Psychopharmacology of Antipsychotics Flashcards
What are the names of first generation antipsychotics?
low potency: chlorpromazine, thioridazine
high potency: perphenazine, fluphenazine, haloperidol, pimozide
What are the names of second generation antipsychotics?
clozapine
risperidone
olanzapine
quentiapine
ziprazidone
paliperidone
What are the names of third generation antipsychotics?
aripiprazole
What are first generation antipsychotics?
chlorpromazine: first discovered in the 1950’s by accident
subsequent antipsychotics discovered through their ability to produce “neurolepsis” in animal models (psychomotor slowing, emotional quieting, affective indifference)
How do first generation antipsychotics affect dopamine (D2) receptors?
by 1970’s, antipsychotic properties were characterized by the ability of neuroleptics to block dopamine (D2) receptors
classification based on potency of binding to D2 receptors, not efficacy of medication (HIGH and LOW potency), also divided into chemical families
positive symptom reduction (psychosis) due to blockade of D2 receptors in the mesolimbic dopamine pathway
side effects of typical antipsychotics due to blockage of D2 receptors throughout the brain, not just in the mesolimbic pathway
What is the nigro-striatal pathway?
movement
EPS, tardive dyskinesia
What is the meso-limbic pathway?
“reward” pathway
positive symptoms of schizophrenia
What is the meso-cortical pathway?
motivation and emotions
negative symptoms of schizophrenia
What is the tubulo-infundibular pathway?
posterior pituitary (hypoprolactinemia)
What are the side effects of first generation antipsychotics in the mesolimbic pathway?
site of nucleus accumbens, “pleasure centre” of the brain and part of normal reward pathway
stimulation –> pleasure
blockage –> apathy, anhedonia, amotivation, lack of interest in social interaction (secondary negative symptoms)
What are the side effects of first generation antipsychotics in the meso-cortical pathway?
to dorsolateral prefrontal cortex (DLPFC): secondary negative symptoms, worsening of cognitive symptoms
to ventromedial prefrontal cortex (VMPFC): secondary negative symptoms, worsening of emotional (affective) symptoms
What are the side effects of first generation antipsychotics in the nigrostriatal pathway?
EPS and TD
unaffected pathway in untreated schizophrenia
blockage of D2 receptors here causes basal ganglia movement disorders (drug-induced parkinsonianism) part of extrapyramidal nervous system
What is tardive dyskinesia (TD)?
long-term side effect of chronic D2 receptor blockade in this pathway with tongue, facial, and limb movements abnormalities
frequently irreversible, even when antipsychotic is discontinued
TD thought to be due to D2 receptors “upregulating” and becoming hypersensitive to dopamine
those developing EPS early in treatment twice as likely to develop TD
risk of onset of TD decreases after 15 years of treatment (likely due to genetic protective factors)
What are the side effects of first generation antipsychotics in the tuberoinfundibular dopamine pathway?
projects from the hypothalamus to the pituitary gland
unaffected in untreated schizophrenia
dopamine D2 blockade elevated plasma prolactin levels (hyperprolactinemia), causing galactorrhea (breast milk secretion) in men and women and amenorrhea (irregular menses) in women
What are the side effects when antipsychotics block alpha-1 adrenergic receptors?
dizziness, drowsiness, postural hypotension
What are the side effects when antipsychotics block histamine-1 receptors?
weight gain, drowsiness
What are the side effects when antipsychotics block muscarinic cholinergic receptors?
blurred vision, dry mouth, constipation, urinary retention, cognitive dysfunction
in the nigrostriatal pathway, dopamine inhibits acetylcholine release, so when there is less dopamine, there is more acetylcholine, increasing likelihood of EPS
can block acetylcholine release with “anticholinergic” medications or give antipsychotic medications with anticholinergic effects to lessen EPS (but not reduce likelihood of TD)
What makes an antipsychotic medication “atypical”?
originally used to describe lower EPS risk associated with clozapine
term expanded later to include greater efficacy in treating cognitive and negative symptoms, lack of prolactin elevation, greater efficacy for treatment-resistant patients
What is the pharmacology of atypical medication?
- rapid dissociation from D2 receptors
- serotonin (5-hydroxytryptamine, 5-HT) dopamine antagonism: increases dopamine by disinhibiting the dopamine neuron
- serotonin (5-hydroxytryptamine, 5-HT) 1A partial agonism
- D2 partial agonism
What are third generation antipsychotics aka “goldilocks drugs”?
stabilizes dopamine transmission between antagonism (like typicals) and full stimulation (like dopamine)
reduce D2 hyperactivity in mesolimbic neurons enough to exert antipsychotic effect without completely blocking D2 receptor but also only partially block the nigrostriatal pathway (not enough to cause EPS since a little bit of the signal still gets through)
What are side effects of second generation antipsychotics?
cardiometabolic risk: not simply due to increased appetite and weight gain, can cause insulin resistance to develop
other risks: orthostatic hypotension, QTc prolongation (risk of cardiac arrhythmias), serious but rare events include diabetic ketoacidosis and neuroleptic malignant syndrome
most common side effect (CATIE study): hypersomnia/sedation, common reasons for discontinuation include weight gain, EPS, sedation
What is clozapine?
unique side effect profile and monitoring requirement of frequent (up to weekly) bloodwork to monitor for agranulocytosis (low white blood cells)
