·
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.
·
Treatment of schizophrenia not
responding to other antip- sychotic agents.
·
Treatment of psychosis in patients
who cannot tolerate extrapyramidal adverse effects.
â– â– 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%.
â– â– 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.
â– â– 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.
â– â– Clozapine causes greater antagonism
of serotonin S2 recep-tors than conventional neuroleptics.
â– â– It also acts as an antagonist at
adrenergic, cholinergic, histaminergic, and serotonergic receptors.
â– â– 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.
â– â– In 2 to 3% of
patients, clozapine can cause haematological problems including leukopenia,
eosinophilia, and agranu-locytosis.
â– â– Neuroleptic
malignant syndrome is uncommon, as also serious extrapyramidal manifestations.
â– â– Hyperglycaemia,
glucose intolerance and new-onset diabetes have been reported with clozapine
therapy.
â– â– 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.
·
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.
·
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.
·
Fatal dose is usually above 2500 mg,
though intake of even 300 to 400 mg can be lethal.
·
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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