10/19 Antipsychotics - Walworth Flashcards
precursors of antipsychotic drugs
1930s: promethazine observed to have antihistaminic and sedative effects
- unsuccessful attempts to treat agitation
- SUCCESSFUL as a clinical anesthetic!
chlorpromazine (promethazine deriv) diminishes arousal and motility, promotes sleep
1950s: chlorpromazine used to treat mental illness, psychomotor excitement, manic states, as well as schizophrenia
mid1960s: introduction of clozapine (shares props with chlorpromazine, but falls into diff category: atypical antipsychotics)
relationship between potency of antipsychotics and DA receptors
clinical efficacy of drugs effective in schizophrenia correlates to binding affinity for D2 receptors
higher potency of drug correlates with higher affinity for D2 effector
dopamine hypothesis
schizophrenia results from increased and dysregulated levels of DA neurotransmission
evidence:
- most antipsychs work by strongly block postsynaptic D2 receptors in CNS (esp mesolimbic-frontal system)
- drugs that incr dopaminergic activity (ex. levodopa, amphetamines, apomorphine) → aggravate schizophrenia, produce psychosis de novo
- DA receptor density is increased in untreated schizophrenic pts post-mortem
- PET scans show incr DA receptor density in treated and untreated patients
- successful tx of schizophrenic pts is reported to change amount of DA metabolite in the urine, CSF, and plasma
dopamine pathways in brain
- nigrostriatal pathway: substantia nigra → striatum
- fx: motor control
- pathology: death of neurons can result in PD
- mesolimbic and mesocortical pathways: VTA → nucleus accumbens, amygdala, hippocampus/prefrontal cortex
- fx:
- memory
- motivation and emotional response
- reward and desire
- addiction
- pathology: dysfx associated with halluciantions and schizophrenia
- tuberoinfundibular pathway: hypothalamus → pituitary
- fx:
- hormonal regulation
- maternal behavior
- pregnancy
- sensory processes
mechanism of action of clinically useful antipsychotics
most antipsychotics block postsynaptic D2 receptors in CNS (esp mesolimbic/frontal system)
- may also block receptors on presyn cell
- may also block postsyn D1 receptors
caveats/limitations of the DA hypothesis
- all evidence to date is circumstantial!
- antipsychotic drugs are only partly effective in most patients
- 2gen drugs (clozapine, olanzapine, quetiapine) are not potent antagonists of D2 receptors but ARE clinically effective!
difference betwen typical and atypical antypsychotics
- side effects
- therapeutic benefit
recall:
pos sx linked to hyperactivity of mesolimbic D2 receptors
neg sx linked to hypoactivity of mesocortical neurons
typical antipsychotics
- side effects: use of drug carries substantial risk of EPS (extrapyramidal side fx)
-
tx benefit: reduce pos sx (not neg)
- block D2 receptors → alleviate pos sx
atypical antipsychotics
- side effects: use of drug carries reduced risk of EPS
-
tx benefit: reduce pos AND neg sx
- block D2 receptors → alleviate pos sx
- also block 5HT2 receptors → reduction in neg sx
typical antipsychotics
block D2 receptors → reduce pos sx
- chlorpromazine
- phenothiazines
- haloperidol
- thioridazine
atypical antipsychotics
block D2 receptors → alleviate pos sx
block 5HT2 receptors → reduce neg sx
- clozapine
- olanzapine
- quetiapine
- risperidone
- ziprasidone
- aripiprazole
antipsychotic tx TOXICITY
8
- reversible neurologic effects (EPS)
- tardive dyskinesia
- neuroleptic malignant syndrome
- endocrine and metabolic effects
- autonomic effects
- sedation (esp phenothiazines)
- QT interval prolongation (quetiapine, ziprasidone)
- agranulocytosis (only clozapine)
reversible neurologic effects
EPS
3 sx
most freq/infreq with…
how to treat
- Parkinson-like syndrome: bradykinesia, rigidity, tremor (max risk 5-30d)
- akathisia (motor restlessness) (max risk 5-60d)
- dystonias (max risk 1-5d)
- acute dystonic rxns are PAINFUL → tx immediately w diphenhydramine or muscarinic blocking agents
occur most freq with
- haloperidol
- potent pierazine side-chain phenothiazines (fluphenazine, trifluoperazine)
occur infreq with
- clozapine
- newer drugs
treat by decreasing dose + admin of antimuscarinic agent
tardive dyskinesia
sx
timecourse
tx
- choreoathetoid movements of muscles of lips and buccal cavity
- may be irreversible
- develop after several years (though have appeared as early as 6mo after drug initiation)
treatment:
- discontinue or reduce dose of antipsych
- aliminate all drugs with central anticholinergic action
- add diazepam to enhance GABAergic activity
neuroleptic malignant syndrome
sx
timecourse
tx
- muscle rigidity
- excessive sweating
- hyperpyrexia
- autonomic instability (poss life threatening)
most severe adverse effect of typical agents (fatal in 10% cases)
believed to arise party from action on DA systems of hypothalamus
may be seen in pt who are sensitive to EPS
can persist for days after stopping tx
max risk within weeks of starting tx
tx:
- dantrolene (muscle relaxant action on ryanodine recpetor to restore CA levels in msucle cells)
- dopamine agonists (bromocriptine)
endocrine and metabolic side effects of antipsychs
endocrine: predictable manifestations of D2 receptor blockade in pituitary
- hyperprolactinemia
- gynecomastia
- amenorrhea-galactorrhea syndrome
- infertiility
metabolic: mech might involve 5HT2c receptor antagonism or leptin levels
- weight gain and hyperglycemia with many atypicals (clozapine, olanzapine; less with aripiprazole, ziprasidone)
- hyperlipidemia
- DM
QT interval prolongation
which drugs?
