1. Poisoning by specificpharmaceutical agentsDr. Mohamed shekhani

2. Paracetamol Acetaminophen) is the drug most commonly used in overdose. Toxicity results from formation of an intermediate reactivemetabolite which binds covalently to cellular proteins, causing celldeath , results in hepatic& occasionally renal failure. In therapeutic doses, the toxic intermediate metabolite isdetoxified in reactions requiring glutathione, but in overdose,glutathione reserves become exhausted. 3. Management Activated charcoal used in patients presenting within 1 hour. Antidotes act by replenishing hepatic glutathione. Acetylcysteine IV (or orally in some countries) is highlyefficacious if administered within 8 hours of the overdose. The efficacy declines thereafter, administration should not bedelayed in patients presenting after 8 hours to await aparacetamol blood concentration result. The antidote can be stopped if the paracetamol concentration isshown to be below the appropriate treatment line. The most important adverse effect is related to dose-relatedhistamine release, the anaphy-actoid reaction, with itching /urticaria,in severe cases, bronchospasm/ hypotension,managed bytemporary discontinuation & an antihistamine. An alternative antidote is methionine 2.5 g orally 4-hourly to atotal of four doses, less effective, especially if delayed. 4. Management If a patient presents >15 hours after ingestion, liver functiontests, PT(or INR), renal function tests& a venous bicarbonateshould be measured, the antidote started& a poisons informationcentre or local liver unit contacted for advice if results areabnormal. ABG should be taken in patients with severe liver functionabnormalities; as metabolic acidosis indicates severe poisoning. Liver transplantation should be considered in individuals whodevelop life- threatening liver failure. If multiple ingestions of paracetamol have taken place over severalhours or days (i.e. a staggered overdose), acetylcysteine shouldbe given when the paracetamol dose exceeds 150 mg/kg /anyone 24-hour period or 75 mg/kg in high-risk groups 5. (Salicylates (aspirin Commonly causes nausea, vomiting, sweating, tinnitus ,deafness. Direct stimulation of the respiratory centre produceshyperventilation &respiratory alkalosis. Peripheral vasodilatation with bounding pulses& profuse sweatingoccurs in moderately severe poisoning. Serious salicylate poisoning is associated with metabolic acidosis,hypoprothrombinaemia, hyperglycaemia, hyperpyrexia, renalfailure, pulmonary oedema, shock &cerebral oedema. Agitation, confusion, coma&fits may occur, especially in children. Toxicity is enhanced by acidosis, which increases salicylate transferacross the BBB. 6. Management Activated charcoal should be administered if presents early. Multiple doses of activated charcoal may enhance salicylateelimination but currently are not routinely recommended. The plasma salicylate concentration should be measured atleast 2 (in symptomatic patients) or 4 hours (asymptomaticpatients) after overdose&repeated in patients with suspectedserious poisoning, since it may continue to rise some hours after . In adults, concentrations >500 -700 mg/L suggest serious & life-threatening poisoning respectively, but clinical status is moreimportant assessing severity. Dehydration should be corrected carefully, as there is a risk ofpulmonary oedema. Metabolic acidosis should be identified and treated with iv sodiumbicarbonate (8.4%), once plasma potassium has been corrected. Urinary alkalinisation is indicated for adults if salicylate >500 mg/L. 7. Management Haemodialysis is very effective at removing salicylate&correcting acidbase & fluid balance abnormalities& should beconsidered when : Serum concentrations >700 mg/L in adult patients with severetoxic features Or when there is renal failure Pulmonary oedema, Coma Convulsions Refractory acidosis 8. (Tricyclic antidepressants (TCAs TCAs used frequently in overdose It carries a high morbidity/mortality relating to their sodiumchannel-blocking, anticholinergic &-adrenoceptor-blocking effects 9. Clinical features Anticholinergic effects are common . Life-threatening complications are frequent, including convulsions,coma, arrhythmias (ventricular tachycardia, ventricular fibrillation, less commonly, heart block) & hypotension, which results frominappropriate vasodilatation or impaired myocardial contractility. Serious complications appear to occur more commonly withdosulepin &amitriptyline. 