Anti depressants 1 Depression : - PowerPoint Presentation

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Anti depressants

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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).

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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 daysFluoxitine , paroxitine potent inhibitors of CYP2D6 (elimination of TCA, neuroleptics, Some antiarrythmics, β-bk. May inhibit other CYP: CYP2C9, CYP3A4, CYP1A2Dose 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

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escitalopram approved for chidhood depression

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verdoses: Lower seizure threshold.Serotonine syndrome: hyperthermia, mucle rigidity, sweating, myoclonus (clonicMuscle 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.

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uloxetine: 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

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Weak D, NE reuptake inhibitor.

Alleviate the symptoms of depression.↓ craving & attenuating withdrawal symptoms of nicotine in tobacco user trying to quit smoking.

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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.

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ilazodone:SSRI + 5HT1A partial agonist. AE: similar to other SSRI & discontinuation syndrome.5. Vortioxetine:SRI, 5HT1A agonist, 5HT3, 5HT7 antagonist.AE: nausea, vomiting, constipation.7

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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.

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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, nortriptylinethe least.9

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.10

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. 11

Treatment of mania & bipolar disorder:

Li+ (mood stabilizer):

Used acutely and prophylactically for bipolar patients, effective in 60-80 % of patientswith 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.

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