Antipsychotic Drugs PDF

ANTIPSYCHOTICS DRUG DR. SADIA KAZI ASSOCIATE PROFESSOR DEPARTMENT OF PHARMACOLOGY  SCHIZOPHRENIA Psychosis a Greek words, Psyche means “mind” & osis means “disease or abnormal condition” Schizophrenia is a type of psychosis th...

ANTIPSYCHOTICS DRUG DR. SADIA KAZI ASSOCIATE PROFESSOR DEPARTMENT OF PHARMACOLOGY  SCHIZOPHRENIA Psychosis a Greek words, Psyche means “mind” & osis means “disease or abnormal condition” Schizophrenia is a type of psychosis that is, a mental disorder caused by some inherent dysfunction of the brain. it affects young people, is often chronic and is usually highly disabling Etiology: hereditary and evidence suggestive of a fundamental biological disorder The main neurotransmitters involved in the pathogenesis of schizophrenia are dopamine and serotonin. Evidence is suggestive of psychosis is due to overactivity of dopamine in the mesolimbic and mesocortical pathway of the brain  CLINICAL FEATURES OF SCHIZOPHRENIA Positive symptoms (are those that can be regarded as abnormality or exaggeration of normal functions): Delusions (often paranoid in nature) Hallucinations (often in the form of voices which may be exhortatory in their message) Thought disorder (comprising wild trains of thought, Abnormal disorganized behavior (such as stereotyped movements, disorientation and aggressive behaviors) Catatonia (can be apparent as immobility or purposeless motor activity). Negative symptoms (a those that indicate a loss or decrease in function): Withdrawal from social contacts Flattening of emotional responses Anhedonia (an inability to experience pleasure) cognitive impairment Reluctance to perform everyday tasks.  HISTORY Antipsychotic drugs have been used in western medicine for more than 50 years. Chlorpromazine and risperidone were the 1st drugs found to be useful in schizophrenia. 1st generation antipsychotics known as typical antipsychotic drugs were discovered in 1950s. 2nd generation antipsychotics known as atypical antipsychotic drugs, clozapine were discovered in 1960s and introduced clinically in 1970s.  ANTIPSYCHOTIC DRUGS The neuroleptic drugs also called antipsychotic drugs or major tranquilizers. Antipsychotic drugs are able to reduce psychotic symptoms in a wide variety of conditions, including schizophrenia, bipolar disorder, psychotic depression, senile psychoses, and drug- induced psychoses (levodopa, CNS stimulants, apomorphine) Neuroleptic drugs are not curative and do not eliminate the fundamental and chronic thought disorder, but they often decrease the intensity of sign & symptoms of patients with schizophrenia to function in a supportive environment.  CLASSIFICATION OF ANTIPSYCHOTIC DRUGS Typical antipsychotic drugs are also Antipsychotic Drugs known as 1st generation antipsychotics while atypical antipsychotic drugs are Typical Antipsychotic Atypical Antipsychotic also known as 2st generation Drugs Drugs antipsychotics. Receptor profile: typical antipsychotics Butyrophenone Phenothiazine Thioxanthene Clozapine Derivatives Derivatives Derivatives are highly bound to dopamine receptors while atypical antipsychotics Haloperidol Chlorpromazine Thiothixene Olanzapine have high affinity for serotonin, dopamine and other receptors as well) Incidence of extrapyramidal side effects Fluphenazine Quetiapine less in atypical antipsychotics as compared to typical antipsychotic Procholrperazine Paliperidone drugs. Typical antipsychotic have efficacy Thioridazine Risperidone against positive symptoms while atypical antipsychotics have efficacy against negative symptoms of Ziprasidone schizophrenia. Aripiprazole  DOPAMINE The synthesis of dopamine is conversion of tyrosine to dopa (the rate-limiting step), followed by decarboxylation to form