7.Antidepressants.pptx..................

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1. ANTIDEPRESSANTS DR. ARVIND CHANSORIA

2. Depression is the most common affective disorder ; disorder of mood rather than disturbances of thought or cognition . It may range from a very mild condition, bordering on normality, to severe depression accompanied by hallucinations & delusions.

3. Biological amine hypothesis: Depression is due to deficiency in neuronal and synaptic catecholamine concentration, such as NE and 5-HT (or of DA) at certain key sites on brain . Based on the ability of NE and 5-HT uptake inhibiting and monoamine oxidase -A inhibiting drugs to facilitate NE/5-HT neurotransmission and to act as effective anti depressant drugs.

4. Classification of antidepressants: I . Tricyclic antidepressants ( TCA) – Non selective NA + 5-HT reuptake inhibitors: imipramine , amitryptyline , trimipramine , clomipramine , Doxepine b) Relatively selective NA reuptake inhibitor : Despiramine , Protryptyline , Nortryptyline , Robexetine , Maprotyline , Lofepramine

5. ii) SNRIS /selective Norepinephrine reuptake inhibitors : Duloxetine , Venlafaxine,Milnacipran iii) SSRIs - selective Serotonine reuptake inhibitors : Fluoxetine Fluvoxamine Paroxetine Sertraline Vortioxetine Citalopram Escitalopram

6. iv) Dopamine and noradrenaline reuptake inhibitors (DNRIs) – Amoxapine , Bupropion v) Atypical Antidepressants- Trazodone,Nefazodone,Bupropion,Mirtazapine , Mianserin,Tineptine,Atomoxetine vi) Monoamine oxidase inhibitors - Irreversible : Hydrazine MAOIs – isocarboxazide , phenelzine Nonhydrazine MAOIs – tranylcypromine Reversible : moclobemide

7. Tricyclic Antidepressants : Imipramine (1949) was first tried as antipsychotic drug for schizophrenia , proved to be insufficient but proved to have antidepressant qualities. Imipramine (prototype) is very good for severe depression , but it causes hypomania and mania. Side effects have made them second line of defense to SSRIs but they are good for resistant depression.

8. Amitriptyline – most widely used , most effective Mechanism of action : Inhibition of NT ( serotonine & NE) uptake : ↑ adrenergic and serotonergic neurotransmission Blocking of receptors : α - adrenergic , histaminic and muscarinic receptors Blocking of these receptors are probably responsible for many of the untoward effects of TCAs

9. Therapeutic uses: Sever major depression Phobias and panic , anxiety disorders – clomipramine Neuropathic pain Obsessive compulsive disorder ADHD Nocturnal enuresis: imipramine has been used to control bed-wetting in children ( older than six years ) by causing contraction of internal sphincter of the bladder . Doxepine – in allergic condition like itching and urtricaria and in atopic dermatitis

10. Toxicity Acute toxicity is common & occurs due to consumption of high dose in severely depressed patients . Toxicity manifest as CNS stimulant effect Delirium Anticholinergic effect similar to atropine Treatment – gastric lavage correction of fluids correction of acidosis by sodium bicarbonates i.v

11. Drug Interactions: Potentiate the effect of directly acting sympathomimetics (causing rise in B.P. and arrythmia )but inhibit indirectly acting SM drugs. T 3 and T 4 potentiate CNS stimulant effects of TCAs MIOIs with TCAs produce synergistic act. Anticholinergic drugs aggravate toxicity of TCAs. Reverse the antihypertensive effect of clonidine .

12. Selective serotonin reuptake inhibitors (SSRIs) Current drugs Fluoxetine,Fluvoxamine,Paroxetine,Sertraline,Citalopram,Escitalopram Mechanism of action : SSRIs act mainly by inhibiting the reuptake of serotonin by the tryptaminergic neurons. They bind to the serotonine receptor (SERT) at the site other than binding site of 5-HT and inhibit the transporter .

13. Pharmacological actions: As effective as TCAs in moderate depression but less effective in severe depression. Because of their selective receptor action they cause less: Antimuscarinic effects Antihistaminic effects including sedation Cardiovascular effects ( bradycardia , hypotension) Therefore they are safer than TCA in elderly. SSRIs are class of drugs that are typically used as antidepressants in the treatment of major depressive disorder and anxiety disorders .

14. Fluoxetine is longest acting in the group . Fluoxetine metabolize to active compound so have longer half life (t1/2 25-95 hr). Fluoxetine additionally have anxiolytic activity so used as effective antidepressant and anxiolytic agent in practice . More imp. Fluoxetine inhibit liver microsomal enzyme so potentiate effect of TCAs and other drugs Fluvoxamine relatively short acting and does not produce active metabolite.

15. Paroxetine Short acting , no active metabolite thus can cause discontinuation reaction when used for anxiety . If used in 1 st trimester can lead to congenital cardiac malformation . Sertraline Long acting , t1/2 22- 35 hr Preferred in elderly because elimination is not affected by age .

16. Currently SSRIs are preferred drug because Starting dose is therapeutic dose so no need to titrate the dose i.e easy to use Well tolerated. Many side effect observed with TCAs are not present. Safe if overdose is consumed. Cost is similar to TCAs so economical.

17. Drug interaction of SSRIs: SSRIs are potent inhibitors of liver microsomal enzymes. Therefore they should not be used in combination with TCAs because they can inhibit their metabolism increasing their toxicity. SSRIs should not be used in combination with MAOIs because of the risk of life threatening “serotonin syndrome”. Both drugs require a washout period of 6 wks before the administration of the other .

