Drugs - Antipsychotics and Antidepressants (Linger) Flashcards
name some common atypical antipsychotics
“dones and pines”
and one prazole
a) Aripiprazole (Abilify)
b) Lurasidone (Latuda)
c) Olanzapine (Zyprexa)
d) Quetiapine (Seroquel)
e) Risperidone (Risperdal)
f) Ziprasidone
special use atypical antipsychotic
colazpine (Clozaril)
typical low potency antipsychotic agent
chlorpromazine
typical high potency antipscyhotic agent
haloperidol and the azines
why are they called atypical antipsychotics
b/c of the dramatic reduction in EPS at clinically effective doses
what is the dopamine hypothesis in schizophrenia
(1) Antipsychotics block postsynaptic D2 receptors in the CNS, especially in the mesolimbic and striatal-frontal system; a few are partial dopamine agonists (e.g., aripiprazole and bifeprunox); D2 binding affinity correlates with antipsychotic potency
(2) Drugs that increase dopaminergic activity by activating receptors (apomorphine or bromocriptine), blocking dopamine reuptake (cocaine), stimulating dopamine release (amphetamines), or enhancing dopamine synthesis (levodopa) cause increased motor activity in rats, and can aggravate schizophrenia psychosis or cause psychosis de novo in humans
(3) Dopamine receptor density is increased in the brains of schizophrenics who have not been treated with antipsychotics
(4) Some (not all) post-mortem studies of schizophrenic subjects report increased dopamine levels and D2 receptor density in the nucleus accumbens, caudate, and putamen
what evidence does NOT support the dopamine hypothesis
(1) Diminished cortical or hippocampal dopaminergic activity has been suggested to underlie the cognitive impairment and negative symptoms of schizophrenia
(2) Many atypical antipsychotics have much lower affinities for D2 receptors and yet are effective in schizophrenia; some of these drugs are even partial agonists at dopamine receptors
(3) These and other inconsistencies strongly suggest that the Dopamine Hypothesis is, at best, an over simplification
what is the serotonin hypothesis in schizophrenia
i) Hallucinogenic drugs (LSD, mescaline) are serotonin receptor (5-HT2A and 5-HT2C) agonists
ii) Atypical antipsychotics are inverse agonists (block constitutive activity) of the 5-HT2A (and sometimes 5-HT2C) receptors
what is the glutamate hypothesis of schizophrenia
i) Hypofunction of NMDA receptors, located on GABAergic interneurons, induces disinhibition of downstream glutamatergic activity and leads to hyperstimulation of cortical neurons through non-NMDA receptors
ii) Evidence for:
(1) Noncompetitive inhibitors of the NMDA receptor (e.g., phencyclidine and ketamine) exacerbate both psychosis and cognitive impairment in schizophrenics
(2) Ampakines (allosteric AMPA receptor agonists) have shown benefit in animal models of schizophrenia and depression, in part by increasing trophic factors such as BDNF
chlorpromazine
prototype phenothiazine derivative
typical antipsychotic
haloperidol
typical antipsychotic
prototype of the butyrophenone derivatives
(2) Tend to be more potent and have fewer autonomic effects but greater EPS than phenothiazines
what is the prototype atypical antipsychotic
clozapine
MOA of atypical antipsychotics
(4) Common pharmacologic attribute is that they exhibit greater effects at 5-HT2A receptors than at D2 receptors resulting in dissociation of EPS and antipsychotic efficacy
(5) Most are partial agonists of 5-HT1A receptors, which is synergistic with 5-HT2A receptor antagonism
pharmacokinetics of most of most of the antipsychotics
i) Most are readily but incompletely absorbed and undergo significant first-pass metabolism
ii) Most are highly lipid soluble and protein bound
iii) Generally have a much longer clinical duration of action than would be estimated from their plasma half-lives (weeks to months after last dose depending on formulation)
vii) Metabolism of most antipsychotics is catalyzed by cytochrome P450 enzymes; drug-drug interactions should be considered when combining antipsychotic drugs (see below)
clozapine discontinuation
iv) Discontinuation is generally well-tolerated, except for clozapine, which can cause cholinergic rebound and withdrawl-emergent movement disorders; chlorpromazine and thioridazine also cause cholinergic rebound
in pt’s who discontinue their antipsychotics, what is the amount of time to relapse usually
6 months
EXCEPT for clozapine where relapse is rapid and severe
MOA of typical antipsychotics
block D2 receptors and increase cAMP
MOA of atypical antipsychotics
iii) Atypical antipsychotics tend to block 5-HT2A receptors more potently than they inhibit D2 receptors
what is the mesolimbic mesocortical pathway
involved in behavior and cognitive function; cell bodies in the ventral tegmental area send projections to the limbic system and neocortex; inhibition of dopaminergic activity in this pathway is thought to play a key role in antipsychotic effects
nigrostriatal pathway involves what?