quetiapine
ziprasidone
agranulocytosis
only clozapine
rare and potentially fatal side effect → clozapine only indicated for tx-resistant schizophrenia
typical antipsychotics
3 chimcally distinct classes and examples
1. penothiazine derivatives
- chlorpromazine (aliphatic side chain)
- thioridazine (piperidine side chain)
- trifluoperazine (piperazine side chain)
- perphenazine
- fluphenazine
2. thioxanthene derivative
- thiothixene
3. butyrophenone
- haloperidol
PK of typical antipsychotics
1. DOPAMINE RECEPTOR BLOCKADE is the major effect correlating with tx benefit for typical agents
- primarily D2 receptors
- haloperidol has highest propensity to block D2 → high potency
- fluphenazine is even more potent
- D2 receptor block → major side effect! EPS resulting in Parkinson’s like syndrome
- most freq with haloperidol. also with fluphenazine, tifluoperazine
- BLOCKADE of peripheral alpha-adrenergic and/or muscarinic receptors → autonomic side effects
- thioridazine has strongest autonomic effects; haloperidol has weakest
-
alpha1 block
- postural hypotension, failure to ejaculate
-
muscarinic blockade
- atropine-like effects with thioridazine and phenotiazines with aliphatic side chains (ex. chlorpromazine)
- antiM CNS effects: toxic confusional state
- urinary retention → need to switch to an agent with less antiM action
PK of atypical antipsychotics
can’t be grouped chemically
exert effect through some D2 blockade but relatively higher 5HT2 blockade (compared to typical agents)
- low affinity antagonists of D2 receptors
- high affinity antagonists of 5HT2a receptors
side effect profile:
- EPS : occurs infrequently with clozapine (neutral effect on D2 receptors)
- autonomic effects : most atypicals have intermediate autonomic effects
clozapine
unique PD property
unique toxicity
clozapine
- limited D2 receptor blocking fx, but has unique PD in high affinity for D4 receptor (highly expressed in limbic system)
- also blocks 5HT2 receptors
possibly as a result, clozapine has a unique toxicity: risk of agranulocytosis
- rare, but potentially fatal, so clozipine is reserved to tx-resistant schizophrenia
aripiprazole : PD properties
diverges form expected profile for atypical antipsychotics
PARTIAL AGONIST at D2 (versus antagonist)
- may diminish come cortical DA hyperfx via simultaneous competitive blocking of DA and enhancing DA neurotransmission in prefrontal cortex (via partial agonist mechanism of action)
effectiveness might be due to ability to block the effect of DA but not eliminate it completely (like haloperidol or other DA receptor antagonists do)
DA, aripriprazole, haloperidol dose-response curve
haloperidol = D2 antagonist
aripiprazole = DA receptor partial agonist
PK properties relating to route of admin
absorption/distribution
- most are readily (but incompletely) abs orally
- high first-pass transformation → bioavailabilty is 25-35%
- 65% haloperidol
- implication: parenteral forms have higher bioavailability
- once absorbed…
- lipid soluble → readily enter CNS, accumulate in brain/lung/other tissues with good blood suppy, enter fetal circ/breastmilk
- many bind extensivly to pl protein (92-99%)
- lots of sequestration in lipid compartments
metabolism
- metabolized by P450 oxidative processes and glucoronidation/sulfation/other conjugation
- metabolites apparently not imp for tx action
- EXCEPTION: mesoridazine (thioridazine metabolite) is more active than parent
- ***high potential for drug interactions!
excretion
- little is excreted unchanged renally
elimination half lives of antipsychs
generally v long half lives
- biological effects usually persist for at least 24hr → once daily dosing possible after pt adjusts to initial side effects
EXCEPTIONS:
- quetiapine (6hr)
- ziprasidone (7.5hr)
antipsychotic agents
preparations available
why use anything but oral?
all drugs available in oral formulation, but other forms also available depending on needs of patient
- sustained release, rectal, IM, depot, extended releast oral
acutely psychotic? IM injection
poor compliance? depot prep (releases over period of months)
drug interactions
many antipsychs are metabolized by CYP3A4, 2D6
- recall CYP inhibitors!
- 3A4: grapefruit, azole antifungals, HIV protease inhibitors
- 2D6: bupropion, fluoxetine, paroxetine
