Antipsychotics Flashcards
Antipsychotics
Primarily used in treatment of schizophrenia but used for any disorder involving psychotic symptoms
- major tranquilizer is the original name (barbs and benzos minor tranquilizers) - antipsychotic effects were discovered when major tranquilizers were used to quiet institutionalized mental pts
- called neuroleptics- based on tendency to produce neurological side effects
Schizophrenia positive symptoms
hallucinations (auditory), delusions (inappropriate beliefs), disorganized
Schizophrenia negative symptoms
flat or inappropriate effect, social isolation or withdrawal, alogia (poverty of speech), avolition, anhedonia, cognitive deficits
Pathogenesis of schizophrenia
- neurodevelopmental
- 50% heritability
- likely involves aberrant dopaminergic, glutamatergic, and/or serotonergic activity
Dopamine neurochemical hypothesis
- positive symptoms arise from hyperactivity of CNS dopamine systems- mesolimbic and mesocortical (from ventral tegmental area to cortical and limbic areas)
- thought to be because L-DOPA can cause psychosis (too much dopamine), amphetamine (releases and blocks reuptake of dopamine) can cause psychosis and makes schizophrenics worse
Serotonin hypothesis
5-HT2a and 5-HT2c receptors mediate hallucinogenic effects
Glutamate
-phencyclidine and ketamine produce effects that resemble aspects of schizophrenia and exacerbate symptoms in schizophrenics
Mechanism of action of antipsychotics
true mechanism is unknown
- all are D2 dopamine receptor antagonists
- serotonin receptors and/or novel D2 like receptors (D3 or D4) may be involved
- also interact with other receptors (a1. Ach, histamine, etc) which contributes to side effects and varies with each drug- dirty drugs
Pharmacological effects of antipsychotics
initial- sedation, decreased agitation
In schizophrenics- positive symptoms improve over weeks to months of treatment (problem with dopamine hypothesis because of compensatory changes leading to upregulation of dopamine receptors lead to antipsychotic effects)
Negative symptoms- improved by newer drugs, but older typical drugs have little effect
In normal persons- dysphoria, disinterest, blunted affect
Antiemetic- blockage of dopamine receptors in CTZ, not useful for motion sickness
Early side effects
Neurological- extrapyramidal effects (EPS)- can cause dystonia (1-5 days), akathisia (5-60 days),
parkinsonian symptoms (tremor, rigidity, bradykinesia; 5-30 days) due to blockage of striatal dopamine receptors –can be treated with anticholinergics
More side effects
increased prolactin release due to blockade of D2 receptors- amenorrhea, gynecomastia, galactorrhea (dopamine inhibits prolactin release)
Weight gain, metabolic syndrome, diabetes
anti-histaminergic effects- sedation
orthostatic hypotension and sexual dysfunction- alpha adrenergic
anticholinergic effects (dry mouth)
CV alterations- prolonged QT
Blurred vision, retinitis pigmentosa (thioridazine)
neuroleptic malignant syndrome- treated with dantrolene- malignant hyperthermia due to impaired muscle activity and sweating
decreased seizure threshold
poikilothermy- can lead to hypothermia
long term side effects
tardive dyskinesia- abnormal movements and facial disfigurement, frequently irreversible
-may be due to long term dopaminergic receptor blockade
perioral tremor (rabbit syndrome)
blood dyscrasias- agranulocytosis can occur with clozapine and some phenothiazines
What drug causes agranulocytosis
clozapine
pharmacokinetics
IM, IV, PO
Highly lipophilic so can get into brain
Drug interactions
potentiate CNS depressants- barbiturates
- block dopamine agonists
- modify cv drugs
- inc risk of seizures with other drugs
Typical antipsychotics
- Effective against positive, but not negative symptoms
- Produce EPS and tardive dyskinesia
- all are D2 antagonists and are antagonists at variety of other receptors- confers unique SE
Phenothiazines
typical antipsychotics
Chlorpromazine- first antpsychotic
Fluphenazine
Thioridazine
Haloperidol
typical antipsychotic
most widely prescribed antipsychotics
relatively more selective for dopamine receptors- highest incidence of EPS
also used for tourettes, huntingtons
Thiothixene
Other structure of typical antipsychotic
Atypical antipsychotic
- No EPS or tardive dyskinesia, antagonist at 5HT2 receptors
- Clozapine- 5HT2>D2
- activity at lots of receptors
- some effect on negative symptoms as well as positive symptoms
agranulocytosis in abt 3% of pts
approved ONLY for treatment resistant pts who must receive regular blood tests
Newer antipsychotic
- trying to achieve atypical profile
- significant 5-HT2 antagonist activity
- generally improved side effects because of fewer extraneous receptor interactions
Resperidone
- newer antipsychotic
- 5HT2=D2
- EPS at higher doses, does not effect negative symptoms
Lurasidone
5HT2, D2, 5HT7
-newer antipsychotic
less incidence of EPS
also used for depression in bipolar disorder
Olanzepine
newer even less EPS 5HT2> D2 high incidence of weight gain and metabolic syndrome may improve negative symptoms
Quetiapine
newer antipsychotic
5Ht2=D2
high incidence of weight gain and metabolic syndrome
may improve negative symptoms
Ziprasidone
newer antipsychotic
D2, 5-HT2A, 5-HT1d antagonist
5-HT1a agonist
Aripiprazole
D2, 5HT1a partial agonist
5-HT2A antagonist
partial agonism at D2 receptors may allow for sufficient stimulation to prevent EPS while preventing over stimulation
used for refractory depression
Other uses of antipsychotics
management of agitation and psychotic symptoms in acute mania and bipolar disorder, delirium, depentia, alcoholic hallucinosis (during heavy drinking, not withdrawal because of inc risk of seizures)
-maintenance of bipolar disorder
dopamine agonist induced psychotic symtpoms- parkinson’s
tourettes, huntingtons, refractory depression, depression in bipolar disease
