Lec 3 Drugs used to treat depression and mania disorders.pdf

Pharmacology III (1801443-3) Lecture 3 Drugs used to treat depression and mania disorders D e p a r t m e n t o f P h a r m a c o l o g y a n d To x i c o l o g y College of Pharmacy...

Pharmacology III (1801443-3) Lecture 3 Drugs used to treat depression and mania disorders D e p a r t m e n t o f P h a r m a c o l o g y a n d To x i c o l o g y College of Pharmacy U m m Al - Q u r a U n i ve r s i t y Learning Outcomes At the end of this lecture, you will be able to: ▪ Explain the pathophysiology of depressive disorders and identify their various types. ▪ Explain the mechanism of action for different classes of antidepressants. ▪ Outline the therapeutic indications of each class of antidepressants. ▪ Recognize the key pharmacokinetics of different antidepressants. ▪ Identify adverse effects and potential drug interactions associated with various types of antidepressants.  Depression Depression is a common mental disorder, characterized by persistent sadness and a lack of interest or pleasure in usual activities causing significant impairment in daily life. Globally, more than 264 million people of all ages suffer from depression. Women are affected more than men. It can be severe and sometimes fatal. 800,000 people die due to SUICIDE every year. Depression (who.int) Theoretical pathophysiology of depression ❑ Genetics: More than 200 genes have been identified to be associated with depression, such as NR3C1, GRM3 and SLC6A4 genes. ❑ Biogenic amine and receptor theory. ❖ Depression is associated with changes in the level of neurotransmitters (serotonin, dopamine, norepinephrine) in the brain and/or changes in the activity of 5HT2A, 5HT2C receptors. ❑ Neurotrophic and cytokines theory. A) Brain-derived neurotrophic factor (BDNF). B) Hypothalamo-pituitary axis dysregulation (HPA). C) Proinflammatory cytokines: IL1, TNF-alpha. Types of Depression: 1-Unipolar (major depressive disorder) ❑ It is characterized by mood swings in the same direction. ❑ Major depressive disorder (~25%): ▪ Occur in childhood to old age (20s-30s). ▪ In 2020, it affected about 4% of world’s population. ▪ Result from combination of genetic, environmental and psychological factors. ▪ Risk factor: major life changes, certain medications, chronic health problems, substance abuse. ▪ Secondary depression (~60%): Drug/alcohol abuse, illness. ▪ 2-7% of adult die by SUICIDE. ▪ However, 60% population die by SUICIDE had depression. Types of Depression: 2-Bipolar (manic depressive disorder) ▪ Incidence 10~15%. ▪ Appears in early adult life (~20’s). ▪ History of one or more major depressive episodes. ▪ Cycles of mood swings, mania and hypomania are phases of bipolar disorder characterized by  in mood and behavior (opposite to depression). ❖ Type I bipolar disorder: Manic episode (hyperactivity & reduced need for sleep) followed by depressive episode. ❖ Type II bipolar disorder: A hypomanic episode (milder form of mood elevation) followed by depressive episode. Unipolar vs Bipolar Types of Depression: 3-Dysthymia (Persistent depressive disorder) ▪ A patient's depressed mood persist for at least for 2 years in adult and 1 year in children and adolescents. ▪ Less severe, chronic, keeps away from functioning at highest level but do not disable. ▪ Patient may have belief that depression is part of their character, may NOT even discuss with doctors, friends or family. Types of Depression: 4- Atypical depression According to DSM-5, the core feature of atypical major depression is mood reactivity (feeling better in response to positive events). Also known as depression with atypical features. Key symptoms include reactivity to pleasurable stimuli, weight gain, hypersomnia, heavy feelings in limbs, feeling rejected. Patient experienced depression first at an early age, during their teenage years. DSM-5: The Diagnostic and Statistical Manual of Mental Disorders Depression diagnostic criteria based on DSM-5 guideline Sadness vs clinically significant depression DSM-5: The Diagnostic and Statistical Manual of Mental Disorders  Antidepressants Drugs ▪ They are used for the relief of symptoms of moderate and severe depression. ✓ Antidepressant drugs enhance alertness →  output of behavior. ✓  neurotransmitters (dopamine, serotonin and noradrenaline) in the synapse. ✓ Antidepressants are taken for at least 4-6 months. ✓ They can be used alone or in combination with other medications. ▪ Classes of antidepressants drugs: 1. Tricyclic anti-depressants (TCAs). 