18. Adverse reaction : GIT – anorexia , nausea , abdominal pain , diarrhoea CNS – anxiety , agitation , akathesia , headache , transient insomnia , and vivid dreams Serotonergic syndrome – due to hyperstimulation of 5HT1 receptor in brainstem , it comparises of hyperthermia, muscle rigidity, tremors, rapid changes in mental status and cardiovascular collapse.

19. like other AD , SSRIs also causes hypomania when given in undiagnosed cases of bipolar depression. sudden stoppage with short t1/2 ( paroxatine and sertraline )can cause withdrawal symptoms leads to discontinuation syndrome such as flu like reaction , anxiety , dizzines , insomnia ,headache, paresthesia ) Many side effect disappear after 4 wk(adaption phase)

20. Therapeutic uses of SSRIs : Major depression / endogenous depression OCD – fluvoxamine is preferred drug Panic disorder – but take several wks . Fluvoxamine School phobia and social phobia- paroxatine Post traumetic stress syndrome – paroxetine with alprazolam is used. Bulimia nervosa Geriatric group

21. MAO inhibitors : Two types of monoamine oxidase present MAO – A predominantly metabolize NA , 5HT & DA present in intestine , peripheral nerve endings and liver . MAO – B preferentially metabolizes dopamine present in brain , platelet , liver. MAO inhibitors Non selective – Tranylcypromine , isocarboxazide , phenelzine Selective MAO – A inhibitor - Moclobemide Selective MAO – B - Selegiline

22. Mechanism of action : 5-HT and NA are stored in granules in the neurons and are released following stimuli . Active amines are liberated on postsynaptic receptors but do not accumulates because they are metabolize by MAO-A . Inhibition of these MAO-A enzyme cause increase in amount of 5HT and NA ,Which is associated with antidepressant action .

23. Non selective MAOIs inhibit both isoforms of MAO (MAO-A &MAO-B) irreversibly . - There anti depressant effect take 3-4 wks to develop As they inhibit MAO irreversibly they can cause cheese reaction . selective MAO A inhibitor – moclebemide is selective and reversibly inhibit MAO-A . Does not exhibit cheese reaction . selective MAO-B inhibitor – selegiline is useful in Parkinsonism .

24. Therapeutic uses of MAOIs: Moclobemide – well tolerated , less sedation ,less cardiac side effect so good for elderly pt. Mild to moderate depression Phobias

25. Adverse reaction of MAOI: Inappropiate increase in appetite causing wt. gain Dizziness Sexual dysfunction Postural hypotension Hypertensive crisis

26. Drug interaction: MAOIs along with TCA or with directly acting and indirectly acting sympathomimetics have synergistic effect leads to HTN , arrythmias , seizures. MOAIs are liver enzyme inhibitors and decrease metabolism of other drugs and cause toxicity 0f Morphine , sulfonylureas , chloroquine .

27. Selective serotonin -NE reuptake inhibitors (SNRIs): Slightly greater efficacy than SSRIs Slightly fewer adverse effect than SSRIs Current drugs are – Venlafexine Duloxetine Milnacipran

28. Mechanism of action SNRIS block NE and 5HT reuptake like TCAs but they are different from TCAs . They are more selective so they lack α 1 adrenergic , H1 histaminic & cholinergic receptors blocking properties. Venlafaxine and duloxetine can be given in chronic pain condition like in DM,PTSD. Side effect : Venlafaxine – HTN , tachycardia , cardiac toxicity Duloxetine – nausea , somnolence , hepatic damage

29. Drugs mainly blocks NE reuptake: Despiramine , Nortryptyline , protriptyline Maprotiline , Amoxapine , Reboxetine ( Newer AD) Predominantely inhibit NE reuptake in synaptic cleft in CNS. Amoxapine blocks postsynaptic D2 receptor and therefore posses some antipsychotic action . Reboxetine cause tachycardia, dry mouth , sexual dysfunction .

30. Atypical antidepressants: Newer AD - Trazodone , Nefazodone , Bupropion , Mirtazapine , Mianserin Bupropion – Norepinephrine &dopamine reuptake inhibitor. May act through dopaminergic or noradrenergic pathway. Pharmacokinetics: Bupropion elimination has a t1/2 of 21 hours . The elimination of bupropion involves both hepatic and renal routes. Major route is CYP2B6.

31. Mirtazapine : Blocks post synaptic 5HT 2A and presynaptic α 2 receptors. Metabolism is through hepatic route side effects – increased appetite, wt gain , marked sedation so given in depression with insomnia.

32. Trazodone & nefazodone : Blocks postsynaptic 5-HT2A and presynaptic α 2 receptors. Metabolize by hepatic CYP3A4. Side effect – Trazodone – nausea , orthostatic hypotension , priapism Nefazodone – dose dependent anti- muscarinic effect, orthostatic hypotension , hepatotxicity

33. Agomelatine - Melatonine analogue , act as selective agonist melatonin(MT1&MT2) and antagonist of 5HT2B and 5-HT 2C receptor . Natural Antidepressant : St.john’s wort – this herbal product derived from plant hypericum perforatum . Has variable beneficial effect in mild to moderate depression . It is an inducer of hepatic CYP450 and hence can reduce plasma levels of several drugs e.g Warfarin ,OCP anticonvulsant , antipsychotic.

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