Anti depressants

Depression : An intense feeling of sadness, hoplessness, in ability to experience pleasure in usual activity, changes in sleep patterns & appetite, loss of energy, suicidal thoughts. Mania: Opposite behavior, enthusiasm, rapid thoughts & speech patterns, extreme self confidnce & impaired judgment. Mechanisms of antidepressant drugs: Biogenic amine theory of depression: Deficiency of MA such as 5HT, NE at certain sites in the brain. * Mania: overproduction of NT. * This theory fails to explain why pharmacologic effects of AD & antimania dugs on NT. Occur immediately while therapeutic response occur over several weeks. Selective 5HT reuptake inhibitors (SSRI) Litle bk. : M, α, H, D. receptors. Replaced TCA, MAOI, safe overdose, fewer AE. Fluoxitine (prototype) & citalopram (racemic mixture), escitalopram (S-enantiomer & more potent), fluvoxamine, paroxitine, sertraline. Actions: ↑ conc. Of NT. Antidepressants activity after 2 wks. Improve mood, maximum benefit after 12 wks. or ˃. Therapeutic uses: Dpression. OCD, panic disorder, GAD, posttraumatic stress disorder, social anxiety disorder, premenistrual dysphoric disorder, bulimia nervosa (fluoxitine only).

Kinetics of SSRI: Well absorbed, peak 2-8 hrs., food ↑ absorption of sertraline. T1/2=16-36 , metabolized to inactive metabolite(s). Fluoxitine t1/2=50 hrs., sustained release used 1/wk. S-norfluoxitine (S-enantiomer active metabolite), t1/2=10 days Fluoxitine , paroxitine potent inhibitors of CYP2D6 (elimination of TCA, neuroleptics, Some antiarrythmics, β-bk. May inhibit other CYP: CYP2C9, CYP3A4, CYP1A2 Dose adjustment in hepatic failure. AE: Headache, sweating, anxiety, agitation, GI: nausea, vomiting, Diarrhoea, weakness Fatigue, sexual dysfunction, weight changes, sleep disturbances, drug-drug interactions, Hyponatraemia (elderly or patients on diuretic). Sleep disturbances: Paroxitine, fluvoxamine (sedating); fluoxitine, sertraline (activating). 2. Sexual dysfunction: ↓ libido, delayed ejaculation, anorgasmia,. Bupropion, mirtazepine fewer sexual SE. 3. Use in children and teens: Used cautiously, 50% children report suicid ideation. Fluoxitine, fluvoxamine, sertraline, FDA approved for OCD. Fluoxitine, escitalopram approved for chidhood depression

4. Overdoses: Lower seizure threshold. Serotonine syndrome: hyperthermia, mucle rigidity, sweating, myoclonus (clonic Muscle twitching), changes in mental status & vital signs when used with MAOI or serotonergic drugs. 5. Discontinuation syndrome: Headache malaise, flu-like syndrome, agitation, irritabtity,nervousness, changes in sleep patterns; fluoxitine has the lowest. 2. 5HT/NE reuptake inhibitors (SNRI): Venlafaxine, desvenlafaxine, duloxitine, levomilnacipram. Used for depression when SSRI are in effective. Useful for depression associated by chronic painful symptoms: neuropathic pain, low back pain, fibromyalgia, post hepatic neuralgia. Little effect at α, M, H. May ppt. discontinuation syndrome. Venlafaxine, desvenlafaxine: Potent inhibitor of 5HT. Medium-higher doses inhibit NE. Venlafaxine minimum inhibition of CYP450 isozymes , metabolized by CYP2D6. Desvenlafaxine active de-CH3 metabolite of venlafaxine. AE: sexual dysfunction, dizziness, insomnia, sedation, constipation. At higher doses: ↑ blood pressure, heart rate.

2. Duloxetine: An inhibitor of 5HT & NE at all doses. Extensively metabolized in the liver to inactive metabolite. C/I : in patients with hepatic dysfunction. AE: GI, dry mouth, constipation, sexual dysfunction, somnolence, insomnia, sweating, ↑ B.P. heart rate, dizziness . Moderate inhibition of CYP2D6 ↑ conc. Of drugs metabolized by this pathwaysuch as antipsychotics. 3. levomilnacipran: Enantiomer of milnacipran (an older SNRI). Used for treament of depression & fibromyalgia. Ae: similar to other SNRI. 1 metabolized by CYP3A4 → affected by enzyme inducer or inhibitors. 3. Atypical antidepressants: Act at different sites. Bupropion, mirtazepine, nefazodone, trazodone, vilazodone, vortioxetine. Bupropion: Weak D, NE reuptake inhibitor. Alleviate the symptoms of depression. ↓ craving & attenuating withdrawal symptoms of nicotine in tobacco user trying to quit smoking.

AE: Dry mouth, nervousness, tremor, low incidence of sexual dysfunction, ↑ risk of seizure. Metabolized by CYP2B6, low risk of drug interactions. Avoided in patients at risk of seizure, eating disorder (bulimia). May inhibits CYP2D6. 2. Mirtazepine: Bk. α2 presynaptic receptors → enhances 5HT, NE. Antidepressant action due to Bk. 5HT2 receptors. Sedative, antihistaminic, ( used in sleep difficulties). No anti-M AE. of TCA or sexual dysfunction of SSRI. ↑ appetite weight gain. 3. Nefazodone & Trazodone: Weak 5HT reuptake inhibitor. Bk. 5HT2A Post synaptic receptors. Both are sedating (bk. H1 receptors). Trazodone cause priapism. Nefazodone hepatotoxic. Trazodone used off-label for insomnia.

