Clozapine, an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative.
The chemical name of clozapine is 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzodiazepine.
Clozapine is a yellow, crystalline powder, very slightly soluble in water.
Clozapine is usually used as a last resort in patients that have not responded to other antipsychotic treatments due to its danger of causing agranulocytosis as well as the costs of having to have blood tests continually during treatment.
It is, however, one of the very effective anti-psychotic treatment choices.
When studies demonstrated that clozapine was more effective against treatment resistant schizophrenia than other antipsychotics, the FDA and health authorities approved its use only for treatment-resistant schizophrenia, and required regular hematological monitoring to detect granulocytopenia, before agranulocytosis develops.
Treatment-resistant schizophrenia,the role of clozapine,1997
Clozapine was also approved for reducing the risk of suicide in schizophrenic or schizoaffective patients judged to be at chronic risk for suicidal behavior.
Schizophrenia has an high impact on the population and the symptoms that make it possible to diagnose this state are divided into positive symptoms (hallucinations, delusions, bizarre behavior and formal thought disorder) and negative symptoms (alogia, affective flattening, lack of volition, and anhedonia) .Possible causes of this disorder are: genetic damage (has highlighted a certain inheritance of the disease), malformations or CNS abnormalities, hyperactivity of the dopaminergic system in the mesolimbic tract in the CNS, glutamatergic system deficit (activation glutamate receptor induces the serotonin system, which in turn induces the dopaminergic system) or hyperactivity of the serotonergic system.
Clozapine is indicated for the management of schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia.
Clozapine versus typical neuroleptic medication for schizophrenia,2009
Because of the significant risk of agranulocytosis and seizure associated with its use, clozapine should be used only in patients who have failed to respond adequately to treatment with appropriate courses of standard drug treatments for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs.
The effectiveness of clozapine in a treatment-resistant schizophrenic population was demonstrated in a 6 week study comparing clozapine and chlorpromazine.
Because of the significant risk of agranulocytosis and seizure, events which both present a
continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically reevaluated.
Clozapine is also indicated for reducing the risk of recurrent suicidal behavior in patients with
schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior
refers to actions by a patient that puts him/herself at risk for death.
Clozapine is effective against the positive and negative symptoms of schizophrenia and is also able to increase the patient's ability to react to the environment and their reintegration in social fields.
METABOLISM and PHARMACOKINETIC
Clozapine is a substrate for many CYP450 isozymes, in particular 1A2, 2D6, and 3A4. The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized.
Nevertheless, caution should be used in patients receiving concomitant treatment with other
drugs that are either inhibitors or inducers of these enzymes.
A subset (3% to 10%) of the population has reduced activity of certain drug metabolizing
enzymes such as the cytochrome P450 isozyme P450 2D6. Such individuals are referred to as
_ “poor metabolizers" _ of drugs such as *debrisoquin, dextromethorphan, the tricyclic
antidepressants, and clozapine* . These individuals may develop higher than expected plasma
concentrations of clozapine when given usual doses. In addition, certain drugs that are
metabolized by this isozyme, including many antidepressants (clozapine, selective serotonin
reuptake inhibitors, and others), may inhibit the activity of this isozyme, and thus may make
normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other
drugs metabolized by this enzyme system, leading to drug interaction.
The absorption of clozapine is almost complete, but the oral bioavailability is only 60 to 70% due to first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine. The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).
Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for elimination in the urine and faeces. The major metabolite, norclozapine (desmethyl-clozapine), is pharmacologically active. The cytochrome P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well.
Agents that induce (e.g., cigarette smoke) or inhibit (e.g., theophylline, ciprofloxacin, fluvoxamine ) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine. For example, the induction of metabolism caused by smoking means that smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.
Clozapine and norclozapine plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age. Monitoring of plasma levels of clozapine and norclozapine has been shown to be useful in assessment of compliance, metabolic status, prevention of toxicity, and in dose optimization.
• Bioavailability :60 to 70%
• Metabolism : Hepatic, by several CYP isozymes
• Half-life :6 to 26 hours (mean value 14.2 hours in steady state conditions)
• Excretion :80% in metabolized state: 30% biliary and renal
Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics,1999.
