiple enzymes and transporters may be involved in the pharmacokinetics of a

single drug. Polymorphism in genes that encode determinants of the pharmacokinetics of a



drug, particularly metabolizing enzymes and transporters, affect drug concentrations, and are

therefore major determinants of therapeutic efficacy and adverse drug reactions (ADRs);

oftentimes dosage adjustment may be necessary.

The toxicity of some drugs can be predicted by the occurrence of particular genes encoding

drug‐metabolising enzymes. A retrospective study, showed that 49% of ADRs were associated

with drugs that are substrates for polymorphic drug metabolizing enzymes, a proportion larger

than estimated for all drugs (22%) or for top-selling drugs (7%). Consequently, prospective

genotype determinations may result in the ability to prevent adverse drug reactions. Well-

defined and clinically relevant genetic polymorphisms in both phase I and phase II drug-

metabolizing enzymes exist, consequently distinct population phenotypes of individuals who

have metabolism capabilities ranging from poor (deficient) to extremely fast have been

identified. The major phenotypes with respect to drug metabolism are grouped into poor

metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs) and ultra-

rapid metabolizers (UMs). In another parlance there may be slow and fast metabolizers

(e.g.slow vs. fast acetylators of isoniazid) or poor and extensive metabolizers (e.g. poor vs.

extensive metabolizers of debrisoquine or sparteine).

Examples of polymorphisms in genes that determine the pharmacokinetics of drugs are:

(i). Irinotecan and mercaptopurine toxicity are affected by UDP glucuronosyl transferase 1

family polypeptide A1 (UGT1A1) and thiopurine S-methyltransferase (TPMT) polymorphisms,

respectively.

TPMT is partly responsible for the inactivation of 6-mercaptopurine, in a reaction that prevents

further conversion of mercaptopurine into active, cytotoxic thioguanine nucleotide metabolites.

Polymorphisms in TPMT that result in decreased or absent TPMT activity lead to increased risk

of severe myelosuppression. In some countries approved drug label for mercaptopurine

recommends testing for TPMT activity to identify individuals at risk for myelotoxicity; this is one

of the few examples of pharmacogenetics being translated into and applied in routine clinical

care.

(ii). Polymorphism in dihydropyrimidine dehydrogenase (DPD), associated with deficiency of the

enzyme results in increased toxicity of fluorouracil. The DPD metabolizes fluorouracil and

endogenous pyrimidines.



(iii). Majority of drug metabolism is carried out by cytochrome P450 (CYP450) enzymes. The

polymorphic CYP450 enzymes account for 40% of the phase I drug metabolism. The respective

effective dose of clopidogrel, warfarin, tricyclic antidepressants, tamoxifen, some antipsychotics,

and some other drugs is determined by CYP450 polymorphism. A few examples are:

CYP2C9: CYP2C9 is involved in the metabolism of many commonly used drugs such as

glipizide, tolbutamide, losartan, phenytoin, clopidogrel and warfarin. The CYP2C9*2 and

CYP2C9*3 phenotypes are the two most common variants and are associated with reduced

enzymatic activity. CYP2C9 is the principal enzyme responsible for the metabolism of S-

warfarin. Persons who are CYP2C9 poor metabolizers have reduced S-warfarin clearance,

require lower doses of warfarin and are at an increased risk of excessive anticoagulation.

CYP2C19: CYP2C19 metabolizes many drugs, including proton pump inhibitors, zafirlukast,

citalopram, diazepam, and imipramine. More than 17 variations of CYP2C19, associated with

deficient, reduced, normal, or increased activity, have been identified. Genotyping for

CYP2C19*2 and CYP2C19*3 identifies most CYP2C19 poor metabolizers. The CYP2C19*17

variant is associated with ultra-rapid metabolizers. Omeprazole is primarily metabolized by

CYP2C19 to its inactive metabolite, 5-hydroxyomeprazole. Poor metabolizers of CYP2C19 may

have five-fold higher blood concentrations of omeprazole and experience superior acid

suppression and higher cure rates than the rest of the population. Conversely, blood

concentrations of omeprazole are predicted to be 40% lower in ultra-rapid metabolizers than in

the rest of the population, thus putting CYP2C19 ultra-rapid metabolizers at risk of therapeutic

failure.

CYP2D6: CYP2D6 is involved in the metabolism of an estimated 25% of all drugs. More than

75 allelic variants have been identified, with enzyme activities ranging from deficient to ultra-

rapid. The most common variants associated with poor metabolizer phenotype are CYP2D6*3,

CYP2D6*4, CYP2D6*5, and CYP2D6*6 in whites and CYP2D6*17 in blacks. Codeine is

metabolized by CYP2D6 to its active metabolite, morphine. Clinical studies have shown that

CYP2D6 poor metabolizers have poor analgesic response as a result of the reduced conversion

of codeine to morphine. Conversely, CYP2D6 ultra-rapid metabolizers quickly convert codeine to

morphine and have enhanced analgesic response. Other consequences of the deficient CYP2D6

phenotype include increased risk of toxicity of some antidepressants or antipsychotics

catabolized by the enzyme, and lack of activation of tamoxifen leading to a greater risk of



relapse or recurrence in breast cancer. Conversely, the ultra-rapid metabolizers have extremely

rapid clearance and thus inefficacy of antidepressants.

(b). Drug targets genes

Many drug target (e.g. receptors, enzymes) polymorphisms have been shown to predict

responsiveness to drugs. Some examples are:

(i).β-adrenergic receptor polymorphisms have been linked to asthma responsiveness (degree of

change in forced expiratory volume in 1 second (FEV1) after use of a β agonist).

Several studies have shown that some patients benefit from use of short-acting β2 agonists

while others do not. This variation in response is partly explained by the alteration in the amino

acid sequence or altered transcription of the β2 receptor. Patients with the β2 receptor arginine

genotype experience poor asthma control with frequent symptoms and a decrease in scores on

FEV1 compared with patients who have the glycine genotype. Studies show that 17% of whites

and 20% of blacks carry the arginine genotype.

(ii). Also, variation in the genes involved in the biologic action of inhaled corticosteroids may

explain the variability in response and adverse effects to inhaled corticosteroids. Polymorphisms

in corticotropin-releasing hormone receptor-1 (CRHR1 gene) is associated with enhanced

response to inhaled corticosteroids in asthma patients.

(iii). Polymorphisms in 5-LOX and LTC4 synthase pathways have been identified, and may

determine and predict how a person reacts to therapy with 5-LOX inhibitors and leukotriene

receptor antagonists.

(iv). Serotonin receptor polymorphisms determine and predict not only the responsiveness to

antidepressants, but also the overall risk of depression.

(v). Renal function following therapy with angiotensin-converting enzyme inhibitors.

(vi). Polymorphisms in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have been

linked to the degree of lipid lowering by statins (HMG-CoA reductase inhibitors).

(vii). Ion channel polymorphisms have been linked to a risk of cardiac arrhythmias in the

presence and absence of drug triggers.

(viii). Warfarin exerts its anticoagulant effects by inhibiting hepatic vitamin K epoxide reductase,

an enzyme involved in the synthesis of various clotting factors. Polymorphisms in the vitamin K

epoxide reductase complex subunit 1 (VKORC1) gene have been identified and are believed to

contribute to the variability in response to warfarin therapy.



(ix). Black hypertensive patients require a high dosage of angiotensin-converting enzyme

inhibitors or combined therapy with low-dose diuretics to reduce blood pressure effectively.

(x). Breast cancer patients with expression of the Her2 antigen (i.e HER2 receptor positive ) are

more likely to benefit from the monoclonal antibody trastuzumab than are those who are

negative for Her2 expression.

(c). Disease-modifying genes

Some genes do not directly interact with the drug, but are associated with an underlying

disease being treated. Polymorphisms in such genes may predispose to drug-induced events

and other diseases; such knowledge may be useful to understand and predict possible disease-

predisposing risk factors.

(i). The risk of a drug-induced thrombosis is dependent not only on the use of prothrombotic

drugs, but on environmental and genetic predisposition to thrombosis, which may be affected

by germline polymorphisms in methylene tetrahydrofolate reductase (MTHFR), factor V, and

prothrombin. These polymorphisms do not directly act on the pharmacokinetics or

pharmacodynamics of prothrombotic drugs, such as glucocorticoids, estrogens, and

asparaginase, but may modify the risk of the phenotypic event (thrombosis) in the presence of

the drug.

The methylene tetrahydrofolate reductase gene (MTHFR) polymorphism is associated with

homocysteinemia, which is a possible risk factor for development of coronary artery disease.

Methylene tetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle,

and it is encoded by the MTHFR gene. Methylene tetrahydrofolate reductase catalyzes the

conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for

homocysteine re-methylation to methionine. Natural variation in this gene is common in healthy

people. Some mutations in MTHFR gene are associated with MTHFR deficiency, resulting in

accumulation of homocysteine, homocysteinemia, homocystinuria. Elevated blood levels of

homocysteine leads to intellectual disability, severe mental retardation, psychosis, weakness,

ataxia, spasticity, cardiovascular disease and other disorders.

(ii). Polymorphisms in ion channels (e.g., HERG, KvLQT1, Mink, and MiRP1) may affect the

overall risk of cardiac dysrhythmias, which may be accentuated in the presence of a drug that

can prolong the QT interval in some circumstances (e.g., macrolide antibiotics, antihistamines).

https://en.wikipedia.org/wiki/Enzyme


https://en.wikipedia.org/wiki/5,10-Methylenetetrahydrofolate

https://en.wikipedia.org/wiki/Levomefolic_acid

https://en.wikipedia.org/wiki/Cosubstrate

https://en.wikipedia.org/wiki/Homocysteine

https://en.wikipedia.org/wiki/Methionine


https://en.wikipedia.org/wiki/Methylenetetrahydrofolate_reductase_deficiency

https://en.wikipedia.org/wiki/Methylenetetrahydrofolate_reductase#cite_note-entrez-6



These disease-modifier polymorphisms may impact on the risk of disease phenotypes even in

the absence of drug challenges.

(ii). The importance of pharmacogenetics in the tropics

The importance of study and application of pharmacogenetics in populations in the tropics, and

Nigeria in particular cannot be over-emphasized. Pharmacogenetics will likely impact drug

development and regulatory considerations in Nigeria in several ways, especially considering the

fact that more than 90% of all the drugs used in Nigeria are developed and produced outside

the country.

Unfortunately not much research has focused on identifying the potential role of genetics in the

pathophysiology and management of diseases prevalent in Nigeria. The importance of

pharmacogenetics in the tropics, and particularly in Nigeria, include:

(a). Pharmacogenetics may identify subsets of patients with very high or very low likelihood of

responding to a drug. This will permit testing of the drug in a selected population that is more

likely to respond (e.g, germline variations in 5-lipoxygenase (5-LOX) determine which asthma

patients are likely to respond to 5-LOX inhibitors); thereby allow for optimal definition of

parameters of response in the subset more likely to benefit, and minimize/avoid the possibility

of adverse events in patients who derive no benefit. This role of pharmacogenetics is especially

important in Nigeria, where drugs used were developed using traits and responses from non-

Nigerians outside Nigeria.

(b). Another related role for pharmacogenetics in drug development is to identify which genetic

subset of patients is at highest risk for a serious adverse drug effect, and to avoid use of the

drug in that subset of patients. For example, the identification of human leukocyte antigen

(HLA) subtypes associated with hypersensitivity to the HIV-1 reverse transcriptase inhibitor

abacavir identifies a subset of patients who should receive alternative antiretroviral therapy, and

this has been shown to decrease the frequency of abacavir-induced hypersensitivity reactions.

Hypersensitivity to abacavir is strongly associated with HLA-B*5701, whose prevalence is

reported to be about 0% in Yoruba (Nigeria), 1% in African Americans, 3.3% in Luhya (Kenya),

and 13.6% in Masai (Kenya).

(c). Pharmacogenetic testing may also help to identify patients who require altered dosages,

but not exclusion from use of some drugs.



In summary, application of pharmacogenetics in the tropics could serve to:

Improve drug safety, and reduce adverse drug reactions;

Tailor treatments to meet patients' unique genetic pre-disposition, including

identification and administration of optimal dosing;

Improve drug discovery and development targeted towards diseases encountered in the

region; and

Improve proof of principle/proof of concept in clinical trials.

(iii). Drugs whose response or metabolism are affected by hereditary (genetic)

factors

The response or metabolism of several drugs are affected by genetic polymorphisms (Table1).

Some of such drugs are:

(1). Isoniazid: Human populations show genetic heterogeneity in the rate of acetylation of

isoniazid. There is a bimodal distribution of slow and rapid acetylators due to differences in the

activity of N-acetyltransferase.

Fast acetylation, i.e. high acetyltransferase activity is inherited as an autosomal dominant trait,

while the slow acetylator phenotype is inherited as an autosomal recessive trait. The average

concentration of active isoniazid in the circulation of rapid acetylators is about 30 – 50% of that

in slow acetylators. The mean t1/2 of isoniazid is approximately 70 minutes in fast acetylators,

and 2-5 hours in slow acetylators. More rapid clearance of isoniazid by rapid acetylators is

usually of no therapeutic consequence when appropriate doses are administered daily, but sub-

therapeutic concentrations may occur if drug is administered as a once-weekly dose or if there

is malabsorption. The slow acetylator phenotype is associated with a higher incidence of

isoniazid-induced peripheral neuritis, drug-induced autoimmune disorders, and bicyclic aromatic

amine-induced bladder cancer.

(2). Mercaptopurine: Thiopurine methyltransferase (TPMT), encoded by the TPMT gene,

methylates thiopurines such as mercaptopurine (an anti-leukemic drug that is also the product

of azathioprine metabolism). One in 300 individuals (0.33%) is homozygous deficient, 10% are

heterozygotes (with low enzyme activity), and approximately 90% are homozygous (with

normal enzyme activity) for the wild-type alleles for TPMT. Defects in TPMT gene lead to

decreased methylation and decreased inactivation of 6-mercaptopurine, leading to enhanced



bone marrow toxicity which may cause myelosuppression, anemia, bleeding tendency,

leukopenia and infection. Mercaptopurine has a narrow therapeutic range, and dosing by trial

and error can place patients at higher risk of toxicity; thus, adjustment of thiopurine doses

based on TPMT genotype is recommended. Measurement of TPMT activity is encouraged prior

to commencement of treatment with thiopurine drugs such as azathiopurine, 6-mercaptopurine

and 6-thioguanine.

(3). Warfarin: Warfarin dosing can be challenging because of its narrow therapeutic index and

the serious risk of bleeding with overdosage. Both pharmacokinetic and pharmacodynamic

polymorphisms affect warfarin dosing.

Warfarin exerts its anticoagulant effects by inhibiting hepatic vitamin K epoxide reductase, an

enzyme involved in the synthesis of various clotting factors. Polymorphisms in the vitamin K

epoxide reductase complex subunit 1 gene (VKORC1) have been identified and are believed to

contribute to the variability in responses to warfarin therapy.

Warfarin is metabolized by CYP2C9; CYP2C9 poor metabolizers are associated with lower

warfarin clearance, a higher risk of bleeding complications, and lower dose requirements.

(4). Abacavir: There is genetic polymorphism in hypersentivity reactions to abacavir. In some

countries, drug label for abacavir recommends pre-therapy screening for the HLA-B*5701 allele

and the use of alternative therapy in patients with the allele.

(5). Clopidogrel: Clopidogrel requires biotransformation to active metabolite by CYP450

enzymes. On treatment with clopidogrel, carriers of reduced-function CYP2C19 alleles (CYP2C19

– poor metabolizers) have significantly lower levels of active metabolite, diminished platelet

inhibition, and higher rates of treatment failure and cardiovascular events events such as

stroke, heart attack and death.

(6). Zafirlukast: Zafirlukast, a cysteinyl leukotriene receptor antagonist used in the treatment

of asthma, is extensively metabolized by hepatic CYP2C9. Genetic polymorphisms in LTC4

synthase and CYP2C9 may predict how an individual reacts to treatment with zafirlukast.

Table 1: Clinical consequences of metabolizer phenotypes on drug response

Drug type Metabolizer phenotype

Effect on drug metabolism

Potential consequence

Prodrug, needs to be metabolized to active

Poor to intermediate

Slow -Poor drug efficacy, patient at risk of therapeutic failure



substance (e.g. codeine, clopidogrel)

-Accumulation of prodrug, patient at increased risk of drug-induced adverse effects

Ultrarapid Fast -Good drug efficacy, rapid effect

Active drug metabolized to inactive compound (e.g. omeprazole metabolized to 5-hydroxyomeprazole)

Poor to intermediate

Slow -Good drug efficacy -Accmulation of active drug, patient at increased risk of drug-induced adverse effects - lower dosage may be required

Ultrarapid Fast -Poor dug efficacy, patient at risk of therapeutic failure - higher dosage may be required

Poor metabolizers have markedly reduced or absent enzyme activity; intermediate metabolizers

have reduced enzyme activity; and ultrarapid metabolizers have high enzyme activity.

Table 2: Some drugs whose actions are influenced by genetic polymorphisms

Drug Gene product (gene)

Phenotype Clinical consequencesa

Drug Transport

Metformin Organic cation transporter (SLC22A1, OCT1)

- Affects pharmacological effect and pharmacokinetics

Metformin Organic cation transporter (SLC22A1, OCT2)

- Renal clearance of metformin is affected

Statins Organic anion transporter (SLC01B1)

- Increase in statin plasma levels, and myopathy

Methotrexate - Increase in methotrexate plasma levels and mucositis

Gabapentin Novel organic cation transporter (SLC22A4, OCTN1)

Affects renal clearance

Drug metabolism

Acetaminophen GST PM Impaired GSH conjugation due to gene deletion Busulphan PM

Isoniazid NAT2 (NAT2)

Slow and rapid acetylators

Peripheral neuropathy in slow acetylators

Hydralazine Hydralazine-induced lupus erythematosus-like syndrome in PM

Sulfonamides Hypersensitivity in PM

Procainamide Increase in the antiarrhythmic metabolite, N-acetylprocainamide in rapid acetylators

Mercaptopurine Thiopurine PM Increase in thiopurine toxicity, e.g.



Thioguanine methyltransferase (TPMT)

myelosuppression, risk of second cancers. Dose adjustment may be required

Azathioprine

Fluorouracil Dihydropyrimidine dehydrogenase; DPD (DPYD)

PM Increased toxicity of fluoropyrimidines in DPD deficient individuals Capecitabine

Morphine UGT2B7 - Morphine plasma levels affected by increased or decreased enzyme activity

Levodopa COMT (COMT) PM Lower enzyme activity results in enhanced drug effect

Irinotecan UGT1A1 PM Reduced clearance in poor metabolizers, leading to toxicity such as immunosuppression, GIT dysfunction; dose adjustment may be required.

Succinylcholine BCHE PM Prolonged apnea

Mivacurium PM Prolonged muscle paralysis

Cocaine PM Increased blood pressure, tachycardia, ventricular arrhythmias

Cyclophosphamide CYP2B6 PM Reduced clearance, increased risk of ADRs Ifosfamide

Efavirenz

Repaglinide CYP2C8 PM Reduced clearance, increased risk of ADRs Paclitaxel

Amodiaquine

Chloroquine

Amiodarone

Celecoxib CYP2C9

PM Reduced clearance, increased risk of ADRs Diclofenac

Warfarin PM Highly clinically relevant. Enhanced risk of bleeding, dose adjustment required

Tolbutamide PM Cardiotoxicity

Phenytoin PM Nystagmus, diplopia, ataxia

Omeprazole CYP2C19

PM Increased therapeutic efficacy

Omeprazole EM Reduced therapeutic efficacy

Amitriptyline, clomipramine

PM Reduced clearance, increased risk of ADRs. Dose adjustment required

Citalopram PM Increased risk of gastrointestinal side effects

Clopidogrel PM Reduced activation and reduced therapeutic efficacy

Escitalopram EM Reduced therapeutic efficacy

Tamoxifen EM Increased metabolic activation, increased therapeutic efficacy; reduced risk of relapse. Dose adjustment required



Chlorproguanil EM Increased metabolic activation, increased therapeutic efficacy. Dose adjustment required.

Clopidogrel EM Increased metabolic activation, increased therapeutic efficacy. Dose adjustment required.

Nortriptyline CYP2D6 PM Reduced clearance, increased risk of ADRs

Nortriptyline UM Reduced therapeutic efficacy due to increased clearance

Tamoxifen PM Reduced metabolic activation to endoxifen, and thus reduced therapeutic efficacy

Tramadol PM Increased risk of seizures

Tramadol UM Reduced therapeutic efficacy due to increased clearance

Dextromethophan PM Reduced clearance, increased risk of ADRs

Codeine PM Reduced metabolic activation to morphine, hence reduced analgesia

Codeine UM Increased metabolic activation o morphine, with increased risk of respiratory depression

Drugs metabolized by these enzymes, e.g. macrolides, calcium channel blockers, midazolam, tamoxifen, saquinavir

CYP3A4/3A5/3A7 PM Reduced clearance

Ethanol Aldehyde dehydrogenase 2 (ALDH2*2)

PM Increased acetaldehyde resulting In facial flushing, hypotension, tachycardia, nausea, vomiting (‘hangover’ symptoms)

Drug target (receptors, enzymes, etc) genes

ACE inhibitors (e.g., enalapril)

Angiotensin converting enzyme (ACE)

- Renoprotective effects, hypotension, reduced left ventricular mass, cough. Patients with ACE DD phenotype are resistant to renoprotection by ACEIs.

5-fluorouracil Thymidylate synthase

- Affects response in colorectal cancer chemotherapy

β2 adrenergic receptor agonists, e.g. salbutamol,

β2 adrenergic receptor

- Affects response to agonist therapy (e.g. bronchodilation in asthma). Susceptibility to agonist-induced



terbutaline desensitization, cardiovascular effects (e.g., increased heart rate, cardiac index, peripheral vasodilation)

Leukotriene receptor antagonists

5-lipoxygenase - Altered response to therapy.

Pravastatin HMG-CoA reductase

- Affects degree of lipid lowering

Warfarin Vitamin K epoxide reductase (VKORCI)

- Reduced susceptibility of enzyme to warfarin or increased sensitivity, leading to altered anticoagulant effect and risk of bleeding

Glucocorticoids Corticotropin releasing hormone receptor

Enhanced response (e.g. bronchodilation) to inhaled corticosteroids in asthmatics, osteopenia

Estrogen hormone replacement therapy

Estrogen receptors α and β

- Altered responses, e.g., changes in high density liopoprotein. E.g., some postmenopausal women with ERα IVSI-401 C/C genotype, with coronary disease show augmented response of HDL to hormone replacement therapy

Disease-modifier genes

Dapsone G6PD G6PD deficiency

Methemoglobinemia

Erythromycin, cisapride, clarithromycin, quinidine

Ion channels (HERG, KvLQTI, Mink, MiRPI)

- Increased risk of drug-induced arrhythmias, e.g. torsades de pointes, increased QT interval etc

Statins (e.g. simvastatin)

Apolipoprotein E - Lipid lowering; clinical improvement in Alzheimer’s disease

Estrogens Estrogen receptor β (ER β)

- Associated with breast cancer in women and gynaecomastia in men.

Abacavir, carbamazepine, phenytoin

Human leukocyte antigen

- Hypersensitivity reactions

a Observed or predictable; ADR = adverse drug reaction; PM = poor metabolizer; EM = extensive metabolizer; UM = ultra-rapid metabolizer

(iv). Interactions involving genetic factors: Glucose-6-phosphate dehydrogenase

deficiency

(a). Glucose-6-phosphate dehydrogenase deficiency



Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X-linked recessive

hereditary genetic defect caused by mutations in the G6PD gene, resulting in variants with

different levels of enzyme activity that are associated with a wide range of biochemical and

clinical phenotypes. G6PD is X-linked, and so deficient variants are expressed more commonly

in males than in females.

Glucose-6-phosphate dehydrogenase deficiency (G6PDD) affects about 400 million people

worldwide, with a high prevalence in persons of African, Asian, and Mediterranean descent. The

prevalence of G6PDD in Nigeria ranges from 4 – 26%, with the male population having about

20 – 26%. The following prevalence was reported for Nigerian children Yoruba (16.9%), Igede

(10.5%), Igbo (10.1%) and Tiv (5.0%). Prevalence rate varies from one community to another;

however, there is paucity of documented studies on the pattern of distribution of G6PD activity

in Nigerian population.

G6PD generates NADPH which is a primary defense against oxidative stress in red blood cells

(RBCs). Mutations in the G6PD gene can destabilize the enzyme and reduce its level of activity,

leaving RBCs vulnerable to damage from exogenous triggers, including certain foods, infections

and drugs that may lead to lysis and acute hemolytic anemia.

(b). Variants of Glucose-6-phosphate dehydrogenase gene

Over 300 allelic variants of G6PD gene are currently characterized, some of which express

different levels of enzyme activity ranging from low – normal – high. Some well-known and

described variants are G6PD B, G6PDA+, G6PDA-, G6PD Ijebu-ode, G6PD Mediterranean, G6PD

Canton, G6PD Ibadan-Austin, G6PD Chatham, G6PD Cosenza, G6PD Mahidol, G6PD Orissa,

G6PD Asahi, amongst others. The G6PD A− and G6PD Mediterranean variants are the most

common in human populations. G6PD A− has an occurrence of 10% of Africans and African-

Americans while G6PD Mediterranean is prevalent in the Middle East. In tropical Africa,

including Nigeria, the G6PD-A variant is thought to account for 90% of G6PDD. G6PD-

Mediterranean is associated with low enzyme activity (about <1% of normal), and predisposes

individuals to favism and acute hemolytic anaemia following e.g. primaquine therapy.

Few studies have investigated the variants of known G6PD genes from the African region. In

sub- Saharan Africa, well known and studied G6PD variants with polymorphic gene frequencies

include G6PD B, G6PD A+ and G6PD A-. G6PD B is the wild type and most common in Africa



and worldwide, it has normal enzyme activity. G6PD A+ is next in frequency; it has slightly

reduced enzyme activity, about 80 - 100% of normal enzyme activity and is also not associated

with hemolysis. The third variant is G6PD A- with about 8 -20% of the wild type enzyme

(normal) activity; it is associated with relatively mild enzyme deficiency, and hemolysis may

occur especially after exposure to certain substances like camphor, menthol or drugs like

primaquine, dapsone, sulfadimidine, nitrofurantoin, etc. Primaquine toxicity reported for G6PD

A- was relatively mild and self-limiting. Currently, SNPs of G6PD A- variants in Nigerian and

West African populations have been documented, such as G6PD A-968, G6PD A-202, and others.

These may partly explain the observation of severe reactions requiring transfusions, and

hemolysis induced by fava beans in this populations thought to be associated with ‘mild’ variant

of G6PDD.

The World Health Organization (WHO) classifies G6PD genetic variants into five according to the

level of enzyme activity in RBCs and the clinical manifestations. Class I includes severely

deficient variants that are associated with a chronic non-spherocytic hemolytic anaemia

(CNSHA). Class II variants have less than 10% of residual enzyme activity but without CNSHA

and include the common Mediterranean and common severe oriental variants. Class III variants

are moderately deficient (10-60% residual enzyme activity) and include the common African (A)

form. Class IV variants have normal enzyme activity, and in class V the enzyme activity is

increased. The first three are deficiency states.

Class I: Severe deficiency with chronic non-spherocytic hemolytic anemia (CNSHA)

Class II: Severe deficiency (<10% activity), e.g. G6PD Mediterranean

Class III: Moderate deficiency (10-60% activity), e.g. the common African form, G6PD A

Class IV: Non-deficient variant, no clinical sequelae

Class V: Increased enzyme activity, no clinical sequelae

In practice, clinical manifestations are confined to variants associated with enzyme deficiency,

and the common pathological variants are all in classes II and III. From the public health point

of view, the importance of a variant depends on its clinical implications and its prevalence;

usually, a variant is considered common, or polymorphic, if it occurs with a frequency of 1% or

more among males in a particular population.

Variants of Glucose-6-phosphate dehydrogenase gene in Nigeria



Few studies have been done to determine the variants found in Nigerians. Nevertheless, a study

of a homogenous population in Nigeria, showed that there is a high frequency of G6PD A-

variant in the population. Currently, SNPs of G6PD A- variants in Nigerian and West African

populations have been documented, such as G6PD A-968, G6PD A-202, and others.

Table4: Glucose-6 phosphate dehydrogenase gene variants found in Nigeria

G6PD variant RBC enzyme activity (% of

normal)

Population origin

Population frequency

Class

G6PD B 100 Various Usual - (wild type, normal)

G6PD A+ 80 – 100 African descent Common IV

G6PD A- 8 – 20 African descent Common III

G6PD Ijebu-ode 100 African descent Rare IV

G6PD Ibadan-Austin 72 African descent Rare IV

Adapted from Yoshida et al., 1971

(c). Pathophysiology and clinical manifestations of glucose-6-phosphate

dehydrogenase deficiency

Pathophysiology

Glucose-6-phosphate dehydrogenase (G6PD) is a cytosolic enzyme that is distributed widely in

all cells. It catalyses the first step in pentose phosphate pathway (PPP) (hexose monophosphate

shunt pathway), producing reduced nicotinamide adenosine dinucleotide phosphate (NADPH).

This co-enzyme (NADPH) is required as hydrogen donor for numerous reductive processes of

various biochemical pathways as well as for the stability of catalase and the preservation and

regeneration of reduced glutathione. Catalase and glutathione are both essential for the

detoxification of hydrogen peroxide and free radicals generated during the normal cellular

metabolic processes. The defence of cells against hydrogen peroxide, free radicals and other

forms of oxidative stress, therefore, depends on G6PD for the generation of NADPH.

Since red blood cells (RBCs) do not contain mitochondria, the PPP is their only source of

NADPH; therefore, defence against oxidative damage in RBCs is essentially dependent on G6PD.

The red cells are particularly sensitive to oxidative damage in the absence or reduced activity of

G6PD as they lack other NADPH-producing enzymes.



In individuals with deficiency of G6PD there is low level of reduced glutathione; on exposure to

specific triggers (oxidative stress), when all the remaining reduced glutathione is consumed,

enzymes and other proteins (including hemoglobin) are subsequently damaged by the oxidants,

leading to cross-bonding and protein deposition in the RBC membrane. Damaged RBCs are

phagocytosed and sequestered in the spleen. The hemoglobin is metabolized to bilirubin,

accumulation of which causes hyperbilirubinemia and jaundice.

Triggers: Triggers include moth balls (naphthalene, camphor), stress from a bacterial or viral

infection; foods such as fava beans; certain drugs including aspirin, dapsone, quinine and other

antimalarials derived from quinine (e.g. primaquine, pamaquine, and chloroquine.),

sulfonamides (such as sulfanilamide, sulfamethoxazole, and mafenide). Thiazolesulfone,

methylene blue, certain analgesics (such as phenazopyridine and acetanilide), and some non-

sulfa antibiotics (e.g.nalidixic acid, nitrofurantoin, isoniazid, and furazolidone) should also be

avoided by people with G6PD deficiency as they antagonize folate synthesis. There is evidence

that other antimalarials may also exacerbate G6PD deficiency, but only at higher doses.

Clinical Manifestations

The public health burden of G6PDD is significant. G6PD deficiency causes a clinical spectrum of

illness which includes a purely asymptomatic state, acute hemolytic episodes (elicited by drugs,

infections, ingestion of fava beans, etc.), chronic hemolysis (hereditary non-spherocytic

hemolytic anaemia), and neonatal jaundice. However, many individuals with this disorder

remain asymptomatic throughout their lives and may not be aware of it.

Hemolysis: In G6PD deficient children, exposure to triggers and pro-oxidants could lead to a

rapid imbalance in the redox status in RBCs leading to hemolysis and resultant severe anemia,

heart failure, and death if not recognized early. One of the most curious features of the acute

hemolytic reaction is that it is erratic; the same agent may cause hemolysis in one G6PD

deficient person but not in another, and in the same person at one time but not another.

Neonatal hyperbilirubinemia: G6PD deficiency causes neonatal jaundice which is

accompanied by hyperbilirubinemia and puts infants at risk for kernicterus within the first few

days of life. Kernicterus can lead to hearing deficits, behavior problems, permanent neurologic

damage, spastic cerebral palsy or death.

(d). Glucose-6-phosphate dehydrogenase deficiency and malaria



There is a close association between malaria and G6PD deficiency. Several epidemiological

studies have shown the high frequency of G6PD deficiency in nearly all parts of the world where

malaria is or has been endemic, and that distribution of malaria was nearly the same with

distribution of G6PD deficiency. These infer that (i) G6PD deficiency confers protection against

malaria, particularly Plasmodium falciparum malaria (a similar relationship exists between

malaria and sickle-cell disease); (ii) use of some antimalarial drugs can cause life threatening

hemolytic anaemia in patients with G6PD deficiency; hence, screening for G6PD status is

recommended before treatment with antimalarial drugs.

The protection offered by G6PD deficiency against malaria could be explained by

(i). Cells infected with the Plasmodium parasite are cleared more rapidly by the spleen. This

phenomenon might give G6PD deficiency carriers an evolutionary advantage by increasing their

fitness in malaria endemic environments. In P. falciparum infection, it has been demonstrated

that shorter half-life and rapid clearance of RBCs of G6PD deficient individuals make them less

susceptible to attacks from malaria parasites.

(ii).The G6PD-deficient host has a higher level of oxidative agents, which though generally

tolerated by the host are deadly to the parasite. In vitro studies have demonstrated that P.

falciparum is very sensitive to oxidative damage; hence, there may be impaired growth and

reduced rates of replication of P. falciparum parasites in G6PD deficient RBCs.

(iii). Red cells that are G6PD deficient are resistant to P. falciparum invasion since the parasite

require the enzyme for its normal survival in the host cell.

(e). Management of G6PD deficiency

The main mode of management of G6PD deficiency is avoidance of oxidative stressors. Rarely,

anemia may be severe enough to warrant a blood transfusion, though exchange blood

transfusion may be necessary in some neonates. Phototherapy with bili lights in neonates is

beneficial.

The WHO recommends G6PD status screening in regions where prevalence of G6PD deficiency

is 3–5% or more, but this has yet to become routine practice in Nigeria. Barriers to screening

include cost, underestimation of the public health impact of G6PD deficiency by the medical

community, lack of awareness of G6PD deficiency among lay people, and a paucity of guidelines



regarding which high risk groups should be preferentially screened when general population

screening is not possible.

