Antidepressants

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A power point presentation on drugs used in depressive disorders for the undergraduate MBBS students of Pharmacology

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  • Affective disorders are the diseases of mind. They affect the state of mind of the sufferers. It may be from mild disorder to life threatening one. There is serious biological, social, psychological and behavioural factors invilved.
    One of the common disorder is MANIA where a person is in hyperactivity, irritable mood, reuced sleep, uncontrolled speech and thought
  • Bipolar disorders are special category of disorders which where there is mood swing from depression to mania. This special category is treated by Mood stabilizers. Lithium – instead of NaCl in cardiac patient caused severe intoxication.
  • IP2 – Inositol Biphosphates, IP1 – Inositol Monophosphates, PI – Phosphatidyl inositides, PIP – Phosphadyl Inositol 4,5 Biphosphates
  • NA neruones mostly arise from locus ceruleus (pons) and lateral tegmentum in Midbrain
    Serotonergic neurones arise from raphe nucleus of pons
  • MAO degrades some of NA within the neurones even after uptake. Inhibition of this MAO enzyme may accumulate NA in excess and may cause hypertensive crisis and manic state
    Cheese reactioon – Indirectly acting sympathomimetic amines escape degradation by MAO, reaches systemic circulation and displace large amount of NA from nerve endings leading to hypertensive crisis. Treated with phentolamine and prazosin
  • Continued stimulation of cells with agonist results in desensitization (adaptation/refractoriness/down-regulation) such that the effect followed on subsequent exposure is diminished
  • Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs.
  • Obsessions are involuntary, seemingly uncontrollable thoughts, images, or impulses that occur over and over again in your mind.
    Fear of being contaminated by germs or dirt or contaminating others
    Fear of causing harm to yourself or others
    Compulsions are behaviors or rituals that you feel driven to act out again and again. Usually, compulsions are performed in an attempt to make obsessions go away.
    Phobia - ,specific phobia and social phobia
  • Antidepressants

    1. 1. DRUGS USED IN AFFECTIVE DISORDERS Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
    2. 2. Introduction
    3. 3. What are affective Disorders? 1. Mania 2. Depression • Reactive • Endogenous or Major Depression • Depressive syndromes – Unipolar or Bipolar
    4. 4. Bipolar Disorder - imageBipolar Disorder - image
    5. 5. Bipolar Disorder - image
    6. 6. Drugs used in Mania – MoodDrugs used in Mania – Mood StabilizersStabilizers  Lithium CarbonateLithium Carbonate  Alternative Drugs:Alternative Drugs: – CarbamazepineCarbamazepine – Sodium ValproateSodium Valproate – LamotrigineLamotrigine – TopiramateTopiramate – Atypical anyipsychotics – Olanzapine, risperidoneAtypical anyipsychotics – Olanzapine, risperidone
    7. 7. Lithium Carbonate – PharmacologicalLithium Carbonate – Pharmacological actionsactions  CNS:CNS: – No discernible psychotropic effect in normalNo discernible psychotropic effect in normal individualsindividuals – Similarly, no effect on Manic-depressiveSimilarly, no effect on Manic-depressive patientspatients – On prolonged administration – acts as moodOn prolonged administration – acts as mood stabilizerstabilizer – Suppresses the episodes af attackSuppresses the episodes af attack
    8. 8. Effect of Lithium Salts in Mania:
    9. 9. Lithium Carbonate – Mechanism ofLithium Carbonate – Mechanism of actionaction 1.1. Effect on Electrolyte and ion transport:Effect on Electrolyte and ion transport: – Li is the lightest of the alkali metal atomsLi is the lightest of the alkali metal atoms – Na+ and K+ are important in this familyNa+ and K+ are important in this family – Li distributes evenly in extracellular and intracellular fluidsLi distributes evenly in extracellular and intracellular fluids (contrast to Na+ and K+)(contrast to Na+ and K+) – Build up a small concentration gradient across cellBuild up a small concentration gradient across cell membranemembrane – But, cannot be transported via Na+/K+ ATPaseBut, cannot be transported via Na+/K+ ATPase – Interfere with transuducer mechanism of cell membraneInterfere with transuducer mechanism of cell membrane
    10. 10. Lithium Carbonate – MechanismLithium Carbonate – Mechanism of actionof action 2.2. Effects on 2Effects on 2ndnd MessengerMessenger – IPIP33 and DAG are important 2and DAG are important 2ndnd messenger for alpha andmessenger for alpha and Muscarinic transmissionMuscarinic transmission – Lithium inhibits several enzymes in the normal recycling ofLithium inhibits several enzymes in the normal recycling of PhosphoinositidePhosphoinositide – These include IPThese include IP22 to IPto IP11 and IP to Inositoland IP to Inositol – These leads to depletion of PIPThese leads to depletion of PIP22, the membrane precursor, the membrane precursor of IPof IP33 and DAGand DAG – Ultimate effect may be in G-protein receptors – mayUltimate effect may be in G-protein receptors – may uncouple receptors from G-proteinuncouple receptors from G-protein
    11. 11. Lithium Carbonate, Mechanism –Lithium Carbonate, Mechanism – contd.contd.
