Poisoning by specific pharmaceutical agents Dr. Mohamed shekhani.

Poisoning by specific pharmaceutical agents

Dr. Mohamed shekhani

Paracetamol

• Acetaminophen) is the drug most commonly used in overdose. • Toxicity results from formation of an intermediate reactive

metabolite which binds covalently to cellular proteins, causing cell death , results in hepatic& occasionally renal failure.

• In therapeutic doses, the toxic intermediate metabolite is detoxified in reactions requiring glutathione, but in overdose, glutathione reserves become exhausted.

• Activated charcoal used in patients presenting within 1 hour. • Antidotes act by replenishing hepatic glutathione. • Acetylcysteine IV (or orally in some countries) is highly efficacious if

administered within 8 hours of the overdose. • The efficacy declines thereafter, administration should not be delayed in

patients presenting after 8 hours to await a paracetamol blood concentration result.

• The antidote can be stopped if the paracetamol concentration is shown to be below the appropriate treatment line.

• The most important adverse effect is related to dose-related histamine release, the ‘anaphy-actoid’ reaction, with itching / urticaria,in severe cases, bronchospasm/ hypotension,managed by temporary discontinuation & an antihistamine.

• An alternative antidote is methionine 2.5 g orally 4-hourly to a total of four doses, less effective, especially if delayed.

Management

• If a patient presents >15 hours after ingestion, liver function tests, PT(or INR), renal function tests& a venous bicarbonate should be measured, the antidote started& a poisons information centre or local liver unit contacted for advice if results are abnormal.

• ABG should be taken in patients with severe liver function abnormalities; as metabolic acidosis indicates severe poisoning.

• Liver transplantation should be considered in individuals who develop life- threatening liver failure.

• If multiple ingestions of paracetamol have taken place over several hours or days (i.e. a staggered overdose), acetylcysteine should be given when the paracetamol dose exceeds 150 mg/kg /any one 24-hour period or 75 mg/kg in ‘high-risk groups’

Management

• Commonly causes nausea, vomiting, sweating, tinnitus , deafness.

• Direct stimulation of the respiratory centre produces hyperventilation &respiratory alkalosis.

• Peripheral vasodilatation with bounding pulses& profuse sweating occurs in moderately severe poisoning.

• Serious salicylate poisoning is associated with metabolic acidosis, hypoprothrombinaemia, hyperglycaemia, hyperpyrexia, renal failure, pulmonary oedema, shock &cerebral oedema.

• Agitation, confusion, coma&fits may occur, especially in children. • Toxicity is enhanced by acidosis, which increases salicylate transfer

across the BBB.

Salicylates (aspirin)

• Activated charcoal should be administered if presents early. • Multiple doses of activated charcoal may enhance salicylate elimination

but currently are not routinely recommended.• The plasma salicylate concentration should be measured at least 2 (in

symptomatic patients) or 4 hours (asymptomatic patients) after overdose&repeated in patients with suspected serious 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 more important assessing severity.

• Dehydration should be corrected carefully, as there is a risk of pulmonary oedema.

• Metabolic acidosis should be identified and treated with iv sodium bicarbonate (8.4%), once plasma potassium has been corrected.

• Urinary alkalinisation is indicated for adults if salicylate >500 mg/L.

Management

• Haemodialysis is very effective at removing salicylate &correcting acid–base & fluid balance abnormalities& should be considered when :

• Serum concentrations >700 mg/L in adult patients with severe toxic features

• Or when there is renal failure• Pulmonary oedema,• Coma• Convulsions• Refractory acidosis

Management

• TCAs used frequently in overdose • It carries a high morbidity/mortality relating to their sodium

channel-blocking, anticholinergic &α-adrenoceptor-blocking effects

Tricyclic antidepressants (TCAs)

• Anticholinergic effects are common . • Life-threatening complications are frequent, including convulsions,

coma, arrhythmias (ventricular tachycardia, ventricular fibrillation , less commonly, heart block) & hypotension, which results from inappropriate vasodilatation or impaired myocardial contractility.

