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Antidepressants.pptx
The document discusses the pathogenesis of depression, mechanisms of serotonin synthesis, reuptake, and the classification of various antidepressant drugs including SSRIs, SNRIs, and MAOIs. It details the physiological roles of serotonin in the body, its receptors, and the effects of different antidepressants on serotonin levels. Additionally, it covers general guidelines for antidepressant use, their side effects, and the implications of serotonin modulation in treating anxiety and depression.
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Antidepressants.pptx
- 1. 3rd Year Neurosciences II Antidepressants FaziaRuth Pfau Medical College Department of Pharmacology 1
- 2. Objectives: To explainpathogenesis of Depression To describe the synthesis, degradation and reuptake mechanism of 5HT To classify Antidepressant drugs To describe mechanism of action of Antidepressants. To enlist side effects of Antidepressants. Fazia Ruth Pfau Medical College Department of Pharmacology 2
- 3. The symptomsof depression are feelings of sadness and hopelessness, s well as the inability to experience pleasure in usual activities, changes in sleep patterns and appetite, loss of energy, and suicidal thoughts. Mania is characterized by the opposite behavior: enthusiasm, anger, rapid thought and speech patterns, extreme self-confidence, and impaired judgment. Fazia Ruth Pfau Medical College Department of Pharmacology 3
- 4. Serotonin: 5 HT(5 hydroxy tryptamine) Actions. SEROTONIN is an inhibitory neurotransmitter. Nerve endings: stimulates nociceptive pain mediating nerve endings 5HT3 receptors. CNS: it accounts for 1% of 5HT total body content. Involved in sleep, appetite, thermoregulation & pain perception. Serotonin are necessary for a stable mood and to balance any excessive excitatory (stimulating) neurotransmitter firing in the brain. Stimulant medications or caffeine can cause a depletion of serotonin over time. Serotonin also regulates many other processes such as carbohydrate cravings, sleep cycle, pain control and appropriate digestion. Fazia Ruth Pfau Medical College Department of Pharmacology 4
- 5. Serotonin: 5 HT(5 hydroxy tryptamine) Synthesis: Tryptophan – tryptophan hydroxylase(enzyme limited to 5HT producing cells) – 5 hydroxy tryptophan in chromaffin cells & neurons – decarboxylase – 5HT (5hydroxytryptamine). Degradation: by Monoamine oxidase inhibitor(MAO-A) – 5HIAA (5hydroxyindoleacetic acid) – excreted in urine. Serves as marker of 5HT production as diagnostic evidence in carcinoid syndromes. 5HT is transported into cells by SERT (serotonin uptake transporters) Fazia Ruth Pfau Medical College Department of Pharmacology 5
- 6. Serotonin: 5 HT(5 hydroxy tryptamine) Found in following 3 places. In the walls of intestine 90 - 98% as enterochromaffin cells which are endocrine cells mainly in stomach and small intestine in between mucosal cells. Some in myenteric plexuses where it act as excitatory neurotransmitter High conc in platelets – get uploaded with 5HT when they pass through intestinal circulation which has high conc of 5HT – released when platelets aggregate at site of injury. CNS – present in and around mid brain In GIT it facilitates peristalsis, secretions, & visceral sensitivity. SERT rapidly removes 5HT & thereby limiting its actions. SSRI’s used in psychiatry therefore increases 5HT in intestines & causes side effects of diarrhea. Causes smooth muscle contraction. Blood vessels: Large vessels both arteries & veins – constricted (5 HT2A) 5 HT endothelial cells – NO – decrease noradrenaline – vasodilatation, if damaged by atherosclerosis – vasoconstriction Fazia Ruth Pfau Medical College Department of Pharmacology 6
- 7. Receptors All areG protein coupled receptors except 5HT3 - ligand gated cation channel. 5HT1 are inhibitory. 5HT1A in raphe nucleus+ limbic system – targets for treating depression & anxiety. 5HT1B + 5HT1D in basal ganglia & cortex – agonist of 5HT1D used to treat migraine. 5HT2 (5HT2A + 5HT2C) – cortex & limbic system located at both pre & post synaptic sites – target of some antidepressants and methsergide for migraine. 5HT3 are ligand gated cation channels (Ionotropic)found in postrema a region of medulla involved in vomiting & other parts of brain stem – excitatory inotropic - specific antagonist like ondansetron – treatment of nausea & vomiting 5HT4 - GIT, limbic system, basal ganglia, hippocampus, substantia nigra – pre & post synaptic sites – exert facilitatory effect on ACh release – enhances cognitive performance. 5HT6 in CNS – hippocampus cortex & limbic system – potential targets to improve cognition. 5HT7 – thermoregulation & endocrine regulation + mood, cognition & sleep. Fazia Ruth Pfau Medical College Department of Pharmacology 7
- 8. Receptors 5HT4 -GIT, limbic system, basal ganglia, hippocampus, substantia nigra – pre & post synaptic sites – exert facilitatory effect on ACh release – enhances cognitive performance. 5HT6 in CNS – hippocampus cortex & limbic system – potential targets to improve cognition. 5HT7 – thermoregulation & endocrine regulation + mood, cognition & sleep. Fazia Ruth Pfau Medical College Department of Pharmacology 8
- 9. Antidepressants SSRI’s SNRI’s 5-HT2 ANTAGONIST TRICYCLICS TETRACYCLICS MAOI’ Fazia Ruth Pfau Medical College Departmentof Pharmacology 9 SARI (serotonin adrenaline reuptake inhibitors) Classification
- 10.