dopamine. Dopaminergic neurons lack dopamine hydroxylase, and thus do not convert dopamine to noradrenaline. Dopamine receptors: D1 & D5 are Gs coupled, stimulate adenylyl cyclase D2, D3, and D4 are Gi coupled, inhibits adenylyl cyclase & activate potassium channels There are four main dopaminergic pathways: MESOLIMBIC & MESOCORTICAL PATHWAY: Cell bodies in brain project to cerebrocortical and limbic structures. Involved in emotion and behavior, congnitive impairement & sensory perception. NIGROSTRIATAL PATHWAY: Cell bodies in substantia niagra project to straitum Involved in motor control TUBEROFUNDIBULAR PATHWAY: Cell bodies in hypothalamus and project to anterior pituitary. Regulate the prolactin secretions. CHEMORECEPTOR TRIGGER ZONE Causes vomiting. DRUG TARGETS RECEPTOR DISTRIBUTION OF ANTIPSYCHOTIC DRUGS DOPAMINE RECEPTORS: D1, D2, D3, D4, D5 SEROTONIN RECEPTORS: 5HT-1A, 2A, 3, 6, 7 NOREPINEPHRINE RECEPTORS: α1 & α2 MUSCARNIC ACETYLCHOLINE RECEPTORS: mACh 1-4 HISTAMINE RECEPTORS: H-1 & H-2 NMDA GLUTAMATE RECEPTORS MECHANISM OF ACTION OF ANTIPSYCHOTIC DRUGS DOPAMINE RECEPTOR BLOCKING ACTIVITY IN THE BRAIN: All of the older and most of the newer neuroleptic drugs block dopamine receptors in the brain and the periphery. Five types of dopamine receptors have been identified. D1 and D5 receptors activate adenylyl cyclase, often exciting neurons, whereas D2, D3 and D4 receptors inhibit adenylyl cyclase, or mediate membrane K+ channel opening leading to neuronal hyperpolarization. The typical neuroleptic drugs ability to block d2 receptors in the mesolimbic system of the brain. The atypical drugs has higher affinity for the other types dopamine receptor and lower affinity for the d2 receptor. The actions of the neuroleptic drugs are antagonized by agents that raise synaptic dopamine concentrations i-e, levodopa and amphetamine SEROTONIN RECEPTOR BLOCKING ACTIVITY IN THE BRAIN: Most of the newer atypical agents appear to exert part of their unique action through inhibition of serotonin receptors (5-HT), particularly 5-HT2A receptors. Clozapine has high affinity for d1, d4, 5-ht2, muscarinic, and α- adrenergic receptors. Risperidone & olanzapine blocks 5-ht2a receptors to a greater extent than it does d2 receptors. The atypical neuroleptic aripiprazole is a partial agonist at d2 and 5-ht1a receptors as well as a blocker of 5-ht2a receptors. Quetiapine blocks d2 receptors for short period more potently than 5ht2a receptors. OTHER RECEPTOR BLOCKING ACTIVITY: Some typical neuroleptics i-e chlorpromazine, thiothixenes and most typical neuroleptics blocks other receptors as well. Those receptors may be α- adrenergic, muscarinic and histamine. PHARMAKOKINETICS OF ANTIPSYCHOTIC DRUGS The antipsychotic drugs are well absorbed when given orally. Parenteral forms of many agents (eg, fluphenazine, haloperidol) are available for both rapid initiation of therapy and depot treatment. They have long plasma half-lives that permit once daily dosing. As they are lipid soluble, they readily enter the CNS and most other body tissues. Many are bound extensively to plasma proteins. These drugs require metabolism by liver enzymes so other drugs that inhibit cytochrome P450 enzymes can prolong the half-lives of antipsychotic agents. GROUP ACTIONS OF ANTIPSYCHOTIC DRUGS ANTIPSYCHOTIC ACTIONS: Blocking of dopamine receptors in the mesolimbic & mesocortical pathway probably causes antipsychotic action. All of the neuroleptic drugs can reduce the hallucinations and delusions (positive symptoms) associated with schizophrenia by blocking dopamine receptors in the mesolimbic system of the brain. Blunted affect, anhedonia, apathy, and impaired attention, as well as cognitive impairment (negative symptoms) are reduced by