Drugs Used in Depression Old &

Drugs used in depression Old & New

 Realize neurotransmitter defects in different types of depression.  Elaborate on how antidepressants generally act.  Classify the existing antidepressant into elder (TCAs & MAO Is) and newer groups (SSRIs, SNRIs, NRIs, NAASs, NDRIs, SARIs).  Expand on pharmacology of each group; setting examples, discussing pharmacodynamic potentials, pharmacokinetic . Additional Notes differences, varied indications, contraindications and side effects. . Important  Enumerate augmenter drugs used in depression.

For any correction, suggestion or any useful information do not hesitate to contact us: [email protected] Mind Map INTRODUCTION . of mania of Extreme irritability Extreme . ( disturbance of mood ) mood of disturbance . ( Symptoms Rapid, unpredictable Rapid, emotional unpredictable changes A high energy level with decreased need for sleep need with high A for decreased level energy Unwarranted or exaggerated belief in one's own ability own in one's belief exaggerated or Unwarranted % of the population at some period in their lifetime in period some at the population of % 20 depression and/or mania and/or depression of Depression Feelings of worthlessness. Feelings Loss of energy and energy interest of Loss Symptoms

Recurring thoughts about and suicide. death thoughts Recurring

Decreased or increased sleeping or increased or appetite. Decreased Incidence of depression : affect at least least at : affect depression Incidence of Changes in mood are associated with associated are mood in Changes Depression : is a very common psychiatric disorder that is related to the mood the to is related that disorder psychiatric common very : is a Depression Depression INTRODUCTION down down depression. Mania Depression monoamines weeks) indicating that secondary that indicating weeks) . 3   . a state of deficiency in in deficiency of a state ? Creates Creates Norepinephrine Norepinephrine Norepinephrine → receptors. 2 regulates mood. alertness, arousal, appetite, reward & drives, may may drives, & reward appetite, alertness, arousal, mood. regulates Dysregulation Dysregulation HT - depression 5 which which and cause the sleep problems, irritability and anxiety associated with associated anxiety and irritability the sleep problems, cause 2  - NE, NE, may may alpa important for pleasure, sex & psychomotor activity psychomotor & sex pleasure, for important level of of level is is beta, beta, of

deficiency deficiency

Serotonin Serotonin

- Drugs used to treat depression increase the level these neurotransmitters of the level increase depression treat used to Drugs contribute to the fatigue and depressed mood of the illness the of mood depressed and the fatigue to contribute Dopamine 5 Decreased

Amphetamine Ass with mania while reserpine and methyldopa produce depression. produce methyldopa and reserpine Ass mania while with Amphetamine What is the evidence to support this theory this support to evidence is the What adaptive changes. The most consistent adaptive change seen with antidepressant drugs is is the drugs antidepressant with seen change adaptive consistent most The changes. adaptive regulation Antidepressants do not act immediately (show clinical effects after after effects clinical (show act immediately do not Antidepressants Antidepressants •    Neurotransmitter Imbalances & Neurotransmitter Pathophysiology of Pathophysiology Biochemical theory affective disorder theory affective Biochemical ANTI-DEPRESSANTS GROUPS

Old Antidepressants Imipramine, Desipramine, Clomipramine, Amitriptyline, Tricyclics (TCAs) Nortriptyline, Protriptyline , Doxepin, Trimipramine Tetracyclics Amoxapine, Maprotiline. Monoamine Oxidase Inhibitors (MAOIs) Tranylcypramine, Phenelzine, Moclobemide

New Antidepressants

Fluoxetine, Fluvoxamine, Citalopram, Sertraline, Selective Serotonin Reuptake Inhibitors (SSRIs) Paroxetine, Escitralopram

Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) Venlafaxine, Duloxetine Serotonin-2 Antagonist and Reuptake Inhibitors (SARIs) Nefazodone, Trazodone Norepinephrine and Dopamine Reuptake Inhibitor (NDRI) Bupropion

Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs) Mirtazapine

Noradrenaline Reuptake Inhibitor (NRI) Reboxetine Serotonin Reuptake Enhancer Tianeptine INTRODUCTION to nortriptyline Amitriptyline , ring nucleus ring - receptors ) receptors 2 HT 5 more potent on NE reuptake pump onmore potent NE reuptake desipramine Desipramine to to Imipramine cholinergic receptors , receptors cholinergic 1 by competing for binding site of the transport protein. of protein. site the transport binding for competing by clomipramine the oldest class of antidepressant drugs with drugs three of class the antidepressant oldest Old antidepressants Old . sexual dysfunction & impotence dysfunction . sexual histamines receptors , M receptors histamines 7 1 amitryptyline TH reuptake pump TH reuptake - " in nature, well absorbed in GIT & cross BBB. the GIT & cross absorbed in well nature, in " 5 HT and NE nerve in terminals 5 Metabolized in the liver by demethylation ( demethylation by the liver in Metabolized lipophilic . Hypomania 6 re " re A Cardiovascular effects (Tachycardia and hypotension) and (Tachycardia effects Cardiovascular Dry mouth, constipation, urinaryDry retention mouth, constipation, More on potent More Sedation, confusion confusion Sedation, effects, cardiac arrhythmias, sudden death arrhythmias, cardiac effects, . Seizure . Seizure - 5 hours. adrenergic receptors , H receptors adrenergic 6 1 - α 2 ) & by hydroxylation >metabolites that retain ofactivity the compounds. biologicalthe parent retain that >metabolites ) & by hydroxylation : hepatic oxidation. hepatic :

histamine: Adrenergic: cholinergic: imipramine conc. of NE & serotonin in the synaptic cleft & at the receptor site the receptor & at cleft of the synaptic conc. NE in & serotonin - - - depressed patients sedation, confusion & motor incoordination incoordination & motor confusion sedation, patients depressed - ↑

TCAs are highly protein bound and have a large volume of distribution therefore hemodialysis is not effective for Rx of TCA for is not effective hemodialysis therefore of volume distribution a large bound have and protein highly are TCAs toxicity. Anti gain Weight coma, depression, respiratory , convulsions, delirium excitement, develop; can >toxicity index therapeutic narrow have TCAs like atropine Anti Anti TRICYCLIC ANTIDEPRESSANTS (TCAs) (TCAs) ANTIDEPRESSANTS TRICYCLIC block reuptake pumps for both for pumps block reuptake So • • 3. 4. 1. 2. TCAs block: ( block: TCAs Peak levels: levels: Peak Elimination Nortriptyline Elevate mood, Improve mental alertness, Increase physical activity, activity, alertness,physical Increase mental mood, Improve Elevate non In •

ADEs

MOA Name INTRODUCTION ). like action. like - ring nucleus nucleus ring - by drugs that compete for their plasma protein protein their plasmafor compete thatdrugs by because of theirbecause atropine Oral contraceptives, Antipsychotics, and SSRIs and Antipsychotics, contraceptives, Oral . ” increased , because they tend to "switch" the depressed patient to the to the depressed patient "switch" to tend they because , enlarged prostate prostate enlarged lithium salts lithium in children and geriatric patients as it constricts internal urethral sphincter urethral internal constricts as it patients geriatric and children in or or with , therefore their effect can be reduced by inducers of liver microsomal enzymes enzymes microsomal of liver inducers reduced be by can their effect , therefore their effect can be can their effect the oldest class of antidepressant drugs with drugs three antidepressant class of oldest the depressive illness depressive - ). Old antidepressants Old Glaucoma nocturnal enuresis moderate severe. to moderate Phenylbutazone liver microsomal enzymes microsomal liver contraindicated in manic in contraindicated Depression Aspirin and strongly bound to plasma protein protein to bound plasma strongly or potentiated by inhibitors of liver microsomal enzymes enzymes ( microsomal of liver inhibitors by or potentiated is used for treatment of treatment is used for muscarinic effect). muscarinic

- TRICYCLIC ANTIDEPRESSANTS (TCAs) (TCAs) ANTIDEPRESSANTS TRICYCLIC

Seizure disorders disorders Seizure Barbiturates), Barbiturates), - TCAs should not be used in patients with should not be used patients inTCAs (given alone) are TCAs shouldthey with be combined " phase, therefore, "manic" Attention Deficit Hyperkinetic Disorder Hyperkinetic Disorder (ADHD). Deficit Attention body pains. or unexplained pains neuropathic Chronic Imipramine (anti Disorder (GAD). Anxiety Generalized Disorder (OCD) Compulsive Obsessive Endogenous Endogenous (Major) episode of anxiety. /acute attack Panic binding site like ( like site binding by metabolized are They ( because the are the are because • • • • • • • • • • • •