Bibliography and Further Reading

Ademowo OG, Falushi AG (2002). Molecular epidemiology and activity of erythrocyte G6PD variants in a homogenous Nigerian population. East African Medical Journal, 79(1): 42-44. Bailey DG (2013). Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? Canadian Medical Association Journal, 185(4): 309-316. Buchanan N (1984). Effect of protein-energy malnutrition on drug metabolism in man. World Review of Nutrition and Dietetics, 43: 129-139. Dolan LC, Matulka RA, Burdock GA (2010). Naturally occurring food toxins. Toxins (Basel), 2(9):2289-2332. Egesie OJ, Joseph DE, Isiguzoro I, Egesie UG (2008). Glucose-6-phosphate dehydrogenase (G6PD) activity and deficiency in a population of Nigerian males resident in Jos. Nigerian Journal of Physiological Sciences, 23(1-2): 9-11. Frank JE, Maj MC (2005). Diagnosis and management of G6PD deficiency. American Family Physician, 72: 1277-1282. Howes RE, Dewi M, Piel FB, Monteiro WM, Battle KE, Messina JP, Sakuntabhai A, Satyagraha AW, Williams TN, Baird JK, Hay SI (2013). Spatial distribution of G6PD deficiency variants across malaria-endemic regions. Malaria Journal 12:418. Ibrahim B, Sani AM, Timothy B (2016). Prevalence of glucose-6-phosphate dehydrogenase deficiency among children aged 0-5 years infected with Plasmodium falciparum in Katsina State, Nigeria. Advances in Biochemistry, 4(6): 66-73. Johnson JA, Lima JJ (2003). Drug receptor/effector polymorphisms and pharmacogenetics: Current status and challenges. Pharmacogenetics, 13: 525–534. Luzzatto L, Gordon-Smith EC (2001). Inherited haemolytic anaemia. In: Postgraduate Haemaology. Hoffbrand AV, Lewis SM, Tuddenham EGD (eds.) 4th edition, Arnold, London, pp 120 – 143. Meyer UA, Zanger UM (1997). Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol, 37:269–296. Meyer UA (2000). Pharmacogenetics and adverse drug reactions. Lancet, 356:1667–1671.



Muller O, Krawinkel M (2005). Malnutrition and health in developing countries. Canadian Medical Association Journal, 173: 279-286. Nnakwe N (1995). The effect and causes of protein-energy malnutrition in Nigerian children. Nutrition Research 15: 785-794. Obasa TO, Mokuolu OA, Ojuawo A (2011). Glucose-6-phosphate dehydrogenase levels in babies delivered at the University of Ilorin Teaching Hospital. Nigerian Journal of Paediatrics, 38(4):165-169. Oshikoya KA, Senbanjo IO (2009). Pathophysiological changes that affect drug disposition in protein-energy malnourished children. Nutrition & Metabolism, 6: 50. Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (2001). Potential role of pharmacogenomics in reducing adverse drug reactions: A systematic review. Journal of American Medical Association, 286:2270–2279. Turkay S, Kus S, Gokalp A, Baskin E, Onal A (1995). Effects of protein energy malnutrition on circulating thyroid hormones. Indian Pediatrics, 32: 193-197. Vesell ES (1991). Genetic and environmental factors causing variation in drug response. Mutation Research, 247:241–257. Weinshilboum R (2003). Inheritance and drug response. New England Journal of Medicine, 348:529–537. Williams O, Gbadero D, Edowhorhu G, Brearley A, Slusher T (2013). Glucose-6-phosphate dehydrogenase deficiency in Nigerian children. PLOS ONE 8(7): 1-8, e68800. World Health Organization Working Group (1989). Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Organ. 67: 601-611. World Health Organization (2000). Management of the child with serious infection or severe malnutrition: Guidelines for care at the first-referral level in developing countries. Yoshida A, Beutler E, Motulsky AG (1971). Human glucose-6-phosphate dehydrogenase variants. Bulletin of the World Health Organization, 45: 243-253.



B. CHEMOTHERAPY

Course Outline

(1). Antimicrobial drugs: Drugs used in tuberculosis and leprosy

(2). Antiprotozoal Drugs: Drugs used in the treatment of malaria, amebiasis,

trypanosomiasis, leishmaniasis

(3). Anthelmintics: Drugs used in ascariasis ancylostomiasis, onchocerciasis,

dracunculiasis, schistosomiasis and tapeworms infestations

Learning Objectives


(a). State the drugs used in the treatment of tuberculosis, their mechanism of action and

adverse effects, including how some of the adverse effects could be ameliorated.

(b). Mention the drugs used in the treatment of leprosy.

(c). State the drugs used to treat malaria, amebiasis, trypanosomiasis and leishmaniasis.

(d). Mention anthelmintics in clinical use. Delineate drugs for infestations by nematodes, filarial

worms, cestodes and trematodes.

(e). For each infection/infestation, particular attention should be paid to first-line and alternative

drugs.

B1. ANTIMICROBIAL DRUGS: DRUGS USED IN TUBERCULOSIS AND LEPROSY

(i). Drugs used in Tuberculosis

Drugs used in the treatment of tuberculosis are grouped into first-line and second-line agents.

First-line drugs combine the greatest efficacy with an acceptable degree of toxicity, and are the

preferred agents. Second-line drugs are usually considered in case of (1) resistance to first-line

agents; (2) failure of clinical response to conventional therapy; and (3) serious treatment-

limiting adverse drug reactions. Majority of patients with tuberculosis are treated successfully

with first-line drugs; however, occasionally it may be necessary to resort to second-line drugs.

Table 1: Antimicrobial drugs used in the treatment of tuberculosis

First-line Agents Second-line Agents



(in approximate order of preference)

Isoniazid Ethionamide

Rifampicin* Aminosalicylic acid

Pyrazinamide Cycloserine

Ethambutol Capreomycin

Streptomycin Amikacin

*Rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected

individuals receiving antiretroviral protease or non-nucleoside reverse transcriptase

inhibitors.

(a). First-line Drugs

Isoniazid

Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains.

Isoniazid penetrates into macrophages and is active against both extracellular and intracellular

organisms.

Mechanism of Action

Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial

cell wall. Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase.

The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM)

and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis and

kills the cell.

Pharmacokinetics

Isoniazid is readily absorbed from the gastrointestinal tract. A 300 mg oral dose (5 mg/kg in

children) achieves peak plasma concentrations of 3–5 µg/ml within 1–2 hours. Isoniazid diffuses

readily into all body fluids and tissues, it penetrates well into caseous material. The

concentration in the central nervous system and cerebrospinal fluid is about 20 - 100% of

serum concentration. Isoniazid is metabolized by mainly acetylation by liver N-

acetyltransferase to acetylisoniazid, and enzymatic hydrolysis to isonicotinic acid. Acetylation by

liver N- acetyltransferase, is genetically determined. Human populations show genetic

heterogeneity in the rate of acetylation of isoniazid; there is a bimodal distribution of slow and

fast acetylators. Isoniazid metabolites and a small amount of unchanged drug are excreted,

mainly in the urine. The dose need not be adjusted in renal failure.



Clinical Uses

For the treatment of all types of tuberculosis.

Pyridoxine should be administered with isoniazid to minimize adverse reactions in malnourished

patients and those predisposed to neuropathy (e.g. the elderly, pregnant women, HIV-infected

individuals, diabetics, alcoholics, etc.)

Adverse Effects

Adverse effects include:

(i). Immunologic reactions with fever and skin rashes.

(ii). Hepatotoxicity - Elevated serum aspartate and alanine transaminases are encountered

commonly; however enzyme levels often normalize even with continued therapy. Hepatitis with

loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain occurs in about 1%

of isoniazid recipients and can be fatal, particularly if the drug is not discontinued promptly.

Development of isoniazid hepatitis contraindicates further use of the drug.

(iii). Peripheral neuropathy - Most commonly paraesthesia of feet and hands. Peripheral

neuropathy is more likely to occur in slow acetylators and patients with predisposing conditions

such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative

pyridoxine deficiency. Isoniazid promotes excretion of pyridoxine, and this toxicity is readily

reversed by administration of pyridoxine (15 – 50 mg/day).

(iv). Central nervous system toxicity is less common, and includes memory loss, psychosis, and

seizures. These effects may also respond to pyridoxine.

(v). Other adverse effects include hematologic abnormalities, provocation of pyridoxine

deficiency anemia, tinnitus and gastrointestinal discomfort.

Drug Interactions

Isoniazid is a potent inhibitor of CYP2C19, CYP3A, and a weak inhibitor of CYP2D6. However,

isoniazid induces CYP2E1. Drugs that are metabolized by these enzymes will potentially be

affected; for example, isoniazid can reduce the metabolism of phenytoin, diazepam,

carbamazepine, increasing their blood level and toxicity. It can induce the metabolism of

acetaminophen, and potentially increase the level of its toxic metabolites.

Rifampicin (Rifampin)



Rifampicin, also known as rifampin, is a semisynthetic derivative of rifamycin, an antibiotic

produced by Streptomyces mediterranei

Rifampicin is bactericidal for mycobacteria. It readily penetrates most tissues, and also

phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as

intracellular organisms and those sequestered in abscesses and lung cavities.

Mechanism of Action

Rifampin binds to the β subunit of bacterial DNA-dependent RNA polymerase, thereby inhibiting

RNA synthesis. Human RNA polymerase does not bind rifampicin and is not inhibited by it.

Pharmacokinetics

Rifampin is well absorbed after oral administration, relatively highly protein bound, and excreted

mainly through the liver into bile. It then undergoes enterohepatic recirculation, with the bulk

excreted as a deacylated metabolite in feces and a small amount excreted in the urine. Dosage

adjustment for renal or hepatic insufficiency is not necessary. It is distributed widely in body

fluids and tissues; however adequate cerebrospinal fluid concentrations are achieved only in the

presence of meningeal inflammation.

Clinical Uses

In combination with other mycobacterial agents to treat tuberculosis and leprosy.

In bacterial infections such as meningococcal disease, staphylococcal infection, and as

prophylaxis in H. influenza type b.

Adverse Effects

Rifampicin imparts an orange-red colour to urine, feces, saliva, sputum, sweat and tears. Other

adverse effects include rashes, nausea, vomiting, thrombocytopenia, nephritis, cholestatic

jaundice, flu-like syndrome (characterized by fever, chills, myalgias and anemia), and rarely

hepatitis.

Drug Interactions

Rifampin strongly induces most cytochrome P450 isoforms (1A2, 2C9, 2C19, 2D6, and 3A4),

thereby increasing the elimination of many drugs including HIV protease and non-nucleoside

reverse transcriptase inhibitors, coumarin anticoagulants e.g. warfarin, digoxin, ketoconazole,

propranolol, quinidine, methadone, cyclosporine, some anticonvulsants, oral contraceptives, and

others. Co-administration of rifampin results in significantly lower serum levels of these drugs.



Ethambutol

Mechanism of Action

Ethambutol inhibits mycobacterial arabinosyl transferases, which are encoded by the embCAB

operon, thereby disrupting arabinogalactan synthesis. Arabinosyl transferases are involved in

the polymerization of arabinogalactan, an essential component of the mycobacterial cell wall.

Disruption of arabinogalactan synthesis results in increased permeability of the mycobacterial

cell wall.

Pharmacokinetics

Ethambutol is well absorbed from the gastrointestinal tract, and well distributed in body tissues

and fluids. After ingestion of 25 mg/kg, a peak blood level of 2–5 µ/ml is reached in 2–4 hours.

About 20% of the unchanged drug is excreted in feces and 50% in urine. Ethambutol

accumulates in renal failure, and the dose should be reduced by half if creatinine clearance is

less than 10 ml/min. Ethambutol crosses the blood-brain barrier only when the meninges are

inflamed. Concentrations in cerebrospinal fluid are highly variable, ranging from 4 - 64% of

serum levels in meningeal inflammation.

Clinical Uses

In the treatment of tuberculosis. As with all antituberculosis drugs, resistance to ethambutol

emerges rapidly when the drug is used alone. Therefore, ethambutol is always given in

combination with other antituberculosis drugs.

Adverse Effects

The most common serious adverse reaction is retrobulbar (optic) neuritis, resulting in loss of

visual acuity and red-green color blindness (i.e. loss of ability to differentiate red from green).

This dose-related adverse effect is more likely to occur at 25 mg/kg/day continued for several

months. At 15 mg/kg/day or less, visual disturbances are rare. Periodic visual acuity testing is

desirable if the 25 mg/kg/day is used. Ethambutol is relatively contraindicated in children too

young to assess visual acuity and red-green color discrimination. Another common adverse

effect is increased concentration of urate in the blood (due to decreased renal excretion of uric

acid). Other adverse effects include rash, fever, pruritus, joint pain, gastrointestinal upset,

mental confusion, disorientation, hallucination, and rarely hypersensitivity reactions.

Pyrazinamide



Pyrazinamide is the synthetic pyrazine analog of nicotinamide. It is stable and slightly soluble in

water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli at concentrations of

approximately 20 µg/ml. Pyrazinamide is taken up by macrophages and exerts its activity

against mycobacteria residing within the acidic environment of lysosomes.

Mechanism of Action

Pyrazinamide is converted to its active metabolite, pyrazinoic acid, by mycobacterial

pyrazinamidase. Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport

functions.

Pharmacokinetics

Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed in body

tissues, including inflamed meninges. On oral administration of 25 mg/kg/day, serum

concentrations of 30–50 µg/ml are achieved after 1–2 hours. The plasma t1/2 is 8–11 hours. The

parent compound is metabolized by the liver, but metabolites are renally cleared; therefore,

pyrazinamide should be administered at 25–35 mg/kg three times weekly (not daily) in

hemodialysis patients and those in whom the creatinine clearance is less than 30 ml/min. In

patients with normal renal function, a dose of 40–50 mg/kg is administered two to three times

weekly.

Clinical Uses

In tuberculosis, in combination with isoniazid and rifampin.

Adverse Effects

Adverse effects include hepatotoxicity, and hyperuricemia due to inhibition of urate excretion

(may provoke acute gouty arthritis). Other untoward effects include arthralgias, anorexia,

nausea and vomiting, dysuria, malaise, and fever.

Streptomycin

Streptomycin, an aminoglycoside, penetrates into cells poorly and is active mainly against

extracellular tubercle bacilli. Streptomycin crosses the blood-brain barrier and achieves

therapeutic concentrations with inflamed meninges.

Clinical Uses

In tuberculosis, especially when parenteral administration is desirable and in cases resistant to

other antituberculosis drugs.



Adverse Reactions

Adverse effects include ototoxicity and nephrotoxicity. Vertigo and hearing loss are the most

common adverse effects and may be permanent. Toxicity is dose-related, and the risk is

increased in the elderly. As with all aminoglycosides, the dose must be adjusted according to

renal function. Toxicity can be reduced by limiting therapy to no more than 6 months when

possible.

(b). Second-line Drugs

Ethionamide

It is poorly water soluble and available only in oral form.

Mechanism of Action

Ethionamide is chemically related to isoniazid and also blocks the synthesis of mycolic acids,

with consequent impairment of mycobacterial cell wall synthesis.

Pharmacokinetics

The oral bioavailability of ethionamide approaches 100%, with peak concentrations achieved

about 3 hours after oral administration. It is rapidly and widely distributed in the body, the

concentrations in the blood and various organs including the cerebrospinal fluid are

approximately equal. The t1/2 is about 2 hours. It is metabolized in the liver. Metabolites are

eliminated in the urine, with <1% of ethionamide excreted in an active form.

Clinical Uses

Ethionamide is administered only orally, as a second-line antituberculosis drug.

Adverse Effects

Gastrointestinal distress manifesting as anorexia, nausea, vomiting may occur; this may reduce

compliance and could be ameliorated by taking the drug with food. Other adverse effects

include hepatotoxicity (regular monitoring of liver function is required), metallic taste, central

effects (mental depression, drowsiness, asthenia, psychiatric disturbances, and encephalopathy)

and peripheral neuropathy. The concomitant use of pyridoxine is recommended in patients on

ethionamide, as it may reduce these effects.

Drug Interactions



Ethionamide may worsen the adverse effects of other antituberculosis drugs administered

concurrently, e.g. it increases levels of isoniazid when taken together and can lead to increased

peripheral neuropathy and hepatotoxicity.

Aminosalicylic Acid (para-Aminosalicylic acid; PAS)

Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against M.

tuberculosis. It is structurally similar to p- aminobenzoic acid (PABA) and sulphonamides.

Mechanism of Action

Aminosalicylic acid is a structural analog of PABA, the substrate of dihydropteroate synthase

(DHPS; folP1/P2). PAS is recognised by DHPS as efficiently as its natural substrate PABA. PAS is

a pro-drug that is incorporated into the folate pathway by DHPS and dihydrofolate synthase

(DHFS) to generate a hydroxyl dihydrofolate antimetabolite, which in turn inhibits dihydrofolate

reductase (DHFR) enzymatic activity.

Pharmacokinetics

Aminosalicylic acid is readily absorbed from the gastrointestinal tract, with oral bioavailability

>90%. It is widely distributed in tissues and body fluids except the cerebrospinal fluid. It

reaches high concentrations in pleural and caseous fluids. More than 80% is excreted in the

urine, partly as active aminosalicylic acid, and also as the acetylated compound (>50%) and

other metabolic products. Very high concentrations of aminosalicylic acid are reached in the

urine, which can result in crystalluria. Excretion of PAS acid is reduced by renal dysfunction;

thus the dose must be reduced in renal dysfunction.

Clinical Uses

In the treatment of tuberculosis, however, its use has decreased markedly due to availability of

more active and better tolerated drugs.

Adverse Effects

Gastrointestinal symptoms (anorexia, nausea, epigastric pain, abdominal distress, and diarrhea)

are predominant and may be diminished by giving the drug with meals and with antacids.

Gastrointestinal distress often leads to poor compliance. Other adverse effects include, peptic

ulceration and hemorrhage, hematological abnormalities, generalized malaise, joint pains and

sore throat. Hypersensitivity reactions manifested by fever, joint pains, skin rashes,

hepatosplenomegaly, hepatitis, adenopathy, and granulocytopenia often occur after 3–8 weeks



of aminosalicylic acid therapy, making it necessary to stop drug administration temporarily or

permanently.

Cycloserine

Mechanism of Action

Cycloserine is an inhibitor of cell wall synthesis.

Pharmacokinetics

Peak concentrations of cycloserine are reached 3 - 4 hours after a single oral dose. It is

distributed throughout body fluids and tissues, and crosses the blood-brain barrier.

Concentrations in cerebrospinal fluid are same as those in plasma. Cycloserine is cleared

renally, mainly as the unchanged drug; the dose should be reduced by half if creatinine

clearance is less than 50 ml/min.

Clinical Uses

It is used along with other antituberculosis drugs when re-treatment is necessary, if one or

more first-line drugs cannot be used, or for active drug resistant tuberculosis especially multiple

drug-resistant and extensively drug-resistant strains of M. tuberculosis.

Adverse Effects

The most serious adverse effects are peripheral neuropathy and central nervous system

dysfunction. Central manifestations include depression, psychotic reactions with suicidal

tendencies, paranoid reactions, headaches, visual disturbance, drowsiness, dizziness, vertigo,

confusion, paresthesia, dysarthria, paresis, hyperirritability, tonic-clonic or absence seizures,

and tremors. Alcohol consumption may increase the risk of seizures.

Pyridoxine (150 mg/day), should be given with cycloserine to ameliorate neurologic toxicity.

Capreomycin

Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces

capreolus.

Clinical Uses

Capreomycin, a second-line antituberculosis drug, is an important injectable agent for treatment

of drug-resistant tuberculosis. Strains of M. tuberculosis that are resistant to streptomycin or

amikacin usually are susceptible to capreomycin.

https://en.wikipedia.org/wiki/Antituberculosis_medication

https://en.wikipedia.org/wiki/Drug_resistant_tuberculosis

https://en.wikipedia.org/wiki/Vertigo

https://en.wikipedia.org/wiki/Paresthesias

https://en.wikipedia.org/wiki/Dysarthria



Adverse Effects

Capreomycin is nephrotoxic and ototoxic; tinnitus, deafness, and vestibular disturbances may

occur. The injection causes significant local pain, and sterile abscesses may occur.

Kanamycin & Amikacin

Kanamycin has been used for treatment of tuberculosis caused by streptomycin-resistant

strains, but the availability of less toxic alternatives (e.g. capreomycin and amikacin) has

rendered it obsolete.

Amikacin is an aminoglycoside that interferes with the function of the 30S subunit of the

bacterial ribosome, thereby inhibiting protein synthesis. Amikacin is also active against atypical

mycobacteria. Its role in the treatment of tuberculosis has increased with increasing incidence

and prevalence of multidrug-resistant tuberculosis. Prevalence of amikacin-resistant strains is

low, and most multidrug-resistant strains remain amikacin-susceptible. There is no cross-

resistance between streptomycin and amikacin, but kanamycin resistance often indicates

resistance to amikacin as well.

Clinical Uses

Amikacin is indicated for treatment of streptomycin-resistant or multidrug-resistant strains of M.

tuberculosis. It is used in combination with at least one, and preferably two or three other

drugs to which the isolate is susceptible for treatment of drug-resistant cases.

Adverse effects include ototoxicity, nephrotoxicity, and paralysis which may result in inability

to breathe. Its use in pregnancy may cause permanent deafness in the baby.

Fluoroquinolones

In addition to their activity against many gram-positive and gram-negative bacteria,

ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of M. tuberculosis at

concentrations less than 2 µg/ml. They are also active against atypical mycobacteria.

Ofloxacin and ciprofloxacin have been second-line antituberculosis drugs for many years, but

their use is limited by the rapid development of resistance. Moxifloxacin is the most active

against M. tuberculosis by weight in vitro. Levofloxacin tends to be slightly more active than

ciprofloxacin against M. tuberculosis, whereas ciprofloxacin is slightly more active against

https://en.wikipedia.org/wiki/30S_ribosomal_subunit

https://en.wikipedia.org/wiki/Protein



atypical mycobacteria. Fluoroquinolones are used in combination with two or more active

antituberculosis agents in disease resistant to first-line agents.

Rifabutin

Rifabutin is derived from rifamycin and is related to rifampicin. It has significant activity against

M. tuberculosis, Mycobacterium avium complex (MAC), and M. fortuitum. Its activity is similar to

that of rifampicin, and cross-resistance with rifampin is virtually complete.

Rifabutin is both substrate and inducer of cytochrome P450 enzymes; however, it is a less

potent inducer, and also affects fewer types of CYP enzymes compared to rifampicin. Therefore

it is used in place of rifampicin for treatment of tuberculosis in patients with HIV infection who

are receiving antiretroviral therapy with a protease inhibitor or with a non-nucleoside reverse

transcriptase inhibitor (e.g., efavirenz), drugs that also are cytochrome P450 substrates. The

typical dosage of rifabutin is 300 mg/day, however in patients receiving a protease inhibitor the

dosage should be reduced to 150 mg/day. If efavirenz (also a cytochrome P450 inducer) is

used, the recommended dosage of rifabutin is 450 mg/day. Rifabutin is effective in prevention

and treatment of disseminated atypical mycobacterial infection in AIDS patients with CD4

counts below 50/μL. It is also effective for preventive therapy of tuberculosis, either alone in a

3–4 month regimen or with pyrazinamide in a 2 month regimen.

Rifapentine

Rifapentine, an analog of rifampicin, is active against both M. tuberculosis and MAC. As with all

rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampicin

and rifapentine is complete. Like rifampicin, rifapentine is a potent inducer of cytochrome P450

enzymes, and it has the same drug interaction profile. Compared to rifabutin and rifampin, the

CYP-inducing effects of rifapentine are intermediate. Toxicity is similar to that of rifampicin.

Clinical Uses

Rifapentine is indicated for treatment of tuberculosis caused by rifampicin-susceptible strains

during the continuation phase only (i.e. after the first 2 months of therapy and ideally after

conversion of sputum cultures to negative). Rifapentine should not be used to treat patients

with HIV infection because of high relapse rate with rifampicin resistant organisms.



(ii). Drugs used in Leprosy

Four major clinical types of leprosy are:

(a). Tuberculoid leprosy, also termed paucibacillary leprosy because the bacterial burden is low

and M. leprae is rarely found in smears.

(b). Lepromatous leprosy, characterized by a disseminated infection and high bacillary burden.

(c). Borderline (dimorphous) tuberculoid disease, which has features of both tuberculoid and

lepromatous leprosy.

(d). Indeterminate disease, which has early hypopigmented lesions without features of the

lepromatous and tuberculoid leprosy.

The last two are the major intermediate forms of leprosy.

Multi-drug regimens consisting of rifampicin, clofazimine, and dapsone are used in the

treatment of leprosy. Multidrug therapy is used in leprosy to (i) reduce the development of

resistance, (ii) provide adequate therapy when primary resistance already exists, and (iii)

reduce the duration of therapy.

Dapsone

Mechanism of Action

Dapsone (diaminodiphenylsulfone) is a structural analog of para aminobenzoic acid (PABA) and

a competitive inhibitor of dihydropteroate synthase (folP1/P2) in the folate pathway, ultimately

inhibiting folate synthesis.

Pharmacokinetics

After oral administration, the absorption of dapsone is complete, with elimination half-life of 20-

30 hours. Dapsone is retained in the skin, muscle, liver and kidney. Skin heavily infected with

M. leprae may contain several times more drug than normal skin. Dapsone undergoes N-

acetylation by NAT2, and N-oxidation to dapsone hydroxylamine via CYP2E1 and to a lesser

extent by CYP2C. Dapsone hydroxylamine enters red blood cells, leading to methemoglobin

formation. Intestinal reabsorption of dapsone excreted in the bile contributes to long-term

retention in the bloodstream; consequently, periodic interruption of treatment is recommended.

Approximately 70-80% of a dose of dapsone is excreted in the urine as an acid-labile mono-N-

glucuronide and mono-N-sulphamate.



Clinical Uses

Dapsone is used in combination with rifampin and clofazimine for initial therapy of leprosy as

resistance can emerge, e.g. in lepromatous leprosy, if very low doses are given. Dapsone is

used to prevent and treat Pneumocystis jiroveci pneumonia. It is combined with chlorproguanil

for the treatment of malaria.

Adverse Effects

Dapsone is usually well tolerated. Many patients develop hemolysis, particularly if they have

G6PD deficiency. It is recommended that G6PD deficiency testing should be performed prior to

use of dapsone if possible. Other adverse effects are methemoglobinemia, gastrointestinal

intolerance, fever, pruritus, and rashes. During dapsone therapy of lepromatous leprosy,

erythema nodosum leprosum often develops. It is sometimes difficult to distinguish reactions to

dapsone from manifestations of the underlying illness. Erythema nodosum leprosum may be

suppressed by corticosteroids or by thalidomide.

Rifampicin/Rifampin

Rifampicin is highly effective in lepromatous leprosy. It is given in combination with dapsone or

clofazimine because of the probable risk of emergence of rifampicin-resistant M. leprae.

Clofazimine

The mechanism of action of clofazimine has not been clearly elucidated. Absorption of

clofazimine from the gut is variable, and a major portion of the drug is excreted in feces.

Clofazimine is stored widely in reticuloendothelial tissues and skin, and its crystals can be seen

inside phagocytic reticuloendothelial cells. It is slowly released from these deposits, therefore

the serum t1/2 may be 2 months. Clofazimine is used in dapsone-resistant leprosy or in patients

intolerant to dapsone.

Discoloration of body secretions, eye and skin occur in most patients and can lead to depression

in some patients. Gastrointestinal problems are encountered in 40-50% of patients and include

abdominal pain, diarrhea, nausea, and vomiting.

Treatment of Reactions in Leprosy



During the course of leprosy, immunologically mediated episodes of acute or subacute

inflammation known as reactions may occur in patients. Leprosy reactions include reversal

reaction and erythema nodosum leprosum.

Patients with tuberculoid leprosy may develop reversal reactions, which are manifestations of

delayed hypersensitivity to antigens of M. leprae. Cutaneous ulcerations and deficits of

peripheral nerve function may occur. Early therapy with corticosteroids or clofazimine is

effective.

Erythema nodosum leprosum is an immune-mediated complication of leprosy, characterized by

the presence of multiple, tender inflammatory cutaneous nodules; and systemic symptoms such

as fever, malaise, arthritis, iritis, neuritis and lymphadenitis. It is thought to be initiated by the

release of mycobacterial antigens, which trigger the formation of immune complexes. Antigen-

antibody complexes deposited in the circulation and tissues, activate the complement.

Treatment with clofazimine or thalidomide is effective.

Rifampin is a highly effective anti-leprosy drug, however, due to high kill rates and massive

release of bacterial antigens, it is not often given during a reversal reaction or in patients with

erythema nodosum leprosum. Clofazimine is only bacteriostatic against M. leprae; however, it

also has anti-inflammatory effects and is used to treat reversal reactions and erythema

nodosum leprosum.

B2. ANTIPROTOZOAL DRUGS: DRUGS USED IN THE TREATMENT OF MALARIA, AMOEBIASIS, TRYPANOSOMIASIS, LEISHMANIASIS (i). Drugs Used in the Treatment of Malaria Classification of anitmalarial drugs

Antimalarials can be classified by the stage of parasite that they affect and their clinical uses.

Some drugs have more than one type of antimalarial activity.

(1). Drugs used for casual prophylaxis

These act on primary tissue forms of Plasmodia, which will, in less than one month initiate the

erythrocytic stage of infection. Invasion of erythrocytes and further transmission of infection are

thereby prevented e.g. proguanil (the prototype). Primaquine also has such activity against P.

falciparum, but it is reserved for other clinical applications because of its toxicity.



(2). Drugs used to prevent relapse

These drugs act on latent tissue forms of P. vivax and P. ovale remaining after the primary

hepatic forms have been released into the circulation. Such latent tissue forms eventually

mature, invade the circulation and produce malarial attacks i.e. relapse, months or years after

the initial infection.

Drugs active against latent tissue forms are used for terminal prophylaxis and for radical cure of

relapsing malarial infections. Primaquine is the prototype drug used to prevent relapse. For

terminal prophylaxis, regimens with such a drug are initiated shortly before or after a person

leaves an endemic area. To achieve radical cure, this type of drug is taken either during the

long-term latent period of infection or during an acute attack. In the latter case, the agent is

given together with an appropriate drug, e.g. artemisinins, quinine, chloroquine, etc. to

eradicate erythrocytic stages of P. vivax and P. ovale.

(3). Drugs (blood schizontocides) used for clinical and suppressive cure

These agents act on asexual erythrocytic stages of malarial parasites to interrupt erythrocytic

schizogony and thereby terminate clinical disease i.e. effect clinical cure.

Such drugs also may produce suppressive cure, which refers to complete elimination of

parasites from the body by continued therapy. Inadequate therapy with blood schizontocides

may result in recrudescence of infection due to erythrocytic schizogony.

These agents can be divided into 2 groups:

(a). Rapidly acting blood schizontocides e.g. artemisinins; classical antimalarial alkaloids e.g.

chloroquine, quinine and the related derivatives quinidine and mefloquine; atovaquone and

others.

(b). Slower-acting blood schizontocides e.g. antifolate (e.g. pyrimethamine), and antibacterial

antimalarials (e.g. sulfadoxine, sulfadiazine). These drugs are mostly used in conjunction with

the rapidly acting ones.

(4). Gametocytocides

These agents act against sexual erythrocytic forms of plasmodia, thereby preventing

transmission of malaria to mosquitoes. Chloroquine and quinine have gametocytocidal activity

against P. vivax, P. ovale and P. malariae, whereas primaquine displays especially potent

activity against gametocytes of P. falciparum. However, antimalarials are not used clinically just

for gamecytocidal action.



(5). Sporontocides

They ablate transmission of malaria by preventing or inhibiting formation of malarial oocysts

and sporozoites in infected mosquitoes. They render gametocytes non-infective in the mosquito

e.g. pyrimethamine, proguanil. Although chloroquine prevents normal plasmodia development

within the mosquito, neither it nor other antimalarial agents are used clinically for this purpose.

Antimalarial agents are also classified into:

1. Class I: Are effective against the asexual erythrocytic forms of Plasmodium. They may be

used to prevent or treat clinically symptomatic malaria. They include artemisinins, chloroquine,

mefloquine, quinine, quinidine, pyrimethamine, sulfadoxine, tetracyclines.

2. Class II: Are effective against the asexual erythrocytic forms and the primary liver stages of

P. falciparum. This additional activity shortens to several days the required period for post-

exposure prophylaxis. They include atovaquone and proguanil.

3. Class III: Effective against primary and latent liver stages, as well as gametocytes.

Primaquine is used to eradicate the hypnozoites of P. vivax and P. ovale, which are responsible

for relape.

Antimalarial drugs include: Artemisinin derivatives (artesunate, arthemeter, -dihydroartemisinin,

etc); 4-aminoquinolines (chloroquine, amodiaquine, etc.); 8-aminoquinolines (primaquine);

quinoline-methanols (quinine, mefloquine, etc); drugs affecting the synthesis or utilization of

folate (pyrimethamine, proguanil, some sulfonamides, dapsone, etc); and antibacterial

antimalarials (some sulfonamides, tetracyclines, etc.).

Artemisinins

Chinese scientists isolated qinghaosu (artemisinin), the major antimalarial ingredient from the

weed, Artemisia annua (Qing hao; sweet wormwood; annual wormwood). The Chinese have

been using this plant to cure fevers, and relieve symptoms of malaria for more than 2,000

years. The more potent semi-synthetic derivatives of artemisinin; dihydroartemisinin,

artesunate, artemether, arteether (α/β-arteether) or artemotil (β-arteether) are now in clinical

use.

Mechanism of Action



Artemisinin is a sesquiterpene lactone endoperoxide; the endoperoxide moiety is essential for

antimalarial activity. Artemisinin action involves 2 steps:

(1) Intraparasitic heme iron of infected erythrocytes catalyzes cleavage of the endoperoxide

bridge.

(2) Then intramolecular rearrangement to produce carbon- centered radicals that covalently

modify and damage specific macromolecules in the parasite.

Artemisinin and its derivatives also inhibit an essential calcium adenosine triphosphatase,

PfATPase.

Pharmacokinetics

The semisynthetic artemisinins have been formulated for administration through oral

(dihydroartemisinin, artesunate and artemether), intramuscular (artesunate and artemether),

intravenous (artesunate), and rectal (artesunate) routes. Artemether and artesunate are both

converted extensively to dihydroartemisinin, which elicits their antimalarial activity.

Bioavailability after oral administration is about 30%. Although artemisinins rapidly achieve peak

serum levels; intramuscular administration of the lipid-soluble artemether peaks in 2-6 hours,

due to a depot effect at the injection site. Both artesunate and artemether have modest levels

of plasma protein binding, ranging from 43-82%. These derivatives are extensively metabolized

and converted to dihydroartemisinin, which has a plasma t1/2 of 1-2 hours. Rectal administration

of artesunate is an important administration route, especially in tropical countries including

Nigeria where it can be lifesaving. However, bioavailability via rectal administration is highly

variable among patients. With repeated dosing, artemisinin and artesunate induce their own

CYP-mediated metabolism, primarily via CYPs 2B6 and 3A4. This may enhance clearance by up

to 5-fold.

Clinical Uses

The artemisinins are used to treat malaria, including infections due to chloroquine and

multidrug resistant strains of P. falciparum. They are not recommended for prophylactic use.

Artemisinins act more rapidly and produce less toxicity than the antimalarial alkaloids and they

are just as effective against cerebral malaria. Although artemisinins can be used as single

agents, infections often relapse unless therapy is continued for 5 - 7 days. When given with a

longer acting antimalarial, (e.g a quinoline such as mefloquine; Artequin®) for a shorter course,

relapse and development of drug resistance are usually prevented or delayed. Hence,



artemisinins are currently used as constituents of combination therapy called artemisinin-based

combination therapy or artemisinin combination therapy (ACT).

Adverse Effects

They are relatively safe in humans at therapeutic doses, side effects include those similar to

symptoms of malaria: nausea, vomiting, anorexia and dizziness. Also transient first degree

block, dose-related reversible decreases in reticulocyte and neutrophil counts, and temporary

elevation of serum aspartate aminotransferase activity have been reported. A rare but serious

adverse effect is allergic reaction.

