Poisoning by specific drugs (including substances of abuse) - clinical features and treatment Amfetamines to diuretics - technical
Amfetamines and ecstasy (MDMA)
Amfetamines, particularly metamfetamine (‘crystal meth’, ‘ice’) and MDMA, are abused widely. Features of poisoning are related predominantly to stimulation of central and peripheral adrenergic receptors and, in addition, hyperthermia and hyponatraemia (secondary to inappropriate ADH secretion) may develop in severe MDMA toxicity. Poisoning is usually the result of recreational use.
These drugs cause increased alertness and self-confidence, euphoria, extrovert behaviour, increased talkativeness with rapid speech, lack of desire to eat or sleep, tremor, dilated pupils, tachycardia, and hypertension. More severe intoxication is associated with excitability, agitation, paranoid delusions, hallucinations with violent behaviour, hypertonia, and hyperreflexia. Convulsions, rhabdomyolysis, hyperthermia, and cardiac arrhythmias may develop in the most severe cases. Rarely, intracerebral and subarachnoid haemorrhage and acute cardiomyopathy occur and may be fatal.
In the case of MDMA, hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure, and hyponatraemia are observed commonly in severe cases, in addition to those features described earlier. Death occurred in 2 of 17 patients with serum sodium concentrations of 107 to 128 mmol/litre. Their clinical course was remarkably similar; initial vomiting and disturbed behaviour was followed by seizures, drowsiness, a mute state, and disorientation. Severe hepatic damage, including fulminant hepatic failure, has also been reported. The serotonin syndrome has been described.
Intravenous fluids should be given for dehydration. Diazepam 10 to 20 mg intravenously or haloperidol 2.5 to 5.0 mg intramuscularly or intravenously are effective in controlling agitation. The peripheral sympathomimetic actions of amfetamines may be antagonized by β-adrenergic blocking drugs. Although acidification of the urine increases renal elimination of amfetamines, sedation is usually all that is required. Dantrolene 1 mg/kg intravenous should be administered for hyperthermia. In most cases, hyponatraemia responds to fluid restriction alone. Transplantation may be indicated in patients who develop MDMA-induced fulminant hepatic failure.
Angiotensin-converting enzyme (ACE) inhibitors
Overdose commonly causes hypotension and occasional drowsiness. Heart rate is rarely raised above 100 to 120 bpm. Angioedema and metabolic changes, specifically moderate increases in serum potassium, are also seen. The fall in blood pressure is often much greater than from therapeutic doses, and the suggestion that ACE inhibitors have a ‘ceiling’ effect on blood pressure is clearly incorrect.
ACE inhibitors are likely to bind to activated charcoal, which should be administered in early presentations. The principles of supportive care include volume expansion and subsequent use of inotropes. Since most patients who take this overdose are on treatment for hypertension or heart failure, they may already have impaired myocardial function. Naloxone does not correct hypotension.
Since ACE inhibitors are teratogenic, women exposed in the first trimester of pregnancy need appropriate counselling. They also cause in utero growth retardation.
Clinical features and management
Antibiotic overdose is usually asymptomatic and requires no treatment. Transient nausea, vomiting, and diarrhoea may occur, or adverse effects of therapeutic doses may be exaggerated. There have been single case reports of renal failure after overdosage with co-trimoxazole or aminoglycosides, pancreatitis with erythromycin, haemorrhagic cystitis with amoxicillin, and seizures with other β-lactam antibiotics.
The principal sign of rifampicin poisoning is the colouration of body fluids including sweat and saliva, which become orange-red in colour. These appearances are due to the colouration of the drug and its metabolites, but do not in themselves indicate toxicity. At high concentrations, nausea, vomiting and abdominal pain, and convulsions have been observed. Hepatic induction is seen with rifampicin, and this also results in hepatitis in occasional patients. Changes in liver function tests usually resolve over 72 h.
This is supportive and usually no intervention is necessary.
Carbamazepine is structurally related to the tricyclic antidepressants and has similar anticholinergic actions. Overdose causes dry mouth, coma, convulsions, nystagmus, ataxia, and incoordination. The pupils are often dilated, divergent strabismus may be present, and complete external ophthalmoplegia has been reported. Hallucinations may occur, particularly in the recovery phase.
MDAC has been shown to significantly increase elimination of carbamazepine and is as effective as charcoal haemoperfusion. Activated charcoal should therefore be given in severe cases of carbamazepine poisoning in an initial dose of 50 to 100 g for adults, with repeated doses of 12.5 g/h (or the equivalent).