• Serious complications appear to occur more commonly with dosulepin &amitriptyline.

Clinical features

• 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) indicates severe

sodium channel blockade associated with an increased risk of arrhythmia .

• ABGs be measured in patients with suspected severe poisoning.• In patients with arrhythmias, severe ECG effects or acidosis, IV sodium

bicarbonate (50 mL of 8.4% solution) should be administered &repeated to correct pH.

• The correction of the acidosis &sodium loading that result is often associated with rapid improvement in ECG & arrhythmias.

• Hypoxia &electrolyte abnormalities should also be corrected. • Anti-arrhythmic drugs should only be given on specialist advice. • Prolonged convulsions should be treated with IV benzodiazepines.

Management

Cardiotoxic drugs:

• Often prescribed for patients at high risk of self-harm or suicide, &commonly encountered in overdose.

Antipsychotics

• Drowsiness, tachycardia,hypotension are frequently found. • Anticholinergic features& acute dystonias (e.g. oculogyric crisis,

torticollis &trismus) may occur after overdose with typical antipsychot-ics such as haloperidol or chlorpromazine.

• QT interval prolongation &torsades de pointes may occur with some antipsychotics, either typical (e.g. thioridazine, haloperidol) or atypical (e.g. quetiapine, ziprasidone).

• Convulsions may occur.

Clinical features

• 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 at

complications

Management

• Commonly causing toxicity in over-dose include the sulphonylureas (chlorpropamide, glibenclamide, gliclazide, glipizide, tolbutamide), biguanides (metformin and phenformin)& insulins.

Antidiabetic agents

• Sulphonylureas &parenteral insulin cause hypoglycaemia when taken in overdose, but insulin is non-toxic if ingested.

• The duration of hypoglycaemia depends on the half-life or release characteristics of the preparation& may be prolonged over several 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 is prolonged.

• Hypoglycaemia can be diagnosed using bedside glucose strips but venous blood should also be sent for laboratory confirmation.

Clinical features

• Metformin is uncommonly associated with hypoglycaemia. • Its major toxic effect in overdose is lactic acidosis, which can be

associated with a high mortality, particularly common in elder &those with renal or hepatic impairment, or ethanol coingestion.

• Other featuresare nausea ,vomiting, diarrhoea, abdominal pain, drowsiness, coma, hypotension &CV collapse.

Clinical features

• Activated charcoal should be considered for all patients who present within 1 hour of ingestion of a substantial overdose of an oral hypoglycaemic agent.

• Venous blood glucose, urea, electrolytes should be measured &repeated regularly.

• Hypoglycaemia should be corrected using oral or IV glucose (50 mL of 50% dextrose); an infusion of 10–20% dextrose may be required to prevent recurrence.

• Intramuscular glucagon can be used as an alternative, especially if IV access is unavailable.

• Failure to regain consciousness within a few minutes of normalisation of the blood glucose can indicate (CNS) depressant has also been ingested, the hypoglycaemia has been prolonged, or there is another cause for the coma (e.g. cerebral haem-orrhage or oedema).

Management

• ABG should be taken after metformin overdose to assess the extent of acidosis.

• If present, plasma lactate should be measured &acidosis should be corrected 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.

Management:

• Widely used as pesticides, especially in developing countries. • The case fatality rate following deliberate ingestion of OP pesticides

in devel-oping countries in Asia is 5–20%.• Nerve agents developed for chemical warfare are derived from

OP insecticides but are much more toxic. • ‘G’ agents are volatile, are absorbed by inhalation or via the

skin&dissipate rapidly after use. • ‘V’ agents are contact poisons unless aerosolised,contaminate

ground for weeks or months.• The toxicology and management of nerve agent&pesticide

poisoning are similar.

Organophosphorus (op) insecticides/ nerve agents

• OP compounds phosphonylate the active site of acetylcholinesterase (AChE), inactivating the enzyme,leading to the accumulation of acetylcholine (ACh) in cholinergic synapses.

• Spontaneous hydrolysis of the OP-enzyme complex allows reactivation of the enzyme.