blocking serotonin and other receptors as well. Positive symptoms: usually respond to typical antipsychotic drugs Negative symptoms: usually respond to atypical antipsychotic drugs EXTRAPYRAMIDAL EFFECTS: Blocking of dopamine receptors in the nigrostriatal pathway probably causes these unwanted movement symptoms & Blockade of dopamine receptors increases the activity of acetylcholine so over activity of acetylcholine causes EPSE. Dystonia (sustained contraction of muscles leading to twisting distorted postures), Parkinson-like symptoms, akathisia (motor restlessness) Tardive dyskinesia (involuntary movements of the tongue, lips, neck, trunk, and limbs) occur with chronic treatment. The typical neuroleptics have high incidence of these symptoms as compared to atypical neuroleptics. ANTIEMETIC EFFECTS: Most of the typical antipsychotic drugs have antiemetic effects that are mediated by blocking D2-dopaminergic receptors of the chemoreceptor trigger zone of the medulla. The atypical antipsychotic drugs are not used as antiemetics. HYPERPROLACTINEMIA: In the pituitary, typical antipsychotic drugs block D2 receptors, leading to an increase in prolactin release. In males: gynecomastia In females: menstrual disturbances Atypical neuroleptics are less likely to produce prolactin elevations. BLOCKADE OF CHOLINERGIC RECEPTORS: Blurred vision, dry mouth, confusion, and inhibition of gastrointestinal and urinary tract smooth muscle, leading to constipation and urinary retention. This anticholinergic property may actually assist in reducing the risk of eps with these agents. BLOCKADE OF α-ADRENERGIC RECEPTORS: Orthostatic hypotension and light-headedness. BLOCKADE OF H1-HISTAMINE RECEPTOR : Sedation OTHER EFFECTS: Sexual dysfunction, weight gain, temperature regulation problems. CLINICAL USES OF ANTIPSYCHOTIC DRUGS Treatment of schizophrenia: Typical Antipsychotic drugs reduce some of the positive symptoms of schizophrenia, including hyperactivity, hallucinations, and delusions while Newer atypical drugs are used to improve the negative symptoms of schizophrenia, including emotional blunting, social withdrawal, and lack of motivation. clozapine is effective in some schizophrenic patients resistant to treatment with other antipsychotic drugs. Beneficial effects may take several weeks to develop. Mania (bipolar disorder): INITIAL TREATMENT OF MANIA: atypical antipsychotics are used with lithium MAINTAINANCE OF MANIA: olanzapine, aripiprazole and quetiapine are approved ADJUVENT TO ANTIDEPRESSENTS FOR TREATMENT OF REFACTORY DEPRESSION: aripiprazole and quetiapine are used.  As tranqulizer to manage agitated and disruptive behavior. Pimozide is used for treatment of psychotic symptoms i-e motor and phonic tics of tourette's disorder. However, risperidone and haloperidol are also commonly prescribed for this tic disorder. Antipsychotics are used for management of toxic psychoses caused by overdosage of certain cns stimulants. Risperidone is now approved for the management of disruptive behavior and irritability secondary to autism. Prevention of severe drug nausea and vomiting: prochlorperazine Treatment of chronic pain with severe anxiety adjuvant with opioids. Hiccups: chlorpromazine Antipuritis & sedtion: promethazine  SIDE EFFECTS OF ANTIPSYCHOTIC DRUGS EXTRAPYRAMIDAL SIDE EFFECTS (BLOCKING OF DOPAMINE RECEPTORS IN THE NIGROSTRIATAL PATHWAY OR OVER ACTIVITY OF ACETYLCHOLINE DUE TO BLOCKADE OF DOPAMINE RECEPTORS) Extrapyramidal effects are in dose-dependent. Extrapyramidal toxicity occurs most frequently occurs with typical neuroleptic drugs such as haloperidol and fluphenazine as compared to atypical neuroleptics. EARLY PHASE (REVERSIBLE): Dystonia (sustained contraction of muscles leading to twisting distorted postures) Akathisia (motor restlessness). Parkinson-like syndrome with bradykinesia, rigidity, and tremor. This toxicity can be reversed antagonized by concomitant use of muscarinic blocking agents.  