Acute overdose results in nausea, vomiting, headache, tremor, cerebellar ataxia, nystagmus, and rarely, loss of consciousness. Management MDAC may increase elimination though this has not been confirmed.
Most frequently there is drowsiness, impairment of consciousness, and respiratory depression. In severe poisoning, myoclonic jerks and seizures may occur and cerebral oedema has been reported. Liver damage and metabolic acidosis, perhaps due to changes in fatty acid metabolism, are very unusual but potential complications.
Treatment is symptomatic and supportive. Haemodialysis is effective in removing sodium valproate and should be employed in severe poisoning, particularly if severe hyperammonaemia and electrolyte and acid–base disturbances are present.
Clinical features and management
Lethargy, ataxia, slurred speech, and gastrointestinal symptoms may develop. Management is supportive. Lamotrigine Clinical features and management Lethargy, coma, ataxia, nystagmus, seizures, and cardiac conduction abnormalities have been reported. Management is supportive.
Clinical features and management
Lethargy, coma, and respiratory depression have been observed. Management is supportive.
Clinical features and management
Lethargy, facial grimacing, nystagmus, posturing, agitation, coma, hallucinations, and seizures have been reported. Management is supportive.
Clinical features and management
Lethargy, ataxia, nystagmus, myoclonus, coma, seizures, and a normal anion gap metabolic acidosis have been observed; the latter may be due to inhibition of renal cortical carbonic anhydrase. Metabolic acidosis can appear within hours of ingestion and persist for days. Management is supportive.
These fall into a variety of pharmacological groups but share the common effect of altering central monoamine function. Toxicity is largely affected by other properties of these drugs.
Several different pharmacological actions determine the features of overdose. Reuptake of monoamines (noradrenaline and serotonin) into central and peripheral neurones is blocked. Anticholinergic actions cause reduced gut motility, dry mouth and tachycardia. They are sodium channel blockers with class I antiarrhythmic action prolonging the QRS complex. They are α-adrenergic and histamine antagonists resulting in hypotension and sedation.
Clinical features evolve as the drug is absorbed, usually within 30 to 60 min of ingestion. Patients who remain conscious six hours after ingestion are unlikely to have taken much drug. Early features include drowsiness, sinus tachycardia, dry mouth, and dilated pupils. Urinary retention, increased reflexes, extensor plantar responses, and gaze palsies may then develop. Patients who become unconscious, Glasgow Coma Score (GCS) <8, or are unresponsive to pain, are at increased risk of more serious complications, particularly seizures. Risk of ventricular arrhythmia may be predicted from the length of the QRS complex. Changes in repolarization pattern may also be seen with abnormal T-waves and apparent changes in the ventricular axis. This pattern mimics the Brugada syndrome, the congenital abnormality associated with ventricular fibrillation. Features include ST elevation in leads V1–3, with right bundle block often associated with serious ventricular arrhythmias.
Patients with depressed consciousness and prolonged QRS interval are at risk of fits and arrhythmias. Maintenance of acid–base balance in these patients is crucial. Early and prompt treatment with sodium bicarbonate, even in patients who are not overtly acidotic, ameliorates cardiac effects of tricyclics. Sodium bicarbonate (50 mmol doses, 50 ml of 8.4%) should be administered. If given into a peripheral vein, there is a risk of necrosis if it extravasates. Indications for bicarbonate include QRS duration greater than 120 ms, existing arrhythmias, or hypotension resistant to fluid resuscitation. The aim is to maintain the arterial pH in the range 7.5 to 7.55 without producing greater alkalaemia. Specific antiarrhythmic drugs, such as lidocaine (lignocaine), are also sodium channel blockers, and therefore may worsen arrhythmias. Convulsions should be treated conventionally with diazepam (10–20 mg intravenously, in an adult) or lorazepam (3–4 mg).
The α-adrenoreceptor blocking properties of tricyclics can cause severe hypotension. Noradrenaline is the most appropriate inotrope to use in this situation.
In the past, physostigmine was advocated to counteract the anticholinergic action of tricyclic antidepressants, but most European toxicologists do not recommend this.
During recovery from tricyclic poisoning, there may be a prolonged period of delirium with auditory and visual hallucinations. Sedation with diazepam is appropriate until the patient recovers.
All tricyclic antidepressants may cause these features but dosulepine (dothiepin) is the most toxic in overdose, followed by amitriptyline.
Selective serotonin reuptake inhibitors (SSRIs)
Citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, antidepressants that inhibit serotonin reuptake (SSRIs), lack the anticholinergic actions of tricyclic antidepressants.