• Loss of a chemical group from the OP-enzyme complex prevents further enzyme reactivation‘ageing’),after which, praladoxime(enzyme reactivator will not be effective) & new enzyme needs to be synthesised before function can be restored. The rate of ageing is is more rapid with dimethyl compounds (3.7 hours) than diethyl compounds (31 hours),especially rapid after exposure to nerve agents (soman in particular), which cause ageing within minutes.

Mechanism of toxicity

• OP poisoning causes an acute cholinergic phase, occasionally followed by the intermediate syndrome or organophosphate-induced delayed polyneuropathy (OPIDN).

• The onset, severity and duration of poisoning depend on the route of exposure & agent involved.

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 cause severe

respiratory compromise. • Miosis is characteristic &muscle fasciculations strongly suggests the diagnosis,

although often absent, even in serious poisoning. • Subsequently, generalised flaccid paralysis which can affect respiratory &

ocular muscles &result in respiratory failure. • Ataxia, coma,convulsions may occur. • In severe poisoning, cardiac repolarisation abnormalities& torsades de pointes

may occur. • Other early complications include extrapyramidal features, pancreatitis,

hepatic dysfunction &pyrexia.

Clinical features

• If external contamination, further exposure should be prevented, contaminated clothing&contact lenses removed, the skin washed with 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 1 hour 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 in

patients with severe toxicity. • Atropine reverses ACh-induced bronchospasm

Management

• Atropine reverses ACh-induced bronchospasm,bronchorhea, bradycardia ,hypotension.

• A marked increase in heart rate associated with skin flushing after a 1 mg intravenous dose makes OP poisoning unlikely.

• In OP poisoning, atropine should be administered in doses of 0.6–2 mg i.v., repeated every 10–25 mins until secretions are controlled, the skin is dry and there is a sinus tachycardia.

• Large doses may be needed but excessive doses may cause anticholinergic effects.

• In patients requiring atropine, an oxime such as pralidoxime chloride (or obidoxime), if available, should also be administered, as this may reverse or prevent muscle weakness, convulsions or coma, especially if administered rapidly after exposure.

• The dose for an adult is 2 g i.v. over 4 mins, repeated 4–6-hourly.

Management

• Oximes re-activating AChE that has not undergone ‘ageing’ &are less effective with dimethyl compounds &nerve agents, especially soman.

• Oximes may provoke hypotension, especially if rapidly.• Ventilatory support should be instituted before the patient develops

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, although values are usually less than 10% in severe poisoning, 20–50% in moderate poisoning ,> 50% in subclinical poisoning.

• The acute cholinergic phase usually lasts 48–72 hours, with most patients requiring intensive cardiorespiratory support& monitoring.

Management

• 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 produced alcohol.

• Both are rapidly absorbed after ingestion. • They are converted via alcohol dehydrogenase to toxic metabolites

largely responsible for their clinical effects.• are no longer detectable.

Ethylene glycol/Methanol

• Early feature: ataxia, drowsiness, dysarthria and nystagmus, often associated 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 renal precipitation

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.

Clinical features

• Urea, electrolytes, chloride, bicarbonate, glucose, calcium, magnesium, albumin&plasma osmolarity,ABG, should be measured in all patients.

• The osmolal & anion gaps should be calculated. • Initially, poisoning is associated with an increased osmolar gap, but as

toxic metabolites are produced, an increased anion gap associated with metabolic acidosis will develop.

• The diagnosis can be confirmed by measurement of ethylene glycol or methanol concentrations,but not widely available.

• An antidote, either ethanol or fomepizole, should be administered to all patients with suspected significant exposure while awaiting the results of laboratory investigations.

• These block alcohol dehydrogenase&delay the formation of toxic metabolites until the drug is eliminated naturally or by dialysis.

Management

• The antidote should be continued until ethylene glycol or methanol concentrations 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 be

corrected if there are severe ECG features or seizures occur, since this may increase calcium oxalate crystal formation.

• Haemodialysis or haemodiafiltration should be used in severe poisoning, especially if renal failure is present or there is visual loss in the context of methanol poisoning.

