factors modifying drug effect

7/28/2019 Factors Modifying Drug Effect

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FACTORS MODIFYING A

DRUG EFFECT


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Drug effect

Refers to the normal spectrum of biological response evoked

by a drug when used at a recommended dose.

Variations in drug response are attributable to :

Factors that influence drug action qualitatively and/or

quantitatively.

Broadly divided into 4 groups:

Drug related

Exposure conditions

Individual: Subject

Environmental conditions.


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Types of dosage

form Type of salt form

Type of formulation

Physico-chemicalproperties of drug

Dose

Route of administration

Rate of administration

Time of administration

Schedule of dosage

Duration and frequencyof administration

Concentration

Drug interactions


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Species

Breeds Strains

Sex

Age

Pregnancy

Lactation Hormonal status

Body weight and composition

Genetic status

Nutritional status

Emotional status andtemperament

Tolerance

Individual variations

Physiological/ Pathological states

Temperature

pH Atmospheric pressure and

altitude

Light and other radiations

Relative humidity

Environmental pollution


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The dosage form of that drug.

For a given drug, 2 to 5 fold or more

difference could be observed in the

oral bioavailability of a drugdepending on the nature and type of

dosage form.

As a general rule, absorption andaction of drug from solution are

fastest, whereas from a sustained

release product are slowest.

I. THE DRUG RELATED FACTORS

i) Types of dosage form:


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ii) Type of salt form:

Most drugs are weak electrolytes

The nature and type of salt formation influence drug

solubility and bioavailability.

For example; choline and isopropanolamine salts of

theophylline dissolve 3 to 4 times more rapidly than the

ethylene diamine salt and show better bioavailability.


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iii) Type of formulation:

The pharmacological effect of a drug may be influenced by thetype and number of excipients (non-drug components) presentin the formulation.

For example,

Physiological surfactants like bile salts and LysolecithinHydrophobic drugs (steroids, oil soluble vitamins

and griseofulvin)

On the other hand, certain dyes (e.g. brilliant blue) when usedas colorants inhibit impair absorption of hydrophobic drugs.

The macromolecular gums (e.g., sodium carboxymethylcellulose and methyl cellulose) often used as mechanicalbarrier to diffusion of drug by forming a viscid layer on the GI

mucosa.


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iv) Physico-chemical properties of drug:Important physico-chemical properties that

influence drug effect are partition coefficient,degree of ionisation and molecular size.

a) Partition coefficient: Drugs having high oil: water

coefficient (high lipid solubility) - readily absorbed

For example; Thiopentone, a derivative of barbituric acid, has

high partition coefficient, so it is rapidly absorbed and

rapidly produces anaesthesia.

On the other hand, barbituric acid has low lipid solubility and

it is inefficient as an anaesthetic agent.


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b) Degree of ionisation: Ionised- more water-soluble less absorption

Unionised- have greater penetrability across the biologicalmembranes.

For example, quaternary ammonium compounds remain

ionised at plasma pH, therefore, they do not cross the bloodbrain barrier and have no effect on CNS.

c) Molecular size and weight:Drugs of low molecular weight

and size are more rapidly absorbed and distributed than those

having large complex molecules.


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II. EXPOSURE/ ADMINISTRATION CONDITIONS

RELATED FACTORS

Dose: The magnitude of pharmacologic effect depends on the amount

of drug absorbed into blood stream that further depends on the

dose administered.

Normally, response of a drug increases with increase in the

dose, but within a limit.

A sufficiently large dose of an ordinarily harmless drug (e.g.,

sodium chloride) may prove fatal


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Route of administration:

Route of drug administration governs the speed and intensity

of drug response. For some drugs, type of drug effect may vary with the route

of drug administration.

For example;

Magnesium sulphate (orally) Purgation, applied topicallyon inflamed area decreases swelling

Intravenously Muscle relaxation, CNS depression,

hypotension and even cardiac arrest.

Similarly, lignocaine infiltrated into the vicinity of a nerve

produces local anaesthetic effect

Intravenously Antiarrhythmic effect.