10. Management Activated charcoal should be given if presents sufficiently early. All patients with possible TCAD overdose should have a 12-lead ECG& ongoing cardiac monitoring for at least 6 hours. Prolongation of the QRS interval (especially if > 0.16 s) indicatessevere sodium channel blockade associated with an increasedrisk of arrhythmia . ABGs be measured in patients with suspected severe poisoning. In patients with arrhythmias, severe ECG effects or acidosis, IVsodium bicarbonate (50 mL of 8.4% solution) should beadministered &repeated to correct pH. The correction of the acidosis &sodium loading that result isoften associated with rapid improvement in ECG & arrhythmias. Hypoxia &electrolyte abnormalities should also be corrected. Anti-arrhythmic drugs should only be given on specialist advice. 11. :Cardiotoxic drugs 12. Antipsychotics Often prescribed for patients at high risk of self-harm or suicide,&commonly encountered in overdose. 13. Clinical features Drowsiness, tachycardia,hypotension are frequently found. Anticholinergic features& acute dystonias (e.g. oculogyric crisis,torticollis &trismus) may occur after overdose with typicalantipsychot-ics such as haloperidol or chlorpromazine. QT interval prolongation &torsades de pointes may occur withsome antipsychotics, either typical (e.g. thioridazine,haloperidol) or atypical (e.g. quetiapine, ziprasidone). Convulsions may occur. 14. Management Activated charcoal may be of benefit if given sufficiently early. Cardiac monitoring should be undertaken for at least 6 hours. Management is largely supportive, with treatment directed atcomplications 15. Antidiabetic agents Commonly causing toxicity in over-dose include the sulphonylureas(chlorpropamide, glibenclamide, gliclazide, glipizide, tolbutamide),biguanides (metformin and phenformin)& insulins. 16. Clinical features Sulphonylureas &parenteral insulin cause hypoglycaemia whentaken in overdose, but insulin is non-toxic if ingested. The duration of hypoglycaemia depends on the half-life or releasecharacteristics of the preparation& may be prolonged overseveral days with long-acting agents such as chlorpropamide,insulin zinc suspension or insulin glargine. Features of hypoglycaemia include nausea, agitation, sweating,aggression, behavioural disturbances, confusion, tachycardia,hypothermia, drowsiness, coma or convulsions . Permanent neurological damage can occur if hypoglycaemia isprolonged. Hypoglycaemia can be diagnosed using bedside glucose strips butvenous blood should also be sent for laboratory confirmation. 17. Clinical features Metformin is uncommonly associated with hypoglycaemia. Its major toxic effect in overdose is lactic acidosis, which can beassociated with a high mortality, particularly common in elder&those with renal or hepatic impairment, or ethanolcoingestion. Other featuresare nausea ,vomiting, diarrhoea, abdominal pain,drowsiness, coma, hypotension &CV collapse. 18. Management Activated charcoal should be considered for all patients whopresent within 1 hour of ingestion of a substantial overdose of anoral hypoglycaemic agent. Venous blood glucose, urea, electrolytes should be measured&repeated regularly. Hypoglycaemia should be corrected using oral or IV glucose (50mL of 50% dextrose); an infusion of 1020% dextrose may berequired to prevent recurrence. Intramuscular glucagon can be used as an alternative, especially ifIV access is unavailable. Failure to regain consciousness within a few minutes ofnormalisation of the blood glucose can indicate (CNS) depressanthas also been ingested, the hypoglycaemia has been prolonged,or there is another cause for the coma (e.g. cerebral haem-orrhageor oedema). 