Antipsychotics

Kiran Kaur 1000819428

Dopamine Receptor Antagonists: Typical Antipsychotics

Chlorpromazine (Thorazine), introduced in the 1950s, was the first drug to significantly and consistently reduced symptoms of psychosis. Antipsychotic activity was related to high affinity antagonism of dopamine D2 receptors, and are therefore called dopamine receptor antagonists (DRAs). They are no longer the mainstay of treatment and are quickly being replaced by newer antipsychotic agents i.e SDAs and PDAs

Butyrophenones Haloperidol (Haldol, Serenace) Droperidol (Droleptan) Thioxanthenes Chlorprothixene (Cloxan, Taractan, Truxal) Clopenthixol (Sordinol)

Phenothiazines Chlorpromazine (Thorazine, Largactil) Fluphenazine (Prolixin) - Available in decanoate (long-acting) form Perphenazine (Trilafon) Prochlorperazine (Compazine) Thioridazine (Mellaril, Melleril) Trifluoperazine (Stelazine) Mesoridazine Periciazine Promazine

Pharmacological Actions

All the DRAs are well absorbed after oral administration, with liquid>tablets/capsules Peak plasma concentration are reached

1-4 hours after oral admin., and 30-60 minutes after parenteral admin.

Smoking, coffee, antacids and food interfere with absorption. Steady state levels are reached in 3-5 days

Antipsychotic activity derives from inhibition of dopaminergic neurotransmission. The DRAs are effective when approximately 60% of D2 receptors are occupied. At 80% one begins to see the extrapyramidal signs. The DRAs also block noradrenergic, cholinergic and histaminergic.

Factors Influencing the Pharmacokinetics of Antipsychotics

Age

Elderly patients may demonstrate reduced clearance rates Decreased hepatic blood flow can reduce clearance Hepatic disease can decrease clearance Carbamazepine, phenytoin, ethambutol, barbiturates SSRIs, tricyclic antidepressants, cimetidine, beta-blockers Hypoalbuminemia can occur in malnutrition or hepatic failure

Medical condition

Enzyme inducers

Clearance inhibitors

Changes in binding protein

Therapeutic Indications
Acute psychotic episodes in schizophrenia and schizoaffective disorder Maintenance treatment in schizophrenia and schizoaffective disorders Mania Depression with psychotic symptoms Delusional disorder Borderline personality disorder Substance induced psychotic disorder Delirium and dementia

Schizophrenia and Schizoaffective Disorder

DRAs are effective in both short-term and longterm management of schizophrenia and schizoaffective disorder. Reduce acute symptoms and prevent future exacerbations DRAs produce their most dramatic effects against the positive symptoms of schizophrenia (i.e hallucinations, delusions, agitation) Less effect on negative symptoms (i.e emotional withdrawal and ambivalence) and might even appear to worsen because these

Mania

The DRAs are effective to treat psychotic symptoms of acute mania. Because antimanic agents have slower onset than antipsychotics in the treatment of acute symptoms, it is standard practice to combine a DRA or an SDA with an antimanic and then slowly withdraw the antipsychotic.

Precautions and Adverse Reactions

Neuroleptic Malignant Syndrome Seizure Threshold

Some DRAs may lower seizure threshold Blockade of H1 receptors cause sedation Giving dose at bedtime eliminate problems, and tolerance often develops

Sedation

Central Anticholinergic Effects

Cardiac Effects

Decrease cardiac contractility Disrupt enzyme contractility Increase circulating levels of cathecholamines Prolong conduction time and refractory periods

Sudden Death Orthostatic (Postural) Hypotension Hematologic Effects Peripheral Anticholinergic Effects

Endocrine Effects Sexual Adverse Effects Skin and Eye Effects Jaundice Overdoses Pregnancy and Lactation

Neuroleptic Malignant Syndrome (NMS)

Potentially fatal side-effect of DRA treatment Symptoms include:

Extreme hyperthermia Severe muscular rigidity and dystonia Akinesia Mutism Confusion Agitation Increased pulse rate and BP

The symptoms usually evolve over 24 to 72 hours, and untreated symptoms lasts 10-14 days. If NMS is suspected, DRA is discontinued and the following is done

Medical support to cool the person Monitoring of vital signs, electrolytes, fluid balance, & renal output Symptomatic treatment of fever

Dosage And Clinical Guidelines

Contraindications

History of serious allergic response Possible ingestion of a substance that will cause CNS depression i.e alcohol, opioids, barbiturates, benzodiazepines Presence of severe cardiac abnormalities High risk for seizures Presence of narrow angle glaucoma or BPH if a drug with high anticholinergic activity is to be used.