| Mechanism and Kinetics | Binding Profile of Clozapine and its primary active metabolite | Plasma levels | Impact of smoking, caffeine and genetic polymorphisms | Misc. |
|---|---|---|---|---|
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alpha adrenergic
Clozapine has a high affinity for muscarinic, histaminergic, and ____receptors
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norclozapine
what is its primary active metabolite
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downregulation
increased clozapine levels
serious bacterial or viral infections can be associated with __*upregulation/downregulation*____ of CYP450 activity, resulting in ____ levels
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no- aryl hydrocarbons from burning leaf
substrate for cypa12- not inhibitor, but competor. SO- too much caffiene means increased clozapine levels. 40-1000mg/day caffiene in nonsmoker caused 19% increase in clozapine epxosure and 14% dec in clearance
Does nicotine itself play a role induce CYP A12?
Caffiene? |
presynaptic dopaminergic neurons in NS pathway
Inverse agonists at 5ht2a receptors mitigate development of EPS akathisia through binding to (presynaptic/postsynaptic dopaminergic neurons in nigrostriatal pathway
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4-66 hours
half life?
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glutamate
(PCP is nmda antagonist) Let to the idea of " Glutamate Hypofunction Hypothesis" meaning that NMDA receptor hypofunction in psychosis.
PCP causing psychosis-like activity and cognitive disruption made us realize that psychosis may have something to do with THIS receptor that clozapaine acts on
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12 h
check every time you increase 50mg FYI - levels as high as 1000-3000ish is called "dose of futility"
when tracking clozapine levels, response correlates best with _____ hour trough level
START at 100mg and do it a week after they have been on 100mgs Once you get to upper limit of ther. range (700 nml/L)--how often due you check the clozapine level as you titrate beyond that? |
1 week (5 half lives is 8 days)
could result in toxicity -- ca12 saturated with nonlinear kinetics
after smoking cessation for _____ *time*____ clozapine levels will rise 50% or more
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weaker
Both clozapine and norclozapine have ___(stronger/weaker)___D2 antagonist activity compared to risperidone
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oral tab, ODT, solution, IM (25mg/ml) in some countries
Formulations of Clozapine? There are 4
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worsen
trialed showed worsened positive symptoms.
NMDA is bound by glutamate and glycine. In theory, giving glycine will __(improve/worsen)__ psychosis in clozapine patients
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350 ng/ml or 1070 nmol/L
likelihood of response is low with clozapine levels below ____
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7-12
smoking as few as ___ cigarettes/day can cause cyp 1a2 induction
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mirtazepine works by antagonizing the adrenergic alpha2-autoreceptors and alpha2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors.
We realized that inverse agnozing 5ht2a helps psychosis. Too much 5ht2a is BAD so if mirtazepine does that, that helps out the antipsychotic
mirtazepine MOA, and why that would be helpful for akathisia
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100%
Strong 2d6 3a4 inhibitors can increase clozapine levels as much as what percent?
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antagonist - blocks ligand activity but doesnt actually do anything. basal activity continues
inverse agonist- stops the g protein coupled receptors basal activity. FAUCETS ANALOGY
what is the difference between antagonist and inverse agonist
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2-3 weeks
nonresponders should not be left on same dose waiting for late response....titrate up if tolerated
once dose is increased, wait THIS amount of time to respond before further titration
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10% q48h till 50% reduced
tkae plasna kevels on day 7 and 14 to help guide you
when outpt smoker on clozapine is in situation w/o access to cigarete more than 48 hours, how often should you lower dose
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(Orthostasis)-------------[a1 antagonism]
(constipation)------------[M1 and M3 antagonism], (sialorrhea)---------------[M1-M5 agonism] (sedation/WG)-----------[H1 antagonism]
Match the 4 side effect to the 4 MOA:
(Orthostasis) (constipation), (sialorrhea), (sedation/WG) [M1 and M3 antagonism], [H1 antagonism], [M1-M6 agonism] [a1 antagonism] |
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cyp 1a2
In descending order : CYPs 1A2, 2c19,3a4 , 2c9, 2d6
Which cyp450 enzyme is responsible for upto 45-55% of clozapine biotransformation?
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limits CNS penetration
Nor clozapine has a high affinity for a PGP efflux transporter which makes it not as good as clozapine because it
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1) No not reflexively...50% published cases say they had clinical sympt from the increase (sedation may not be that theyre ill, it might be their clozapine!!)
2) Dont be abrupt- could have anticholinergic rebound and psychosis rebound!! ******Check levels weekly ...you can have cytokines lingering even after the infection which effect clozapine! *********
1) Person is infected, on clozapine. Should you decrease the dose?
2) If you do, what should you be concerned about? |
1.08 if nonsmoker, .67 smoker
1.32 if nonsmoker .8 smoker
For a 40 y.o male (80kg) you can guestimate concentration of clozapine by multiplying their dose times ___
for a 40 y.o (70kg) female multiply oral dose by ___ |
Levels. Fluctuating levels=nonadherance. (30& normal. >50% not normal)
consistently low=poor absorption (nonsmoker)
How do you tell between nonadherance and bad absorption?
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