Clinical features of these agents are principally due to serotonin-like effects, and include nausea and vomiting, agitation, and tachycardia. Convulsions may occur after larger ingestions. Hypertonia and marked clonus are common features of significant poisoning, and increased muscle activity results in rise in serum creatine kinase activity. Citalopram is the most toxic of the group in overdose. All SSRIs cause occasional arrhythmias.
In patients who consume more than one drug affecting serotonin receptors (e.g. tricyclic antidepressants, monoamine oxidase inhibitors, drugs of abuse, including, in particular, ecstasy), the serotonin syndrome may occur. Features include marked agitation and increased muscle activity resulting in hyperpyrexia. About half the patients have central nervous system features including delirium and hallucinations. Other features include autonomic instability with tachycardia and labile blood pressure. Specific serotonin antagonists such as ciproheptadine may be useful. Alternatively, benzodiazepines (e.g. diazepam orally or parenterally) may help reduce agitation.
Venlafaxine is a drug that inhibits the reuptake of serotonin and noradrenaline (SNRI). In overdose, it has features of both SSRIs and tricyclic antidepressants but it lacks anticholinergic activity.
Drowsiness and convulsions are the main central nervous system effects. Tachycardia, ventricular arrhythmias, and changes in blood pressure are the main cardiovascular effects.
Management of metabolic acidosis is important to reduce the risk of arrhythmias, which are more common in patients who have had convulsions. Convulsions are managed conventionally with diazepam (10–20 mg intravenously) or lorazepam (3–4 mg intravenously). Activated charcoal should be considered if more than 12.5 mg/kg was ingested within the previous hour. Venlafaxine prolongs the QT interval so that torsades de pointes is a risk that should be treated conventionally by correcting acidosis and with intravenous magnesium.
Monoamine oxidase inhibitors (MAOIs)
These have well-established adverse interactions with foods containing tyramine. The classical MAOIs such as phenelzine, isocarboxacid, and tranylcypramine are now rarely used, and the new more specific inhibitors of MAOI type A (moclobemide) and type B (selegilene) produce less serious adverse effects in overdose.
Classical MAOIs prevent the breakdown of catecholamines within the nerve ending, and result in excess sympathomimetic effects peripherally, and excess adrenergic effects centrally. In patients who are naive to the drugs, onset of inhibition of enzyme takes several hours, and clinical features may not be seen immediately. In patients on chronic therapy, the onset will be more rapid.
Principal effects are central nervous system stimulation with excitement, restlessness, hyperpyrexia, hyperreflexia, convulsions, and coma. These may go on to cause rhabdomyolysis. Cardiovascular effects include tachycardia and changes in blood pressure, depending on whether the effects of adrenaline (vasodilation) or noradrenaline (vasoconstriction) predominate.
Treatment is supportive, with careful monitoring. Patients who develop central excitation should be treated with large doses of diazepam. This will reduce centrally stimulated muscle contraction and hence pyrexia and muscle damage. Cardiovascular monitoring is essential. Changes in blood pressure should be managed where possible with drugs that are not sympathomimetic agonists. Use of β-blockade may result in unopposed α-agonist effect causing large rises in blood pressure. Hypertension is best controlled with an intravenous nitrate such as glyceryl trinitrate.
First-generation antihistamines include brompheniramine, chlorphenamine, cyclizine, diphenhydramine, promethazine, and trimeprazine. Second-generation drugs include cetirizine, loratidine, fexofenadine, astemizole, and terfenadine.
Older antihistamines have anticholinergic actions but less potent central nervous system toxicity than other anticholinergic drugs. Delirium may be a particular problem in very young children and older people, following a substantial acute overdose. Rhabdomyolysis is a well-recognized complication of severe antihistamine poisoning. The second-generation drugs generally cause less sedation and less psychomotor impairment but some, notably astemizole and terfenadine, have been associated with cardiotoxicity causing QTc interval prolongation and ventricular tachycardia, including torsade de pointes. Astemizole and terfenadine have been withdrawn from use in many countries for this reason.
A 12-lead ECG and cardiac monitoring for at least 12 h is recommended after a substantial overdose. Management should otherwise follow the same principles as for tricyclic antidepressant poisoning (see above).
Toxicity can result from doses greater than 1 g (c.6 tablets) in adults.