19. :Management ABG should be taken after metformin overdose to assess theextent of acidosis. If present, plasma lactate should be measured &acidosis should becorrected with intravenous sodium bicarbonate (e.g. 250 mL 1.26%solution or 50 mL 8.4% solution, repeated as necessary). In severe cases haemodialysis or haemo-diafiltration is used. 20. Organophosphorus (op) insecticides/ nerve agents Widely used as pesticides, especially in developing countries. The case fatality rate following deliberate ingestion of OP pesticidesin devel-oping countries in Asia is 520%. Nerve agents developed for chemical warfare are derived fromOP insecticides but are much more toxic. G agents are volatile, are absorbed by inhalation or via theskin&dissipate rapidly after use. V agents are contact poisons unless aerosolised,contaminateground for weeks or months. The toxicology and management of nerve agent&pesticidepoisoning are similar. 21. Mechanism of toxicity OP compounds phosphonylate the active site ofacetylcholinesterase (AChE), inactivating the enzyme,leading to theaccumulation of acetylcholine (ACh) in cholinergic synapses. Spontaneous hydrolysis of the OP-enzyme complex allowsreactivation of the enzyme. Loss of a chemical group from the OP-enzyme complex preventsfurther enzyme reactivationageing),after which,praladoxime(enzyme reactivator will not be effective) & newenzyme needs to be synthesised before function can be restored.The rate of ageing is is more rapid with dimethyl compounds (3.7hours) than diethyl compounds (31 hours),especially rapid afterexposure to nerve agents (soman in particular), which causeageing within minutes. 22. Clinical features OP poisoning causes an acute cholinergic phase, occasionallyfollowed by the intermediate syndrome or organophosphate-induced delayed polyneuropathy (OPIDN). The onset, severity and duration of poisoning depend on theroute of exposure & agent involved. 23. Clinical features Acute cholinergic syndrome Usually starts within a few minutes of exposure. Nicotinic or muscarinic features may be present. Vomiting ,profuse diarrhoea are typical following oral ingestion. Bronchoconstriction, bronchorrhoea and salivation may causesevere respiratory compromise.Miosis is characteristic &muscle fasciculations strongly suggeststhe diagnosis, although often absent, even in serious poisoning. Subsequently, generalised flaccid paralysis which can affectrespiratory & ocular muscles &result in respiratory failure. Ataxia, coma,convulsions may occur. In severe poisoning, cardiac repolarisation abnormalities& torsadesde pointes may occur. Other early complications include extrapyramidal features, 24. Management If external contamination, further exposure should be prevented,contaminated clothing&contact lenses removed, the skin washedwith soap and water& the eyes irrigated. The airway should be cleared of excessive secretions & high-flow oxygen administered. Intravenous access should be obtained. Gastric lavage or activated charcoal may be considered within 1hour of ingestion. Convulsions should be treated The ECG, oxygen saturation, blood gases, temperature, urea ,electrolytes, amylase, glucose should be monitored closely. Early use of sufficient doses of atropine is potentially lifesaving inpatients with severe toxicity. Atropine reverses ACh-induced bronchospasm 25. Management Atropine reverses ACh-induced bronchospasm,bronchorhea,bradycardia ,hypotension. A marked increase in heart rate associated with skin flushingafter a 1 mg intravenous dose makes OP poisoning unlikely. In OP poisoning, atropine should be administered in doses of 0.62mg i.v., repeated every 1025 mins until secretions arecontrolled, the skin is dry and there is a sinus tachycardia. Large doses may be needed but excessive doses may causeanticholinergic effects. In patients requiring atropine, an oxime such as pralidoximechloride (or obidoxime), if available, should also be administered,as this may reverse or prevent muscle weakness, convulsions orcoma, especially if administered rapidly after exposure. The dose for an adult is 2 g i.v. over 4 mins, repeated 46-hourly. 