- 11. SSRIs Fazia Ruth Pfau Medical College Departmentof Pharmacology 11 Selective Serotonin reuptake inhibitor (SSRI) occupies the serotonin reuptake pump (the serotonin transporter, or SERT), causing an antidepressant effect. Common property of serotonin transporter (SERT) inhibition.
- 12. Fazia Ruth Pfau Medical College Departmentof Pharmacology 12
- 13. General guidelines forantidepressant use Antidepressant efficacy is similar so selection is based on past history of a response, side effect profile and coexisting medical conditions. There is a delay typically of 3-6 weeks after a therapeutic dose is achieved before symptoms improve. If no improvement is seen after a trial of adequate length (at least 2 months) and adequate dose, either switch to another antidepressant or augment with another agent. Fazia Ruth Pfau Medical College Department of Pharmacology 13
- 14. Fazia Ruth Pfau Medical College Departmentof Pharmacology 14 Released 5HT activates pre & post synaptic receptors and undergoes reuptake by presynaptic neuron In presence of TCA, SSRI or SNRI reuptake is blocked and 5HT increases in synapse. With continued use of TCA, SSRI or SNRI the increased synaptic 5HT cause down regulation of presynaptic auto receptors and an increase in firing rate of raphe neurons
- 15. Fluoxetine (Prozac) Fluoxetine(half life 2.5 days) is well absorbed and metabolized to norfluoxetine Pros Long half-life so decreased incidence of discontinuation syndromes. Good for pts with medication noncompliance issues Cons Long half life and active metabolite may build up (e.g. not a good choice in patients with hepatic illness) Significant P450 (inhibition) interactions so this may not be a good choice in pts already on a number of medicines. Initial activation may increase anxiety and insomnia Fazia Ruth Pfau Medical College Department of Pharmacology 15 In addition to serotonin reuptake inhibition, fluoxetine has norepinephrine reuptake inhibition (NRI) and serotonin 2C (5HT2C) antagonist actions. Fluoxetine’s activating effects may be due to its actions at 5HT2C receptors. Norepinephrine reuptake inhibition may be clinically relevant only at very high doses.
- 16. Citalopram (Celexa) Pros Low inhibition of P450 enzymes so fewer drug-drug interactions Intermediate ½ life Cons Dose-dependent QT interval prolongation with doses of 10- 30mg daily- due to this risk doses of >40mg/day not recommended! GI side effects (less than sertraline) Escitalopram (Lexapro) Fazia Ruth Pfau Medical College Department of Pharmacology 16 The S enantiomer of citalopram has been developed and marketed as the antidepressant Escitralopram. More effective than Citalopram in acute response and remission Citalopram consists of two enantiomers, R and S. The R enantiomer has weak antihistamine properties and is a weak inhibitor of CYP2D6. Can be sedating (has mild antagonism at H1 histamine receptor) The R and S enantiomers of citalopram are mirror images of each other but have slightly different clinical properties. The R enantiomer has weak antihistamine property and weak inhibition of CYP 2D6, while the S enantiomer does not have these properties. The R and S enantiomers also differ in their effects at serotonin transporter.