Cardiac arrest is commonly the first clinical manifestation of poisoning, but hypotension usually precedes it and may progress to cardiogenic shock with pulmonary oedema. Electrocardiographic abnormalities, bradyarrhythmias, and tachyarrhythmias are common and are similar to those seen in quinine poisoning. Visual disturbance, agitation, drowsiness, acute psychosis, dystonic reactions, seizures, and coma may ensue. Hypokalaemia is common and is due to potassium channel blockade.
Supportive measures should be employed and hypokalaemia corrected. There is no specific antidote. Sodium bicarbonate 50 to 200 mmol (50–200 ml of 8.4%) is indicated if the ECG shows intraventricular block but will exacerbate hypokalaemia, which should be corrected first. Mechanical ventilation, the administration of epinephrine 1 to 10 µg/kg.min and high-doses of diazepam (1 mg/kg as a loading dose and 0.25–0.4 mg/kg per h maintenance) may reduce the mortality to 10% in severe poisoning. MDAC may enhance chloroquine elimination. Extracorporeal elimination techniques do not have a role. Extracorporeal life support has been utilized successfully in severely poisoned patients unresponsive to conventional measures.
Quinine cardiotoxicity is due to sodium channel blockade.
Cinchonism (tinnitus, deafness, vertigo, nausea, headache, and diarrhoea) is common at plasma concentrations greater than 5 mg/litre. In more serious poisoning, collapse with impairment of consciousness (due to ventricular arrhythmias) convulsions, hypotension, pulmonary oedema, and cardiorespiratory arrest may be observed. The latter is often preceded by ECG conduction abnormalities, particularly QT prolongation. Hypoglycaemia, resulting from insulin release, occurs even with therapeutic doses and must be excluded in all cases. About 40% of patients develop ocular features, which may be unilateral, including blindness, contracted visual fields, scotomata, dilated pupils, blurred disc margins, macular oedema, arteriolar spasm, and late optic atrophy. Oculotoxicity is likely when plasma concentrations exceed 10 mg/litre. Visual loss is permanent in about 50% of cases.
MDAC increases quinine clearance. Extracorporeal elimination techniques and stellate ganglion block are of no value. Electrolyte and acid–base disturbances and hypoglycaemia should be corrected. Hypertonic sodium bicarbonate will correct acidosis that persists despite fluid resuscitation and adequate oxygenation and is recommended first-line therapy for conduction abnormalities due to sodium channel blockade, including QRS and QT prolongation. Overdrive pacing may be required if torsade de pointes occurs and does not respond to magnesium sulphate infusion.
The main concern about primaquine is its ability to cause methaemoglobinaemia in overdose. Other adverse effects reported are headache, nausea, abdominal pain, haemolytic anaemia particularly in patients with glucose-6-dehydrogenase deficiency, and leucopenia.
Treatment is supportive. Clinically significant methaemoglobinaemia (generally >30%) is treated conventionally with intravenous methylthioninium chloride (methylene blue) 1 to 2 mg/kg body weight.
Antipsychotic drugs are thought to act predominantly by effects on dopamine D2 receptors. Older antipsychotics were phenothiazines, such as chlorpromazine, and butyrophenones, such as haloperidol. More recent selective antipsychotic drugs were sulpiride and later clozapine, olanzapine, quetiapine, and risperidone (termed ‘atypical antipsychotics’).
These antipsychotics have many actions, including antihistamine and anticholinergic activity. Chlorpromazine blocks α-, β-, and 5HT-receptors in vitro. Features such as postural hypotension are likely to be due to the sum of these effects.
In overdose, the predominant clinical features of all of this class of drugs is sedation, loss of consciousness, and hypotension. Respiratory depression may occur in more severe cases. Hypotension and vasodilatation are features of chlorpromazine poisoning. Thioridazine (now withdrawn in many countries) causes prolonged QT syndrome. ECG abnormalities have been seen with some of the newer atypical antipsychotics but they cause less cardiovascular disturbance than the older drugs. Muscle contraction due to central extrapyramidal effects may result in rhabdomyolysis in severe cases. Neuroleptic malignant syndrome, seen during therapeutic use of these compounds, is uncommon in acute poisoning and should be treated conventionally.
Management is supportive. Dystonic reactions may occur, particularly in young adults. These should be treated conventionally with benztropine (1–2 mg intravenously), procyclidine (5–10 mg intravenously), or diazepam (10–20 mg intravenously or oral).
Haloperidol is the most widely used of the butyrophenones.