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Time of administration:

Response to a drug may be related to the time of day at which itis administered. This may be related to the eating and sleeping

habits of the animal or to the diurnal factors.

For example;

Nocturnal animals like rats, there is more food in stomach in

the morning than that in the afternoon. So absorption of drugis variable depending on time of its administration.

Dosing with glucocorticoids at night has been recommended

for cats in order to mimic endogenous release patterns.

In humans, hypnotics are more effective during night, becausedarkness itself has sedative effect and also because peoplesleep during night.


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Schedule of dosage:

Generally, a single large dose produces more response thanthe same amount given in divided doses.

However for a drug that is cumulative in nature, divided

doses may produce more pharmacological effect.

For example, cardiac glycosides have a low therapeutic

index; therefore multiple divided doses are recommended

over a period of 24 to 36 hours for the initial digitalisation.


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For some agents, pharmacological or toxicological effects of

single administration are quite different from those produced byrepeated administration.

For example, some organophosphorus insecticides (e.g.,

monocrotophos) in acute toxicity produce characteristic anti-cholinesterase manifestations like salivation, muscle

tremors,dyspnoea and convulsions, but they on repeated

exposure produce delayed neuropathy (e.g.,

paralysis of limbs).

Duration and frequency of administration:


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Concentration:

Greater the concentration of a drug in a preparation, faster is

the rate of absorption and rapid onset of pharmacological

effect.

For some drugs, the pharmacological effect may vary with

different concentrations.

Eg:

weak solution of iodine (2.5%)-antiseptic; strong solution of

iodine (10%) -counterirritant and parasiticide.

Red mercuric iodide ointment at lower strength (1:40)-

rubefacient action; higher concentration (1:4 or 1: 8)- vesicant

action.


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Drug Interaction during metabolism

Enzme induction:

Liver micsrosomal enzymes are induced by a wide varietyof drugs and these affect the metabolism of other drugsreducing their concentration and hence effect.

Eg, loss of anticougulant effect of Warfarin leading todanger of thrombosis if barbiturates are administered.

Chronic Use of alcohal shows tolerance to generalanesthetics.

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Enzyme inhibition

Certain drugs inhibit the liver microsomal enzymes,hence increase the activity of drugs which are to be

metabolized by these enzymes.

Eg. Cimetidine potenciates the effects of propranolol

,theophylline, warfarin and others

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Enzyme inducers

Phenobarbital

Rifampin

Griseofulvin

Phenytoin

Ethanol

Carbamazepine

Enzyme inhibitors

Phenylbutazone

Metronidazole

Cimetidine

Omperazole

Chloramphenicol

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III. FACTORS RELATED TO THE SUBJECT

Species:

There is wide biological diversity among different species inthe rate and pattern of metabolism to detoxify a compound.

For example,

Belladonna or atropine is toxic to most species, but not to

rabbits due to the presence of liver enzyme atropinase, which

rapidly hydrolyses it.

Morphine produces CNS depression in human beings,

monkeys and dogs but it causes CNS excitation in cats.


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The extent of drug absorption following oral administration

also varies with species and is related mainly to their

digestive tract.

The absorption of drugs following oral administration is fast

and complete in monogastric animals, and comparatively

slow and incomplete in ruminants.

Several drugs (e.g., antibiotics) are not effective by oral route

in ruminants because these drugs are either inactivated by

ruminal micro flora or they may fail to diffuse into the largecompartments of the G-I tract.


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Breeds:

Breed differences influence the drug effect, although theyhave not been well described.

For example,

Greyhounds are more susceptible to thiobarbiturates becausetheir lean body weight provides little fat for drug

redistribution.

Brachycephalic breeds are more susceptible to cardiacarrhythmias (sinoatrial block) caused by acepromazine.

Some breeds of pigs (e.g., Poland China and Pietrain) arefound to be highly susceptible to halothane induced malignanthyperpyrexia.


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Strains:

Different strains of same animal may show variations in drug

response.

For example, different strains of mice vary widely in their

ability to metabolise barbiturates and consequently the

magnitude of pharmacological response.

In humans, differences have been observed in the metabolismof drugs among different races called as ethnic variations.