• It should be continued until acute toxic features are no longer present and ethylene glycol or methanol concentrations are not detectable.

Management

• CO is a colourless / odourless gas produced by faulty appliances burning organic fuelsvehicle exhaust fumes,house fires smoke.

• It causes toxicity by binding with haemoglobin &cytochrome oxidase, which reduces tissue oxygen delivery&inhibits cellular respiration.

• It is a common cause of death by poisoning& most patients who die before reaching hospital.

CO poisoning

• Early clinical features : headache, nausea, irritability, weakness& tachypnoea, are non- specific, so correct diagnosis will not be obvious if the exposure is occult, e.g. faulty domestic appliance.

• Subsequently, ataxia, nystagmus, drowsiness and hyperreflexia may 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 to

myoglobinuria &renal failure. • In those who recover from acute toxicity, longer-term neuropsychiatric

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& intrauterine death.

CO poisoning: Clinical features

• Patients should be removed from exposure as soon as possible &resuscitated as necessary.

• Oxygen should be administered in as high a concentration as possible via a tightly fitting facemask, as this reduces the half-life of carboxyhaemoglobin from 4–6 hours to about 40 minutes.

• Measurement of carb-oxyhaemoglobin is useful for confirming exposure, but results do not correlate well with the severity of poisoning, partly because concentrations fall rapidly after removal of the patient from exposure, especially if supplemental oxygen has been given.

• An ECG should be performed in all patients with acute poisoning, especially those with pre-existing heart disease.

• Arterial blood gas analysis should be checked in those with serious poisoning.

CO poisoning: Management

• Oxygen saturation readings by pulse oximetry are misleading since 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 of

carboxyhae-moglobin to 20 minutes& increases the amount of dissolved oxygen by a factor of 10.

CO poisoning: Management

• 1.The antidote of paracetamol can be only be given:• A.Oraly alone.• B. IV alone.• C.Rectally.• D.IM.• E. IV / or orally.

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.


• 3. The paracetamol antidote should be given within:• A. 16 hours.• B. 4 hours.• C. 8 hours.• D. 24 hours.• E.35 hours.


• 4.Paracetamol drug level in paracetamol poisoning is best measured after ingestion of:

• A. 16 hours.• B. 4 hours.• C. 8 hours.• D. 24 hours.• E.35 hours.


• 5.Paracetamol poisoning causes:• A.Heopatic failure alone.• B. Renal failure.• C. Both.• D. Neither.• E. Respiratory failure.


• 6.High risk for paracetamol poisoning with lower doses include all the following except:

• A. Chronic alcoholics.• B. Eating disorders patients.• C. Epileptics on treatment.• D. Asthmatics.• E. Maluarished persons.


• 7. In symptomatic aspirin poisoning patients drug level is best taken after ingestion of:

• A. 2 HOURS.• B.4 hours.• C.6 hours.• D.8 hours.• E.10 hours.


• 8. In symptomatic aspirin poisoning patients, hemodialysis is indicated 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.


• 9. The most serious effects of aspirin poisoning is:• A. Hypoglycemia.• B.Hypocalcemia.• C. Metabolic acidosis.• D. Respiratory alkalosis.• E.Bleeding tendencies.


• 10.All these drugs are cardiotoxic if taken in overdose except:• A.Trcyclic antidepressants.• B.Antipsychotics.• C. CO.• D.Paracetamol.• E.SSRI.


• 11.Oximes are least effects in organophosphorous poisoning with:• A. Soman.• B.Dimethyl compounds.• C. Diethyl compounds.• D. All.• E.None.


• 12.CO poisoning is best diagnosed by:• A.Pulseoximetry.• B. Carboxyhemoglobin blood level.• C. Clinical features.• D.All.• E.Neither.


• 13. CO poisoning is best treated by:• A. Usual ward oxygen.• B. Hyperbaric oxygen.• C. Only supportive measures.• D. All.• E. None.


Poisoning by specific pharmaceutical agents Dr. Mohamed shekhani.

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