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PH1.19-Antidepressants and Antimanic Drugs

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PH1.19-Antidepressants and Antimanic Drugs . he PH1.19-Antidepressants and Antimanic drugs Dr Anusha Vohra Objectives DEPRESSION Should be able to � Classify antidepressants and enumerate them. � Describe their mechanism of action, adverse effect and clinical uses. � Describe the advantages and disadvantages of SSRIs. � Explain what are SNRIs and atypical antidepressant and their important characteristics. DEPRESSION Limbic Reactive depression:- Psychotherapy alone or system with antidepressants. Endogenous depression:- Antidepressants alone or with electroconvulsive therapy (ECT). Increased DA Depletion of MDP (bipolar depression):-Lithium, Increased NA antidepressants and antipsychotics, with or activity NA &/ 5HT activity without ECT. Behavioural Depression Schizophrenia (psychosis/neur Mania (Psychosis) osis) 1 . Pathophysiology of depression Mechanism Of Action � Monoamine hypothesis � Neurotropic hypothesis � Neuroendocrine hypothesis Classification 1. Reversible inhibitors of MAO- A (RIMAs) � Moclobemide, Clorgyline 2. Tricyclicantidepressants (TCAs) � NA + 5-HT reuptake inhibitors: Imipramine, Amitriptylline, Doxepin, Dothiepin, Clomipramine � Predominantly NA reuptake inhibitors: Desipramine, Nortriptylline, Amoxapine, Reboxetine 3. Selective serotonin reuptake inhibitors (SSRIs) � Fluoxetine, fluvoxamine, Paroxetine, Sertraline, Citalopram, Escitalopram, Dapoxetine 4. Serotonin and noradrenalinereuptake inhibitors (SNRIs) � Venlafaxine, Desvenlafaxine, Duloxetine, Milnacipran, levomilnacipran Atypical Antagonist MONOAMINE OXIDASE (MAO) 1.5-HT2 Antagonist:Trazodone, Nafazodone � MAO catalyze deaminationof intracellular 2.Presynaptic alpha 2 antagonists: Mianserin, monoamines Mirtazapine � Two types Of MAO enzyme:- 3. Increase presynaptic release of CAs: Bupropion (NDRI) � MAO- A 4.Serotonin Reuptake Enhancers:Tianeptine, � MAO- B Amineptine 5. 5-HT1 agonist with serotonin reuptake inhibitor: Vortioxetine, Vilazodone 6.Selective NA reuptake inhibitor: Atomoxetine 2 . MAOIS � Reversible Moclobemide inhibitors of MAO- A �Reversible and selective (RIMAs) MAO- AI � Moclobemide are �Short duration of action used �Relatively free of food and drug interactions. �Lack antiadrenergic, anticholinergic, antihistaminergiceffect �Used in elderly patientsand patients with heart disease �-Mild to moderate depression �-Social phobia MAOIs SIDE EFFECTS ???? � Side effects : Nausea, dizziness, Which of the following is a selective MAO- B inhibitor: Headache, Insomnia, rarely Excitement A. Selegiline and Liver damage B. Clorgyline C. Moclobemide � MAO-A inhibitors interfere with D. Tranylcypromine breakdown of tyramine The nonselective MAO inhibitors are not used clinically High tyraminelevels cause hypertensive as antidepressants because of their: A. Low antidepressant efficacy crisis (the “cheese effect”) B. Higher toxicity Can be controlled with restricted diet C. Potential to interact with many foods and drugs � MAOIs interact with certain drugs D. Both 'B' and 'C' are correct Serotonin syndrome (muscle rigidity, fever, seizures) SSRIs and TCAs, Pethidine must be avoided I. Tricyclicantidepressants (TCAs) REUPTAKE INHIBITORS � NA + 5-HT reuptake inhibitors: Imipramine, Amitriptylline, Doxepin, I. -NON SELECTIVE Clomipramine II. -SELECTIVE � Predominantly NA reuptake inhibitors: Desipramine, Nortriptylline, Amoxapine (D2 block) � In addition they have direct effect on adrenergic, cholinergic and histaminergic receptors 3 . TCAS MECHANISM OF ACTION � TCAs inhibit serotonin, norepinephrinetransporters, slowing reuptake � TCAs also allow for the desensitiseof pre-synaptic autoreceptors � Adaptive changes in pre and postsynaptic receptors as well as amine turnover of brain � Enhanced NA and/or5-HT transmission. TCAS SIDE EFFECTS Muscarinic M1 receptor antagonism - anticholinergic effects including dry mouth, blurred vision, � ADs having CNS stimulant effect ? constipation, � Why therapeutic drug monitoring is needed?? urinary retention, hyperthermia, flushing � Imipramine given to nondepressed individuals Histamine H1 receptor antagonism - sedation and produces: weight gain A. Euphoria Adrenergic α receptor antagonism - postural B. Insomnia hypotension, tachycardia. C. Lethargy and light headedness Direct membrane effects - reduced seizure threshold, D. Inappropriate behavior arrhythmia Sexual distress: especially delay or interference with erection, ejaculation and occasionally orgasm Switch over Sweating , fine tremors, insomnia Acute poisoning ???? � The mechanisms involved in the causation of dangerous cardiac ???? arrhythmias due to overdose of tricyclic antidepressants include the following except: � Of the following, choose the antidepressant having both high sedative and high anticholinergic