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Pharmacotherapy of Depression: A Guide to Antidepressant Classification, Mechanisms of Action, Pharmacokinetics, Clinical Use, and Drug Interactions
- 1. Pharmacotherapy of depression Dr Manish mohan Junior resident SRGMCFR,Trivandrum
- 2. Contents • Introduction • Pathophysiology • Classification of antidepressants • Pharmacokinetics and pharmacodynamics • Adverse effects and drug interactions • CYP enzymes and antidepressants
- 3. MAJOR DEPRESSIVE DISORDER • SAD MOOD • LOSS OF INTEREST • LOW ENERGY • GUILT • PSYCHOMOTOR RETARDATION • SUICIDAL THOUGHTS • MELANCHOLIA
- 4. Pathophysiology of Major Depression • Monoamine hypothesis • Neurotrophic hypothesis • Neuroendocrine Factors
- 5. Neurotrophic hypothesis Brain-derived neurotrophic factor (BDNF) - neural plasticity - resilience - neurogenesis Tyrosine kinase receptor B in both neurons and glia BDNF - atrophic changes in hippocampus , medial frontal cortex and anterior cingulate
- 7. Monoamine hypothesis Deficiency - nor-adrenaline (NE) and dopamine (DA) and serotonin(5ht) in the CNS Evidence – Reserpine, which has antihypertensive actions due to its ability to deplete catecholamines (DA and NE) and 5HT from peripheral sympathetic nerve endings, caused depression Drugs that promote catecholamines and serotonin in the synapse relieved depression – MAOI – block metabolism of DA and NE – TCA – block reuptake of NE and 5HT
- 9. Neuroendocrine Factors MDD- - elevated cortisol levels - no suppression of ACTH release in the dexamethasone suppression test - chronically elevated levels of corticotropin-releasing hormone Abnormal thyroid function
- 10. ANTIDEPRESSANT CLASSIFICATION • Selective Serotonin Reuptake Inhibitors • Selective Serotonin And Noradrenaline Reuptake Inhibitors • Tricyclic Antidepressants • Tetracyclic and Unicyclic Antidepressants • 5 –HT Receptor Modulators • Monoamine Oxide Inhibitors
- 11. Selective Serotonin Reuptake Inhibitors • Inhibition of the serotonin transporter (SERT) • Fluoxetine was introduced in the United States in 1988 • Fluoxetine • Paroxetine • Sertraline • Citalopram • Escitalopram • Dapoxetine
- 13. Pharmacokinetics
- 14. Selective Serotonin Reuptake Inhibitors
- 15. Pharmacodynamics • Extracellular serotonin Receptors on the transporter Serotonin, Na and cl- Conformational change • SSRIs allosterically inhibit the transporter • At therapeutic doses, about 80% of the activity of the transporter is inhibited
- 17. Side Effects of SSRIs • Nausea , diarrhea and emesis (5HT3) • Insomnia, increased anxiety, irritability, and decreased libido (5HT2) • Paroxetine ---weight gain
- 18. SSRI Discontinuation Syndrome *SSRIs should NOT be stopped Abruptly • Dizziness, nausea, fatigue, headache, insomnia, restlessness, unstable gait and shock like sensations (rare) • More apparent with short acting SSRIs (paroxetine > fluvoxamine > sertraline > citalopram >> fluoxetine)
- 19. Drug Interactions Paroxetine and Fluoxetine CYP2D6 inhibitors TCA Fluvoxamine CYP3A4 inhibitor Diltiazem SSRIs + MAOI Serotonin syndrome
- 20. Advantages of SSRIs • Ease of use • Better tolerability • Produce little /no sedation • Do not interfere with psychomotor function • No anticholinergic side effects • No alpha adrenergic blocking action • Do not inhibit cardiac function
- 21. Serotonin-Norepinephrine Reuptake Inhibitors • Selective Serotonin- Norepinephrine reuptake inhibitors (SNRIs) • TCAs
- 24. • venlafaxine (bicyclic compound) • Desvenlafaxine • Duloxetine (3 ring structure ) • Milnacipran ( cyclopropane ring) • Other uses - generalized anxiety - stress - urinary incontinence - vasomotor symptoms of menopause.