    12. 12. Lithium Carbonate, Mechanism –Lithium Carbonate, Mechanism – contd.contd. 3.3. Neurotransmitters:Neurotransmitters: – Enhances the action of SerotoninEnhances the action of Serotonin – Decrease the noradrenaline and dopamineDecrease the noradrenaline and dopamine turnover – antimanic actionturnover – antimanic action – Augment synthesis of AcetylcholineAugment synthesis of Acetylcholine
    13. 13. Lithium Carbonate - PharmacokineticsLithium Carbonate - Pharmacokinetics •Initial Dose is 600 mg/day and gradually increased (600 to 1200 mg/day  Well absorbed orally, but slowlyWell absorbed orally, but slowly  Not metabolized and not protein boundNot metabolized and not protein bound  Attains uniform distribution in total bodyAttains uniform distribution in total body waterwater  Apparent Vd – 0.8L/kg at steady stateApparent Vd – 0.8L/kg at steady state
    14. 14. Lithium, Pharmacokinetics –Lithium, Pharmacokinetics – contd.contd.  Li is actively reabsorbed from proximal tubule in theLi is actively reabsorbed from proximal tubule in the kidney similar to Na+kidney similar to Na+  When Na+ is restricted larger portion of Na+ isWhen Na+ is restricted larger portion of Na+ is reabsorbed - similar is in case of Lireabsorbed - similar is in case of Li  Initially rapid excretion, then slower in later phase.Initially rapid excretion, then slower in later phase.  T1/2 is 16 to 30 HrsT1/2 is 16 to 30 Hrs  Clearance is 20% of creatinineClearance is 20% of creatinine  Steady state is attained in 5-7 daysSteady state is attained in 5-7 days  Available as 300 and 400 mg tabletsAvailable as 300 and 400 mg tablets
    15. 15. Lithium – Monitoring of TreatmentLithium – Monitoring of Treatment  Individual variation in the rate of excretionIndividual variation in the rate of excretion  Narrow margin of safetyNarrow margin of safety  Done 5 days after the start of treatmentDone 5 days after the start of treatment  Measurement is done 12 Hrs after the last doseMeasurement is done 12 Hrs after the last dose  If no therapeutic improvement, chnge the doseIf no therapeutic improvement, chnge the dose  New dose = desired plasma level/present levelNew dose = desired plasma level/present level  Monitor the new dose level after 5 days againMonitor the new dose level after 5 days again  If steady state (0.5 to 0.8 mEq/L – increase theIf steady state (0.5 to 0.8 mEq/L – increase the interval of monitoringinterval of monitoring
    16. 16. Lithium – Adverse EffectsLithium – Adverse Effects 1.1. CNS:CNS: – Tremor is frequentTremor is frequent – Coarse tremor, giddiness, ataxia, motor incoordination,Coarse tremor, giddiness, ataxia, motor incoordination, nystagmus etc. – delirium, comanystagmus etc. – delirium, coma – Occurs mainly when plasma level is high (2mEq/L)Occurs mainly when plasma level is high (2mEq/L) – Treat with propranolol, atenolol etc.Treat with propranolol, atenolol etc. – If required – Osmotic diuretics for Li excretionIf required – Osmotic diuretics for Li excretion 1.1. Renal: Polyuria and PolydipsiaRenal: Polyuria and Polydipsia – Loss of ability of collecting tubules to conserve water by influenceLoss of ability of collecting tubules to conserve water by influence of ADH (G protein)of ADH (G protein) – Excessive free water clearanceExcessive free water clearance – Nephrogenic Diabetes InsipidusNephrogenic Diabetes Insipidus
    17. 17. Lithium, Adverse Effects – contd.Lithium, Adverse Effects – contd. 3.3. Cardiac Effects:Cardiac Effects: Sick-sinus syndrome –Sick-sinus syndrome – contraindicated – flattening of T wavecontraindicated – flattening of T wave 4.4. Thyroid Function:Thyroid Function: Decrease in thyroidDecrease in thyroid Function – goitre (G protein)Function – goitre (G protein) 5.5. PregnancyPregnancy – contraindicated– contraindicated – Foetal goitre, congenital abnormalities (cardiac)Foetal goitre, congenital abnormalities (cardiac)
