DEPRESSION2011-Part2-publish.key - Antidepressants Part II...

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Unformatted text preview: Antidepressants Part II PMY 406/512/516 Spring 2011 Monoamine oxidase inhibitors Tranylcypromine (Parnate) Phenelzine (Nardil) Tricyclic antidepressants Imipramine (Tofranil) Doxepin (Sinaquan) Amitriptyline (Elavil) ✔ ✔ SSRIs Escitalopram (Lexapro) Citalopram (Celexa) Paroxetine (Paxil) Fluoxetine (Prozac) Sertraline (Zoloft) SNRIs Duloxetine (Cymbalta) Venlafaxine (Effexor) Desvenlafaxine (Pristiq) Serotonin receptor antagonists Bupropion (Wellbutrin) Trazodone Nefazodone Placebo effect Therapeutic Uses of Fluoxetine • • • • • • • • Major depression Obsessive-compulsive disorder Bulimia nervosa Premenstrual dysphoric disorder Panic disorder Post-traumatic stress disorder Generalized anxiety disorder Social anxiety disorder SSRIs - Advantages • • • Fewer side-effects • Nausea, headaches, etc. Very high therapeutic index Not cardiotoxic Adverse Effects • • • • • • • • • • Sexual dysfunction Weight gain Serotonin syndrome Withdrawal syndrome Neonatal withdrawal syndrome Extrapyramidal side effects Bruxism Bleeding disorders Suicide risk Teratogenesis c urrent concepts ch potentially rules out what are now recmild, early, or subacute cases of the dishird, clinicians cannot diagnose a conhich they are unaware, even though the syndrome is not rare and has been identients of all ages, including the elderly, nd newborn infants.10,12-14 ng number of drugs and drug combinabeen associated with the serotonin synle 1). These include monoamine oxidase MAOIs), tricyclic antidepressants, SSRIs, lgesics, over-the-counter cough medibiotics, weight-reduction agents, antintimigraine agents, drugs of abuse, and ducts; the withdrawal of medications has ssociated with the syndrome.1,4,12,15-23 erapeutic dose of an SSRI has caused the syndrome.12 Moreover, the addition of inhibit cytochrome isoforms CYP2D6 4 to therapeutic SSRI regimens has been with the condition.16,24,25 Administraotonergic agents within five weeks after tinuation of fluoxetine therapy has proug interaction culminating in the serotome, presumably the result of the demethluoxetine to norfluoxetine, a serotonergic with a longer serum half-life than its parund.13 Specific drugs, such as MAOIs eversible or nonselective or that inhibit e oxidase subtype A, are strongly assosevere cases of the syndrome, especially e agents are used in combination with e, dextromethorphan, SSRIs, or meth- Figure 1. Spectrum of Clinical Findings. Manifestations of the serotonin syndrome range from mild to life-threatening. The vertical arrows suggest the approximate point at which clinical findings initially appear in the spectrum of the disease, but all findings may not be consistently present in a single patient with the serotonin syndrome. Severe signs may mask other clinical findings. For example, muscular hypertonicity can overwhelm tremor and hyperreflexia. skin color. Interestingly, the hyperreflexia and clonus seen in moderate cases may be considerably greater in the lower extremities than in the upper extremities; patellar deep-tendon reflexes often Boyer a sindemonstrate clonus for several seconds afterand Shannon (2005) NEJM, 352, 1112-1120. gle tap of the tendon, whereas the brachioradialis reflex is only slightly increased. Patients may exhibit horizontal ocular clonus. Changes in mental status include mild agitation or hypervigilance, as well as Adverse Effects • • • • • • • • • • Sexual dysfunction Weight gain Serotonin syndrome Withdrawal syndrome Neonatal withdrawal syndrome Extrapyramidal side effects Bruxism Bleeding disorders Suicide risk Teratogenesis Drug Interactions • • • • Monoamine oxidase inhibitors Warfarin Tricyclic antidepressants Lithium Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) • Venlafaxine (Effexor) • Desvenlafaxine (Pristiq) • Duloxetine (Cymbalta) Venlafaxine [Effexor] • • • • • • Major depression Generalized anxiety disorder Social anxiety disorder (social phobia) Blocks NE and serotonin uptake Does not block cholinergic, histaminergic or alpha1-adrenergic receptors. Serious reactions if combined with MAOIs Venlafaxine [Effexor] (cont’d) • Side effects • • • • • • Nausea Headache Anorexia Nervousness Sweating Somnolence • • • • • • Insomnia Weight loss/anorexia Diastolic hypertension Sexual dysfunction Hyponatremia (in elderly) Neonatal withdrawal syndrome Duloxetine (Cymbalta) • Mechanism of action and therapeutic use • • • • • • • • • • • Inhibits serotonin and NE reuptake Weakly inhibits dopamine reuptake Relieves depression Fibromyalgia Generalized anxiety disorder Relieves pain of diabetic peripheral neuropathy Pharmacokinetics Well absorbed following oral administration Food reduces rate of absorption Highly bound to albumin in the blood Half-life is 12 hours Duloxetine (Cymbalta) (cont’d) • • • • • • • • • • Adverse effects Nausea Somnolence Dry mouth Sweating Insomnia Blurred vision Effects in pregnancy and lactation Drug interactions Alcohol MAO inhibitor Drugs that inhibit CYP1A2 or CYP2D6 Preparations, dosage, and administration • • • TCA SSRI SNRI TCA 5HT1D and α2 autoreceptors SERT and NET Postsynaptic receptors Defect: abnormally low baseline level of post-synaptic receptor signaling Golan, Figure 13-4a Acute use of antidepressants → ↓ release/duration of NT in synapse Response to ↑ NTs → ↓regulation of autoreceptors → acutely ↓ regulates RDS enzymes (TPH and TH) → acutely ↓ rate of neuronal firing Golan, Figure 13-4b ¿ Postsynaptic receptors ? Chronic drug administration → ↓ regulation /desensitization of presynaptic autoreceptors ↓ exocytosis Net effect: ↑ Postsynaptic receptor activity → Therapeutic response Golan, Figure 13-4c Serotonin receptor antagonists Trazodone • • • Weak 5HT2 receptor blocker Less side-effects than tricyclic antidepressants Highly sedating *** Bupropion (Wellbutrin) • • • • • • Mechanism of action unknown Inhibits dopamine reuptake Possibly down-regulates β-adrenergic receptors Low incidence of side-effects Causes CNS stimulation Contraindicated in patients with seizure disorders ➡ (0.4% incidence). • • Actions and Uses Similar in structure to amphetamine • • • • • • • Acts as stimulant and suppresses appetite Antidepressant effects begins in 1 to 3 weeks Equal to that of TCA and SSRIs Does not affect serotonergic, cholinergic, or histaminergic transmission ¿ Mechanism ? ¿ Blockade of DA reuptake ? ¿ ↑ 5HT in brain ? Does not cause weight gain Does not cause sexual dysfunction • • • • • • • • Adverse Effects (cont’d) Dry mouth, GI upset, Constipation, Weight loss Drug Interactions MAOIs can increase the risk of bupropion toxicity Preparations, dosage, and administration Immediate-release, sustained-release, or extendedrelease tablets ...
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  • Spring '11
  • Berman
  • Selective serotonin reuptake inhibitor, Antidepressant, Serotonin Syndrome, Neonatal Withdrawal Syndrome, Serotonin syndrome Withdrawal

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