Transcript Antipsychotic_agents

By
S.Bohlooli PhD
 Neuroleptic: synonym for antipsychotic drug;
originally indicated drug with antipsychotic efficacy
but also neurologic (extrapyramidal motor) side
effects
 Typical neuroleptic: older agents fitting
this description
 Atypical neuroleptic: newer agents:
antipsychotic efficacy with reduced or
no neurologic side effects
 TYPICAL NEUROLEPTICS:
 PHENOTHIAZINES:
 Chlorpromazine
 Thioridazine
 Fluphenazine
 THIOXANTHENE
 Thiothixene
 BUTYROPHENONES
 Haloperidol
 ATYPICAL NEUROLEPTICS:
 Risperidone
 Clozapine
 Olanzapine
 Quetiapine
 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.
 The older, typical neuroleptics are effective antipsychotic
agents with neurologic side effects involving the
extrapyramidal motor system.
 Typical neuroleptics block the dopamine-2 receptor.
 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.
 Typical neuroleptics are generally more effective
against positive (active) symptoms of schizophrenia
than the negative (passive) symptoms.
thought
disturbances, delusions, hallucinations
 Positive/active symptoms include
social
withdrawal, loss of drive, diminished affect,
paucity of speech. impaired personal
hygiene
 Negative/passive symptoms include
 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
 Relapse, recurrence of symptoms is common ( approx.
50% within two years).
 Noncompliance is common.
 Adverse effects are common.
 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
DOPAMINE-2 RECEPTOR BLOCKADE IN THE BASAL GANGLIA
RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS).
 DYSTONIA
 NEUROLEPTIC MALIGNANT SYNDROME
 PARKINSONISM
 TARDIVE DYSKINESIA
 AKATHISIA
 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)
 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.
 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
 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 >> hyperdopamine state >> tardive dyskinesia
 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
 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
 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
 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)
 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
 Blockade of alpha-1 adrenergic receptors
 Blockade of muscarinic cholinergic receptors
 Blockade of histamine-1 receptor
 Other adverse effects;
 Weight gain
 Increased salivation
 Increased risk of seizures
 Risk of agranulocytosis requires continual
monitoring
 Olanzapine is clozapine without the agranulocytosis.
 Same therapeutic effectiveness
 Same side effect profile
 Quetiapine is olanzapine without the anticholinergic
effects.
 Same therapeutic effectiveness
 Same side effect profile
 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
 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
 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.