Artemisinin Combination Therapy (ACT)

Artemisinin combination therapy (ACT) is a drug regimen/formulation containing an artemisinin

derivative and other antimalarial drug(s).

Artemisinins are used for the treatment of P. falciparum infections, but low bioavailability, poor

pharmacokinetic properties, high rate of recrudescence, and high cost are a major limitation;

consequently, other drugs are required to clear the body of all parasites and prevent

recurrence. Use of an artemisinins as monotherapy is explicitly discouraged by the WHO, as

there have been signs of development of resistance to the drugs. Due to the limitations of

artemisinins as monotherapy, and to prevent development of resistance, the WHO has

recommended ACT as the first-line therapy for P. falciparum malaria worldwide. Combinations

are effective because the artemisinin component kills the majority of parasites at the start of

the treatment, while the other drug clears the remaining parasites. ACT is well tolerated in

patients, and is now standard treatment worldwide for P. falciparum malaria.

Several fixed-dose ACTs are now available containing an artemisinin component and another

drug which has a long half-life, such as mefloquine (e.g. Artequin®), lumefantrine (e.g

Coartem®, Lokmal®, Lonart®), amodiaquine (e.g. Camosunate®), piperaquine (e.g. Waipa®),

and pyronaridine.

Chloroquine

Chloroquine is a 4 – aminoquinoline that is particularly effective against intra-erythrocytic forms

because it is concentrated within the parasitized erythrocyte, probably due to a preferential

https://en.wikipedia.org/wiki/Artemisinin-combination_therapy

https://en.wikipedia.org/wiki/Pharmacokinetic

https://en.wikipedia.org/wiki/Recrudescence

https://en.wikipedia.org/wiki/Monotherapy

https://en.wikipedia.org/wiki/WHO

https://en.wikipedia.org/wiki/Mefloquine

https://en.wikipedia.org/wiki/Lumefantrine

https://en.wikipedia.org/wiki/Coartem

https://en.wikipedia.org/wiki/Amodiaquine

https://en.wikipedia.org/wiki/Piperaquine

https://en.wikipedia.org/wiki/Pyronaridine



specific uptake mechanism present in the parasite. As with other 4 – aminoquinolines, it does

not produce radical cure.

Mechanism of Action

It acts by inhibition of heme polymerization. Asexual malaria parasites flourish in host

erythrocytes by digesting hemoglobin in their acidic food vacuoles, a process that generate free

radicals and heme (ferriprotoporphyrin IX) as highly reactive by-products. After nucleation aided

by histidine rich proteins and possibly lipids, heme polymerizes into an insoluble, unreactive

non-toxic, malaria pigment termed hemozoin.

Quinoline blood schizontocides that behave as weak bases concentrate in food vacuoles of

susceptible plasmodia, where they increase pH, inhibit the peroxidative activity of heme, and

disrupt its non-enzymatic polymerization to hemozoin. Failure to inactivate heme then kills the

parasites via oxidative damage to membranes, digestive proteases and possibly other critical

biomolecules.

Antimalarial Spectrum

It is effective against all four malaria parasites with the exception of chloroquine – resistant P.

falciparum.The disease will probably relapse in P. vivax and P. ovale malaria, unless the liver

stages are sequentially treated, first with chloroquine and then with primaquine. Chloroquine

also can be used for prophylaxis.

Pharmacokinetics

Chloroquine is rapidly and completely absorbed from the gastrointestinal tract. It is distributed

widely and is extensively bound to body tissues, with the liver containing 500 times the blood

concentration. Due to extensive tissue binding, a loading dose is required to produce effective

concentrations in plasma. Desethylchloroquine (has similar activity against P. falciparum) is the

major metabolite formed by hepatic metabolism. Both the parent compound and its metabolites

are slowly eliminated renally. The t1/2 is 6 - 7 days, with terminal elimination t1/2 of 1 – 2

months.

After parental administration, rapid entry together with a slow exit of chloroquine from a small

compartment can result in transiently high and potentially lethal concentrations of the drug in

plasma. Hence, chloroquine is given either slowly by continuous I.V. infusion or in small divided

doses by S.C or I.M. Absorption is also rapid following I.M and S.C administration.



Resistance is related to genetic changes in transporters (PfCRT, PfMDR), which reduce the

concentration of chloroquine at its site of action, the parasite’s food vacuole.

Clinical Uses

1. As an antimalarial, though its used is limited and has diminished due to resistance.

2. In extraintestinal amoebiasis

3. Chloroquine is used in the treatment of rheumatoid arthritis and lupus erythematosus,

because it concentrates in lysosomes and has anti-inflammatory properties.

4. In photoallergic reactions.

Adverse Effects

Dizziness, headache, itching, skin rash, vomiting, blurred vision may occur at low doses. In

higher doses, these symptoms are more common and exacerbation or unmasking of lupus

erythematosus or discoid lupus as well as toxic effects in skin, blood and eyes can occur. Since

the drug concentrates in melanin containing structures, prolonged administration of high doses

can result in corneal deposits and lead to retinopathy and blindness. Prolonged medication with

suppressive doses may result in headache, blurred vision, diplopia, confusion, convulsions,

bleaching of hair, widening of QRS interval, and T- wave abnormalities.

Chloroquine is contraindicated in the presence of retinal or visual field changes, epilepsy and

myaesthenia gravis.

Chloroquine has a low safety margin, and is very dangerous in overdose.

Amodiaquine

Amodiaquine is also a 4 – aminoquinoline derivative. Its antimalarial spectrum and adverse

reactions are similar to those of chloroquine, although chloroquine resistant parasites may not

be amodiaquine resistant to the same degree. Prolonged treatment may result in pigmentation

of the palate, nail beds and skin.

Primaquine

Primaquine is a very important antimalarial because it is the only drug effective against the liver

(exoerythrocytic) forms of the malarial parasite. It also kills the gametocytes; patients

recovering from P. falciparum malaria can be given primaquine for its gametocytocidal



properties. Primaquine is relatively ineffective against the asexual erythrocyte forms. Its

greatest use is in the radical cure of P. vivax and P. ovale malaria.

Pharmacokinetics

It causes significant hypotension after parenteral administration. And therefore, it is given only

orally. It is readily absorbed from the gastrointestinal tract and unlike chloroquine, it is not

bound extensively to tissues. It is rapidly metabolized to active compounds.

Clinical Uses

Primaquine is primarily used to prevent relapse of malaria due to P. vivax and P. ovale. It is

recommended to be used for primary prophylaxis prior to travel to areas with a high incidence

of P. vivax and P. ovale, and for terminal prophylaxis after travel.

Adverse Effects

Adverse effects of primaquine include gastrointestinal distress, nausea, headache, pruritus,

leucopenia and agranulocytosis especially with higher doses or prolonged use. It is

contraindicated in G6PD deficient individuals as it can cause a lethal hemolysis.

Quinine

Quinine is one of the several alkaloids derived from the bark of the cinchona tree. It also

concentrates in the Plasmodium acidic food vacuoles to inhibit the non-enzymatic

polymerization of the highly reactive toxic heme molecule into the non-toxic polymer pigment,

hemozoin.

Antimalarial Spectrum: It is effective against chloroquine resistant P. falciparum malaria. It

is a blood schizontocide; it has little effect on sporozoites or pre-erythrocytic forms of

plasmodia, therefore it is not used for prophylaxis.

Clinical Uses

(1) Despite its toxicity, it is still an important blood schizontocide for the suppressive treatment

and cure of chloroquine resistant and multidrug resistant P. falciparum malaria.

(2) Prevention and treatment of nocturnal leg muscle cramps (especially those due to arthritis,

diabetes, thrombophlebitis, arteriosclerosis and varicose veins.

Pharmacokinetics: Quinine is well absorbed on oral or I.M. administration.

Adverse Effects

https://en.wikipedia.org/wiki/Plasmodium_vivax

https://en.wikipedia.org/wiki/Plasmodium_ovale

https://en.wikipedia.org/wiki/Plasmodium_ovale



Adverse effects of quinine include cinchonism, hypoglycemia, and hypotension. Cinchonism is

the toxic state induced by excessive plasma levels of free quinine. Symptoms of cinchonism

include; sweating, ringing in the ears, impaired hearing, blurred vision, nausea, vomiting and

diarrhea. Quinine is a potent stimulus to insulin secretion, and also a gastrointestinal mucosa

irritant. It may produce a variety of relatively rare hematological changes e.g. leucopenia, and

agranulocytosis.

Mefloquine

Mefloquine is a 4–quinoline methanol derivative. It is a more effective and less toxic antimalarial

than cinchona alkaloids. It is a highly effective blood schizontocide especially against mature

trophozoites and schizont forms of malaria parasites. The exact mechanism of action has not

been clearly elucidated.

Pharmacokinetics

It is well absorbed on oral administration, absorption is increased by the presence of food. It is

taken orally because parenteral administration causes severe local reactions. It undergoes

enterohepatic recycling.

Clinical Uses

Prevention and treatment of malaria especially those caused by chloroquine resistant and

multidrug resistant P. falciparum.

Adverse Effects

Adverse effects of mefloquine include nausea, vomiting, abdominal pain, diarrhea, dizziness,

headache, disorientation, seizures and encephalopathy.

Contraindications: In patients with history of seizures, use of quinoline antimalarials (quinine,

chloroquine and quinidine) should be avoided because of increased risk of convulsions and

cardiotoxicity. Although mefloquine can be taken safely 12 hours after a last dose of quinine,

taking quinine shortly after mefloquine can be very hazardous because the latter is eliminated

slowly.

Pyrimethamine

It is a 2, 4 – diaminopyrimidine like trimethoprim (antibacterial agent).

Mechanism of Action



It inhibits DHFR of plasmodia at concentrations far lower than those required to produce

comparable inhibition of the mammalian enzyme, ultimately inhibiting synthesis of folic acid in

the parasite. Parasites cannot use preformed folic acid and therefore must synthesize this

compound from the following precursors obtained from their host; p–amino benzoic acid

(PABA), pteridine and glutamic acid. The dihydrofolic acid formed from these precursors is then

hydrogenated to form tetrahydrofolic acid. Tetrahydrofolic acid is the co-enzyme that acts as an

acceptor of a variety of one–carbon units. The transfer of one carbon units is important in the

synthesis of the pyrimidines and purines which are essential in nucleic acid synthesis.

Note: Inhibition by antifolate is manifested late in the life cycle of malarial parasites by failure

of nuclear division at the time of schizont formation in erythrocytes and the liver. This

mechanism is consistent with the slow onset of action of the antifolates, compared with the

quinoline antimalarials.

Whereas the sulfonamides and sulfones compete with PABA for dihydropteroate synthetase and

inhibit the initial step whereby PABA and the pteridine moiety combine to form dihydropteroic

acid, pyimethamine and trimethoprim inhibit the conversion of dihydrofolic acid to

tetrahydrofolic acid, a reaction catalyzed by dihydrofolate reductase.

The combined use of sulfonamides or sulfones with dihydrofolate reductase inhibitors such as

trimethoprim (Co-trimoxazole, Septrin®) or pyrimethamine (Fansidar®) is a good example of

the synergistic possibilities that exist in multiple-drug chemotherapy. This type of impairment of

the parasite’s metabolism is called sequential blockade. Using drugs that inhibit at two

different points in the same biochemical pathway produces parasite lethality at low drug

concentrations than is possible when either drug is used alone.

Clinical Uses

(1). Prophylaxis of malaria

(2). Treatment of toxoplasmosis at 10-20 times higher doses.

Pyrimethamine is recommended for prophylactic use against all susceptible strains of Plasmodia.

It should not be used as the sole therapeutic agent for treating acute malarial attack.

Sulfonamides should always be co-administered with pyrimethamine since the combined

antimalarial activity of the two drugs is significantly greater than when either drug is used

alone. Resistance also develops more slowly to the combination.



Pharmacokinetics

After oral administration, pyrimethamine is slowly but completely absorbed, reaching peak

plasma levels in 2-6 hours. It is significantly distributed in the tissues and is approximately 90%

bound to plasma proteins. Pyrimethamine is slowly eliminated from plasma with a t1/2 of about

3-4 days. Several metabolites of pyrimethamine appear in the urine; however, they have not

been fully characterized. Pyrimethamine also enters the milk of nursing mothers.

Adverse effects include rashes, insomnia, and depression of hematopoiesis with high doses.

Proguanil /chloroguanide/chlorguanide

Mechanism of Action: The active triazine metabolite of proguanil i.e. cycloguanil selectively

inhibits the bifunctional dihydrofolate reductase-thymidylate synthetase of sensitive plasmodia,

resulting in inhibition of DNA synthesis and depletion of folate cofactors.

This explains the slow antimalarial action of the antifolate biguanides compared to the quinoline

antimalarials. It is slowly but adequately absorbed from the gastrointestinal tract.

Adverse effects include abdominal pain, nausea, diarrhea, headache and fever.

Halofantrine

Halofantrine is a phenanthrene methanol derivative. It is a blood schizontocide, highly effective

against the asexual erythrocytic stage of plasmodia. It has no activity against exoerythrocytic or

gametocytes stages of malaria parasite.

Pharmacokinetics

It is given orally with slow and erratic absorption and bioavailability. The absorption is increased

approximately six–fold when taken with a fatty meal. Therefore, halofantrine should be given

on an empty stomach, and fatty foods avoided 24 hours thereafter.

Adverse effects include nausea, abdominal pain, diarrhea, pruritus, skin rash, serious but rare

fatal ventricular dysrhythmias, and prolongation of the QTc interval.

Clinical Uses: Halofantrine is used in the treatment of acute malaria caused by single or mixed

infections of P. falciparum or P. vivax.

Drug Interactions: There is a further prolongation of the QT interval when halofanrine is

administered with mefloquine, therefore both should not be used concomitantly. It has been

shown to exhibit extensive cross- resistance with mefloquine.



Atovaquone

Atovaquone, a hydroxynaphthoquinone, selectively interferes with mitochondrial electron

transport and related processes such as ATP and pyrimidine biosynthesis. It acts selectively at

the cytochrome bc1 complex of malaria parasite mitochondria to inhibit electron transport and

collapse the mitochondrial membrane potential.

When used alone, there are high rates of relapse especially in patients with uncomplicated P.

falciparum malaria. But when used as a fixed combination of atovaquone with proguanil (e.g.

Malarone®), high cure rates, few relapses and minimal toxicity are achieved.

Synergism between the two is possibly due to the ability of proguanil to enhance the membrane

collapsing activity of atovaquone.

Pharmacokinetics

Its bioavailability depends on the formulation as it has a low water solubility. A microfine

suspension has a two times greater oral bioavailability than tablets. Absorption on a single oral

dose is slow, erratic and variable, it is increased two to three fold by fatty food.

Clinical Uses

Atovaquone is used in combination with a biguanide to treat malaria; e.g. 250 mg of

atovaquone +100mg of proguanil HCl.

Adverse effects are rash, fever, vomiting, diarrhea and headache.

Antibacterial Antimalarials

(1). Sulfonamides and sulfones

They include sulfonamides e.g. sulfadoxine (a long acting sulfonamide) + pyrimethamine

(Fansidar®, Amalar®, etc.); the sulfone, Dapsone + chlorproguanil (Lapdap®) for therapy of

chloroquine resistant falciparum malaria; and pyrimethamine + dapsone (Maloprim®).

The sulfonamides and sulfones are slow-acting blood schizontocides that are more active

against P. falciparum than P. vivax. As p-aminobenzoic acid analogs that competitively inhibit

dihydropteroate synthase of P. falciparum, the sulphonamides are used together with an

inhibitor of parasite dihydrofolate reductase (e.g. pyrimethamine) to enhance their

antiplasmodial action.



(2). Tetracyclines: The tetracyclines, usually tetracycline or doxycycline, are slow-acting blood

schizontocides that are used alone for short-term prophylaxis and combined with quinine for the

treatment of malaria due to multidrug-resistant strains of P. falciparum. They are particularly

useful for the treatment of malaria due to multidrug resistant strains of P. falciparum that show

partial resistance to quinine. Their relatively slow action makes concurrent treatment with

quinine mandatory for rapid control of parasitemia.

NOTE: Tetracyclines are not administered to pregnant women or children less than 8 years,

due to their adverse effects on bones and teeth.

Other antimalarial drugs include:

Lumefantrine (benflumetol): It belongs to the aryl aminoalcohol group of antimalarials,

which include quinine, mefloquine, halofantrine, and it has similar mechanism of action. It is

available as an oral preparation co-formulated with artemether.

- Piperaquine

-Pyronaridine

(ii). Drugs used in the treatment of Amoebiasis

Drugs used to treat amoebiasis are classified into luminal, systemic and mixed amoebicides.

Luminal amoebicides are only active against intestinal forms of amoeba, e.g. diloxanide

furoate, iodoquinol, paromomycin. They can be used alone to treat asymptomatic or mild

intestinal forms of amoebiasis or after a systemic or mixed amoebicide to eradicate the

infection.

Systemic amoebicides are effective only against invasive forms of amoebiasis. They are used

primarily to treat severe amoebic dysentery e.g. dehydroemetine, or hepatic abscesses e.g.

dehydroemetine, chloroquine. However, they are not usually recommended unless other drugs

fail or cause unacceptable side effects.

Mixed amoebicides are active against both intestinal and systemic forms of amoebiasis e.g.

metronidazole (prototype), tinidazole, ornidazole, secnidazole.

Diloxanide furoate



It is a dichloroacetamide derivative; other dichloroacetamides include clefamide, teclozan, and

etofamide.

It is effective in cases of acute intestinal amoebiasis. It is effective against trophozoites in the

intestinal tract. It is only administered orally and is rapidly absorbed from the gastrointestinal

tract following hydrolysis of the ester group (in the intestinal lumen or mucosa). It is hydrolyzed

to diloxanide and furoic acid; only diloxanide appears in the systemic circulation.

Adverse effects are uncommon, but occasionally, flatulence, abdominal distension, anorexia,

nausea, vomiting, diarrhea, pruritus and urticaria occur. Diloxanide is excreted in the urine, and

4 - 9% in the faeces largely as the glucuronide.

Clinical Uses

Used alone, diloxanide furoate is effective for treatment of asymptomatic passers of amoebic

cysts. It is ineffective when administered alone in the treatment of extraintestinal amoebiasis. It

is used with or after an appropriate systemic amoebicide to effect a cure of invasive and

extraintestinal amoebiasis.

Emetine and Dehydroemetine

Emetine an alkaloid from Ipecacuanha (Brazil root), was used years back as a direct-acting

systemic amoebicide. Dehydroemetine has similar pharmacological properties but is less toxic.

Although both drugs have been widely used to treat severe invasive intestinal amoebiasis, they

have been largely replaced by the mixed amoebicide metronidazole, which is as effective and

much safer. Thus emetine and dehydroemetine should not be used unless metronidazole is

ineffective or contraindicated.

Mechanism of Action

They inhibit protein synthesis in eukaryotic cells by preventing translocation of peptidyl- transfer

RNA, from the acceptor site to the donor site on the ribosome. They do not inhibit protein

synthesis in mammalian cells.

Antimicrobial spectrum

They kill the trophozoite stage of E. histolytica, but only when it is in tissues. They have no

effect on either the cyst or trophozoite forms present in the intestinal lumen.

They are rapidly absorbed from the injection site and are concentrated and stored in several

tissues, including the liver, lungs, spleen and kidney. Renal excretion of emetine is slow and the



drug can readily accumulate. Dehydroemetine is excreted more rapidly than emetine, which

probably accounts for its lower toxicity.

Clinical Uses

They are not widely used. They are given in combination with other drugs in alternative

regimens for the treatment of severe intestinal amoebiasis and hepatic abscess caused by

metronidazole resistant E. histolytica.

Adverse Effects

They are irritants and they produce pain, tenderness and muscular weakness at the site of

injection. Other adverse effects are diarrhea, cramps, vomiting, hypotension, tachycardia and

shortness of breath.

Iodoquinol

Iodoquinol (diiodohydroxyquin) is a halogenated 8-hydroxyquinoline derivative, whose precise

mechanism of action is unknown. It kills the trophozoite form of E. histolytica. It is absorbed

from the gastrointestinal tract, and excreted in the urine and feces.

Clinical Uses: In amoebiasis.

Adverse effects are related to the iodine content of the drug; skin reactions, thyroid

enlargement, interference with thyroid function studies, headache, and diarrhea.

Since diloxanide furoate is also available as a luminal amoebicide and is safer, routine use of

iodoquinol is not strongly recommended.

Chronic use of clioquinol (iodochlorhydroxyquin), a closely related agent has been linked to a

myelitis-like illness as well as optic atrophy with permanent loss of vision.

Antibacterial agents

(1). Erythromycin and tetracycline do not have a direct effect on protozoa, but act by altering

intestinal bacterial flora and preventing secondary infection. Tetracycline also reduces the

normal gastrointestinal bacterial flora on which the amoeba depend for growth.

(2). Paromomycin is directly amoebicidal. It is not absorbed from the gastrointestinal tract, and

thus has its primary effect on bacteria, some amebas (e.g. E. histolytica), T. vaginalis, and

some helminths found in the gastrointestinal tract lumen. Adverse effects include diarrhea and

gastrointestinal upset.



Metronidazole

It is a nitroimidazole which exerts activity against most anaerobic bacteria and several protozoa.

Metronidazole freely penetrates protozoal and bacterial cells but not mammalian cells.

Mechanism of Action

Metronidazole is a prodrug. Metronidazole can function as an election sink and because it does

so, its 5-nitro group is reduced. Nitroreductase present in anaerobic organisms, reduces

metronidazole and thereby activates the drug. Reduced metronidazole disrupts replication and

transcription and inhibits DNA repair.

Antibacterial Spectrum

It inhibits E. histolytica, Giardia lamblia, T. vaginalis, Blastocystis hominis, Balantidium coli, and

the helminth Dracunculus medinensis. It is also bactericidal for obligate anaerobic gram-positive

and gram-negative bacteria, with the exception of Actinomyces species. It is not active against

aerobes or facultative anaerobes. Metronidazole resistance is rare.

Pharmacokinetics

Metronidazole is well absorbed from the gastrointestinal tract. Food delays but does not reduce

absorption. It is well distributed in body fluids, vaginal secretions, and seminal fluid. High levels

are found in plasma and cerebrospinal fluid. It is metabolised in the liver and mainly excreted

by the kidney, although small amounts can be found in saliva and breast milk.

Clinical Uses

(1). Metronidazole is the most effective agent available for the treatment of all forms of

amoebiasis with, perhaps, the exception of the person who is asymptomatic but continues to

excrete cysts. In that case, an effective intraluminal amoebicide, such as diloxanide furoate,

paromomycin sulphate or diiodohydroxyquin is indicated. Metronidazole is active against

intestinal and extraintestinal cysts and trophozoites.

Since metronidazole is well absorbed and therefore may not reach the large intestine in

therapeutic concentrations; it is likely to be more effective against systemic amoebiasis than

intestinal amoebiasis. Antibiotics such as paromomycin or a tetracycline can be used in

conjunction with metronidazole to treat severe forms of intestinal amoebiasis. Treatment with

metronidazole is generally followed by a luminal amoebicide e.g. diloxanide to effect a cure.

(2). Treatment of giardiasis.



(3). Treatment of Trichomonas vaginalis infection in males and females.

(4). Treatment of susceptible bacterial infection due to the following anaerobic bacteria;

Bacteroides, Clostridium, Helicobacter, etc.

(5). Prophylaxis of postsurgical mixed bacterial infections.

(6). Gastric infections with H. pylori when taken in various regimens that include proton pump

inhibitors.

Adverse Effects

Most frequent adverse effects of metronidazole are nausea, vomiting, cramps, diarrhea, metallic

taste, urine is often dark or reddish brown. Unsteadiness, vertigo, ataxia, peripheral

neuropathy, encephalopathy and neutropenia may also occur.

Alcohol must be avoided during treatment with metronidazole, which is a weak inhibitor of

alcohol dehydrogenase, since disulfiram- like and psychotic reactions may occur.

Drug Interactions

Metronidazole interferes with the metabolism of warfarin and may potentiate its anticoagulant

activity. Phenobarbital, rifampicin and corticosteroids (e.g. prednisone) lower metronidazole

plasma levels by increasing its metabolism. Cimetidine raises metronidazole levels by reducing

its metabolism.

Metronidazole is not recommended for use during pregnancy.

Others are tinidazole, ornidazole, secnidazole.

Chloroquine

The therapeutic value of chloroquine for extraintestinal amoebiasis in human relates to its direct

toxic action against trophozoites of E. histolytica together with the fact that it is highly

concentrated in the liver.

Chloroquine is used as a systemic amoebicide to treat hepatic amoebiasis only when treatment

with metronidazole is unsuccessful or contraindicated. The clinical response to chloroquine in

patients with hepatic amoebiasis is usually prompt, and there is no evidence of resistance to

chloroquine.

Chloroquine is far less effective in intestinal amoebiasis because it is almost completely

absorbed from the small intestine and attains only low concentrations in the intestinal wall.

Colonic infection with E. histolytica is always the source of extraintestinal amoebiasis, so a drug



effective in intestinal amoebiasis is given routinely to all patients receiving chloroquine for

hepatic amoebiasis; such therapy reduces the relapse rate.

(iii). Drugs used in the Treatment of Trypanosomiasis Trypanosomiasis refers to several diseases in vertebrates caused by parasitic protozoan

trypanosomes of the genus Trypanosoma. In humans this includes African trypanosomiasis and

Chagas disease (American trypanosomiasis). The tsetse fly serves as both a host and vector for

the trypanosome parasites.

There are two types of African trypanosomiasis (sleeping sickness), the East African

(Rhodesian) and West African (Gambian), caused by T. brucei rhodesiense and T. brucei

gambiense, respectively. T. brucei rhodesiense produces a progressive and rapidly fatal disease

marked by early involvement of the central nervous system (CNS) and frequent terminal cardiac

failure; whereas T. brucei gambiense causes illness that is characterized by later involvement of

the CNS and a longer disease course that progresses to the classical symptoms of sleeping

sickness over months to years. Neurological symptoms include confusion, poor coordination,

sensory deficits, an array of psychiatric signs, disruption of the sleep cycle, and eventual

progression into coma and death.

The parasite is entirely extracellular, and early human infection is characterized by the presence

of replicating parasites in the bloodstream or lymph without CNS involvement (stage 1); in

stage 2 disease, the parasite has crossed the blood-brain barrier and infected the CNS.

Symptoms of early-stage disease include fever, lymphadenopathy, splenomegaly, muscle and

joint pains, headache and malaise. In the later stage there is evidence of CNS involvement with

personality changes, daytime sleepiness with night-time sleep disturbance, progressive

confusion, mental deterioration, and other neurologic symptoms.

Stage I of human African trypanosomiasis is usually treated with intramuscular injection or

intravenous infusion (with adequate monitoring) of pentamidine for T. brucei gambiense or

suramin for T. brucei rhodesiense. Stage II of the disease is typically treated with melarsoprol

or eflornithine preferably administered intravenously. Melarsoprol is very effective but has many

serious side effects, including neurological damage, however, the drug is the last hope in many

late stage cases. Eflornithine is expensive and less toxic than melarsoprol. In regions where the

disease is common, eflornithine is provided for free by WHO.

https://en.wikipedia.org/wiki/Vertebrates


https://en.wikipedia.org/wiki/Protozoa

https://en.wikipedia.org/wiki/Trypanosoma

https://en.wikipedia.org/wiki/Trypanosoma

https://en.wikipedia.org/wiki/African_trypanosomiasis

https://en.wikipedia.org/wiki/Chagas_disease

https://en.wikipedia.org/wiki/Pentamidine

https://en.wikipedia.org/wiki/Suramin

https://en.wikipedia.org/wiki/Melarsoprol

https://en.wikipedia.org/wiki/Eflornithine



Pentamidine

Pentamidine has activity against trypanosomatid protozoans and against Pneumocystis jirovecii,

but toxicity is significant. Pentamidine is used for the treatment of early-stage T. brucei

gambiense infection, but is ineffective in the treatment of late-stage disease and has reduced

efficacy against T. brucei rhodesiense. The mechanism of action of pentamidine is unknown.

Pharmacokinetics

Pentamidine is administered parenterally or by inhalation. After parenteral administration, it

leaves the circulation rapidly with an initial t1/2 of about 6 hours. It is bound avidly to tissues,

and thus accumulates and is eliminated very slowly with a terminal elimination half-life of about

12 days. The drug can be detected in urine 6 or more weeks after treatment. Only trace

amounts of pentamidine appear in the central nervous system, so it is not effective against

central nervous system African trypanosomiasis. Pentamidine can also be inhaled as a nebulized

powder for the prevention of pneumocystosis. Absorption into the systemic circulation after

inhalation appears to be minimal. Pentamidine is primarily metabolized by hepatic CYP450

enzymes, about 12% is eliminated unchanged in the urine.

Clinical Uses

1. It is the drug of choice to treat the early hemolymphatic stage (first stage) of disease caused

by Trypanosoma brucei gambiense (West African sleeping sickness), before central nervous

system involvement. Pentamidine should not be used to treat late trypanosomiasis with central

nervous system involvement. Pentamidine has also been used for chemoprophylaxis against

African trypanosomiasis.

2. As an alternative to sodium stibogluconate in the treatment of visceral leishmaniasis; it has

similar efficacy, although resistance has been reported.

3. In the treatment and prevention of pneumocystis pneumonia, including in

immunocompromised persons.

Adverse Effects

Pentamidine is a highly toxic drug, with adverse effects noted in about 50% of patients

receiving 4 mg/kg/day. Rapid intravenous administration can lead to severe hypotension,

tachycardia, dizziness, and dyspnea, so the drug should be administered slowly (over 2 hours),

and patients should be recumbent and monitored closely during treatment. With intramuscular

administration, pain at the injection site is common, and sterile abscesses may develop. Other

https://en.wikipedia.org/wiki/Cytochrome_P450



adverse effects include pancreatic toxicity (hypoglycemia may be followed by hyperglycemia),

reversible renal dysfunction including nephrotoxicity, rash, metallic taste, fever, gastrointestinal

symptoms, abnormal liver function tests, acute pancreatitis, thrombocytopenia, hallucinations,

and cardiac arrhythmias. Inhaled pentamidine is generally well tolerated but may cause cough,

dyspnea, and bronchospasm.

Suramin Suramin’s mechanism of action is unknown. It is administered intravenously and displays

complex pharmacokinetics with very tight protein binding. Suramin has a short initial half-life

but a terminal elimination half-life of about 50 days. It is slowly cleared by renal excretion.

Suramin is administered after a 200-mg intravenous test dose. Regimens that have been used

include 1 g on days 1, 3, 7, 14, and 21 or 1 g each week for 5 weeks. Combination therapy with

pentamidine may improve efficacy.

Clinical Uses

It is the first-line therapy for early hemolymphatic East African trypanosomiasis, but because it

does not enter the central nervous system it is not effective against advanced disease.

Although it shows activity against T. brucei gambiense, suramin is not used in West African

trypanosomiasis because of the availability of other effective drugs that lack the high activity of

suramin against Onchocerca and Brugia, and possible immunological reactions resulting from

killing of these parasites. Since only small amounts of suramin enter the brain, it is used only

for the treatment of early-stage African trypanosomiasis (before CNS involvement). Suramin will

clear the hemolymphatic system of trypanosomes even in late-stage disease, so it is often

administered before initiating melarsoprol to reduce the risk of reactive encephalopathy

associated with the administration of melarsoprol.

Adverse Effects

Adverse reactions are common, and immediate effects include fatigue, nausea and vomiting.

Later reactions include fever, rash, headache, paresthesias, neuropathy, renal abnormalities

including proteinuria, chronic diarrhea, hemolytic anemia and agranulocytosis. Rarely, seizures,

shock, loss of consciousness and death may occur.

Melarsoprol



Melarsoprol is a trivalent arsenical that has been available for the treatment of late-stage

trypanosomiasis since 1949. Despite the fact that it causes an often fatal encephalopathy in 2-

10% of the patients, melarsoprol has remained the only drug for the treatment of late (CNS)

stages of East African trypanosomiasis caused by T. brucei rhodesiense. Although melarsoprol is

also effective against late-stage West African trypanosomiasis caused by T. brucei gambiense,

eflornithine is the first-line treatment for this disease.

Pharmacokinetics

Melarsoprol is always administered intravenously. A small but therapeutically significant amount

of the drug enters the cerebrospinal fluid and has a lethal effect on trypanosomes infecting the

CNS. The compound is excreted rapidly, with 70-80% of the arsenic appearing in the feces.

Clinical Uses

Melarsoprol is used as first-line therapy for advanced central nervous system East African

trypanosomiasis, and second-line therapy (after eflornithine) for advanced West African

trypanosomiasis.

Adverse Effects

Treatment with melarsoprol is associated with significant toxicity and morbidity. The use of such

a toxic drug is justified only by the severity of advanced trypanosomiasis and the lack of

available alternatives. Immediate adverse effects include fever, vomiting, abdominal pain, and

arthralgias. The most important toxicity is a reactive encephalopathy that generally appears

within the first week of therapy, and is probably due to disruption of trypanosomes in the

central nervous system. Common consequences of the encephalopathy include cerebral edema,

seizures, coma, and death. Other serious toxicities include peripheral neuropathy, albuminuria,

hepatic dysfunction, hypertension, myocardial damage, and hypersensitivity reactions.

Failure rates with melarsoprol appear to have increased recently in parts of Africa, suggesting

the possibility of drug resistance.

Eflornithine

Eflornithine (α-D, L difluoromethylornithine; DFMO) is superior to melarsoprol with respect to

both safety and efficacy; the case fatality rate for eflornithine is significantly lower than for

melarsoprol.

Mechanism of Action



Eflornithine is an irreversible catalytic (suicide) inhibitor of ornithine decarboxylase, the enzyme

that catalyzes the first and rate-limiting step in the biosynthesis of polyamines. The

polyamines—putrescine, spermidine, and in mammals, spermine—are required for cell division

and for normal cell differentiation. In trypanosomes, spermidine additionally is required for the

synthesis of trypanothione, which is a conjugate of spermidine and glutathione that replaces

many of the functions of glutathione in the parasite cell.

Pharmacokinetics

Eflornithine is administered intravenously, and adequate levels are achieved in the central

nervous system. The elimination half-life is about 3 hours. There is rapid renal clearance after

intravenous administration with >80% of the drug cleared by the kidney largely in unchanged

form.

Clinical Uses

Eflornithine is the first-line drug for advanced West African trypanosomiasis (adequate care

should be provided for its administration), but is not effective for East African disease.

Eflornithine is safer and has greater efficacy than melarsoprol for late-stage Gambiense sleeping

sickness.

Adverse Effects

Toxicity from eflornithine is significant, but are generally reversible on drug withdrawal. Adverse

effects include reactions at the injection site, abdominal pain, diarrhea, vomiting, headache,

anemia, thrombocytopenia, leukopenia, and seizures.

Nifurtimox

Nifurtimox, a nitrofuran, is the most commonly used drug for American trypanosomiasis

(Chagas’ disease). Nifurtimox is used in combination with eflornithine (nifurtimox-eflornithine

combination treatment; NECT) to treat late stage T. brucei gambiense sleeping sickness.

Adverse effects are common and include nausea, vomiting, abdominal pain, fever, rash,

restlessness, insomnia, neuropathy and seizures. These effects are generally reversible but

often lead to cessation of therapy before completion of a standard course.

