Lecture 5: Drugs Used in Treatment of Affective Disorders PDF

Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar DRUGS USED IN TREATMENT OF AFFECTIVE DISORDERS (MOOD DISORDERS) Learning Objectives: Demonstrate understanding of the pathophysiology of depression and mania. Classify antidepressants accordin...

Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar DRUGS USED IN TREATMENT OF AFFECTIVE DISORDERS (MOOD DISORDERS) Learning Objectives: Demonstrate understanding of the pathophysiology of depression and mania. Classify antidepressants according to their mechanism of action. Enumerate clinical uses of antidepressants. Compare side effects of various antidepressants. The affective disorders include depression & mania. 1. Uni-polar depression → patient is always in depressed mood; most common. Signs of depression: Emotional symptoms: sadness, hopelessness, frustration, apathy, feeling of low self-esteem, and loss of motivation and interest in usual activities (anhedonia), feeling of guilt and suicidal thoughts. Biological symptoms (psychosomatic): loss of libido, sleep disturbances, anorexia, chronic pain. 2. Bipolar depression (manic depressive illness) → it is characterized by occurring episodes of elevated & depressed mood. Signs of mania: enthusiasm,  self-confidence, anger, rapid thought and speech patterns (non-stop talk), impaired judgment. Monoamines like Pathophysiology of Depression serotonin, dopam and adrenaline/ “Biogenic amine theory; monoamine theory of mental depression” noradrenaline Depression is due to  of monoamines especially NE and/or 5-HT in brain, whereas (epinephrine/ mania is due to  monoamines in brain. norepinephrine)  expression of brain receptors 5HT2A, 5HT2C Neurotrophic and cytokines theory:  brain neurotrophic factor (BDNF), hypothalamus- pituitary axis dysregulation,  proinflammatory cytokines e.g: IL-1; IL-6; TNF-α Genetic (endogenous; major depressive disorder MDD; may not be associated with easily recognized causes) and social factors (exogenous or reactive depression) are involved. Episodes of MDD may occur at intervals throughout one’s lifetime.  Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar ANTIDEPRESSANT DRUGS Treatment goal = NA and /or  5-HT in brain. Monoamine Typical antidepressants: NA and /or  5-HT in brain. Oxidase-A is a Atypical antidepressants: work by other mechanisms. enzyme that bre down 1. MONOAMINE OXIDASE INHIBITORS (MAOIs) neurotransmitt like serotonin Non-selective irreversible MAO inhibitors (blocks MAOA& MAOB) dopamine, an (Phenelzine, Isocarboxazid, Tranylcypromine). norepinephrin Selective MAOB inhibitors: Selegiline (Only antidepressant available as transdermal patch) MOA: MAOIs  inactivate MAO (reversible or irreversible) metabolism of NA, 5-HT, dopamine →  NA & 5-HT & dopamine leakage of greater amounts into synaptic space → activation of NE and 5-HT receptors → antidepressant effect. ## switching to another drug (wait for 2 weeks) N.B. Their antidepressant effect is delayed for 2 weeks or more, and it persists for 2-3 weeks after stopping the drug [time taken for regeneration of a new enzyme]. Sympathomimetics are drugs that mimic the stimulation of the sympathetic nervous system. They are classified as directly acting (act directly on α or β receptors), Contraindications and precautions on use: indirectly acting (act by providing more norepinephrine to act on α or β receptors), or mixed acting (act by both mechanisms) MAOIs should not be taken with indirect acting sympathomimetics including tyramine that is present in aged cheese, yeast products, smoked fish, herring, chicken liver and red wine Why?? Tyramine (Metabolized by MAO in gut and liver)→ release NE→  blood pressure MAOIs →  NE release  blood pressure Tyramine + MAOIs hypertensive crisis ( due to NE release blood pressure) Symptoms of hypertensive crisis: occipital headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures, and possibly stroke Management of hypertensive crisis: −blockers e.g. phentolamine Certain sympathetic drugs used in the treatment of cold symptoms (decongestants) interact with MAO inhibitors causing the potentiation of the effect of sympathetic agents. Uses: Last line antidepressants in unresponsive patients The use of MAOI is now limited due to dietary restrictions.  Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar 2. TRICYCLIC ANTI DEPRESSANTS (TCAs); named after Tyline / pramine their 3 ringed structure Amitriptyline, Clomipramine, Trimipramine, Nortriptyline, Protriptyline, Imipramine, Desipramine, Doxepin MOA TCAs inhibit the neuronal re-uptake of NE and 5-HT→  NE and 5-HT in the Brain.1 → antidepressant action (elevates mood). Effect is delayed for 2-3 weeks. maximum benefit may require up to 12 weeks or more. 2. Muscarinic antagonists, Have strong Anticholinergic activity “Strong Atropine actions”. 3. H1-blocker “Anti-histaminic” Sedative. 