For example,

45% of whites in USA and Canada are slow acetylators and

55% are rapid acetylators of isoniazid. Dose adjustment in slow acetylators is essential because they

are susceptible to isoniazid induced peripheral neuritis-and

hepatic damage.


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Sex:

sex related differences in the rate of biotransformation andelimination of drugs are related mainly to variation in sex

hormones.For example,

Male mice are highly susceptible to nephrotoxic effect ofchloroform, but female mice show little effect.

Female rats are 2 times more susceptible to red squill toxicitythan male rats.

In humans, ephedrine more frequently produces excitation andtremors in women than in men.

In experimental studies it has been demonstrated thatcastration increases chances of drug toxicity in males, whileadministration of testosterone in females increases resistanceto poisoning.


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Age:

Very young (neonates) and very old (geriatric) animals are

more susceptible to harmful effect of drugs when compared

with adults.

Neonates have under-developed and inefficient hepatic

microsomal enzyme system, while geriatric animals have

reduced liver mass, decreased hepatic blood flow and deceased

microsomal enzyme activity.

For example half-life of chloramphenicol in piglets is about 6-7times more than in adults. Chloramphenicol induced grey-baby

syndrome in human infants is due to inadequate conjugation of

the drug with glucuronic acid.


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Pregnancy:

Pregnancy causes marked hormonal and metabolic changes thus

affecting response of certain drugs.

For example,

oral anticoagulants are more toxic to pregnant animal.

During pregnancy, plasma and ECF volume expands,

therefore, volume of drug distribution may increase.

Renal blood flow also increases markedly during pregnancy as

a result of which renal excretion of some drugs


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High progesterone levels during pregnancy may

increase hepatic microsomal enzymes

Lactation: Similar to pregnancy, lactation alters

pharmacokinetics of certain drugs.

Lactation may enhance excretion of some lipophilic drugs

and toxicants (e.g., DDT, polychlorinated biphenyls) in the

milk.

Drugs in milk may have their own unwanted effects on the

suckling youngones and consumers.


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Hormonal status:

For example,hyperthyroidism and hypothyroidism can affect

drug disposition.

In human beings, the elevated thyroid hormones activate some

cytochrome P-450 enzymes (e.g., hydroxylation), while

activities of others (e.g.,N-demethylation) are decreased.

Digoxin doses necessary to induce clinical response are in

general increased in hyperthyroidism, whereas smaller doses

than normal are needed in hypothyroidism.

Adrenalectomised rats are generally more susceptible to

adverse effects of drugs due to low levels of anti-stress

hormone adrenaline.


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Body weight and composition:

Normally dose of a drug is adjusted on the basis of body weight(i.e., mg/kg).

Differences between body weight and true lean body weightshould be taken when dealing with conditions like obesity,starvation, ascites, generalised oedema, starvation, old age, etc.

In obese animals, water soluble drugs generally do notdistribute into increased body fat which may result in higherthan expected plasma drug concentration and hence adverseeffects.

On the other hand, highly lipid soluble drugs (e.g., anaesthetics)are required in high dosage in an obese animal


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Nutritional status:

In animals suffering from protein caloric malnutrition,

absorption, distribution, metabolism and excretion processesmay all be impaired.

Starvation for few hours may reduce blood glucose level and

result in decreased amount ofglucuronides formed than thenormal conditions.

Protein deficiency for longer period results in lesser percentage

ofmicrosomal enzyme activity and thus increases in toxicity ofa variety of drugs and poisons.


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For example, paracetamol is more hepatotoxic in protein

deficient animals, possibly due to decreased hepatic

glutathione levels.

Additionally, deficiency of any essential vitamin or trace

elements is injurious in itself.

For example,

vitamins deficiency, especially antioxidant vitamins E and C

can result in increased damage from free radicals.

Dietary deficiency of vitamins (e.g., vitamins A, B2, B3, Cand E) and minerals (e.g., Fe, Ca, Mg, Cu, and Zn) retard

metabolic activity of several enzymes.


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Emotional status and temperament:

This is particularly applicable to centrally acting drugs. Forexample, an excited animal may require higher dose of a CNS

depressant than the animal which is already depressed.

