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Pp antidepressants final
This document provides information on drugs used to treat depression. It begins by classifying various types of antidepressants including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs). It then describes the pharmacological actions and side effects of these different classes of antidepressants. Finally, it discusses the clinical uses and limitations of antidepressant therapies in managing conditions like depression, anxiety disorders, and bipolar disorder.
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Pp antidepressants final
- 1. Drugs used toTreat Depression
- 2. At the endof the session, student will be able to • Classify antidepressants with examples. • Describe the pharmacological actions of TCs. • Enumerate TCs and mention their ADR • Enumerate SSRIs and SSNRIs • Describe the role of drug therapy in management of endogenous depression.
- 3. Definition of Depression “Anaffective disorder characterized by loss of interest or pleasure in almost all a person’s usual activities or pastimes”
- 4. What Is Depression? •Range of symptoms – Negative views – Worthlessness – Incapacity – Guilt – Sleep disturbance – Diurnal mood variation – Loss of energy – Impaired concentration
- 5. What Is Depression? –Impairedwork ability –Poor social functioning –Psychomotor retardation –Pessimism –Better off dead –Thoughts of suicide –Suicide / action –Fear / belief of bodily illness
- 6. Vulnerabilities • Losses • Stressfullife events • Lack of social support • Physical illness • Familial factors • Genetic factors
- 7. DEPRESSION • Major depressionand mania are two affective disorders with mood changes. • Depression is characterized by sad mood, loss of interest in self and surroundings, low energy, guilt, agitation, worthlessness , loss of appetite, sleep, melancholia. • In bipolar disease there are swings of moods from mania to depression. • Anti depressants are the drugs which elevate mood in depressive illness.
- 8. Symptoms Associated WithDepression Sadness, Despair, Guilt, Pessimism Decrease in energy Decrease in sex drive Insomnia and fatigue Thoughts of death and suicide Mental slowing, lack of concentration
- 9. Evolution of drugtherapy Antidepressants discovered accidentally while investigating antipsychotic efficacy of structural modification of phenothiazines Imipramine - first antidepressant discovered Around the same time, MAOI were identified
- 10. Classification of Antidepressants •Tricyclic antidepressents: Imipramine, Desipramine, Amitrptyline, Nortriptyline, Doxepin, dothiepin • SSRI: Fluoxetine, Paroxetine, Fluvoxamine.sertraline,citalopram, Escitalopram • MAO-A inhibitors: Clorgyline, moclobemide • Atypical Antidepressants: Trazodone, Bupropion, Mianeserin,duloxetine. • Newer Antidepressants: Nefazodone, Venlafaxine, Reboxitine.
- 11. Classification of antidepressants 1.Block both NE and 5HT uptake inhibitors: Imipramine, Amitriptyline, Desipramine, Nortriptyline- Tricyclic antidepressents 1. Selective Serotonin Reuptake inhibitors (SSRI): Sertraline, Fluoxetine, Citalopram, escitalopram, fluoxamine 3. Selective Serotonin norepinephrine reuptake inhibitors (SSNRIs): Venlafaxine, Desvenlafaxine,
- 12. Classification of antidepressants 4.Atypical antidepressants: Mianserine, Bupropion, amineptine 5. MAOI – Non-selective: Tranylcypromine – Selective (MAO-A): Moclobemide 4. Natural products – St.John’s wort
- 13. Tricyclic Antidepressants (TCA) Prototype: Imipramine and Amitriptyline Desipramine – pharmacologically active intermediate metabolite of imipramine Nortriptyline – an active intermediate metabolite of amitriptyline
- 14.
- 15. Pharmacokinetics Well absorbedupon oral administration Relatively long half-lives Metabolized in the liver Converted into intermediates that are later detoxified Readily cross the placenta
- 16. Properties of TCA Effectively relieve depression with anxiolytic and analgesic action Pharmacological properties – Block presynaptic NE reuptake transporter – Block presynaptic 5-HT reuptake transporter – Block postsynaptic histamine receptors – Block postsynaptic ACh receptors
- 17. Tricyclic Antidepressant m1 H1 α1 SRI NRI Receptor interaction Tremor, tachycardia, erectile/ejaculatory dysfunction, increasedpressure effects GIT disturbances, increased anxiety, EP, sexual dysfunction CNS sedation, Wt gain, hypotension Blurred vision,, dryness of mouth, urinary inconsistency, constipation
- 18. Drug interaction • Proteinbinding: TCAs get displaced by powerful protein binding drugs • Potentiation: –CNS depressants –Sympathomimetics –anticholinergics
- 19. Clinical uses ofTCA • Depression, PTSD (post-traumactic stress disorder),OCD (obsessive compulsive disorder), ADHD (attention defecit hyperkinetic disorder), • Anxiety disorders, dysthymia, chronic (neuropathic) pain, enuresis, migraine and behavioral problems in children, obesity, alcohol abuse, etc.