Table 2: Drugs used for the treatment of African trypanosomiasis

Disease Stage First-line Alternative drugs



drugs

West African Early Pentamidine Suramin, eflornithine

CNS involvement Eflornithine Melarsoprol, nifurtimox-eflornithine (NECT)

East African Early Suramin Pentamidine

CNS involvement Melarsoprol -

(iv). Drugs used in the treatment of Leishmaniasis

Various forms of leishmaniasis affect people in tropical and subtropical regions of the world, and

southern Europe.

Leishmaniasis is a complex vector-borne zoonosis caused by about 20 different species of

obligate intramacrophage protozoa of the genus Leishmania. Small mammals and canines

generally serve as reservoirs for these pathogens, which can be transmitted to humans by the

bite of about 30 different species of female Phlebotomine sand fly (disease vector).

Flagellated extracellular free promastigotes, regurgitated by feeding flies, enter the host, where

they attach to and become phagocytized by tissue macrophages. These transform into

amastigotes, which reside and multiply within phagolysosomes until the cell bursts. Released

amastigotes then propagate the infection by invading more macrophages. Amastigotes taken up

by feeding sandflies transform back into promastigotes, thereby completing the transformation

cycle.

The particular localized or systemic disease syndrome caused by Leishmania depends on the

species or subspecies of infecting parasite, the distribution of infected macrophages, and

particularly the host’s immune response. In increasing order of systemic involvement and

potential clinical severity, major syndromes of human leishmaniasis is classified into cutaneous,

mucocutaneous, diffuse cutaneous, and visceral (kala azar) forms. Cutaneous forms of

leishmaniasis generally are self-limiting, with cures occurring in 3-18 months after infection.

However, this form of the disease can leave disfiguring scars. The mucocutaneous, diffuse

cutaneous, and visceral forms of the disease do not resolve without therapy. Visceral

leishmaniasis caused by L. donovani is fatal unless treated.

Leishmaniasis is increasingly becoming recognized as an AIDS-associated opportunistic

infection.



Pharmacotherapy of leishmaniasis

Pentavalent antimonials: Sodium stibogluconate and meglumine antimoniate

The mechanism of action of the antimonials is unknown.

Pharmacokinetics

They are rapidly absorbed and distributed after intravenous (preferred) or intramuscular

administration and eliminated in two phases, with short initial half-life (about 2 hours) and

much longer terminal half-life (33 - 76 hours).

Clinical Uses

Sodium stibogluconate (sodium antimony gluconate) and meglumine antimoniate, are generally

considered first-line agents for cutaneous, mucocutaneous and visceral leishmaniasis.

Their efficacy against different species may vary, possibly based on local drug resistance

patterns (e.g. their efficacy has diminished in parts of India).

Adverse Effects

Few adverse effects occur initially, but toxicity of stibogluconate increases over the course of

therapy. Most common are gastrointestinal symptoms, fever, headache, myalgias, arthralgias,

and rash. Intramuscular injections can be very painful and lead to sterile abscesses.

Electrocardiographic changes may occur, most commonly T-wave changes and QT prolongation.

These changes are generally reversible, but continued therapy may lead to dangerous

arrhythmias. Thus, the electrocardiogram should be monitored during therapy. Hemolytic

anemia and serious liver, renal, and cardiac effects are rare.

Miltefosine

Miltefosine is an alkylphosphocholine analog that is the first effective oral drug for visceral

leishmaniasis. Miltefosine is used for the treatment of visceral leishmaniasis.

Adverse effects include vomiting, diarrhea transient elevations in liver enzymes and

nephrotoxicity. Miltefosine is contraindicated in pregnancy or in women who may become

pregnant within 2 months of treatment, because of its teratogenic effects.

Liposomal amphotericin B and Paromomycin are also used to treat leishmaniasis in some

countries.



B3. ANTHELMINTICS: DRUGS USED IN ASCARIASIS, ANCYLOSTOMIASIS, ONCHOCERCIASIS, DRACUNCULIASIS, SCHISTOSOMIASIS AND TAPEWORMS INFESTATIONS Helminths (parasitic worms) pathogenic in humans are nematodes (roundworms), cestodes

(tapeworms), and trematodes (flukes). Cestodes and trematodes are flatworms

(platyhelminthes). In regions of rural poverty in the tropics including Nigeria, with high

prevalence of helminthiasis, simultaneous infection with more than one type of helminth is

common. Soil-transmited helminth (STH) infections such as ascariasis, trichuriasis and

hookworm infestation are among the most prevalent in developing countries.

Anthelmintics are drugs that act either locally within the gut lumen to cause expulsion of worms

from the gastrointestinal tract, or systemically against helminths residing outside the

gastrointestinal tract.

Nematodes (Roundworms)

The major nematode parasites of humans include the soil-transmitted helminths (STHs;

sometimes referred to as geohelminths) and the filarial nematodes.

Soil-transmited helminths include Ascaris lumbricoides (roundworm), Trichuris trichuira

(whipworm), and hookworm (Necator americanus and Ancylostoma duodenale). Other

nematodes are Strongyloides stercoralis (threadworm), Enterobius vermicularis (pinworm),

Trichinella spiralis, etc.

Filarial nematodes include lymphatic filarial and tissue-migrating filarial parasites. Lymphatic

filarial worms are Wuchereria bancrofti, Brugia malayi, Brugia timori. Tissue-migrating filarial

worms are Loa loa, Onchocerca volvulus, Dracunculus medinensis (guinea worm).

Cestodes

Cestodes include Taenia saginata (beef tapeworm), T. solium (pork tapeworm),

Diphyllobothrium latum (fish tapeworm), Hymenolepis nana (dwarf tapeworm), and

Echinococcus species. Humans serve as one of several intermediate hosts for larval forms of

Echinococcus species that cause cystic (E. granulosus) and alveolar (E. multilocularis and E.

vogeli) echinococcosis. Cystic echinococcosis is also known as hydatid disease.

Trematodes (Flukes)



Blood flukes that cause human schistosomiasis include Schistosoma haematobium, S. mansoni

and S. japonicum. Other flukes include Paragonimus westermani and other Paragonimus

species (lung flukes), Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus, Fasciola

hepatica, Fasciolopsis buski (liver flukes), Heterophyes heterophyes, Metagonimus yokogawai,

Nanophyetus salmincola, etc.

Ascariasis is a disease due to infestation by the parasitic Ascaris lumbricoides.

Trichuriasis is an infection by Trichuris trichiura (whipworm).

Ancylostomiasis (anchylostomiasis, ankylostomiasis) is a hookworm disease caused by infection

with Ancylostoma hookworms (N. americanus and A. duodenale). Certain species of hookworms

also cause cutaneous larva migrans (CLM). Cutaneous larva migrans is a zoonotic skin disease

in humans, caused by the larvae of various species of hookworms, most commonly Ancylostoma

braziliense. These parasites live in the intestines of dogs, cats, and wild animals and are

different from Ancylostoma duodenale and Necator americanus, for which humans are definitive

hosts. Enterobiasis is caused by pinworm infection; the most common symptom is itching in the

anal area.

Strongyloidiasis is caused by the nematode, Strongyloides stercoralis, or sometimes S.

fülleborni. Schistosomiasis (snail fever, bilharzia; bilharziasis) is a disease caused by parasitic

flatworms, schistosomes. The urinary tract or the intestines may be infected. The disease is

spread by contact with fresh water contaminated with the parasites; freshwater snails are the

disease vector. Schistosomiasis is especially common among children in developing countries as

they are more likely to play in contaminated water. Other high risk groups include farmers,

fishermen, and people using unclean water.

Onchocerciasis (river blindness), is a disease caused by infection with the parasitic worm

Onchocerca volvulus. Symptoms include severe itching, bumps under the skin, and blindness.

The parasite worm is spread by the bites of Simulium black fly, which live near rivers, hence

river blindess.

Dracunculiasis is an infection by Dracunculus medinensis (guinea worm).

Diseases caused by tapeworm infestations are taeniasis, cysticercosis, neurocysticercosis, and

hydatid disease. Taeniasis is a parasitic disease due to infection with tapeworms belonging to

the genus Taenia; two most important human pathogens in the genus are Taenia solium (pork

https://en.wikipedia.org/wiki/Ascaris_lumbricoides

https://en.wikipedia.org/wiki/Trichuris_trichiura

https://en.wikipedia.org/wiki/Hookworm_disease

https://en.wikipedia.org/wiki/Ancylostoma

https://en.wikipedia.org/wiki/Hookworm

https://en.wikipedia.org/wiki/Hookworm

https://en.wikipedia.org/wiki/Ancylostoma_braziliense

https://en.wikipedia.org/wiki/Ancylostoma_braziliense

https://en.wikipedia.org/wiki/Ancylostoma_duodenale

https://en.wikipedia.org/wiki/Necator_americanus

https://en.wikipedia.org/wiki/Host_(biology)

https://en.wikipedia.org/wiki/Itch

https://en.wikipedia.org/wiki/Anus

https://en.wikipedia.org/wiki/Nematode

https://en.wikipedia.org/wiki/Strongyloides_stercoralis

https://en.wikipedia.org/wiki/Helminthiasis

https://en.wikipedia.org/wiki/Parasitism

https://en.wikipedia.org/wiki/Flatworm

https://en.wikipedia.org/wiki/Schistosome

https://en.wikipedia.org/wiki/Urinary_tract

https://en.wikipedia.org/wiki/Intestines

https://en.wikipedia.org/wiki/Fresh_water

https://en.wikipedia.org/wiki/Freshwater_snail

https://en.wikipedia.org/wiki/Parasitic_worm

https://en.wikipedia.org/wiki/Onchocerca_volvulus

https://en.wikipedia.org/wiki/Blindness

https://en.wikipedia.org/wiki/Simulium

https://en.wikipedia.org/wiki/Black_fly


https://en.wikipedia.org/wiki/Infection

https://en.wikipedia.org/wiki/Tapeworms

https://en.wikipedia.org/wiki/Taenia_(genus)

https://en.wikipedia.org/wiki/Pathogens

https://en.wikipedia.org/wiki/Taenia_solium



tapeworm) and Taenia saginata (beef tapeworm). Cysticercosis is a parasitic tissue infection

caused by larval cysts of the tapeworm Taenia solium. These larval cysts infect the central

nervous system (neurocysticercosis), muscle, or other tissues, and are a major cause of adult

onset seizures in most low-income countries. Hydatid disease in humans is caused mainly by

infection by the larval stage of the dog tapeworm Echinococcus granulosus.

(i). Anthelmintics used to treat infections by nematodes

Benzimidazoles

Anthelmintic benzimidazoles are albendazole, mebendazole and thiabendazole. The primary

mechanism of action of benzimidazoles is inhibition of microtubule polymerization by binding to

β –tubulin.

Albendazole

Mechanism of Action

Albendazole, a benzimidazole, inhibits microtubule synthesis in nematodes. It also has larvicidal

effects in hydatid disease, cysticercosis, ascariasis, and hookworm infection; and ovicidal effects

in ascariasis, ancylostomiasis, and trichuriasis.

Pharmacokinetics

After oral administration, albendazole is erratically absorbed (absorption is increased with a

fatty meal) and then rapidly undergoes first-pass metabolism in the liver to the active

metabolite albendazole sulfoxide. It reaches variable maximum plasma concentrations about 3

hours after a 400 mg oral dose, and its plasma half-life is 8–12 hours. The sulfoxide is mostly

protein-bound, distributes well to tissues, and enters bile, cerebrospinal fluid, and hydatid cysts.

Albendazole metabolites are excreted in the urine.

Clinical Uses

1. It is effective in Ascaris, Trichuris, Hookworm and Pinworm infestations.

2. In hydatid disease, neurocysticercosis, and other infections such as cutaneous larva migrans,

visceral larva migrans, intestinal capillariasis, amongst others.

Albendazole should be administered on an empty stomach when used against intraluminal

parasites, but with a fatty meal when used against tissue parasites.

Adverse Effects

https://en.wikipedia.org/wiki/Tapeworm

https://en.wikipedia.org/wiki/Taenia_saginata



Albendazole is nearly free of significant adverse effects, when used for 1–3 days. However,

adverse effects include mild and transient epigastric distress, diarrhea, headache, nausea,

dizziness, lassitude and insomnia.

Mebendazole

Mechanism of Action

Mebendazole, a benzimidazole, acts by inhibiting microtubule synthesis. It kills hookworm,

Ascaris and Trichuris eggs.

Pharmacokinetics

Less than 10% of orally administered mebendazole is absorbed; absorption is increased if the

drug is ingested with a fatty meal. The absorbed drug is about 95% protein-bound, rapidly

converted to inactive metabolites (primarily during its first pass in the liver) and has a half-life

of 2–6 hours. The low systemic bioavailability of mebendazole results from a combination of

poor absorption and rapid first-pass hepatic metabolism. It is excreted mostly in the urine,

principally as decarboxylated derivatives. Also, a portion of absorbed drug and its derivatives

are excreted in the bile.

Clinical Uses

Mebendazole is used in ascariasis, trichuriasis, hookworm and pinworm infections, and certain

other helminthic infections like intestinal capilliarisis.

Adverse Effects

Short-term mebendazole therapy for intestinal nematodes is nearly free of adverse effects,

however, nausea, vomiting, diarrhea, and abdominal pain may occur. Rare adverse effects,

usually with high-dose therapy, include hypersensitivity reactions (rash, urticaria),

agranulocytosis, alopecia, and elevation of liver enzymes.

Drug Interactions: Concomitant use of carbamazepine or phenytoin may decrease, while

cimetidine may increase the plasma levels of mebendazole.

Thiabendazole

Thiabendazole is active against a wide range of nematodes, but its clinical use has declined

markedly because of its toxicity relative to other equally effective drugs.

Mechanism of Action



Thiabendazole is a benzimidazole compound, its mechanism of action is the same as that of

other benzimidazoles.

Pharmacokinetics

Thiabendazole is rapidly absorbed after ingestion. Peak plasma levels are achieved within 1–2

hours after a standard dose; the half-life is 1.2 hours. The drug is almost completely

metabolized in the liver to the 5-hydroxy form; 90% is excreted in the urine in 48 hours, largely

as the glucuronide or sulfonate conjugate. Thiabendazole can also be absorbed from the skin.

Clinical Uses

Thiabendazole is an alternative to ivermectin or albendazole for the treatment of

strongyloidiasis and cutaneous larva migrans. Thiabendazole is much more toxic than other

benzimidazoles and more toxic than ivermectin, so other agents are now preferred for most

indications.

Adverse Effects

Adverse effects of thiabendazole include dizziness, anorexia, nausea, vomiting, epigastric pain,

abdominal cramps, diarrhea, pruritus, headache, drowsiness, and neuropsychiatric symptoms.

Irreversible liver failure and fatal Stevens-Johnson syndrome may occur.

Cautions and Contraindications

Thiabendazole should not be used in pregnancy or in the presence of hepatic or renal disease.

Pyrantel Pamoate

Pyrantel pamoate, a tetrahydropyrimidine derivative, is a broad-spectrum anthelmintic highly

effective for the treatment of pinworm, Ascaris, and Trichostrongylus orientalis infections. It is

moderately effective against both species of hookworm (N. americanus and A. duodenale). It is

not effective in trichuriasis or strongyloidiasis.

Mechanism of Action

Pyrantel is a depolarizing neuromuscular blocker that causes persistent activation of nicotinic

acetylcholine receptors, resulting in spastic paralysis of the worm. Pyrantel also inhibits

cholinesterases, resulting in paralysis of worms. Consequently, the worm will be expelled from

the body.



It is effective against mature and immature forms of susceptible helminths within the intestinal

tract, but not against migratory stages in the tissues or against ova. It is poorly absorbed from

the gastrointestinal tract and active mainly against luminal organisms.

Pharmacokinetics

Pyrantel pamoate is poorly absorbed from the gastrointestinal tract, peak plasma levels are

reached in 1–3 hours. Less than 15% is excreted in the urine as parent drug and metabolites.

Over 50% of the administered dose is recovered unchanged in the feces.

Clinical Uses

In the treatment of ascariasis, pinworm (enterobiasis) and hookworm infestations.

Adverse Effects

Adverse effects are infrequent, mild, and transient. They include nausea, vomiting, diarrhea,

abdominal cramps, dizziness, drowsiness, headache, insomnia, rash, fever and weakness.

Caution

Pyrantel should be used with caution in patients with liver dysfunction, because low, transient

elevation of aminotransferases may occur.

Piperazine

Piperazine is highly effective against A. lumbricoides and E. vermicularis.

Mechanism of Action

Piperazine acts as a GABA-receptor agonist, thereby increasing chloride ion conductance of the

parasite’s muscle membrane, producing hyperpolarization and reduced excitability that leads to

muscle relaxation and flaccid paralysis. The worm is subsequently expelled by normal

peristalsis.

Pharmacokinetics

Piperazine is available as the hexahydrate, citrate and a variety of salts. It is readily absorbed,

and maximum plasma levels are reached in 2–4 hours. Most of the drug is excreted unchanged

in the urine in 2–6 hours, and excretion is complete within 24 hours.

Clinical Uses

Piperazine has been superseded as a first-line anthelmintic by the better tolerated and more

easily administered benzimidazole anthelmintics. Piperazine is an alternative for the treatment

of ascariasis.



Adverse Effects

Occasional mild adverse effects include nausea, vomiting, diarrhea, abdominal pain, dizziness,

and headache. Neurotoxicity and allergic reactions are rare.

Contraindications

Piperazine compounds are contraindicated in pregnant women, in patients with impaired renal

or hepatic function, or those with a history of epilepsy or chronic neurologic disease.

(ii). Anthelmintics used to treat infections by cestodes and trematodes

Praziquantel

Praziquantel is active against most cestodes and trematodes that infect humans, whereas

nematodes generally are unaffected. The drug is best studied and most commonly used for

treatment of schistosomiasis caused by S. mansoni, S. haematobium, and S. japonicum.

Mechanism of Action

The exact mechanism of action of praziquantel is unclear, but it seems to increase the

permeability of trematode and cestode cell membranes to calcium, resulting in paralysis,

dislodgement and death of the parasites.

Pharmacokinetics

It is rapidly absorbed, with a bioavailability of about 80% after oral administration. Peak serum

concentration is reached 1–3 hours after a therapeutic dose. Plasma concentrations of

praziquantel increase when it is taken with a high-carbohydrate meal. Cerebrospinal fluid

concentration is about 14–20% of the drug’s plasma concentration. About 80% of the drug is

bound to plasma proteins. Most of the drug rapidly undergoes hepatic first-pass metabolism to

inactive mono- and polyhydroxylated products, hence only a relatively small amount enters the

systemic circulation. The half-life is 0.8–3 hours, depending on the dose. Praziquantel is

metabolized by CYP3A4. Praziquantel and its metabolites are mainly excreted via the kidneys

(60–80%) and bile (15–35%).

Clinical Uses

Praziquantel is effective in the treatment of schistosome infections of all species

(schistosomiasis) and most other trematode and cestode infections, including taeniasis,

cysticercosis, neurocysticercosis, hydatid disease, clonorchiasis, opisthorchiasis and other

tapeworm and fluke (e.g. Fasciolopsis buski, Heterophyes heterophyes, etc) infections.

https://en.wikipedia.org/wiki/Trematoda



Praziquantel is useful in mass treatment of infections by several helminths because of its safety

and effectiveness as a single oral dose.

Praziquantel tablets are taken with liquid after a meal; they should be swallowed without

chewing because their bitter taste can induce retching and vomiting.

Praziquantel should not be used for worm infections of the eye.

Adverse Effects

Mild and transient adverse effects are common, and include headache, dizziness, drowsiness,

and lassitude. Others include mild and transient elevations of liver enzymes, nausea, vomiting,

abdominal pain, loose stools, pruritus, urticaria, arthralgia, myalgia and low-grade fever.

Several days after starting praziquantel, low-grade fever, pruritus, and skin rashes (macular and

urticarial), sometimes associated with worsened eosinophilia, may occur, probably due to the

release of proteins from dying worms and the consequent host immune reaction, rather than

direct drug toxicity.The heavier the parasite burden, the heavier and more frequent the side

effects. The intensity and frequency of adverse effects increase with dosage such that they

occur in up to 50% of patients who receive 25 mg/kg three times in one day.These side effects

may be life-threatening and can be reduced by co-administration of corticosteroids.

In neurocysticercosis, neurologic abnormalities may be exacerbated by inflammatory reactions

around dying parasites. Also, corticosteroids are commonly used with praziquantel in the

treatment of neurocysticercosis to decrease the inflammatory reaction.

The use of corticosteroids to ameliorate the adverse reactions to praziquantel is controversial

and complicated by the observation that corticosteroids decrease the plasma level of

praziquantel up to 50%.


Tasks requiring mental alertness (e.g., driving, operating machinery) should be avoided shortly

after taking Praziquantel.

Praziquantel is contraindicated in ocular cysticercosis, because parasite destruction in the eye

may cause irreparable damage. Caution is also advised in the use of the drug in spinal

neurocysticercosis.

Drug Interactions

Inducers of CYP3A4 such as rifampicin, carbamazepine and phenytoin decreases plasma

concentrations of praziquantel. Cimetidine increases its bioavailabilty.

https://en.wikipedia.org/wiki/Corticosteroid

https://en.wikipedia.org/wiki/Rifampicin

https://en.wikipedia.org/wiki/Carbamazepine

https://en.wikipedia.org/wiki/Phenytoin



Oxamniquine

Oxamniquine is an alternative to praziquantel for the treatment of Schistosoma mansoni

infections. It has also been used extensively for mass treatment. It is not effective against other

Schistosoma spp -S. haematobium or S. japonicum.

Mechanism of Action

The mechanism of action is unknown. Contraction and paralysis of the worms results in

detachment from terminal venules in the mesentery and transit to the liver, where many die;

surviving females return to the mesenteric vessels but cease to lay eggs.

Oxamniquine is active against both mature and immature stages of S. mansoni but does not

appear to be cercaricidal.

Pharmacokinetics

Oxamniquine is readily absorbed on oral administration; it should be taken with food. Its plasma

t1/2 is about 2.5 hours. The drug is extensively metabolized to inactive metabolites and excreted

in the urine; up to 75% in the first 24 hours.

Clinical Uses

Oxamniquine is safe and effective in all stages of S. mansoni disease, including advanced

hepatosplenomegaly. It is generally less effective in children, who require higher doses than

adults. It is better tolerated with food.

Oxamniquine is effective in praziquantel resistance.

Oxamniquine is used in combination with metrifonate, in the treatment of mixed schistosome

infections.

Optimal dosage schedules for therapy with oxamniquine vary for different regions of the world.

In the western hemisphere and western Africa, the adult oxamniquine dosage is 12–15 mg/kg

given once. In northern and southern Africa, standard schedules are 15 mg/kg twice daily for 2

days. In eastern Africa and the Arabian Peninsula, standard dosage is 15–20 mg/kg twice in 1

day.

Adverse Effects

Adverse effects are generally mild, and include central nervous system symptoms (dizziness,

headache and drowsiness), nausea, vomiting, diarrhea, colic, pruritus, urticaria, low-grade



fever, an orange to red discoloration of the urine, proteinuria, microscopic hematuria, and a

transient decrease in leukocytes.


Oxamniquine should be used with caution in patients whose work or activity requires mental

alertness, as it causes dizziness and drowsiness. It should be used with caution in those with a

history of epilepsy. Oxamniquine is contraindicated in pregnancy.

Metrifonate (Trichlorfon)

Metrifonate is a safe, low-cost alternative drug for the treatment of S. haematobium infections.

It is not effective against S. haematobium eggs; live eggs continue to pass in the urine for

several months after all adult worms have been killed. Metrifonate is not active against

S.mansoni or S. japonicum.

Mechanism of Action

Metrifonate is an irreversible organophosphate acetylcholinesterase inhibitor. It is a prodrug

which is activated non-enzymatically into 2,2-dichlorovinyl dimethyl phosphate (DDVP;

dichlorvos). The inhibition of acetylcholinesterase paralyzes the adult worms, resulting in their

shift from the bladder venous plexus to small arterioles of the lungs, where they are trapped,

encased by the immune system, and die.

Pharmacokinetics

Metrifonate is rapidly absorbed after oral administration. After the standard oral dose, peak

blood levels are reached in 1–2 hours; the half-life is about 1.5 hours. Clearance appears to be

through non-enzymatic transformation to dichlorvos, its active metabolite. Metrifonate and

dichlorvos are well distributed to the tissues and are completely eliminated in 24–48 hours.

Clinical Uses

In the treatment of S. haematobium infection.

In prophylaxis of S. haematobium infections, especially in mass treatment programs in highly

endemic areas.

Metrifonate is used in combination with oxamniquine, in the treatment of mixed infections with

S. haematobium and S. mansoni.

Niclosamide

https://en.wikipedia.org/wiki/Organophosphate

https://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor

https://en.wikipedia.org/wiki/2,2-dichlorovinyl_dimethyl_phosphate



Niclosamide is a second-line drug for the treatment of most tapeworm infestations.

Mechanism of Action

Niclosamide inhibits glucose uptake, oxidative phosphorylation, and anaerobic metabolism in

the tapeworm.

Pharmacokinetics

It appears to be minimally absorbed from the gastrointestinal tract; neither the drug nor its

metabolites have been recovered from the blood or urine.

Clinical Uses

1. In the treatment of Taenia saginata (Beef Tapeworm), T. solium (Pork Tapeworm),

Diphyllobothrium latum (Fish Tapeworm), and some other tapeworm infestations.

Adverse Effects

Infrequent, mild, and transitory adverse effects include nausea, vomiting, diarrhea, and

abdominal discomfort.


The consumption of alcohol should be avoided on the day of treatment and for one day

afterward. The safety of the drug has not been established in pregnancy or for children younger

than 2 years of age.

Therapy with niclosamide poses a risk to people infected with T. solium because ova released

from drug-damaged gravid worms develop into larvae that can cause cysticercosis, a dangerous

infection that responds poorly to chemotherapy.

(iii). Anthelmintics used to treat infections by filarial nematodes Ivermectin Ivermectin, a semisynthetic macrocyclic lactone, is a mixture of avermectin B 1a and B 1b. It is

derived from the soil actinomycete, Streptomyces avermitilis. Ivermectin is the drug of choice in

strongyloidiasis and onchocerciasis. It is also an alternative drug for a number of other

helminthic infections.

In humans infected with O. volvulus, ivermectin causes a rapid, marked decrease in microfilarial

counts in the skin and ocular tissues that lasts for 6-12 months. It has little discernible effect on

adult parasites, even at doses as high as 800 μg/kg, but affects developing larvae and blocks

egress of microfilariae from the uterus of adult female worms. By reducing microfilariae in the

https://en.wikipedia.org/wiki/Glucose

https://en.wikipedia.org/wiki/Phosphorylation



skin, ivermectin decreases transmission to the Simulium black fly vector. Regular treatment with

ivermectin is believed to act prophylactically against the development of Onchocerca infection.

Ivermectin also is effective against microfilaria but not against adult worms of W. bancrofti, B.

malayi, L. loa, and M. ozzardi. It is also effective in human against Ascaris lumbricoides,

Strongyloides stercoralis, and cutaneous larva migrans.

Mechanism of Action

Ivermection enhances inhibitory neurotransmission. It binds to glutamate-gated chloride

channels (GluCls) in the membranes of invertebrate nerve and muscle cells, causing increased

permeability to chloride ions, resulting in cellular hyperpolarization, followed by paralysis and

death. GluCls are invertebrate-specific members of the Cys-loop family of ligand-gated ion

channels present in neurons and myocytes. Ivermectin is also known to bind with high affinity

to GABA-gated chloride channels.

In onchocerciasis, ivermectin is microfilaricidal. It does not effectively kill adult worms but

blocks the release of microfilariae for some months after therapy. After a single standard dose,

microfilariae in the skin diminish rapidly within 2–3 days, remain low for months, and then

gradually increase; microfilariae in the anterior chamber of the eye decrease slowly over

months, eventually clear, and then gradually return. Repeated doses of ivermectin, appears to

have a low level macrofilaricidal action and permanently reduce microfilarial production.

Pharmacokinetics

Ivermectin is used only orally in humans. It is rapidly absorbed, reaching peak plasma

concentrations 4-5 hours after oral administration. It has a wide tissue distribution and a

volume of distribution of about 50 L; it is about 93% bound to plasma proteins. Its terminal

half-life is about 57 hours. The drug is extensively converted by hepatic CYP3A4 to at least ten

metabolites, mostly hydroxylated and demethylated derivatives. Ivermectin and its metabolites

are excreted almost exclusively in the feces.

Clinical Uses

1. In the treatment of onchocerciasis. With the first treatment only, patients with microfilariae

in the cornea or anterior chamber may be treated with corticosteroids to avoid inflammatory

eye reactions.

https://en.wikipedia.org/wiki/Chloride_channels

https://en.wikipedia.org/wiki/Chloride_channels

https://en.wikipedia.org/wiki/Invertebrate

https://en.wikipedia.org/wiki/Cys-loop

https://en.wikipedia.org/wiki/Ligand-gated_ion_channel

https://en.wikipedia.org/wiki/Ligand-gated_ion_channel

https://en.wikipedia.org/wiki/Neuron

https://en.wikipedia.org/wiki/Myocyte



Ivermectin is beneficial in onchocerciasis control in Nigeria and other countries; annual mass

treatments have reduced the transmission of the disease.

2. In the treatment of lymphatic filariasis.

Single annual doses of ivermectin (400 μg/kg) is both effective and safe for mass chemotherapy

of infections with W. bancrofti and B. malayi. Ivermectin is as effective as diethylcarbamazine

(DEC) for controlling lymphatic filariasis, but unlike DEC, it can be used in regions where

onchocerciasis, loiasis, or both are endemic.

Although ivermectin as a single agent can reduce W. bancrofti microfilaremia, a single annual

dose of ivermectin (200 μg/kg) and albendazole (400 mg) is more effective in controlling

lymphatic filariasis than either drug used alone. The duration of treatment is at least 5 years,

based on the estimated fecundity of the adult worms. This dual-drug regimen also reduces

infections with intestinal nematodes. Facilitated by corporate donation of ivermectin and

albendazole, the drug combination now serves as the treatment standard for mass

chemotherapy and control of lymphatic filariasis.

3. In the treatment of strongyloidiasis. Ivermectin administered as a single dose of 150 to 200

μg/kg is the drug of choice for treatment of human strongyloidiasis. It is at least as active as

the older drug of choice, thiabendazole, and significantly better tolerated. It is generally

recommended that a second dose be administered a week following the first dose. It is more

efficacious than a 3-day course of albendazole.

4. Ivermectin is also effective in controlling scabies, lice and cutaneous larva migrans, and in

eliminating a large proportion of ascarid worms.

Adverse Effects

In onchocerciasis treatment, adverse effects are principally due to killing of microfilariae and

may include fever, headache, dizziness, somnolence, weakness, rash, increased pruritus,

diarrhea, joint and muscle pains, hypotension, tachycardia, lymphadenitis, lymphangitis, and

peripheral edema. This reaction starts on the first day and peaks on the second day after

treatment. This reaction occurs in 5–30% of persons and is generally mild, but it may be more

frequent and more severe in individuals who are not long term residents of onchocerciasis-

endemic areas. A more intense reaction occurs in 1–3% of persons and a severe reaction in

0.1%, including high fever, hypotension, and bronchospasm. Corticosteroids are indicated in

these cases, at times for several days. Toxicity diminishes with repeated dosing. Swellings and



abscesses occasionally occur at 1–3 weeks, presumably at sites of adult worms. Some patients

develop corneal opacities and other eye lesions several days after treatment. These are rarely

severe and generally resolve without corticosteroid treatment.

In strongyloidiasis treatment, infrequent adverse effects include fatigue, dizziness, nausea,

vomiting, abdominal pain, and rashes.


It is best to avoid concomitant use of ivermectin with other drugs that enhance GABA activity,

eg, barbiturates, benzodiazepines, and valproic acid. Ivermectin should not be used during

pregnancy. Safety in children younger than 5 years has not been established.

Diethylcarbamazine citrate

Diethylcarbamazine (DEC) is a drug of choice in the treatment of filariasis, loiasis, and tropical

eosinophilia. It has been replaced by ivermectin for the treatment of onchocerciasis.

Diethylcarbamazine is active against microfilariae of W. bancrofti, B. malayi, L. loa and O.

volvulus. It has some activity against the adult forms of W. bancrofti, B. malayi, and L. loa but

negligible activity against adult O. volvulus. It is not used for the treatment of onchocerciasis

because it causes severe reactions related to microfilarial destruction, including worsening

ocular lesions. However, diethylcarbamazine remains the best drug available to treat loiasis.

Mechanism of Action

Diethylcarbamazine inhibits arachidonic acid metabolism in microfilaria, thereby immobilising

the microfilariae, altering their surface structure and displacing them from tissues. Ultimately,

the micorfilariae are more susceptible to destruction by host defense mechanisms. The mode of

action against adult worms is unknown.

Pharmacokinetics

Diethylcarbamazine is rapidly absorbed from the gastrointestinal tract; peak plasma levels are

reached within 1–2 hours after a 0.5 mg/kg dose. The plasma half-life is 2–3 hours in the

presence of acidic urine, but about 10 hours if the urine is alkaline. The drug rapidly equilibrates

with all tissues except fat. Diethylcarbamazine is excreted by both urinary and extra-urinary

routes; greater than 50% of an oral dose appears in acidic urine as the unchanged drug, but

this value is decreased when the urine is alkaline. Alkalinizing the urine can elevate plasma

levels, prolong the plasma t1/2, and increase both the therapeutic effect and toxicity of

https://en.wikipedia.org/wiki/Arachidonic_acid

https://en.wikipedia.org/wiki/Microfilaria



diethylcarbamazine. Therefore, dosage reduction may be required for people with renal

dysfunction or persistent urinary alkalosis. Metabolism is rapid and extensive; a major

metabolite, diethylcarbamazine-N-oxide, is active.

Clinical Uses

1. Diethylcarbamazine is the drug of choice for treatment of W.bancrofti, B. malayi, B. timori,

and L. loa infections because of its efficacy and lack of serious toxicity. Microfilariae of all the

species are rapidly killed; adult parasites are killed more slowly, often requiring several courses

of treatment. The drug is highly effective against adult L. loa.

These infections are treated for 2 or (for L. loa) 3 weeks, with initial low doses to reduce the

incidence of allergic reactions to dying microfilariae. Antihistamines may be given for the first

few days of therapy to limit allergic reactions, and corticosteroids should be started and doses

of diethylcarbamazine lowered or interrupted if severe reactions occur.

2. An important application of diethylcarbamazine is in mass treatment to reduce the prevalence

of W.bancrofti infection, generally in combination with ivermectin or albendazole.

This strategy has led to excellent progress in disease control in Nigeria and other countries.

3. For tropical eosinophilia in Mansonella streptocerca infections since it kills both adult worms

and microfilariae.

Diethylcarbamazine should be taken after meals.

Adverse Effects

Generally mild and transient adverse reactions to DEC include headache, malaise, anorexia,

weakness, nausea, vomiting, and dizziness.

Adverse effects also occur as a result of the release of proteins from dying microfilariae or adult

worms. Reactions are particularly severe with onchocerciasis (Mazzotti reaction), but

diethylcarbamazine is no longer used for this infection, because ivermectin is equally efficacious

and less toxic. Reactions to dying microfilariae are usually mild in W.bancrofti, more intense in

B. malayi, and occasionally severe in L. loa infections. Reactions include fever, malaise, papular

rash, headache, gastrointestinal symptoms, cough, chest pain, and muscle or joint pain.