LATE PHASE (IRREVERSIBLE): Tardive dyskinesia (involuntary movements of the tongue, lips, neck, trunk, and limbs) occurs with after months or years of treatment. Tardive dyskinesia results from an increased number of dopamine receptors that are synthesized as a compensatory response to long- term dopamine-receptor blockade. This makes the neuron supersensitive to the actions of dopamine, causing excess involuntary movement in the patient. Tardive dyskinesia may be attenuated temporarily by increasing neuroleptic dosage. NB: Anticholinergic drugs increases the tardive dyskinesia.  ENDOCRINE EFFECTS (DUE TO BLOCKADE OF DOPAMINE D2 RECEPTOR IN THE PITUITARY ): Endocrine effects include hyperprolactinemia, In males: gynecomastia, infertility In females: menstrual disturbances i-e amenorrhea-galactorrhea Elevated prolactin is prominent all typical neuroleptic drugs and with risperidone. Significant weight gain occur with several of the atypical agents, especially clozapine and olanzapine. Glucose and lipid profiles be monitored in patients taking antipsychotics due to the potential for the atypical agents to increase these laboratory parameters and the possible exacerbation of preexisting diabetes mellitus or hyperlipidemia. NEUROLEPTIC MALIGNANT SYNDROME Patients who are particularly sensitive to the extrapyramidal effects of antipsychotic drugs may develop a malignant hyperthermia syndrome. The symptoms include muscle rigidity, impairment of sweating, hyperpyrexia, and autonomic instability, which may be life threatening. Treatment includes, Discontinue neuroleptic drugs Dantrolene Diazepam Bromocriptine AUTONOMIC EFFECTS: MUSCARINIC RECEPTOR BLOCKADE: dry mouth, constipation, urinary retention, and visual problems are often pronounced with the use of thioridazine, Chlorpromazine, clozapine α-RECEPTOR BLOCKADE: postural hypotension caused by older drugs, especially chlorpromazine, clozapine and ziprasidone. In the elderly, measures must be Failure to ejaculate is common in men treated with the chlorpromazine. H1 RECEPTOR BLOCKADE : Sedation is more marked with chlorpromazine than with other antipsychotics MISCELLANEOUS TOXICITIES: Visual impairment caused by retinal deposits has occurred with thioridazine At high doses, thioridazine may also cause severe conduction defects in the heart resulting in fatal ventricular arrhythmias. Most of the atypicals, especially quetiapine and ziprasidone, prolong the qt interval of the ECG, the underlying myocardial effect could lead to cardiac arrhythmias (eg, torsades) in some patients. Clozapine should be reserved for severely schizophrenic patients who are refractory to traditional therapy as they causes a small but important (1–2%) incidence of bone marrow suppression and at high doses has caused seizures and cardiovascular side effects. Risk of severe agranulocytosis necessitates frequent monitoring of white-blood-cell counts CAUTIONS AND CONTRAINDICATIONS: Acute agitation accompanying withdrawal from alcohol or other drugs may be aggravated by the neuroleptics. Stabilization with a simple sedative, such as a benzodiazepine, is the preferred treatment. Chlorpromazine and clozapine are contraindicated in patients with seizure disorders, as they can aggravate preexisting epilepsy The high incidence of agranulocytosis with clozapine may limit its use to patients who are resistant to other drugs. All of the atypical antipsychotics have increased risk for mortality when used in elderly patients with dementia-related behavioral disturbances and psychosis.