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Home , Dapoxetine

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he PH1.19- 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 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 , 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: , Amitriptylline , , Dothiepin, � Predominantly NA reuptake inhibitors: , Nortriptylline, , 3. Selective reuptake inhibitors (SSRIs) � , , , , , , Dapoxetine 4. Serotonin and noradrenaline reuptake inhibitors (SNRIs) � , , , ,

Atypical Antagonist MONOAMINE OXIDASE (MAO)

1.5-HT2 Antagonist:, Nafazodone � MAO catalyze deamination of intracellular 2.Presynaptic alpha 2 antagonists: , monoamines � Two types Of MAO :- 3. Increase presynaptic release of CAs: (NDRI) � MAO- A 4.Serotonin Reuptake Enhancers:Tianeptine, � MAO- B 5. 5-HT1 agonist with serotonin reuptake inhibitor: , 6.Selective NA reuptake inhibitor:

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 , , 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, , rarely Excitement A. Selegiline and damage B. Clorgyline C. Moclobemide � MAO-A inhibitors interfere with D. Tranylcypromine breakdown of tyramine The nonselective MAO inhibitors are not used clinically High tyramine levels 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, 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 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. 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 anticholinergic effects � � 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 disorders, body dysmorphic disorder, compulsive buying, kleptomania and � Serotonin syndrome??? . � 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: 5HT 1A 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 prophylaxis of 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: Bupropion prevent switch over in bipolar depression � ECT can be used initially in severe cases

6 .

??? ????? � Mechanism of antidepressant action? � Safest SSRI to be used with warfarin � Uses of antidepressants ?? � Longest and shortest acting SSRI � Most specific SSRI � Most teratogenic SSRI � Faster acting antidepressants � Therapeutic window phenomenon

Recent advances � : nonselective noncompetetive antagonist of NMDA receptors Anti-manic/ Mood Stabilizers � Treatment resistant depression in adults � Intranasal spray given weekly � Side effects: Sedation, vertigo

� Brexanolone:- GABA receptor modulator (GABAA) � Postpartum depression � Side effects: Sedation, vertigo

Objectives Anti-manic Mood Stabilizers

Should be able to- � Anti-manic: � Classify antimanic drugs � Means these drugs control mania symptoms � Describe Lithium mechanism of action, important � Mood Stabilizer: uses, adverse effects and drug interactions. � Means they make the mood stable and prevent mood swings in Bipolar disorder � Describe use of other drugs in Mania

7 .

Antimanic- Mood Stabilizers

Main Agent Anticonvulsa nts •Atypical Lithium Carbonate Antipsychotics Sodium Valproate Olanzapine Carbamazepine Risperidone Lamotrigine Aripiprazole

Lithium: Lithium: Pharmacodynamics � Absorption: � Virtually complete within 6-8 hours � Other mechanisms: � Peak plasma levels in 30 min. to 2 hours � Since Li+ is closely related to Na+, it may substitute for Na+ in � Distribution: generating action potentials & Na+ exchange � In total body water � Inhibit noradrenaline and dopamine turnover � Slow entry into intracellular compartment � Inhibition of noradrenaline sensitive adenyl cyclase enzyme � No protein binding � Uncoupling of receptors from their G- proteins � Freely crosses placenta and secreted in milk: Absolutely contra-indicated in pregnancy and lactation) � Effects on specific protein kinase C affecting the production of proteins and causing long term mood stabilization � : � Action: � None (Also liver is not affected by Lithium) � Selective inhibition of overactive neurons � Antimaniceffect in Mania � : � Mood stabilization in the bipolar disorder � In urine with a half-life of about 20 hours � Lithium clearance is about 20% of creatinine clearance � No noticeable effect on normal individuals (Serum creatinine levels must be done before starting the � Not a sedative or antidepressant treatment besides, blood counts, electrolytes, pregnancy � Other actions ?? test and thyroid function test not liver function test) � Excretion ↑ by: ↑ saltintake* , mannitol and alkalization of urine � Excretion ↓ by: ↓ salt intake, diuretics and newer NSAIDs

Lithium: Clinical Use Lithium: Dosage � � Dose: Acute Mania � Start with 300 mg bid or tid → then increased gradually Valproate/Atypical antipsychotics � Usual dose range is 600 to 1200 mg/ day ± BZDs � Plasma Lithium concentration should be approximately 1 After episode is under control- Lithium for 6-12m mEq/ L (range 0.6 to 1.4 mEq / L) �Prophylaxis in bipolar disorder � Plasma Lithium concentration monitoring is necessary 0.5– 0.8 mEq /L –lithium plasma level is maintained because of Therapy is given based on type, cycle length, comorbid � its very low therapeutic index (Low safety margin Toxicity > 1.5 mEq /L) condition and concurrent medication. � Considerable individual variation in the rate of Li excretion Gradually introduced and gradually withdrawn � Recurrent neuropsychiatric illness, cluster headache and as adjuvant to antidepressants in resistant nonbipolar major depression

8 .