26. Management Oximes re-activating AChE that has not undergone ageing &areless effective with dimethyl compounds &nerve agents,especially soman. Oximes may provoke hypotension, especially if rapidly. Ventilatory support should be instituted before the patientdevelops respiratory failure . Benzodiazepines may be used to reduce agitation,fasciculations,&treat convulsions&sedate patients during mechanical ventilation. Exposure is confirmed by measurement of plasma(butyrylcholinesterase) or red blood cell cholinesterase activity.,correlate poorly with the severity of clinical features, althoughvalues are usually less than 10% in severe poisoning, 2050% inmoderate poisoning ,> 50% in subclinical poisoning. The acute cholinergic phase usually lasts 4872 hours, with mostpatients requiring intensive cardiorespiratory support& monitoring. 27. Ethylene glycol/Methanol Found in antifreeze, brake fluids and, in lower concentrations,windscreen washes. Methanol is present in some antifreeze products& commercially available industrial solvents, methylated spirits,illi-citly producedalcohol. Both are rapidly absorbed after ingestion. They are converted via alcohol dehydrogenase to toxic metaboliteslargely responsible for their clinical effects. are no longer detectable. 28. Clinical features Early feature: ataxia, drowsiness, dysarthria and nystagmus, oftenassociated with vomiting. As the toxic metabolites are formed, metabolic acidosis,tachypnoea, coma,seizures may develop. Toxic effects of ethylene glycol toxicity include : ophthalmoplegia, cranial nerve palsies, hyporeflexia ,myoclonus. Renal pain / acute tubular necrosis occur because of renalprecipitation of calcium oxalate . Hypocalcaemia, hypomagnesaemia,hyperkalaemia are common. Methanol poisoning features: headache, confusion , vertigo. Visual impairment & photophobia develop. Blindness may be permanent, although some recovery may occur Pancreatitis & abnormal liver function reported. 29. Management Urea, electrolytes, chloride, bicarbonate, glucose, calcium,magnesium, albumin&plasma osmolarity,ABG, should be measuredin all patients. The osmolal & anion gaps should be calculated. Initially, poisoning is associated with an increased osmolar gap, butas toxic metabolites are produced, an increased anion gapassociated with metabolic acidosis will develop. The diagnosis can be confirmed by measurement of ethylene glycolor methanol concentrations,but not widely available. An antidote, either ethanol or fomepizole, should beadministered to all patients with suspected significant exposurewhile awaiting the results of laboratory investigations. These block alcohol dehydrogenase&delay the formation of toxicmetabolites until the drug is eliminated naturally or by dialysis. 30. Management The antidote should be continued until ethylene glycol or methanolconcentrations are undetectable. Metabolic acidosis should be corrected with sodium bicarbonate (e.g. 250 mL of 1.26% solution, repeated as necessary). Convulsions should be treated with an IV benzodiazepine. In ethylene glycol poisoning, hypocalcaemia should only becorrected if there are severe ECG features or seizures occur, sincethis may increase calcium oxalate crystal formation. Haemodialysis or haemodiafiltration should be used in severepoisoning, especially if renal failure is present or there is visualloss in the context of methanol poisoning. It should be continued until acute toxic features are no longerpresent and ethylene glycol or methanol concentrations are notdetectable. 31. CO poisoning CO is a colourless / odourless gas produced by faulty appliancesburning organic fuelsvehicle exhaust fumes,house fires smoke. It causes toxicity by binding with haemoglobin &cytochromeoxidase, which reduces tissue oxygen delivery&inhibits cellularrespiration. It is a common cause of death by poisoning& most patients who die before reaching hospital. 