Overdose generally causes drowsiness and hypotension. These drugs are dopamine receptor antagonists and may cause vasodilatation, and there are occasional reports of ECG abnormalities. In young adults, the commonest complication is acute dystonia; parkinsonian effects may be seen in older people. Neuroleptic malignant syndrome is unusual in acute poisoning.
Treatment is supportive, and acute dystonic reactions respond to either anticholinergics such as benztropine (1–2 mg) or procyclidine (5–10 mg) intravenously for an adult, or an intravenous benzodiazepine such as diazepam.
These agents cause sedation as their primary effect. Some have caused QT prolongation in overdose. Occasionally fits are reported. Treatment is supportive. A 12-lead ECG should be obtained to check QT duration.
Except for phenobarbital, barbiturates are now prescribed rarely and therefore overdose with other barbiturates is now rare.
Impairment of consciousness, respiratory depression, hypotension, and hypothermia are typical and potentiated by alcohol. There are no specific neurological signs. Hypotonia and hyporeflexia are the rule and the plantar responses are either flexor or absent. Skin blisters, and rhabdomyolysis may develop. During recovery from coma, with or without hypothermia, it is common to observe a peak of temperature, which cannot be explained by infection. Most deaths result from respiratory complications.
Supportive measures should be used as appropriate. Phenobarbital can be removed efficiently by MDAC; urine alkalinization is less effective.
These are widely used as tranquillizers, hypnotics, and sedatives.
Although many benzodiazepines have active metabolites accounting for their sometimes prolonged sedative effects, all are remarkably safe when taken alone in overdosage. As many as 70 or 80 tablets of any of them is unlikely to produce anything more than mild effects in most adults. However, there is individual variation in response, influenced by habituation and tolerance, which develop during chronic therapy; some otherwise healthy elderly people respond to an overdose with prolonged toxicity. Benzodiazepines potentiate the effects of other central nervous system depressants, particularly alcohol, tricyclic antidepressants, and barbiturates. Dizziness, drowsiness, ataxia, and slurred speech are the usual features; coma, respiratory depression, and hypotension are uncommon and usually mild. Flurazepam is most likely to cause significant central nervous system depression. Amnesia of events during the period of drug effect is also seen.
Flumazenil (also known as flumazepil) is a specific benzodiazepine receptor antagonist primarily available by injection only. The use of flumazenil is potentially hazardous in patients who have co-ingested other drugs, particularly tricyclics (risk of fits and lethal arrhythmias), or who are habituated to benzodiazepines from therapeutic use (risk of acute withdrawal and fits). Flumazenil should therefore not be used routinely in benzodiazepine poisoning, nor as a diagnostic test. It should be given to avoid assisted ventilation in a patient who is otherwise going to require intubation, particularly in those with existing chronic airways obstruction. Flumazenil has a relatively short half-life and therefore repeated doses may be required.
β-Adrenoceptor blocking drugs (β-blockers)
β-Adrenoceptor blocking drugs (β-blockers) exert their toxic effects in overdose not only by blocking the β1- and β2-adrenoreceptors, but also by virtue of their membrane stabilizing activity, which results in a quinidine-like effect on the action potential as a result of sodium channel blockade; this produces QRS widening, which predisposes to ventricular arrhythmias.
Symptoms usually occur within 6 h of ingestion of non-sustained release preparations. Sinus bradycardia may be the only feature after a small overdose, but if a substantial amount has been ingested, coma, convulsions (particularly with propranolol), profound bradycardia, and hypotension may occur. Other effects include drowsiness, delirium, hallucinations, low-output cardiac failure, and cardiorespiratory arrest (asystole or ventricular fibrillation). Bronchospasm and hypoglycaemia occur rarely.
First-degree heart block, intraventricular conduction defects, right and left bundle branch block, ST segment elevation, ventricular extrasystoles, and disappearance of the P-wave may be noted on the electrocardiogram. Sotalol has been reported to cause QT interval prolongation and ventricular arrhythmias and asystole may follow severe overdose from any β-adrenoceptor blocking drug.
A delay in treatment may be fatal in patients who are severely poisoned. The blood pressure and cardiac rhythm of the patient should be monitored immediately in an intensive care area and supportive measures implemented.
Glucagon is the drug of choice for severe hypotension; it bypasses the blocked β-receptor, thus activating adenyl cyclase and promoting the formation of cAMP (which has a direct β-stimulant effect on the heart) from ATP. It should be given in a bolus dose of 50 to 150 µg/kg (typically 10 mg in an adult) over 1 min, followed by an infusion of 1 to 5 mg/h according to response. Conventional inotropes are less effective than glucagon in severe cases.