C.I

D.I Uses Monoamine Oxidase a - Tyramine in octopamine A. - has No has cheese severe severe hypertension, ; MAO This occurs occurs This when and may andresult NE in food in is normally degraded in from from food ingested absorbed, is reaction reaction Moclobemide inby the gut rich foods rich are withtaken MAOIs. Tyramine the Since the enzyme by MAOIs,is inhibited tyramine thenneurons up intoand taken adrenergic where is converted it into transmitter falsewhich causes massive release of hypertensive crisis severe intracranialfatalheadache and haemorrhage Note : reaction occurs with its use. cheese cheese • • • • Important metabolism metabolism. It also metabolizes tyramine of ingested food. of ingested tyramine metabolizes Italso metabolism. oxidase? HT HT - dopamine 5 responsible for NE, NE, for responsible A for selective more is B - -

is a mitochondrial enzyme found in nearly all tissues and they exist in two forms : is a mitochondrial nearlyin enzyme found forms in all tissuestwo and exist they MAO MAO

2. 1. What is monoamine monoamine is What MAO INTRODUCTION leading to leading to ----- Selegiline . B) treatment of Parkinsonism B) treatment - cause severe hyperpyrexia, hyperpyrexia, severe cause (MAO . ( so much NE ) Selective Inhibitors Inhibitors Selective can interact with MAOIs causing the liberation of the liberation causing with MAOIs interact can ------but it is likely that an abnormal pethidine metabolite is an that pethidine abnormal metabolite but it likely is A) Short acting – leading to hypertensive crisis hypertensive leading to - Moclobemide (MAO . sympathomimetics leading to hypertensive crisis hypertensive leading to Old antidepressants Old ------Reversible Reversible Tranylcypromine Indirectly acting Indirectly . The mechanism still unclear . The mechanism still Monoamine Oxidase Inhibitors (MAOIs) Inhibitors Oxidase Monoamine Low benefit/risk ratio Low benefit/risk and in atypical depression where phobia and anxiety are prominent symptoms. prominent phobia are where and depression anxiety and in atypical syndrome muscarinic effects, Postural hypotension, gain Sedation, sleep hypotension, disturbance, Weight Postural muscarinic effects, - . ( so much NE ) Serotonin : Anti Non Selective Inhibitors Inhibitors Non Selective Precursor of dopamine can interact with MAOIs of dopamine interact can Precursor MAOIs interact with the opioid receptor agonist (pethidine) (pethidine) which agonist with the may opioid receptor interact MAOIs refractory cases cases refractory high adverse effect reactions (food and drug interactions.) and drug interactions.) (food reactions effect high adverse SSRIs & Phenelzine (inhibitors of monoamine reuptake) can interact with MAOIs (inhibitors of monoamine degradation) (inhibitors with MAOIs interact can of monoamine reuptake) (inhibitors Irreversible long long acting Irreversible MAOIs MAOIs Amphetamine and Ephedrine: Amphetamine Pethidine: Levodopa: Sexual Dysfunction Sexual Hepatotoxicity they have have they = efficacy antidepressant low TCAs TCAs

- - - - -

hypertensive crisis hypertensive 5 3 accumulated monoamines in neuronal terminals 4 1 hypotension coma, restlessness, produced because of inhibition pathway. of normal demethylation 2 limited usesbecause:limited • • • • Only used for

