2- antipsychosis Flashcards
what is psychosis
mental disorders in which there is a loss of contact with reality, affecting abilities to think feel and act
what are the main clusters of symptoms in schizophrenia
+, -, mood, and disorganized symptoms
memory deficits
what are the 3 biochemical theories of schizophrenia
excess dopamine
reduced serotonin
reduced glutamate or GABA
what is the dopamine hypothesis
that psychotic symptoms are caused by an excess of dopamine
how did they come up with the dopamine hypothesis
drugs that stimulate DA can cause psychotic symptoms
how do first gen antipsychotics FGAs work
they block DA receptors as their main target
how do second gen antipsuchotics work
they blcok serotonin receptors
how did they come up with the reduced serotonin theory
LSD are serotonin agonists
how did they come up with the reduced glutamate or GABA hypothesis
PCP, glu receptor inhibitor, induced +and- symptoms of schizo
what is the mesolimbic/mesocortical system
structures that mediate memory, learning, affect and thought organization
what happens when the mesolimbic/mesocortical system is disturbed
psychotic Symptoms
what does DA do in the tuberoinfuncibular system
effects secretion of some pituitary hormones, like prolactive and growth hormones
what is the nigrostriatal system
pathway thought to be involved in parkinson’s life symptoms after using t neuroleptic drugs, like tardive dyskinesias
what do D1 dopamine receptors do
stimulate Gs pathway
target for antipsychotics, but it may not be clinically relevant
what do D2 dopamine receptors do
Gi pathway (inhibit AC) and couple with other effector systems
what happens when you block the D2 receptor
clinical antipsychotic potency
reduce positive symptoms
what happens with 5-HT2A antagonist
improves + and - symptoms
how does 5-HT2A reduce positive symptoms
positive symptoms by reducing excitation of glutamate neurons in the prefrontal cortex
how does 5-HT2A reduce - symptoms
5-HT2A antagonism releases DA in the prefrontal cortex
what happens when there is an increase in DA in the prefrontal cortex (antagonize 5-HT2A)
may improve negative, cognitive and affective symptoms of schizophrenia
what do 5-HT1A receptors act as for DA release
accelerators
what do 5-HT2A receptors act as for DA release
brakes
what does 5-HT1A agonism do
increases DA release and decreases glutamate release in prefrontal cortex
what does 5-HT2A antagonism stimulate
DA release in nigrostriatal pathway, the increase DA competes with drug at D2 and less receptors binding to drug
what reduces the risk of actrapyramidal symptoms
5-HT2A antagonism, because more DA is released and competes with the drug
what do 5HT cells release to communicate to DA neurons
GABA
what happens when 5HT blocks 5HT2A receptors on GABA neuron
is it direct or indirect
GABA isnt released, and dopamine isnt released
indirect because goes through GABA
are typical antipsychotics gen 1 or 2
1
are atypical antipsychotics gen 1 or 2
2
how do all 1 gen work
target DA receptors
how does 1 gen efficacy depend on
D2 receptor antagonism
what is haloperidol
1st gen
what is chlorpromazine
1st gen
what is clozapine
2nd gen
what is risperidone
2nd gen
how do most 2 gen work
affinity for 5-HT receptors and D2 receptors
why do 2 gen have less dopamine related side effects than gen 1
they bind looser and dissociate faster
how much D2 occupation is required to produce antispychotic effects
60-80%
what happens over 80% D2 receptor occupancy with gen 1
extrapyrimidal (physical parkinson like symptoms), elevated prolactin and tardive dyskinesias
what is haloperidol kinetics
fast on slow off compounds
1st gen
how does haloperidol work
fast rebinding at D2 and hard to insurmound (slow dissociation)
what does haloperidol cause
increase EPS (extrapyramidal side effects) and increase prolactin release
what are chlorpromazine kinetics
fast on and fast off
gen 1
what happens in chlorpromazine side effects
fast rate=high EPS
fast off=normal prolactin
what is kinetics of clozapine
slow on fast off
what symptoms clozapine
slow on=less EPS
fast off=normal prolactin
what does slow dissociation rates cause
high prolactin
what does fast dissociation rates cause
normal prolactin
what does slow binding rates cause
normal EPS
what does fast binding rates cause
high EPS
which drug causes agranulocytosis
clozapine
what is agranulocytosis
severe reduction in WBC
what are the receptor affinities for haloperidol
D2(most), D1, D4, alpha-adrenergic, 5-HT2
what are the receptor affinities for chlorpromazine
D1(most), D2, 5-HT2A, aloha adrenergic
what are the receptor affinities for risperidone
low dose: 5-HT2A
high dose: D2 5-HT7
what are the main bad side effects of first gen
EPS, tardive dyskinesia, prolactin increase
what are the main bad side effects of 2 gen
cardiovascular bad, metabolic bad, diabetes and weight gain, and life span decrease
how long before they start to work
hours or days, but 4-6 weeks for full effect
where is haloperidol metabolized and by what
half life
extensively in liver CYP3A4
1.5days
highly sedating
chlorpromazine metabolism and half life
accelerates its own metabolism by inducing CYP enzymes, over 100 metabolist, 1 day
clozapine metabolism and half life
CYP1A2 and CYP3A4 to norclozapine (similar D2 and 5-HT2A affinity as clozapine)
0.5 days
risperidone metabolism and half life
CYP2D6 indo paliperidone (which is also marketed as an antispychotic)
1day
which gen is better for + symptoms
both
which gen is better for - symptoms
second gen
what happens when 5HT blocks 5HT2A receptors on DA neuron
is it direct or indirect
DA isnt released
directly
what happens when 5HT binds to 5HT-1A receptors
5HT causes inhibition of its own release
the lack of 5HT results in a disinhibition of DA release
Raises DA
what does 5HT1A agonism cause
increase DA release in prefrontal cortex
what does 5HT2A antagonism cause
released DA in prefrontal cortex and in nigrostriatal pathway
how does GABA release effect DA release
GABA release stimulates DA release
which CYP enzymes for haloperidol and what active metabolite
CYP3A4
none we know of
which CYP enzymes for clozapine and what active metabolite
CYP1A2 and CYP3A4
norclozapine
which CYP enzymes for chlorpromazine and what active metabolite
100 metabolites
induces CYP to accelerate its own metablism
which CYP enzymes for risperidone and what active metabolite
CYP2d6 into paliperidone
which drug is fast on slow off
haloperidol
which drug is fast on fast off
chlorpromazine
which drug is slow on fast off
chlozapine