- 20. Treatment of toxicity Physostigmine: counteract mucarinic side effects Bicarbonate: counteract acidosis, promote excretion Diazepam: counteract convulsion Lignocaine/ propranolol: arrhythmias Gastric lavage: Supportive measure: respiration, blood volume
- 21. Clinical Limitations ofTCA’s Slow onset of action (3 wks) Wide variety of effects on CNS (adverse side effects): – Can directly impair attention, motor speed, dexterity, and memory Cardiotoxic and potentially fatal in overdoses
- 22. Serotonin Specific ReuptakeInhibitors (SSRI’s) Allows for more serotonin to be available to stimulate postsynaptic receptors Available to treat depression, anxiety disorders, PTSD (post- traumactic stress disorder),OCD (obsessive compulsive disorder), ADHD (attention defecit hyperkinetic disorder), obesity, alcohol abuse, childhood anxiety, etc. SRI SSRI
- 23.
- 24. Advantages of SSRIsover TCAs Less sedation Onset is faster Long duration Minimum CVS side effects Bearable anticholinergic side effect: so preferred in geriatrics Wide safety margin
- 25. SSRIs • Fluoxetine –first SSRI available, long half life due to its active metabolite (norfluoxetine), onset of action compared to TCA faster, can cause sexual dysfunction, anxiety, insomnia and agitation • Sertraline – low risk of toxicity, few interactions, more selective and potent than Fluoxetine • Fluvoxamine – structural derivative of Fluoxetine, short acting, also treats PTSD, dysphoria, panic disorder, and social phobia
- 26. SSRIs • Paroxetine –more selective than Fluoxetine, highly effective in reducing anxiety and post traumatic stress disorder (PTSD) as well as OCD, panic disorder, social phobia, premenstrual dysphoric disorder, and chronic headache
- 27. SSRI’s • Citalopram –well absorbed orally, few drug interactions, treats major depression, social phobia, panic disorder and OCD • Escitalopram – more potent than citalopram
- 28. Adverse effects (SSRIs) •Headache, nervousness, dizziness, insomnia, • Nausea, vomiting, weight loss, sweating, rash, pharyngitis, • Painful menstruation in females • Sexual dysfunction/ejaculatory problem in males
- 29. Serotonin syndrome At highdoses or combined with other drugs an exaggerated response can occur – This is due to increased amounts of serotonin – Alters cognitive function, autonomic function and neuromuscular function – Potentially fatal
- 30. Serotonin withdrawal syndrome –Withdiscontinuation of any SSRI onset of withdrawal symptoms occur within a few days and can persist 3-4 weeks –Symptoms: disequilibrium, gastrointestinal problems, flu-like symptoms, sensory disturbances, sleep disturbances
- 31. SSNRIs • Inhibit uptakeof NE and 5HT (similar to TCAs) • No anticholinergic action, no adrenergic blocking, no antihistaminic actions ( not similar to TCAs) • Many side effects reduced • Examples: Venlafaxine, Desvenlafaxine
- 32. Monoamine Oxidase Inhibitors(MAOIs) Long acting, irreversible inhibitors of monoamine oxidase Have been used since the 1950’s Has potential for serious side effects and potentially fatal interactions with other drugs and food MAO : two types: MAO-A metabolizes NE, 5HT; MAO-B metabolizes dopamine MAOI-A: antidepressant activity MAOI-B: antiparkinson activity
- 33. Irreversible MAOI’s Nonselective: blockboth A and B types Enzyme function returns only as new enzyme is biosynthesized Inhibition occurs slowly No use currently – Ex: phenelzine (Nardil), tranylcypomine (Parnate), isocarboxazid (Marplan)
- 34. Atypical antidepressant • Modeof action and chemical configurations are diversified. • Mianserin: Cholinergic, histaminic, α2 blocker, no inhibition of NE and 5HT uptake. • Trazodone: Mild serotonin uptake inhibitor, α-blocker, not anticholinergic
- 35. MAO Inhibitors • Examples:Clorgyline, Tranylcypromine, Moclobemide • MAO is an enzyme which metabolizes Adrenaline, NA, DA, 5HT • Isoenzymes – MAO-A deaminates 5HT & NA: • Present in peripheral adrenergic nerve endings, intestinal mucosa – MAO-B deaminates phenyl ethylamine : • Present in brain, placenta and liver – Dopamine is degraded by both isoenzymes
- 36. Reversible MAOI’s Highly selectivein inhibiting MAO-A Much safer than irreversible MAOIs Side effects are minimal – Ex: Brofaromine, Pirlindole, Toloxatone, and Moclobemide
- 37. Reversible inhibitors ofMAO-A (RIMAs) Moclobemide: – Reversible & selective MAO –A inhibitor with short duration of action – Activity restored in 1-2 days of stoppage – Effective antidepressant equal to TCA – No anticholinergic, sedative, cognitive, psychomotor & CVS adverse events – Safe in overdose – Use: elderly & heart patients – Well tolerated in mild to moderate depression and in social phobia
- 38. • Cheese reaction: Withfoods like cheese , wine beer, yogurt, ripe bananas etc. • Serotonin syndrome: Hyperthermia,restlesssness,sweating,mus cular rigidity, aggressive behaviour, tremors, seizures coma.