D.I D.I

type

Uses ADRS

ADRS

Name Specific Specific INTRODUCTION . Paroxetine Paroxetine blockers. - Anorexia nervosa nervosa Anorexia (fluoxetine), (fluoxetine), ” days. Setraline Sertraline, Paroxetine, Citalopram. Citalopram. Paroxetine, Sertraline, 2 2 10 / 1 → hrs), Available as sustained release release as sustained hrs), Available Choice 50 ( hr) hr) st 1 vomiting food vomiting 2 2 24 / ” 1 nor sedative effects Except Paroxetine. Except nor effects sedative : Escitalopram Escitalopram bulimia nervosa bulimia A). It has a longer t longer hasIt a 2 - = potent as parent drug t as parent = potent ) Moderate length ( length ) Moderate 2 HT - 5 metabolism of TCA, neuroleptic, some antiarrhythmic ,B some antiarrhythmic neuroleptic, of TCA, metabolism interaction . interaction antimuscarinic → → ↓ so no ) → ↓ norfluoxetine → enzymes then conjugation enzymes then conjugation ) Eating disorders ) Eating New antidepressants New 3 450 Citalopram Citalopram as MAOI . as MAOI Fluoxetine ( Prozac). ( Prozac). Fluoxetine parpxetine → Adrenoceptor Adrenoceptor 1 days) days) HT levels in synapse in HT levels 11 - - 5 3 ) Anxiety Disorder. Disorder. ) Anxiety , H, or a  premature ejaculation (via stim of stim (via ejaculation premature once weekly, Metabolite Metabolite once weekly, 2 Selective Serotonin Reuptake Inhibitors (SSRIs) Inhibitors Reuptake Serotonin Selective → inhibit cytochrome cytochrome P inhibit → mAch Fluvoxamine ) Too ( long ) Too 1 : do not have cheese cheese do reaction not have 2 weak inhibitors ( sertraline, citalopram ) ) citalopram ( sertraline, inhibitors weak ( Fluoxetine, inhibitors Strong / ) Post traumatic stress disorder. disorder. stress traumatic ) Post disorder. dysphonic ) Premenstrual Hyperkinetic Disorder. Deficit ) Attention of ) Treatment ) Depression. ) Depression. 1 4 5 6 7 1 Metabolism : Metabolism of classmembers from this in: others differs Fluoxetine preparations conditions in the following effective addition in TCA, Same as for They are nearly of comparable efficacy but of preferential response response in individual each but of preferential efficacy nearly of are comparable They t Binds to SERT Binds to SERT on NET No effect No block to ‐ ‐ ) The most commonly prescribed ) antidepressants. commonly prescribed The most to TCA. compared side effects of and) anticholinergic CVS lacks ) They ( risk ) low of . overdose ) Safer . or less TCA MOAI thanis ) toxicity Acute 5 1 2 3 4 • • • • • • • • Fluoxetine

PK Uses MOA

Name Advantages INTRODUCTION A). 2 HT - 5 Choice Choice st 1 weeks before the administration of the other. the administration before weeks 6 period period of TCAs TCAs ” delayed ejaculation (stimulation of (stimulation ejaculation delayed stimulation ) & diarrhea. stimulation MAOIs MAOIs 3 HT - 5 "serotonin syndrome" syndrome" "serotonin New antidepressants New : Loss of libido, period period without drugs “ weight loss weight - threatening threatening - ) 3 washout washout HT - 5 (The most drugs) Selective Serotonin Reuptake Inhibitors (SSRIs) Inhibitors Reuptake Serotonin Selective are potent inhibitors of liver microsomal enzymes. enzymes. microsomal of liver inhibitors potent are withshould not be used combination in Both drugs require a Both drugs require because they can inhibit their metabolism increasing their toxicity. increasing metabolism inhibit theircan they because of because the risk of life and death). collapse cardiovascular hyperthermia, (tremors, SSRIs SSRIs withshouldthey not be used combination in Therefore SSRIs Anxiety & Tremors. Anxiety dysfunction Sexual GIT symptoms: Nausea vomiting (due (due to Nausea vomiting symptoms: GIT ( appetite in Changes with Fluvoxamine. Drowsiness Sleep disturbances: ‐ ‐ ‐ Discontinuation syndrome: Discontinuation & nervousness. , irritability agitation symptoms, like & flu headache ,malaise are Symptoms • • • • • • •

D.I Side Effects New antidepressants Noradrenergic and Specific Serotonergic Antidepressant (NaSSA) Serotonin-2A Antagonist and Reuptake Inhibitors (SARI) Mirtazapine Trazodone & Nefazodone • Alpha 2 antagonist. •  NE & 5HT.