Symptoms are most likely to occur in patients with heavy loads of microfilariae.

Other adverse effects include leukocytosis, eosinophilia, proteinuria, retinal hemorrhages and,

rarely, encephalopathy. Between the third and twelfth days of treatment, local reactions may

occur in the vicinity of dying adult or immature worms. These include lymphangitis with



localized swellings in W. bancrofti and B. malayi, small wheals in the skin in L. loa, and flat

papules in M. streptocerca infections. Patients with attacks of lymphangitis due to W. bancrofti

or B. malayi should be treated during a quiescent period between attacks.


Population-based therapy with DEC should be avoided where onchocerciasis or loiasis is

endemic.

Note: Annual single dose co-administration of DEC with either albendazole or ivermectin is

effective in reducing microfilaremia, for the control of lymphatic filariasis in regions where

onchocerciasis, loiasis, or both are not endemic.

Dracunculiasis

Dracunculiasis (guinea worm disease) is caused by the parasitic nematode Dracunculus

medinensis (guinea, dragon, or Medina worm). Infection is by drinking water containing

copepods that carry infective larvae. After about 1 year, the adult female worms migrate and

emerge through the skin, usually of the lower legs or feet. Through the advocacy and work of

the Carter Center in partnership with WHO, strategies such as filtering drinking water and

reducing contact of infected individuals with water have markedly reduced the transmission and

prevalence of dracunculiasis in most endemic regions, including Nigeria.

There is no effective drug for treatment or prevention of D. medinensis infection. Traditional

treatment for this disabling condition is to draw the live adult female worm out day by day by

applying gentle traction, and rolling it onto a small piece of wood or matchstick. This procedure

risks significant secondary bacterial infection.

Optimal management of guinea worm disease involves the following steps:

1. First, each day the affected body part is immersed in a container of water to encourage

more of the worm to come out. To prevent contamination, the infected person is not allowed to

enter drinking water sources.

2. Next, the wound is cleaned.

3. Then, gentle traction is applied to the worm to slowly pull it out. Pulling stops when

resistance is met to avoid breaking the worm. Because the worm can be as long as one meter

in length, full extraction can take several days to weeks.



4. The worm is then wrapped around a rolled piece of gauze or a stick to maintain some

tension on the worm and encourage more of the worm to emerge. This also prevents the worm

from slipping back inside.

5. Afterwards, topical antibiotics are applied to the wound to prevent secondary bacterial

infections.

6. The affected body part is then bandaged with fresh gauze to protect the site. Medicines,

such as aspirin or ibuprofen, are given to help ease the pain of this process and reduce

inflammation.

7. These steps are repeated every day until the whole worm is successfully pulled out.

Table 3: Drugs used to treat helminthic infections

Infecting helminth Drug(s) of Choice Alternative Drug(s)

Roundworms (Nematodes)

Ascaris lumbricoides (roundworm) Albendazole, mebendazole, pyrantel pamoate

Piperazine, ivermectin

Trichuris trichiura (whipworm) Mebendazole, albendazole Ivermectin

Necator americanus, Ancylostoma duodunale (hookworms)

Albendazole, mebendazole, pyrantel pamoate

-

Enterobius vermicularis (pinworm) Mebendazole, pyrantel pamoate

Albendazole

Strongyloides stercoralis (threadworm) Ivermectin Albendazole, thiabendazole

Ancylostoma braziliense (Cutaneous larva migrans)

Albendazole, ivermectin Thiabendazole (topical)

Baylisascaris procyonis, Toxocara canis, Toxocara cati, Ascaris suum (Visceral larva migrans)

Albendazole Mebendazole

Wuchereria bancrofti (filariasis); Brugia malayi (filariasis); Loa loa (loiasis); Wuchereria bancrofti (tropical eosinophilia)

Diethylcarbamzine Ivermectin

Onchocerca volvulus (onchocerciasis) Ivermectin -

Capillaria phillippinensis (intestinal capillariasis)

Albendazole Mebendazole

Dracunculus medinensis (guinea worm) - -

Tapeworms (Cestodes)

Taenia saginata (beef tapeworm) Praziquantel Niclosamide

Taenia solium (pork tapeworm) Praziquantel -*

Diphyllobothrium latum (fish tapeworm) Praziquantel Niclosamide

Hymenolepis nana (dwarf tapeworm) Praziquantel Niclosamide



Echinococcus granulosus ; hydatid disease

Albendazole -

Echinococcus multilocularis Albendazole -

Pork tapeworm larva; cysticercosis Albendazole Praziquantel

Flukes (Trematodes)

Schistosoma haematobium Praziquantel Metrifonate

Schistosoma mansoni Praziquantel Oxamniquine

Schistosoma japonicum Praziquantel -

*Niclosamide is effective in T. solium infections, however its use may cause cysticercosis in people infected with T. solium. It is not used in some countries.


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AIDS Info (2018). Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. Available at: http://aidsinfo.nih.gov/guidelines Drugs for parasitic infections (2007). Med Lett Drugs Ther, Suppl 1. Drugs for parasitic infections. (2010). Med Lett Drugs Ther, Supplement. Efferth T, Kaina B (2010). Toxicity of the antimalarial artemisinin and its derivatives. Critical Reviews in Toxicology, 40:405 - 421. Fox LM (2006). Ivermectin: Uses and impact 20 years on. Current Opinion in Infectious Diseases, 19:588 - 593. Greenwood BM, Bojang K, Whitty CJM, Targett GAT (2005). Malaria. Lancet, 365:1487 – 1498. Haque R, Huston CD, Hughes M, Houpt E, Petri WA (2003). Amebiasis. New England Journal of Medicine, 348:1565 - 1573. Horton J (2002). Albendazole: A broad spectrum anthelminthic for treatment of individuals and populations. Current Opinion in Infectious Diseases, 15:599 - 608. Keiser J, Utzinger J (2008). Efficacy of current drugs against soil-transmitted helminth infections: Systematic review and meta-analysis. Journal of American Medical Association, 299:1937 - 1948. Levis WR, Ernst JD (2005). Mycobacterium leprae (Leprosy, Hansen’s disease). In: Mandell, Douglas, and Bennett’s Principles and Practices of Infectious Diseases (Mandell GL, Bennett JE, Dolin R, eds.), Elsevier Churchill Livingstone, Philadelphia, pp. 2886–2896. Molyneux DH, Bradley M, Hoerauf A, Kyelem D, Taylor MJ (2003). Mass drug treatment for lymphatic filariasis and onchocerciasis. Trends in Parasitology, 19:516–522. Murray HW, Berman J, Davies CR, Saravia NG (2005). Advances in leishmaniasis. Lancet, 366:1561 - 1577. Nosten F, White NJ (2007). Artemisinin-based combination treatment of falciparum malaria. American Journal of Tropical Mediicne and Hygeine, 77(Suppl 6):181 -192. Petri WA (2003). Therapy of intestinal protozoa. Trends in Parasitology, 19:523 - 526. Pierce KK, Kirkpatrick BD (2009). Update on human infections caused by intestinal protozoa. Current Opinion in Gastroenterology, 25:12 - 17. Priotto G, Kasparian S, Mutombo W, Ngouama D et al (2009). Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: A multicentre, randomised, phase III, non-inferiority trial. Lancet, 374:56 - 64.



Pritt BS, Clark CG (2008). Amebiasis. Mayo Clinic Proceedings, 83:1154 - 1160. Rassi A, Rassi A, Marin-Neto JA (2010). Chagas disease. Lancet, 375:1388 - 1402. Reithinger R, Dujardin J, Louzir H, Primez C, Alexander B, Brooker S (2007). Cutaneous leishmaniasis. Lancet Infectious Diseases, 7:581 - 596. Tisch DJ, Michael E, Kazura JW (2005). Mass chemotherapy options to control lymphatic filariasis: A systematic review. Lancet Infectious Diseases, 5:514 - 523. Udall DN (2007). Recent updates on onchocerciasis: Diagnosis and treatment. Clinical Infectious Diseases, 44:53 - 60. World Health Organization (1998). WHO Model Prescribing Information: Drugs used in leprosy. World Health Organization, Geneva. World Health Organization (2010). Guidelines for the treatment of malaria. Geneva. http://www.who.int/malaria/publications/atoz/9789241547925/en/ index.html



C. TOXICOLOGY

Course Outline

1. Management of poisoning

2. Drug toxicity: Definition and mechanisms

3. Animal poisons: snakebite, scorpion stings, bee stings and their management

4. Local food poisoning

5. Pesticides

6. Solvents, vapours and gases

7. Heavy metals and their antagonists

Learning Objectives


(a). Outline measures for emergency management of poisoning due to drugs and other

substances.

(b). Mention known specific antidotes for poisons.

(c). Mention the chelators used in the treatment of poisoning by specific heavy metals.

(d). State sources of poisons in the home, workplace and environment.

(e). State the measures and steps involved in the management of snakebite, scorpion and bee

stings.

(f). Outline the dos and don’ts in the management of snake bite.

(g). Name some pesticides that have been banned globally.

(h). Outline the steps involved in the management of poisoning due to commonly used

insecticides (pyrethrins, etc.) and solvents.

(i). State the steps involved in the treatment of carbon monoxide poisoning

(j). Outline the steps involved in the management of cyanide, kerosene and petrol poisoning.

(k). Identify the classes of insecticides commonly used in Nigeria; and management of poisoning due to same. Definition of Toxicology



Toxicology is a discipline concerned with the study of the harmful effects of chemical, biological

and physical agents on biological systems. Toxicology comprises the detection of the toxic

agent, mechanism by which the harmful effect is induced, the condition(s) under which it

occurs, and the treatment of the toxicity.

Divisions of toxicology include environmental toxicology, occupational toxicology, forensic

toxicology, food toxicology, and clinical toxicology.

C1. Management of Poisoning

It is pertinent to discuss the management of poisoning in general, before discussing the

poisons. Management of specific poisons shall be discussed, as appropriate under the individual

poisons.

(i). Poisoning

Poisoning is a condition or process in which an organism, e.g. humans, becomes harmed

(poisoned) by a toxic substance (poison). Poisoning could be acute or chronic.

Poisons are substances which on entering the body by whatever route (ingestion, inhalation,

absorption through the skin, etc) produce harmful effects. The effects may be damage to the

tissues or a disruption of body function. Poisonous substances may be drugs, air pollutants,

water contaminants, food residues or contaminants, soil contaminants, animal venoms, plant

toxins, etc.

Poisoning could be from drugs; industrial exposure of workers and others to toxic substances

(e.g. workers exposed to mercury, arsenic, paraquat, dibromochloropropane, etc); ingestion of

contaminated foo;, snake bites, bee sting and other animal venom or plant toxins; accidental

eating of poisonous food, like poisonous mushrooms or improperly processed food (like

cassava, with cases of cyanide poisoning); and ingestion, inhalation or contact with chemicals

and other poisonous substances.

Some of these potential toxic substances or poisons are normally found in the home as drugs;

household materials for cooking and other purposes like kerosene, fuel, diesel, detergents, etc.;

cosmetics like shampoo, hair dyes; and pesticides. These cause accidental poisoning,

particularly among children. Poisoning in adults may be accidental or suicidal.



Generally, substances involved mostly in acute poisoning include drugs, cleaning substances,

cosmetics and personal care products, animal bites and envenomations, fumes/vapors,

pesticides, plants, food products, food poisoning, alcohols, hydrocarbons, chemical and

solvents.

(ii). Management of acute poisoning

Some general principles are applicable in the management of poisoning, whether due to drugs,

chemicals, gases, pesticides, bacteria, plant and animal toxins etc. These general principles

would be disccussed here, specific and other measures shall be discussed under the individual

poison, as appropriate.

(a). Preventive measures at home and work place

Most of the acute poisoning in the home can be prevented by:

(a). Keeping drugs in tamper-proof containers, out of the reach of children.

(b). Keeping household chemicals, e.g. detergents, bleaches, cosmetics, polish, pesticides

(insecticides, rodenticides, and others), petroleum products, etc. away from foodstuffs, under

lock and key, and out of easy reach. They should also be kept in properly labelled containers.

(c). Ensuring that all medicines are taken as directed; unused medicines should be properly

disposed.

At the workplace, there should be necessary and adequate precautions to avoid exposure to

hazardous substances including:

(a). Provision of personal protective equipment (PPE) such as coveralls, nose masks, etc.

(b). Provision of SoPs for handling and disposal of hazardous substances.

(c). Routine drills and training of staff on health and safety measures, and potential challenges

in the workplace.

(b). Treatment of acute poisoning

Emergency measures at home and work place

The essence of these measures is to remove the poison from the point of contact with the body

and prevent further damage.



(1). If the poison was ingested, vomiting may be induced if the poison is not a corrosive

material (e.g. acid, alkali, etc), a petroleum product (e.g. kerosene, petrol, paint thinner, etc) or

a central nervous system stimulant. Vomiting can also be induced mechanically by stroking the

posterior pharynx.

NOTE: Don’t induce vomiting if the patient is drowsy or if the poison is a central nervous

system stimulant (vomiting may induce convulsion), corrosive material or a petroleum product.

(2). If the poison was inhaled, move the person immediately to area of fresh air, and give

artificial respiration if necessary.

(3). In cases of contamination of the skin, drench the skin with copious amount of water, after

removal of clothing. Then clean the skin with soap and water, if applicable.

(4). In cases of contamination of the eye, wash the affected eye with running water for about

15 minutes.

After the emergency intervention at home or in the work place, the patient should be taken to

the hospital for treatment. The poison in its container should be taken along for identification

and better treatment.

Emergency treatment of acute poisoning

Treatment of acute poisoning must be prompt, and is carried out in the hospital by well trained

personnel. The treatment goals are (i) supportive care and symptomatic treatment to maintain

vital functions; (ii) to keep the concentration of poison in the vital tissues as low as possible by

preventing absorption, and enhancing removal and elimination of the poison; (iii) to combat the

pharmacological and toxicological effects at the effector sites by neutralising the effect of the

poisons by administration of an antidote where available.

It is important to note that specific antidotes are available for only a few toxic agents. Even

these are not always effective, particularly if the poisoning is severe. The best treatment begins

with supportive care and maintenance of vital functions; this includes resuscitation (if

necessary), maintenance of respiratory and cardiovascular functions, correction of fluid and

electrolytes imbalance, etc.

I. General Supportive care and symptomatic treatment of poisoned patients in the

hospital



Supportive care and symptomatic treatment is the mainstay of management of the poisoned

patient. The adage, ‘treat the patient, not the poison,’ remains the most basic and important

principle of management of poisoning. Maintenance of respiration, blood pressure and other

vital functions are crucial. Serial measurement and charting of vital signs and important reflexes

help to judge the progress of intoxication, response to therapy, and need for additional

treatment. This monitoring usually requires hospitalization. Supportive measures and

symptomatic treatment include:

(1). Improvement of respiration: Assisted ventilation and oxygen should be provided if

necessary.

Note: Respiratory stimulants are not beneficial, and are potentially dangerous.

(2). Normalisation of blood pressure: For example hypotension is common in severe poisoning

with central nervous system depressants (barbiturates, benzodiazepine, etc), β-blockers, etc,

and may lead to irreversible brain damage or renal tubular damage, among others. Therefore,

timely normalisation of the blood pressure is important.

(3). Cardiac arrhythmias, and other conduction defects are corrected. Arrhythmias often

respond to corrections of underlying hypoxia or acidosis.

(4). Normalisation of body temperature as there may be hypo- or hyperthermia.

(5). Treatment of convulsions with e.g. diazepam.

(6). Correction of fluid and electrolyte imbalance.

II. Removal and elimination of poisons

(a). Removal of the poison from the skin, eye and gastrointestinal tract

The poison should be removed from the skin, eyes and the gastrointestinal tract (GIT), as

applicable.

(i). Initial treatment of all types of chemical injuries to the eye must be rapid. Thorough

irrigation of the contaminated eye with water for 15 minutes should be performed immediately.

(ii). The contaminated skin should be washed thoroughly with water. Contaminated clothing

should be removed.

(iii). If the poison was inhaled, the patient should be removed immediately from the source of

exposure to area of fresh, uncontaminated air, and artificial respiration administered if

necessary.



(iv). Gastrointestinal tract - Ingestion is the most common route of poisoning. Poison can be

removed from the GIT by the following means:

Emesis

The routine induction of emesis in emergency rooms is declining. Although emesis still may be

indicated for immediate intervention after poisoning by oral ingestion of chemicals, it is

contraindicated if the patient (i) has ingested a corrosive poison, such as a strong acid or alkali

(e.g., drain cleaners) - emesis increases the likelihood of gastric perforation and further necrosis

of the esophagus; (ii) is comatose or in a state of stupor or delirium - emesis may cause

aspiration of the gastric contents; (iii) has ingested a central nervous system stimulant - further

stimulation associated with vomiting may precipitate convulsions; and (iv) has ingested a

petroleum product (e.g., kerosene, petrol, petroleum-based liquid furniture polish, etc) -

regurgitated hydrocarbons can be aspirated readily and cause chemical pneumonitis. The ability

of various hydrocarbons to produce pneumonitis is generally inversely proportional to their

viscosity. If the viscosity is high, as with oils and greases, the risk is limited; if the viscosity is

low, as with mineral seal oil found in liquid furniture polishes, the risk of aspiration is high.

Emesis should be considered if the ingested solution contains potentially dangerous compounds,

such as pesticides.

Vomiting can also be induced mechanically by stroking the posterior pharynx.

Gastric lavage

Gastric lavage is done by inserting a tube into the stomach and washing the stomach with

water, normal saline, or one-half normal saline to remove the unabsorbed poison. The

procedure should be performed as soon as possible, but only if vital functions are adequate or

supportive procedures have been implemented.

The contraindications to this procedure generally are the same as for emesis, and there is the

additional potential complication of mechanical injury to the throat, esophagus, and stomach. It

is recommended that gastric lavage should not be used routinely in the management of the

poisoned patient but should be reserved for patients who have ingested a potentially life-

threatening amount of poison and when the procedure can be undertaken within 60 minutes of

ingestion.

Purgation/Catharsis



Purgation (catharsis) is used to induce the removal of unabsorbed poisons from the

gastrointestinal tract by enhancing their passage through the GIT. The rationale for using an

osmotic cathartic is to minimize absorption by hastening the passage of the toxicant through

the GIT. Cathartics are indicated after the ingestion of enteric coated tablets, when the time

after ingestion is >1 hour, and for poisoning by volatile hydrocarbons. Cathartics generally are

considered harmless unless the poison has injured the GIT.

Osmotic cathartics include sorbitol, sodium sulphate and magnesium sulphate. Sorbitol is the

most effective, but sodium sulfate and magnesium sulfate also are used; all act promptly and

usually have minimal toxicity. However, MgSO4 should be used cautiously in patients with renal

failure or in those likely to develop renal dysfunction, and Na+-containing cathartics should be

avoided in patients with congestive heart failure.

Whole-bowel irrigation

Whole-bowel irrigation (WBI) is a process that involves the rapid administration of large

volumes of an osmotically balanced macrogol solution, either orally or via a nasogatric tube, to

flush out the entire GIT. Whole-bowel irrigation promotes defecation and eliminates the entire

contents of the intestines; usually, a high-molecular-weight polyethylene glycol and isomolar

electrolyte solution (PEG-ES) that does not alter serum electrolytes is used. It is recommended

that WBI should not be used routinely in the management of the poisoned patient, however, it

may be considered in cases of acute poisoning by sustained-release or enteric-coated drugs and

possibly toxic ingestions of iron, lead, zinc, or packets of illicit drugs.

(b). Prevention of absorption of ingested poisons from the gastrointestinal tract

Activated charcoal may be used to prevent absorption of ingested poisons from the GIT.

Activated charcoal avidly adsorbs many drugs and chemicals on the surfaces of the charcoal

particles, thereby preventing absorption and toxicity. Charcoal is ineffective for some poisons,

such as strong acids or alkali, cyanide, iron, arsenic, methanol, ethanol, ethylene glycol and

lithium. The effectiveness of charcoal depends on the time since the ingestion and on the dose

of charcoal; a charcoal–drug ratio of at least 10:1 is optimal. Activated charcoal also can

interrupt the enterohepatic circulation of drugs and enhance the net rate of diffusion of the

chemical from the body into the GIT, e.g. serial doses of activated charcoal have been shown to

enhance the elimination of theophylline and phenobarbital.



Activated charcoal usually is prepared as a mixture of at least 50 g (about 10 heaped

tablespoons) in a glass of water. The mixture is then administered either orally or via a gastric

tube. Because most poisons do not appear to desorb from the charcoal if charcoal is present in

excess, the adsorbed poison need not be removed from the GIT.

Generally, it is recommended that the use of activated charcoal should be considered only if a

patient has ingested a life-threatening amount of some substances such as carbamazepine,

dapsone, phenobarbital, quinine, or theophylline.

Note: Charcoal also may adsorb and decrease the effectiveness of specific antidotes.

(c). Active elimination of drugs and poisons

Drugs and poisons could be actively eliminated from the body by:

(1). Oral administration of repeated doses of activated charcoal

Oral administration of repeated doses (50 g initially, then repeated every 4 hours) of activated

charcoal enhances the elimination of some drugs (after they have been absorbed) e.g.

carbamazepine, phenobarbital, phenytoin, dapsone, theophylline and quinine.

(2). Dialysis

Haemodialysis, peritoneal dialysis and hemoperfusion could be carried out.

(3). Forced diuresis or changes in pH of urine

Renal excretion of poisons is enhanced through forced diuresis or changes in urinary pH.

Forced diuresis is indicated for a poison that is passively reabsorbed after filtration into the

glomeruli. Osmotic diuretics, like mannitol or intrvenous infusion of furosemide are used. They

inhibit sodium and water reabsorption and cause enhanced excretion of the poison.

Changes in urinary pH could also enhance renal excretion of poison. Alkalinization of the urine

using e.g an infusion of sodium bicarbonate will increase the ionization of phenobarbitone,

salicylates, arsine, lithium and isoniazid thereby increasing their excretion in urine. Acidification

of the urine will enhance the excretion of bases like amphetamine, quinine, quinidine and

strychnine. Oral or intravenous infusion of ascorbic acid or ammonium chloride is used to acidify

the urine.

Combination of osmotic diuresis and changes in urinary pH is effective for elimination of poison.

The procedure is normally carried out in the intensive care unit. Blood and urine electrolytes,



pH, fluid intake and urine ouput should be monitored to avoid electrolyte imbalance, acid-base

imbalance, water intoxication, pulmonary and cerebral edema.

III. Neutralisation of the poison

(a). Administration of antidote

Antidotes are substances that neutralise poisons, thereby counteracting the effects of the

poison. There are two types, local and systemic antidotes. Most drugs and poisons do not have

specific antidote, ane there is no universal antidote.

Table 1: Some specific antidotes for drugs, chemicals and other substances

Substance Antidote

Drugs

Paracetamol N-acetylcysteine

Iron salts (e.g. ferrous tablets) Deferoxamine

Narcotics, opioids, diphenoxylate, propoxyphene, other opioid derivatives

Naloxone

Atropine, anticholinergics Physostigmine

Anticholinesterase intoxication: Physostigmine, neostigmine, carbamates

Atropine

Organophosphates Atropine and pralidoxime

Heparin Protamine

Warfarin Vitamin K1

Benzodiazepines Flumazenil

Digoxin and related cardiac glycosides Digoxin antibodies

Benzodiazepines Flumazenil

Calcium channel blockers Calcium

Chemicals and other substances

Methanol Ethanol, Fomepizole

Ethylene glycol Ethanol, Fomepizole

Cyanide Hydroxocobalamin, Sodium nitrate, Sodium thiosulphate, Dicobalt edetate

Fluoride Calcium, e.g. calcium gluconate

C2. Definition and mechanisms of drug toxicity

On the administration of therapeutic doses of a drug, adverse drug reactions (undesirable drug

effects, side effects, adverse effects) could occur. Adverse effects of a drug is a noxious and



unintended response to a drug that occurs at doses normally used in man for the modification

of physiological function , prophylaxis, diagnosis or therapy of disease.

As exposure to the drug increases beyond the therapeutic dose, toxicity occurs. For example

paracetamol (acetaminophen) is an over the counter analgesic and antipyretic that elicits dose-

dependent toxicity; it is safe at therapeutic concentrations but causes severe hepatotoxicity

above therapeutic doses.

(i). Definition: Drug toxicity occurs as a result of accumulation of excess drug in the system,

leading to damage. The accumulation could be incidental and intentional, or accidental and

unintentional.

However, with certain medications, drug toxicity can also occur as an adverse drug reaction

(ADR). In this case, the normally given therapeutic dose of the drug can cause unintentional,

harmful and unwanted side effects. According to Paracelsus, ‘the dose makes the poison.’

The focus of this discourse is on drug toxicity due to incidental or accidental drug overdosage.

Drug overdose/overdose is the ingestion or application of a drug or other substances in

quantities greater than are recommended or used in routinely in clinical practice. An overdose

may result in toxicity or death.

(ii). Mechanisms of drug toxicity

Toxicity produced by a drug may be due to the following general mechanisms:

(a). On-target adverse effects/toxicity: This is as a result of the drug binding to its

intended receptor, but at an inappropriate concentration, with suboptimal kinetics, or in the

incorrect tissue, e.g atropine, barbiturates. The toxic effects of such drugs derive from, and are

extensions of their pharmacological actions.

(b). Off-target adverse effects/toxicity: Due to the drug binding to a target or receptor for

which it was not intended, e.g. anticholinergic toxic effects produced by overdose of

promethazine (H1 receptor antagonist).

(c). Production of toxic metabolites: A typical example of toxicity by this mechanism is that

of acetaminophen (paracetamol). Paracetamol is normally metabolised by conjugation to

sulphate and glucuronide, and these as well as the unchanged paracetamol are not toxic. They

are excreted in the urine. However, a small fraction of paracetamol is converted by CYP450

enzyme to a reactive metabolite, N-acetyl-p-benzoquinoneimine which is hepatotoxic. This toxic

metabolite is normally detoxified by conjugation to glutathione and excreted in the urine.

https://www.verywellhealth.com/what-is-an-adverse-reaction-3959900



However, in overdose, the glutathione is readily depleted and the reactive metabolite then

binds to cellular constituents of the liver leading to hepatooxicity.

(d). Production of harmful immune responses: The use of some drugs e.g penicillin,

abacavir, result in serious hypersensitivity reactions.

(e). Genotoxic effects: Many environmental chemicals, including drugs are known to injure DNA

and other genetic materials, and may lead to mutagenic or carcinogenic toxicities. For example,

many cancer chemotherapeutic agents may be genotoxic.

(e). Idiosyncratic reactions: Idiosyncratic reactions are abnormal responses to a drug that is

peculiar to a given individual. The idiosyncratic response may take the form of extreme

sensitivity to low doses or extreme insensitivity to high doses of drugs. Idiosyncratic reactions

can result from genetic polymorphisms that cause individual differences in drug

pharmacokinetics, pharmacodynamic factors such as drug-receptor interactions, or from

variability in expression of enzyme activity, etc.

(iii). Management of acute drug poisoning

Most of the principles, measures and procedures discussed under management of poisoning,

also apply in the management of acute drug poisoning. In addition, when necessary a specific

antidote if available is used.



C3. Animal Poisons: Snakebite, Scorpion stings, Bee stings and Their Management

(i). Snake bite and management

Poisonous snakes include

(1). Pit vipers/Crotalin snakes (Crotalinae)

(2). Sea snakes/Hydrophis (Hydrophiinae; Elapidae)

(3). Elapid snakes/Cobras (Elapidae), e.g Naja melanoleuca (black cobra), Naja nigricollis

(black-necked spitting cobra)

(4). Viperid snakes (Viperidae), e.g. Echis ocellatus, Echis carinatus, Bitis arietans (puff adder,

African puff adder)

(5). Some Colubrids, e.g genus Boiga, Rhabdophis

Some important poisonous species are Echis ocellatus, Naja naja (Indian Cobra), Naja

nigricollis, Naja melanoleuca, Echis carinatus, Bitis arietans, B. gabonica, Dendroaspis viridis, D.

jamesoni, D. angusticeps, Causus maculatus, etc.

Common venomous snakes found in Nigeria include Elapid snakes such as Naja melanoleuca

and Naja nigricollis; and Viperid snakes such as Echis ocellatus and Bitis arietans. Echis

ocellatus (West African carpet viper, ocellated viper) is responsible for more human fatalities

due to snake bite than all other African species combined.

Snake venom is highly modified saliva containing zootoxins which facilitate the immobilization

and digestion of prey, and defense against threats. The glands that store and secrete the

venom are a modification of the parotid salivary gland found in other vertebrates, and are

usually situated on each side of the head, below and behind the eye, and encapsulated in a

muscular sheath. The synthesized vemon is stored in large alveoli of the glands, before being

conveyed by a duct to the base of channeled or tubular fangs through which it is ejected. The

snake venom is injected by unique fangs after a bite, and some species are also able to spit.

About 0.1 – 1.5 ml (5 ml for some large vipers) may be injected. The lethality of the venom

depends on the potency of the venom, quantity injected and size of the victim.

Snake venoms contain more than 20 different compounds, mostly proteins and polypeptides.

Snake venom contains neurotoxins, cytotoxins (some venoms have cytotoxic activity on

erythrocytes, blood vessels, kidney, heart muscles, etc), cardiotoxins, enzymes (e.g.

acetylcholinesterase, phospholipae A2, phosphodiesterase, phosphomonoesterase,

hyaluronidase, etc.), various other peptides, polypeptides and proteins. Some of the proteins



have very specific effects on various biological functions including blood coagulation, blood

pressure regulation, and transmission of impulses, and have been developed for use as

pharmacological or diagnostic tools, and useful drugs.

Snake toxins vary greatly in their functions. Two broad classes of toxins found in snake venoms

are neurotoxins (mostly found in elapids) and hemotoxins (mostly found in viperids). However,

there are exceptions — the venom of Naja nigricollis, an elapid, consists mainly of cytotoxins,

while that of the Mojave rattlesnake (Crotalus scutulatus), a viperid, is primarily neurotoxic.

There are numerous other types of toxins which may be present in the venoms of both elapids

and viperids.

Effects and symptoms of snakebite

Elapid venom contain mainly neurotoxins, although many of them also possess several other

types of toxins, including cardiotoxins and cytotoxins. Elapids bites may produce pain and

slowly developing swelling. There may be drowsiness; weakness; salivation; headache;

hypotension; paralysis (due to the neurotoxin) of facial muscles, tongue, lips, larynx and eyes;

ptosis, blurred vision and respiratory difficulty. Venoms from Elapid snakes may produce death

due to respiratoty paralysis, but do not produce severe local reaction.

Viperid venoms typically contain an abundance of proteases which produce severe local

reactions with pain, swelling, necrosis, bleeding from the wound (due to haemotoxins),

ecchymosis, tissue damage. There may be internal haemorrhage from cardiovascular damage

complicated by disruption of the blood-clotting system and coagulopathy. Death is usually

caused by collapse in blood pressure and shock.

Management of snakebite

The followings steps or stages are often involved in the management of snake bite:

(1). First aid treatment

First aid treatment is carried out immediately or very soon after the bite, before the patient

reaches a dispensary or hospital. It can be performed by the snake-bite victim or anyone else

who is present and able.

Unfortunately, most of the traditional, popular, available and affordable first-aid methods have

proved to be useless or dangerous. These methods include: making local incisions or

https://en.wikipedia.org/wiki/Toxin

https://en.wikipedia.org/wiki/Cardiotoxin

https://en.wikipedia.org/wiki/Cytotoxin

https://en.wikipedia.org/wiki/Protease



pricks/punctures at the site of the bite or in the bitten limb, attempts to suck the venom out of

the wound, use of (black) snake stones, tying tight bands (tourniquets) around the limb,

electric shock, topical instillation or application of chemicals, or ice packs.

It is dangerous to delay medical treatment

The goals of first aid is to (i) attempt to retard systemic absorption of venom; (ii) preserve life

and prevent complications before the victim can receive medical care; (iii) control distressing or

dangerous early symptoms of envenomation; (iv) arrange transport of the victim to a place

where they can receive medical care; (v) do no harm!

Do not attempt to kill the snake as this may be dangerous. However, if the snake has already

been killed, it should be taken to the dispensary or hospital with the victim in case it can be

identified. However, the snake should not be handled with bare hands as even a severed head

can bite (envenomate).

Snakebite first aid recommendations vary, partly because different snakes have different types

of venom. Some have little local effect, but life-threatening systemic effects (e.g Elapids), in

which case containing the venom in the region of the bite by pressure immobilization is

desirable. Other venoms elicit localized tissue damage around the bitten area, and

immobilization may increase the severity of the damage in this area, but also reduce the total

area affected (the benefit of this measure in this case is equivocal).

Recommended first aid measures include:

(i). Reassure the victim who may be very anxious

(ii). Immobilize the whole of the patient’s body by laying him/her down in a comfortable and

safe position and, especially, immobilize the bitten limb with a splint or sling. The patient must

not be allowed to walk, run, and take alcohol or stimulants. Any movement or muscular

contraction increases absorption of venom into the bloodstream and lymphatics.

If the necessary equipment and skills are available, pressure-immobilization or pressure pad (to

contain the venom in the region of the bite) are recommended for bites by neurotoxic elapid

snakes.

Pressure Immobilization: Pressure immobilization serves to contain venom within a bitten

limb and prevent it from moving through the lymphatic system to the vital organs. This therapy

has two components: pressure to prevent lymphatic drainage, and immobilization of the bitten



limb. It is recommended for snakebites due to elapids which are neurotoxic. Generally, it is not

recommended for bites from non-neurotoxic snakes; however, in some regions, pressure

immobilization is recommended in all cases where the type of snake is unknown.

(iii). Avoid any interference with the bite wound (e.g. incisions, rubbing, vigorous cleaning,

massage, application of herbs or chemicals) as this may introduce infection, increase absorption

of the venom and increase local bleeding.

(iv). Tight bands, bandages and ligatures used, should not be released until the patient is under

medical care in hospital, resuscitation facilities are available and antivenom treatment has been

started.

Traditional first aid methods should be discouraged, as they do more harm than good.

List of DO NOTs in management of snake bite

Do not pick up the snake or try to wrap it up or kill it, as this will increase the chance of getting another bite. Even a dead snake is able to bite (envenomate).

Do not apply a tourniquet. Do not cut across the site of the bite marks. Do not try to suck out the venom. Do not apply ice, electric shock, etc. Do not immerse the wounded area in water. Do not take alcohol, beverages with caffeine, other stimulants

(2). Transport to hospital - The greatest fear is that a snakebite victim might develop fatal

respiratory paralysis or shock before reaching a place where they may be resuscitated. This risk

may be reduced by speeding up transport to hospital. The patient must be transported to a

place where he can receive adequate medical care as quickly, but as safely and comfortably, as

possible. Any movement especially movement of the bitten limb, must be reduced to an

absolute minimum to avoid increasing the systemic absorption of venom. Any muscular

contraction will increase the spread of venom from the site of the bite. A stretcher, bicycle,

motorbike, cart, horse, motor vehicle, train or boat, etc. may be used, or the patient can be

carried (e.g. using the Fireman’s Lift technique). If possible, patients should be placed in the

recovery position, in case they vomit.

