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

Antipsychotic agents

ByS.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-HT2A-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-HT2C-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 D2

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 D2 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

Chemical Types

Chemical Types

Antipsychotic Drugs: Relation of Chemical Structure to Potency and Toxicities

Chemical Class

Drug D2/5-HT2A

Ratio1

Clinical Potency

Extrapyramidal Toxicity

Sedative Action

Hypotensive Actions

Phenothiazines

  Aliphatic Chlorpromazine High Low Medium High High

  Piperazine Fluphenazine High High High Low Very low

Thioxanthene Thiothixene Very high High Medium Medium Medium

Butyrophenone

Haloperidol Medium High Very high Low Very low

Dibenzodiazepine

Clozapine Very low Medium Very low Low Medium

Benzisoxazole Risperidone Very low High Low2

 Low Low

Thienobenzodiazepine

Olanzapine Low High Very Low Medium Low

Dibenzothiazepine

Quetiapine Low Low Very Low Medium Low to Medium

Dihydroindolone

Ziprasidone Low Medium Very Low Low Very Low

Dihydrocarbostyril

Aripiprazole Medium High Very Low Very 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-HT2A > D2 > D1

Haloperidol: D2 > 1 > D4 > 5-HT2A > D1 > H1

Clozapine: D4 = 1 > 5-HT2A > D2 = D1

Olanzapine: 5-HT2A > H1 > D4 > D2 > 1 > D1

Aripiprazole: D2 = 5-HT2A > D4 > 1 = H1 >> D1

Quetiapine: H1 > 1 > M1,3 > D2 > 5-HT2A

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

Type Manifestations Mechanism

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 state Muscarinic blockade

Endocrine system Amenorrhea-galactorrhea, infertility, impotence

Dopamine-receptor blockade resulting in hyperprolactinemia

Other Weight gain Possibly combined H1 and 5-

HT2 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