Antipsychotics PDF

First generation (low potency) - Chlorpromazine - Thioridazine First generation (high potency) - Fluphenazine - Haloperidol - Loxapine - Molindone - Perphenazine - Pimozide - Prochlorperazine - Thiothixene - Trifluperazine Also called conventional/typical antipsychotics Competitive blocker of dopami...

First generation (low potency) - Chlorpromazine - Thioridazine First generation (high potency) - Fluphenazine - Haloperidol - Loxapine - Molindone - Perphenazine - Pimozide - Prochlorperazine - Thiothixene - Trifluperazine Also called conventional/typical antipsychotics Competitive blocker of dopamine D2 receptors More likely to be associated with extrapyramidal symptoms (EPS) ……especially haloperidol - less likely with chlorpromazine (binds less potently) No one drug is clinically more effective than the other MOA Second generation (atypical antipsychotics) - Risperidone - Ziprasidone - Paliperidone - Iloperidone - Lurasidone - Olanzapine - Quetiapine - Clozapine - Asenapine Third generation: Aripripazole Brexipiprazole Cariprazine Also called atypical antipsychotics Lower incidence of EPS High risk of metabolic adverse effects (diabetes, hypercholesterolemia, weight gain) Block serotonin and dopamine receptors Used as first line drugs for schizophrenia More efficacious than first generation drugs Dopamine antagonism: All the 1st generation and most of the 2nd generation receptors block D2 receptors in the brain and the periphery Serotonin receptor blocking activity: Most 2nd generation agents block 5-HT receptors (esp. 5-HT2A) partial agonists at D2 and 5-HT1A, antagonist at 5-HT1A Clozapine: has high affinity for D1, D4, 5HT2, M and α receptors, but weak D2 receptor antagonist. Risperidone/ Olanzapine: blocks 5-HT2A receptor to a greater extent than D2. Quetiapine: weak blocker of D2 and 5HT2A (low risk of EPS is due to relatively short period of time that it bind to D2 receptor). Pimavanserin: inverse agonist of 5-HT2A; antagonist of 5-HT2C....indicated for psychosis associated with Parkinson’s ds. The antipsychotic action is due to blockade at dopamine and/or serotonin receptors. However, many agents also block cholinergic, adrenergic, and histaminergic receptors……resulting in undesirable side effects Most antipsychotic drugs bind to D2 dopamine receptors and block the action of dopamine. Antipsychotic effects Extrapyradimal effects Antiemetics effects Anticholinergic effects Other effects actions Antipsychotic actions Hallucinations and delusions (positive symptoms) are reduced.... … by blocking dopamine receptors in the mesolimbic system Negative effects (blunted affect, anhedonia, apathy), Impaired attention, Cognitive impairment are Not improved by typical antipsychotics… it is Improved by atypical antipsychotics (clozapine) Antiemetic Actions Block D2 receptors on chemoreceptor trigger zone (CTZ)…….leading to antiemetic action (except aripiprazole and thioridazine) Atypical antipsychotic drugs are not used as antiemetics Used for nausea due to: Vertigo, Motion sickness, Cancer chemotherapy Antimuscarini c Actions Some of the neuroleptics, particularly thioridazine, chlorpromazine, clozapine, and olanzapine, produce anticholinergic effects: Blurred vision Dry mouth (exception: clozapine increase salivation) Confusion Constipation and urinary retention The anticholinergic property may actually assist in reducing the risk of EPS with these agents Actions of Antipsychotics Orthostatic hypotension…..due to alpha receptor blockade Poikilothermia….due to alteration of temperature-regulating mechanisms Increased prolactin release….due to D2 blockade in pituitary (Atypical neuroleptics are less likely to produce prolactin elevations) Sedation…. H1-histamine receptor blockade due to chlorpromazine, olanzapine, quetiapine, and clozapine. Sexual dysfunction Weight gain….with 2nd generation agents Therapeutic uses Schizophrenia - Traditional antipsychotics are most effective in treating positive symptoms of schizophrenia (delusions, hallucinations, thought processing, and agitation) - Atypical antipsychotics with 5-HT2A receptor blocking activity may be effective in many patients who are resistant to the traditional agents - Clozapine is reserved for the treatment of refractory patients (10-20% cases), because its use is associated with bone marrow suppression, seizures and orthostasis Prevention of severe nausea and vomiting As tranquilizers to manage agitated and disruptive behavior secondary to other disorders. Treatment of chronic pain with severe anxiety (used along with opioids) Chlorpromazine is used to treat intractable hiccups.. Pimozide is indicated for treatment of the motor and phonic tics of Tourette's