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50 Cards in this Set
- Front
- Back
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mental illnesses that can be treated- characterized by ____
into what 4 disease states |
DSM-IV
(psychosis, schizo, anxiety, depression) |
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psychosis definition (2)
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mental state where you have loss of contact with reality
more severe psychiatric disorders |
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schizophrenia (2)
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sx of delusions, sensory hallucinations
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anxiety- definition (3)
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retained sense of reality (they know they're fucked up) but
mood changes (anxiety...obsession/fears) behavioral disturbances-rituals, avoidance, compulsions- disabling |
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psychotrophic drug properties (causes changes in what 5 things)
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cross BBB
changes in perception mood consciousness behavior cognition |
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dopamine hypothesis of schizophrenia (2)
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schizo results from increased DA neuro transmission
approaches to lower DA transmission may alleviate psych sx |
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phenothiazines (drug for schizo)
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affected brain DA metabolism- basis for DA hypothesis
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antipsychotic compound efficacy/side effects- linked to what?
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effectiveness of antipsychotic compounds was directly linked to affinity for D2 receptor
EPS side effects linked to D2 antagonisms |
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D2 receptor interaction (and therapeutic actions) is complex and involves what 3 modes of action (at receptor)
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antagonisms, inverse agonism, partial agonism
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functional selectivity- what is it?
how does it work? (3) |
GPCRs can couple to multiple different Ga subunits (not at the same time) depending on conformation of receptor
this confers different conformations of the receptor which can recognize different ligands leads to different signalling pathways |
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example of ligand that exhibits functional selectivity
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aripiprazole- D2 ligand
depending on context (type of tissue, etc)- it can act as antagonist or inverse agonist |
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name for antipsychotic drugs
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neuroleptics- lepsis means to "take hold" (of conscious mind)
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2 types of neuroleptics
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typical vs atypical
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how do the atypicals generally work, mechanism wise?
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atypical act through other mechanisms instead of or in addition to D2 antagonism
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typical antipsychotics- MoA (general)
this results in what? |
typical act on post synaptic D2 receptors (antagonists)
antagonists related to EPS- so more AE |
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general MoA of antipsychotics- specific tract that it targets
focuses on what receptor (and what type of ligand activities) |
modulate Da pathways- specifically mesolimbic-mesocortical tracts
focus on D2 receptor as antag, inverse agonist, or partial agonists (works same as agonist but don't get full activation) |
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major side effect of neuroleptics
(3) |
EPS- PD like side effects
grimacing restlessness shuffling gait (derp you are antagonizing DA...so...similar to PD) |
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"other" side effects (not EPS) from neuroleptics (3)
mechanism of these other effects? |
reactivity with other receptors:
H1, a1/2, M1, HT sedation, hypotension, sexual dysfunction |
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phenothiazine- where did it come from?
led to development of what drug |
basic structure of phenothiazines (know structure) was developed from work on antihistamine of benzodioxane variety
further mod, over time -->led to chlorpromazine (structure- know) (CPZ) |
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some major issues with chlorpromazine (CPZ)- (3)
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EPS
tardives dyskinesia- uncontrollable motions (grimacing, lip smacking...eye blinking, ataxia- like PD) IRREVERSIBLE |
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phenothiazine/chlorpromazine- related to what type of drug
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many related to antihistamines (diphenhydramine)
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SAR for phenothiazine (7)
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nucleus is essential for antipsychotic activity
substitution on 2 position increases potency sub on other positions- or disubstitution- causes decrease in activity position 10 (where amine is) optimally will have...3 carbon chain? what (branched substituents have no effect) terminus of 3 carbon chain at position 10 end with tertiary amine (NR3) if central ring is a piperazine (2 Ns instead of S/N) will has less sedation and hypotension if central ring is a piperidine- it is active, with less EPS |
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thioxanthene example
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chlorprothiexene
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thioxanthenes- which enantiomer is more active
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cis more active than trans (in relation to double bond)
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butyrophenone- drug example
SAR (2) |
haloperidol
has fluorine group at 4 position (POTENT! MOST POTENT!) and ketone |
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most potent neuroleptics derived from phenothiazine have what SAR?
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F group at 4 position
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haloperidol properties/AE incidence (2)
3 other receptors it affects |
affects D2, 5HT2, sigma2?? (dirty drug)
high incidence of EPS but less than chlorpromazine (CPZ) |
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benzamide example
describe the structure |
benzamide- benzene with amide attached to it
metoclopramide- |
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benzamides- derived from what?
targets what receptors (2) |
derived from local anesthetics
bind to D2 and D3 receptors (weakly) |
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benzamides- besides DA receptors also binds non selectively to what (4)
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has AchE activity, blocks M3, 5HT1a, 5HT3
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4 benzazepines
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clozapine
olanzapine loxapine quetiapine |
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benzazepine class of drug - significance (2)
atpyical or typical |
benzazepine derivatives- "balanced solution"
bind to D2 receptors AND act through 5HT2A receptors (antagonizes both) ATYPICALS |
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what does inhibiting 5HT2a receptors do (what benzazepines do)
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5HT2a receptors- in neurons- normally inhibit dopamine release in striatum. so if you inhibit these guys, you can counter the DA antagonisms effect in striatum (where AE occurs) and decrease EPS
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clozapine MoA
usage route |
acts at 5HT2a and D2 receptors
can be used longer term- do not produce tardive dyskinesia orally active |
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clozapine AE
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AE: 1-2% agranulocytosis
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olanzapine- same MoA as shit as clozapine- compare the 2 drugs (2)
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more potent at D2 receptors than clozapine
very long half life of 20-50 hours- aids in compliance |
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quetiapine/loxampine- primarily affect what receptor
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primarily D2 activity
(but also some 5HT2a) |
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quetiapine also binds to what receptors (3)
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quetiapine also binds to H1, a1/2
and has low affinity for muscarinic receptors |
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benzisoxazoles- describe the structure and what is unique about it (2)
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combine potent D2 antagonists- which have benzamine
potent 5HT2a antagonists- have benzothiazolyl combines both of these to get benzisoxazole |
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3 examples of benzisoxazoles
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tiospirone
risperidone ziprasidone |
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risperidone MoA
absorption half life |
risperidone- has D2 and 5HT2a antagonisms
well absorbed orally half life 22 hrs |
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5 categories of neuroleptics
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thioxanthenes
butyrophenone benzamide benzazepine (atypical) benzisoxazoles misc. (aripiprazole) |
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aripiprazole- what "type" of drug is it (chemical name/category)
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aripiprazole- arylpiperazine quinolinone derivative
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MoA of aripiprazole (2) and address it's EPS activity
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complex functional activity- high affinity for D2 receptors (antagonist) and also at 5HT2a receptors
you would think this means more EPS- but at some D2 receptors, it is a partial agonist- which also helps to modulate EPS (low incidence even though it is high affinity for D2) |
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2 targets of anti anxiety drugs- describe structures of both
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GABAa (Cl channels) (ligand gated with multiple binding sites)
GABAb- GPCR dimer of GABAb mono-unit, but one unit doesn't have binding site...so still represents one binding site even though it is dimer |
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bdz's can be used as...(3)
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can be used as anxiolytics, muscle relaxants, sleep aids
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main drug for treating anxiety
why? (2) |
benzodiazepines-
highly efficacious for anxiety most rapid onset |
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bdz "receptor"
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bdz receptor- name for site on GABA receptor that binds it
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flumazenil
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bdz antagonist
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imidazenil
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partial agonist at bdz
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