- 17. SELECTIVE SEROTONIN REUPTAKEINHIBITORS. (Common Adverse Effects) Fazia Ruth Pfau Medical College Department of Pharmacology 17
- 18. Serotonin/Norepinephrine reuptake inhibitors (SNRIs) SNRIs have two and half actions: 1-Block SERT increase 5-HT in all brain areas. 2-Block NET increase NE in all brain areas. ½- Block NET increase DA in Prefrontal Cortex Inhibit both serotonin and noradrenergic reuptake like the TCAS but without the antihistamine, antiadrenergic or anticholinergic side effects Used for depression, anxiety and possibly neuropathic pain Fazia Ruth Pfau Medical College Department of Pharmacology 18
- 19. Venlafaxine & Desvenlafaxine Pros Minimal drug interactions. Short half life and fast renal clearance avoids build-up (good for geriatric populations) Cons Can cause a 10-15 mmHG dose dependent increase in diastolic BP. May cause significant nausea, primarily with immediate- release (IR) tabs Can cause a bad discontinuation syndrome, and taper recommended after 2 weeks of administration Noted to cause QT prolongation Sexual side effects in >30% Fazia Ruth Pfau Medical College Department of Pharmacology 19 Venlafaxine inhibits reuptake of both serotonin (SRI) and norepinephrine (NRI), thus combining two therapeutic mechanisms in one agent. Venlafaxine’s serotonergic actions are present at low doses, while its noradrenergic actions are progressively enhanced as dose increases. Venlafaxine is converted to its active metabolite, desvenlafaxine, by CYP 2D6.
- 20. Monoamine Oxidase Inhibitors(MAOIs) Bind irreversibly to monoamine oxidase thereby preventing inactivation of biogenic amines such as norepinephrine, dopamine and serotonin leading to increased synaptic levels. Are very effective for depression Side effects include orthostatic hypotension, weight gain, dry mouth, sedation, sexual dysfunction and sleep disturbance Hypertensive crisis can develop when MAOI’s are taken with tyramine-rich foods or sympathomimetics. Serotonin Syndrome can develop if MAOI given with meds that increase serotonin or have sympathomimetic actions. Serotonin syndrome include abdominal pain, diarrhea, sweats, tachycardia, HTN, myoclonus, irritability, delirium. Can lead to hyperpyrexia, cardiovascular shock and death. To avoid need to wait 2 weeks before switching from an SSRI to an MAOI. The exception of fluoxetine where need to wait 5 weeks because of long half-life. Fazia Ruth Pfau Medical College Department of Pharmacology 20
- 21. This means thatMAO-A inhibition increases 5HT, NE, and DA but that the increase in DA is not as great as that of 5HT and NE. Inhibition of MAO-A is an efficacious antidepressant strategy. Fazia Ruth Pfau Medical College Department of Pharmacology 21 MAO-A metabolizes serotonin (5HT) and norepinephrine (NE) as well as dopamine (DA). Monoamine oxidase B (MAO-B) also metabolizes DA, but it metabolizes 5HT and NE only at high concentrations. Monoamine oxidase A
- 22. However, inhibition ofMAO-B does increase DA to some extent, which can be therapeutic in other disease states, such as Parkinson’s disease. Fazia Ruth Pfau Medical College Department of Pharmacology 22 Monoamine oxidase B Selective inhibitors of MAO-B do not have antidepressant efficacy, because MAO-B metabolizes serotonin (5HT) & norepinephrine (NE) only at high concentrations Since MAO-B’s role in destroying 5HT and NE is small, its inhibition is not likely to be relevant to the concentrations of these neurotransmitters Selective inhibition of MAO-B also has somewhat limited effects on dopamine (DA) concentrations, because MAO-A continues to destroy DA.
