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Chapter: Modern Medical Toxicology: Neurotoxic Poisons: Drugs Used in Psychiatry

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Dibenzodiazepines - Atypical Neuroleptics

Clozapine is an atypical neuroleptic, antipsychotic drug with a tricyclic dibenzodiazepine structure.

ATYPICAL NEUROLEPTICS

Dibenzodiazepines

·              Clozapine is an atypical neuroleptic, antipsychotic drug with a tricyclic dibenzodiazepine structure. It is the most important member of this group and is known for its low-risk of producing extrapyramidal reactions. It has low affinity for D2 receptors, but is an active alpha-adrenergic antagonist.

Uses

·              Treatment of schizophrenia not responding to other antip- sychotic agents.

·              Treatment of psychosis in patients who cannot tolerate extrapyramidal adverse effects.

Toxicokinetics

■■Clozapine is rapidly absorbed on oral administration and peak plasma levels are reached in 2 hours. Elimination half-life is about 12 hours, while the mean volume of distribution is 2.0 to 5.1 L/kg. Binding to plasma proteins is to the extent of 95%.

■■Clozapine undergoes extensive first-pass metabolism in the liver and gut, and about 80% appears in the urine or faeces as metabolites. 2 to 5% of the dose is excreted unchanged in the urine; 49% of a dose is excreted as metabolites in the urine. 38% of a dose is excreted as metabolites in the faeces.

Mode of Action

■■Clozapine differs from classical neuroleptics in that it blocks D1 more than D2 receptors, raises plasma prolactin levels only slightly, and does not induce supersensitivity in striatal dopamine systems. The actual mode of action may be differential modulation of D1 and D2 receptors in the extrapyramidal, limbic and cortical systems.

■■Clozapine causes greater antagonism of serotonin S2 recep-tors than conventional neuroleptics.

■■It also acts as an antagonist at adrenergic, cholinergic, histaminergic, and serotonergic receptors.

Adverse Effects

■■   Common effects following long-term use include nausea, vomiting, weight gain, vertigo, hypotension, salivation, constipation, tachycardia, and sedation. Hypertension sometimes occurs. Seizures are not infrequent.

■■   In 2 to 3% of patients, clozapine can cause haematological problems including leukopenia, eosinophilia, and agranu-locytosis.

■■   Neuroleptic malignant syndrome is uncommon, as also serious extrapyramidal manifestations.

■■   Hyperglycaemia, glucose intolerance and new-onset diabetes have been reported with clozapine therapy.

■■   Sudden cessation of clozapine therapy can cause a with-drawal reaction. In one case series, withdrawal of clozapine resulted in delirium and psychosis which rapidly resolved when low dose clozapine was resumed.

Drug Interactions

·              Benztropine—Concurrent use may result in excessive anticholinergic effects.

·              Carbamazepine—Concurrent use may result in bone marrow suppression.

·              Cimetidine—Concurrent use may result in increased clozapine serum levels and risk of clozapine toxicity.

·              Erythromycin—Concurrent use may result in increased clozapine serum levels and risk of clozapine toxicity.

·              Lithium—Concurrent use may result in neuromotor effects or myelosuppression.

·              Ritonavir—Concurrent use may result in increased risk of haematologic abnormalities, excessive sedation, dizziness, and hypotension.

·              Venlafaxine—Concurrent use may result in increased serum concentrations of both drugs.

·              Benzodiazepines—Concurrent use may result in elevated clozapine serum levels and toxic clozapine effects such as sedation, cognitive impairment, respiratory depression and cardiovascular complications.

·              Fluoxetine—Increased clozapine levels with possible clozapine toxicity may occur when these two drugs are administered concomitantly.

·              Fluvoxamine—Concurrent use may result in elevated serum clozapine levels and toxic clozapine effects (dizziness and hypotension).

·              Zidovudine—Concurrent use with clozapine may result in additive bone marrow toxicity, with subsequent decrease in WBC and possible agranulocytosis.

·              Risperidone—Concurrent use of risperidone and clozapine can result in neuroleptic malignant syndrome.

·              Tobacco—Tobacco products may induce CYP1A2 activity in patients on clozapine. Therefore, smoking cessation can increase clozapine levels leading to toxic symptoms.

Clinical (Toxic) Features

·              Overdose with clozapine results in antimuscarinic or anti-cholinergic effects: restlessness, lethargy, disorientation, confusion, agitation, delirium, mydriasis, blurred vision, convulsions, hypo- or hypertension, tachycardia, arrhyth-mias (atrio -ventricular block, extrasystoles, ventricular fibrillation, ST prolongation), hypothermia, salivation,* dry skin, urinary retention, constipation, ARDS, and myocar-ditis.

·      Other features include agranulocytosis, fasciculations, tremor, myoclonus, and coma. Sudden death can occur.

·      Effects of overdose in children comprise tachycardia, ataxia, confusion, myoclonus, drooling, nystagmus, muscle rigidity, lethargy, and decreased muscle tone. Children may develop severe symptoms of intoxication with a relatively small exposure (>100 mg).

·      Postmarketing safety data suggested that clozapine is asso-ciated with increased risk of fatal myocarditis. This is of greatest concern during the first month of therapy.

Usual Fatal Dose

·              Fatal dose is usually above 2500 mg, though intake of even 300 to 400 mg can be lethal.

Treatment

·            Decontamination: Gastric lavage may be beneficial in the first 1 or 2 hours post-ingestion. Activated charcoal may also be beneficial.

·            Diazepam or phenytoin for convulsions. Valproic acid may also be given, but carbamazepine is contraindicated (enhances risk of agranulocytosis). 

·            Treatment of hypotension by Trendelenberg position, IV fluids, plama expanders, and vasopressors (dopamine or noradrenaline). Adrenaline is contraindicated.

·            Treatment of arrhythmias with lignocaine, phenytoin, or pacing. Quinidine, procainamide, and disopyramide are contraindicated.

·            Treatment of agranulocytosis with granulocyte colony-stimulating factor (G-CSF). Filgrastim should be consid-ered in selected patients with severe granulocytopenia. Starting dose is usually 5 mcg/kg/day in adults by subcutaneous injection or intravenous infusion. Monitor CBC and absolute granulocyte count. An initial leukocyte count with differential should be obtained at admission following a potential clozapine overdose. The leukocyte and granulocyte count should then be monitored once or twice weekly for four weeks following overdose.

·            Physostigmine may reverse clozapine-induced delirium.

·            Clozapine has been associated with a rise in liver enzymes. Monitoring is advisable.

·            Renal function must also be monitored during therapeutic use and overdose with clozapine.

·            Metabolic acidosis has been reported in a few cases, and will require the usual treatment measures.

·              Haemodialysis, haemoperfusion, forced diuresis, and exchange transfusion are unlikely to be useful in clozapine overdose because of the relatively large volume of distribution and high degree of protein binding.

 

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