activity: A. Intraventricular conduction block B. Potentiation of noradrenaline A. Imipramine C. Antagonism of acetylcholine B. Amitriptyline D. Increased vagal tone C. Fluoxetine � A 65-year -old man was brought to the hospital with complaints of D. Trazodone pain in lower abdomen and not having passed urine for 16 hours. � Imipramine produces the following actions except: The bladder was found to be full. His son informed that he was depressed for the last 2 years and only the day before a doctor had A. Euphoria given him some medicine. Which of the following drugs is he most B. Dryness of mouth likely to have received? C. Tachycardia � Tricyclic antidepressants abolish the antihypertensive action of the D. Lowering of seizure threshold following drug ? A. Enalapril, B. Clonidine, C. Atenolol, D. Diltiazem 4 . SELECTIVE SEROTONIN REUPTAKE INHIBITORS Advantages over TCAs Most commonly prescribed class. why ??? � No anticholinergiceffects � � Major limitations of TCAs No postural hypotension-suitable in elderly � 1. Frequent anticholinergic, cardiovascular and No sedation neurological side effects. � Do not precipitate convulsions 2. Relatively low safety margin.. � Do not cause cardiac arrhythmias 3. Lag time of 2– 4 weeks before antidepressant � No effect on cognitive or psychomotor function action manifests. � Relative safety and better acceptability 4. Significant number of patients respond � Longer t1/2 due to its active metabolites incompletely and some do not respond. Side effects of SSRI SSRIs � Citalopram safe with warfarin � Dapoxetineused to treat PME � Escitalopram most specific SSRI � Fluoxetine (prototype)longest acting � Fluvoxamine (shortest) � Paroxetine (most teratogenic) � Sertraline safe with warfarin SSRIS SIDE EFFECTS USES � � Epistaxis/ecchymosis, loose motion, Major Depressive Disorder teratogenic etc � Prophylaxis of recurrent depression (should be � Many disappear within 4 weeks (adaption combined with lithium/valproate). phase) � 1st choice drugs for OCD, panic disorder, social � Side effects more manageable compared to phobia, eating disorders, premenstrual tension MAOIs and TCAs syndrome and PTSD. � � Sexual side effects are common. Also in anxiety disorders, body dysmorphic disorder, compulsive buying, kleptomania and � Serotonin syndrome??? premature ejaculation. � SIADH (citalopram and fluoxetine) � Chronic somatic illness � Discontinuation reaction (fluvoxamine and paroxetine) � Inhibit CYP2D6 and CYP3A4 5 . SEROTONIN- NOREPINEPHRINE ???? REUPTAKE INHIBITORS (SNRIS) � The antidepressant which selectively blocks 5- � Current drug of choice for severe depression hydroxytryptamine uptake is: � Venlafaxine(fastest) and minimum drug interaction A. Fluoxetine � Duloxetine(longest) B. Amoxapine � Milnacipran C. Desipramine � Mechanism of Action D. Dothiepin � Very similar to SSRIs � � Advantages of selective serotonin reuptake inhibitors Works on both neurotransmitters (SSRIs) include the following except: � Side effects A. No interference with ejaculation and orgasm � Similar to SSRIs � Hypertension B. Minimal sedative action USES C. Unlikely to cause fall in BP Similar to SSRIs D. Lack of seizure precipitating potential Duloxetine& Milnacipran: fibromyalgia Duloxetine: diabetic neuropathic pain & stress urinary incontinence ???? Atypical antidepressants � Classify antidepressants � Trazodone: Blocks 5-HT reuptake and 5-HT2 - antagonist; blocks α1 -adrenergic receptors � Describe the advantages and disadvantages of SSRIs. � Mianserin: Increases NA releases by blocking presynapticα 2-receptors (block-H 1, 5-HT2 & 5- HT1c ) � Mirtazapine: Increases NA and 5-HT release. (block H1 , 5-HT2 & 5-HT 3 ) NSSA?? � Bupropion: Blocks NA and DA reuptake. Useful for smoking cessation. � Tianeptine, Amineptine : rather increase 5-HT uptake. � Atomoxetine: NA reuptake inhibitor-Use in ADHD. � Vortioxetine: 5HT1A agonist with serotonin reuptake inhibitor (5- HT3 blocker) Cont- USES 2. OCD/phobic states-Fluvoxamine (SSRI) preferred 1.Endogenous(major) depression-2 nd gen. AD are used as 3. Anxiety disorder-SSRI with BZD 1rst line therapy and in non responsive or not tolerating it – 4. Prurites-Topical Doxepin TCA can be tried. 5. ADHD- Imipramine/Nortryptyline /Amoxapine/Atomoxetine � Juviniledepression -Fluoxetine/Sertraline 6. Premature Ejaculation-Dapoxetine -rapid effect/ � Elderly/heart patients-Moclobemide Clomipramine-slow effect � After treating depression AD has to be continued for 6-12 7. Enuresis- Imipramine25 mg at bed time months in maintenance phase to prevent recurrence 8. Neuropathic pain- Amytryptaline, Duloxetine/ ± � SSRI– also used as prophylaxisof recurrent depression Pregabalin/gabapentin � They are combined with 9. Migraine-Amytryptaline - prop. Esp. in mixed headache Lithium/Valproate /lamotrigine /atypical antipsychotics-to 10. Smoking cessation:
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