TOXICOLOGY

Contents Toxicology .................................................................................................................................. 2

Defination ................................................................................................................................... 2

Toxicokinetics ............................................................................................................................ 2

Absorption into the body ......................................................................................................... 2

Distribution within the body ..................................................................................................... 2

Metabolism/ biotransformation of toxic substances ................................................................. 2

Toxicodynamics ......................................................................................................................... 2

Management of the Poisoned Patient ........................................................................................ 3

The initial management .......................................................................................................... 3

History and Physical Examination ........................................................................................... 3

History ................................................................................................................................ 3

Physical Examination .......................................................................................................... 3

Laboratory and Imaging Procedures ....................................................................................... 4

Artial Blood Gas .................................................................................................................. 4

Electrolytes ......................................................................................................................... 4

Renal funtion test ................................................................................................................ 5

Serum osmolality ................................................................................................................ 5

Electrocardiagram ............................................................................................................... 5

Imaging finding ................................................................................................................... 5

Decontamination .................................................................................................................... 5

Skin ..................................................................................................................................... 5

GIT...................................................................................................................................... 5

Method of enhancing elimination of toxiin ............................................................................... 5

Peritoneal dialysis ............................................................................................................... 5

Hemodialysis ...................................................................................................................... 5

TOXICOLOGY

Defination The study of the symptoms, mechanism, diagnosis and treatment or management of biological poison. Toxicology is the study of how natural or man-made poisons cause undesirable effects in living organisms chemicals could be toxic but the degree of harm that a chemical can inflict on a human or any other living being depends on the dose or the degree of exposure as well as on other factors. In other words the risk (i.e. that product of the likelihood and the severity of harm) from a toxic hazard depends on the exposure. Over 1 million cases of acute poisoning occur in the USA each year, although only small number are fetal. Most death are due to intentional suicidal overdose by an adolescent or adult. Childhood deaths due to accidental ingestion of the drug or toxic household products.

Toxicokinetics Absorption into the body

As a general rule, fat soluble liquids are readily absorbed through the skin and fat soluble vapours are readily absorbed through the lungs. Notably these routes apply to organic solvents such as hexane, toluene, trichlorethylene and many others.

Distribution within the body Many factors affect the distribution of a toxic substance but water or fat solubility is very important. Thus for example water soluble compounds of lead are found (amongst other places) in the red blood cells, while fat soluble ones concentrate in the central nervous system (CNS). The distribution of a toxic substance determines its concentration at a particular tissue and therefore the number and type of cells exposed to high concentrations of it.

Metabolism/ biotransformation of toxic substances Toxic substances may be converted into other substances (metabolites) by organs such as the liver and kidneys Thus non-polar and therefore not water soluble organic compounds tend to be oxidised within the liver e.g.:

trichloroethane oxidised to trichloroethanol trichloroacetaldehyde and trichloroacetic acid dichloromethane (methylene chloride CH2Cl2) oxidised to carbon monoxide (CO)

Water soluble metabolites are then more easily excreted by the kidney Metabolism or biotransformation does not necessarily result in less toxic compunds. For example benzene may be oxidised to an expoxide which then inflicts damage on the DNA in genes, i.e. it is genotoxic and hence carcinogenic

Toxicodynamics Acute effects refer to the short term consequences of exposure.Chronic effects relate to a much longer time scale, while sub-acute are in between acute and chronic). Some effects may be dose related - the higher the exposure the worse it gets e.g. irritant effects on the skin, asthma, asbestosis etc. Other effects are 'all or none' and for a given exposure there is an element of chance (stochastic) as to whether or not the disease develops.For example, the development of cancer (carcinogenesis) or some forms of developmental damage to the foetus (teratogenesis)

An understanding of common mechanisms of death due to poisoning can help prepare the caregiver to treat patient effectively. Many toxins depress the CNS, resulting in coma. Comatose patients frequently lose their airway protective reflexes and their respiratory drive. Thus, they may die as a result of airway obstruction by flaccid tongue, aspiration of gastric contents in the tracheobronchial tree, or respiratory arrest. E.g Narcotics, sedative and hypnotics. Cardiovascular toxicity is also frequently encountered in poisoning. Peripheral vascular colapse due to the blockage of -adrenoreceptor mediated vascular tone or cardiac arrhythmias. Lethal arrhythmias such as ventricular tachcardia and fibrilation can occur with overdoses of many cardioactive drugs such as ephedrine, amphetamine, cocaine, digitalis nad theophylline. Seizures, muscular hyperactivity, and rigidity may result in the death. Seizure may cause pulmonary aspiration, hypoxia and brain damage. Drugs and poison that often cause seizure include antidepressant, cocaine, INH, diphenhydramine. Finally, some patient may die before hospitalization because the behavioral effects of ingested drug may result in traumatic injury. Intoxication of alcohol and other sedative and hypnotic drugs is a common contributing factor to motor vehicle accidents.

Management of the Poisoned Patient The initial management

The initial management of a patient with coma, seizures, or otherwise altered mental status should follow the same approach regardless of the poison involved: Supportive measures are the basic (ABCD) A-Airway should be cleared of vomitus or any other obstruction and an oral airway or endotracheal tube inserted if needed. B- Breathing should be assessed by the observation and pulse oximetry. If doubt the patient should be intubated and mechanically ventilated. C-Circulation- should be assessed by the continous monitoring of pulse rate, blood pressure, urinary output and evaluation of peripheral perfusion. An intravenous line should be placed and blood drawn for serum glucose and other routine determination. D-Dextrose- Every patient with altered mental status should receive a challenge with concentrated dextrose unless the a rapid bedside blood glucose test demonstrates that the patient is not hypoglcemic. Adult are given 50ml of 50% dextrose solution intravenously. Children 0.5mg/kg. The opioid antagonist naloxone may be given in a dose of 0.4-2 mg intravenously. Naloxone reverses respiratory and CNS depression due to all verities of opioid drugs.

