Antidepressants Flashcards
CYP450 important for AD/mood stabiliser
1A2-> imipramine and clomipramine are substrates (active drug), fluvoxamine inhibits, therefore others not metabolised as well. Smoking induces
2D6-> TCA substrates, SSRI inibition (paroxetine, fluoxetine, fluvoxamine ++, sertraline, citalopram (least)-> raise levels of TCA
2C9
2C`9
34A->alprazolam substrate-> fluoxetine, fluvox inhibit= raise level. Carbamazepine induces + is substrate, levels need to be increased over time
How were MOA discovered
By accident when used as an antituberculosis drug
Difference in MOAi A and MOAi B
A linked to antidepressant effects
B linked to prevention of neurodegenerative
Actions of TCA
Block reutake NE, 5HT
+ H1I, a1, antimuscarinic Na channels also blocked
Allosteric modulators
5 prominent members in SSRI, include secondary binding properties
Fluoxetine- 5HT2c, CYP3A4, CYP2D6, NRI Sertraline- sigma, DRI Paroxetine- NOS, m-Ach, CYP 2D6 Fluvoxamine- sigma, 1A2, CYP3A4 Citalopram- SRI
where does serotonin first increase when given SSRI
somatodendritic area
explain the side effects when treatment initiated
how does tolerance to side effects develop
increase 5HT at somatodendritic autoreceptors, causes them to down regulate
how does autoreceptor downsensitisation relate to therapeutic action
when desensitised, serotonin no longer inhibits its own release.
area of therapeutic action of SSRI
From midbrain raphe to frontal cortex
which receptor subtypes mediate side effects of SSRI
2A/C, 3, 4
2A/C-> to limbic area, mediating agitation/panic
2A in basal ganglia-> inhibition of DA here, movement, akathisia, retardation, dystonic
2A in brain stem myoclonus during night, nocturnal awakenings
2A in spinal cord- sexual dysfunction
2A in mesocortical, reduces DA, apathy
3 hypoT-> N and V, GIT cramps/diarrhea
Why is ruboxetine a reasonable complement to SSRI
Truly selective NRI, lacking undesirable binding properties of TCA
notion re who might respond better to SRI vs NRI
- Serotonin deficiency depression-> anxiety, panic, phobia, PTSD, obsessions, compulsions-> SRI
- NE deficiency depression-> fatigue, apathy, cognitive disturbances, attention, working memory-> NRI
location of therapeutic action in NRI
LC to frontal cortex. B1 postsynaptic R
cognitive actions mediated by a2 NE
SE of NE- receptors and location
b1 in cerebellum, PNS tremor Limbic-> agitation BP b1-> HR SNS-> reduction in parasympathetic cholinergic= "pseudo" anticholinergic
action of buproprion
"Pro-drug" weak NRI and DRI does not have significant sexual side effects like SSRI boosting decreases smoking cravings