- 25. Pharmacokinetics CYP2D6 • Venlafaxine O -desmethylvenlafaxine
- 26. Pharmacodynamics • NET - 12-transmembrane domain complex that allosterically binds NE • Venlafaxine is a weak inhibitor of NET • Desvenlafaxine • Duloxetine NET + SERT • Milnacipran • SNRIs lack – antihistamine, alpha adrenergic blocking and anticholinergic effects of TCA
- 28. ADVERSE EFFECTS • Nausea, constipation, insomnia, headaches, and sexual dysfunction. • Immediate-release formulation of venlafaxine sustained diastolic hypertension(10-15%) • Duloxetine ----hepatotoxic • Discontinuation syndrome
- 29. Drug Interactions Duloxetine (moderate inhibitor of CYP2D6 ) Elevate TCA • Milnacipran----------CYP3A4---------KETOCONAZOLE SNRIs are contraindicated in combination with MAOIs
- 31. Other uses for TCAs • Treatment of pain conditions • Enuresis • Insomnia
- 33. MOA • Antagonism of SERT and NET • NET (desipramine, nortriptyline, protriptyline, amoxapine) • SERT and NET (imipramine, amitriptyline, clomipramine ,doxepin) • (H1 histamine, 5HT2, α1 adrenergic, and muscarinic cholinergic receptors)
- 34. Pharmacokinetics • well absorbed • long half-lives • Metabolism - demethylation - aromatic hydroxylation - glucuronide conjugation • Metabolism –CYP2D6
- 37. Adverse effects • Anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, and confusion) • α-blocking property orthostatic hypotension • H 1 antagonism by the TCAs is associated with weight gain and sedation • The TCAs are class 1A antiarrhythmic agents and arrhythmogenic at higher doses
- 38. Drug Interactions • CYP2D6 inhibitors elevate TCA • MAOIS + TCA Serious toxicity • TCAs potentiates CNS depressants (alcohol) • Carbamazepine TCA metabolism
- 39. 5-HT receptor modulators Trazodone m-chlorphenylpiperazine (m-cpp) Nefazodone hydroxynefazodone and m-cpp
- 40. CONT……. Vortioxetine ------(newer agent ) 5-HT3, 5-HT7,5-HT 1D receptor blocker + SERT BLOCKER
- 41. • MOA: blockade of the 5-HT receptor • 5-HT 2A receptor is G protein coupled receptor Neocortex
- 42. Pharmacokinetics Nefazodone is a potent inhibitor of the CYP3A4 Vortioxetine (oxidation)--------CYP2D6
- 43. Pharmacodynamics • Nefazodone is a weak inhibitor of SERT and NET Potent antagonist of the postsynaptic 5-HT 2A receptor • Trazodone - selective inhibitor of SERT + - presynaptic α-adrenergic–blocking property + - modest antagonist of the H 1 receptor
- 45. Adverse Effects • sedation and gastrointestinal disturbances • Trazodone- can induce priapism • orthostatic hypotension • Hepatotoxicity (Nefazodone )
- 46. Drug Interactions • Triazolam levels are increased by concurrent administration of nefazodone Nefazodone with simvastatin 20-fold increase in plasma levels of simvastatin ritonavir or ketoconazole ------ increases in trazodone
- 47. Tetracyclic and Unicyclic Antidepressants • Bupropion (unicyclic aminoketone structure) • Mirtazapine • Amoxapine tetracyclic chemical structure • Maprotiline • Vilazodone – multi ring structure .
- 48. Pharmacokinetics • Bupropion - rapidly absorbed - protein binding of 85% - undergoes extensive hepatic metabolism - Bupropion has a biphasic elimination Amoxapine 7-hydroxyamoxapine(D2 blocker)
- 49. vilazodone 72 25 ND ND ND
- 50. Pharmacodynamics • Bupropion – moderate inhibitors of NE and 5-HT reuptake - pre synaptic release of catecholamines • Mirtazapine – antagonist of presynaptic alpha 2 auto receptor. • Amoxapine and Maprotiline Potent NET inhibitors • Vilazodone is a potent serotonin reuptake inhibitor + partial agonist of 5 HT 1A receptor.