Toxicity of drugs like amphetamine and other CNS stimulantsis affected by crowding (more number of animals per cage),

size of cage, bedding and handling of animals.


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Individual variations:

Individual variations to drugs are common in a homogenouspopulation.

Within a population, some animals are hypersensitive and

some are hyposensitive to drugs.

For example, first generation antihistamines produce variabledegree of drowsiness and sedation in individuals in a

population.


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Pathological states:Liver diseases:

i) Liver diseases may reduce activity ofmicrosomal enzymes,thus altering biotransformation and action of drugs and

toxicants.

ii) Liver diseases can also reduce synthesis ofprotective binding

molecules (e.g., glutathione) allowing increased adverseeffect of drugs.

iii) Reduce synthesis ofplasma proteins, particularly albumin,

may alter the drug binding capacity.

For example, hepatitis impairs biotransformation and prolongsaction of IV anaesthetics as a result of which ultra-short

acting barbiturates become toxic.


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ii) Kidney diseases:

Kidney diseases often result in decreased drug clearance and,

thus slower removal of drug from the body.

A usual dosage regimen in such cases leads to accumulation of

drug in body and ultimately to

toxicity.

Drug induced toxicity in renal insufficiency may also result

either from increased sensitivity to the drug due to uraemia-

induced alterations in tissue receptors or from derangement of

acid-base balance.

For example, in patients with impaired renal function, drugs like

streptomycin, gentamicin, penicillins, etc. may accumulate to

toxic levels in body.

iii) Other diseases:


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iii) Other diseases:

Several GI diseases can alter the absorption rates of drug

administered by oral route. Conditions like diarrhoea and

constipation

Cardiovascular insufficiency either due to cardiac failure or due

to circulatory shock potentially affects disposition of drugs by

altering drug distribution and elimination.

For example, decompensated heart results in decreased volume

of distribution and decreased clearance of several drugs like

lignocaine, procainamide and quinidine.

Similarly, neurological disturbances may influence animal's

response to several CNS acting drugs. Inflammation of meninges

may precipitate toxicity of several drugs (e.g., penicillins) by

allowing their penetration into the brain.


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Ethanol toxicity also increases in winter because cutaneous

vasodilation caused by ethanol results inexcessive heat loss

on exposure to cold.

Toxicity of some insecticides like organochlorines and

pyrethroids show negative correlation with environmental

temperature (more toxic in winter).

However, pesticides like oxidative uncouplers (e.g.

dinitrophenols) increase body temperature and, thus, are

more toxic in hot conditions.


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Li h d h di i


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Light and other radiations:

Radiation exposure is known to affect blood-tissue barriers,

modify enzyme systems and produce disturbances in the

normal excretory pattern of numerous species.

Toxicity of atropine usually increases if the intoxicated animal

is exposed to direct sunlight because the drug has mydriatic and

cycloplegic effects on eyes.

Certain drugs (e.g., phenothiazine, demeclocycline, tar

products) show photosensitization reactions when the

individual is exposed to sunlight or UV radiations.

Whole body irradiation has been shown to produce a dose-

dependent decrease in the pseudocholinesterase activity of ilea

of intestine in rodents thus changing response to drug like

acetylcholine and physostigmine.


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Relative humidity:

Relative humidity might influence the response of some drugs,

especially those applied by dermal routes.

For example, dermal absorption of some ectoparasiticides (e.g.,

organophosphorus insecticides) is more in hot and humid

environment because more blood is diverted to skin (so rapidabsorption) to affect cooling.


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Environmental pollution:

Several chemicals in environment, especially in air and water,

- can substantially alter the pharmacokinetics andpharmacodynamics of many drugs.

Eg:

Insecticides (e.g., DDT) and tobacco smoke-induce drug

metabolism. Chronic exposure to air pollutants (e.g., sulphur oxide gases)

causes thickening of respiratory tract mucous membranes that

may impair absorption and action of some inhalant drugs.

Long-term inhalation of dusts containing minerals andorganic matter produces pulmonary diseases, which may

indirectly affect action of some drugs.


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factors modifying drug effect

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