2. Monoamine oxidase inhibitors (MAOIs). 3. Selective serotonin reuptake inhibitors (SSRIs). 4. Serotonin/norepinephrine uptake inhibitors (SNRIs). 5. Atypical anti-depressants. 6. Serotonin modulators.  Mechanism of action of tricyclic anti-depressants (TCAs) ▪ TCAs → inhibit reuptake of norepinephrine and serotonin →  levels in synaptic cleft. ▪ TCAs→ block histamine, cholinergic, and α-adrenergic receptors → responsible for  the risk of side effects more than producing antidepressant activity.  Tricyclic Antidepressants (TCAS) Drug subclasses 1-Tertiary amine tricyclics are more effective at blocking serotonin reuptake. and therapeutic ▪ Amitriptyline → most effective and widely used antidepressant. indication It is used for migraine prophylaxis, fibromyalgia. (2-8 weeks clinical ▪ Doxepin → depression and insomnia. effects) ▪ Imipramine → sever major depression disorders and nocturnal enuresis in children. ▪ Trimipramine → depression, insomnia and pain. 2-Secondary amine tricyclics are more effective at blocking norepinephrine reuptake→ less likely cause sedation, hypotension and anti-cholinergic effects. ▪ Desipramine → neuropathic pain. ▪ Nortriptyline → sever major depression disorders. ▪ Protriptyline → unique as it is energizing rather than sedating. ▪ Well-absorbed orally. Pharmacokinetic ▪ High protein binding and lipid soluble → penetrate to CNS easily. ▪ Metabolised in the liver (significant first-pass, which conjugated with glucuronic acid). ▪ Excreted in the kidney.  Tricyclic Antidepressants (TCAS), cont. ▪ Histamine blocker → sedation. ▪ α-adrenergic blocker → orthostatic hypotension → reflex tachycardia. ▪ Muscarinic receptors blocker → anticholinergic SEs (atropine like action) Adverse effects → dry skin, dilated pupils, blurred vision, constipation, urinary retention. ▪ Sodium channel blocker → cardiac arrhythmia → prolongation of the QT. interval. ▪ Lowering of the seizure threshold → Convulsion. ▪ Hepatotoxicity → Cholestatic jaundice. ▪ TCAs + MAOIs → sever convulsion and coma.  Mechanism of action of monoamine oxidase inhibitors (MAOIs) ❖ MAOIs → inhibit the metabolism of neurotransmitters →  levels. ❖ MAO is a mitochondrial enzyme found in CNS, liver and GI tract → inhibit metabolism of catecholamine neurotransmitter (norepinephrine, serotonin, and dopamine) →  concentration in the brain. ❖ MAO-A enzyme ❖ Present in the cytoplasm of CNS neurons → inactivation of norepinephrine or serotonin that may leak out of presynaptic storage. ❖ Block of the MAO-A enzyme → accumulate of these neurotransmitters in the vesicles → released in the synapse. ❖ MAO-B enzyme ❖ Present mainly in the CNS → it metabolizes dopamine.  Monoamine oxidase inhibitors (MAOIs) ▪ Isocarboxacid. ▪ Phenelzine. Drug subclasses ▪ Tranylcypromine. ▪ Selegiline → selectively inhibit MAO-B at low doses → anti-parkinson's disease. inhibit MAO-A and B at high doses→ antidepressant. Therapeutic ▪ Major depression → unresponsive or allergic to TCAs. indication ▪ Atypical depression → associated with phobia or psychotic features. Pharmacokinetic ▪ Well absorbed orally. ▪ Metabolised by acetylation in the liver. ▪ Require 2-4 weeks of treatment to reach steady-state plasma level. Drug-Food ▪ Hypertensive crisis → headache, hypertension, arrhythmia, possibly stroke → if combined interaction with tyramine rich food (yogurt or cheese) → inactivate by MAO. Drug-Drug When combined with SSRIs, can cause a toxic synergism called serotonin syndrome→ interaction tachycardia, hyperthermia, hypertension, tremor, diaphoresis, anxiety and agitation. Adverse effects ▪ CNS stimulation → agitation and seizure. ▪ Orthostatic hypotension. ▪ Sexual dysfunction → delayed orgasm.  Mechanism of action of selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine uptake inhibitors (SNRIs) ▪ SSRIs → inhibit reuptake of serotonin →  levels in synaptic cleft. → No significant effects on norephedrine, histamine, muscarinic, or α-adrenergic receptors. ▪ SNRIs → inhibit reuptake of norepinephrine and serotonin →  levels in synaptic cleft.  