You are on page 1of 13

DEPARTMENT OF NEUROLOGY MADURAI MEDICAL COLLEGE MADURAI.

ANTI PSYCHOTIC DRUGS


FIRST GENERATION ANTI PSYCHOTICS (DOPAMINE RECEPTOR ANTAGONIST-DRA) I.PHENOTHIZINES Chlorpromazine Promazine Triflupromazine II PIPERZINE Fluphenazine Trifluperazine Perphenazine Prochlorperazine Trifluoperazine III THIOXANTHENES Chlorprothixene Thiothixene IV DIBENZOXAPINE Loxapine V DIHYDROINDOLE Molindone

VI Butyro phenones Droperidol Haloperidol

DISTRIBUTION antacids, coffee, smoking, and fatty foods interfere oral absorption Highly lipophilic Highly protein bound Accumulate in fat, lung, brain Malnutrition alter the bioavailability

METABOLISM & ELIMINATION Conjugation with glucuronic acid, hydroxylation, oxidation, demethylation, and sulfoxide formation FGAs are metabolized by the cytochrome P450 2D6 and P450 3A subfamilies in the liver. Same isoenzymes also metabolize a number of drugs that are commonly combined with antipsychotics, a number of important drugdrug interactions are possible.

ANTI PSYCHOTICS EQUIVALENT Chlorpromazine 100 mg = Fluphenazine 2 mg Trifluoperazine 5 mg Flupentixol 3 mg Haloperidol 3 mg Pimozide 2 mg Haloperidol depot 15 mg Flupentixol 10 mg 1

Medical condition Enzyme inducers Clearance inhibitors Changes in binding protein

Decreased Hepatic blood flow reduce clearance Carbamazipine, Phenytoin, Ethambutol, Barbiturates SSRI, TCA, Erythromycin, Cimetidine, blocker, Isoniazid,

Hypoalbuminemia- Malnutrition, Hepatic failure.

Indications for Dopamine Receptor Antagonists Acute psychotic episodes in schizophrenia and schizoaffective dsorder Maintenance treatment in schizophrenia and schizoaffective disiorders Mania Depression with psychotic symptoms Delusional disorder Borderline personality disorder Substance-induced psychotic disorder Delirium and dementia Mental disorders due to a medical condition Childhood schizophrenia Tourette's syndrome Huntington's disease

Tourette's Syndrome A neurobehavioral disorder marked by motor and vocal tics. Haloperidol and pimozide are the drugs most frequently used. Clonidine - lower risk of neurologic side effects. Pimozide has cardiac effects.

DEMENTIA AND DELIRIUM About two thirds of agitated, elderly patients with various forms of dementia with DRA. Low doses of high-potency drugs (e.g., 0.5 to 1 mg a day of haloperidol) are used. DRAs are also used to treat psychotic symptoms and agitation associated with delirium. The cause of the delirium needs to be determined, because toxic deliriums caused by anticholinergic agents can be exacerbated by low-potency DRAs, which often have significant antimuscarinic activity.

Substance-Induced Psychotic Disorder Intoxication with cocaine, amphetamines, alcohol, phencyclidine, or other drugs can cause psychotic symptoms. Symptoms tend to be time limited- avoid use of a DRA unless the patient is severely agitated and aggressive. Benzodiazepines can be used to calm the patient. 2

Patients are experiencing hallucinations or delusions as a result of alcohol withdrawal, DRAs may increase the risk of seizure

Seizure Threshold lower the seizure threshold. Chlorpromazine, thioridazine, and other low-potency drugs are thought to be more epileptogenic than are high-potency drugs. Molindone may be the least epileptogenic of the DRA drugs.

Sedation Block histamine H1 receptors Chlorpromazine is the most sedating typical antipsychotic. Bedtime dose eliminates from sedation, and tolerance for this adverse effect often develops.