(3). Rapid clinical assessment and resuscitation - Airway patency, respiratory function, arterial

pulse and level of consciousness must be checked immediately. The patient should also be

protected from cold if necessary.



(4). Detailed clinical assessment and species diagnosis – Detailed clinical assessment include

precise history of the circumstances of the bite and the progression of local and systemic

symptoms and signs, physical and general examination, etc., by the physician.

If the dead snake has been brought, it may be possible to identify it but this requires skill and

even experienced medical personnel may mistake harmless snakes for venomous ones or

confuse different venomous species. Also, the species responsible may be inferred indirectly

from the patient’s description of the snake, circumstances of the bite (e.g. nocturnal bites of

people sleeping on the ground, by kraits) and the clinical syndrome of symptoms and signs. A

wrong species diagnosis may result in futile administration of antivenom.

(5). Investigations/laboratory tests such as 20-minute whole blood clotting test (20WBCT) to

test for coagulopathy, hemoglobin concentration/hematocrit, platelet count, white blood cell

count, liver enzymes, urine examination, etc. may be carried out.

(6). Antivenom treatment - If possible, it should be confirmed if the patient was actually bitten

by a poisonous snake, before treatment with antivenom. If possible, a sensitivity test should be

done before the antivenom is administered.

Monovalent antivenoms treat the bite of a specific type of snake, while polyvalent antivenoms

can treat bites from a number of snakes found in a particular geographic region.

The antisnake venom serum available in any country is determined by the types of poisonous

snakes in that country. In Nigeria, one of the available antisnake venom serums is effective

against Echis, Bitis and Naja.

(7). Observing the response to antivenom - Reactions to antivenom could be treated with

adrenaline, H1- antagonists or corticosteroids.

(8). Deciding whether further dose(s) of antivenom are needed - There is need for close

monitoring of the patient to determine whether the initial dose of the antivenom would be

repeated.

(9). Supportive/ancillary treatment such as treatment of the bitten part and general wound

care; artificial respiration with oxygen if there is respiratory paralysis; administration of tetanus

antitoxin, antibiotics, analgesics, etc. as necessary; treatment of hypovolemic shock, renal

dialysis, etc.

(11). Rehabilitation

(12). Treatment of chronic complications



(ii). Scorpion stings

Some scorpions are poisonous and the stings can cause pain and discomfort. One of the most

poisonous ones is Androctonus australis. Scorpion venom contain neurotoxins and enzymes.

Signs and symptoms of scorpion sting

The sting produces a burning sensation at the site of the sting, and this spreads to extremities.

Spasm in the throat, restlessness, abdominal cramps, muscular fibrillation, convulsion, cardiac

arrhythmia, pulmonary edema and respiratory edema may develop. The smaller the patient, the

greater the effect of the sting.

Treatment of scorpion sting

1. The patient and the bitten part are immobilized and a constriction band applied as in a snake

bite.

2. A cold pack (10-15°C) should be applied on the affected part for a few hours to reduce the

rate of absorption of the venom.

3. Artificial respiration with oxygen should be given if necessary.

4. Calcium gluconate (10 ml of a 10% solution) administered by slow intravenous infusion will

help relieve muscle spasm.

5. A local anaesthetic may be injected into the area of sting, or an analgesic administered to

reduce pain.

6. Convulsion should be treated with diazepam.

7. A specific antiserum should be given as an antidote, after a sensitivity test.

(iii). Bee stings

The venom of a bee sting contains histamine, peptides (apamin and melittin), hyaluronidase,

phospholipase and proteins.

Symptoms of bee sting

Multiple stings induce a fall in blood pressure, peripheral neuritis and difficulty in breathing.

Hypesensivity reactions may lead to bronchial constriction, edema of face and lips, itching,

collapse and death.

Treatment of bee sting



For minor cases, topical antihistamine should be applied, and the sting if present should be

removed.

For severe cases, adrenaline (0.2 – 0.5 ml in 1:1000) should be given by subcutaneous or

intravenous route, followed by an antihistamine.

In severe collapse, hydrocortisone should be administered.

C4. Local food poisoning

Sources of food poisoning include:

(i). Food Additives - Thousands of substances are added to foods to enhance appearance, taste,

texture, storage properties, or nutritive value, any of which may cause toxicity in susceptible

individuals.

(ii). Toxins produced by microorganisms that infest foodstuffs including produce, such as

protozoa, fungi, bacteria, etc.

(iii). Also, microbial contamination (by e.g. fungi, bacteria, etc.) of food in the farm, during

processing or storage can introduce potent toxins into food.

(iv). Chemicals from pesticides, preservatives or containers used to store food.

(v). Poisoning may also result from consumption of poisonous food, e.g. mushrooms, or

improperly processed food (e.g. improperly processed cassava, consumption of which has led to

some deaths in Nigeria).

Food toxins/poisons include:

(a). Mycotoxins

Mycotoxins are toxic substances produced by microscopic fungi which infest food substances.

Ingestion of food containing the toxins causes adverse health effects in human. Four classes of

mycotoxins identified as health hazard to humans and animals are aflatoxins, ochratoxins,

zearalenones and trichothecenes.

Aflatoxins

Aflatoxins are mycotoxins produced by Aspergillus species of fungi, such as A. flavus and A.

parasiticus which contaminate and grow on certain foodstuffs and animal feeds. The fungi may

infect growing crops and the toxin may be produced before harvest, during harvest or storage.

Aflatoxins have been detected on many seeds grown in Nigeria like groundnuts, maize and

beans; and feeds made from them. The fungi could be identified as small discoloured or



differently coloured spots on the seeds which are where the toxin is concentrated; therefore,

visual inspection is important. Furthermore, animals fed contaminated food can pass aflatoxin

transformation products into eggs, milk products and meat. Aflatoxins include aflatoxin B1 and

B2, aflatoxin G1 and G2, aflatoxin M1 and M2, and aflatoxicol.

Toxicokinetics: Aflatoxin is metabolized in the body; aflatoxin B1 is metabolized to aflatoxin

M1, which is further detoxified by conjugation with taurocholic and glucuronic acids and is

excreted in the bile or urine.

Effects: Aflatoxins are hepatotoxic, and may lead to development of liver and gall bladder

cancer.

Ochratoxins

Ochratoxins are mainly found in Aspergillus ochraceus, A. niger and some Penicillium species,

especially P. verrucosum and P. carbonarius. There are three ochratoxins; ochratoxin A, B and

C. Ochratoxin A is the most prevalent, while ochratoxins B and C are of lesser importance.

Ochratoxin A is found in many foodstuffs like dried fruit, maize, wheat, oats, other cereals, and

feeds made from maize.

Toxicokinetics: Ochratoxin A is absorbed from the gastrointestinal tract and distributed in

many tissues, particularly the kidney (highest level), liver and muscles.

Effects: Ochratoxin A is nephrotoxic, and a possible human carcinogen.

C5. Pesticides

Pesticides are agents that kill pests; they are used to control pests. Generally, a pesticide is a

chemical or biological agent (plant, virus, bacterium, fungus, etc.) that deters, incapacitates,

kills, or otherwise discourages pests. Target pests include insects, plant pathogens, weeds,

molluscs, birds, mammals, fish, nematodes, and microbes that destroy property, cause

nuisance, spread disease, or are disease vectors.

Pesticides decrease or prevent the occurrence of diseases such as malaria, yellow fever,

bubonic plague, amongst others. They increase crop and food production, and decrease the

work force needed to produce food. Most pesticides serve as plant protection products (crop

protection products), which in general, protect plants from weeds, fungi, or insects. However,

the use of pesticides in agriculture is declining with use of genetically engineered plants.

https://en.wikipedia.org/wiki/Virus

https://en.wikipedia.org/wiki/Bacterium

https://en.wikipedia.org/wiki/Entomopathogenic_fungus

https://en.wikipedia.org/wiki/Pathogen

https://en.wikipedia.org/wiki/Mollusca

https://en.wikipedia.org/wiki/Bird

https://en.wikipedia.org/wiki/Mammal

https://en.wikipedia.org/wiki/Fish

https://en.wikipedia.org/wiki/Nematode

https://en.wikipedia.org/wiki/Microbe

https://en.wikipedia.org/wiki/Vector_(epidemiology)

https://en.wikipedia.org/wiki/Weed

https://en.wikipedia.org/wiki/Insect



Although pesticides have benefits, some also have drawbacks, such as potential toxicity to

humans and other species. Though all produce some degree of toxicity in humans, selective

toxicity of pesticides is extremely desirable and important.

Pesticides include herbicides, insecticides (which may include insect growth regulators,

termiticides, etc.) nematicides, molluscicides, piscicides, avicides, rodenticides, bactericides,

insect repellents, animal repellents, antimicrobials, and fungicides. Our focus here shall be on

insecticides, rodenticides, fungicides, herbicides and fumigants.

I. INSECTICIDES

Incidents of acute poisoning from insecticides have resulted from accidental poisoning,

including in children; eating food that was grossly contaminated in the farm, during storage or

transportation; or exposure to low levels of chemicals retained on produce.

(a). Organophosphorous insecticides

Some commonly used organophosphorous insecticides are parathion, malathion, parathion-

methyl, dichlorvos, fenitrothion, azinphos-methyl, chlorfenvinphos, diazinon, diamethoate,

fenitrothion and trichlorfon.

They have largely replaced the chlorinated hydrocarbons. Organophosphorus pesticides are not

considered to be persistent pesticides, i.e. they do not persist in the environment. They are

relatively unstable and break down in the environment due to hydrolysis and photolysis. They

are considered to have a small impact on the environment despite their acute effects on

organisms. They have an extremely low carcinogenic potential, but they have a much higher

acute toxicity in humans. Parathion is the pesticide most frequently involved in fatal poisoning.

Toxicodynamics

Mechanism of insecticidal action and toxicity

In mammals as well as insects, the main mechanism of action is inhibition of

acetylcholinesterase through phosphorylation of the esteratic site. The signs and symptoms that

characterize acute intoxication are due to inhibition of this enzyme and accumulation of

acetylcholine. Some of the agents also possess direct cholinergic activity.

Also, some of these agents phosphorylate another enzyme present in neural tissue, neuropathy

target esterase. This results in progressive demyelination of the longest nerves; associated with

https://en.wikipedia.org/wiki/Pesticide_poisoning

https://en.wikipedia.org/wiki/Herbicide

https://en.wikipedia.org/wiki/Insecticide

https://en.wikipedia.org/wiki/Insect_growth_regulator

https://en.wikipedia.org/wiki/Nematicide

https://en.wikipedia.org/wiki/Molluscicide

https://en.wikipedia.org/wiki/Piscicide

https://en.wikipedia.org/wiki/Avicide

https://en.wikipedia.org/wiki/Rodenticide

https://en.wikipedia.org/wiki/Bactericide

https://en.wikipedia.org/wiki/Insect_repellent

https://en.wikipedia.org/wiki/Animal_repellent

https://en.wikipedia.org/wiki/Antimicrobial

https://en.wikipedia.org/wiki/Fungicide



paralysis and axonal degeneration, this lesion is sometimes called organophosphorus ester-

induced delayed polyneuropathy (OPIDP). Delayed central and autonomic neuropathy may

occur in some patients poisoned with e.g. dichlorvos and trichlorfon.

Toxicokinetics

The organophosphates are absorbed through all routes, including by inhalation, ingestion and

through the skin. All organophosphates except echothiophate are distributed to all parts of the

body, including the central nervous system. Therefore, central nervous system toxicity is an

important component of poisoning with these agents.

Malathion and a few other organophosphate insecticides are also rapidly metabolized by other

pathways to inactive products in birds and mammals but not in insects; therefore they are

considered safe for use by the general public. Fish cannot detoxify malathion, and significant

numbers of fish have died from the heavy use of this agent on and near waterways. Parathion

is not detoxified effectively in vertebrates; thus, it is considerably more dangerous than

malathion to humans and livestock and its use has been banned or restricted in most countries.

Organ system effects

Their primary action is to amplify the actions of endogenous acetylcholine, so they produce the

same pharmacological effects as excess acetylcholoine.

Signs and symptoms of organophosphorous poisoning

The dominant initial signs are those of excessive stimulation of muscarinic receptors; miosis,

salivation, sweating, bronchial constriction, vomiting, and diarrhea. Central nervous system

involvement (manifesting as cognitive disturbances, convulsions, and coma) usually follows

rapidly, accompanied by peripheral nicotinic effects, especially depolarizing neuromuscular

blockade.

Treatment of poisoning by organophosphorus insecticides

Acute intoxication must be recognized and treated promptly.

1. Decontamination to prevent further absorption—this may require removal of all clothing

and washing of the skin in cases of exposure to dusts and sprays.

2. If the poison was ingested, gastric lavage or emesis may be beneficial if applied before

the symptoms appear.

3. Maintenance of vital signs—e.g. respiration may be impaired.



4. Atropine sulphate is administered, 1 - 2 mg IM, every 5 – 15 minutes until the person is

fully atropinized (indicated by the appearance of dry mouth, dilated pupils and fast

pulse). This is maintained with 2 mg atropine.

5. A cholinesterase reactivator like pralidoxime administered by IV infusion (1 -2 g, given

over 15 – 30 minutes), only when the patient is fully atropinized, and if aging has not

occurred. However, pralidoxime is ineffective in reversing the central effects of

organophosphate poisoning because it has positively charged quaternary ammonium

groups that prevent entry into the central nervous system.

6. Administration of benzodiazepines for seizures.

(b). Carbamate insecticides

The carbamates are considered to be non-persistent pesticides, and exert only a small impact

on the environment. Carbamate insecticides include carbaryl, aldicarb, aminocarb, propoxur,

bendiocarb, carbofuran, fenobucarb, oxamyl and methomyl.

The clinical effects due to carbamates are of shorter duration than those observed with

organophosphorus compounds. The range between the doses that cause minor intoxication and

those that result in lethality is larger with carbamates than with the organophosphorus agents.

Spontaneous reactivation of cholinesterase is more rapid after inhibition by the carbamates.

Toxicodynamics

Mechanism of insecticide action and toxicity

Carbamate pesticides inhibit acetylcholinesterase by carbamoylation of the esteratic site.

Treatment of poisoning by carbamate insecticides

Treatment of poisoning by carbamate insecticides is similar to that of organophosphorus

compounds, but pralidoxime is contraindicated.

(c). Organochlorine insecticides

Organochlorine insecticides were used widely in agriculture and malaria control programmes,

from 1940 to 1970. However, they have largely been abandoned because they cause severe

environmental damage. Organochlorine insecticides include

(i). Chlorinated ethane derivatives e.g. dichlorodiphenyltrichloroethane (DDT), methoxychlor,

(ii). Chlorinated cyclodienes e.g. chlordane, aldrin, dieldrin, heptachlor, endrin



(iii). Hexachlorocyclohexanes e.g. lindane, toxaphene, mirex, chlordecone

(i). Chlorinated ethane derivatives

Chlorinated ethane derivatives include dichlorodiphenyltrichloroethane and methoxychlor

Dichlorodiphenyltrichloroethane

Dichlorodiphenyltrichloroethane (chlorophenothane; DDT) is the most common of the

chlorinated ethane derivatives. The use of DDT has been banned in many countries, however, it

is still used in some tropical countries to control malaria. Prior to placement of major restrictions

on its use in many countries, DDT was a widely used synthetic insecticide. DDT is a prime

candidate for biomagnification, as it is degraded very slowly in the environment and is stored in

the fat of animals.

Toxicodynamics


In insects, DDT opens Na+ channels across neuronal membranes, resulting in prolonged action

potentials, repetitive firing after a single stimulus and spontaneous trains of action potentials.

Spontaneous firing of neuronal Na+ channels prevents normal repolarization, leading to spasms

and death of the insect.

In humans, DDT disrupts the transfer of nerve impulse by inhibiting K+ and Ca2+ ATPase which

control the active transfer of ions across membranes. It inhibits Na+ influx and K+ efflux in

neurons in the brain and periphery. The resultant excess intracellular K+ in the neuron partially

depolarizes the cell; the threshold for another action potential is decreased leading to

premature depolarization of the neuron.

DDT is also an endocrine disruptor in humans.

Toxicokinetics

DDT is highly soluble in fat but has a very low solubility in water. It is readily absorbed when

dissolved in oils, fats or lipid solvents (e.g. kerosene), but poorly absorbed as an aqueous

suspension or a dry powder. Once absorbed, DDT concentrates in adipose tissues; this is

protective, as it decreases the amount of DDT at its site of toxic action - the brain. At a

constant rate of intake, the concentration of DDT in adipose tissue reaches steady state and

remains relatively constant. DDT crosses the placenta, and its concentration in the umbilical

cord blood is in the same range as that in the blood of the exposed mother. The first step in the



metabolism of DDT is the formation of dichlorodiphenyldichloroethane (DDD) and

dichlorodiphenyldichloroethylene (DDE). These metabolites are usually converted to several

hydroxylated compounds, and eliminated in a conjugated form in bile and urine. DDT, DDE and

to a lesser extend DDD are lipophilic compounds which accumulate in adipose tissue. On

cessation of exposure, DDT is eliminated from the body slowly; about 1% of stored DDT is

excreted daily. The DDD and DDE are the major metabolites and environmental breakdown

products of DDT.

Signs and Symptoms of DDT poisoning

The major effect is central nervous system stimulation, manifesting initially as tremor with

possible progression to convulsions. Other signs and symptoms include paresthesia of the

tongue, lips and face; apprehension; hypersusceptibility to stimuli; irritability; dizziness; tremor;

tonic and clonic convulsions. DDT may cause leukemia, brain and lung cancer (it is classified as

probably carcinogenic in humans). Death probably results from the kerosene solvent.

Treatment of poisoning by DDT and organochlorines

Supportive care and observation for signs of end-organ damage (e.g., central nervous system,

heart, lung and liver) are the mainstays of therapy. No specific antidotes are available for

organochlorine poisoning.

The following measures may be undertaken:

1. Use of activated charcoal followed by gastric lavage or emesis.

2. Catharsis with sodium sulphate helps to remove the organochlorine compound.

3. Artificial respiration with oxygen may be applied if necessary.

4. An anticonvulsant e.g. phenobarbital, diazepam, is useful in severe convulsion.

This treatment serves for all organochlorine derivatives

Note: Adrenaline is contraindicated as it can induce ventricular fibrillation.

Drug interactions

Relatively low doses of DDT induce CYP450 enzymes leading to altered metabolism of drugs,

xenobiotics, steroid hormones, etc.

Methoxychlor



Methoxychlor is a chlorinated ethane derivative. It was intended as an alternative to DDT, but

has been banned due to its acute toxicity, bioaccumulation and endocrine disruption activity. It

is stored in adipose tissues to about 0.2% of the extent of DDT. It has estrogenic activity and

reduces biosynthesis of testosterone.

(ii). Chlorinated cyclodienes

Chlorinated cyclodienes (pesticides derived from hexachlorocyclopentadiene) include aldrin,

dieldrin, endrin, heptachlor, chlordane and endosulfan. They also have carcinogenic potential.

Aldrin and related cyclodiene pesticides are classified as persistent organic pollutants, as they

do not easily break down. Furthermore, they biomagnify as they pass along the food chain.

Long-term exposure has proven toxic to a very wide range of animals including humans, far

greater than to the original insect targets. Consequently, some of them have been banned in

some countries.

Aldrin is not toxic to insects, but it is oxidized in the insect to form dieldrin which is the active

compound. Endrin is a stereoisomer of dieldrin.

Toxicodynamics

Mechanism of Toxicity

The cyclodienes are antagonists at GABAA ionotropic receptors, thereby decreasing the uptake

of Cl-, resulting in partial repolarization of the neurons and a state of uncontrolled excitation.

They produce convulsions before other less serious signs of illness appear.

Toxicokinetics

Like DDT, they are highly lipid soluble and are stored in adipose tissue. They induce CYP450

enzymes, are degraded slowly, persist in the environment and undergo biomagnification

through the food chain of animals.

Signs and symptoms of poisoning

They cause stimulation of the CNS. Symptoms include headache, nausea, vomiting, dizziness,

mild clonic jerking, hyperactivity, lack of coordination, staggering, tremors and convulsions.

(iv). Other chlorinated hydrocarbons; hexachlorobenzene, hexachlorocyclohexanes,

and others

These include hexachlorobenzene, lindane, toxaphene, mirex and chlordecone.

https://en.wikipedia.org/wiki/Hexachlorocyclopentadiene

https://en.wikipedia.org/wiki/Persistent_organic_pollutant

https://en.wikipedia.org/wiki/Biodegradation

https://en.wikipedia.org/wiki/Biomagnify

https://en.wikipedia.org/wiki/Food_chain

https://en.wikipedia.org/wiki/Endrin

https://en.wikipedia.org/wiki/Stereoisomer



Hexachlorobenzene

Hexachlorobenzene (perchlorobenzene), an organochloride, is a fungicide formerly used to treat

seeds e.g. to control the fungal disease bunt in wheat. It is an animal carcinogen and a

probable human carcinogen. It has been banned globally under the Stockholm Convention on

Persistent Organic Pollutants.

Lindane

Lindane (γ-hexachlorocyclohexane; γ-HCCH; gammallin; gammaxene) is the γ isomer of

hexachlorocyclohexane.

The WHO classifies lindane as ‘moderately hazardous’, and its international trade is restricted

and regulated under the Rotterdam Convention on Prior Informed Consent. In 2009, the

production and agricultural use of lindane was banned under the Stockholm Convention on

persistent organic pollutants. A specific exemption to that ban allows it to be used as a second-

line drug for treatment of lice and scabies.

Lindane is a neurotoxin that binds at the picrotoxin binding site on the GABAA receptor, thereby

blocking the effects of GABA. Signs and symptoms of poisoning resemble those of DDT, and

include tremors, ataxia, convulsions, etc. It persists less in the environment. Lindane induces

cytochrome P450 enzymes. It is used clinically as an ectoparasite for lice and scabies.

Toxaphene

Toxaphene is a synthetic organic mixture composed of over 670 chemicals (mostly

chlorobornanes, chlorocamphenes, and other bicyclic chloroorganic compounds), formed by the

chlorination of camphene to an overall chlorine content of 67–69% by weight. Toxaphene was

banned in some countries in 1990s, and was banned globally by the 2001 Stockholm

Convention on Persistent Organic Pollutants. It is a very persistent chemical that can remain in

the environment for 1–14 years without degrading, particularly in the soil.

Mirex and Chlordecone

Mirex is an organochloride that was used as an insecticide and later banned because of its

impact on the environment. Its used has been banned in several countries, it is prohibited by

the Stockholm Convention on Persistent Organic Pollutants.

https://en.wikipedia.org/wiki/Organochloride

https://en.wikipedia.org/wiki/Fungicide

https://en.wikipedia.org/wiki/Karnal_bunt

https://en.wikipedia.org/wiki/Stockholm_Convention_on_Persistent_Organic_Pollutants


https://en.wikipedia.org/wiki/Rotterdam_Convention

https://en.wikipedia.org/wiki/Stockholm_Convention

https://en.wikipedia.org/wiki/Persistent_organic_pollutants

https://en.wikipedia.org/wiki/Scabies

https://en.wikipedia.org/wiki/Organic_compound

https://en.wikipedia.org/wiki/Bicyclic

https://en.wikipedia.org/wiki/Halogenation

https://en.wikipedia.org/wiki/Camphene



https://en.wikipedia.org/wiki/Organochloride





Chlordecone (Kepone), a colourless solid, is an organochlorine compound and. It is an obsolete

insecticide related to Mirex and DDT. Its use was so disastrous that it is now prohibited in the

western world, though after many millions of kilograms had been produced. Kepone is a known

persistent organic pollutant (POP), classified among the ‘dirty dozen’ and banned globally by the

Stockholm Convention on Persistent Organic Pollutants as of 2011.

Mirex and Chlordecone are extremely persistent hydrocarbon insecticides, and they are

concentrated several thousand-fold in the food chain. Mirex and chlordecone are classified as

POP, and are among the ‘dirty dozen’ that are banned globally by the Stockholm Convention on

Persistent Organic Pollutants (a United Nations Treaty) as of 2011, because of their impact on

the environment.

Toxicodynamics

Mirex is oxidized to chlordecone. Mirex and chlordecone cause central nervous system

stimulation and hepatic injury. Chlordecone has a direct estrogenic activity resulting in testicular

atrophy, reduced sperm production and motility.

Toxicokinetics

Mirex is oxidized to chlordecone. They induce cytochrome P450 enzymes. Chlordecone is mainly

excreted via the feces.

Chlordecone has been detected in the milk of women, cows and rats; milk from contaminated

cows could be a source of human exposure.

Signs and Symptoms of Toxicity

Signs and symptoms of toxicity include neurological effects (tremors, ocular flutter i.e.

opsoclonus), hepatomegaly, splenomegaly, rashes, mental changes, widened gait, decreased

sperm count and motility.

Treatment of Poisoning

Supportive care and symptomatic therapy is employed. Cholestyramine is administered to

patients poisoned with chlordecone. Cholestyramine increases the faecal excretion of

chlordecone 3 – 18 fold, decreases its plasma t1/2 from 140 – 80 days, and enhances the rate of

recovery from toxic manifestations.

(d). Botanical Insecticides

Pesticides derived from plants include nicotine, rotenone, and pyrethrum.

https://en.wikipedia.org/wiki/Organochlorine_compound


https://en.wikipedia.org/wiki/Mirex

https://en.wikipedia.org/wiki/DDT

https://en.wikipedia.org/wiki/Persistent_organic_pollutant




(i). Pyrethrum and structurally related agents

Pyrethrum is an allergenic insecticide obtained from flowers of Chrysanthemum cinerariifolium

and C. coccineum. Pyrethrins are organic compounds with potent insecticidal activity, derived

from Chrysanthemum cinerariifolium flowers. Naturally occurring pyrethrins are Pyrethrin I,

Cinerin I, Jasmolin I, Pyrethrin II, Cinerin II and Jasmolin II. Pyrethrin I has the greatest

insecticidal activity.

Pyrethroids are synthetic pyrethrin derivatives. Pyrethroids include allethrin (first synthesized

pyrethroid), permethrin (dichlorovinyl derivative of pyrethrin, and the most widely used

pyrethroid), bifenthrin, cyfluthrin, cypermethrin, cyphenothrin, deltamethrin, imiprothrin,

phenothrin, prallethrin, resmethrin, sumithrin, tetramethrin, transfluthrin, amongst others.

Cyfluthrin, prallethrin and transfluthrin are active ingredients in Baygon®.

Preparations containing pyrethrins or synthetic pyrethroids are far less likely to cause allergic

reactions than are preparations made from pyrethrum. Pyrethrins and pyrethroids are widely

used in many household insecticides because of their rapid action and safety profile. Pyrethrum

and analogs are generally rated as the safest insecticides because the primary toxicity is low.

The low toxicity in mammals is largely due to their rapid transformation by ester hydrolysis and

/or hydroxylation. The slow biotransformation of pyrethrum in insects is further decreased by its

formulation with piperonyl butoxide (inhibits cytochrome P450), which increases insecticidal

efficacy.

Aquatic organisms are extremely sensitive to pyrethroids.


They cause a remarkable increase in the duration of opening of the neuronal membrane Na+

channel, leading to a prolonged flow of Na+. Consequently, there is elevation and prolongation

of depolarization after potential which on reaching the threshold membrane potential initiates

repetitive after discharges. When the toxin keeps the channels in their open state, the nerves

cannot repolarize, leaving the membrane depolarized for unusually long period, thereby

paralyzing the organism. Pyrethroids are much more toxic to insects than to mammals, due to

species differences in the sodium channels.

Toxicokinetics

Pyrethrum may be absorbed after inhalation or ingestion; absorption from the skin is not

significant. The esters are extensively biotransformed.

https://en.wikipedia.org/wiki/Repolarization

https://en.wikipedia.org/wiki/Depolarization



(ii). Rotenone

Rotenone the first rotenoid to be described; is an odorless, colorless, crystalline isoflavone used

as a broad-spectrum insecticide, piscicide, and pesticide. It occurs naturally in the roots, stems

and seeds of several tropical and subtropical plants, such as Pachyrhizus erosus (jicama vine

plant), some species of Derris (e.g D. elliptica, D. involuta), Lonchocarpus (e.g. L. nicou, L.

urucu), Millettia and Tephrosia.

Rotenone is classified by WHO as moderately hazardous. It is mildly toxic to humans and other

mammals, but extremely toxic to insects and aquatic life, including fish. This higher toxicity in

fish and insects is because the lipophilic rotenone is easily taken up through the gills or trachea,

but not as easily through the skin or the gastrointestinal tract.

Rotenone rapidly biodegrades under warm conditions, so harmful residues are minimal.

Toxicodynamics


Rotenone interferes with the electron transport chain in mitochondria. It inhibits the transfer of

electrons from iron-sulfur centers in NADH ubiquinone oxidoreductase (NADH dehydrogenase;

complex I) to ubiquinone (CoQ). This interferes with NADH during the generation of ATP. It

inhibits the oxidation of NADH to NAD, thereby blocking the oxidation of e.g. glutamate, α-

ketoglutarate and pyruvate by NAD. Complex I is unable to pass off its electron to CoQ,

therefore electrons accumulate within the mitochondrial matrix. Cellular oxygen is reduced to

the radical, creating reactive oxygen species, which can damage DNA and other components of

the mitochondria. Rotenone also inhibits microtubule assembly.

Signs and symptoms of Poisoning

Oral ingestion causes gastrointestinal irritation, nausea and vomiting. Inhalation of the dust is

more hazardous, causing respiratory stimulation followed by depression, and convulsion.

Treatment of rotenone poisoning is symptomatic.

Uses

Rotenone is used as a pesticide, insecticide, and as a non-selective piscicide. Rotenone has

been used as an organic pesticide dust for gardens. Non-selective in action, it kills for example

potato beetles, cucumber beetles, flea beetles, cabbage worms, and most other arthropods. A

https://en.wikipedia.org/wiki/Crystalline

https://en.wikipedia.org/wiki/Isoflavone


https://en.wikipedia.org/wiki/Piscicide


https://en.wikipedia.org/wiki/Jicama

https://en.wikipedia.org/wiki/Human

https://en.wikipedia.org/wiki/Mammal

https://en.wikipedia.org/wiki/Lipophilic

https://en.wikipedia.org/wiki/Gill

https://en.wikipedia.org/wiki/Invertebrate_trachea

https://en.wikipedia.org/wiki/Gastrointestinal_tract

https://en.wikipedia.org/wiki/Electron_transport_chain

https://en.wikipedia.org/wiki/Mitochondria

https://en.wikipedia.org/wiki/Complex_I

https://en.wikipedia.org/wiki/Ubiquinone

https://en.wikipedia.org/wiki/Nicotinamide_adenine_dinucleotide

https://en.wikipedia.org/wiki/Adenosine_triphosphate

https://en.wikipedia.org/wiki/CoQ

https://en.wikipedia.org/wiki/Reactive_oxygen_species

https://en.wikipedia.org/wiki/DNA

https://en.wikipedia.org/wiki/Microtubule

https://en.wikipedia.org/wiki/Organic_farming

https://en.wikipedia.org/wiki/Potato_beetle

https://en.wikipedia.org/wiki/Cucumber_beetle

https://en.wikipedia.org/wiki/Flea_beetle

https://en.wikipedia.org/wiki/Cabbage_worm



light dusting on the leaves of plants will control insects for several days. It is commercially

available alone, or in synergistic combination with other insecticides.

Rotenone is also used in powdered form to treat scabies and head lice on humans, and parasitic

mites on chickens, livestock, and pet animals.

(iii). Nicotine and neonicotinoids

Nicotine is present in the leaves of Nicotiana rustica and in the tobacco plant Nicotiana

tabacum.

Nicotine functions as an antiherbivore compound (secondary metabolite involved in plant

defense); consequently, nicotine was widely used as an insecticide in the past.

Toxicodynamics


Nicotine stimulates the nicotinic acetylcholine receptor resulting in depolarization of the

membrane. Nicotine is a depolarizing blocker; i.e. toxic doses cause stimulation rapidly followed

by blockade of transmission.

Toxicokinetics

Nicotine is rapidly absorbed from mucosal surfaces; the free alkaloid, but not the salt, is readily

absorbed from the skin.

Nicotine one of the most toxic insecticides, is regarded as a potentially lethal poison. However,

due to its toxicity profile, nicotine was replaced by neonicotinoids. Today nicotine is less

commonly used in agricultural insecticides, which was a main source of poisoning.

Signs and symptoms of nicotine poisoning

The toxic effects of a large dose of nicotine are extensions of its pharmacological actions. The

most dangerous are (1) central stimulant actions, which cause convulsions and may progress to

coma and respiratory arrest; (2) skeletal muscle end plate depolarization, which may lead to

depolarization blockade and respiratory paralysis; and (3) hypertension and cardiac

arrhythmias.

Treatment of nicotine poisoning

Treatment of nicotine poisoning involves maintenance of vital signs and symptomatic therapy.

Muscarinic excess resulting from parasympathetic ganglion stimulation can be controlled with

atropine. Central stimulation is usually treated with parenteral anticonvulsants such as

https://en.wikipedia.org/wiki/Synergy

https://en.wikipedia.org/wiki/Scabies

https://en.wikipedia.org/wiki/Head_lice

https://en.wikipedia.org/wiki/Parasitic

https://en.wikipedia.org/wiki/Mite

https://en.wikipedia.org/wiki/Chickens

https://en.wikipedia.org/wiki/Livestock

https://en.wikipedia.org/wiki/Pet

https://en.wikipedia.org/wiki/Plant_defense_against_herbivory


https://en.wikipedia.org/wiki/Neonicotinoids




diazepam. Neuromuscular blockade is not responsive to pharmacologic treatment and may

require mechanical ventilation. Nicotine is metabolized and excreted relatively rapidly; patients

who survive the first 4 hours usually recover completely if hypoxia and brain damage have not

occurred.

Neonicotinoids

Neonicotinoids (neonics) are a class of neuroactive insecticides chemically similar to nicotine.

Neonicotinoids include acetamiprid, clothianidin, imidacloprid, nitenpyram, nithiazine, thiacloprid

and thiamethoxam. Compared to organophosphate and carbamate insecticides, neonicotinoids

cause less toxicity in birds and mammals than insects. Some metabolic products are also toxic

to insects.

Neonicotinoid use has been linked in a range of studies to adverse ecological effects, including

honey-bee colony collapse disorder and loss of birds due to a reduction in insect populations;

however, the findings have been conflicting, and thus controversial. Their use has been

restricted or banned by several countries and International Treaties, out of concern for

pollinators and bees.


Neonicotinoids, like nicotine, bind to and stimulate nicotinic acetylcholine receptors (nAChRs).

In mammals, nicotinic acetylcholine receptors are located in cells of both the central nervous

system and peripheral nervous systems. In insects these receptors are limited to the central

nervous system. Excessive stimulation of nAchRs by neonicotinoids block the receptors, causing

paralysis and death. Acetylcholinesterase cannot deactivate neonicotinoids, thus their binding is

irreversible.

(e). Avermectins

The avermectins were originally isolated from a culture of the soil actinomycete, Streptomyces

avermitilis.The avermectins are a group of drugs and pesticides with potent anthelmintic and

insecticidal properties. They include ivermectin, selamectin, doramectin, and abamectin.