Selective Serotonin Reuptake Inhibitors (SSRIs) ▪ Fluoxetine → potent CYP450 inhibitors. Drug subclasses ▪ Paroxetine → potent CYP450 inhibitors. ▪ Sertraline → preferred antidepressant following acute MI. ▪ Fluvoxamine. ▪ Citalopram. ▪ Escitalopram. Therapeutic ▪ Major depression. indication ▪ Obsessive compulsive disorders. ▪ Generalized anxiety disorder. ▪ Well absorbed orally. Pharmacokinetic ▪ High protein binding and lipid soluble → penetrate to CNS easily. ▪ Metabolised in the liver. ▪ Excreted in the kidney. ▪ GIT upset → nausea, vomiting and diarrhea. ▪ CNS → nervousness, dizziness and insomnia. Adverse effects ▪ Sexual dysfunction → impotence and decrease libido. ▪ If abruptly stopped the treatment → discontinuation syndrome (dizziness, paresthesia, anxiety). * SSRI should be gradually tapered over 4 weeks to reduces the risk of relapse.  Serotonin/norepinephrine uptake inhibitors (SNRIs) ▪ Venlafaxine. Drug subclasses ▪ Desvenlafaxine. ▪ Duloxetine. ▪ Levomilnacipran. ▪ Milnacipran. Therapeutic indication ▪ Depression in patients for whom SSRIs are ineffective. ▪ Neuropathic pain and fibromyalgia. ▪ Well absorbed orally. Pharmacokinetic ▪ Metabolized in the liver. ▪ Excreted in the kidney. ▪ GIT upset → nausea and constipation. ▪ CNS activation → headache, dizziness, insomnia. Adverse effects ▪ Sexual dysfunction → impotence and decrease libido. ▪ Increase blood pressure and heart rate → noradrenergic effects. ▪ Abrupt discontinuation led to discontinuation syndrome (dizziness, paresthesia, anxiety) → they should be gradually tapered.  Atypical antidepressants Drug subclasses ▪ Bupropion → norepinephrine and dopamine reuptake inhibitor. and mechanism of ▪ Mirtazapine acts by: action -Block presynaptic α2 receptors → enhances the release NE and serotonin. -Block postsynaptic serotonin 5-HT2 and 5-HT3 receptors. -Potent H1 antagonist. ▪ Major depression → in patients with inadequate responses or intolerable SEs of Therapeutic SSRIs. indication ▪ Desirable characteristic → sexual side effect and weight gain → occur less often with bupropion than SSRIs. ▪ Smoking cessation → bupropion. ▪ Well absorbed orally. Pharmacokinetic ▪ Metabolized in the liver. ▪ Excreted in the kidney. ▪ Insomnia, agitation, tachycardia → bupropion. Adverse effects ▪ Marked sedation, increased appetite, weight gain → Mirtazapine.  Serotonin modulators ▪ Trazodone → inhibits serotine reuptake and blocks postsynaptic serotonin 5-HT2A Drug subclasses and receptors. mechanism of action ▪ Vilazodone → inhibits serotine reuptake and partial agonist at postsynaptic serotonin 5-HT1A receptors. ▪ Vortioxetine → inhibits serotine reuptake and full agonist at the 5-HT1A receptor. Therapeutic indication ▪ Major depressive disorder. ▪ Metabolized in the liver. Pharmacokinetic ▪ Excreted in the kidney. ▪ Nausea, vomiting. Adverse effects ▪ Dizziness. ▪ Trazodone → orthostatic hypotension due to α1 receptor blocking. ▪ Abrupt discontinuation of trazodone led to withdrawal syndrome (gastrointestinal distress, anxiety, sleep disturbances) → it should be gradually tapered.  Antimanic agents (Lithium) Mechanism of action Block enzyme inositol-1-phosphatase → affect neurotransmitters release. Therapeutic ▪ Bipolar disorders → both manic and depression episodes. indication ▪ Major depression → adjuvant with antidepressant. ▪ Schizophrenia → adjuvant with antipsychotic. ▪ Excreted by kidney: ~ 80% of Lithium is reabsorbed in the proximal tubules. Pharmacokinetic ▪ Lithium competes with Na+ for reabsorption. ▪ Lithium absorption increases with Na+ loss (e.g. diuretic use, diarrhea, dehydration). Drug-drug When combined with Fluoxetine or Paroxetine (SSRIs) →  the risk of serotonin interaction syndrome → requires monitoring. ▪ GIT upset → vomiting, abdominal cramps, diarrhea and weight gain. Adverse effects ▪ Cardiac → T wave depression. ▪ Renal → nephrogenic diabetes insipidus. ▪ Acute intoxication (CNS effects) → sever tremor, ataxia, seizures, confusion and Toxicity coma. ▪ Toxicity management: using sodium bicarbonate or dialysis. Thiazide diuretics should be avoided for lithium toxicity management. Reference ▪ Basic & clinical pharmacology, Bertram G. Ketzung, 12th edition. ▪ Lippincott Review of Pharmacology 6th edition (2014). ▪ Bertram G. Katzung, Marieke Kruidering-Hall, Anthony J. Trevor – Katzung & Trevor’s. Pharmacology. Thirteenth Edition. ▪Goodman & Gilman’s Manual of Pharmacology and Therapeutics, 5th edition. ▪Norkeviciene A, Gocentiene R, Sestokaite A, Sabaliauskaite R, Dabkeviciene D, Jarmalaite S, Bulotiene G. A Systematic Review of Candidate Genes for Major Depression. Medicina. 2022; 58(2):285. ▪Serotonin modulators: Pharmacology, administration, and side effects.