MECHANISM OF ACTION:
Clozapine is classified as an ‘atypical’ antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine-mediated behaviors differ from those exhibited by more typical antipsychotic drug products. In particular, although clozapine does interfere with the binding of dopamine at D1, D2, D3, and D5 receptors, and has a high affinity for the D4 receptor, it does not induce catalepsy nor inhibit apomorphine-induced stereotypy. This evidence, consistent with the view that clozapine is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of clozapine from extrapyramidal side effects. Clozapine also acts as an antagonist at adrenergic , cholinergic , histaminergic , and serotonergic receptors.
• agonist and / or partial agonist of D2 receptors, D3, δ-opioid, M1, M2, M3, M4, M5
• antagonist / inverse agonist of 5-HT2A receptors and 5-HT2C.
• partial agonist of 5-HT1A receptor
• strong antagonist in different subtypes of adrenergic, cholinergic and histaminergic (the latter two are mainly responsible for its side effects).
In summary, clozapine acts at several receptor:
• BLOCK D2 in the basal ganglia ONLY 40-60%
• BLOCK 5HT2 to 90%
• BLOCK D1
• BLOCK D4 (with high affinity related to plasma concentration)
• BLOCK 5HT3
• BLOCK 5HT2C
• BLOCK H1, alpha 1, M1
• Therapeutic effect on positive and negative symptoms
• Effectiveness in 30-40% of drug-resistant schizophrenic patients
• Low incidence of extrapyramidal effects
• Risk of agranulocytosis in 0.5-1% of patients treated
• Absence of hyperprolactinemia
Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine.
Phenytoin , tobacco smoke , and rifampin may decrease clozapine plasma levels, resulting in a decrease in effectiveness of a previously effective clozapine dose.
Concomitant administration of drugs known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine.
Cimetidine, caffeine , citalopram , ciprofloxacin , and erythromycin may increase plasma levels of clozapine, potentially resulting in adverse effects.
Although concomitant use of clozapine and carbamazepine is not recommended, it should be noted that discontinuation of concomitant carbamazepine administration may result in an
increase in clozapine plasma levels.
Concomitant use of clozapine with other drugs metabolized by cytochrome P450 2D6 may require lower doses than usually prescribed for either clozapine or the other drug. Therefore,
coadministration of clozapine with other drugs that are metabolized by this isozyme, including
antidepressants, phenothiazines, carbamazepine, and antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.
Clozapine may cause many side effects. The following side effects are grouped by the body system affected:
• Cardiovascular: decreases of blood pressure, especially on arising from a seated or lying position, which may cause dizziness or fainting; rapid heart rate, changes in heart rhythm and electrocardiogram.
• Nervous system: sedation, increased seizure tendency.
• Digestive system: increased appetite, excessive salivation, nausea, constipation, abnormal liver tests, elevated blood sugar.
• Autonomic: blurred vision, exacerbation of glaucoma, dry mouth, nasal congestion, decreased sweating; difficulty urinating, particularly in men with enlarged prostate.
• Skin: rashes.
• Body as a whole: weight gain, fever.
• Cardiac toxicity
• Gastrointestinal hypomotility
• Toxicity in the central nervous system
Clozapine is contraindicated in patients with a previous hypersensitivity to clozapine or any ther component of this drug, in patients with myeloproliferative disorders , uncontrolled epilepsy , paralytic ileus, or a history of clozapine-induced agranulocytosis or severe granulocytopenia. As with more typical antipsychotic drugs, clozapine is contraindicated in severe central nervous system depression or comatose states from any cause.
Clozapine should not be used simultaneously with other agents having a well-known potential to cause agranulocytosis or otherwise suppress bone marrow function. The mechanism of clozapine-induced agranulocytosis is unknown; nonetheless, it is possible that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression.
Clozapine-induced agranulocytosis. Incidence and risk factors in the United States,1993
Orthostatic hypotension in patients taking clozapine can, in rare cases (approximately 1 case per 3,000 patients), be accompanied by profound collapse and respiratory and/or cardiac arrest.
Some of the cases of collapse/respiratory arrest/cardiac arrest during initial treatment occurred in patients who were being administered benzodiazepines; similar events have been reported in patients taking other psychotropic drugs or even clozapine by itself. Although it has not been established that there is an interaction between clozapine and benzodiazepines or other psychotropics, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug.
Clozapine may potentiate the hypotensive effects of antihypertensive drugs and the anticholinergic effects of atropine-type drugs. The administration of epinephrine should be avoided in the treatment of drug-induced hypotension because of a possible reverse epinephrine effect.
Many male patients have also presented a decreased ejaculation as a side effect of clozapine.