Antipsychotic Drugs Flashcards
What tract is the source of psychosis?
Mesolimbic Tract
What is thought to be the cause of schizophrenia?
Too much DOPA activity
What about the medications used to treat schizophrenia supported the dopamine hypothesis?
The greater the D2 antagonistic binding affinity of a drug, the less of that drug that was needed to reach a therapeutic dose in schizophrenia.
What were the problems with the 1st generation treatments of schizophrenia?
They only treated the positive symptoms and a large proportion of patients did not respond to treatment.
What was the first antipsychotic medication?
Chlorpromazine
What is the main MOA of 1st generation antipsychotic drugs?
Blockage of D2 receptors in the mesolimbic tract
What other receptors can chlorpramazine (low potency antipsychotic) bind to that leads to other SE?
- Muscarinic
- Adrenergic
- Histamine
- Non-mesolimbic dopamine (nigrostriatal, tuberoinfundibular)
Chlorpromazine Ocular SE
Corneal deposits
Thioridazine Ocular SE
Retinal deposits
Chlorpramazine SE
DOPA - increased prolactin
M1 - blurred vision/urinary retention/dry mouth
α1 - orthostatic hypotension
H1 - sedation/weight gain
What is the cholinergic activity of the low potency antipsychotics like chlorpramazine?
Anti-cholinergic
What is the normal action of DOPA on ACh activity?
Inhibitory
What are the high potency antipsychotics?
- Haloperidol
- Fluphenazine
What other receptors can haloperidol (high potency antipsychotic) bind to that leads to other SE?
- Non-mesolimbic dopamine
Haloperidol SE
- Parkinsonian-like effects
- Akathesia
- Tardive dyskinesia
What patients are at greater risk for acute/tardive dyskinesia on haloperidol?
Young males
What are the classic tardive dyskinesia movements?
Oro-facial movements of blinking and tongue movements
What are the SE that occur due to action of antipsychotics on the tuberoinfundibular tract?
Increased prolactin leads to galactorrhea with interruption of menstruation and osteopenia.
What are the most important 1st generation antipsychotics?
- Chlorpromazine
- Thiothixene
- Haloperidol
What is the MOA of the 2nd generation antipsychotics?
5HT and DOPA dual antagonism blocking the dopamine and serotonin receptors
How does serotonin antagonism reverse DOPA antagonism?
Serotonin normally acts on pre-synaptic DOPA neurons to inhibit the release of DOPA. Blockage of this receptor will cause the pouring out of DOPA from the presynaptic terminal.
Risperidone SE
- Exrapyramidal effects
- Orthostatic hypotension
NO M1 or H1 effects
Ziprasidone SE
- Extrapyramidal effects
- Orthostatic hypotension
- Sedation
Quetiapine SE
- Orthostatic hypotension
- Anticholinergic effects
- Sedation
Olanzapine SE
- Extrapyramidal effects
- Orthostatic hypotension
- Anticholinergic effects
- Sedation
Clozapine SE
- Agranulocytosis
- Myocarditis
- Increased seizures
- Orthostatic hypotension
- Anticholinergic effects
- Sedation
What is a side effect that all of the 2nd generation antipsychotics have?
Metabolic syndrome - weight gain/glucose intolerance
Aripiprazole MOA
Partial agonist of the D2 receptors that is unique because it will keep less than 80% of the D2 receptor blocked but also more than 65% by switching from agonist to antagonist
What is a unique benefit of clozapine?
Decreases risk of suicide
Neuroleptic Malignant Syndrome
DOPA systems goes haywire leading to fever, muscle rigidity and tremor and increased CPK
What is the treatment for neuroleptic malignant syndrome?
Stop the DOPA blocker - use dantrolene as treatment but it’s still controversial
What is a rare SE of antipsychotics in the elderly with dementia?
Rare increase in sudden death
Which of the 2nd generation antipsychotic has the longest half life?
Aripiprazole - around 3 days
What 2nd generation antipsychotic can increase the QT interval?
Ziprasidone
What is a unique SE of lurasidone?
Akathesia
What is the metabolite of risperidone?
Palliperidone
What is an advantage of haloperidol over chlorpromazine?
Haloperidol does not have any of the muscarinic, adrenergic or histamine related side effects.
Hit and Run Concept
Atypical drug-induced blockade of DA2 receptors is looser and not as long-lasting as with typical drugs. The blockade is present long enough to have the antipsychotic therapeutic effect but not long enough to cause side effects.