Ivermectin is also used for pediculosis.

(f). Insecticides used as ectoparasiticides


https://en.wikipedia.org/wiki/Nicotine

https://en.wikipedia.org/wiki/Acetamiprid

https://en.wikipedia.org/wiki/Clothianidin

https://en.wikipedia.org/wiki/Imidacloprid

https://en.wikipedia.org/wiki/Nitenpyram

https://en.wikipedia.org/wiki/Nithiazine

https://en.wikipedia.org/wiki/Thiacloprid

https://en.wikipedia.org/wiki/Thiamethoxam

https://en.wikipedia.org/wiki/Organophosphate#Organophosphate_pesticides

https://en.wikipedia.org/wiki/Carbamate#Carbamate_insecticides

https://en.wikipedia.org/wiki/Honey-bee

https://en.wikipedia.org/wiki/Colony_collapse_disorder

https://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor

https://en.wikipedia.org/wiki/Central_nervous_system

https://en.wikipedia.org/wiki/Central_nervous_system

https://en.wikipedia.org/wiki/Peripheral_nervous_system

https://en.wikipedia.org/wiki/Paralysis

https://en.wikipedia.org/wiki/Drug


https://en.wikipedia.org/wiki/Anthelmintic


https://en.wikipedia.org/wiki/Ivermectin

https://en.wikipedia.org/wiki/Selamectin

https://en.wikipedia.org/wiki/Doramectin

https://en.wikipedia.org/wiki/Abamectin



Some insecticides are also ectoparasiticides used as pediculocides and miticides (especially

scabicides). They include:

(i). Lindane is a miticide, used for the treatment of scabies. It is also a very active pediculocide

effective in the treatment of pediculosis pubis (Phthirus pubis), pediculosis capitis, pediculosis

corporis.

(ii). Malathion, an organophosphorous insecticide, is rapidly pediculocidal and niticidal; lice and

their eggs (nits) are killed within 3 seconds by 0.003% and 0.06% malathion in acetone

respectively.

(iii). Permethrin is an insecticide used to treat scabies and pediculosis

(iii). Benzylbenzoate is an insect repellent also used to treat scabies and pediculosis.

Table 2: Active constituents of some brands of insecticides commonly used in Nigeria

Brand of insecticide

Active constituents

Baygon® Imiprothrin 0.05%, prallethrin 0.05%, cyfluthrin 0.015%,

Raid® D-allethrin 0.25%, tetramethrin 0.015%, deltamethrin 0.015%

Mortein® Imiprothrin 0.02%, d-phenothrin 0.03%, D-trans allethrin 0.10%

Mobil® insecticide Neo-pynamin (tetramethrin) 0.25%, prallethrin 0.04%, cyphenothrin 0.05%

II. HERBICIDES

Herbicides are chemicals used for destruction of noxious weeds. Herbicides include:

(a). Chlorophenoxy compounds – 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-

trichlorophenoxyacetic acid (2,4,5-T). They do not accumulate in animals.

(b). Dinitrophenols e.g. dinitroorthocresol (DNOC)

(c). Bipyridyl compounds – e.g. Paraquat

(d). Phosphonomethyl amino acids

(e). Others such as carbamates (e.g. asulam, propham, barban); substituted ureas (e.g.

monuron, diuron); triazines (e.g. atrazine); aniline derivatives (e.g. alachlor, propachlor,

propanil); dinitroaniline derivatives (e.g. triflualin); and benzoic acid derivatives (e.g. amiben).

III. FUNGICIDES

Fungicides are agents used to kill fungi or their spores, and include:

(1). Dithiocarbamates – Dimethyldithiocarbamates and the ethylenebisdithiocarbamates



Dithiocarbamate fungicides are analogs of disulfiram, and they can produce a disulfiram-like

response on concomitant intake with alcohol.

(2). Hexachlorobenzene

(3). Pentachlorophenol – It is used as an insecticide, herbicide, fungicide, with major application

as a wood preservative.

IV. RODENTICIDES

Rodenticides are pesticides used to kill rodents. Rodenticides include:

(1). Warfarin

(2). Bulbs of red squill containing cardiotonic scillaren glycosides

(3). Sodium fluoroacetate (sodium monofluoroacetate; Compound 1080). This is among the

most potent rodenticides. Sodium fluoroacetate produces its toxic action by inhibiting the citric

acid cycle. Fluoroacetate occurs in all parts of Dichapetalum cymosum, a plant which grows in

Nigeria, and is used as rat poison.

(4). Strychnine, an alkaloid present in Strychnous nux vomica - is a highly toxic, colorless,

bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as

birds and rodents. Strychnine, when inhaled, ingested, or absorbed through the eyes or mouth,

causes poisoning which results in muscular convulsions, including opisthotonus and eventually

death through asphyxia.

(5). White or yellow elemental phosphorous has poisoned human beings on ingestion of bread

on which it was spread to bait rodents. Shortly after ingestion, phosphorus produces severe

gastrointestinal irritation, and with sufficient doses haemorrhage and cardiovascular failure may

result in death within 24 hours.

(6). Zinc phosphide - Zinc phosphide reacts with water and hydrochloric acid in the

gastrointestinal tract to produce phosphine gas, which causes severe gastrointestinal tract

irritation.

(7). α-naphthylthiourea

(8). Thallium salts – They lack selective toxicity; therefore, their use has been restricted or

banned in many countries.

V. FUMIGANTS

https://en.wikipedia.org/wiki/Toxicity

https://en.wikipedia.org/wiki/Crystal

https://en.wikipedia.org/wiki/Alkaloid


https://en.wikipedia.org/wiki/Vertebrate

https://en.wikipedia.org/wiki/Bird

https://en.wikipedia.org/wiki/Rodent

https://en.wikipedia.org/wiki/Strychnine_poisoning

https://en.wikipedia.org/wiki/Convulsion

https://en.wikipedia.org/wiki/Asphyxia



A fumigant is a gaseous pesticide used to control insects, rodents, soil nematodes, and other

animals or plants that damage stored foods or seeds, human dwellings, clothing, nursery stock,

etc. It is used to control pests in buildings, soil, grain, and produce, and also during processing

of goods to be imported or exported to prevent transfer of certain organisms. Fumigants exert

pesticidal action in gaseous form and are used because they can penetrate otherwise

inaccessible areas. Fumigation is a method of pest control that completely fills an area with

gaseous pesticides (fumigants), to poison the pests therein.

Fumigants used to protect stored food stuffs include hydrogen cyanide, carbon tetrachloride,

acrylonitrile, carbon disulphide, dibromochloropropane, ethylene dibromide, chloropicrin,

ethylene oxide, methyl bromide, phosphine, amongst others.

Hydrogen cyanide

Cyanide (hydrocyanic acid; prussic acid; HCN) is one of the most rapidly acting poisons; victims

may die within minutes of exposure. Cyanide is used:

(i).To fumigate ships and buildings

(ii). To sterilize soil

(iii). In metallurgy, electroplating and metal cleaning, because of its ability to form

complexes with metals.

(iv). As a constituent of silver polish, insecticides, rodenticides

(v). Cyanide is found in some plants e.g. cassava, and fruit seeds e.g. apple, apricot,

almond, etc.

(vi). It is a metabolite of organic nitriles, organic thiocyanates, nitroprusside, and nitrogen

containing plastics

(vii). It is used for executions in gas chambers.

Toxicodynamics


Cyanide has a very high affinity for ferric iron (Fe3+). On absorption, HCN reacts readily with

Fe3+ of cytochrome oxidase in mitochondria. Consequently, cellular respiration is inhibited,

resulting in lactic acidosis and cytotoxic hypoxia.

Since cellular respiration is inhibited, and utilization of oxygen is blocked, venous blood is

oxygenated and is almost as bright red as arterial blood. Respiration is stimulated because


https://en.wikipedia.org/wiki/Introduced_species

https://en.wikipedia.org/wiki/Pest_control



chemoreceptors respond as they do in hypoxia. A transient stage of central nervous system

stimulation with hyperpnea and headache occurs; finally hypoxic convulsions occur, and death

is due to respiratory arrest.

Treatment of cyanide poisoning

Treatment must be rapid to be effective. Diagnosis may be aided by the characteristic odour of

cyanide (oil of bitter almonds).

1. Cyanide is removed from the body through its enzymatic conversion by the

mitochondrial enzyme rhodanese (transsulfurase), to thiocyanate, which is relatively

non-toxic.

To accelerate detoxification sodium thiosulphate (50 ml of a 25% aqueous solution) is

administered IV, and the thiocyanate formed is readily excreted in the urine.

Sodium thiosulphate accelerates the conversion of cyanide to thiocyanide, therefore

facilitating detoxification.

2. Hydroxocobalamin is also used to treat cyanide poisoning as it combines with cyanide to

form cyanocobalamin (vitamin B12).

3. Administration of substances that oxidize hemoglobin to methemoglobin (MetHb). Such

substances are:

(a). Nitrite e.g. amyl nitrite administered by inhalation and sodium nitrite for intravenous

administration.

MetHb competes with cytochrome oxidase for the cyanide ion; MetHb is favoured in the

reaction because of mass action. CyanmetHb is formed, and cytochrome oxidase is

restored (spared). The cyanmetHb slowly releases the cyanide, which is converted to

thiocyanate. Thiocyanate is relatively non-toxic and is excreted in urine.

(b). 4-dimethylaminophenol (3 mg/kg IV) also oxidizes hemoglobin to MetHb.

4. Oxygen alone, even at hyperbaric pressure has only a slight protective effect in cyanide

poisoning. However, oxygen markedly potentiates the protective effects of thiosulphate,

or nitrite and thiosulphate.

5. Cobalt compounds have a high affinity for cyanide; e.g. Dicobalt edetate (dicobalt

ethylenediaminetetraacetate; Co2EDTA).

6. If HCN has been ingested, gastric lavage should follow, and not precede initiation of

more specific treatment.



(ii). Methyl bromide

Methyl bromide (bromomethane) is used as an insecticidal fumigant for soil, stored dried

foodstuffs, and disinfection of fresh fruits and vegetables. It is used as a refrigerant, and is also

a constituent of some fire extinguishers. Since it is very toxic, chloropicrin (2%w/w) a powerful

stimulator of lacrimation is added as a warning of methyl bromide exposure.

(iii). Dibromochloropropane and ethylene dibromide (dibromoethane) are soil

fumigants used to control nematodes. Dibromochloropropane was observed to cause sterility

and/or abnormally low sperm counts in workmen engaged in its manufacture, while ethylene

dibromide is a known carcinogen. Their use has decreased due to carcinogenic and adverse

effects on reproductive function.

(iv). Phosphine

Phosphine (PH3) is a fumigant for grain. Following the ban of the use of methyl bromide in most

countries under the Montreal Protocol, phosphine is a widely used, cost-effective, rapidly acting

fumigant that does not leave residues on the stored product.

Phosphine is more toxic than methyl bromide; however, as less phosphine is needed to

fumigate a given volume of grain, phosphine has been proven to be safer. Deaths have resulted

from accidental exposure to fumigation materials containing aluminum phosphide or phosphine.

Phosphine gas is heavier than air so stays nearer the floor where children are likely to play.

Nevertheless, the use of phosphine gas is strictly regulated in most countries, and permitted to

be used only as an agricultural pesticide; and not to be used in spaces like homes or hotels.

Fumigators are required to acquire six months of training before they are able and authorized

to handle the toxin.

Phosphine is released gradually from pellets/tablets of aluminum phosphide, calcium

phosphide, or zinc phosphide upon contact with atmospheric water or rodents' stomach acid.

These pellets also contain agents to reduce the potential for ignition or explosion of the

released phosphine. An alternative is the use of phosphine gas itself which requires dilution with

either CO2, N2 or air to bring it below the flammability point. Use of the gas avoids issues

related with solid residues left by metal phosphide and results in faster, more efficient control of

target pests.

https://en.wikipedia.org/wiki/Methyl_bromide

https://en.wikipedia.org/wiki/Montreal_Protocol

https://en.wikipedia.org/wiki/Aluminum_phosphide

https://en.wikipedia.org/wiki/Aluminium_phosphide

https://en.wikipedia.org/wiki/Calcium_phosphide

https://en.wikipedia.org/wiki/Calcium_phosphide

https://en.wikipedia.org/wiki/Zinc_phosphide

https://en.wikipedia.org/wiki/Combustion

https://en.wikipedia.org/wiki/Explosion



Phosphine gas can be absorbed either by inhalation or transdermally. It acts on the central

nervous system, respiratory and other body systems. It affects the transport of oxygen and

interferes with the utilization of oxygen by various cells in the body.

Signs and symptoms of poisoning include a fall in blood pressure, pulmonary edema, convulsion

and coma. The first sign of chronic poisoning is toothache followed by swelling of the jaw and

necrosis of the mandible (phossy jaw). There may be anaemia and spontaneous fractures.

Treatment of phosphine poisoning is mainly symptomatic. Calcium gluconate (10 ml of 10%

solution) may be given intravenously to maintain serum calcium.

C6. SOLVENTS, VAPOURS, GASES

(i). Halogenated aliphatic hydrocarbons

The halogenated hydrocarbons are among the most widely used industrial solvents, due to their

excellent solvent properties and low flammability.

Halogenated aliphatic hydrocarbons include carbon tetrachloride, chloroform, trichloroethylene,

tetrachloroethylene (perchloroethylene), dichloromethane (used as paint stripper), 1,1,1-

trichloroethane (methyl chloroform), bromodichloromethane. Chloroform is produced from

naturally occurring precursors during chlorination of water. Halogenated hydrocarbons were

formerly widely use as industrial solvents, degreasing and cleaning agents. Due to their

carcinogenic potential, carbon tetrachloride and trichloroethylene have largely been removed

from the workplace. Perchloroethylene and trichloroethane are still in use for dry cleaning and

degreasing, but it is likely that their use will be very limited in the future. Dry cleaning as an

occupation is classified as a carcinogenic activity.

The common halogenated aliphatic solvents are persistent water pollutants. They are widely

found in both groundwater and drinking water as a result of poor disposal practices. The

halogenated hydrocarbons are also common at toxic waste sites, and thus have the potential to

contaminate drinking water supply. Several are also carcinogenic in animals and are considered

probable carcinogens in humans. This has raised concern about the exposure of a large

percentage of the population to these chemicals in drinking water.

Chlorinated HCs e.g. chlorofluorocarbons (CFCs) have a detrimental effect on the ozone layer.

Filtration or treatment of water with chemicals prior to chlorination effectively reduces formation

of chlorinated hydrocarbons.

https://en.wikipedia.org/wiki/Inhalation

https://en.wikipedia.org/wiki/Transdermal



Toxicokinetics

They are readily absorbed after ingestion or inhalation, as they are extremely lipid soluble.

Effects on body organs/systems

They depress the central nervous system in humans; chloroform is the most potent. Chronic

exposure to tetrachloroethylene and possibly 1,1,1-trichloroethane can cause impaired memory

and peripheral neuropathy. Hepatotoxicity is also a common toxic effect that can occur in

humans after acute or chronic exposures; carbon tetrachloride is the most potent.

Nephrotoxicity can occur in humans exposed to carbon tetrachloride, chloroform, and

trichloroethylene. With chloroform, carbon tetrachloride, trichloroethylene, and

tetrachloroethylene, carcinogenicity has been observed in lifetime exposure studies performed

in rats and mice and in some human epidemiologic studies. Several studies have shown

statistically significant associations between exposure to various halogenated aliphatic

hydrocarbon solvents including trichloroethylene and tetrachloroethylene and renal, prostate,

and testicular cancer.

Carbon tetrachloride

Carbon tetrachloride (CCl4) was once commonly used as spot remover and carpet cleaner, but

safer alternatives are now available. It is still used in the fumigation of grain and as an

insecticide.

Transient exposure to toxic concentrations of CCl4 vapour result in the following symptoms,

which disappear on termination of exposure: irritation of the eyes, nose, throat, nausea and

vomiting, a sense of fullness of the head, dizziness and headache. Continued exposure or

absorption of larger quantities, may cause stupor, convulsions, coma or death from CNS

depression. Sudden death may result from ventricular fibrillation or depression of vital

medullary centers. Delayed toxic effects include nausea, vomiting, abdominal pain, diarrhea and

hematemesis. The most serious delayed toxic effects result from its hepatotoxic and

nephrotoxic actions.

Carbon tetrachloride is one of the most potent hepatotoxins; it is widely used in scientific

research to induce hepatotoxicity.

Other halogenated aliphatic hydrocarbons

Chloroform, trichloroethylene and tetrachloroethylene produce majorly similar toxic effects as

carbon tetrachloride. They are hepatotoxic and also have the potential to sensitize the heart to



arrhythmias produced by catecholamines. Chloroform and tetrachloroethylene are nephrotoxic.

Trichloroethylene and tetrachloroethylene are widely used as dry cleaning agents and industrial

solvents, because they produce less organ damage than carbon tetrachloride and chloroform.

Treatment of acute poisoning by halogenated aliphatic hydrocarbons

There is no specific treatment for acute intoxication resulting from exposure to halogenated

aliphatic hydrocarbons. Supportive and symptomatic management is given, depending on the

organ system involved.

1. Move patient to area with fresh, uncontaminated air.

2. Gastrointestinal decontamination with activated charcoal

3. Prevent hypoxia, if patient is first seen in the stage of advanced CNS depression.

4. Treat acute hepatic and renal insufficiency.

Note: Do not use sympathomimetic drugs because of the risk of producing serious arrhythmias

in the sensitized myocardium.

(ii). Aliphatic alcohols

Ethanol

Ethanol (alcohol, ethyl alcohol, grain alcohol, drinking alcohol) is a volatile, flammable, colorless

liquid with a slight characteristic odor. It is a psychoactive substance and is the main type of

alcohol found in alcoholic drinks.

Ethanol is naturally produced by the fermentation of sugars by yeasts or via petrochemical

processes, and is most commonly consumed as a popular recreational substance. Ethanol is a

versatile solvent, miscible with water and many organic solvents. Ethanol is widely used as a

solvent in various laboratory procedures, including synthesis of other organic compounds; as a

vital substance in different manufacturing industries; as an engine fuel and fuel additive,

amongst other uses. It also has medical applications as an antiseptic and disinfectant; and as

an antidote in methanol and ethylene glycol poisoning.

Due to its wide availability and versatility, ethanol could be a potential source of poisoning.

Toxicokinetics

After oral administration, ethanol is absorbed rapidly into the bloodstream from the stomach

and small intestine and distributes into total-body water (0.5-0.7 L/kg). Peak blood levels occur

about 30 minutes after ingestion of ethanol when the stomach is empty. Because absorption

https://en.wikipedia.org/wiki/Volatility_(chemistry)

https://en.wikipedia.org/wiki/Flammability

https://en.wikipedia.org/wiki/Alcohol_(drug)

https://en.wikipedia.org/wiki/Alcoholic_drink

https://en.wikipedia.org/wiki/Fermentation

https://en.wikipedia.org/wiki/Sugar

https://en.wikipedia.org/wiki/Yeast

https://en.wikipedia.org/wiki/Petrochemistry

https://en.wikipedia.org/wiki/Recreational_drug

https://en.wikipedia.org/wiki/Miscible

https://en.wikipedia.org/wiki/Solvent

https://en.wikipedia.org/wiki/Chemical_synthesis

https://en.wikipedia.org/wiki/Organic_compound

https://en.wikipedia.org/wiki/Fuel

https://en.wikipedia.org/wiki/Fuel_additive

https://en.wikipedia.org/wiki/Antiseptic

https://en.wikipedia.org/wiki/Disinfectant

https://en.wikipedia.org/wiki/Antidote

https://en.wikipedia.org/wiki/Ethylene_glycol



occurs more rapidly from the small intestine than from the stomach, delay in gastric emptying

(e.g. due to the presence of food) slows ethanol absorption.

Gastric metabolism of ethanol is lower in women than in men, which may contribute to the

greater susceptibility of women to ethanol. Ethanol undergoes first-pass metabolism by gastric

and liver alcohol dehydrogenase (ADH); this leads to lower blood alcohol level (BAL) after oral

ingestion, than would be obtained if the same quantity were administered intravenously.

Ethanol is metabolized largely by sequential hepatic oxidation, first to acetaldehyde by ADH and

then to acetic acid by aldehyde dehydrogenase (ALDH).

Although, 90-98% of ingested ethanol is metabolized to acetate, mostly by hepatic ADH and

ADLH, small amounts are excreted in urine, sweat, and breath.

Signs and symptoms of ethanol poisoning

Ingestion of lower doses of ethanol could produce symptoms such as mild sedation and poor

coordination. At higher doses, there may be slurred speech, difficulty walking, and vomiting.

Toxic doses may result in respiratory depression, coma, or death. Complications may include

seizures, aspiration pneumonia, injuries including suicide, and hypoglycemia.

Alcohol intoxication, also known as drunkenness or alcohol poisoning, is negative behavior and

physical effects due to the recent consumption / drinking of large amounts of ethanol (alcohol).

Legally, alcohol intoxication is often defined as a blood alcohol level (BAL) of greater than 25–

80 mg/dL or 0.025-0.080%. This can be measured using the blood or breath.

Management of Ethanol poisoning

Management of ethanol intoxication involves supportive care and symptomatic treatment, based

on the severity of respiratory and CNS depression. Measures include:

(1). Keep the patient warm, and in the recovery position.

(2). Ensure adequate breathing, maintain patent airways, provide artificial oxygen if needed.

Patients who are comatose and who exhibit evidence of respiratory depression should be

intubated to protect the airway and to provide ventilatory assistance.

(3). Since ethanol is freely miscible with water, ethanol can be removed from blood by

hemodialysis.

(4). Acute alcohol intoxication is not always associated with coma, and careful observation is

fundamental. Repeated assessments may be required to rule out other potential causes of a

person’s symptoms.

https://en.wikipedia.org/wiki/Sedation

https://en.wikipedia.org/wiki/Slurred_speech

https://en.wikipedia.org/wiki/Vomiting

https://en.wikipedia.org/wiki/Coma

https://en.wikipedia.org/wiki/Death

https://en.wikipedia.org/wiki/Seizures

https://en.wikipedia.org/wiki/Aspiration_pneumonia

https://en.wikipedia.org/wiki/Injuries

https://en.wikipedia.org/wiki/Suicide

https://en.wikipedia.org/wiki/Hypoglycemia

https://en.wikipedia.org/wiki/Ethanol

https://en.wikipedia.org/wiki/Blood_alcohol_concentration

https://en.wikipedia.org/wiki/Breathalyzer

https://en.wikipedia.org/wiki/Supportive_care

https://en.wikipedia.org/wiki/Recovery_position



Usual care involves observing the patient in the emergency room for 4-6 hours while the patient

metabolizes the ingested ethanol. Blood alcohol levels will be reduced by approximately 15

mg/dl per hour.

Methanol

Methanol (methyl alcohol, wood alcohol) is a common industrial solvent. It is used as an

antifreeze fluid, a solvent for shellac and some paints and varnishes, and a component of paint

removers.

Methanol poisoning majorly results from ingestion, though there are rare cases of poisoning by

inhalation and dermal absorption.


Methanol has relatively low toxicity, but it is transformed to toxic metabolites. Methanol is

oxidized by alcohol dehydrogenase (ADH) to formaldehyde. Formaldehyde is oxidized to formic

acid in a reaction catalyzed by formaldehyde dehydrogenase. Formic acid is converted to

carbon dioxide and water by 10-formyl tetrahydrofolate synthetase.

In methanol poisoning, there is accumulation of formic acid leading to acidosis, ocular toxicity,

and some other toxic effects of methanol poisoning

Toxicokinetics

Methanol is rapidly absorbed via the oral route, inhalation, and through the skin; the latter two

routes are most pertinent to industrial settings.Peak methanol concentrations occur within 30 –

60 minutes following oral absorption. It is metabolized in humans by the same enzymes that

metabolize ethanol, i.e. alcohol dehydrogenase and aldehyde dehydrogenase, to toxic

intermediates formaldehyde and formic acid.

Signs and symptoms of methanol poisoning

Signs and symptoms of methanol poisoning include headache, difficulty in breathing, dilation of

pupils, blurred vision, blindness (complete or partial), hypotension, difficulty walking, confusion,

dizziness, seizures, bluish-coloured lips and fingernails, abdominal pain, nausea, vomiting,

diarrhea, pancreatitis, hepatotoxicity (including jaundice), weakness and fatigue. The most

pronounced laboratory finding is severe anion-gap metabolic acidosis - the result of oxidation of

methanol to formic acid, which accumulates. The elevated concentration of formic acid also

causes ocular toxicity, which results in bilateral blindness. Death is usually due to respiratory



failure. Death from methanol is nearly always preceded by blindness. As little as 15 ml of

methanol can cause blindness; ingestion of 70-100 ml is usually fatal unless the patient is

treated.

Management of methanol poisoning

(i). Standard supportive care.

(ii). The correction of metabolic acidosis, by administration of sodium bicarbonate IV.

(iii). Administration of antidotes - fomepizole, ethanol. This will stop further generation of the

toxic metabolite (formic acid).

For example, 10% ethanol solution administered IV. Ethanol is recommended when plasma

methanol concentrations are >20 mg/dl, when ingested doses are> 30 ml and there is evidence

of acidosis or visual abnormalities.

(iv). Administration of intravenous folinic acid to enhanve metabolism of formic acid.

(v). Hemolysis may be necessary to correct severe metabolic abnormalities, and to enhance

elimination of methanol and formate.

Competition between methanol and ethanol for alcohol dehydrogenase (ADH) forms the basis

of the use of ethanol in methanol poisoning. Ethanol is a competitive substrate for ADH as it

has about 100x greater affinity for ADH than methanol. Inhibition of methanol metabolism

decreases the concentration of formaldehyde and formic acid in the blood, and thereby

decreases the toxicity.

Fomepizole (4-methylpyrazole) is a competitive inhibitor of ADH that inhibits the metabolism of

methanol to its toxic metabolite, formic acid. It is used in methanol and ethylene glycol

poisoning. By competitively inhibiting the first enzyme in the metabolism of methanol and

ethylene glycol, fomepizole slows the production of formic acid. The slower rate of metabolite

production allows the liver to process and excrete the metabolites as they are produced, limiting

the accumulation in tissues such as the kidney and eye. As a result, much of the organ damage

is avoided. Fomepizole is most effective when given soon after ingestion of ethylene glycol or

methanol. Delaying its administration allows for the generation of harmful metabolites.

Fomepizole reduced the rate of elimination of ethanol in healthy volunteers.

(iii). Aromatic hydrocarbon solvents



Benzene

Benzene is a versatile solvent, classified as a known human carcinogen. It is widely used as an

intermediate in the synthesis of other chemicals; and it is a natural and important constituent of

automobile fuels.

The acute toxic effect of benzene is depression of the central nervous system. Exposure to

concentrations ranging from 250 to 500 ppm may result in vertigo, drowsiness, headache, and

nausea. Exposure to concentrations larger than 3000 ppm may cause euphoria, nausea,

locomotor problems, and coma. Exposure to 7500 ppm for 30 minutes can be fatal.

Chronic exposure to benzene can result in very serious toxic effects, the most significant of

which is bone marrow injury leading to aplastic anemia with associated pancytopenia, leukemia,

lymphomas, myeloma, and myelodysplastic syndrome.

Treatment of poisoning with benzene and other aromatic hydrocarbon solvents

Treatment of benzene poisoning is by providing supportive care and management of symptoms.

Toluene (methylbenzene) does not possess the myelotoxic properties of benzene, nor has it

been associated with leukemia. It is a central nervous system depressant and a skin and eye

irritant. It is also fetotoxic.

Xylenes (dimethylbenzene) has been substituted for benzene in many solvent degreasing

operations. Like toluene, xylenes do not possess the myelotoxic properties of benzene, nor have

they been associated with leukemia. Xylene is a central nervous system depressant and a skin

irritant.

Less refined grades of toluene and xylenes contain benzene.

Kerosene and Petrol

Kerosene and petrol are petroleum distillates gotten from the fractionation of crude petroleum

oil. They contain aliphatic, aromatic and a variety of branched and unsaturated hydrocarbons.

They are used as fuels (motor, illuminating and heating fuels), vehicles for many pesticides,

cleaning agents and paint thinners. Petrol contains benzene (up to 5% v/v), and has the

potential to cause leukemia on chronic exposure.

Workers and other individuals where these solvents are used are exposed to it. In addition,

because they are often stored in containers previously used for bevarages, or similar to, or



same one for other household use, they are a common cause of accidental poisoning in homes,

especially in children.

Routes of exposure

Exposure to kerosene and petrol, and poisoning thereof could be by ingestion, inhalation of the

vapour, skin and eye contact. Ingestion is more hazardous, because the liquids have a low

surface tension and can be easily aspirated into the respiratory tract by vomiting or eructation.

Signs and symptoms of poisoning

Ingestion of kerosene or petrol produces initial cough and maybe vomiting; later persistent

cough; cyanosis; burning in the stomach; aspiration pneumonitis leading to hypoxia and

respiratory distress; lethargy; coma; seizures; and arrhythmias.

Treatment of kerosene or petrol poisoning

Treatment of poisoning due to kerosene or petrol is by symptomatic and supportive care.

(i). Immediately remove the victim from the source of poisoning, and ensure patent airway.

(ii). Remove contaminated clothing and thoroughly wash the skin with soap and water.

(iii). Perform pulse oximetry if possible, and give oxygen if indicated. Intubation and mechanical

ventilation may be required in a patient with severe hupoxia, respiratory distress or decreased

consciousness.

(iv). Catharsis may be induced with Mg or Na sulphate.

(v). Fluid and electrolyte imbalances should be corrected.

(vi). Antibiotics are used if there is a specific indication e.g. bacterial pneumonitis.

(vii). Emesis or gastric lavage should be avoided because of the danger of inhalation/aspiration

and possibly pneumonitis. However, if very large quantities have been ingested less than an

hour earlier or if the risk is justified by the presence of additional toxic substances in the

petroleum product, then gastric lavage may be considered if the airway can be protected by

expert intubation.

Adrenaline and related substances should be avoided as they may induce cardiac arrhythmias.

(iv). Carbon monoxide

Carbon monoxide (CO) is an air pollutant. Five substances account for nearly 98% of air

pollution: CO (52%), sulphur oxides (14%), nitrogen oxides (14%), volatile organic compounds

(14%) and particulate matter (4%). The sources of these pollutants in increasing order of



significance are; transportation, industry, generation of electric power, space heating, and

refuse disposal. The average atmospheric concentration of CO is about 0.1 ppm; in heavy

traffic, the concentration may exceed 100 ppm. About 90% of atmospheric CO is from natural

sources (forest fires, ocean [microorganisms produce CO], atmospheric oxidation of methane,

etc.), 10% is from human activity (cars, inadequate venting of furnaces, smoking). Most victims

of closed-space fire die from acute CO poisoning rather than from burns.

Carbon monoxide (CO), a colorless, tasteless, odorless, and non-irritating gas, is a by-product

of incomplete combustion of organic matter. It is the most abundant pollutant found in lower

atmosphere, and a large number of accidental and suicidal deaths occur yearly from its

inhalation.

Ambient air pollution has been implicated as a contributing factor in various repiratory diseases

such as bronchitis, obstructive pulmonary disease, pulmonary emphysema, bronchial asthma,

lung cancer, amongst others.

Carbon monoxide is synthesized in the body during the degradation of heme, however, its

physiological role is unclear.

Toxicodynamics


The toxicity of CO is due to

(a). Its reaction with hemoglobin (Hb) to form carboxyhemoglobin (CoHb). Carbon monoxide

acts by (i) reducing the oxygen carrying capacity of Hb, (ii) inhibiting the dissociation of oxygen

from oxyhemoglobin (O2Hb), thereby preventing O2 from interacting with body cells.

Carbon monoxide combines reversibly with the oxygen-binding sites of hemoglobin and has an

affinity for hemoglobin that is about 220 times that of oxygen. The product formed—

carboxyhemoglobin— cannot transport oxygen. Furthermore, the presence of

carboxyhemoglobin inhibits the dissociation of oxygen from the remaining oxyhemoglobin, thus

reducing the transfer of oxygen to tissues.

(b). Direct toxic effect by binding to myoglobin and mitochondrial cytochrome oxidase. The

brain and the heart are the organs most affected.

Normal non-smoking adults have carboxyhemoglobin levels of less than 1% saturation (1% of

total hemoglobin is in the form of carboxyhemoglobin); this level has been attributed to the

endogenous formation of CO from heme catabolism. Smokers may exhibit 5–10% saturation,



depending on their smoking habits. A person breathing air containing 0.1% CO (1000 ppm)

would have a carboxyhemoglobin level of about 50%.

Signs and Symptoms of CO intoxication

The principal signs of CO intoxication are those of hypoxia and progress in the following

sequence: (1) psychomotor impairment; (2) headache and tightness in the temporal area; (3)

confusion and loss of visual acuity; (4) tachycardia, tachypnea, syncope, and coma; and (5)

deep coma, convulsions, shock, respiratory failure, irreversible damage to the brain and

myocardium, death. There is great variability in individual responses to a given

carboxyhemoglobin concentration.

Treatment of carbon monoxide poisoning

Treatment is directed toward the relief of tissue hypoxia and the removal of CO from the body.

Carboxyhemoglobin is fully dissociable, and once acute exposure is terminated, the CO is

excreted via the lungs; only small quantity is oxidized to CO2.

In cases of acute intoxication, removal of the individual from the source of exposure and

maintenance of respiration are essential, followed by administration of oxygen—the specific

antagonist to CO—within the limits of oxygen toxicity.

1. The patient is removed from the source of exposure, and transferred to area with fresh,

uncontaminated air.

2. If there is respiratory failure, artificial respiration is instituted immediately.

3. Provision of adequate supply of O2.

4. Rapid elimination of CO, e.g. by rapid administration of 100% O2 (normobaric) or in

severe poisoning, 100% O2 in a hyperbaric chamber (hyperbaric oxygen therapy; air

pressure is about 2-3x higher than normal pressure).

5. Hypotension and acidosis should be treated and corrected.

6. Respiratory and cardiac functions should be monitored, and symptomatic treatment

given if required.

7. Treatment of seizures, hypotension, cardiac abnormalities, pulmonary edema, etc. as

applicable.

8. Close and extensive follow-up in case of delayed neurological or other damage.



Note: With room air at 1 atm, the elimination half-time of CO is about 320 minutes; with 100%

oxygen, the half-time is about 80 minutes; and with hyperbaric oxygen (2–3 atm), the half-time

can be reduced to about 20 minutes. If a hyperbaric oxygen chamber is readily available, it

should be used in the treatment of CO poisoning for severely poisoned patients; however, there

remain questions about its effectiveness.

Progressive recovery from effectively treated CO poisoning, even of a severe degree, is often

complete, although some patients demonstrate persistent impairment for a prolonged period of

time.

Corrosives

Corrosives, as environmental toxic agents, include acids and acid-like substances as well as

bases/ alkalis. They are widely used in industries and many are found in the home.

Acids

Corrosive acids include inorganic acids such as sulfuric, hydrochloric and nitric acids; and

organic acids like acetic, trichloroacetic and formic acids. They are found in the homes as

battery acids (e.g sulphuric acid), drain and toilet bowl cleaners (may contain e.g. sodium

bisulphite which forms sulphuric acid with water) and some dishwasher detergents, which

contain substances such as sodium hydroxide and sulfuric acid. Industrial products are usually

more concentrated than household products and are more damaging.

