\u00a0<\/span><\/h3>\nThe schizophrenia spectrum and other psychotic disorders are among devastating mental illnesses. These conditions are characterized by hallucinations, delusions, abnormal motor behavior, disorganized thought, and speech which collectively impair the social, occupational, and personal functioning of an individual. Consequently, they necessitate treatment. Interventions for schizophrenia spectrum and psychotic disorders are principally by antipsychotics. However, psychoeducation as an adjunct is central to preventing relapses. Antipsychotics are broadly categorized as typical and atypical antipsychotics. Atypical antipsychotics are the newer agents known for their less extrapyramidal side effects. All antipsychotics except clozapine have similar clinical effectiveness. Therefore, the choice of a particular antipsychotic will largely depend on the adverse effect profile and the patient\u2019s clinical status. This piece of paper will extensively explore clozapine including its mechanism of action, pharmacokinetics, pharmacodynamics, dosing, and side effects among other aspects.<\/span>\u00a0<\/span><\/p>\nClozapine<\/span><\/b>\u00a0<\/span><\/h2>\n\n- Clozapine is a second-generation antipsychotic. It is a dibenzodiazepine derivative. <\/span>Clozaril, FazaClo ODT, and Versacloz are the chief brand names for this medication <\/span>(Khokhar et al., 2018)<\/span>.\u00a0<\/span>\u00a0<\/span><\/li>\n
- It is FDA approved for the treatment of treatment-resistant schizophrenia <\/span>(Khokhar et al., 2018)<\/span>. Schizophrenia is considered treatment-resistant if an adequate trial of 2 antipsychotic agents (at least one-second generation) offers suboptimal resistance.<\/span>\u00a0<\/span><\/li>\n
- Clozapine is deployed in the reduction of suicidal risk particularly in patients with schizoaffective disorder or schizophrenia.\u00a0<\/span>\u00a0<\/span><\/li>\n
- Off-label uses of clozapine include management of dopaminomimetic psychosis and adolescents with bipolar disorder although its adverse effects have limited these clinical benefits <\/span>(Rachamallu et al., 2019)<\/span>.\u00a0<\/span>\u00a0<\/span><\/li>\n<\/ul>\n
\u00a0<\/span><\/p>\nPharmacokinetics<\/span><\/b>\u00a0<\/span><\/h2>\n\n- Pharmacokinetics refers to what the body does to the drug. It includes aspects such as absorption, distribution, metabolism, and excretion.\u00a0<\/span>\u00a0<\/span><\/li>\n
- Clozapine is rapidly and well absorbed after oral administration. Peak plasma concentrations are achieved after approximately 1.5 to 2.5 hours <\/span>(Khokhar et al., 2018)<\/span>. Following oral administration, sedation is apparent within 15 minutes but optimal after 1 to 6 hours. The antipsychotic effect is delayed for 1 to numerous weeks after commencement.\u00a0<\/span>\u00a0<\/span><\/li>\n
- The duration of action of clozapine spans from 4 to 12 hours <\/span>(Khokhar et al., 2018)<\/span>. However, food appears not to have any effect on clozapine. The drug is rapidly and extensively distributed. It crosses the blood-brain barrier and the placenta. An estimated 97% of the drug is ordinarily plasma protein bonded.\u00a0<\/span>\u00a0<\/span><\/li>\n
- The drug undergoes the first pass effect. It is metabolized by the liver (CYP1A2, CYP2D6, and CYP3A4 isoenzymes <\/span>(Khokhar et al., 2018)<\/span>. Finally, 50% of the metabolized drug is excreted in the urine while 30% is via feces.<\/span>\u00a0<\/span><\/li>\n<\/ul>\n
Pharmacodynamics<\/span><\/b>\u00a0<\/span><\/h2>\n\n- The precise antipsychotic mechanism is not fully known. However, a combination of adrenergic, cholinergic, and serotonergic neurotransmitter systems plays a crucial role alongside the more dominant dopaminergic system.\u00a0<\/span>\u00a0<\/span><\/li>\n
- The principal mechanism of action of clozapine is antagonism at D<\/span>2<\/span> receptors and 5-HT<\/span>2A<\/span> receptors leading to diminished schizophrenic and suicidal behavior.\u00a0<\/span>\u00a0<\/span><\/li>\n
- Clozapine also binds to H<\/span>1 <\/span>receptors, alpha 1 and alpha 2 adrenergic receptors, and muscarinic M<\/span>1 <\/span>receptors. Antagonism at these receptor sites considerably contributes to therapeutic and adverse effects including constipation, somnolence, and orthostatic hypotension.<\/span>\u00a0<\/span><\/li>\n<\/ul>\n
\u00a0<\/span><\/p>\nDosing, Administration Route, and Considerations<\/span><\/b>\u00a0<\/span><\/h2>\n\n- Clozapine is administered orally. In adults, it is usually started at 25 mg given once or two times daily. This dosage is then increased by 25 to 50 mg\/day over 2 weeks up to a target dose of 300 to 450 mg\/day <\/span>(Wells & McCormack, 2020)<\/span>. A further increase by 100 mg\/day may be required once or twice daily although the total daily dosage should not exceed 900 mg\/day <\/span>(Wells & McCormack, 2020)<\/span>. <\/span>\u00a0<\/span><\/li>\n
- A treatment period of at least 2 years is recommended. Safety of clozapine has not been established in children less than 16 years while elderly patients are at increased risk of mortality in the presence of dementia-related psychosis.\u00a0<\/span>\u00a0<\/span><\/li>\n
- Should never be used in pregnancy unless the benefits outweigh the risks. Finally, the drug should be discontinued during lactation or the mother may bottle-feed<\/span>\u00a0<\/span><\/li>\n<\/ul>\n
Half-Life<\/span><\/b>\u00a0<\/span><\/h2>\n\n- Refers to the duration it takes for the amount of its active substance in the body to diminish by half.\u00a0<\/span>\u00a0<\/span><\/li>\n
- Directly proportional to the rate of metabolism and elimination of the drug. The half-life varies considerably across various pharmacological agents. It is used to determine the dosing frequency.\u00a0<\/span>\u00a0<\/span><\/li>\n
- The half-life of clozapine is approximately 8 to 12 hours.<\/span>\u00a0<\/span><\/li>\n<\/ul>\n
Side Effects and Contraindications<\/span><\/b>\u00a0<\/span><\/h2>\n\n- Clozapine is contraindicated in patients with bone marrow suppression, uncontrolled epilepsy, severe CNS depression, and hypersensitivity <\/span>(de Leon et al., 2020)<\/span>.\u00a0<\/span>\u00a0<\/span><\/li>\n
- The side effects of this drug include neuroleptic malignant syndrome, sedation, dizziness, QT interval prolongation, ventricular arrhythmias, agranulocytosis, leukopenia, hypotension, tachycardia, dry mouth, increased salivation, rash, sweating, visual disturbances, and extrapyramidal reactions <\/span>(de Leon et al., 2020)<\/span>.\u00a0<\/span>