If bradycardia is refractory to atropine 0.6 to 1.2 mg intravenously, repeated as necessary, transcutaneous or transvenous pacing should be considered. Sodium bicarbonate may reverse the cardiotoxic effects of β-blockers with membrane stabilizing activity and should be considered for the treatment of ventricular dysrhythmias. Occasionally, diazepam 10 to 20 mg intravenously may be needed for convulsions. If bronchospasm supervenes, salbutamol (albuterol) by nebulizer, should be employed. Hypoglycaemia should be corrected.
Poisoning with β2-adrenoceptor stimulants, including fenoterol, pirbuterol, reprobuterol, rimiterol, salbutamol (albuterol), and terbutaline, has followed deliberate and accidental ingestion of these drugs and has also resulted from confusion over the difference between oral and parenteral doses.
Mechanisms of toxicity
β2-Agonists act on β2-adrenergic receptors and increase intracellular cAMP. In addition to initiating relaxation of bronchial, vascular, and uterine smooth muscle, β2-agonists cause glycogenolysis in skeletal muscle and hepatic glycogenolysis and gluconeogenesis. Hypokalaemia is caused by β2-receptor-mediated activation of Na+-K+-ATPase, with extracellular potassium being shifted into the intracellular compartment; hypokalaemia may precipitate supraventricular and ventricular arrhythmias.
Tremor, sinus tachycardia, agitation, convulsions, supraventricular and ventricular arrhythmias, hypokalaemia, hyperglycaemia, and ketoacidosis are the typical features of severe poisoning with β2-agonists. Psychosis and hallucinations are observed occasionally.
Hypokalaemia should be corrected as soon as possible by the administration of an infusion of potassium at a rate of 40 to 60 mmol/h diluted in 5% dextrose. A non-selective β-blocker, such as propanolol 1 to 5 mg by slow intravenous injection, will also reverse hypokalaemia and sinus tachycardia, but its use may exacerbate pre-existing obstructive airways disease.
Supraventricular tachycardia has been treated successfully with adenosine. If myocardial ischaemia occurs as a result of the tachyarrhythmia, propranolol, 1 to 5 mg intravenously, should be administered. Convulsions are usually single and short-lived but, if necessary, diazepam, 5 to 10 mg intravenously, may be given.
Bismuth chelate (tripotassium dicitratobismuthate)
Although bismuth absorption from bismuth chelate is low after a therapeutic dose, a significant quantity may be absorbed after overdose.
Self-poisoning with large doses of bismuth chelate has caused reversible renal failure 2 and 10 days after overdose and at least one death. During prolonged (and sometimes high-dose) therapy, bismuth-induced encephalopathy has been reported.
Dimercaprol can lower brain bismuth concentrations though there is no evidence that it can prevent nephrotoxicity. DMPS and DMSA are effective oral alternatives.
Calcium channel blockers
Calcium channel blockers act by blocking voltage-gated calcium channels at cardiac conducting and contractile tissue and vascular smooth muscle.
In overdose, calcium channel blockers cause nausea, vomiting, dizziness, slurred speech, confusion, sinus bradycardia and tachycardia, prolonged atrioventricular conduction, atrioventricular dissociation, hypotension, pulmonary oedema, convulsions, coma, hyperglycaemia, and metabolic acidosis. When a sustained release preparation has been ingested, the onset of severe features may be delayed for more than 12 h. Cardiac complications are usually more serious following overdose with verapamil or diltiazem than with the dihydropyridines such as nifedipine and amlodipine. Large overdoses carry a poor prognosis, particularly in patients with ischaemic heart disease and in those taking β-blockers.
Calcium chloride (10%, 5 to 10 ml at 1–2 ml/min) or calcium gluconate (10% solution 10–20 ml intravenously) may reverse prolonged intracardiac conduction times. If significant hypotension persists despite volume replacement, intravenous glucagon 10 mg (150 µg/kg) should be given to an adult and can be followed by an infusion 5 to 10 mg/h depending on response. If hypotension persists, administer a sympathomimetic amine intravenously. Insulin–dextrose euglycaemia has been shown to improve myocardial contractility and systemic perfusion and may be used as an adjuvant to a sympathomimetic amine. There is increasing evidence that intravenous Intralipid is useful in patients who do not respond to other measures. Cardiac pacing may have a role if there is evidence of atrioventricular conduction delay, but there may be failure to capture. Successful use of intra-aortic balloon pumping, cardiac bypass and extracorporeal membrane oxygenation (ECMO) have been reported in extremely severe cases.
