lecture 53 Flashcards
rochet - pharmacology of antipsychotic drugs
what are the implications that arise from the fact that multiple receptors can be targeted for beneficial antipsychotic activity?
unable to predict effectiveness of each therapy for individual pt
need to individualize therapy based on pt response
multiple receptors –> many SE –> poor adherence
what are the critical NT targets of haloperidol?
D2 > D4 > 5HT2a
what are the critical NT targets of aripiprazole?
D2 = 5HT2a > D4
what are the critical NT targets of clozapine?
D4 > 5HT2a > D2
what are the critical NT targets of quetiapine?
D2 > 5HT2a
what are the critical NT targets of olanzapine?
5HT2a > D4 > D2
what are the critical NT targets of chlorpromazine?
5HT2a > or = D2
what are the autonomic manifestations and corresponding mechanism of antipsychotics?
muscarinic cholinoreceptor blockade – dry mouth, constipation, difficulty urinating
alpha adrenoreceptor blockade – orthostatic hypotension
what are CNS manifestations and corresponding mechanism of antipsychotics?
DA receptor blockade – parkinsonian’s syndroma, akathasia, dystonias
supersensitivity of DA receptors – tardive dyskinesia
muscarinic blockade – toxic confusional state
histamine receptor blockade – sedation
what do typical (first-generation) antipsychotics target?
D2 antagonist –> effect mesolimbic system
what drugs are typical antipsychotics?
drugs that have a chemical structure with a phenothiazine nucleus (like chlorpromazine) or chemical structure with a butyrophenone (like haloperidol)
why are typical antipsychotics no longer a first line drug?
chlorpromazine has multiple undesired targets (such as being an antihistaine)
haloperidol also has unfavorable SE (EPS)
how does butyrophenone antipsychotics differ from phenothiazine antipsychotics?
butyrophenone (haloperidol) is more selective D2 antagonist
what is the delay phase?
blockade at postsynaptic D2 receptors, initially offset by antagonist to D2 autoreceptors
similar to bell curve
what is the antagonism phase?
D2 receptors are internalized (desensitization) and D2 autoreceptors response better to DA inhibitory effect (sensitization)
similar to linear
how does D2 antagonist affect the mesolimbic?
primary therapeutic effect for antipsychotics
for typical antipsychotics, what % of receptor occupancy has what effect?
70-80% – therapeutic efficacy
over 80% – extrapyramidal symptoms (EPS)
what is action of D2 antagonist in the basal ganglia?
motor effects
EPS
what is the action of D2 receptor antagonist in the mesocortical?
hypofunction in schizophrenia
antagonist may exacerbate cognitive deficits
what is the action of D2 antagonist in the hypothalamus and endocrine systems?
hyperprolactinemia
what is the action of D2 antagonist in the medulla?
chemoreceptor trigger zone
anti-emetic effect
when does EPS appear?
early so in the days/weeks after start of treatment
reversible
what are the symptoms of EPS?
dystonia (increased muscle tone)
pseudoparkinsonism (muscle rigidity)
tremor
akathisia (restlessness)
what drugs are used to treat EPS?
anticholinergic agents (benztropine, trihexyphenidyl, akineton)
antihistamines (benadryl)
amantadine
beta-blockers (propranolol, specifically for akathisia)
when does tardive dyskinesia appear?
late (months to years)
IRREVERSIBLE
what are the symptoms of tardive dyskinesia?
rhythmic involuntary movements of the mouth
choreiform movements (irregular purposelessness)
athetoid (worm-like) movements
axial hyperkinesia
what is the MOA of tardive dyskinesia?
not well understood
possible neuroadaptive response so antagonist induced supersensitivity of receptors to dopamine?
how should pts be monitored for tardive dyskinesia?
AIMS (abnormal involuntary movement scale) checked every 6 months
what are the treatments of tardive dyskinesia?
prevention (least risky agent at lowest dose possible and monitor)
reduce dose of current agent
change to different drug
eliminate anticholinergic drugs
VMAT2 inhibitors
what drugs are VMAT2 inhibitors?
tetrabenazine
valbenazine
deutrabenazine
when does neuroleptic malignant syndrome (NMS) appear?
few days to 2 weeks after start
how does NMS present?
EPS symptoms with fever
impaired cognition (Agitation, delirium, coma)
muscle rigidity
what is the treatment of NMS?
restore DA balance
d/c drug
use DA receptor agonist, diazepam, or dantrolene
what is the MOA of atypical antipsychotics?
some activity as D2 antagonist in the mesolimbic system
also acts as 5HT2a antagonists
what are the clinical features of atypical antipsychotics?
controls positive symptoms (psychosis, bipolar, depression) and sometimes better management of negative symptoms
lower risk of EPS
some metabolic problems (weight gain, diabetes)
what drugs are atypical antipsychotics?
clozapine, olanzapine, quetipaine, asenapine
risperidone, ziprasidone, lurasidone
aripiprazole
pimavanserin
why do atypical antipsychotics have a lower risk of EPS?
presynaptic 5HT2a receptors on DA neurons projecting from the SNpc to the striatum play a key role
typical – blocks POST synaptic
what are the clinical features of clozapine (clozaril)?
1st atypical antipsychotic drug
high efficacy especially for positive symptoms, but also for some negative symptoms
lower D2 potency, so reduced risk of EPS
what is the SE profile of clozapine (clozaril)?
anticholinergic, sedation, and orthostatic hypotension
metabolic – weight gain, risk of DM
agranulocytosis
what is agranulocytosis?
serious SE of clozapine involving a drop in neutrophil counts
occurs in 1-2% of individuals within 6 months
weekly blood monitoring is needed
what are the clinical features of olanzapine (zyprexa)?
similar to clozapine with similar SE but usually less severe (no agranulocytosis)
what are the clinical features of quetiapine (seroquel)?
similar to clozapine/olanzapine
antagonizes D2, 5HT2a with a low risk of EPS
same SE as olanzapine
low antimuscarinic activity
what atypical antipsychotics are most likely to experience SE?
clozapine = olanzapine > quetiapine = risperidone asenapine > ziprasidone = lurasidone = aripiprazole
what are the clinical features of risperidone (risperidol)?
rationally designed to be a combined D2 and 5HT2a antagonist with low risk of EPS
SE similar to quetiapine with low antimuscarinic activity
what are the clinical features of ziprasidone (geodon/zeldox) and lurasidone (latuda)?
similar to risperidone but usually less severe
what are the clinical features of aripiprazole (abilify)?
high affinity for D2/D3, but also acts as 5HT2a antagonist
low risk of EPS
with SE similar to ziprasidone
low risk of weight gain, risk of diabetes
how does aripiprazole act on the D2 receptor?
acts as partial agonist so that drug action varies with the level of DA in different brain regions
how does aripiprazole act when DA is high?
lowers the DA response, but only to an intermediate level
used in the limbic system of schizophrenia pts
reduces positive systems in the limbic system
how does aripiprazole act when DA levels are low?
increases the DA response to the same intermediate level
works in the striatum or cortex of schizophrenia pts
by staying in normal range in striatum, reduces risk of EPS
in the cortex, reduces negative symtpoms
what are the clinical features of pimavanserin (nuplazid)?
inverse agonist targeting 5HT2a
used to reduce PD psychosis, including hallucinations and delusion created by DA treatments (L-DOPA or DA receptor agonists)
what is cobenfy (KarXT)?
first ever approved schizophrenia drug that doesn’t target the D2 receptor
