Antipsychotic drugs Flashcards
antipsychotic targeting implications
-multiple receptors targeted w benefit
-unable to predict efficacy
-need to individualize tx based on response
-multiple receptors = more side effects = poor adherence
Autonomic antipsychotic mech and side effects
-muscarinic cholinoceptor blockade:
-dry mouth
-constipation
-difficulty urinating
-alpha block:
-orthostatic hypotension
CNS antipsychotic mech and side effects
-dopamine block: PD, akathasia, dystonias
-supersensitivity of DA receptors: tardive dykinesia
-muscarinic block: toxic-confusional state
-histamine block: sedation
Typical (1st gen) antipsychotic drugs
-phenothiazines (chloropromazine)
-butyrophenones (haloperidol)
Typical antipsychotics MOA
-strong D2 ANTAgonists
-affect mesolimbic system
-D1 antagonists not effective
slide 5
typical antipsychotic clinical features
-effective in positive symptoms
-extrapyramidal sx side effect
-risk of tardive dykinesia after months/years of tx
typical antipsychotic structure (chlorpromazine)
-phenothiazine nucleus
-3 ring in row, middle one not aromatic and has N on bottom S on top
Phenothiazine drugs
-chlorpromazine
-promazine
-triflupromazine
Chlorpromazine (phenothiazine)
-first drug that worked well
-D2 antagonist w 5HT2A activity
-multiple undesired targets (dirty drug) (antihistamine)
-no longer first line
Butyrophenone drugs
-haloperidol
-droperidol +/- fentanyl
-aromatic ring w F on one end and chain with 2 rings at other end
Haloperidol
-butyrphenone
-more selective D2 ANTAgonist than chlorpromazine
-no longer first line bc EPS
Delayed onset of typical antipsychotics
-takes days to weeks
-delay phase: block D2 receptors, initially offset by D2 antagonism
-antagonism phase: D2 internalized (desensitization) and D2 autoreceptors respond better to DA inhibitory effect (sensitation)
-post-synaptic vs pre-synaptic?
-
slide 9 idk
De
Delay phase
-blockade at postsynaptic D2 receptors, initially offset by
antagonist binding to D2 autoreceptors
-dopamine metabolites inc initially after start of antipsychotic tx
-graph is bell curve
antagonism phase
-D2 internalized (desensitization) and D2 autoreceptors respond better to DA inhibitory effect (sensitation)
-post-synaptic vs pre-synaptic?
-as dopamine metabolite levels dec, efficacy inc
-graph is line inc
Actions of D2 antagonists in different brain regions
-mesolimbic : primary tx effects!!!
-basal ganglia: motor, EPS
-mesocorticol: hypofunction in scz, antagonists may cause cognitive deficits
-hypothalmus and endocrine: hyperprolactinemia
-medulla: chemoreceptor trigger zone, anti-emetic
Receptor occupancy of antipsychotics
-determines balance between tx effects and EPS
-70-80% receptor occupancy ideal
->80% = EPS
Movement disorders induced by D2 antagonists
-EPS
-tardive dyskinesia
-neuroleptic malignant syndrome (NMS)
Extrapyramidal Symptoms (EPS)
-30-50% pt will experience
-days/weeks after initiation
-reversible
-dystonia (inc muscle tone)
-pseudoparkinsonism (muscle rigidity)
-tremor
-akathisia (restlessness)
Drug therapy for EPS
-anticholinergics: benztropine, trihexyphenidyl, akineton
-antihistamines: diphenhydramine
-amantadine (dopamine releasing agent)
-beta blockers: propranolol for akathisia
Neurons involved in EPS
-nigrostriatial pathway
-excitatory amplified and inhbitory diminished under D2 antagonism
Tardive Dykinesia sx
-late
-IRREVERSIBLE
-rhythmic involuntary movements of the mouth
-choreiform movements: irregular purposelessness (HD)
-athetoid (worm-like) movements
-axial hyperkinesias (to and fro movements
Tardive Dykinesia MOA
-not well understoof
-maybe adaptive response, antagonist supersensitivity of receptors to dopamine?