- 52. Adverse effects • AMOXAPIN ---PARKINSONIAN SYNDROME ( D2 blocking action ) • Mirtazapine -----sedative effect • Maprotiline -----seizures • Bupropion -------agitation, insomnia and anorexia • Vilazodone -----GI upset, diarrhea ,nausea
- 53. Drug interactions • Bupropion -------------CYP2B6------------cyclophosphamide (-) Hydroxy bupropion --------------- ------ desipramine level • ( -CYP2D6) • Mirtazapine ( 2D6, 3A4, and 1A2)
- 54. Monoamine oxidase inhibitors • Mitochondrial enzyme involved in the oxidative deamination of biogenic amines • MAOA metabolizes 5HT ,NE and DA • MAOB ------- 5HT and DA • Rarely used ( toxicity and drug interactions )
- 55. Cont…… • MAO-A -Peripheral adrenergic nerve endings -intestinal mucosa -Human placenta MAO-B -Brain -Platelets
- 56. Monoamine oxidase inhibitors • Phenelzine • Isocarboxazid • Tranylcypromine • Selegiline • Moclobemide Hydrazine derivatives Non-hydrazine
- 57. • MAO-A ---------CLORGYLINE, MOCLOBEMIDE • MAO-B-----SELIGILINE
- 58. Moclobemide • Reversible inhibitor of MAO-A • Lacks anticholinergic ,sedative, cognitive, psychomotor and cardiovascular adverse effects • Useful in social phobia • s/e : nausea ,dizziness ,headache, insomnia
- 59. Pharmacokinetics The MAOIs are metabolized by acetylation
- 61. Adverse effects • Orthostatic hypotension • Weight gain • Confusion • Sedative effect (Phenelzine) • Discontinuation syndrome ( delirium like ) • Impotence
- 62. Cheese reaction Certain varieties of cheese,beer,wines,pickled meat, and fish Large quantity of tyramine and dopa MAOI ------indirect sympathomimetic stimulation Hypertensive crisis, cerebrovascular accidents
- 63. Drug interaction MAOI vs SSRIs/SNRIs/TCA Serotonin syndrome MAOI vs Tyramine Malignant hypertension Stroke/ myocardial infarction
- 64. ATYPICAL ANTIDEPRESSANTS 1.MIANSERIN -Block presynaptic alpha 2 receptor -Antagonism of 5-HT 2, 5-HT 1c Adverse effect- blood dyscrasias , liver dysfunction
- 65. 2. TIANEPTIN enhance 5-HT uptake 3.AMINEPTINE
- 67. 1. Major depression • SSRI/SNRIs • Trial therapy – 8-12 weeks at therapeutic dose • Goal- remission of all the symptoms • Inadequate response ----(SSRI +SNRI) + atypical antidepressants • Long term maintenance needed -----2 or more serious MDD in the previous 5 years or 3 or more serious episodes in the life time .
- 68. 2. Anxiety disorders • PTSD • OCD ( clomipramine, fluvoxamine ) • Social anxiety disorder SSRI/SNRI + BZD • GAD • Panic disorder
- 69. 3. Pain disorders • Diabetic neuropathy -------Duloxetine • Fibromyalgia • Post herpetic neuralgia------amitriptyline
- 70. 4.Premenstrual dysphoric disorder • Sertraline • Fluoxetine
- 71. 5.Attention deficit hyperactivity disorder • TCA -------Imipramine Nortriptyline 1st line drugs Amoxapine
- 72. 6. Smoking cessation • Bupropion • Mechanism –unknown • Nortriptyline
- 73. 6.Enuresis • Imipramine 25 mg at bed time • 7.Migraine • Amitriptyline
- 75. Summary • Pathophysiology • Classification of antidepressants • Pharmacokinetics and pharmacodynamics • Adverse effects and drug interactions • CYP enzymes and antidepressants
- 76. Thank you
Editor's Notes
- steroid -suppression of transcription of the BDNF gene Cyclic AMP responsive binding protein
- Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms Escitalopram is the S enantiomer of citalopram Paroxetine and fluvoxamine are not optically active
- fluoxetine and paroxetine are potent inhibitors of the CYP2D6 fluvoxamine is an inhibitor of CYP3A4
- Fluoxetine to norfluoxetine
- SERT is a glycoprotein with 12 transmembrane regions embedded in the axon terminal and cell body membranes of serotonergic neurons.
- Agitation ,restlessness,rigidity,hyperthermia,delirium,twitching followed by convulsion
- CYP2D6,CYP1A2
- NET is structurally very similar to the 5-HT transporter
- TRICYCLIC CORE
- SEDATIVE EFFECT SO NIGHT TIME DOSE Therapuetic window ---50-200ng/ml imipramine,amitryptiline,nortryptiline
- Fluoxetine, paroxetine, duloxetine, hydroxybupropion, methadone
- 2 antagonist. Trazodone was among the most commonly prescribed antidepressants until it was supplanted by the SSRIs in the late 1980s……..unlabeled hypnotic
- 2A
- n efazodone is an inhibitor of the CYP3A4 isoenzyme
- Amoxapine is N –methylated metabolite of loxapine
- with the first phase lasting about 1 hour and the second phase lasting 14 hours
- MIRTAZAPINE ----NORADRENERGIC AND SPECIFIC SEROTONERGIC ANTIDEPRESSANT
- Psychosis, excitation, confusion
- Similar reaction can occur with ephedrine , SSRIs, SNRIs and levodopa
- Bupropion can be added
- Pregabalin ,gabapentin can be added to this group