- 23. Combined inhibition ofMAO-A and MAO-B may have marked antidepressant actions owing to increases not only in serotonin (5HT) and norepinephrine (NE) but also dopamine (DA). Fazia Ruth Pfau Medical College Department of Pharmacology 23
- 24. Benzodiazapines Used totreat insomnia, parasomnias and anxiety disorders. Often used for CNS depressant withdrawal protocols ex. ETOH withdrawal. Side effects/cons Somnolence Cognitive deficits Amnesia Disinhibition Tolerance Dependence Fazia Ruth Pfau Medical College Department of Pharmacology 24
- 25. Fazia Ruth Pfau Medical College Departmentof Pharmacology 25
- 26. (B) When GABAbinds to its sites on GABAA receptor, it increases frequency of opening of chloride channel and thus allows more chloride to pass through. (D) When a positive allosteric modulator such as a benzodiazepine binds to the GABAA receptor in presence of GABA, it causes the channel to open even more frequently than when GABA alone is present. Positive allosteric modulation of GABAA receptors. (A) Benzodiazepine-sensitive GABAA receptors, consist of five subunits with a central chloride channel and have binding sites not only for GABA but also for positive allosteric modulators like benzodiazepines (C) When a positive allosteric modulator such as benzodiazepine binds to GABAA receptor in absence of GABA, it has no effect on the chloride channel. Flumazenil - BDZ receptor antagonist is able to reverse a full agonist BDZ acting at its site on GABAA receptor. This may be helpful in reversing the sedative effects of full agonist benzodiazepines when administered for anesthetic purposes or when taken in overdose by a patient. Fazia Ruth Pfau Medical College Department of Pharmacology 26
- 27. (C) Agents thatbind to the α2δ subunit of presynaptic N and P/Q voltage- sensitive calcium channels can block excessive release of glutamate in amygdala & thereby reduce anxiety. Potential therapeutic actions of anxiolytics on anxiety / fear. (A) Pathological anxiety/fear may be caused by over activation of amygdala circuits (B) GABAergic agents such as benzodiazepines may alleviate anxiety/ fear by enhancing phasic inhibitory actions at postsynaptic GABAA receptors within the amygdala. (D) The amygdala receives input from serotonergic neurons, which can have an inhibitory effect on some of its outputs. Thus, serotonergic agents may alleviate anxiety/fear by enhancing serotonin input to the amygdala. Fazia Ruth Pfau Medical College Department of Pharmacology 27
- 28. (D) Prefrontal cortex,striatum, & thalamus receive input from serotonergic neurons, which can have an inhibitory effect on output. Thus, serotonergic agents may alleviate worry by enhancing serotonin input within CSTC circuits. Hyperactive CSTC Circuits and Worry Potential therapeutic actions of anxiolytics on worry (A) Pathological worry may be caused by over activation of corticostriato-thalamo-cortical (CSTC) circuits. (B) GABAergic agents such as BDZ may alleviate worry by enhancing actions of inhibitory GABA interneurons within prefrontal cortex. (C) Agents that bind to α2δ subunit of presynaptic N and P/Q voltage-sensitive calcium channels can block excessive release of glutamate in CSTC circuits and thereby reduce worry. Fazia Ruth Pfau Medical College Department of Pharmacology 28
- 29. 5HT1A partial agonistssuch as buspirone may reduce anxiety by actions both at presynaptic somatodendritic autoreceptors and at postsynaptic receptors. The onset of action of buspirone, like that of antidepressants, is delayed, suggesting that the therapeutic effects are actually related to downstream adaptive changes rather than acute actions at these receptors. Noradrenergic hyperactivity in worry. Delayed Therapeutic Actions of NET Inhibitors Hyperactive CSTC Circuits and Worry 5HT1A Partial Agonist (SPA) Actions in Anxiety (B) Noradrenergic hyperactivity in CSTC circuits may be blocked by administration of a norepinephrine transporter (NET) inhibitor, which can have downstream effect of downregulating β1-adrenergic receptors. Reduced stimulation via β1-adrenergic receptors could therefore lead to alleviation of worry (A) Pathological worry may be caused by over activation of cortico-striato-thalamo-cortical (CSTC) circuits. Specifically, excessive noradrenergic activity within these circuits can reduce efficiency of information processing and theoretically cause worry.. Fazia Ruth Pfau Medical College Department of Pharmacology 29