- 39. Atypical Antidepressants • Drugs: –Trazodone – Mianserin – Bupropion – Venlafaxine – Mirtazepine
- 40. Therapeutic uses of antidepressents •.Endogenous depression (TCA’s are most effective) Moclobemide better tolerated for mild or moderate depression Maintainance dose of imipramine is 100mg/day • ECT • TCA/SSRIs+lithium carbonate in bipolar disease
- 41. Uses contd.. • Obsessivecompulsive /phobia states. SSRIs drug of choice ex:Bulmia nervosa • Anxiety states • ADHD • Enuresis in children • Migraine • Neuropathic pain in diabetes • Pruritis: Topical doxepin is used in releiving itching in atopic dermatitis
- 42. Antimaniac drugs (Mood stabilizingdrugs) • Lithium carbonate: monovalent cation. • Actions and mechanism: CNS-In acute mania it suppresses episode in 1-2 weeks. • Continued use prevents cyclic mood changes • Mood stablizer and normalises sleep pattern. • Mechanism / hypothesis: Li+ replaces Na+ and is distributed equally inside/outside of cell. • It corrects the imbalance of brain monoamines (normalises DA levels in limbic system) • Li + inhibits hydrolysis of inositol-po4 .
- 43. Site of actionof lithium
- 44. • Therefore depletesIP3 and DAG , thus reducing the hyperactivity of neurons • Other actions:insulin like actions, decreases thyroxine synthesis, causes diabetes incipidus. • Pharmacokinetics:narrow margin of safety • monitor 0.8-1.1 meq/l lithium • Uses: • 1.acute maniac episodes • 2.Bipolar disease. • 3.Recurrent unipolar depression
- 45. Lithium contd…. • Adverseeffects:CNS toxicity as tremors, giddiness, ataxia, delirium, twitchings, and convulsions. • Contraindications: In pregnancy - foetal goiter
- 46. • Trazodone: • Firstatypical antidepressant • Better tolerated & safe • Blocks 5HT uptake & α-receptors also has 5HT2 antagonist action • Sedative & anxiolytic • No seizures, arrhythmias, and anti-cholinergic S/E • Suited for elderly • Better tolerated and safe in overdose • Due to α-blockade : Postural hypotension, impotence, priapism
- 47. • Mainserin: • Itblocks presynaptic α2 receptors, ↑ NA in the brain • Does not inhibit NA/5HT uptake • Blocks 5HT2, 5HT1C, & H1 receptors • Sedative (relieves anxiety & panic attacks) • Side effects: – Mild anticholinergic & cardiac effects – ↑↑ seizures – Blood dyscrasias & liver dysfunction ( reduced use).
- 48. • Venlafaxine: • Novelantidepressent • Serotonin & NA Reuptake inhibitor (SNRI) • No: cholinergic, adrenergic or histaminergic receptor interaction and no sedation • Rapid onset of action • ↑ BP • S/E: – Nausea, sweating, anxiety, dizziness, impotence
- 49. Bupropion • Inhibits DAand NA uptake • Has excitant effect and no sedative property • Use: – Nicotine/ smokers to reduce the withdrawal symptoms • Side effects: – Insomnia, agitation, dry mouth, nausea – ↑ seizures
- 50. • Mirtazepine: • Blocksα2 auto and hetero 5HT receptors • ↑ NA and 5 HT release • Labeled as Noradrenergic and Specific Serotonergic Antidepressants (NASSA) • It has Histamine blocker activity • No anticholinergic, antidopaminergic effect • Efficacy: mild to severe depression effects seen after 1 week
- 51.