what happens with inhibition of this system
(2) Nigrostriatal pathway is involved in coordination of voluntary movement; neurons project from the substantia nigra to the dorsal striatum (caudate/putamen); inhibition of dopaminergic activity in this pathway causes EPS
tuberoinfundibular system
(3) Tuberoinfundibular system regulates prolactin release (dopamine is inhibitory); arcuate nucleus and periventricular neurons project to the hypothalamus and posterior pituitary; hyperprolactinemia can be a side effect of the older antipsychotics resulting from inhibition of this pathway (see “Adverse Effects” below)
D1 like receptors (D1 and D5)
activation?
location?
increase cAMP via activation of Gs-coupled activation of adenylyl cyclase;
D1 receptors are mainly located in the putamen, nucleus accumbens, olfactory tubercle, and cortex;
D5 receptors are primarily localized in the hippocampus and hypothalamus
D2 like receptors (D2, 3, 4)
decrease cAMP via Gi and inhibit Ca channels, open K channels
D2 receptors are found both pre- and post-synaptically in the caudate-putamen, nucleus accumbens, and olfactory tubercle
which dopamine receptors are shown to play a role in the action of antipsychotics
(4) D2 receptors are the only dopamine receptors shown to play a role in the action of antipsychotics; selective antagonists of D1, D3, and D4 receptors have been extensively tested without producing evidence of antipsychotic action
what percent occupancy of striatal D2 receptors by TYPICAL antipsychotics must be achieved to have antipsychotic efficacy
what percent for EPS symptoms
60%
EPS is produced when occupancy is ≥ 80%
atypical antipscyhotics must have what percent occupancy of D2 receptors to be efficient
Atypical antipsychotic agents are effective at lower D2 receptor occupancy levels (30-50%), likely because of their concurrent high occupancy of 5-HT2A receptors
primary use of antipscyhotics
schizophrenia
ii) Also useful in management of other psychotic disorders including acute mania, bipolar disorder, schizoaffective disorders, behavioral disturbances in dementias, behavioral disturbances in children and adolescents, and disorders associated with problems of impulse control
what are some non psychiatric uses of antipsychotics
(1) Antiemesis (due to dopamine receptor blockade in the medulla and stomach): Metoclopramide (Reglan), Prochlorperazine (Compazine), Chlorpromazine (Thorazin), Promethazine (Phenergan), Trimethobenzamide (Tigan)
(2) Neuroleptanesthesia (analgesia & amnesia): Droperidol (a butyrophenone D2 blocker) + fentanyl + nitrous oxide
(3) Low doses of some antipsychotics, particularly quetiapine, are commonly, but mistakenly prescribed to promote sleep onset and maintenance; there are safer sleep medications and these drug are not FDA-approved for sleep
what are the advantages of the new atypical antipsychotics
ii) The major advantage of these newer agents is their much lower tendency to cause the severe extrapyramidal symptoms and tardive dyskinesia associated with the typical antipsychotics
iii) Atypical antipsychotics have been shown in some studies to be more effective than older drugs for treating negative symptoms
which two drugs are the exception to the statement that all antipsychs are equally effective for reducing psychosis
i) Broadly, all the antipsychotics, except clozapine and olanzapine, are considered equally effective for reducing psychosis; 30-50% of patients refractory to standard doses of other antipsychotics respond to clozapine or high-dose olanzapine
ADR’s of clozapine and what pt’s is it used in
iv) Because of its potential serious side effects (agranulocytosis, myocarditis), clozapine is generally reserved for use with patients who have become refractory to high doses of other agents or who have made life-threatening suicide attempts
how long does it take for antipscyh’s to start working
v) Psychotic symptoms can improve within 1 week; treatment for 16-20 weeks is often required before full effect is observed; the drugs are usually tried for at least 4-6 weeks or longer; maintenance therapy may last a lifetime; these drugs are not “habit forming”
is polypharmacys in psychotic treatment ok?
