Antipsychotic agents [3] Flashcards
Clinical features of schizophrenia
overactivity of DA neurons in limbic system (MESOLIMBIC PATHWAY)
- present with positive symptoms (delusions, halluc, disordered thoughts)
- so antipsychotics block D2 DA receptor or 5HT 2A
- negative symptoms seen later (hypoactivity of DA neurons)
Too much Glutamate making you psychotic or too little?
which drugs makes you psychotic, NMDA agonist or antagonists?
Antagonist
ketamine, phencyclidine
DA hypothesis of schizophrenia
overactivity in brain DA pathways
- virtually all antipsychotic drugs block DA D2 receptors
(but Glu and 5HT and ACh also seem to play role, and blocking D2 receptors occur immediately, but psychoses improvement isnt for 3-6 weeks)
Brain DA pathways
- Mesolimbic pathway
- Mesocortical pathway
- Nigrostriatal pathway
- Tuberoinfundibular pathway
Mesolimbic pathway
Brain DA pathway
integration of sensory input and motor responses with
AFFECTIVE or EMOTIONAL data
Mesocortical pathway
Brain DA pathway
involved in COMMUNICATION and SOCIAL abilities
Nigrostriatal pathway
Brain DA pathway
part of basal ganglia (extrapyramidal tract)
plays central role in PLANNED, COORDINATED MOVEMENT
Tuberoinfundibular pathway
Brain DA pathway
hypothalamic neurons release DA in pituitary to INHIBIT PROLACTIN RELEASE
- antipsychotic D2 receptor blockers side effects: hyperprolactinemia
Serotonin hypothesis
5HT2A receptor effect on Mesocortical vs Mesolimbic pathway
Mesocortical: 5HT2A receptors on DA neurons in PFC (heteroreceptor) → DECREASES (breaks) DA release
- get negative symptoms
Mesolimbic: 5HT2A on glutamate pyramidal cells in PFC→ INCREASE DA release
- get positive symptoms
Can block these receptors w/ atypical agents → increased DA release
Typical vs Atypical antipsychotics
Block D2 receptors with typical → decreased DA release
Can block 5HT2A receptors w/ atypical agents → increased DA release
(therapeutic utility of antagonist of both D2 and 5HT2A receptors in schizo - improvement in both positive and negative symptoms)
Glutamate hypofunction hypothesis
- mesolimbic pathway
Normally:
cortical glutamate → activates cortical GABA neurons → inhibits cortical Glu neurons → regulates DA (keeps it from accumulating)
so. . . with Hypofxn of cortical glutamate → loss of cortical GABA inhibition → increased activity of Glu neurons → HYPERactivity in MESOLIMBIC pathway (↑DA) → POSITIVE symp of schizo
Glutamate hypofunction hypothesis
- mesocortical pathway (regulates DA release indirectly)
Hypofxn of cortical glutamate → loss of cortical GABA inhibition → increased activity of Glu neurons → HYPOactivity in MESOCORTICAL pathway (↓DA) → NEGATIVE symp of schizo
POSITIVE symp of schizo result from?
overactivity of DA neurons in the mesoLIMBIC system (↑DA)
NEGATIVE symp of schizo result from?
HYPOactivity in MESOCORTICAL pathway (↓DA)
Typical antipsychotic agents
D2 antagonist
(D2 blocks - High D2/5HT2A)
Good efficacy against POSTIVE symptoms
- Chlorpromazine
- Haloperidol
ATypical antipsychotic agents
5HT2 Antagonist
(and slight D2 block so low D2/5HT2A ratio)
Good efficacy against Negative symptoms
Reduced indicence of extrapyramidal toxicity (EPSE)
- Clozapine
- Quetiapine
Haloperidol vs Chlorpromazine
Typical antipsychotic agents
Haloperidol
- high potency
- high extrapyramidal toxicity (DA block)
- -> dystonia, akathisia, pseudoparkisonium, dyskinesia
Chlorpromazine
- low potency (need so much, so it spills over and causes ANS effects)
- antimuscarinic (no pee, no spit), anti Histamine, alpha 1 block (M-H-a1 block)
Atypical antipsychotic agents such as clozapine are distinguished from typical agents such as haloperidol bc they are associated with lower incidence of:
Extrapyramidal side effects
clozapine, aka wet pillow syndrome - hypersalivation
Typical low potency drug side effects
Chlorpromazine (low potency - use so much it spills over)
- muscarinic block (no pee . . .)
- a1 block (orthostatic HYPOtension)
- H1 histamine block (weight gain –> Type II diabetes)
Diff between treating Parkinsons vs Pseudoparkinsonium
Parkinsons: DA enhancing drugs
Pseudoparkinsonium: anticholinergic agents
- extrapyramidal side effect with typical high potency antipsychotic agent (Haloperidol)
- due to antipsychotic block of D2 (blocking D2, increases ACh)
Appetite increase, weight gain, diabetes are common side effects of antipsychotics use that result from block of DA rctprs at which site?
Hypothalamus
Block hypothalamic DA receptors - esp with atypical agents
Agranulocytosis (low white blood cell count) think
clozapine
ATypical antipsychotic agents
5HT2 Antagonist
but Good efficacy against Negative symptoms
Low potency Typical antipsychotic agents have significant effects on which receptor blocking activity (other than D2)?
Chlorpromazine (low potency - use so much it spills over)
alpha adrenergic receptor
(so if you give EPI, which acts on a1-b2, a1 usually wins out. but if pt is on chlorpromazine, which is a1 blocker, then b2 wins and you get paradoxical b2 vasodilation + hypotension)
(but dont forget typicals are D2 antagonist )
which of following therapeutic actions of antipsychotic agents does not result from blockade of DA receptors?
Orthostatic Hypotension (a1)
