Pharmacology of Antipsychotic Drugs Part A Flashcards
Autonomic Side effects: manifestations of antipsychotic drugs.
dry mouth, difficulty urinating, constipation: muscarinic cholinoceptor blockade
orthostatic hypotension: Alpha adrenoceptor blockade
Central nervous system SE manifestations
parkinsons syndrome akathasia dystonias: Dopamine receptor blockade
Tardive dyskinesia: supersensitivity of dopamine receptors
Toxic confusional state: muscarinic blockade
Sedation:Histamine receptor blockade
First generation antipsychotics
Strong D2 antagonists-> primary therapeutic effect in the mesolimbic system. D1 not effective.
effective in controlling positive symptoms important SE extrapyramidal symptoms risk of tardive dyskinesia after months or years of tx
What structure is seen in some typical first generation antipsychotics?
phenothiazine nucleus or butyrophenone
phenothiazine nucleus
Chlorpromazine (thorazine)
a first generation antipshychotic, the first drug that worked well.
D2 antagonist (with activity at 5HT2A that is likely clinically important. known as a dirty drug as it has multiple undisired targets like antihistimine, no longer used as first line drug.
Promazine (sparine)
a first generation antipsychotic
Triflupromazine (vesprin)
a first generation antipsychotic
promethazine (Phenergan)
a first generation antipsychotic. phenothiazine that serves as an antihistamine
trimeprazine (Temaril)
a first generation antipsychotic phenothiazine that serves as an antihistamine
haloperidol (haldol)
a first generation antipsychotic that is more selective D2 antagonist than chlorpromazine and is no longer used as a first line drug due to unfavorable SE
droperidol (Inapsine)
a first generation antipsychotic that is highly sedative (anesthetic) and anxiolytic
Droperidol with fentanyl (innovar)
a first generation antipsychotic has chemical structure of butyrophenone
What does DA binding to autoreceptor result in?
It reduces the DA synthesis and release; antagonist binding has the opposite effect.
what are the possible mechanisms of a first generation antipsychotic?
delay phase
antagonism phase
What is the onset of antipsychotic efficacy?
occurs within days to the first week
what happens in the delay phase?
blockade at postsynaptic D2 receptors initially offset by antagonist bind to D2 autoreceptors.dopamine metabolites in the CSF (representative of dopamine levels in the brain) increase initially after the initiation of antipsychotic phase
What happens in the antagonism phase?
D2 receptors are internalized (desitization) and D2 autoreceptors respond better to DA inhibitory effect (sensitization) As the dopamine metabolite levels in the CSF decrease the therapeutic efficacy of the drug increases
what is the actions of D2 antagonists in the CNS
(1) basal ganglia (nigrostriatal pathway): motor effects, EPS
(2) mesolimbic: primary therapeutic effects
(3) mesocortical: hypofunction in schizophrenia; antagonists may
exacerbate cognitive deficits
(4) hypothalamus and endocrine systems: hyperprolactinemia
(5) medulla: chemoreceptor trigger zone; anti-emetic (anti-nausea)
effect
what does receptor occupancy determine?
it determines the balance between antipsychotic effects and extrapyramidal symptoms.
70-80% occupancy required for therapeutic effect.
>80% occupancy leads to extrapyramidal symptoms.
what drug therapy is used to tx EPS?
anticholinergic agents:benztropine (cogentin),trihexyphenidyl (Artane) akineton (Biperiden)
antihistamines:dihenhydramine(benadryl)
amantadine(symmetrel) a dopamine releasing agent.
BB: propranalol used for akathisia
What movement orders are induced by D2 antagonists?
extrapyramidal symptoms, tardive dyskinesia, Neuroleptic Malignant Syndrome
What is EPS?
extrapyramidal symptoms (most pts will experience this due to long term therapy) timing: early (days/weeks after start of tx) reversible. symptoms like dystonia, pseudoparkinsonism, tremor, akathisia
what is tardive dyskinesia?
timing: late 9months to years after start of therapy (irreversible)
symptoms: rhythmic involuntary movements of the mouth choreiform movements irregular purposelessness, athetoid (worm like movements), axial hyperkinesias (to and fro movement)
MOA: not well understood, neuroadaptive responsive antagonist-
induced supersensitivity of receptors to dopamine
what are the tx for tardive dyskinesia?
Prevention! Use the least risky agent at the lowest dose possible and monitor, reduce dose of current agent, change to a different drug; possibly a newer agent eliminate anticholinergic drugs
New therapies:VMAT2 inhibitors tetrabenazine, valbenazine, and deutetrabenazine
what is Neuroleptic Malignant Syndrome?
very serious syndrome caused by D2 blockade
a few days to 2 weeks after the start of tx
Symptoms: EPS symptoms with fever impaired cognition (agitation delerium coma) and muscle rigidity
what are the tx for Neuroleptic Malignant Syndrome?
overall goal is to restore dopamine balance discontinue drug, dopamine receptor agonists, diazepam, and dantrolene