32. CO poisoning: Clinical features Early clinical features : headache, nausea, irritability, weakness& tachypnoea, are non- specific, so correct diagnosis will not beobvious if the exposure is occult, e.g. faulty domestic appliance. Subsequently, ataxia, nystagmus, drowsiness and hyperreflexiamay develop, progressing to coma, convulsions, hypotension,respiratory depression, cardiovascular collapse &death. Myocardial ischaemia may result in arrhythmias or AMI. Cerebral oedema is common &rhabdomyolysis may lead tomyoglobinuria &renal failure. In those who recover from acute toxicity, longer-termneuropsychiatric effects are common,as personality change,memory loss , concentration impairment,extrapyramidal effects,urinary or faecal incontinence, gait disturbance. Poisoning during pregnancy may cause fetal hypoxia& intrauterinedeath. 33. CO poisoning: Management Patients should be removed from exposure as soon as possible&resuscitated as necessary. Oxygen should be administered in as high a concentration aspossible via a tightly fitting facemask, as this reduces the half-life of carboxyhaemoglobin from 46 hours to about 40minutes. Measurement of carb-oxyhaemoglobin is useful for confirmingexposure, but results do not correlate well with the severity ofpoisoning, partly because concentrations fall rapidly after removalof the patient from exposure, especially if supplemental oxygen hasbeen given. An ECG should be performed in all patients with acutepoisoning, especially those with pre-existing heart disease. Arterial blood gas analysis should be checked in those with seriouspoisoning. 34. CO poisoning: Management Oxygen saturation readings by pulse oximetry are misleadingsince both carboxyhaemoglobin &oxyhaemoglobin are measured. Excessive IVF should be avoided, particularly in the elderly,because of the risk of pulmonary & cerebral oedema. Convulsions should be controlled with diazepam. Hyperbaric oxygen therapy is controversial. In theory, at 2.5 atmospheres, it reduces the half-life ofcarboxyhae-moglobin to 20 minutes& increases the amount ofdissolved oxygen by a factor of 10. 35. Single-best choice MCQs: 1.The antidote of paracetamol can be only be given: A.Oraly alone. B. IV alone. C.Rectally. D.IM. E. IV / or orally. 36. Single-best choice MCQs: 2. The antidote of paracetamol: A.Replenishes glutathione liver stores. B. Activates drug metabolizing enzymes. C. Inhibits drug metabolizing enzyme. D.All. E.None. 37. Single-best choice MCQs: 3. The paracetamol antidote should be given within: A. 16 hours. B. 4 hours. C. 8 hours. D. 24 hours. E.35 hours. 38. Single-best choice MCQs: 4.Paracetamol drug level in paracetamol poisoning is bestmeasured after ingestion of: A. 16 hours. B. 4 hours. C. 8 hours. D. 24 hours. E.35 hours. 39. Single-best choice MCQs: 5.Paracetamol poisoning causes: A.Heopatic failure alone. B. Renal failure. C. Both. D. Neither. E. Respiratory failure. 40. Single-best choice MCQs: 6.High risk for paracetamol poisoning with lower doses include allthe following except: A. Chronic alcoholics. B. Eating disorders patients. C. Epileptics on treatment. D. Asthmatics. E. Maluarished persons. 41. Single-best choice MCQs: 7. In symptomatic aspirin poisoning patients drug level is best takenafter ingestion of: A. 2 HOURS. B.4 hours. C.6 hours. D.8 hours. E.10 hours. 42. Single-best choice MCQs: 8. In symptomatic aspirin poisoning patients, hemodialysis isindicated if blood level is above: A. 400 mgm/l. B. 300 mgm/l. C 200 mgm/l. D. 600 mgm/l. E. 700 mgm/l. 43. Single-best choice MCQs: 9. The most serious effects of aspirin poisoning is: A. Hypoglycemia. B.Hypocalcemia. C. Metabolic acidosis. D. Respiratory alkalosis. E.Bleeding tendencies. 44. Single-best choice MCQs: 10.All these drugs are cardiotoxic if taken in overdose except: A.Trcyclic antidepressants. B.Antipsychotics. C. CO. D.Paracetamol. E.SSRI. 45. Single-best choice MCQs: 11.Oximes are least effects in organophosphorous poisoning with: A. Soman. B.Dimethyl compounds. C. Diethyl compounds. D. All. E.None. 46. Single-best choice MCQs: 12.CO poisoning is best diagnosed by: A.Pulseoximetry. B. Carboxyhemoglobin blood level. C. Clinical features. D.All. E.Neither. 47. Single-best choice MCQs: 13. CO poisoning is best treated by: A. Usual ward oxygen. B. Hyperbaric oxygen. C. Only supportive measures. D. All. E. None.