Tardive monitoring and Tx
-AIMS (abnormal involuntary movement scale)
-rating scale, check q6 months
-prevention: use low dose of low risk agent
-reduce dose
-eliminate anticholinergic drugs
-VMAT2 inhibitors
Newer drug therapies for tardive dyskinesia
-VMAT2 inhibitors
- -benazines used for huntington;s chorea
VMAT2
-channel protein that transports dopamine from cytosol into synaptic vesicles
-inhibitors drugs used to tx tardive dyskinesia
Neuroleptic Malignant Syndrome (NMS)
-potentially fatal caused by D2 block
-few days-2 weeks after start of tx
-EPS w fever
-impaired cognition
-muscle rigidity
Neuroleptic Malignant Syndrome (NMS) tx
-overall goal is to restore dopamine balance
-d/c drug
-dopamine agonist
-diazepam or dantrolene (muscle relaxant)
NMS tetrad
Atypical (2nd,3rd gen) antipsychotic drugs
-clozapine, olanzapine, quetiapine, asenapine
-risperidone, zipraidone, lurasidone
-aripiprazole
-pimavanserin
Why do atypicals have lower risk of EPS than typicals
-presynaptic 5HT2A receptors on dopamergic neurons projecting from SN pars compacta to striatum play key role
-regular binding of serotonin to pre 5HT2A reduces amount of dopamine released into synapse
-in presence of typicals, post D2 receptors are blocked and serotonin reduces amount of dopamine into synapse (double whammy)
-in atypicals, post D2 receptors are blocked but they also ANTAgonize presynaptic 5-HT2A = more dopamine release into synapse= maybe offset D2 antagonism = fewer EPS
Clozapine
-1st atypical
-high efficacy for positive, some for neg
-lower D2 potency = dec EPS risk
Clozapine side effects
-anticholinergic: sedation (H1) and orthostatic hypotension (a1)
-weight gain
-diabetes risk
-agranulocytosis: drop in neutrophil counts = need to monitor blood weekly
-QTc prolongation
Olanzapine
-similar to clozapine
-same side effects but less severe
-NO risk of agranulocytosis
-risk of DRESS
Quetiapine
-antagonizes D2, 5-HT2A
-low antimuscarinic activity (less sedation??)
-antidepressant activity
-prolong QTc
Asenapine
-lower sedation and antimuscarinic activity than quetiapine
-prolongs QTc interval
-pine side effects
-anticholinergic: sedation (H1) and orthostatic hypotension (a1)
-weight gain
-diabetes risk
-agranulocytosis in clozapine
-DRESS in olanzapine, no QTc
side effect severity of atypicals
- (most) clozapine = olanzapine
- quetiapine, asenapine, -peridones, cariprazine, brexpiprazole
- Ziprasidone, lurasidone, aripiprazole
-done drugs
-combined D2 5HT2A ANTAgonist
-low EPS risk
-sedation
-orthostatic hypotension
-low antimuscarinic activity
-weight gain
-diabetes
-DRESS and QTc in ziprasidone
Risperidone
Ziprasidone
-DRESS and QTc prolongation
Lurasidone
-highly potent
-less severe side effects than risperidone
-DRESS and QTc?
Apiprazole MOA
-high affinity for D2/D3 also 5HT2A antagonist
-D2 partial agonist: action varies w level of dopamine in different brain regions
-partial 5HT1A agonist (good for depression
Apiprazole side effects
-low risk EPS
-sedation
-orthostatic hypotension
-lower risk of wt gain, diabetes
-akathisia
dose-response curves of aripiprazole
-when DA high, aripiprazole lowers DA response to intermediate level
-when DA low, aripiprazole inc DA response to same intermediate level
Dopamine level-dependent activity of aripiprazole (partial agonism)
-by loweing D2 in LIMBIC system to normal range, ari reduces positive sx of SZ
-by keeping D2 normal, ari dec EPS risk
-by inc D2 into normal range in the CORTEX, ari reduces negative sx of SZ
Pimavanserin
-inverse agonist targeting 5HT2A
-used to reduce PD psychosis, hallucinations, and delusions caused by dopamine tx
-prolongs QTc
Cobenfy
-first SZ drug that doesnt target D2
-new
Which one of the statements below regarding atypical
antipsychotics is INCORRECT:
(A) Atypical antipsychotics like clozapine and olanzapine are
effective in controlling positive symptoms and may improve
some negative symptoms.
(B) The lower risk of EPS in atypical antipsychotics is partly due
to antagonism of presynaptic 5-HT 2A receptors in the
striatum.
(C) Quetiapine has greater anticholinergic activity than
clozapine.
(D) Aripiprazole modulates dopamine levels differently in the
limbic system versus the striatum.
-(C) Quetiapine has greater anticholinergic activity than
clozapine
