[8.29] Autoreceptors in therapy Flashcards
where are autoreceptors found + function + property
location: presynaptic nerve cell membranes
function: negative feedback loop
selective: sensitivity to NTs from presynaptic neuron
3
what are the monoamine neurotransmitters (+ function)
- NA: for energy + interest
- DOPA: drive/motivation
- 5-HT: impulse/sleep
how is depression treated? (drug and non-drug)
DRUG:
1. MAOIs
2. TCAs
3. SSRIs
NONDRUG:
1. ECT
2. Psychological treatments
3. Lithium
SSRIs: treating? MOA? eg? cautions? s/e?
related to?
treatment: clinical depression, anxiety disorders, panic, OCD, eating, chronic pain
MOA: incr extracellular [5-HT] by inhibiting its reuptake into the presynaptic cell = incr availability for postsynaptic uptake
eg. citalopram, fluoxetine (prozac), paroxetine, fluvoxamine maleate
cautions: not with MAOIs, incr blood levels and toxicity risk (warfarin, anti-arrhythmics, B-blockers, benzos, carba); X alcohol, other antideps, diuretics, sympathomimetics, lihium, zolpidem
s/e: GI (n+v), diarrhoea, headaches, drowsiness, weight loss/gain, suicidal ideation, vivid dreams (crossing BBB), teeth clenching
similar: SNRIs, SNDRIs
negative counteracting feedback of SSRIs?
increasing synaptic 5-HT levels flood autoreceptors, feedback sensor to cell
results in downstream transporter inhibition - cell is unable to counterbalance this increase, body gradually adapts to this situation by **downregulating autoreceptor sensitivity **
–> results in long-term adaptive modification of serotonin/receptor ratio
result of this? takes several weeks to effect - why increased anxiety is a common s/e in the first few days/week of use (overstimulation of 5-HT receptors)
describe SSRIs’ discontinuation syndrome
not ‘addictive’; but produces somatic and psychological withdrawal symptoms
- ‘brain zaps’ / ‘fever jolts’ (overexcitation)
- last from weeks to months; potentially distressing
TCAs: treating? MOA? eg? cautions? s/e?
treating: depression (but lower use than SSRIs due to higher likelihood for s/e); other applications, neuropathic pain, nocturnal enuresis, ADHD
MOA: inhibiting reuptake of NA / 5-HT from synaptic cleft; increases sensitivity of postsynaptic 5-HT1A receptors in the hippocampus = increases serotonergic transmission and elevates mood
eg: imipramine, amitriptyline, clomipramine
types of amines
- tertiary amines (amitript, imipramine, clomipramine): boost serotonin + NA, produce more sedation, anticholinergic effects
- secondary amines (nortiptyline, desirpamine): NA only
MAOIs: treating? MOA? eg? cautions?
most significant risk associated wit the use of MAOIs?
MOA: NT inactivation + MAO dysfunction = decr release of active metabolites (of catecholamines) for excitatory pathway
reversible inhibitors (following generations - eg. moclobemide
eg. isocarboxazid, phenelzine, tranylcypromine
cautions: potential for interactions with OTC and prescription meds, illicit drugs and supplements (eg St John’ Wort); X combine with other psychoactive substances (eg SSRIs, tricyclics) except under expert care
describe the MAO enzymes and what they metabolise
MAO-A: preferential deamination of serotonin, melatonin, ADR and NA +DOPA
(higher risk of serotonin syndrome and/or hypertensive crisis + tyramine (dietary amine) is broken down by MAO-A: hence excessive buildup of MAO-A can have serious side effects
- CHEESE SYNDROME!! - hypertensive crisis
- hyperserotonemia (trp a/a)
MAO-B: preferential deamination of phenylethylamine and trace amines +DOPA
function of serotonin
synthesised in serotonergic neurones in the CNS + enterochromaffin cells in the GI tract
- regulation of body temp, mood, sleep, vomiting, sexuality, appetite
low [5-HT] = clinical depression, migraine, IBS,
what is the normal tyramine pathway?
how does tyramine accumulation cause a hypertensive reaction?
- tyrosine (precursor) is decarboxylated into tyramine
- tyramine is normally then deaminated by MAO-A into inactive metabolite, but with MAOI this is blocked (!!)
- tyramine levels then climb; tyramine competes with tyrosine for aromatic amino acid transporter for transport across BBB, into adrenergic nerve terminals
- transported via VMAT into synaptic vesicles, which displace NA from storage vesicles into extracellular space (causes a cascade with excessive amounts of NA)
- this mass transfer results in precipitation of hypertensive crisis (resulting in stroke/cardiac arrhythmia)
effects of long term antidepressant treatment?
- moderated compensatory effect –> decreasing number of serotonergic and catechalominergic receptors
- gradual decrease in autoreceptor responsiveness (sensitivity and consequently decrease inhibition of NT release)
–> moderation of NT response; efficacy of drug effect within 2 - 3 week window
–> high selectivity for serotonin reuptake
- increase [NT], decreasing receptor sensitivity to the NT
octopamines … do what? how what? idk go see later.