Cannabis is obtained from the plant Cannabis sativa which contains over 400 compounds including over 60 cannabinoids. The most potent cannabinoid is Δ9-tetrahydrocannabinol (THC), which is responsible for the psychoactive effects seen with cannabis use; other cannabinoids include Δ8-tetrahydrocannabinol, cannabinol, and cannabidiol. Smoking is the usual route of use, but cannabis is occasionally ingested as a ‘cake’, made into a ‘tea’, or injected intravenously.
Features include euphoria, distorted and heightened images, colours and sounds, altered tactile sensations, sinus tachycardia, hypotension, and ataxia. Visual and auditory hallucinations, depersonalization, and acute psychosis are particularly likely to occur after substantial ingestion in naive cannabis users.
Cannabis impairs all stages of memory including encoding, consolidation, and retrieval. Memory impairment following acute use may persist for months following abstinence. Cannabis infusions injected intravenously may cause nausea, vomiting, and chills within minutes; after about 1 h, profuse watery diarrhoea, tachycardia, hypotension, and arthralgia may develop. Marked neutrophil leucocytosis is often present, and hypoglycaemia has been reported occasionally.
Heavy users suffer impairment of memory and attention and poor academic performance. There is an increased risk of anxiety and depression. Regular users are at risk of dependence. Cannabis use results in an overall increase in the relative risk for later schizophrenia and psychotic episodes. Cannabis smoke is probably carcinogenic.
Most acutely intoxicated patients require no more than reassurance and supportive care. Sedation with diazepam, 10 mg intravenously, repeated as necessary, should be administered to patients who are disruptive or distressed. Haloperidol, 2.5 to 5 mg intramuscular repeated as necessary, is occasionally required.
In overdose this drug may cause coma, respiratory depression, reduced muscle tone, hypotension, and excessive salivation. The characteristic odour of clomethiazole is often detected on the breath.
Treatment is supportive.
In recent years, there has been a considerable increase in the recreational use of cocaine. It is a powerful local anaesthetic and vasoconstrictor and may be abused by smoking, ingestion, injection, or by ‘snorting’ it intranasally. Users, body packers, and those who swallow the drug to avoid being found in possession of it (‘stuffers’), are at risk of overdose. ‘Street’ cocaine is cocaine hydrochloride which is water soluble so can be injected or snorted. It may be dissolved in an alkaline solution from which the cocaine is extracted into ether which is then evaporated to leave relatively pure (‘freebase’) cocaine. ‘Crack’ (cocaine also without the hydrochloride moiety) is extracted by using baking soda (sodium bicarbonate). Other drugs such as ethanol, cannabis, and conventional hypnotics and sedatives are frequently taken with cocaine to reduce the intensity of its less pleasant effects.
The features of cocaine overdosage are similar to those of amphetamine. In addition to euphoria, it also has sympathomimetic effects including agitation, tachycardia, hypertension, sweating, and hallucinations. Prolonged convulsions with metabolic acidosis, hyperthermia, rhabdomyolysis, ventricular arrhythmias, and cardiorespiratory arrest may follow in the most severe cases. Less common features include dissection of the aorta, myocarditis, myocardial infarction, dilated cardiomyopathy, subarachnoid haemorrhage, cerebral haemorrhage, and cerebral vasculitis.
A number of rare complications of the method of use of cocaine have been reported. These include pulmonary oedema after intravenous injection of freebase cocaine and pneumomediastinum and pneumothorax after sniffing it. In addition, chronic ‘snorting’ has caused perforation of the nasal septum, rhinorrhoea of cerebrospinal fluid due to thinning of the cribriform plate, and pulmonary granulomata.
Users who are intoxicated may require sedation with diazepam to control agitation or convulsions; very large doses of diazepam may be required. Measures to prevent further absorption are usually irrelevant. Hypertension and severe tachycardia may be controlled with a β-blocker but, in one case at least, the use of propranolol caused paradoxical hypertension. Accelerated idioventricular rhythm should not normally require treatment but ventricular fibrillation and asystole should be managed in the usual way.
Dapsone is predominantly used in the management of leprosy and dermatitis herpetiformis.
Dapsone poisoning is potentially very severe, resulting in methaemoglobinaemia, haemolysis, hepatitis, central effects (including drowsiness, coma, and seizures), and a metabolic acidosis.
Management is supportive. MDAC increases dapsone elimination. Methaemoglobinaemia will reduce the oxygen-carrying capacity of the blood, and at concentrations above 30%, treatment with methylthioninium chloride (methylene blue) 1 to 2 mg/kg intravenously over 5 min should be considered.