    18. 18. Lithium – Drug InteractionsLithium – Drug Interactions  Diuretics: Renal clearance of Lithium is reduced byDiuretics: Renal clearance of Lithium is reduced by 25% with Diuretic e.g. furosemide, Thiazides25% with Diuretic e.g. furosemide, Thiazides  NSAIDS: Renal clearance of Lithium is reduced byNSAIDS: Renal clearance of Lithium is reduced by 25%25%  All Neuroleptics, except clozapine – increased EPSAll Neuroleptics, except clozapine – increased EPS  Insulin and oral hypoglycaemics: enhanceInsulin and oral hypoglycaemics: enhance hypoglycaemiahypoglycaemia
    19. 19. Antimanic – Other Drugs  Carbamazepine: – Prolong remission – Relapse with Li+ therapy and rapid cycling of Mood – Li + CBZ  Sodium Valproate: – Ist line in acute mania – Lithium resistance cases – Lithium + Valproate – resistance to monotherapy
    20. 20. Antimanic Drugs - contd.  Lamotrigine: – Not for acute cases but Bipolar disorders – Used as monotherapy as well as with Lithium  Atypical antipsychotics: – 1st line in acute mania in combination with BZD except patient requiring parenteral therapy – Olanzapine in maintenance therapy and prophylaxis
    21. 21. ANTIDEPRESSANTS ANTIDEPRESSANTS Drugs which can Elevate Mood (Mood Elevators)
    22. 22. ANTIDEPRESSANTS 1. MAO inhibitors: – Irreversible: Isocarboxazid, Iproniazid, Phenelzine and Tranylcypromine – Reversible: Moclobemide and Clorgyline 1. Tricyclic antidepressants (TCAs)  NA and 5 HT reuptake inhibitors – Imipramine, Amitryptiline, Doxepin, Dothiepin and Clomipramine  NA reuptake inhibitors – Desimipramine, Nortryptyline, Amoxapine 1. Selective Serotonin reuptake inhibitors: – Fluoxetine, Fluvoxamine, Sertraline and Citalopram 1. Atypical antidepressants: – Trazodone, Mianserin, Mirtazapine, Venlafaxine, Duloxetine, Bupropion and Tianeptine
    23. 23. Causes of Depression and Mechanism of antidepressants  The Monoamine Theory:  Adrenaline, Noradrenaline, Dopamine and 5-HT are neurotransmitters (Biogenic amines)  Called Noradrenergic, Serotonergic or Dopaminergic etc. neurones  Normally NA and 5 HT are in adequate numbers at post synaptic region  In DEPRESSION – Deficiency of NA or 5 HT or BOTH
    24. 24. Mechanism of antidepressants – contd.  Drugs act by increasing the local availability of NA or 5 HT  MAO Inhibitors: MAO is a Mitochondrial Enzyme involved in Oxidative deamination of these amines  MAO-A: Peripheral nerve endings, Intestine and Placenta (5-HT and NA)  MAO-B: Brain and in Platelets and Mainly Serotonergic (Phenylalanine)  Selective MAO-A inhibitors (RIMA) have antidepressant property
    25. 25. Mechanism of antidepressants – contd.  TCAs: – NA, 5 HT and Dopamine are present in Nerve endings – Normally, there are reuptake mechanism and termination of action – TCAs inhibit reuptake and make more monoamines available for action  SSRIs: – Serotonins also reuptaken by Nerve terminals – SSRIs inhibit the reuptake mechanism and make more 5 HT available for action
    26. 26. Mechanism of Antidepressants
    27. 27. MAO inhibitors  Drugs: Irreversible: Isocarboxazid, Iproniazid, Phenelzine and Tranylcypromine, Reversible: Moclobemide and Clorgyline  Not popular now except irreversible selective MAO-A inhibitors: – Strict dietary restrictions – Irreversible action – Drug-drug interactions – Safer drugs are available now  Major drawbacks: – Manic state or hypertensive crisis – Cheese reactions – Other drug interactions
    28. 28. MAO inhibitors (Drawbacks) – contd.  Drug Interactions: – Ephedrine (drugs of cold and cough): hypertensive reaction – Reserpine, guanethidine: excitement and rise in BP – Levodopa: excitement and rise in BP (delayed degradation of NA and DA) – Antiparkinsonian anticholinergics: Hallucinations and symptoms of atropine poisoning – MAOI and SSRI: Serotonin Syndrome (Mental confusion, hallucinations, sweating, hyperthermia, twitching of muscle, clonus and convulsion)
    29. 29. MAO inhibitors – contd.  Moclobomide: Advantages – Reversible action (1-2 days after stoppage) – Potentiation of pressor response to dietary amines is weak – Dietary restriction not required – Lack of anticholinergic, sedative,, cognitive and CVS adverse effects – Used in elderly patients and with heart diseases – Mild to moderate depression - alternative to TCAs
