Antipsychotic Drugs PDF

Antipsychotics Indications: Antipsychotic agents (also referred to as neuroleptics) are indicated for the treatment of schizophrenia also used for: Brief psychotic disorder. Schizophreniform Schizoaffective disorder Bipolar and mood disorders with...

Antipsychotics Indications: Antipsychotic agents (also referred to as neuroleptics) are indicated for the treatment of schizophrenia also used for: Brief psychotic disorder. Schizophreniform Schizoaffective disorder Bipolar and mood disorders with psychotic symptoms Dementia or delirium when psychotic symptoms are present Treatment of substance-induced psychotic disorders Psychotic symptoms associated with certain personality disorders (borderline).  Pharmacology Typical and atypical antipsychotics are distinguished by the unique receptor-binding with dopamine and serotonin receptors. The efficacy of typical antipsychotic agents is primarily related to their binding to dopamine D2 receptors. Atypical antipsychotics have replaced the typical agents because of their greater tolerability and increased efficacy Dopamine receptors are widely distributed within the brain where they play critical modulator roles on: Motor functions Motivation Sensation Drive Cognition.  Typical antipsychotic agents may be divided into high, moderate and low potency categories based on their level of dopamine receptor antagonism. a. High-potency agents have the highest affinity for D2 receptors and are effective at relatively lower doses. b. Low-potency agents have lower D2 affinity and require larger doses to elicit an antipsychotic effect.  Atypical agents (serotonin-dopamine antagonists) are prominent antagonism at the serotonin receptor in addition to D2 blockade. 1. These agents appears to be more selectivity for the mesolimbic dopamine pathway, which is thought to be a site of antipsychotic action. 2. There is relatively less action on the nigrostriatal pathway where extrapyramidal side effects are thought to originate.  Pharmacokinetics 1. After oral absorption, peak plasma levels of antipsychotics usually occur within 2-4 hours. 2. IM injections reach peak levels In30-60 minutes. 3. Antipsychotic agents undergo extensive hepatic metabolism. 4. Antipsychotics are 85-90% protein bound and highly lipophilic. 4. Plasma levels are established in 4-10 days. 5. Switching: When changing to an atypical antipsychotic,the new medication should be added while the former medication is usually tapered over time (2-3 weeks).  Clinical Guidelines A. Choosing an Antipsychotic Agent 1. The choice of neuroleptic should be based on past history of neuroleptic response and side effects 2. Atypical antipsychotics have gained acceptance as first line drugs for treatment of psychosis. They provide a superior long-term outcome in treatment of schizophrenia compared to typical antipsychotics. At least two weeks of treatment is required before a significant antipsychotic effect is achieved. 3. Poor response of negative symptoms (affective flattening) is an indication for a trial of an atypical agent. 4. Patients with tardive dyskinesia (TD) should be considered for treatment with an atypical agent to avoid progression of neurological impairment ,Clozapine is not associated with tardive dyskinesia  5. Positive Symptoms: With the exception of clozapine, no differences have been clearly shown in the efficacy of typical and atypical agents in the treatment of positive symptoms (eg, hallucinations, delusions, disorganization) ,Clozapine is more effective than typical agents. 6. Negative Symptoms: Atypical agents may be more effective in the treatment of negative symptoms (eg, affective flattening, anhedonia, avolition) associated with psychotic disorders. 7. Treatment-Resistant Psychosis: Clozapine is the only to support efficacy in treatment-resistant psychosis.  Adverse Drug Reactions 1. Dystonic reactions Are characterized by painful, acute involuntary muscle spasms. They are common side effects of typical antipsychotic agents. Commonly involve the extremities, neck (torticollis), and ocular muscles (oculogyric crisis). The muscle contractions are not life-threatening unless they involve airway passages (eg, larynx) and lead to airway obstruction. Treatment may include: a. Intramuscular or Intravenous Antiparkinsonian agent (1) Benztropine 1-2 mg PO, IM, IV OR (2) Diphenhydramine 50 mg PO, IM, IV. b. Consider change of antipsychotic. Prophylaxis against further episodes of dystonia is accomplished with an oral anticholinergic agent such as benztropine 2 mg PO bid for 1-2 months. If dystonic reactions occur after discontinuing the anticholinergic agent, longer prophylactic treatment should be provided 3-6 months.  