- 52. Normal versus PathologicAnxiety • Normal anxiety is adaptive. It is an inborn response to threat or to the absence of people or objects that signify safety can result in cognitive (worry) and somatic (racing heart, sweating, shaking, freezing, etc.) symptoms. • Pathologic anxiety is anxiety that is excessive, impairs function.
- 53. Anxiety disorders • Specificphobia • Social anxiety disorder (SAD) • Panic disorder (PD) • Agoraphobia • Generalized anxiety disorder (GAD) • Anxiety Disorder due to a General Medical Condition • Substance-Induced Anxiety Disorder • Anxiety Disorder NOS
- 54. Social Anxiety Disorder(SAD) • Marked fear of one or more social or performance situations in which the person is exposed to the possible scrutiny of others and fears he will act in a way that will be humiliating • Exposure to the feared situation almost invariably provokes anxiety • Anxiety is out of proportion to the actual threat posed by the situation • The anxiety lasts more than 6 months • The feared situation is avoided or endured with distress • The avoidance, fear or distress significantly interferes with their routine or function
- 55. Incidence of socialanxiety disorders and the consistent risk for secondary depression in the first three decades of life. Arch Gen Psychiatry 2007 Mar(4):221-232 SAD epidemiology • 7% of general population • Age of onset teens; more common in women. Stein found half of SAD patients had onset of sx by age 13 and 90% by age 23. • Causes significant disability • Increased depressive disorders
- 56. A Panic Attackis: • Palpitations or rapid heart rate • Sweating • Trembling or shaking • Shortness of breath • Feeling of choking • Chest pain or discomfort • Nausea • Chills or heat sensations • Paresthesias • Feeling dizzy or faint • Derealization or depersonalization • Fear of losing control or going crazy • Fear of dying A discrete period of intense fear in which 4 of the following Symptoms abruptly develop and peak within 10 minutes:
- 57.
- 58. Agoraphobia • Marked fearor anxiety for more than 6 months about two or more of the following 5 situations: – Using public transportation – Being in open spaces – Being in enclosed spaces – Standing in line or being in a crowd – Being outside of the home alone
- 59.
- 60. CLASSIFICATION • Benzodiazepines –Short acting: Triazolam, Oxazepam, Midazolam –Intermediate acting : Lorazepam, Alprazoram, Temazepam, Nitrazepam –Long acting : Diazepam, Flurazepam, Clonazepam, Chlordiazepoxide
- 61.
- 62. • Barbiturates –Long acting: Phenobarbitone, Mephobarbitone anticonvulsants –Short acting : Pentobarbitone, Secobarbitone, Amobarbitone hypnotics –Ultra-short acting : Thiopentone, Methohexitone inducing agent in general anesthesia
- 63. • Miscellaneous Group –Melatonin – Ramelteon – Hydroxyzine – Promethazine – Chloral hydrate – Meprobamate – Methaqualone – Paraldehyde Earlier drugs and no longer used
- 64.
- 65. Short Acting Triazolam Oxazepam Midazolam Intermediate Acting Alprazolam Estazolam Temazepam Lorazepam Nitrazepam LongActing Diazepam Flurazepam Clonazepam Chlordiazepoxide
- 67. Agonist = Facilitate •Benzodiazepines bind to a site near the GABA binding site thus facilitating the action of GABA
- 68. BenzodiazepinesBenzodiazepines Bind to specificsite on GABA-A-BZD receptor Chloride ion channel complex Increase the frequency of opening of chloride ion channels Increase in GABA-mediated chloride conductance Membrane hyperpolarization CNS Depression
- 69.