Central Anticholinergic Effects severe agitation; disorientation to time, person, and place; hallucinations; seizures; high fever; and dilated pupils. Stupor and coma. The treatment of anticholinergic toxicity consists of discontinuing the causal agent or agents, close medical supervision, and physostigmine 2 mg by slow intravenous (IV) infusion, repeated within 1 hour as necessary. Too much physostigmine is dangerous, and symptoms of physostigmine toxicity include hyper salivation and sweating. Atropine sulfate (0.5 mg) can reverse the effects of physostigmine toxicity.

Orthostatic (Postural) Hypotension most common with low-potency drugs chlorpromazine, thioridazine, and chlorprothixene. Orthostatic hypotension is mediated by adrenergic blockade Occurs most frequently during the first few days of treatment. Tolerance often develops for this side effect. Patients should avoid caffeine and alcohol Drink at least 2 L of fluid a day

Peripheral Anticholinergic Effects dry mouth and nose, blurred vision, constipation, urinary retention, and mydriasis, are common with low-potency DRAs, -, chlorpromazine, thioridazine. Weight gain

Endocrine Effects Increased secretion of prolactin-breast enlargement, galactorrhea, amenorrhea, and inhibited orgasm in women and impotence in men. Risperidone- associated with an increase in prolactin levels

Sexual Adverse Effects Both men and women -can experience anorgasmia and decreased libido.

As many as 50 percent of men taking antipsychotics report ejaculatory and erectile disturbances. Sildenafil, vardenafil, or tadalafil are often used to treat psychotropic-induced orgasmic dysfunction Thioridazine is particularly associated with decreased libido and retrograde ejaculation in men.

Skin and Eye Effects Allergic dermatitis and photosensitivity - with low-potency agents. Urticarial, maculopapular, petechial, and edematous eruptions can occur early in treatment, generally in the first few weeks, and remit spontaneously. Resembles a severe sunburn -Chlorpromazine. Spend not more than 30 to 60 minutes in the sun, and use sunscreens. Long-term chlorpromazine use -blue-gray discoloration of skin areas exposed to sunlight. Discolorations resolve when the patient is switched to another medication. Irreversible retinal pigmentation is associated with use of thioridazine at dosages above 1,000 mg a day. The pigmentation can progress even after thioridazine administration is stopped resulting in blindness. Maximal recommended dosage of thioridazine is 800 mg per day. Chlorpromazine -whitish brown granular deposits concentrated in the anterior lens and posterior cornea and visible only by slit-lens examination. Conjunctiva is discolored by a brown pigment. No retinal damage is seen, and vision is almost never impaired. This condition gradually resolves when the chlorpromazine is discontinued.

PREGNANCY AND LACTATION A low correlation exists between the use of antipsychotics during pregnancy and congenital malformations. Nevertheless, antipsychotics should be avoided during pregnancy, particularly in the first trimester High-potency drugs, particularly fluphenazine are preferable to low-potency drugs, because the low-potency drugs are associated with hypotension. The DRAs are secreted in the breast milk Women taking these agents should be advised against breast-feeding.

Neurological Side Effects of Dopamine Receptor Antagonists I. Acute extrapyramidal syndromes Akathisia Acute dystonia Drug-induced parkinsonism Neuroleptic malignant syndrome

II. Chronic extrapyramidal syndromes Tardive dyskinesia 4

Perioral tremor

AKATHISIA Greek word akathizein, -inability to sit still. It is the most common acute manifestation of EPS and often the most distressing. shifting the weight from foot to foot, walking on the spot, inability to keep the legs still, feelings of inner restlessness, and the shifting of body positions in a chair. Patients with akathisia may describe a compelling urge to walk or to initiate movement. In mild cases, patients may experience a subjective feeling of restlessness, but not show increased motor activity. Akathisia may appear in the second or third day of antipsychotic treatment, but more frequently has its onset after 5 days.