4. Vilazodone: SSRI + 5HT1A partial agonist. AE: similar to other SSRI & discontinuation syndrome. 5. Vortioxetine: SRI, 5HT1A agonist, 5HT3, 5HT7 antagonist. AE: nausea, vomiting, constipation.

4. TCA: Bk. 5HT & NE. reuptake similar to SNRI but with different AE. Tertiary amine : imipramine (prototype), amitriptyline, clomipramine, doxipine, trimipramine. 2ndry amine: desipramine, nortriptyline (N-de-CH3 of imipramine), protriptyline. Tetracyclic AD: maprotiline, amoxapine. Patient who do not respond to one AD, may respond to others. Mechanism of AD: Inhibition of NT. Reuptake: TCA & amoxapine potent inhibitors of normal reuptake of NE , 5HT. Maprotiline & desipramine are relatively selective inhibitors of NE. reuptake. 2. Bk. Receptors: TCA bk. 5HT, H1, M receptors. AE of TCA are related to bk. Of these receptors. Amoxapine bk. 5HT2 & D2 receptors. Actions: TCA : elevate mood, improve mental alertness, ↑ physical activity. Reduce morbid. preoccupation 50-70 % individuals with major depression. Slow onset of mood elevation 2wks or more. Do not produce CNS stimulation or mood elevation in normal individuals. Rare physical & psychological dependence, slow withdrawal to minimize discontinuation syndrome & cholinergic rebound effects.

Dose adjustment according to patient response. Therapeutic uses: Moderate- severe depression. Panic disorder. Imipramine for bed-wetting in children, replaced by desmopressin and non pharmacological treatment. Amitriptyline migraine headache, chronic pain syndrome (neuropathic pain), Or conditions of pain with unknown causes. Doxipine low doses for insomnia. Kinetics of TCA: Lipopholic , well absorbed , widely distributed, readily penetrate CNS. 1-st pass metabolism in liver, TCA have low & inconsistent bioavailability. Metabolized by CYP450, subjected to enzyme (inhibitors/inducers), conjugated, excreted/urine. AE: Bk. M, blurred vision, xerostomia, urinary retention, sinus tachycardia, constipation, aggravation of narrow angle glaucoma. Quinidine like effect on the heart. α 1 bk. ,hypotension, dizziness, reflex tachycardia (elderly), imipramine more, nortriptyline the least.

H1 bk. Sedation . Weight gain. Sexual dysfunction but lower incidence than SSRI. Used with precautions: Bipolar disorder may cause manic behavior. Low TI ex. Imipramine is lethal at 5-6 X therapeutic doses. Suicidal attempt. Exacerbate angina, epilepsy, preexisting arrhythmias, BPH. 5. MAOI: MAO mitochondrial enzyme in neurons & other tissues gut, liver. Safety-valve in neurons oxidatively-deaminate & in activate excess NTs (NE, 5HT, D). MAOI reversibly or irreversibly inactivate the enzyme → accumulation of NT presynaptically → antidepressant action (indirect). MAOI: phenelzine, tranylcypromine, isocarboxazide, anti-Parkinson’s selegiline (transdermal). They also inhibit MAO of gut & liver that catalyze oxid-deam. of drugs & toxic substances ex. Tyramine in certain foods. MAOI: have limited uses due to dietary restriction required during treatment & high incidence of drug interactions.

Actions: MAO fully inhibited after several days of treatment. AD action delayed several wks. Similar to that of SSRI & TCA. Selegiline, tranylcypromine: have amphitamine-like action → stimulant effect → agitation, insomnia. Therapeutic uses: Depression unresponsive to other AD, allergic to TCA or experience strong anxiety. For atypical depression. Kinetics: Well absorbed . Enzyme regeneration requires several wks. → 2 wks. Of delay allowed before shifting to other AD. MAOI metabolized, excreted/urine. AE: Drug & food interactions. Drowziness, orthostatic hypotension, blurred vision, dry mouth, constipation. MAOI+SSRI → serotonin syndrome (2 wks. wash-out is required for both). Fluoxetine requires 6 wks discontinuation before MAOI initiation.

Treatment of mania & bipolar disorder: Li+ (mood stabilizer): Used acutely and prophylactically for bipolar patients, effective in 60-80 % of patients with mania & hypomania. Mechanism: unknown. AE: Low TI , toxic, headache, dry mouth, polyuria, polyphagia, GI, fine hand tremor, dizziness, fatigue, dermatological reactions, sedation. At high doses: ataxia, slurred speech, coarse tremors, confusion, convulsion. ↓ thyroid function. Eliminated by kidney, caution in renal disease, best choice in hepatic impairment. 2. Antiepileptics: carbamazepine, valproic acid, lamotrigine, approved by FDA as mood stabilizer in bipolar disorder. 3. Antipsychotics: Older: chlorpromazine, haloperidol. Newer (atypical antipsychotics): risperidone, olanzapine, ziprasidone, aripiprazole, asenapine, quetiapine, for mania. Quetiapine , lurasidone, (olanzapine + fluoxetine) for bipolar depression.