Alkalis

Alkalis, e.g. sodium hydroxide and potassium hydroxide are used widely in the manufacture of

many chemicals and household products; thus they are possible sources of poisoning, including

in the home.

Signs and symptoms of poisoning by corrosives

When ingested, corrosives burn upper GIT tissues, sometimes resulting in esophageal or gastric

perforation. Symptoms may include drooling, dysphagia, and pain in the mouth, chest, or

stomach; strictures may develop later. Diagnostic endoscopy may be required.

Treatment of poisoning by corrosives

Treatment is supportive and symptomatic. Gastric emptying and activated charcoal are

contraindicated. Gastric emptying by emesis or lavage on ingestion of a corrosive re-exposes

the upper GIT to the corrosive. The caustic should be diluted as soon as possible after ingestion



by administration of water or milk (about 100 times the volume of ingested caustic). Perforation

is treated with antibiotics and surgery. Do not attempt to neutralize an acid with an alkaline

substance, and vice versa, because heat will be produced that may worsen tissue damage.

For eye contact, the eyes should be washed with a lot of water for 15 minutes. An

ophthalmologist should be consulted for eye examination

Bleaching agents, soaps and detergents

Bleaching agents, soaps and detergents are available in the home. In many homes, they are

accessible to children, and constitute environmental hazards. They should be kept out of the

reach of children.

Bleaching agents

Bleach refers to any chemical product used industrially and domestically to disinfect surfaces,

remove stains and whiten clothes. Household bleaching solutions are usually 3-6% solutions of

sodium hypochlorite in water. Products for industrial use contain higher concentrations and are

as corrosive as sodium hydroxide. Some contain sodium peroxide or sodium perborate.

Bleaching agents are mild irritants and can induce skin, eye or gastrointestinal tract irritation.

Ingetion can cause vomiting, oral burns, damage to the esophagus and stomach, possibly

leading to death. Contact with the skin or eyes, may cause irritation, drying and burns.

Inhalation of bleach fumes can damage the lungs.

Treatment of poisoning by bleaching agents

Treatment is supportive and symptomatic. Milk may be administered to dilute the ingested

bleaching agent. Emesis and gastric lavage are contraindicated. Skin or eye contact should be

treated by irrigation with copious amount of water.

Soaps and detergents

Generally, soaps have low toxicity and can produce mild irritation of the eye, skin and

gastrointestinal tract. Ingestion of a large amount may cause emesis or diarrhea.

Non-ionic detergents have low toxicity, and may not produce any serious harm on ingestion.

Anionic detergents are skin irritants, and may cause cracking and blistering of the skin,

particularly in sensitive persons. Ingestion of anionic detergents may cause irritation of the

pharynx and mouth, abdominal discomfort, diarrhea and vomitiong. Cationic detergents are

more toxic than anionic or non-ionic detergents. Ingestion of cationic detergents may lead to



nausea, vomiting, irritation, corrosion of the oesophagus and mucus membranes, hypotension,

convulsion, coma and death.

Treatment of poisoning by soaps and detergents

Milk may be administered to dilute the ingested soap or detergent. Skin or eye contact should

be treated by irrigation with copious amount of water. Supportive care and symptomatic

treatment should be given.

C7. HEAVY METALS AND THEIR ANTAGONISTS

(i). Heavy Metals

(a). Basic mechanism of toxicity

Heavy metals exert their toxic effects by combining with one or more reactive groups (ligands)

essential for normal physiological functions. Heavy metals, particularly those in the transition

series, may react in the body with ligands containing oxygen (=OH, - COOH, -OPO3H-, >C=O),

sulfur (-SH, -S-S-), and nitrogen (-NH2, >NH). The resultant metal-ligand complex (coordination

compound) affect cellular components, thus interfering with cellular metabolism and function.

Heavy metal antagonists are designed specifically to compete with the ligands for the metals;

and thus prevent or reverse the toxic effects, and enhance the excretion of the heavy metals.

(b). Poisoning by some heavy metals

Lead

Lead exists (i) in its metallic form (ii) as divalent or (iii) tetravalent cation. Divalent lead is the

primary environmental form. Inorganic tetravalent lead compounds do not occur naturally;

however, organo-lead complexes primarily occur with tetravalent lead e.g. tetraethyl lead.

Sources of exposure

Notwithstanding the bans and elimination of the use of lead pipes for water, lead carbonate and

lead oxide in paint, and tetraethyl lead in petrol, their erstwhile use remains the primary

sources of lead exposure. Lead is not degradable and remains throughout the environment in

dust, soil, and the paint of older homes. Young children often are exposed to lead by nibbling

sweet-tasting paint chips or eating dust and soil in and around older homes. Renovation or

demolition of older buildings may cause substantial lead exposure. Lead was commonly used in

plumbing and can leach into drinking water. Acidic foods and beverages dissolve lead when



stored in containers with lead in their glaze or lead-soldered cans. Other sources of exposure to

lead include lead toys, calabash chalk (‘nzu’ in Igbo dialect) eaten by Nigerians, cosmetics,

retained bullets, artists’ paint pigments, ashes and fumes from painted wood, jewelers’ wastes,

and home battery manufacture.

Occupational exposure generally is through inhalation of lead containing dust and lead fumes.

Workers in lead smelters and in storage battery factories are at a great risk of exposure to lead

because fumes are generated and dust containing lead oxide is deposited in their environment.

Other workers at risk of exposure to lead are those associated with steel welding or cutting,

construction, rubber and plastic industries, printing, firing ranges, radiator repair shops, and any

industry where lead is flame soldered. Occupational exposure to lead also has decreased

markedly because of protective regulations.

Toxicodynamics


Lead toxicity results from molecular mimicry of other divalent metals. Lead takes the place of

zinc or calcium in some important proteins. Because of its size and electron affinity, lead alters

protein structure and can inappropriately activate or inhibit protein function.

Toxicokinetics

Exposure to lead occurs through ingestion or inhalation. Gastrointestinal absorption of lead

varies considerably with age and diet. Children absorb a much higher percentage of ingested

lead (about 40% on average) than adults (<20%). Absorption of ingested lead is increased by

fasting, dietary calcium or iron deficiencies. The absorption of inhaled lead generally is much

more efficient (about 90%), particularly with smaller particles. Tetraethyl lead is readily

absorbed through the skin, but this is not a route of exposure for inorganic lead.

About 99% of lead in the bloodstream binds to hemoglobin. Lead initially distributes in the soft

tissues, particularly in the tubular epithelium of the kidney and the liver. Over time, lead is

redistributed and deposited in bone, teeth, and hair. About 95% of the adult body burden of

lead is found in bone. Growing bones will accumulate higher levels of lead and can form lead

lines visible by radiography. Bone lead is very slowly reabsorbed into the bloodstream, except

when calcium levels are depleted, such as during pregnancy. Small quantities of lead

accumulate in the brain, mostly in gray matter and the basal ganglia. Lead readily crosses the

placenta.



Lead is excreted primarily in the urine, although there is some biliary excretion. The

concentration of lead in urine is directly proportional to its concentration in plasma, but because

most lead is in erythrocytes, only a small quantity of total lead is removed by glomerular

filtration. Lead is excreted in milk and sweat and deposited in hair and nails. The serum t1/2 of

lead is 1-2 months, with a steady state achieved in about 6 months. Lead accumulates in bone,

where its t1/2 is estimated to be 20-30 years.

Effects on body /biological systems and body functions

Nervous system: Lead is neurotoxic. The developing nervous system is very sensitive to the

toxic effects of lead, leading to cognitive delays and behavior changes in children. Lead

interferes with the pruning of synapses, neuronal migration, and the interactions between

neurons and glial cells. Together, these alterations in brain development result in decreased IQ,

poor performance on examinations, and behavioral problems such as distractibility. Children

with very high lead levels (>70 μg/dL) are at risk for encephalopathy. Symptoms of lead-

induced encephalopathy include lethargy, vomiting, irritability, anorexia, and vertigo, which can

progress to ataxia, delirium, and eventually coma and death. Most survivors of lead-induced

encephalopathy develop long-term sequelae such as seizures and severe cognitive deficits.

Adults also develop lead-induced encephalopathy (at blood lead levels >100 μg/dL), although

they are less sensitive than children. Workers chronically exposed to lead may develop lead

palsy, characterized by neuromuscular deficits with symptoms including wrist drop and foot

drop; these symptoms were commonly associated with painters and other workers exposed to

lead; currently these are very rare. Lead induces degeneration of motor neurons, usually

without affecting sensory neurons. Studies in older adults have shown associations between

lead exposure and decreased performance on cognitive function tests, suggesting that lead

accelerates neurodegeneration due to aging.

Cardiovascular system: Lead exposure causes elevated blood pressure, and an increased risk

of death due to cardiovascular and cerebrovascular disease.

Renal: Lead poisoning results in lead nephropathy. Low level lead exposure (blood levels <10

μg/dL) depresses glomerular filtration. Higher levels (>30 μg/dL) cause proteinuria and

impaired transport, while very high levels (>50 μg/dL) cause permanent morphological damage,



including proximal tubular nephropathy and glomerulosclerosis. Impaired glomerular filtration

and elevated blood pressure are closely interrelated and may likely affect one another.

Hematological effects: Chronic lead intoxication is associated with hypochromic microcytic

anemia, which is observed more frequently in children and is morphologically similar to iron-

deficient anemia.

Gastrointestinal system: Lead affects the gastrointestinal smooth muscles, initially causing a

persistent metallic taste, mild anorexia, muscle discomfort, malaise, headache, and usually

constipation. Occasionally, diarrhea replaces constipation. As intoxication advances, symptoms

worsen and include intestinal spasms that cause severe intestinal pain (lead colic). Intravenous

calcium gluconate can relieve this pain.

Carcinogenesis: Epidemiological studies have shown associations between lead exposure and

cancers of the lung, brain, kidney, and stomach. Lead is classified as probably carcinogenic to

humans.

Treatment of lead poisoning

Management of lead poisoning involves supportive measures and symptomatic treatment.

(1). Prevention of further exposure

(2). Supportive measures and symptomatic treatment. Seizures are treated with diazepam; fluid

and electrolyte balances are maintained; cerebral edema is treated with mannitol and

dexamethasone.

(3). Chelation therapy with CaNa2EDTA, dimercaprol, D-penicillamine or succimer. The blood

lead concentration should be determined, or a blood sample for analysis obtained, prior to

initiation of chelation therapy.

Mercury

There are three forms of mercury of concern to human health:

(i). Metallic, or elemental, mercury (Hg0) is the liquid metal found in thermometers and dental

amalgam; it is volatile, and exposure is often to the vapor form.

(ii). Inorganic mercury can be either monovalent (mercurous, Hg+) or divalent (mercuric, Hg2+)

and forms a variety of salts.

(iii). Organic mercury compounds consist of divalent mercury complexed with one or two alkyl

groups, e.g. methyl mercury, ethyl mercury. Methyl mercury (MeHg+) is of toxicological



importance, and is formed in the environment by interaction between inorganic mercury and

aquatic microorganisms.

Sources of exposure

Inorganic mercury cations and metallic mercury are found in the Earth’s crust, and mercury

vapor is released naturally into the environment through volcanic activity and off-gassing from

soils. Mercury also enters the atmosphere through human activities such as combustion of fossil

fuels. Once in the air, metallic mercury is photooxidized to inorganic mercury, which is

deposited in aquatic environments during rain. Aquatic microorganisms then conjugate

inorganic mercury to form methyl mercury. Methyl mercury concentrates in lipids and

bioaccumulates up the food chain so that concentrations in aquatic organisms at the top of the

food chain, such as swordfish or sharks, are quite high.

The primary source of exposure to metallic mercury in the general population is vaporization of

mercury in dental amalgam, which often contains >50% Hg0 mixed with silver and other

metals; chewing enhances release of mercury. There is also limited exposure through broken

thermometers and other mercury-containing devices. Human exposure to organic mercury

primarily is through the consumption of fish. Other foods contain lower levels of inorganic

mercury.

Workers are exposed to metallic and inorganic mercury, most commonly though exposure to

vapors. The highest risk for exposure is in the chloralkali industry and other chemical processes

in which mercury is used as a catalyst. Mercury is a component of many devices, including

alkaline batteries, fluorescent bulbs, thermometers, and scientific equipment, and exposure

occurs during the production of these devices. Dentists also are exposed to mercury from

amalgam. Mercury can be used to extract gold during mining, which results in substantial

occupational exposure, because the last step involves vaporization of the mercury. This process

is still commonly used in developing countries. Mercuric salts are used as pigments in paints.

Mercury salts were once found in a number of medications, including antiseptics, antidiuretics,

skin-lightening creams, and laxatives; these have been replaced by safer and more effective

agents. Thimerosal is an antimicrobial agent once widely used as a preservative in vaccines.

Toxicodynamics




Both Hg2+ and MeHg+ readily form covalent bonds with sulfur, which causes most of the

biological effects of mercury. At very low concentrations, mercury reacts with sulfhydryl

residues on proteins thereby disrupting their functions.

Toxicokinetics

Shortly after exposure, some Hg0 vapour is eliminated in exhaled air, and some are readily

absorbed through the lungs (70-80%); gastrointestinal absorption of metallic mercury (Hg0) is

negligible. Once absorbed, Hg0 distributes throughout the body and crosses the blood-brain

barrier, placenta and other body membranes via diffusion. Hg0 is oxidized by catalase in the

erythrocytes and other cells to form Hg2+. After a few hours, distribution and elimination of Hg0

resemble that of Hg2+.

Hg2+ is primarily excreted in the urine and feces; a small amount is reduced to Hg0 and exhaled.

With acute exposure, the fecal pathway predominates, but following chronic exposure, urinary

excretion is dominant. All forms of mercury also are excreted in sweat and breast milk, and

deposited in hair and nails. The t1/2 of inorganic mercury is approximately 1-2 months.

Orally ingested MeHg+ is almost completely absorbed from the gastrointestinal tract. MeHg+

readily crosses the blood-brain barrier and the placenta and distributes evenly to the tissues,

with highest concentration in the kidneys. MeHg+ can be demethylated to form inorganic Hg2+.

The liver and kidney exhibit the highest rates of demethylation, but this also occurs in the brain.

MeHg+ is excreted in the urine and feces, with the fecal pathway dominating. The t1/2 of MeHg+

is about 2 months.

Toxic Effects

Effects on body systems and functions

Metallic mercury: Inhalation of high levels of mercury vapor over a short duration is acutely

toxic to the lung, with symptoms such as cough, tightness in the chest, interstitial pneumonitis

and severely compromised respiratory function. Other initial symptoms include weakness, chills,

metallic taste, nausea, vomiting, diarrhea, and dyspnea. Acute exposure to high doses of

mercury is also toxic to the central nervous system, with symptoms similar to those of chronic

exposure. These symptoms include tremors (particularly of the hands), irritability, shyness, loss

of confidence, nervousness, insomnia, memory loss, muscular atrophy, weakness, paresthesia,

and cognitive deficits. These symptoms intensify and become irreversible, as duration and

concentration of exposure increase.



Other common symptoms of chronic mercury exposure include tachycardia, labile pulse, severe

salivation, and gingivitis. Prolonged exposure to mercury also causes kidney damage.

Inorganic salts of mercury: Precipitation of mucous membrane proteins by mercuric salts

results in intense irritation of the GIT mucosa and an ashen-gray appearance of the mucosa of

the mouth, pharynx, and intestine; this also causes intense pain, which may be accompanied by

vomiting and diarrhea. The local corrosive effect of ionic inorganic mercury on the

gastrointestinal mucosa results in severe hematochezia with evidence of mucosal sloughing in

the stool.

Both acute and chronic poisoning with inorganic mercury produces renal toxicity resulting in

tubular necrosis, decreased urine output and often renal failure.

Organic mercury. The CNS is the primary target of methyl mercury toxicity, with symptoms

such as visual disturbances, ataxia, paresthesia, fatigue, hearing loss, dysarthria, cognitive

deficits, muscle tremor, movement disorders; and following severe exposure, paralysis and

death. The developing nervous system exhibits increased sensitivity to methyl mercury. Children

exposed in utero can develop severe symptoms, including mental retardation and

neuromuscular deficits, even in the absence of symptoms in the mother.

Treatment of mercury poisoning

With exposure to metallic mercury, termination of exposure is critical and respiratory support

may be required. Emesis maybe used within 30-60 minutes of exposure to inorganic mercury,

provided the patient is awake and alert and there is no corrosive injury. Maintenance of

electrolyte balance and fluids is important for patients exposed to inorganic mercury. Chelation

therapy is beneficial in patients with acute inorganic or metallic mercury exposure.Chelation

therapy with dimercaprol for high-level exposures or symptomatic patients; penicillamine for

low-level exposures or asymptomatic patients is routinely used to treat poisoning with either

inorganic or elemental mercury. Succimer is also beneficial.

There are limited treatment options for methyl mercury poisoning. Chelation therapy does not

provide clinical benefits, and several chelators potentiate the toxic effects of methyl mercury.

Non-absorbed thiol resins may be beneficial by preventing reabsorption of methyl mercury from

the gastrointestinal tract.

Arsenic



Arsenic is a metalloid that is common in rocks and soil. Arsenic compounds have been used for

over 2400 years as both therapeutic agents and poisons. The organic arsenic compound

arsphenamine was once used for the treatment of syphilis and trypanosomiasis. The use of

arsenic in drugs has been mostly phased out, but arsenic trioxide (ATO) is still used as an

effective chemotherapy agent for acute promyelocytic leukemia.

Arsenic exists in its elemental form, trivalent (arsenites/arsenious acid) and pentavalent

(arsenates/arsenic acid) states. Arsine is a gaseous hydride of trivalent arsenic that exhibits

toxicities that are distinct from other forms. Organic compounds containing either valence state

of arsenic are formed in animals. The toxicity of a given arsenical is related to the rate of its

clearance from the body and its ability to concentrate in tissues. In general, toxicity increases in

the sequence: organic arsenicals < As5+ < As3+ < arsine gas (AsH3).

Sources of exposure

The primary source of exposure to arsenic is through drinking water. Arsenic naturally leaches

out of soil and rocks into well and spring water. Arsenic also can enter the environment through

the use of arsenic-containing pesticides, mining, and burning of coal. Food, particularly seafood,

often is contaminated with arsenic.

The major source of occupational exposure to arsenic is in the production and use of organic

arsenicals as herbicides and insecticides. Exposure to metallic arsenic, arsine, arsenic trioxide,

and gallium arsenide also occurs in high technology industries, such as the manufacture of

computer chips and semiconductors.

Toxicodynamics


Like mercury, trivalent arsenic compounds form covalent bonds with sulfhydryl groups. The

pyruvate dehydrogenase system is particularly sensitive to inhibition by trivalent arsenicals

because the two sulfhydryl groups of lipoic acid react with arsenic to form a six-membered ring.

Inorganic arsenate (pentavalent) inhibits the electron transport chain. Arsenate appears to

competitively substitute for phosphate during the formation of adenosine triphosphate, forming

an unstable arsenate ester that is rapidly hydrolyzed.

Toxicokinetics

The absorption of arsenic compounds is directly related to their solubility. Poorly water-soluble

forms such as arsenic sulfide, lead arsenate, and arsenic trioxide are not well absorbed. Water-



soluble arsenic compounds are readily absorbed afer both inhalation and ingestion.

Gastrointestinal absorption of arsenic dissolved in drinking water is >90%.

At low doses, arsenic is evenly distributed throughout the tissues of the body, with high

concentrations in nails and hair due to their high sulfhydryl content. After an acute high dose of

arsenic (i.e., fatal poisoning), arsenic is preferentially deposited in the liver and, to a lesser

extent, kidney, with elevated levels also observed in the muscle, heart, spleen, pancreas, lungs,

and cerebellum. Arsenic readily crosses the placenta and blood-brain barrier. Arsenic undergoes

biotransformation in humans to monomethylarsenic compounds.

Elimination of arsenicals by humans primarily is in the urine, although some are also excreted in

feces, sweat, hair, nails, skin, and exhaled air.

Effects on body systems and functions

Though humans are the most sensitive species to the toxic effects of inorganic arsenic, they are

exposed to large amounts organic arsenic compounds in fish, which are relatively nontoxic.

Inorganic arsenic exhibits a broad range of toxicities, although some body systems are much

more sensitive than others. With the exception of arsine gas, the various forms of inorganic

arsenic exhibit similar toxic effects.

Acute exposure to large doses of arsenic (>70 - 180 mg) often is fatal. Death immediately

following arsenic poisoning typically is the result of its effects on the heart and GIT. Death

sometimes occurs later as a result of arsenic’s combined effect on multiple organs.

Cardiovascular system: Acute and chronic arsenic exposure cause myocardial depolarization,

cardiac arrhythmias, and ischemic heart disease; these are also known adverse effects of

arsenic trioxide in the treatment of leukemia. Chronic exposure to arsenic causes peripheral

vascular diseases, e.g. ‘blackfoot disease,’ a condition characterized by cyanosis of the

extremities, particularly the feet, progressing to gangrene.

Skin: The skin is very sensitive to chronic arsenic exposure. Dermal symptoms often are

diagnostic of arsenic exposure. Arsenic induces hyperkeratinization of the skin (including

formation of multiple corns or warts), particularly of the palms of the hands and the soles of the

feet. It also causes areas of hyperpigmentation interspersed with spots of hypopigmentation.

Hyperpigmentation can be observed after 6 months of exposure, while hyperkeratinization takes

years. Children are more likely to develop these effects than adults.



Gastrointestinal tract: Acute or subacute exposure to high-dose arsenic by ingestion is

associated with GIT symptoms ranging from mild cramps, diarrhea, and vomiting to

hemorrhage and death; these symptoms are caused by increased capillary permeability, leading

to fluid loss. At higher doses, fluid forms vesicles that can burst, leading to inflammation and

necrosis of the submucosa and then rupture of the intestinal wall.

Nervous System: The most common neurological effect of acute or subacute arsenic

exposure is peripheral neuropathy involving both sensory and motor neuron, characterized by

the loss of sensation in the hands and feet, followed by muscle weakness. Neuropathy occurs

several days after exposure to arsenic and can be reversible following cessation of exposure,

although recovery usually is not complete. Acute high-dose arsenic causes encephalopathy in

rare cases, with symptoms such as headache, lethargy, mental confusion, hallucination,

seizures, and coma.

Other body systems: Acute and chronic arsenic exposures induce anemia and leukopenia.

Arsenic also may inhibit heme synthesis. In the liver, arsenic causes fatty infiltrations, central

necrosis, and cirrhosis of varying severity. The action of arsenic on renal capillaries, tubules,

and glomeruli can cause severe kidney damage. Inhaled arsenic is irritating to the lungs, and

ingested arsenic may induce bronchitis progressing to bronchopneumonia in some individuals.

Chronic exposure to arsenic is associated with an increased risk of diabetes.

Carcinogenesis: Arsenic compounds were among the first recognized human carcinogens,

arsenic is classified as a carcinogenic to humans. Exposure to arsenic has been associated with

cancer of the skin, bladder, lung, liver, kidney, and prostate.

Arsine Gas. Arsine gas, formed by electrolytic or metallic reduction of arsenic, is a rare cause

of industrial poisoning. Arsine induces rapid and often fatal hemolysis, headache, anorexia,

vomiting, paresthesia, abdominal pain, chills, hemoglobinuria, bilirubinemia, anuria, jaundice,

and renal toxicities that can progress to kidney failure and death.

Treatment of arsenic poisoning

Following acute exposure to arsenic,

(1). The patient should be stabilized and further absorption of the poison prevented.

(2). Close monitoring of fluid levels is important because arsenic can cause fatal hypovolemic

shock. Hypotension may necessitate fluid replacement and use of pressor agents (e.g.

dopamine).



(3). Chelation therapy is effective following short-term exposure to arsenic but has very little or

no benefit in chronically exposed individuals. Chelators used in arsenic poisoning include

dimercaprol, penicillamine, and succimer

(4).Exchange transfusion to restore blood cells and remove arsenic often is necessary following

arsine gas exposure.

(ii). Heavy Metal Antagonists

Treatment of acute heavy metal intoxications often involves the use of heavy metal antagonists

or chelators. A chelator is a compound that forms stable complexes with metals, typically as

five- or six-membered rings. Formation of complexes between chelators and metals should

prevent or reverse metal binding to biological ligands.

(a).Properties of an ideal chelating agent

The ideal chelator should have the following properties:

(i). High solubility in water.

(ii). Resistance to biotransformation.

(iii). Ability to reach sites of metal storage.

(iv). Ability to form stable and non-toxic complexes with toxic metals.

(v). Ready excretion of the metal-chelator complex.

(vi). A low affinity for the essential metals – such as calcium and zinc – is also desirable,

because toxic metals often act through competition with these metals for protein binding.

(b). Chelating agents

Dimercaprol

Dimercaprol (British anti-lewisite; BAL) was developed during World War II as a therapeutic

antidote against poisoning by the arsenic-containing warfare agent lewisite.

Dimercaprol is an oily, colourless liquid with pungent, disagreeable odour. Because aqueous

solutions of dimercaprol are unstable and oxidize readily, it is dispensed in 10% solution in

peanut oil and must be administered by intramuscular injection, which is often painful.

Mechanism of Action



Dimercaprol acts through the formation of chelation complexes between its sulfhydryl groups (-

SH) and metals. Dimercaprol is more effective when given soon after exposure to the metal,

because it more effectively prevents inhibition of sulfhydryl enzyme than in reactivating them.

Pharmacokinetics

Dimercaprol cannot be administered orally; it is given by deep intramuscular injection as a 100

mg/ml solution in peanut oil and should not be used in patients who are allergic to peanuts or

peanut products. Peak concentrations in blood are attained in 30-60 minutes. The t1/2 is short,

and metabolic degradation and excretion are complete within 4 hours. Dimercaprol and its

chelates are excreted in both urine and bile.

Adverse Effects

Adverse effects of dimercaprol include hypertension; tachycardia; nausea and vomiting;

headache; a burning sensation in the lips, mouth and throat, and a feeling of constriction,

sometimes pain in the throat, chest or hands; conjunctivitis; lacrimation; salivation; fever

(particularly in children); pain at the injection site; thrombocytopenia and increased

prothrombin time (these may limit intramuscular injection because of the risk of hematoma

formation at the injection site).

Ethylenediaminetetracetic acid (EDTA) and its derivatives

Ethylenediaminetetracetic acid and its various salts are effective chelators of divalent and

trivalent metals. However, not all salts are used therapeutically, for example rapid intravenous

administration of Na2EDTA causes hypocalcemic tetany. In contrast, CaNa2EDTA can be

administered intravenously with negligible change in the concentration of Ca2+ in plasma and

total body. Therefore, to prevent potentially life-threatening depletion of calcium, the calcium

disodium salt is used.

Calcium disodium EDTA (CaNa2EDTA) is the preferred EDTA salt for metal poisoning, provided

that the metal has a higher affinity for EDTA than calcium. CaNa2EDTA is effective for the

treatment of acute lead poisoning, particularly in combination with dimercaprol, but is not an

effective chelator of mercury or arsenic in vivo.

Mechanism of Action

The pharmacological effects of CaNa2EDTA result from chelation of divalent and trivalent metals

in the body. Accessible metal ions (both exogenous and endogenous) with a higher affinity for



CaNa2EDTA than Ca2+ are chelated, mobilized, and usually excreted. CaNa2EDTA mobilizes

several endogenous metallic cations, including those of zinc, manganese, and iron. Additional

supplementation with zinc following chelation therapy may be beneficial. Since it is charged at

physiological pH, EDTA does not significantly penetrate cell membranes and therefore chelates

extracellular metal ions much more effectively than intracellular ions.

Pharmacokinetics

Less than 5% of CaNa2EDTA is absorbed from the GIT, hence it is not used orally. After

intravenous administration, CaNa2EDTA has a t1/2 of 20-60 minutes. In blood, CaNa2EDTA is

found only in the plasma. It is distributed mainly in the extracellular fluids; very little enters the

spinal fluid (5% of the plasma concentration). There is very little metabolic degradation of

EDTA. CaNa2EDTA is excreted in the urine by glomerular filtration, so adequate renal function is

necessary for successful therapy. Altering either the pH or the rate of urine flow has no effect

on the rate of excretion.

Adverse Effects

The principal toxic effect of CaNa2EDTA is renal toxicity. Other adverse effects include malaise,

fatigue and excessive thirst, followed by the sudden appearance of chills and fever and

subsequent myalgia; frontal headache; anorexia; occasional nausea and vomiting; and rarely,

increased urinary frequency and urgency. Sneezing, nasal congestion and lacrimation;

glycosuria; anemia; dermatitis with lesions strikingly similar to those of vitamin B6 deficiency;

transient lowering of systolic and diastolic blood pressures; prolonged prothrombin time; and T-

wave inversion on the electrocardiogram, may also occur.

Penicillamine

Penicillamine is a white crystalline, water-soluble derivative of penicillin. D-Penicillamine is less

toxic than the L-isomer, and consequently is the preferred therapeutic form. Penicillamine is an

effective chelator of copper, mercury, zinc and lead, and promotes the excretion of these

metals in the urine.

Penicillamine is more toxic and is less potent and selective for chelation of heavy metals relative

to other available chelators. It is therefore not a first-line treatment for acute intoxication with

lead, mercury, or arsenic. However, because it is inexpensive and orally bioavailable, it is often

given at fairly low doses following treatment with CaNa2EDTA and/or dimercaprol to ensure that



the concentration of metal in the blood stays low following the patient’s release from the

hospital.

Mechanism of Action

Penicillamine binds to some heavy metals; the penicillamine-metal complex is then eliminated

from the body.

Pharmacokinetics

Penicillamine is available for oral administration. It should be given on an empty stomach to

avoid interference by metals in food. Penicillamine is well absorbed (40-70%) from the GIT.

Food, antacids, and iron reduce its absorption. Peak concentrations in blood are obtained

between 1 and 3 hours after administration. Penicillamine is primarily degraded by hepatic

biotransformation, and very little drug is excreted unchanged. Metabolites are found in both

urine and feces.

Adverse Effects

Most common adverse effect of penicillamine is hypersensitivity reactions including rash,

pruritus, and drug fever. Penicillamine should be used with extreme caution, if at all, in patients

with a history of penicillin allergy. Other adverse effects include renal toxicity with proteinuria

and haematuria; haematological reactions with leukopenia, aplastic anaemia, pancytopenia and

agranulocytosis. Toxicity to the pulmonary system is uncommon, but severe dyspnea has been

reported from penicillamine-induced bronchoalveolitis. Less serious side effects include nausea,

vomiting, diarrhea, dyspepsia, anorexia, and a transient loss of taste for sweet and salt, which

is relieved by supplementation of the diet with copper.

With long-term use, penicillamine induces several cutaneous lesions, including urticaria, macular

or papular reactions, pemphigoid lesions, lupus erythematosus, dermatomyositis, adverse

effects on collagen; and other less serious reactions, such as dryness and scaling. Cross-

reactivity with penicillin may be responsible for some episodes of urticarial or maculopapular

reactions with generalized edema, pruritus, and fever that occur in as many as one-third of

patients taking penicillamine.

Contraindications to penicillamine therapy include pregnancy, renal insufficiency, or a previous

history of penicillamine-induced agranulocytosis or aplastic anemia.

Succimer



Succimer (2,3-dimercaptosuccinic acid; DMSA) is an orally effective chelator that is chemically

similar to dimercaprol but contains two carboxylic acids that modify the spectrum of absorption,

distribution, and chelation of the drug. It has an improved toxicity profile over dimercaprol.

Succimer has several desirable features over other chelators. It is orally bioavailable, and

because of its hydrophilic nature, does not mobilize metals to the brain or enter cells. It also

does not significantly chelate essential metals such as zinc, copper, or iron. As a result of these

properties, succimer exhibits a much better toxicity profile relative to other chelators. Succimer

is a chelator of lead, arsenic, cadmium, mercury, and other toxic metals.

Mechanisms of Action

Succimer binds to some heavy metals, leading to the elimination of the metal from the body.

Adverse Effects

Succimer is much less toxic than dimercaprol. Adverse effects include nausea, vomiting,

diarrhea, loss of appetite, rashes and transient elevations in hepatic transaminases.

Deferoxamine mesylate

Deferoxamine is isolated as the iron chelate from Streptomyces pilosus; and it undergoes

chemical modification to obtain the metal-free ligand.

Deferoxamine has some desirable properties such as, a remarkably high affinity for ferric iron, a

very low affinity for calcium, and it does not remove iron from hemoglobin or cytochromes.

Mechanism of Action

Deferoxamine binds with high affinity to iron, thereby enhancing its elimination from the body.

Pharmacokinetics

Deferoxamine is poorly absorbed after oral administration, and may increase iron absorption

when given by this route. Hence, parenteral administration is preferred. In severe iron toxicity

(serum iron levels >500 μg/dL), the intravenous route is preferred. Deferoxamine is

metabolized, but the pathways are unknown. The iron- chelator complex is excreted in the

urine, often turning the urine an orange-red color.

Adverse Effects

Deferoxamine causes a number of allergic reactions, including pruritus, wheals, rash, and

anaphylaxis. Other adverse effects include dysuria, abdominal discomfort, diarrhea, fever, leg

cramps, tachycardia, and cataract formation. Pulmonary complications (e.g., acute respiratory



distress syndrome; tachypnea, hypoxemia, fever, and eosinophilia are prominent symptoms)

have been reported in some patients undergoing deferoxamine infusions lasting longer than 24

hours; and neurotoxicity and increased susceptibility to certain infections (e.g., with Yersinia

enterocolitica) have been reported after long-term therapy of iron overload conditions (e.g.,

thalassemia major).

Deferoxamine is contraindicated in renal insufficiency and anuria. It should be used during

pregnancy only if clearly indicated.

Deferasirox

Deferasirox is an orally administered chelator of iron, with a high affinity for iron and low

affinity for other metals, e.g., zinc and copper. It is well absorbed on oral administration. It

binds iron in the circulation, and the complex is excreted in bile.

Adverse Effects

Long-term daily use of deferasirox is generally well tolerated, most common adverse effects

include mild to moderate gastrointestinal disturbances and skin rash.

Trientine

Trientine (triethylenetetramine dihydrochloride) is an orally effective acceptable alternative to

penicillamine in Wilson’s disease. Although it may be less potent than penicillamine, it could be

used in patients that may not tolerate the undesirable effects/toxicities of penicillamine.

Trientine may cause iron deficiency; this can be overcome with short courses of iron therapy,

but iron and trientine should not be ingested within 2 hours of each other.

Unithiol

Unithiol (Sodium 2,3-Dimercaptopropane Sulfonate; DMPS), a dimercapto chelating agent, is a

water-soluble analog of dimercaprol. Unithiol is a clinically effective chelator of lead, arsenic,

and especially mercury. It is negatively charged and exhibits distribution properties similar to

those of succimer. It is less toxic than dimercaprol, but mobilizes zinc and copper and thus is

more toxic than succimer.

Unithiol can be administered orally and intravenously. Bioavailability by the oral route is

approximately 50%, with peak blood levels occurring in approximately 3.7 hours. It is rapidly



excreted, primarily through the kidneys. Over 80% of an intravenous dose is excreted in the

urine, mainly as cyclic DMPS sulfides. Unithiol increases the excretion of mercury, arsenic, and

lead in humans.


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