4. α1 blocker USES 1. Depression 2. Nocturnal enuresis (especially IMIPRAMINE due to Anticholinergic=Atropine like actions). 3. Panic disorder. and phobia 4. Severe chronic pain as diabetic peripheral neuropathy, trigeminal neuralgia. 5. Insomnia. 6. Prevent migraine (particularly Amitriptyline) Adverse effects: 1. Anticholinergic (Atropine) adverse effects; dry mouth, constipation, urine retention (C.I. in Prostatic patients), tachycardia, blurred vision, aggravating glaucoma,..etc. 2. Sedation due to H1 blocking activity (given at night) 3. Orthostatic (postural) hypotension and reflex tachycardia due to 1 blocking activity. 4. Weight gain. Over dose: 3Cs: Coma (excessive sedation), Convulsions, Cardiac arrhythmias (depress cardiac conduction) N.B. Because depressed patients might attempt suicide, the safety of an antidepressant in overdose is an important consideration when selecting a drug for a particular patient. Treatment of Adverse Effects: arrhythmia can be treated by the intravenous administration of sodium bicarbonate. Sodium bicarbonate increases the ratio of nonionized TCA to ionized TCA and thereby decreases the binding to the sodium channel in cardiac membranes. N.B. 1. Tolerance to the Anticholinergic properties and autonomic effects of the TCAs develops within a short time BUT NO tolerance to the antidepressant effect. 2. Therapeutic index: narrow, Monitoring is essential  Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar 2. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) xetine / opram Fluoxetine [prototype], Paroxetine, Sertraline, Fluvoxamine, Citalopram, Escitalopram (S-enantiomer of citalopram) Mechanism of action: SSRIs  U1 of 5-HT mainly  selectively inhibit the neuronal reuptake of 5-HT → 5-HT level in the synapse → antidepressant effect after 2-3 weeks, maximum benefit may require up to 12 weeks or more. Little blocking of muscarinic, α-adrenergic, and histamine H1 receptors → less side effects than TCAs. Clinical uses: 1. Depression (Expensive drugs opposite to TCAs), Drug of Choice 2. Generalized anxiety disorder (GAD). 3. Eating disorders “Bulimia nervosa and anorexia nervosa”. Fluoxetine is FDA-approved for treating bulimia. 4. Premenstrual dysphoric disorder (PMDD). 5. Panic disorder. 6. Obsessive compulsive disorder (OCD). 7. Posttraumatic stress disorder (PTSD). 8. Social anxiety disorder Adverse effects: 1. Gastrointestinal side effects (nausea, diarrhea), take after food. 2. Agitation & Insomnia (given at day time) 3. Sexual dysfunction. 4. Changes in weight Advantages over TCAs: NO anticholinergic side effects, NO sedation, Less weight gain. Dapoxetine Increase blood pressure Drug interactions: 1. Most SSRIs inhibit HME (hepatic microsomal enzymes=CytP450)  activity of drugs that are metabolized by CytP450 Toxicity e.g. TCAs, -blockers. SSRIs (inhibit reuptake of 5-HT) + MAOIs (inhibit destruction of 5-HT)  5-.3 HT life threatening serotonin syndrome (agitation, restlessness, confusion, insomnia, hypertension, and gastrointestinal symptoms and if severe may cause hyperthermia, muscle rigidity, sweating, seizures and changes in mental status  Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar and vital signs). Both types of drugs require at least 2 weeks washout period before the other type starts. N.B. Serotonin syndrome also occurs due to over dose of SSRIs. Discontinuation syndrome: Occurs after abrupt withdrawal, Symptoms: headache, malaise, and flu-like symptoms, agitation and irritability, nervousness, and changes in sleep pattern. Gradual tapering of the SSRIs is recommended to preventor reduce symptoms of discontinuation syndrome 4. Serotonin/Norepinephrine reuptake inhibitors (SNRIs) faxine/ipran Venlafaxine, Desvenlafaxine (demethylated venlafaxine; active metabolite of venlafaxine), Duloxetine, Milnacipran, Levomilnacipran MOA: inhibit the reuptake of both 5-HT and NE. as TCAs SNRIs, unlike the TCAs, have little activity at α, M, H receptors →  adverse effects than the TCAs. Uses: 1- Depression in patients in whom SSRIs are ineffective aye 7aga bt3aleg NE bt3aleg el alam 2- Chronic painful symptoms accompanying depression (e.g. back and muscle aches). This pain is modulated by both 5-HT and NE pathways therefore SSRIs are relatively ineffective 3- Chronic neuropathic pain (diabetic peripheral neuropathy, fibromyalgia, postherpetic neuralgia, low back pain). 4- Generalized anxiety disorder. Adverse effects: Gastrointestinal issues: Nausea, constipation, dry mouth. Central Nervous System effects: Headache, dizziness, insomnia. Cardiovascular effects: Increased blood pressure and heart rate. Sexual dysfunction: Decreased libido, erectile dysfunction. Other: Sweating, weight changes. May precipitate a discontinuation syndrome if abruptly stopped.  Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar ATYPICAL ANTIDEPRESSANTS Mixed group of agents that have actions at several different sites. 