Unit 3 - Antidepressants Flashcards
what is the biogenic amine hypothesis of mood disorders?
depression is too little CNS NE and/or 5-HT over amounts and/or activity
-thus, most antidepressant drugs block reuptake of both NE and 5-HT
what is the discrepancy between pharmacological effect and clinical improvements of antidepressants?
PE happens within minutes to hours (increasing nt in synapse)
CI happens in 6-8 weeks (mech are matter of conjecture)
-receptor re-regulation?
-increasd BDNF gene trascription?
-induced synaptogenesis?
what is the neurotrophic hypothesis?
brain derived neurotrophic factor (BDNF) drops in depression, so therapy should increase BDNF gene transcription and neurogenesis
what is the Hamilton Depression Rating Scale?
8-13: mild depression
14-18: moderate depression
19-22: severe depression
>23: very severe depression
what does MAO-A VS MAO-B do?
A: oxidizes mainly NE, 5-HT, tyramine
B: oxidizes mainly DA, phenyethylamine
what drug class are Tranylcypromine and Phenelzine in?
MAOi
- inhibit both A and B for depression
- tranylcypromine is readily absorbed and persists in system for 7 days
what drug class are Selegiline and rasagiline?
MAO-B selective for Parkinson’s
-Selegiline at high doses inhibits A and B for depression
what are side effects of MAOi?
some anticholinergic, pronounced orthostatic hypotension, sexual dysfunction, weight gain, and sedation
-life threatening: potential hypertensive crisis if consume tyramine, as liver MAO is also inhibited
what is serotonin syndrome?
potentially lethal effect from taking MAOi + SSRIs (drug-drug interaction)
- looks like malignant hyperthermia and potentially lethal
- hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status and vital signs
- due to increased 5-HT and inhibited reuptake
what are amine reuptake inhibitors? features?
tricyclics, SSRIs, and “atypicals”
- drug-to-drug widely varying potencies and varying selectivity spectrum to inhibit reuptake transporter for NE or 5-HT or both
- many have active metabolites (N-demethylated) which are usually much longer acting than the parent compound
what are desipramine, imipramine, amitriptyline, and nortriptyline? what do they do?
TCAs
- inhibitors of NE and 5-HT reuptake to varying degrees of potency and selectivity (therapeutic effect from 8 to 100 hours)
- -depends on formation of active metabolites
- high protein binding and high lipid solubility, so very large Vd
why are TCAs “dirty drugs”?
produce varying degrees of block at muscarinic, a-adrenergic, DA uptake pump, and histamien receptors, to cause many side effects
what is the general reuptake inhibitor metabolism for TCAs?
N-demethylation followed by P450 oxidation followed by glucuronide conjugation
what are adverse effects of TCAs?
- anti-muscarnic: blurred vision, constipation, confusion, dry throat, hypotension
- a-antagonistic: orthostatic hypotension
- histamine antagonist: sedation (additive with alcohol)
- sympathomimetic: tremor, insomnia
- overdoses: cardiac arrhythmias, conduction defects
which antidepressants are used more now? why?
SSRIs and atypicals are replacing MAOis and TCAs
- newer ones have less intense side effects (thus more compliance)
- although TCAs have higher efficacy per mg, their side effects are not manageable
what are fluoxetine, paroxetine, sertraline, escitalopram, and citalopram? which one forms active metabolites?
SSRIs
-fluoxetine forms active metabolites
what are duloxetine and venlafaxine?
SNRIs
how are SSRIs different from TCAs?
- SSRIs have longer duration of action
- some inhibit P450 enzymes (esp. fluoxetine and paroxetine), so can interfere with metabolism of other drugs
- much safer in OD (no seizures or cardiac arrythmias)
- less side effects
- more N/V and complaints of decreased sexual function
what are adverse reactions of SSRIs?
potent inhibitors of P450 enzymes, and serotonin syndrome
what are tetracyclics and unicyclics (bupropion, mirtazapine) and ketamine?
atypical antidepressants
what are the unique things of bupropion?
- notable selectivity for DA uptake transporter
- potential side effect of lowering seizure threshold
- improves nicotine abstinence in quitting smokers
what is ketamine?
NMDA receptor antagonist with rapid antidepressant response (within hours) in treatment-resistant depressed patients
-rapidly increases synaptogenesis, including increased density and function of spine synapses in PFC
how does Lithium work?
unclear mechanism, but causes depletion of IP3 and DAG second messengers in a-adrenergic and muscarinic-cholinergic transmission
-may cause selective depression of overactive circuits
what are ASE of lithium?
low margin of safety
- drowsiness, weight gain, tremor, polydipsia, polyuria
- neurotoxicity, cardiac toxicity, renal dysfunction
- N/V is early awrning of OD
what are carbamazepine and valproate?
anti-convulsants