disorder (Risperidone & haloperidol are also commonly prescribed for this tic disorder) Risperidone & Aripiprazole is now approved for the management of disruptive behavior and irritability secondary to autism Management of manic and mixed symptoms of bipolar disorder Lurasidone and quetiapine are used for bipolar depression Paliperidone is used for schizoaffective disorder Also used as adjunctive drugs for refractory depression Pharmacokine tics Variable absorption through oral route Absorption is unaffected by food Readily pass into the brain, have a large volume of distribution, bind well to plasma proteins, and are metabolized to many different substances, usually by the cytochrome P450 system in the liver Long acting injectable (LAI) formulations: Fluphenazine decanoate, haloperidol decanoate, risperidone microspheres, paliperidone palmitate are LAIs Act for 2 – 4 weeks (some for 6-12 weeks) Used to treat outpatients who are non-adherent to medications Adverse effects Extrapyramidal effects - Occur after weeks to months - Treated with central anticholinergics (benztropine) Tardive dyskinesia - Occurs after months or years of treatment - Resolves after prolonged holiday from antipsychotics but may be irreversible - Valbenazine and Deutetrabenazine is used for management (vesicular monoamine transporter inhibitors) Neuroleptic malignant syndrome - Potentially fatal reaction - Fever, muscle rigidity, altered mental status, unstable BP, myoglobinemia - Supportive therapy (Dantrolene may be used) Others: - Drowsiness, confusion - Antimuscarinic side effects - Orthostatic hypotension - Depression of hypothalamus leading to amenorrhoea, galactorrhoea, infertility - Weight gain - Abnormal glucose and lipid profiles Cautions & Contraindicati ons All antipsychotics may lower the seizure threshold Increased risk of seizure from alcohol withdrawal All of the atypical antipsychotics also carry the warning of increased risk for mortality when used in elderly patients with dementia-related behavioral disturbances and psychosis There can be worsening of mood and suicidal ideation when used for mood disorders….monitoring required Key points First generation/typical antipsychotics: Block D2 receptors and differ significantly in potency.Low potency drugs like chlorpromazine are highly sedative whereas high potency drug cause less sedation. High potency drugs are more likely to causes extra pyramidal side effect. High potency drugs have low anticholinergic and autonomic side effects as compared to low potency drugs. All of these agents are potent antiemetic drugs Haloperidol is the most potent typical antipsychotic drugs whereas risperidone is most potent atypical antipychotic agent. Risk of Extrapyramidal side effect is negligible with clozapine, aripiprazole and quetiapine. Chloropromazine, thioridazine and clozapine posses strongest anticholinergic activity. Fluphenazine and haloperidol are long acting injectable (s.c or i.m) forms of typical antipsychotic. Risperidone is the atypical antipsychotic available in injectable form. Most commonly used antipsychotic by intravenous route is haloperidol Individual drugs: review Thioridazine: least Haloperidol: These are highly incidence of potent drugs and have least α extrapyramidal blocking , anticholinergic and symptoms among typical sedative action. anti psychotic drugs due Pimozide: Selectively block D2 to low potency D2 receptors without affecting α and blocking action. muscarinic receptors. It also possesses long duration of action. It carries the risk of arrhythmia. Clozapine ( Atypical Anti psychotic Drug): It is atypical anti psychotic drug having weak D2 blocking action. It mainly act by blacking 5HT receptors , α receptor and D2 receptors. It suppress both positive and negative symptom of schizophrenia. Most common adverse effect of clozapine is sedation. It has powerful anticholinergic effects. It is used as reserve drug due to risk of precipitation of sezures. Resiperidone: It act by blocking 5HT, α receptor and D2 receptors. It is more potent D2 blocker than clozapine and causes extra pyramidal symptom at high dose. Risk of precipitation of seizure is less in compare to clozapine. Olanzapine: It has similar mode of action then clozapine. it has potent anticholinergic drug and can cause dryness of mouth and constipation. Apart from schizophrenia, it is also used in acute mania and bipolar depression Calming effect and reduce spontaneous physical movement Do not depress the intellectual functioning Motor incoordination is minimal Improvement take several days to weeks to occur …therapeutic effects are related to secondary changes in corticostriatal pathways. Done by Sara Alzahrani Best of luck 1