Antipsychotic agents By S.Bohlooli PhD School of Medicine, Ardabil University of Medical Sciences

 Neuroleptic: synonym for antipsychotic drug; originally indicated drug with antipsychotic efficacy but also neurologic (extrapyramidal motor) side effects, now claimed as subtype of antipsychotic drugs  Typical neuroleptic: older agents fitting this description  atypical" antipsychotic : newer agents: antipsychotic efficacy with reduced or no neurologic side effects Introduction

 Reserpine  Chlorpromazine: neuroleptic agent  The discovery of clozapine was in 1959  antipsychotic drugs need not cause EPS History

 The presence of delusions (false beliefs)  Various types of hallucinations, usually auditory or visual, but sometimes tactile or olfactory  Disorganized thinking in a clear sensorium Nature of Psychosis & Schizophrenia

 Hallucinogens such as LSD (lysergic acid diethylamide) and mescaline are serotonin (5-HT) agonists  5-HT 2A -receptor blockade is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs such as clozapine and quetiapine.  5-HT 2C -receptor stimulation provides a further means of modulating The Serotonin Hypothesis of Schizophrenia

 Was the first neurotransmitter-based concept  Excessive limbic dopaminergic activity plays a role in psychosis  Many antipsychotic drugs strongly block postsynaptic D 2 receptors:  Includes partial dopamine agonists, such as aripiprazole and bifeprunox  Drugs that increase dopaminergic activity either aggravate schizophrenia psychosis or produce psychosis de novo  Dopamine-receptor density is high postmortem  The atypical antipsychotic drugs  Much less effect on D 2 receptors  Role of other dopamine receptors and to nondopamine receptors The Dopamine Hypothesis of Schizophrenia

 Glutamate is the major excitatory neurotransmitter in the brain  Phencyclidine and ketamine are noncompetitive inhibitors of the NMDA receptor  Hypofunction of NMDA receptors, located on GABAergic interneurons The Glutamate Hypothesis of Schizophrenia

Basic Pharmacology of Antipsychotic Agents

Chemical Types

Antipsychotic Drugs: Relation of Chemical Structure to Potency and Toxicities Chemical ClassDrug D 2 /5-HT 2A Ratio 1 Clinical Potency Extrapyramidal Toxicity Sedative Action Hypotensive Actions Phenothiazines AliphaticChlorpromazineHighLowMediumHigh PiperazineFluphenazineHigh LowVery low ThioxantheneThiothixeneVery highHighMedium ButyrophenoneHaloperidolMediumHighVery highLowVery low DibenzodiazepineClozapineVery lowMediumVery lowLowMedium BenzisoxazoleRisperidoneVery lowHigh Low 2 Low Thienobenzodiaze pine OlanzapineLowHighVery LowMediumLow DibenzothiazepineQuetiapineLow Very LowMediumLow to Medium DihydroindoloneZiprasidoneLowMediumVery LowLowVery Low DihydrocarbostyrilAripiprazoleMediumHighVery Low Low

 Absorption and Distribution  Readily but incompletely absorbed  Significant first-pass metabolism  Highly lipid-soluble and protein-bound  Metabolism  Almost completely metabolized  Drug-drug interactions should be considered Pharmacokinetics

Pharmacodynamics

 All neuroleptics are equally effective in treating psychoses, including schizophrenia, but differ in their tolerability.  All neuroleptics  block one or more types of DOPAMINE receptor, but differ in their other neurochemical effects.  show a significant delay before they become effective.  produce significant adverse effects. KEY CONCEPTS:

 The older, typical neuroleptics are effective antipsychotic agents with neurologic side effects involving the extrapyramidal motor system.  Typical neuroleptics block the dopamine-2 receptor. GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS

 Typical neuroleptics do not produce a general depression of the CNS, e.g. respiratory depression  Abuse, addiction, physical dependence do not develop to typical neuroleptics. GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS

 Typical neuroleptics are generally more effective against positive (active) symptoms of schizophrenia than the negative (passive) symptoms. GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS

 Positive/active symptoms include thought disturbances, delusions, hallucinations  Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech, impaired personal hygiene

 All appear equally effective; choice usually based on tolerability of side effects  Most common are haloperidol,chlorpromazine and thioridazine  Latency to beneficial effects; 4-6 week delay until full response is common  70-80% of patients respond, but 30-40% show only partial response THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS

 Relapse, recurrence of symptoms is common ( approx. 50% within two years).  Noncompliance is common.  Adverse effects are common. THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS (Continued)

 Anticholinergic (antimuscarinic) side effects:  Dry mouth, blurred vision, tachycardia, constipation, urinary retention, impotence  Antiadrenergic (Alpha-1) side effects:  Orthostatic hypotension, reflex tachycardia  Sedation  Antihistamine effect: sedation, weight gain ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS

 DYSTONIA  NEUROLEPTIC MALIGNANT SYNDROME  PARKINSONISM  TARDIVE DYSKINESIA  AKATHISIA KEY CONCEPT: DOPAMINE-2 RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS).