i) Polypharmacy (treatment with more than one drug), is the norm for treatment of psychotic disorders, as it is often difficult to fully control symptoms with one medication alone
what are some behavioral effects of older (typical) antipsychs
anhedonia- inability to experience pleasure
akinesia
toxic confusional states (high doses)
sedatino
what are some side effects of the high potency typical pscyh meds (haloperidol)
HIgh EPS
what are some side effects of the low potency psych meds (chlorpromazine)
cause lots of nonspecific side effects
-orthostatic hypotension
male sexual dysfunction (alpha blockade)
constipation, dry mouth, urinary retention (treat with antimuscarinic - benztropine or benadryl antihistamine )
sedation
what are some early onset and reversible Extrapyrimidal side effects
dystonia - involuntary contraction of face, neck, tongue, EOM’s
- responds to anticholinergics
- peak at 1 week
parkinsonism - akinesia (2 weeks), muscle rigidity (3 weeks), tremor 6 weeks, shuffling gait
akathisia - motor restlessness and urge to move
give benzodiazepine
-peak at 10 weeks
what are some late onset and irreversible extrapyramidal side effects of antipsychs
tardive dyskinesia
- involuntary repetitive movements (tongue, face, body)
- due to supersensitivity of dopamine receptors
worsened by anticholinergics
which agents have the lowest risk for tardive dyskinesia
quetiapine or clozapine
why does weight gain occur with antipsychs
possibly combined H1 and 5 HT2 blockade
what happens with sexual function with antipsychs
Orthostatic hypotension, impotence, failure to ejaculate, sedation, dizziness
due to alpha block
which antipsych meds have significant affinity for muscarinic cholinergic receptors and alpha receptors and what happens when bound?
Older typical antipsychotics have significant affinity for muscarinic cholinergic and α1-adrenergic receptors (as well as histamine H1 and 5-HT2 receptors). Blockade of these receptors can lead to anti-parasympathetic (anti-muscarinic) side effects such as loss of accommodation, dry mouth, difficulty urinating, and constipation and anti-α-adrenergic side effects such as orthostatic hypotension, dizziness, sedation, impotence, and failure to ejaculate. Patients who present with these symptoms should be switched to a newer atypical agent.
what are two big metabolic/endocrine effects of antipsychs
weight gain
-hyperglycemia
hyperprolactinemia
which drugs have the highest potential for causing weight gain
lowest risk?
clozapine and olanzapine
Lowest risk: Aripiprazole, Lurasidone, Ziprasidone
what are complications of weight gain with antipsychs
(1) Weight gain is very common, especially with clozapine and olanzapine and requires monitoring food intake, BMI, and fasting blood sugar and lipids. Hyperglycemia may develop, can be serious (ketoacidosis) and definitely complicates pre-existing diabetes. Whether hyperglycemia is secondary to weight gain-associated insulin resistance or other potential mechanism is unknown. Hyperlipidemia can also be a problem.