• Block 5HT2A & 5HT3   ADRs of Anxiety & sexual dysfunction. • Block 5HT uptake “selective” • Block 5HT2C & H1 receptors  sedation & weight gain. • 5HT2A antagonist  stimulate 5HT1A help to reduce depression. • Use In cancer patient b/c:- • 5HT2A antagonism  anxiety & sexual dysfunction & sedation. 1) Improve appetite. • Nefazodone  has less sedative effect & doesn't block Alpha

2)  Nausea & vomiting (5HT3 blockers). receptors. 3)  Body weight. • Inhibit P450 3A4 isoenzyme. like SSRI 4) Sedation. (Potent antihistamine). 5) Less sexual dysfunction (5HT2A blockers) 6) No anti-muscarinic effect. Serotonin and Noradrenaline NE Selective Reuptake Inhibitors Norepinephrine and Dopamine Reuptake Inhibitor (NDRI) Reuptake Inhibitors (SNRIs) (NRIs) Venlafaxine “Effexor” Bupropion Reboxetine • For mainly depression, generalized • NE & DA reuptake inhibitors with no direct action on 5HT. • Block only NE. & social anxiety disorder • use for 1) Depression & bipolar depression 2) Smoking cessation. • Safe combination with SSRIs. • Selective 5HT & NE uptake • Advantages :- • ADRs :- blockers. 1) No sexual dysfunction. 1) Tremor. • Similar to TCAs but more selective 2) No weight gain.(no 5HT effect). 2) Tachycardia. • Desyenlafaxine  metabolite of 3) No orthostatic hypotension. 3) Urinary hesitancy called Venalavaxine. • ADRs  seizure, by lowering the threshold of neuronal firing. urinary retention. Clinical uses of antidepressants Endogenous depression SSRIs (1st choice) , Tricyclic

Panic disorder SSRIs , Imipramine

Obsessive compulsive disorder SSRIs , Clomipramine , Amitriptyline (chronic pain)

Anorexia nervosa & Bulimia SSRIs

Schizoaffective disorders SSRIs , Amoxapine , Haloperidol

Premature ejaculation SSRIs

Anxiety disorders Amitriptyline

Migraine & Anxiety & IBS “Irritable bowel syndrome” Amitriptyline

Nocturnal Enuresis in children “Bedwetting” Imipramine

Neuropathic pain NE & 5HT reuptake Blockers Summary Old antidepressants Drugs TCA’s MAOI Block reuptake pumps for 5HT and NE. With variable potency MOA depending on drug. Inhibits MAO which is responsible for NE, and 5-HT catabolism

 Endogenous Depression  Panic Attacks Refractory cases Uses  GAD, OCD, ADHD Atypical depression  Chronic neuropathic pain  Imipramine Nocturnal Enuresis Anti-cholinergic effects (M1), Anti-histaminic effects (H1) Antimuscarinic effects, Postural hypotension, Sexual dysfunction ADEs Anti-adrenergic effects (a1), Weight gain, sexual dysfunction & (phenelzine.), Sedation, sleep disturbance. impotence, Lower seizure threshold Weight gain, Hepatotoxicity ( phenelzine). Glaucoma, Enlarged Prostate, Monotherapy in manic------C.I depressive illness, Seizure disorders • Aspirin, and Phenylbutazone (compete for plasma protein • Pethidine (severe hyperpyrexia, coma, hypotension) binding site) • Levodopa, amphetamines, Ephedrine, and TCAs(Hypertensive D.I • Barbiturates (Reduce effect) crisis) • Oral contraceptives, antipsychotics, SSRI (potentiate effect) • SSRI (serotonin syndrome) • MAOI (Hypertensive crisis)