2. Drug-induced parkinsonian symptoms Include bradykinesia, tremor, cogwheel rigidity, masked facies, and shuffling gait. Treatments include: a. Decreasing antipsychotic dose. b. Use of anticholinergic drug (eg, benztropine). c. Changing to lower-potency or atypical agent. d. Tremor can be treated with propranolol, 10-40 mg PO bid to qid. 3. Akathisia Is characterized by an intense sense of restlessness or anxiety. Treatments include: a. Decreasing antipsychotic dose. b. Trial of anticholinergic agent (eg, benztropine 2 mg PO bid). c. Trial of beta-adrenergic antagonist such as propranolol,10-40 mg PO bid to qid. d. Trial of a benzodiazepine, such as clonazepam, 0.5 mg PO bid. e. Consider changing to lower-potency or atypical agent  4. Tardive dyskinesia (TD) Is a long-term, often permanent, resulting from use of typical antipsychotics. Characterized by involuntary, irregular movements that can affect any striated muscle in the body including the diaphragm. Primarily limited to patients with a history of chronic typical neuroleptic (greater than two months). Atypical agents have minimal risk of TD. TD may not resolve after discontinuation of the neuroleptic and may be permanent. TDs are characterized by involuntary jerking movements of the face, trunk, neck or extremities. Treatment start to reduce or stop antipsychotic if possible. If continued antipsychotic is necessary, consider a change to an atypical agent.  5. Neuroleptic malignant syndrome Is uncommon, potentially fatal due to adverse reaction to typical antipsychotics. Although some risk of neuroleptic malignant syndrome may be present with risperidone use, this risk is minimal with clozapine. Symptoms are elevated temperature, autonomic instability, delirium, and rigid muscle tone, developing over 24-72 hours. Risk factors for NMS include dehydration, heat exhaustion, and poor nutrition. Treatment involves discontinuing the neuroleptic immediately, along with supportive treatment and medications such as amantadine, bromocriptine, and dantrolene, patients may require treatment in an intensive care unit.  6. Metabolic Side Effects Atypical antipsychotics are associated with type II diabetes and hyperlipidemia. Blood pressure and fasting glucose and lipids should be monitored periodically. If diabetes or hyperlipidemia develop, patients should be switched to atypical agents associated with less weight gain and diabetes. If switching is not possible, lifestyle modifications are recommended, and the patient should be monitored closely. 7. Agranulocytosis is most common with clozapine (1-2% incidence). Clozapine should be discontinued if the WBC drops below 3,000/ mcL 8. Other side effects: a. Muscarinic (cholinergic): Dry mouth, constipation, urinary retention, blurred vision, precipitation of narrow angle glaucoma, ECG changes.  b. Alpha-1-adrenergic: Orthostatic hypotension, tachycardia, sedation and sexual dysfunction. c. Histamine-1: Sedation, weight gain, fatigue d. Non-Specific Side Effects: Include hyperthermia, hypothermia, hepatitis, jaundice, photosensitivity, lowered seizure threshold, hematologic changes, hepatitis, and rash. Overdose 1. Death is uncommon with antipsychotic overdose. Risk of fatality is increased with concurrent use of alcohol or other CNS depressants. 3. CNS depression, hypotension, seizures, fever, ECG changes, hypothermia, and hyperthermia are possible. Treatment may include gastric lavage,, IV diazepam for treatment of seizure, and medical treatment of hypotension.  Drug Interactions Anticholinergics, antihistamines, Additive effects. Antihypertensives may potentiate hypotension. Antidepressants (tricyclics and SSRIs) may reduce metabolism and increase levels of antipsychotics. Antipsychotics may increase levels of tricyclics. CNS depressants (including benzodiazepines, narcotics, and alcohol) enhance sedative effects of antipsychotics. Oral Contraceptives may increase levels of antipsychotics. Lithium. Possible risk of neuroleptic-induced Antacids and cimetidine. Absorption of antipsychotics may be inhibited. Anticonvulsants may induce metabolism and decrease level of antipsychotic; phenothiazines may decrease metabolism or increase the level of phenytoin. Barbiturates reduce levels of antipsychotics by enzyme induction and may cause respiratory depression Cigarettes may increase metabolism and decrease level of antipsychotics. Bromocriptine may worsen psychotic symptoms. Antipsychotics will decrease effect of bromocriptine. Stimulants. (Amphetamine) may worsen psychotic symptoms. Antipsychotics will lessen effects of stimulants. 11. Digoxin absorption may be increased. 12. Isoniazid may increase risk of hepatic toxicity. Pre-Existing Medical Conditions 1. Cardiac History. Use high-potency agents (other than pimozide) or atypicals (other than clozapine) to avoid conduction abnormalities.  2. Elderly patients are more sensitive to side effects; atypical drugs should be utilized initially. Most experience is with Risperidone and Quetiapine. If typical agents are used, start with a low dose of a high- potency agent (0.5 mg of haloperidol) and increase slowly 3. Hematologic Disorder. Clozapine is contraindicated. 4. Hepatic, Renal, Cardiac, Respiratory Disease. Use antipsychotics with caution; monitor renal, cardiac, and liver function. 5. Parkinson's Disease. Atypical agents with lower incidence of EPS (quetiapine,) preferred due to selectivity for mesolimbic dopamine tract. THANKS