- 30. (B) Noradrenergic hyperactivity is blockedby α1- adrenergic blockers, which can lead to alleviation of anxiety and other stress-related symptoms. Noradrenergic hyperactivity in anxiety/fear. (A) Norepinephrine provides input not only to amygdala but also to many regions to which the amygdala projects; thus it plays an important role in the fear response. Noradrenergic hyperactivation can lead to anxiety, panic attacks, tremors, sweating, tachycardia, hyperarousal, and nightmares. α1- and β1-adrenergic receptors may be specifically involved in these reactions. (C) Noradrenergic hyperactivity may also be blocked by administration of a norepinephrine transporter (NET) inhibitor, which can have the downstream effect of downregulating β1-adrenergic receptors. Reduced stimulation via β1-adrenergic receptors could therefore lead to alleviation of anxiety and stress-related symptoms. Fazia Ruth Pfau Medical College Department of Pharmacology 30
- 31. Fazia Ruth Pfau Medical College Departmentof Pharmacology 31
- 32. Fazia Ruth Pfau Medical College Departmentof Pharmacology 32
- 33. TCAs All tricyclicantidepressants block reuptake of norepinephrine and are antagonists at H1-histaminic, α1-adrenergic, and muscarinic cholinergic receptors; they also block voltage-sensitive sodium channels (A, B, and C). Some tricyclic antidepressants are also potent inhibitors of the Serotonin reuptake pump (A), and some may additionally be antagonists at Serotonin 2A and 2C receptors (C). Side chains are prone to cross react with other types of receptors which leads to more side effects including antihistaminic (sedation and weight gain), anticholinergic (dry mouth, dry eyes, constipation, memory deficits and potentially delirium), antiadrenergic (orthostatic hypotension, sedation, sexual dysfunction) Act predominantly on serotonin receptors Examples: Imipramine, amitriptyline, doxepin, clomipramine Have long half lives ranging from 18-20 hrs. Fazia Ruth Pfau Medical College Department of Pharmacology 33
- 34. SRI Inserted NRI Inserted 5HT2AInserted 5HT2C Inserted TCA’s Actions Side effects Fazia Ruth Pfau Medical College Department of Pharmacology 34
- 35. TCAs Very effectivebut potentially unacceptable side effect profile i.e. antihistaminic, anticholinergic, antiadrenergic Lethal in overdose (even a one week supply can be lethal!) Can cause QT lengthening even at a therapeutic serum level Fazia Ruth Pfau Medical College Department of Pharmacology 35
- 36. DRUG SEDATION ANTICHOLINERGIC EFFECTS ORTHOSTATIC HYPOTENSION CARDIACCONDUCTION DISTURBANCES Tricyclic Antidepressants (TCAs) Amitriptyline ++++ ++++ +++ +++ Clomipramine ++++ ++++ ++ +++ Desipramine ++ ++ ++ ++ Imipramine +++ +++ +++ +++ Nortriptyline ++ ++ ++ ++ Selective Serotonin Reuptake Inhibitors (SSRIs) Fluoxetine 0 0 0 0 Fluvoxamine + 0 0 0 Paroxetine + + 0 0 Sertraline 0 0 0 0 Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) Venlafaxine + + 0 + Monoamine Oxidase Inhibitors (MAOIs) Phenelzine ++ ++ ++ + Tranylcypromin e + ++ ++ + ADVERSE EFFECTS OF ANTIDEPRESSANT DRUGS Fazia Ruth Pfau Medical College Department of Pharmacology 36
- 37. TETRACYCLIC antidepressants Mirtazapine (Remeron) It is an antagonist of presynaptic alpha 2 autoreceptor and enhances the release of both nor epinenephrine & 5-HT. It is an antagonist of 5-HT2 & 5-HT3 receptor. It is potent agonist of H1 receptor and thus produce sedation. Pros Different mechanism of action may provide a good augmentation strategy to SSRIs. Is a 5HT2 and 5HT3 receptor antagonist Cons Increases serum cholesterol and triglycerides by 20% in 15% in upto 6% of patients Associated with weight gain. Fazia Ruth Pfau Medical College Department of Pharmacology 37
- 38. SUMMARY Fazia Ruth Pfau Medical College Departmentof Pharmacology 38
- 39. Take home points Be clear on the diagnosis you are treating and any comorbid diagnoses when you are selecting an agent to treat- often can get 2 birds with 1 stone! Select the agent based on patients history, current symptom profile and the side effect profile of the medication- there is no one correct answer in most cases. Monitor for efficacy and tolerance and adjust as indicated. If the patient does not improve step back, rethink your diagnosis and treatment plan! Keep an eye on drug-drug interactions Fazia Ruth Pfau Medical College Department of Pharmacology 39 1. Basic & Clinical Pharmacology by Katzung 13th edition. 2. Rang & Dale Pharmacology 8th edition. 3. Pharmacology by Brenner 3rd edition. 4. Board review series Pharmacology 5th edition. 5. Netters Pharmacology. 6. Stahl’s Psychopharmacology 4th edition.