Download Antipsychotic agents

Antipsychotic agents
By
S.Bohlooli PhD
School of Medicine, Ardabil University of Medical Sciences
Introduction
 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
History
 Reserpine
 Chlorpromazine: neuroleptic agent
 The discovery of clozapine was in 1959
 antipsychotic drugs need not cause EPS
Nature of Psychosis & Schizophrenia
 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
The Serotonin Hypothesis of
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 Dopamine 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 Glutamate 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
Basic Pharmacology of
Antipsychotic Agents
Chemical Types
Chemical Types
Chemical Types
Antipsychotic Drugs: Relation of Chemical Structure to
Potency and Toxicities
Drug
D2/5-HT2A Ratio1
Clinical Potency
Extrapyramidal
Toxicity
Sedative Action
Hypotensive
Actions
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
Very low
High
Low2
Low
Low
Thienobenzodiaze Olanzapine
pine
Low
High
Very Low
Medium
Low
Dibenzothiazepine Quetiapine
Low
Low
Very Low
Medium
Low to Medium
Dihydroindolone
Low
Medium
Very Low
Low
Very Low
Medium
High
Very Low
Very Low
Low
Chemical Class
Phenothiazines
Risperidone
Ziprasidone
Dihydrocarbostyril Aripiprazole
Pharmacokinetics
 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
Pharmacodynamics
KEY CONCEPTS:
 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.
GENERAL CHARACTERISTICS OF TYPICAL
NEUROLEPTICS
 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.
 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
THERAPEUTIC EFFECTS OF TYPICAL
NEUROLEPTICS
 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 (Continued)
 Relapse, recurrence of symptoms is common ( approx. 50%
within two years).
 Noncompliance is common.
 Adverse effects are common.
ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
 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
KEY CONCEPT: DOPAMINE-2
RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS
IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS).





DYSTONIA
NEUROLEPTIC MALIGNANT SYNDROME
PARKINSONISM
TARDIVE DYSKINESIA
AKATHISIA
ADVERSE EFFECTS OF TYPICAL
NEUROLEPTICS (Continued)
 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.
MECHANISMS OF ACTION
OF TYPICAL NEUROLEPTICS and Some Side
Effects
 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
LONG TERM EFFECTS OF D2 RECEPTOR
BLOCKADE:
 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
MANAGEMENT OF EPS
 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
ADDITIONAL CLINICAL USES OF TYPICAL
NEUROLEPTICS




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
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
GENERAL CHARACTERISTICS OF ATYPICAL
Antipsychotic
 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
HYPOTHESIZED MECHANISMS OF ACTION OF
ATYPICAL NEUROLEPTICS
 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)
PHARMACOLOGY OF CLOZAPINE
 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 (Continued )
 Other adverse effects;
 Weight gain
 Increased salivation
 Increased risk of seizures
 Risk of agranulocytosis requires
continual monitoring
PHARMACOLOGY OF OLANZAPINE
 Olanzapine is clozapine without the agranulocytosis.
 Same therapeutic effectiveness
 Same side effect profile
PHARMACOLOGY OF QUETIAPINE
 Quetiapine is olanzapine without the anticholinergic effects.
 Same therapeutic effectiveness
 Same side effect profile
Resperidone
 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
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, Dopamine-receptor blockade
dystonias
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
General Therapeutic Principles for Use of
Neuroleptics in Schizophrenia
(NIH Consensus Statement, 1999)
 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
 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.