Lithium: Adverse Effects Lithium: Drug-interactions

eucocytosis � Lithium levels are dangerously increased by: ncrease in weight & oedema � Diuretics � Newer NSAIDs remors& Teratogenesis ( Ebsteinsanomaly and foetal goitre ) (So Lithium’s dose should be reduced with them)

ypothyroidism

ncreased thirst (polydipsia) rineformation increases (polyuria *)

otordisorders e.g. incoordination of movements, ataxia, choreoathetosis , dysphasia and hyperactivity** There is no antidote of Lithium

ALTERNATIVES TO LITHIUM - Valproate Carbamazepine � Widely used now as an antimanic drug � Used as an alternative to Lithium � First line drug in acute mania � In patients not responding to Lithium � Effective even in patients not responding to � Used to treat acute mania and also for prophylaxis Lithium � Used alone or in combination with Lithium � Also being evaluated as a prophylactic � Less effective � Dose: Start with 750 mg/day and then increased � Lamotrigine: maintenance therapy of type II rapidly up to 1500-2000 mg/day bipolar disorder � Advantage here is that the dose can be increased rapidly without much side effects �Atypical antipsychotics � Devalproax

Summarise ????? � Classification of antidepressants � Choose the correct statement about � MAOIs and their role in depression moclobemide: � TCAs, their mechanism of action, adverse effect A. It is a reversible inhibitor of MAO- A with short and limitations duration of action � SSRIs and SNRIs advantages and disadvantages B. Patients taking it need to be cautioned not to � Atypical antidepressants consume tyramine rich food � Antimanicdrugs classification C. It is contraindicated in elderly patients � Lithum mechanism of action, phamacokinetics , D. It produces anticholinergic side effects adverse effect and uses � Other agents used in mania

9 .

????? ????? � Imipramineproduces the following actions The mechanisms involved in the causation of except: dangerous cardiac arrhythmias due to overdose A. Euphoria of tricyclic antidepressants include the following except: B. Dryness of mouth C.Tachycardia A. Intraventricular conduction block B. Potentiation of noradrenaline D.Lowering of seizure threshold C. Antagonism of acetylcholine D. Increased vagal tone

???? ??? A 65-year -old man was brought to the hospital with � Tricyclicantidepressants abolish the complaints of pain in lower abdomen and not antihypertensive action of the following drug: having passed urine for 16 hours. The bladder � A. Enalapril was found to be full. His son informed that he was � B. Clonidine depressed for the last 2 years and only the day � C. Atenolol before a doctor had given him some medicine. Which of the following drugs is he most likely to � D. Diltiazem have received: A. Alprazolam B. Sertraline C. Amitryptyline D. Trazodone

???? ????? � The following is a tetracyclic antidepressant that � Choose the selective serotonin reuptake inhibitor has additional dopamine blocking and neuroleptic that is less likely to inhibit CYP2D6 and CYP3A4 properties, as well as greater propensity to cause resulting in fewer drug interactions: seizures in overdose: � A. Sertraline � A. Amoxapine � B. Paroxetine � B. Doxepin � C. Fluoxetine � C. Dothiepin � D. Fluvoxamine � D. Trazodone

10 .

Dental implications 1. Dry mouth with TCAs 2. Sympathomimeticswith TCAs/MAOIs 3. Serotonin syndrome with 4. NSAIDs with SSRIs 5. TCAs,SSRIs-macrolides antibiotics 6. Bupropion: dry mouth 7. SSRI with BZD 8. Amitryptylineand Dothiepin : atypical facial pain 9. Tramadol/Pethidine with MAOIs– hypertensive episodes 10. Untreated depression: poor oral hygiene 11. Postural hypotension with TCAs 12. Dry mouth/dental caries:lithium 13. NSAIDs/ Metronidazole - increased lithium toxicity

Are you able to :- Classify antidepressants and enumerate them. Describe their mechanism of action, adverse effect and clinical uses. BDNF Describe the advantages and disadvantages of (GSK- 3) SSRIs. Explain what are SNRIs and atypical antidepressant and their important characteristics.

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RV1 RAJAAT VOHRA, 11-01-2020