- 70. A.A. SEDATION &HYPNOSISSEDATION & HYPNOSIS BZDs decrease time required to fall asleep.BZDs decrease time required to fall asleep. Reduce night awakenings & produce refreshing sleepReduce night awakenings & produce refreshing sleep B.B. ANTIANXIETY (ANXIOLYTIC) EFFECTANTIANXIETY (ANXIOLYTIC) EFFECT Commonly used –Commonly used – Alprazolam, Lorazepam, Oxazepam,Alprazolam, Lorazepam, Oxazepam, Diazepam, ChlordiazepoxideDiazepam, Chlordiazepoxide C.C. PREANAESTHETIC MEDICATION & INDUCTION OFPREANAESTHETIC MEDICATION & INDUCTION OF ANAESTHESIAANAESTHESIA Generally used –Generally used – Diazepam, Lorazepam, MidazolamDiazepam, Lorazepam, Midazolam IV MidazolamIV Midazolam is most frequently used as it produces higheris most frequently used as it produces higher degree of amnesia, more rapid onset with shorter durationdegree of amnesia, more rapid onset with shorter duration of action.of action.
- 71. D.D. MUSCLE RELAXANTMUSCLERELAXANT Reduce muscle tone by inhibiting polysynaptic reflexes in the spinalReduce muscle tone by inhibiting polysynaptic reflexes in the spinal cord.cord. DiazepamDiazepam is preferred.is preferred. E.E. ANTICONVULSANTSANTICONVULSANTS Diazepam (slow IV)Diazepam (slow IV) andand Clonazepam (slow IV)Clonazepam (slow IV) are used to treatare used to treat statusstatus epilepticusepilepticus.. ClonazepamClonazepam may also be used formay also be used for myoclonic/petit mal seizuresmyoclonic/petit mal seizures.. Slow IV DiazepamSlow IV Diazepam can be used tocan be used to prevent tetanic spasm.prevent tetanic spasm. F.F. TO TREAT ALCOHOL WITHDRAWALTO TREAT ALCOHOL WITHDRAWAL Diazepam, Oxazepam, ChlordiazepoxidesDiazepam, Oxazepam, Chlordiazepoxides
- 72. Summary……Summary…… D Diagnostic &minor operative procedures I Insomnia A Anticonvulsant Z - E Epilepsy P Preanaesthetic medication A Antianxiety M Muscle relaxant
- 73. ADVANTAGES OF BZDsOVER BARBITURATES ……ADVANTAGES OF BZDs OVER BARBITURATES …… No hang overNo hang over High therapeutic effectHigh therapeutic effect Less enzyme inductionLess enzyme induction Less withdrawal symptomLess withdrawal symptom Less dependenceLess dependence Not produce generalized CNS depressionNot produce generalized CNS depression Specific BZD receptor agonist available (Specific BZD receptor agonist available (flumazenilflumazenil)) for thefor the treatment of overdosagetreatment of overdosage.
- 74.
- 75. BZDs have awide margin of safety, well tolerated. The common side effects are : Drowsiness Confusion Blurred vision Amnesia Disorientation Withdrawal after chronic use causes : Tremor Insomnia Restlessness Nervousness Loss of appetite Use of BZDs during labour respiratory depression & hypotonia in the newborn ( Floppy Baby Syndrome)
- 76. Contra-indications • Myasthenia gravis. •Severe respiratory impairment e.g sleep apnoea, COAD.
- 77. Avoid (if possible) •Pregnancy • Lactation
- 78.
- 79. Preparations • Selective hypnoticaction. • Zolpidem • Zolpiclone • Zaleplon • Eszopiclone
- 80. Mechanism of action Nonbenzodiazepin Bind selectively to BZD1 binding site on GABAA receptor. Facilliated GABA-mediated neuronal inhibition CNS depression (hypnosis)
- 81. • Zolpidem- mainlyproduce hypnotic effect • Zolpiclone-orally effective and use for insomnia. • Zaleplon- shortest acting , useful for sleep onset insomia. • Eszopiclone –for long –term treatment of insomnia
- 82. Advantages When use intherapeutic doses. • Sleep latency & duration of sleep • Near normal sleep cycle with minimal alteration in REM • Minimal hangover effect and rebound insomnia. • Less tolerance and dependence.
- 83. Non benzodiazepin Lack of: •anticonvulsant • antianxiety • Muscle relacxation. metabolized in liver and excreted in urine Reduce the drug in hepatic disease and elderly patient
- 84. Adverse effect • Similaras in BZD. • Common side effect: headache, nausea, vomiting, confusion, drowsiness
- 85.
Editor's Notes
- #55 Initial remembered traumatic event in 58% Genetic/familial (heritability about 30%) Behavioral inhibition in childhood (increased reactivity to novelty, shyness) Cognitive factors
- #68 Benzodiazepines bind to a site near the GABA binding site thus facilitating the action of GABA Drug binds to a site near the binding site for the endogenous transmitter facilitating binding. Also an agonist action.