History and Physical Examination Once the essential initial ABCD intervention have been instituted, one can begin in more detailed evaluation to make a specific diagnosis.

History oral statement about the amount of drug and even the type of drug ingested in toxic emergencies may be unreliable. Even so, family members , police, and fire department or paramedical personnel should be asked to described the environment in which the toxic emergencies occured

Physical Examination A brief examination should be performed, emphasizing those areas most likely to give clue to the toxicological diagnosis. These include, Vital Sign- Careful evaluation of vital sign (BP, pulse, respiration, and temperature) is essential in all toxicologic emergencies.

Hypertension and tachycardia are typical indication of amphetamines, cocaine. Hypertension and bradycardia are indication of CCBs and beta blockers. Rapid respiration are the typical sign of salicylate and carbon monoxide toxicity. Eye- The eye are the valuable source of toxicologic information. Constriction of pupils(miosis) is typical of opioid , clonidine, phenothiazine and deep coma due to sedative drugs. Mydriasis is common with amphetamines ,cocaine ,LSD and atropine Horizontal nsytagmus is characteristic of intoxication with phenytoin, alcohol, barbiturate and other sedative drugs. The presence of both vertical and horizontal nystagmus is strongly sugesstive of phencycylidine poisoning. Mouth- The mouth may show the sign of burn due to corrosive substances or soot from smoke inhalation Typical order of alcohol, hydrocarbon sovents, or ammonia may be noted. Skin- The skin often appears flushed, hot, and dry in poisoning with atropine and other antmuscranic. Exessive sweating occurs with organophosphate, nicotine and sympathomimatic drugs. Cyanosis may be caused by hypoxemia or by the methemoglobinemia. Abdomen- Abdominal examination may reveal ileus, which is typical of poisoning with antimuscarinic, opioid, and sedative drugs. Hyperactive bowel sounds, cramping and diarrhea are common in poisoning with organophosphate, iron, theophylline. Nervous System-A careful neurological examination is essential. Focal seizure or motor deficits suggest a structural lesion (intracranial hamorrhage) Nystagmus, dysartria and ataxia are typical of phenytoin, carbamazepine, alcohol and other sedative intoxication.

Laboratory and Imaging Procedures Artial Blood Gas

Hypoventilation result in an elevated PCO2 (hypercapnia) and low PO2 (hypoxia). The PO2 may also be low with aspiration pneumonia or drug-induced pulmonary edema. Poor tissue oxygenation due hypoxia, hypotension, or cyanide poisoning will result in metabolic acidosis. PO2 measure only oxygen dissolved in the plasma and not total blood oxygen content or oxyhemoglobin saturation. It may appear normal in patient with severe carbon monoxide poisoning. Plus oximetry may also falsely normal results in carbon monooxide intoxication

Electrolytes Sodium, potassium, chloride, and bicarbonate should be measured. The anion gap is then calculated by subtracting the measured anion from cations: Anion gap=(Na+ + K+)-(HCO- + Cl-) Normally, the sum of the cations exceeds the sum of the anions by no more than 12-16 m/Eq/L(or 8-12 mEq/L if the formula used for estimating the anion gap omits the potassium level. A large than expected anions gap is caused by the presence of unmeasured anions (lactate etc) accompanying metabolic acidosis. This may occur with numerous conditions., such as diabetic ketoacidosis, renal failure, or shock induced lactic acidosis. Drugs that may induce an elevated anion gap metabolic acidosis include metformin, methanol, ethylene glycol, isoniazid, and iron. Alteration in the serum potassium level are hazardous because they can result in cardiac arrhythmias.

Drugs that may cause hyperkalemia despite normal renal function include potassium itself, blockers, digitalis glycoside, potassium sparing diuretic.

Renal funtion test Some toxins have direct nepherotoxic effects, in other cases renal failure is due to shock or myoglobinouria. Blood urea nitrigen and creatinine levels should measured and urinalysis performed Elevated serum creatinne kinase (CK) and myoglobin in the urine indicate the muscle necrosis due to seizure or muscular rigidity. Oxalate crstals in large numbers in the urine suggest ethylene glycol poisoning.

Serum osmolality The calculated serum osmolality is dependent mainly on the serum sodium and glucose and the blood urea nitrogen and can be estimated from the following. 2 Na+ (mEq/L)+Glucose (mg/dL) + BUN(mg/dL)

18 3 The calculated value is normally 280-290 mOsm/L. ethanol and other alcohol may contribute significantly to the measured serum osmolality but, since they are not included in the calulation, cause an osmal gap: Osmolar gap= measured osmolality calculated osmolality

Electrocardiagram Widening of the QRS complex duration(to more than 100 milisecond) is typical of tricyclic antidepressant and qunindine overdose. The QTc interval may be prolonged (to more than 440 milliseconds) in many poisonings, including qunindine, antidepressant, antipsychotics, lithium and arsenic

Imaging finding Plain film of abdomen particularly for iron and potassium may radiopaque. Chest X-rays for aspiration pneumonia, hydrocarbon pneumonia or pulmonary edema. CT scan for head trauma

Decontamination Skin GIT

Emesis Gastric lavage Activated charcoal Cathartic

Method of enhancing elimination of toxiin Dialysis procedure

Peritoneal dialysis Hemodialysis

B. Forced diuresis and pH manipulation