BMS 301 Drug Therapy of Depression Fall 2024 PDF

BMS 301 1- Drug Therapy of Depression Mai Ahmed Ebeid lecturer of Clinical Pharmacology Faculty of medicine Fall 2024 Neurotransmission Areas of brain  Depression is a mood disorder Period lasting at least two weeks, with ≥ five...

BMS 301 1- Drug Therapy of Depression Mai Ahmed Ebeid lecturer of Clinical Pharmacology Faculty of medicine Fall 2024 Neurotransmission Areas of brain  Depression is a mood disorder Period lasting at least two weeks, with ≥ five of the following symptoms: Sadness – inability to experience pleasure (anhedonia) – fatigue – disturbance (usually↓) in appetite & sleep - guilt – inability to concentrate – indecisiveness – recurrent suicidal ideation. Psychotic symptoms (hallucinations & delusions) occur in severe depression. Impairment of social & occupational function. Atypical Symptoms may occur including overeating & ↑ sleep -anxiety - phobias – hypochondriasis (multiple body complaints). Depression is classified into: 1. Unipolar depression Major depressive Disorder 2. Bipolar manic depressive disorder Episodes of depression alternating with episodes of mania  Monoamine Theory of Depression Brain norepinephrine (NE) & serotonin (5-HT) are neurotransmitters responsible for mood. ▪ ↓ Activity of these transmitters results in depression, whereas ↑activity leads to mood elevation. NE - 5HT NE - 5HT Depression Antidepressants  Mechanism of Action of Antidepressants 1. Increase in brain biogenic amines (immediately within 12 hours). 2. Down-regulation (Normalization) of brain β & 5-HT2 receptors (delayed for 2-4 weeks). 3. Affect neurotrophic factors essential for survival & function of neurons.  Antidepressant Site(s) of Action MAO inhibitors Presynaptic α2 blocker Amine pump inhibitors  Antidepressant Site(s) of Action Amine Pump Inhibitors MAO Inhibitors Inhibit reuptake of biogenic amines into neurons Inhibit metabolism of biogenic amines by MAO resulting in their accumulation in synaptic cleft, enzyme inside nerve endings   stores available potentiating their action at post synaptic receptors. 1. Tricyclics (TCAs): imipramine – amitriptyline – for release. clomipramine 1. Non-selective:Tranylcypromine-Phenelzine 2. Selective Serotonin Reuptake Inhibitors (SSRI): Fluoxetine – sertraline- escitalopram. 2. Selective on MAO-A :Moclobemide 3. Serotonin Norepinephrine Reuptake Inhibitors (SNRI): Venlafaxine - duloxetine. 4. NA & DA reuptake Inhibitors (NDRI): Bupropion Presynaptic 2 Blockers (Noradrenergic and specific serotonergic antidepressant) (NaSSA) Mirtazapine  NA & 5-HT release into synaptic cleft by preventing 2 auto-inhibition.  I. Tricyclic Antidepressants (TCAs) Mechanism of action of TCAs 1. Block reuptake of both 5-HT, NE, DA 2. Block Receptors : M, α , H (Autonomic)  Adverse effects of TCAs (Limit their use) Autonomic Blockade H1 Sedation Dry mouth, Urinary retention M Constipation, Blurred vision, ↑Glaucoma, Confusion …..  Hypotension Be Cautious in Elderly  Adverse effects of TCAs (Limit their use) Cardiotoxic - Arrhythmia Convulsions Be Cautious in Cardiac & Epileptics  Adverse effects of TCAs (Limit their use) ↓ Safety Margin Sexual dysfunction ↓ Compliance  Adverse effects of TCAs (Limit their use) Drug interactions with TCA: Alcohol- anesthetics →↑ sedation. Hypotensive drugs →↑ postural hypotensive effects of TCAs. TCAs potentiate directly acting sympathomimetics (TCAs ↓uptake of NA). Not to be given with MAOIs.  Adverse effects of Other Antidepressants SSRIs SNRIs NDRIs Presynaptic α2 Fluoxetine Venlafaxine Bupropion blockers Mirtazapine Sexual Sexual ↑ Risk of sedation & weight dysfunction(C.I) dysfunction(C.I) convulsions gain Anxiety, Hypertension Insomnia (C.I) Suicidal tendency? 5HT syndrome with MAOI Advantages of Other Antidepressants over TCAs SSRIs SNRIs NDRIs Presynaptic α2 blockers Fluoxetine Venlafaxine Bupropion Mirtazapine No Autonomic side effects No sexual More rapid effect dysfunction → used in depressed patients with less nausea & intolerant to SSRIs. sexual dysfunction → ↑ NE/DA (↓ craving) → used in used in patients smoking cessation. intolerant to sexual dysfunction of SSRIs.  VI. Monoamine Oxidase Inhibitors (MAOIs) Mechanism of actions MAOIs MAO A&B inhibitors irreversibly inactivate MAO → ↑DA, NE, 5-HT leakage into synaptic cleft.  Uses of MAOIs MAOIs are considered last-line Dangerous Food & Drug Interactions Hypertensive Crisis  Cheese Reaction Tyramine in food is metabolized in GIT by MAO-A & MAO-B. MAOIs allow tyramine in tyramine-rich food to escape metabolism & release ↑↑↑amounts of catecholamines from neurons → hypertensive crisis.  Precautions for patients on MAOIs ▪Warn against serious drug interactions. ▪List of avoided foods. ▪TCAs or SSRIs are allowed after 2 weeks of stopping MAOIs (effect persists for 2 weeks). Q: Therapeutic Uses of Antidepressants? 1. Major Depressive disorders (main use) 2. Anxiety disorders: (generalized anxiety disorder -panic disorder - phobias – obsessive compulsive disorders) (SSRIs & TCA). 3. Pain disorders: e.g. chronic neuropathic pain (SNRIs & TCA) →↑ monamines in descending tracts. 4. Smoking cessation (Bupropion). 5. Urinary incontinence (SNRI), Nocturnal enuresis (TCAs; anticholinergic → contracts urethral sphincter). 6. Eating Disorders: Anorexia Nervosa & Bulimia Nervosa ((SSRIs & TCA). Guidelines for the Use of Antidepressants 1. Antidepressant effect is delayed for 2-4 weeks. 2. Treatment is continued for 4 weeks before considered unsuccessful. 3. If partial improvement occurs, continue for another 4 weeks. 4. Following remission, continue treatment for 6 months. 5. Gradual withdrawal over 4 weeks. 6. Long term maintenance therapy for 2 years may be needed if patient experiences recurrent episodes. 7. SSRIs are the most widely used initial therapy. 8. If resistant to initial therapy switch to a different member of same class or to another class. Guidelines for the Use of Antidepressants 9. TCAs → reserved for resistant cases due to toxicity & drug interactions. 10. MAOIs → reserved for atypical depression & 2nd choice in refractory major depression due to toxicity & serious food & drug interactions. 11. Antidepressants are used together with a BZD in anxiety disorders to calm the patient until the antidepressant becomes effective. 12. Fluoxetine and paroxetine are potent inhibitors for CYP 2D6 → Drug interactions with TCAs, antipsychotic drugs, and some antiarrhythmic and β-blockers. Thank You