ACUTE DYSTONIA Intermittent and sustained spasms of the muscles of the head and the neck, leading to involuntary movements. occur during the first hours to 3 days of drug treatment Opisthotonos and torticollis of the neck; oculogyric crisis, macroglossia and tongue protrusion, which can lead to choking; and laryngeal dystonias. Rarely, dystonias of laryngeal or pharyngeal muscles can lead to sudden death. Younger patients, particularly young males, are more likely to develop dystonias. They are more common when patients are treated with large dosages of high-potency FGAs. Respond rapidly to anti-parkinsonian medications and can usually be prevented by either pretreatment with anti-parkinsonian medications or by limiting the antipsychotic dosage prescribed.

DRUG-INDUCED PARKINSONISM Rigidity, bradykinesia, shuffling gait, and tremor. Occur during the first 5 to 30 days of treatment and may persist until the dosage is lowered or FGAs are discontinued. The first evidence of drug-induced parkinsonism may be a diminished arm swing or decreased facial expressiveness.

NEUROLEPTIC MALIGNANT SYNDROME Fatal side effect of DRA treatment- occur at any time during the course of DRA treatment. Symptoms extreme hyperthermia, severe muscular rigidity and dystonia, akinesia, mutism, confusion, agitation, increased pulse rate and blood pressure (BP) leading to cardiovascular collapse Laboratory findings : 5

Increased white blood cell (WBC) count, Creatinine phosphokinase, liver enzymes, plasma myoglobin, and myoglobinuria, occasionally associated with renal failure. The symptoms usually evolve over 24 to 72 hours, and the untreated syndrome lasts 10 to 14 days. Often missed in the early stages, and the withdrawal or agitation may mistakenly be considered to reflect increased psychosis. Men are affected more frequently than are women, and young persons are affected more commonly than are elderly persons. Rates are also increased when high doses of high-potency agents are used.

A mnemonic used to remember the features of NMS is FEVER. F Fever E Encephalopathy V Vitals unstable E Elevated enzymes (elevated CPK) R Rigidity of muscles Revised mnemonic for NMS: FALTER F Fever A Autonomic instability L Leukocytosis T Tremor E Elevated enzymes (elevated CPK) R Rigidity of muscles

TREATMENT Medical support to cool the person; Monitoring of vital signs, electrolytes, fluid balance, and renal output Symptomatic treatment of fever. Antiparkinsonian medications may reduce some of the muscle rigidity. Dantrolene (Dantrium), a skeletal muscle relaxant (0.8 to 2.5 mg/kg every 6 hours, up to a total dosage of 10 mg a day) Once the person can take oral medications, dantrolene can be given in doses of 100 to 200 mg a day. Bromocriptine (20 to 30 mg a day in four divided doses) or amantadine can be added to the regimen. Treatment should usually be continued for 5 to 10 days. When drug treatment is restarted, -consider switching to a low-potency drug or an SDA

Tardive Dyskinesia Movement disorder - chronic treatment with antipsychotic medications.

DD:

Mouth and tongue movements, such as lip smacking, sucking, and puckering as well as facial grimacing. Choreoathetoid-like movements of the fingers and toes and slow, writhing movements of the trunk. Younger patients tend to develop slower athetoid movements of the trunk, extremities, and neck.

Disorders of the basal ganglia (including Huntington's disease, Wilson's disease, and Sydenham's chorea), striatal hypercalcifications, hyperthyroidism, hypoparathyroidism, Increasing the dosage of medication is only appropriate when the movements are severe. Dosages of antipsychotic medication either decreased or discontinued, abnormal movements may worsen temporarily or appear for the first time and then diminish. Antiparkinsonian medications will often worsen the movements of TD.