5. Serotonin Receptor Antagonists done Nefazodone, Trazodone Mirtazepine - Block the 5-HT2A receptor, a G-protein coupled receptor located in several brain regions. It is believed that post-synaptic 5-HT2A overdensity is involved in the pathogenesis of depression. - Mirtazapine blocks presynaptic 2 autooceptor (responsible for negative feedback of transmission release)→  NE & 5HT release - Nefazodone, Trazodone block 1 receptor → postural hypotension - They are sedatives, because of their potent histamine H1-blocking activity (Useful in depressed patients having difficulty sleeping). Side effects: Sedation, dizziness, dry mouth, Increased appetite, and weight gain. Nefazodone is hepatotoxic therefore was withdrawn from some countries. Trazodone causes priapism (sustained and painful erection in males). 6. Vortioxetine ❑ Vortioxetine increases serotonin concentrations in the brain → utilizes a combination of serotonin reuptake inhibition, 5-HT1a agonism, and 5-HT3 and 5- HT7 antagonism as its suggested mechanisms of action to treat depression. ❑ The common adverse effects include nausea, constipation, and sexual dysfunction (serotonergic mechanisms) 7. Bupropion Weak Norepinephrine and dopamine reuptake inhibitor (NDRI). Nicotinic receptor antagonist. Useful for decreasing cravings and attenuating withdrawal symptoms of nicotine in patients trying to quit smoking. Remember: Varenicline is a partial agonist of nicotinic receptors used in smoking cessation. Very low incidence of sexual dysfunction as it doesn’t or weak inhibitor of serotonin reuptake. May be used in patients who are concerned about the risk of antidepressant-related sexual dysfunction. 8. SEROTONIN–DOPAMINEANTAGONISTS The second-generation antipsychotics block serotonin (5-HT2) and dopamine (D2) receptors. Used as an adjunctive treatment in patients without complete response to antidepressant therapy. E.g: Aripiprazole, olanzapine e, and quetiapine  Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar Extracts of the plant St. John’s wort (Hypericum perforatum) The extracts contain a substance called hypericin and several flavones. Some of these compounds inhibit MAO, whereas others appear to block the neuronal reuptake of serotonin. Hypericum extracts appear to cause fewer adverse effects than other antidepressants but are not as effective as prescription antidepressants. Electroconvulsive therapy (ECT) is a successful physical tool to treat depression that usually acts more rapidly than drugs, and can be used in combination with drugs. N.B. All antidepressant are with delayed onset (2-4 weeks), although their effect on NA, 5- HT level doesn’t require such a long time  this suggest 2ry effects in brain that may be involved in their antidepressant. Treatment of Mania and Bipolar Manic Depression Mood stabilizer 1. Lithium It remains the drug of choice (DOC) for bipolar disorders. MOA: Not fully understood i. Lithium decreases central cAMP, IP3 formation (2nd messengers)→ neuronal response to serotonin and NE. ii. Lithium is a monovalent cation that mimics the role of Na+ in the excitable tissue. It can enter the neuron through the Na+ channel but unlike Na+ it is not pumped out by Na+/K+ ATPase pump  partial loss of intracellular K+ Conc. gradient of K+ form inside to outside  K+ efflux excitation of neurons partial depolarization &  in excitability of nerve tissue. N.B. Narrow therapeutic index so monitoring is essential. Side effects: Polyuira, polydepsia, polyphagia (Diabetes insipidus, it interferes with the action of antidiuretic hormone and thereby inhibits the kidney’s ability to concentrate the urine; manage with amiloride), fine hand tremors (can usually be controlled by β-adrenoceptor antagonist), thyroid function (blocking thyroid hormone synthesis and release). Lithium is renally eliminated and should be used cautiously in renally impaired patients. Teratogenicity: Ebstein’s anomaly (malformed tricuspid valve) 2. Some antiepileptic drugs e.g. carbamazepine, valproic acid, lamotrigine.  Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar 3. Some antipsychotics e.g. chlorpromazine, haloperidol, risperidone, olanzapine, ziprasidone, aripiprazole, quetiapine Some video links: Pathophysiology of Depression https://www.youtube.com/watch?v=QEjWLj5wAFM Unipolar depression https://www.youtube.com/watch?v=tvpVfXAC5Ow Bipolar disorder https://www.youtube.com/watch?v=RrWBhVlD1H8 ANTIDEPRESSANT DRUGS “SSRI” mechanism of action https://www.youtube.com/watch?v=T25jvLC6X0w ANTIDEPRESSANT DRUGS - SSRIs, SNRIs, TCAs, MAOIs, Lithium https://www.youtube.com/watch?v=-EMg12QBUx4 Fluoxetine as SSRI https://www.youtube.com/watch?v=kKDXqlSWovA SNRIs mechanism of action https://www.youtube.com/watch?v=l3N8ThFbBvs Serotonin & depression https://www.youtube.com/watch?v=4D3IlIcqny4 Atypical antidepressants https://www.youtube.com/watch?v=zfTNPKrnfTE Trade names for antidepressant drugs https://www.youtube.com/watch?v=JDaYDWEc15k