Pharm 30

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Major Depressive disorder (MDD) categoration

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depressed mood most of the time for at least 2 weeks and/or loss of interest or pleasure in most activities

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HPA axis

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hypothalamic-pituitary-adrenal

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MDD associations

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HPA axis abnormalities; elevated cortisol, nonsuppression of ACTH release in dexamethasone-suppression test, and chronically elecated CRH; 25% abnormal thyroid fxn

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selective serotonin reuptake inhibitors (SSRIs)

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primary action inhibits serotonin transporter (SERT); highly lipophilic; currently 6 available-most common antidepressants in clinical use (Fluoxetine, sertrealine, citalopram, paroxetine, fluvoxamine, and escitaloprim)

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Serotonin-Norepinephrine reuptake inhibitors (SNRIs)

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venlafaxine (metabolite desvenlafacine), duloxetine; treat depression, neuropathies, and fibromyalgia; chemically unrelated to one another

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what do SNRIs bind

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SERT and norepinephrine transporters (NET); do not have much affinity for other receptors (like TCA)

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Tricyclic antidepressants (TCAs)

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9 available in US-chemical differences subtle

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imipramine

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TCA; highly anticholinergic and is relatively strong serotonin and norepi reuptake inhibitor

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desipramine

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differs from imipramine by 1 methyl group; much less anticholinergic and more potent and somewhat more selective norepi reuptake inhibitor

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5-HT2 antagonists

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trazodone and nefazodone

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most common use of trazodone

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unlabeled hyponotic-highly sedating and not associated with tolerance or dependence

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bupropion

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unicyclic aminoketone structure-resembles amphetamine and has CNS activating properties; 85% protein bound; extensive hepatic metabolism; biphasic elimination

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Mirtazapine

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not associated with sexual side effects

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MAOI used in parkinsons

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selegiline

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hydrazines and tranylcypromine (MAOIs) bind irreversibly and nonselectively with

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MAO-A and B; most other MAOIs are more selective or reversible

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pharmacokinetic features of most antidepressants

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fairly rapid oral absorption, achieve peak plasma levels in 2-3 hours, are tightly bound to plasma proteins, undergo hepatic metabolism, and are renally cleared

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fluoxetine and MAOI administration

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must be discontinued 4 weeks or longer b4 MAOI administered due to risk of serotonin syndrome; has long half-life in active form

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antidepressants that are inhibitors of CYP2D6

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Fluoxetine and paroxetine

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tricyclic antidepressants (TCAs) general specs

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dosed at night due to sedating effects; undergo extensive metabolism; well absorbed, long half-lives

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main difference btwn SNRIs and TCAs

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SNRIs lack potent antihistamine, alpha-adrenergic blocking, and anticholinergic effects

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common adverse effects of TCAs

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dry mouth, constipation, orthostatic effects (especially in older patients)

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agonists of 5-HT

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lysergic acid (LSD) and mescaline; often hallucinogenic and anxiogenic

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nefazodone MOA

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weak inhibitor of both SERT and NET, but potent antagonist of postsynaptic 5-HT2a receptor

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when should maintenance treatment be considered for MDD

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2 or more serious MDD episodes in previous 5 yrs or >3 in a lifetime

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treatment of anxiety disorders

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benzodiazepines provide rapid relief for generalized and panic; antidepressants at least as effective, maybe more in long-term treatment (without risk of tolerance and dependence)

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OCD treatment

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serotonergic antidepressants=clomipramine; often require max or higher than max recommended MDD doses for optimal benefit

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first line treatment of PTSD

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SSRIs

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antidepressants and smoking cessation

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buproprion; noortriptyline

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antidepressants eith least association with sexual side effects

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buproprion, mirtazapine, and nefazodone

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reasons TCAs and MAOIs are 2nd or 3rd line treatments for MDD

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potentially lethal in OD, require titration to achieve therapeutic dose, have serious drug interactions, and many troublesome side effects

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dose of TCAs and SNRIs for use with pain

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TCAs only modest dose (subtherapeutic for MDD) and SNRIs same dose

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SSRI side effects

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increased serotonergic tone=GI nausea, upset, diarrhea; diminished sexual fxn and interests

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TCAs and arrhythmias

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class 1A antiarrhythmic agents

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TCA discontinuation syndrome

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cholinergic rebound and flulike symptoms

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most common adverse effects of 5-HT2 antagonists

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sedation and GI disturbances

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nefazodone side effect (TCA)

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hepatotoxicity; serious rate is 1 in 250,000-300,000 patient-years of treatment

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amoxapine side effect

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parkinsonian syndrome due to D2 blocking action

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MAOI side effects most commonly leading to discontinuation

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orthostatic hypotension and weight gain

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treatment of TCA OD

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cardiac monitoring, airway support, gastric lavage, sodium bicarb (uncouple TCA from cardiac sodium channels)

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cause of serotonin syndrome

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overstimulation of 5-HT receptors in central gray nuclei and the medulla

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symptoms of serotonin syndrome

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triad of cognitive (delirium, coma), autonomic (hypertension, tachycardia, diaphoresis), and somatic (myoclonus, hyperreflexia, tremor) effects

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tyramine and MAOIs

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MAOIs prevent breakdown of tyramine in gut and results in high serum levels that enhance peripheral noradrenergic effects (like raising B{ dramatically)

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tyramine containing foods

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aged cheeses, tap beer, soy products, dried sausages

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over-the counter cold products that should be avoided with MAOIs

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pseudoephedrine and phenylpropanolamine = can cause significant hypertension