Biological mechanism underlying TD is still controversial, - increased sensitivity of dopamine receptors in the basal ganglia. Extra pyramidal symptoms Tardive dyskinesia Sedation, somnolence NMS Orthostatic hypotension Tachycardia Prolactin increase Decreased ejaculatory volume Weight gain Sexual dysfunction D2 + + + + + + D1 5 HT + H1 + + + + 1 + + 2 + + + + + Ach -

SECOND GENERATION AGENTS Serotonine dopamine antagonists (SDAs) Second-generation or Atypical antipsychotic drugs. Risperidone Olanzapine Quetiapine Clozapine. Amisulpride, asenapine, Ziprasidone & aripiprazole 7

SDA CLOZAPINE

Major P450 Drugs that SGA Drugs that SGA pathway LEVELS LEVELS 1A2, 2D6, 3A4 Fluvoxamine Fluvoxamine paroxetine, (paroxetine, fluoxetine, fluoxetine, bupropion, bupropion, Cimetidine Cimetidine Caffeine Caffeine Ciprofloxacin Ciprofloxacin Erythromycin Erythromycin 2D6 Fluoxetine Paroxetine Bupropion Quinidine Fluvoxamine Ciprofloxacin Carbamazepine Phenytoin Phenobarbital Nicotine Carbamazepine Modafinil Omeprazole Carbamazepine Thioridazine Phenytoin Modafinil Carbamazepine Phenytoin Modafinil

RISPERIDONE

OLANZAPINE

1A2

QUETIAPINE

3A4

Nefazodone Ketoconazole Clarithromycin Erythromycin Protease inhibitors Nefazodone Ketoconazole Clarithromycin Erythromycin Protease inhibitors Fluoxetine Paroxetine Bupropion Quinidine Nefazodone Ketoconazole Clarithromycin Erythromycin Protease inhibitors

ZIPRASIDONE

3A4

ARIPIPRAZOLE

2D6, 3A4

Carbamazepine Phenytoin Modafinil

(1) low D2 receptor blocking effects (2) a reduced risk of extrapyramidal side effects -a reduced risk that probably extends to the occurrence of tardive dyskinesia as well (3) proved efficacy as treatments for schizophrenia (4) proved efficacy as treatments for acute mania.

RISPERIDONE Benzisoxazole. Undergoes extensive first-pass hepatic metabolism to 9-hydroxyrisperidone, active metabolite The combined half-life of risperidone and 9-hydroxyrisperidone averages 20 hours, once-daily dosing. Risperidone is an antagonist of the serotonin 5-HT2A, dopamine D2,1- and 2-adrenergic, and histamine H1 receptors. As potent an antagonist of D2 receptors as is haloperidol, risperidone is much less likely (except in high doses) than haloperidol to cause extrapyramidal symptoms in humans.

SIDE EFFECTS Extrapyramidal effects - Dosage dependent Weight gain, anxiety, nausea and vomiting, rhinitis, erectile dysfunction, orgasmic dysfunction, and increased pigmentation Discontinuation of risperidone use hyperkinesias, somnolence, and nausea. are extrapyramidal symptoms, dizziness,

Marked elevation of prolactin can occur. Weight gain occurs more commonly with risperidone use in children than in adults. Risperidone is available in 1-, 2-, 3-, and 4-mg tablets, and a 1-mg/mL oral solution and in M-tab form (rapidly dissolving). The initial dosage is usually 1 to 2 mg at night, which can then be raised to 4 mg per day. Dosages above 6 mg a day are associated with a higher incidence of adverse effects, particularly extrapyramidal symptoms. OLANZAPINE

85 percent is absorbed from the gastrointestinal (GI) tract, 40 percent of the dosage is inactivated by first-pass hepatic metabolism. Peak concentrations are reached in 5 hours, and the half-life averages 31 hours Once-daily dosing. 5-HT2A and D2 antagonism, olanzapine is an antagonist of the D 1, D4,1, 5-HT1A, muscarinic M1 through M5, and H1 receptors. Weight gain than other atypical antipsychotics Somnolence, dry mouth, dizziness, constipation, dyspepsia, increased akathisia, and tremor are associated with olanzapine use. A dose-related - extrapyramidal side effects. Periodic assessment of blood sugar, lipid proflie and transaminases during treatment with olanzapine. Available in 2.5-, 5-, 7.5-, 10-, 15- and 20-mg tablets. The initial dosage for treatment of psychosis is usually 5 or 10 mg For treatment of acute mania is usually 10 or 15 mg, given once daily. 9 appetite,