 Increased prolactin secretion (common with all; from dopamine blockade)  Weight gain (common, antihistamine effect?)  Photosensitivity (v. common w/ phenothiazines)  Lowered seizure threshold (common with all)  Leukopenia, agranulocytosis (rare; w/ phenothiazines)  Retinal pigmentopathy (rare; w/ phenothiazines) ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued)

 Chlorpromazine and thioridazine produce marked autonomic side effects and sedation; EPS tend to be weak (thioridazine) or moderate (chlorpromazine).  Haloperidol, thiothixene and fluphenazine produce weak autonomic and sedative effects, but EPS are marked. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued)

 DOPAMINE-2 receptor blockade in meso-limbic and meso-cortical systems for antipsychotic effect.  DOPAMINE-2 receptor blockade in basal ganglia (nigro-striatal system) for EPS  DOPAMINE-2 receptor supersensitivity in nigrostriatal system for tardive dyskinesia MECHANISMS OF ACTION OF TYPICAL NEUROLEPTICS and Some Side Effects

 Dopamine neurons reduce activity.  Postsynaptic D-2 receptor numbers increase (compensatory response).  When D2 blockade is reduced, DA neurons resume firing and stimulate increased # of receptors >> hyper-dopamine state >> tardive dyskinesia LONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE:

 Dystonia and parkinsonism: anticholinergic antiparkinson drugs  Neuroleptic malignant syndrome: muscle relaxants, DA agonists, supportive  Akathisia: benzodiazepines, propranolol  Tardive dyskinesia: increase neuroleptic dose; switch to clozapine MANAGEMENT OF EPS

 Adjunctive in acute manic episode  Tourette’s syndrome (Haloperidole )  Control of psychosis in depressed patient  Phenothiazines are effective anti-emetics,  Esp. prochlorperazine  Also, anti-migraine effect ADDITIONAL CLINICAL USES OF TYPICAL NEUROLEPTICS

Differences among Antipsychotic Drugs Chlorpromazine:  1 = 5-HT 2A > D 2 > D 1 Haloperidol: D 2 >  1 > D 4 > 5-HT 2A > D 1 > H 1 Clozapine: D 4 =  1 > 5-HT 2A > D 2 = D 1 Olanzapine: 5-HT 2A > H 1 > D 4 > D 2 >  1 > D 1 Aripiprazole: D 2 = 5-HT 2A > D 4 >  1 = H 1 >> D 1 Quetiapine: H 1 >  1 > M 1,3 > D 2 > 5-HT 2A

 Effective antipsychotic agents with greatly reduced or absent EPS, esp. reduced Parkinsonism and tardive dyskinesia  All atypical neuroleptics block dopamine and serotonin receptors; other neurochemical effects differ  Are effective against positive and negative symptoms of schizophrenia; and in patients refractory to typical neuroleptics GENERAL CHARACTERISTICS OF ATYPICAL Antipsychotic

 Combination of Dopamine-4 and Serotonin-2 receptor blockade in cortical and limbic areas for the “pines” like clozapine  Combination of Dopamine-2 and Serotonin-2 receptor blockade (esp. risperidone) HYPOTHESIZED MECHANISMS OF ACTION OF ATYPICAL NEUROLEPTICS

 FDA-approved for patients not responding to other agents or with severe tardive dyskinesia  Effective against negative symptoms  Also effective in bipolar disorder  Little or no parkinsonism, tardive dyskinesia, PRL elevation, neuro-malignant syndrome; some akathisia PHARMACOLOGY OF CLOZAPINE

 Other adverse effects;  Weight gain  Increased salivation  Increased risk of seizures  Risk of agranulocytosis requires continual monitoring PHARMACOLOGY OF CLOZAPINE (Continued )

 Olanzapine is clozapine without the agranulocytosis.  Same therapeutic effectiveness  Same side effect profile PHARMACOLOGY OF OLANZAPINE

 Quetiapine is olanzapine without the anticholinergic effects.  Same therapeutic effectiveness  Same side effect profile PHARMACOLOGY OF QUETIAPINE

 Highly effective against positive and negative symptoms  Adverse effects:  EPS incidence is dose-related  Alpha-1 receptor blockade  Little or no anticholinergic or antihistamine effects  Weight gain, PRL elevation Resperidone

Adverse Pharmacologic Effects of Antipsychotic Drugs TypeManifestationsMechanism Autonomic nervous system Loss of accommodation, dry mouth, difficulty urinating, constipation Muscarinic cholinoceptor blockade Orthostatic hypotension, impotence, failure to ejaculate Adrenoceptor blockade Central nervous system Parkinson's syndrome, akathisia, dystonias Dopamine-receptor blockade Tardivedyskinesia Supersensitivity of dopamine receptors Toxic-confusional stateMuscarinic blockade Endocrine system Amenorrhea-galactorrhea, infertility, impotence Dopamine-receptor blockade resulting in hyperprolactinemia OtherWeight gainPossibly combined H 1 and 5-HT 2 blockade

 Use typical for:  1st acute episode w/ + or +/- symptoms  Switch to atypical if:  Breakthrough after Rx w/ typical  Use typical (depot prep) when:  Patient is noncompliant General Therapeutic Principles for Use of Neuroleptics in Schizophrenia (NIH Consensus Statement, 1999)

 If response is inadequate to:  Typical; switch to Atypical  Atypical; raise dose or switch to another Atypical  Typical and Atypical; switch to clozapine ®  For maintenance, lifetime Rx is required. General Therapeutic Principles for Use of Neuroleptics in Schizophrenia