antipsychotic psychopharmacology

how is dopamine made

tyrosine → DOPA → DA

degrading enzymes in dopaminergic pre synaptic axon terminal

MAO and COMT

what is D2 involved in

psychosis, movement, prolactin regulation

4 main dopamine tracks in the brain

1. nigrostriatal

2. mesolimbic

3. mesocortical

4. tuberoinfundibular

what causes positive symptoms

excess DA in mesolimbic tract

what causes negative symptoms

DA deficit in mesocortical tract (dorso lateral pre frontal cortex and ventro medial pre frontal cortex)

what causes cognitive symptoms

DA deficient in mesocortical tract (dorsolateral pre frontal cortex)

what causes mood symptoms

DA deficit in mesocortical tract (ventromedial pre frontal cortex)

treatment goals of schizophrenia (what do you want to do w/ the tracts and what Sx will it help)

positive symptoms: decrease DA in mesolimbic tract

negative symptoms: increase DA in mesocortical tract (dorsolateral PFC + ventromedial PFC)

cognitive symptoms: increase DA in mesocortical tract (dorsolateral PFC)

mood symptoms: increase DA in mesocortical tract (ventromedial PFC)

**leave the other 2 pathways alone (nigrostriatal and tuberoinfundibular pathways)

1st gen antipsychotics moa (specify all the diff agonist/antagonist effects)

D2 antagonist

M1 antagonists

H1 antagonists

alpha1 antagonist

2nd gen antipsychotics moa (agonist/antagonist and what type)

5HT2>D2 antagonist

3rd gen antipsychotics moa (Agonist/antagonist and what type)

D2 partial agonist

higher potency D2 block is associated with ae

EPS/TD and increased prolactin

low potency D2 block is associated with

anticholinergic effects (M1), alpha1 antiandrenergic effects , antihistaminic effects (H1)

D2 antagonism effects on mesolimbic tract

alleviates positive symptoms

D2 antagonism effects mesocortical tract

may exacerbates negative symptoms

D2 antagonist effects nigrostriatal tract

EPS/TD

D2 antagonist effects in tuberoinfundibular tract

hyperprolactinemia

M1 antagonism causes….

dry eyes, urinary retention, confusion, delirium

alpha 1 antagonism causes

anti adrenergic ae (orthostatic hypotension + reflex tachycardia)

H1 antagonism causes

antihistimic side effects (weight gain, drowsiness)

what type of 5HT receptors are on dopamine neurons

presynaptic heteroreceptors (aka brakes)

what happens when endogenous 5-HT binds to presynaptic heteroreceptors

DA release is inhibited (negative feedback mechanism)

second gen antipsychotics are in love with which receptor

5HT2A

do 5HT2a antagonists stimulate or inhibit DA release

stimulate

Effects of SGA on mesocortical tract

blocks presynaptic 5HT2a receptor therefore endogenous 5HT cannot inhibit dopamine release. So now we have increased dopamine in the mesocortical tract to help with affective, cognitive, negative symptoms (usually not enough for a meaningful increase unless they are a super responder)

Effects of SGA on nigrostriatal and tuberinfundibular tracts

Block the 5HT2A receptor and therefore reduce the D2 blockade that endogenous 5HT would cause (net slight increase in DA). When D2 blockade is reversed it does not cause EPS/hyperprolactinemia

which ae do SGAs not cause that FGAs cause

EPS/TD + hyperprolactinemia

Effect of SGA on mesolimbic tract

There are no presynaptic 5HT2a receptors here therefore acts as an antagonist on D2 receptors. This helps positive symptoms (reduced delusions, hallucinations etc)

Common ae of SGAs and the receptors which causee

5HT2c + H1 antagonism= weight gain + dyslipidemia

M3 antagonism= IGT, T2DM

**remember less likely to cause hyperprolactinemia and EPS/TD than FGA

what causes hyperprolactinemia and EPS/TD

D2 antagonism in nigrostriatal tract tubulofundibulad tract

metabolic liability scale of SGA

olanzapine, clozapine > quetiapine > others

what types of affinities for which receptors are likely to have problems with weight gain and dyslipidemia

at least moderate affinity for one of these receptors plus mod-high affinity for one : H1 and 5HT2C

why do SGAs have less D2 side effects

they have lower affinity for D2 receptor, they prefer 5HT2A receptor

What is unique about risperidone

Can change it’s mind and flip affinity + turn into a first gen and cause EPS/hyperprolactinemia

TGA effects on 4 dopamine tracts

mesolimbic: partial agonist behaves kind of like antagonist since there is too much dopamine here

mesocortical: partial agonist behaves like agonist because there is too little dopamine here

nigrostriatal: less chance of EPS/TD

tuberofundibular: less chance of hypeprolactinemia