A 10 mg injection form is available for treatment of acute agitation in schizophrenia and bipolar disorder QUETIAPINE Dibenzothiazepine structurally related to clozapine Rapidly absorbed from the GI tract, with peak plasma concentrations reached in 1 to 2 hours. Steady-state half-life is about 7 hours Two or three times per day. Antagonist of D2 and 5-HT2, also blocks 5-HT6, Dl and HI, and 1 and 2 receptors. It does not block muscarinic or benzodiazepine receptors. Not associated with extrapyramidal symptoms. Somnolence, postural hypotension, and dizziness are - best managed with initial gradual upward titration of the dosage. Least likely to cause extrapyramidal side effects, Quetiapine is associated with modest weight gain increases in heart rate, constipation, and a transient rise in liver transaminases can also occur. cataract formation Available in 25-, 100-, and 200-mg tablets. Schizophrenia a target of 400 mg a day Mania and bipolar depression 800 mg and 300 mg respectively. Quetiapine in doses of 25 to 300 mg at night has been used for insomnia. ZIPRASIDONE Benzothiazolyl piperazine. Bioavailability doubles when ziprasidone is taken with food. Ziprasidone, - blocks 5-HT2A and D2 receptors. It is also an antagonist of 5-HT1D, 5-HT2C, D3, D4,1, and H1 receptors. It has very low affinity for D1, M1, and 2-receptors. Ziprasidone also has agonist activity at the serotonin 5-HT1A receptors and is a serotonin reuptake inhibitor and a norepinephrine reuptake(SNRI) inhibitor. Ziprasidone has antidepressant-like effects in nonschizophrenic patients. Dosages Ziprasidone is available in 20-, 40-, 60-, and 80-mg capsules. Ziprasidone for IM use comes as a single-use 20 mg/mL vial. Oral ziprasidone dosing should be initiated at 40 mg a day, divided into two daily doses. Somnolence, headache, dizziness, nausea, and lightheadedness. No weight gain and does not cause sustained prolactin elevation. The QTc interval has been shown to increase by an average 4.7 to 1.4 milliseconds in patients treated with 40 and 120 mg per day, respectively. 10

Ziprasidone is contraindicated Prolong the QTc interval. Ziprasidone should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. CLOZAPINE Dibenzodiazepine. Clozapine has two major metabolites, one of which, N-dimethyl clozapine, -pharmacologic activity. Clozapine is an antagonist of 5-HT2A, D1, D3, D4, and receptors. It has relatively low potency as a D2-receptor antagonist. clozapine does not cause EPS.

CLOZAPINE - Special Indications Severe tardive dyskinesia. - Abnormal movements return when discontinued. Intolerant of extrapyramidal side effects caused by other agents, treatment-resistant mania, severe psychotic depression, idiopathic Parkinson's disease, Huntington's disease, suicidal patients with schizophrenia or schizoaffective disorder Sedation, dizziness, syncope, changes, nausea, and vomiting. tachycardia, hypotension, electrocardiogram commonly, (ECG)

Fatigue, weight gain, various GI symptoms (most anticholinergic effects, and subjective muscle weakness.

constipation),

Sialorrhea, or hypersalivation, is a side effect that begins early in treatment and is most evident at night. -Impairment of swallowing - to put a towel over the pillow. Leukopenia, granulocytopenia, agranulocytosis, and fever occur in about 1 percent of patients. Clozapine is available in 25- and 100-mg tablets. The initial dosage is usually 25 mg one or two times daily. Dosages up to 900 mg a day can be used.