Digoxin and digitoxin
Digoxin and digitoxin toxicity occurs in three separate situations:
- in patients on regular therapy who gradually accumulate drug due to excess dosing, or development of incipient renal impairment
- in patients who are receiving digoxin for therapeutic purposes who then take a single, large overdose
- in naive patients who take an overdose of someone else’s digoxin
Interpretation of the clinical and biochemical features differs between these situations.
In acute poisoning, the most significant feature normally seen is bradycardia. Since digoxin acts on a Na+-K+-ATPase, and subsequent changes in the myocardium develop following this, onset of the effects of digoxin in overdose may take up to 12 h. In very large overdoses, however, severe features may develop sooner than this, although in clinical practice very large overdoses are less common. Because digoxin interferes with Na+-K+-ATPase, serum potassium increases, and a very high serum potassium is therefore a useful, rapidly measurable marker for severe digoxin poisoning. Measurement of plasma concentrations of digoxin are also of use. This is particularly the case in patients on chronic therapy who may have less dramatic changes in serum potassium, perhaps because of coexistent diuretic therapy, and where clinical features may be more predominantly tachycardias.
Patients require treatment for cardiovascular compromise, not for blood concentrations. In acute poisoning, blood concentrations may rise to quite high levels (above 5 µg/litre) without necessarily causing particularly severe clinical features. These rises may be transient as the drug redistributes into fatty stores after absorption. In chronic therapy, plasma concentrations give a better indication of the quantities of digoxin present in the body, and in acute overdose in chronically dosed patients, several plasma concentration measurements may need to be taken over a short period to assess the dose absorbed.
Nausea, vomiting, bradycardia, and drowsiness may occur. At high doses, central nervous system features including hallucinations may be present. Sinus bradycardia is the most important and earliest feature in acute poisoning, but in chronic poisoning malignant ventricular arrhythmias are also seen. These will also develop in patients with severe acute poisoning.
In patients who are vomiting, the airway needs to be protected, and consideration should be given to administering charcoal later than 1 h in patients who have ingested significant quantities, as this is such a toxic compound. The temptation to treat moderate hypokalaemia should be resisted as this will interfere with monitoring clinical response. Patients should be treated on the basis of their cardiovascular status, not the plasma concentrations of digoxin alone.
Patients with bradycardia who are symptomatic should receive atropine, and have any acid–base disturbance corrected. In patients with significant bradycardia or malignant ventricular arrhythmias, the most effective therapy is likely to be neutralization of digoxin with digoxin antibody. Doses of antibody recommended by the manufacturers are designed to completely neutralize all digoxin present in the patient. Such an approach is unwarranted, particularly in patients on chronic therapy with digoxin in whom complete reversal of digoxin will unmask the disorder for which they are being treated. It is recommended that half the quantity of the calculated total neutralizing dose be given. Further doses can be given, if necessary. In patients who receive the antibody, clinical improvement will occur rapidly, usually within 20 min. Failure to respond indicates either an incorrect diagnosis or continued absorption of digoxin. Measurement of serum digoxin concentrations is not possible once the digoxin antibody has been administered, since currently available assays measure both bound and free compound. Extracorporeal elimination techniques are ineffective in removing digoxin though MDAC may increase elimination.
Most diuretic overdoses are minor, although inevitably some disturbance of fluid and electrolyte balance will result. When combined diuretic and potassium formulations are ingested, the potassium content is likely to pose the greater risk. More serious consequences are likely if a potassium-sparing diuretic has been ingested.
Symptoms and signs of toxicity include anorexia, nausea, vomiting, diarrhoea, profound diuresis, dehydration, and hypotension. In addition, dizziness, weakness, muscle cramps, tetany, and occasionally, gastrointestinal bleeding may be seen. The electrolyte and metabolic disturbances that may be observed include hyponatraemia, hypoglycaemia or hyperglycaemia, hyperuricaemia, hypokalaemia, and metabolic alkalosis. Hyperkalaemia develops following the ingestion of combined diuretic and potassium preparations and potassium-sparing diuretics, such as amiloride, spironolactone, or triamterene. Small-bowel ulceration and stricture formation has followed poisoning due to diuretics with an enteric-coated core of potassium chloride.
Symptomatic and supportive therapy should be employed with correction of fluid and electrolyte imbalance. Patients with severe hyperkalaemia may need a glucose and insulin infusion followed by oral or rectal administration of an ion-exchange resin.
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