Cheese reaction: (MAOI + food containing tyramine → false Note Lipophilic, Narrow therapeutic index neurotransmitter → Hypertensive crisis) Summary Monoamine Oxidase Inhibitors (MAOIs) Drugs Mechanism Indication ADR Extra info. • Anxiety disorders, • GIT symptoms (5-HT3 • Most common • Bulimia nervosa stimulation) antidepressant • Anorexia nervosa • Drowsiness (by • TCA (potentiate effect. SSRI • Inhibits 5-HT reuptake • PTSD fluvoxamine) “increase toxicity’) transporter • ADHD • Loss of libido, delayed • MAOI (Serotonin • Premenstrual dysphoric disorder ejaculation. (5-HT2A syndrome) • Premature ejaculation stimulation) Preferred in cancer patients because:- a) Improves appetite NaSSA • Blocks presynaptic α2 • Drowsiness b) Reduces nausea and vomiting - • Blocks 5-HT3>5-HT2A • Weight gain c) Less sexual dysfunction d) No anti-muscarinic effect SARI • 5-HT reuptake inhibitor - - - • 5-HT2A antagonist • Depression SNRIs • Selective 5-HT and NE Without α1, M1 cholinergic or • Generalized anxiety disorders - reuptake inhibitors H receptor blocking properties • Social anxiety disorder • No sexual dysfunction → • Major depression NDRI • NE and DA given in young • Bipolar depression Seizures reuptake inhibitor • No weight gain [ No 5HT ] • Smoking cessation • No orthostatic hypotension Limited to ADR system; NRIs • NE reuptake inhibitor - Seizures, tachycardia, and Safe to combine with SSRI urinary hesitancy.

MCQs

. . C C

. .

B B

. . A A in case of of case in

hapetoxity

. . A A

? 5

uesed

. . C childern . . Answers: Answers: Desipramie Imipramine Clormpramie Nortiyine Phenezline Selegiline Mcrolbemide Tranlycyrpromine A. B. C. D. A. B. C. D. nocturnal enuresis in enuresis nocturnal to lead MOAI's of theseone Which Which one of these drug are are drug theseof one Which 4. 2. with moderate depression which one of these drugs these of one which depression moderate with irrevesbal dignoss psychotic. psychotic. - SSRI's TCA MOAI Anti Selegiline Tranlycyrpromine Mcrolbemide Phenezline Imipramine Imipramine Desipramie Amitryptim Clomprine selective MOAI's ? MOAI's selective - B. C. D. A. B. C. D. A. B. C. D. A. Epileptic person has done done has person Epileptic him? to give not should is Which one of these drugs are are drugs of theseone Which non Which one of these drugs has height height has drugs theseof one Which pump? of NE reuptake inhabit for potency 5. 3. 1.

MCQs

. A A .

. B B .

.A .A

10 .B Answers: Answers: Dopa with MOAI's result into ? into result DopawithMOAI's - Hypertensive Crisis Hypertensive Hypotension Hyperpryexia. Coma Mirtazapine Venlafaxine Bupropion Nefazodone A. B. C. D. A. B. C. D. Which one of the following drugs is Preferred in cancer in is Preferred drugs following of the oneWhich patients? Reaction of L of Reaction 9. 7. lead to to lead . . compand . Dopa - TCA TCA L SSRI. phthidine – – – – Bupropion Sertraline Fluvoxamine Mirtazapine MOAI's MOAI's MOAI's MOAI's MOAI's MOAI's Phenezline Trancypromie Isocarboxized Mcroblobemide B. C. D. A. B. C. D. A. B. C. D. A. Which one of the following drugs can be used for smoking cessation? smoking for used be can drugs following of the one Which Which one of theseone Which syndrome? serotonin Which one of these drugs doesn't have have doesn't drugs theseof one Which reaction? cheese 10. 8. 6. SAQs HT) in theHT) - 5 uptake. - synaptic gap by inhibiting its its re inhibiting by gap synaptic Fluoxetine. Fluvoxamine. They act within the brain to increase the level of serotonin ( serotonin of level the increase to the brain within act They Named two Named oftwo them? How its work? How its work? o o o 2. 1. Selective Serotonin Reuptake Inhibitors Reuptake Serotonin Selective What is the most widely using class of antidepressants in clinical in clinical of antidepressants class using widely the most is What currently? practice Good luck! Done by Pharmacology Team 434

• Mishari Alsalem • Qasem Alsultan • Abdulaziz Alsaud • Abdullah Alammari • Moath walbi • Shaikha Aldosari • Mashhoor Alzarie • Lamya Althawadi • Khalid Alduraibi • Maha AlRabiah

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