ARIPIPRAZOLE Potent 5-HT2A antagonist Treatment of both schizophrenia and acute mania. A partial D2 agonist. Partial D2 agonists compete at D2 receptors for endogenous dopamine. Aripiprazole is usually nonsedating and NO increased risk of weight gain and diabetes. Enhancing, neurocognitive functions. Aripiprazole is a quinoline derivative. Metabolized by CYP 3A4 and CYP 2D6 enzymes. 11

Dosages of 15, 20, and 30 mg a day.

EPS Tardive dyskinesia Seizures Sedation somnolence NMS Orthostatic hypotension QTc Agranulocytosis Prolactin release Weight gain

FGA ++ +++ 0-+ +, +++ + +, ++ 0-+ 0 ++ ++

Clozapine 0 0 +++ +++ + 0-+ 0 +++ 0 +++

Risperidone 0 (+) 0 + + + 0 0 ++ +

Olnzapine 0-+ ? + + + + 0 0 0 +++

Quetiapine 0 ? 0 + ? 0 + 0 0 +

Ziprasidone 0 ? 0 + ? 0 +++ 0 0 0

DRUG OF CHOICE I Choice Acute EPS Dyslipidaemia Impaired tolerance Aripiprazole, Olanzapine Aripiprazole, Ziprasidone Glucose Aripiprazole, Ziprasidone Aripiprazole, Quetiapine Aripiprazole Aripiprazole, Quitiapine Aripiprazole, Haloperidol Clozapine Olanzapine, Risperidone Clozapine, Olanzapine II choice Clozapine

Hyper prolactinaemia QT prolongation Sexual dysfunction Weight gain

Liver Impairment Safe Haloperidol Not safe Aripiprazole, Clozapine, Olanzepine, Risperidone Safe

Renal Impairment Not safe Clozapine, Olanzepine

Pregnancy Safe Chlopromazine, Haloperidol, Trifluperazine

Aripiprazole, Haloperidol, Risperidone

Dyslipidaemia Severe Olazepine, Quitiapine Modest risperidone Safe Aripiprazole, Ziprazidone

12

Risk of diabetes and impaired glucose tolerance with different anti psychotic drugs High Clozapine, Olanzapine Moderate Quetiapine, Risperidone Low Haloperidol Minimal Aripiprazole, Amisulpride, Asenapine, Ziprasidone

Anti Psychotic induced weight gain High Clozapine, Olanzapine Moderate Low Asenapine, Haloperidol,

Chlorpromazine, Amisulpride, Iloperidone, Quetiapine, Aripiprazole, Risperidone Ziprazidone

DEPOT PREPARATIONS Drug Flupentixol decanoate Fluphenazine decanoate Haloperidol decanoate zuclopenthixol decanoate Risperidone microspheres Olanzapine pamoate Paliperidone palmitate Injection site Buttock / thigh Gluteal Gluteal Buttock/thigh Deltoid/gluteal Gluteal Deltoid/ Gluteal Dose range (mg/week) 12.5 400 6.25 50 12.5 75 100 600 12.5 25 75 150 6.25 37.5 Dose interval(weeks) 24 25 4 24 2 24 Monthly

Risperidone is not esterified drug. It has to be kept in fridge. Test dose is not required. It takes 3 4 weeks for action. So, oral anti psychotic drug has to be given initial weeks. It is not suitable for treatment refractory Schizophrenia. Paliperidone palmitate is the major active metabolite of Risperidone (9 OH risperidone). It does not require cold storage. Available in pre filled syringe. No oral supplementation is required in the initiation of treatment. No test dose required.

REFERENCES: 1. Prescribing guidelines in Psychiatry 11 th edition David Taylor. 2. Comprehensive Text Book of Psychiatry 9 th Edition 3. Oxford Textbook of Psychiatry II edition. *********

13

You might also like