    30. 30. Tricyclic Antidepressants - Imipramine  NA and 5 HT reuptake inhibitors – Imipramine, Amitryptiline, Doxepin, Dothiepin and Clomipramine; NA reuptake inhibitors – Desimipramine, Nortryptyline, Amoxapine  Analogue of CPZ  Inhibit NET and SERT  Interacts with variety of receptors – alpha, H1, 5HT1, 5HT2 and D2
    31. 31. Imipramine – contd.  Early effects – sedation, no other CNS effect  After 2-4 wks: – Elevation of mood, more communicative – REM sleep suppressed and no night awakening – More sedative ones are for agitated and anxiety patients (amitriptyline, doxepin) – Withdrawn patients – less sedative Imipramine, Nortriptyline – Induce seizure (Clomipramine, bupropion)
    32. 32. Imipramine - Mechanism of action  Inhibit uptake of Biogenic amines – NA and 5-HT  No inhibition of DA uptake except Bupropion  Cocaine and amphetamines are inhibitors of DA uptake – strong CNS stimulant  May facilitate DA transmission in forebrain – elevation of MOOD  Reuptake inhibition causes – increase amines in synaptic cleft  Inhibition of DA – stimulant action  Inhibition of NA and 5-HT – antidepressant action
    33. 33. Imipramine - Mechanism of action – contd.  But, antidepressant action starts after few weeks, whereas blockade starts immediately  Inhibition of uptake is an early step but cascade of events that follow are important  Initially, auto receptors - α2 and 5-HT1 are activated by excess of NA/5HT – negative feed back  Limiting of synaptic availability of NA - homeostasis  On repeated exposure – α2 receptor response diminishes - desensitization of these pre-synaptic receptors  Adaptive changes – in number and sensitivity of pre and postsynaptic pre-synaptic production and release of NA - normal or more  No reuptake and no negative feed back
    34. 34. Imipramine – Pharmacological actions  ANS: Dry mouth, blurring of vision, constipation and urinary hesitancy  CVS: Tachycardia – – NA and anticholinergic action – Postural hypotension – ECG – T wave suppression – Arrhythmia
    35. 35. Effect of Antidepressants Deficient Drive of MOOD to - Normal Rhythmic Drive on Prolonged Treatment
    36. 36. Imipramine - Pharmacokinetics  Good oral absorption but undergo 1st pass effect – variable bioavailablity  Highly bound to plasma protein and high Vd  Metabolized in Liver: Active metaboites: Imipramine – desipramine and amitriptyline – nortriptyline  Excreted via urine, t1/2 – 16 to 24 Hrs  One daily dose – because of active metabolites  Therapeutic window phenomenon: Optimal effect at 50-200 ng/ml  Doses to be individualized and titrated
    37. 37. Imipramine – Adverse effects 1. Anticholinergic effects: Dry mouth, bad taste, constipaton, urinary retention etc. 2. Dysphoric state or mania - suicide 3. CVS:  Postural hypotension – older patient and overdose  Arrhythmia – with IHD 1. Weight gain – not with bupropion and SSRI 2. Seizure – in children 3. Sedation, mental confusion etc. – more with amitriptyline 4. Sweating and fine tremor
    38. 38. Imipramine – Drug Interactions 1. TCAs and Sympathomimetics (Cough and cold) 2. TCAs and MAO inhibitors – Hypertensive crisis 3. TCAs and SSRIs – SSRIs inhibit metabolism of TCAs 4. Anticholinergic property – delay absorption of other drugs
    39. 39. Imipramine - Drawbacks  Low safety margin  Anticholinergic, CVS and neurological side effects  Therapeutic lag (2-4 wks)  Variable patient response
    40. 40. SELECTIVE SEROTONIN REUPTAKE INHIBITORS  Drugs: Fluoxetine, Fluvoxamine, Sertraline and Citalopram  Similar antidepressant action  Relatively safe and better patient acceptability  Some patients not responding to TCAs may respond with SSRIs  Because of absence of psychomotor and cognitive impairment - Preferred in prophylaxis of recurrent depression
    41. 41. SELECTIVE SEROTONIN REUPTAKE INHIBITORS  Relative advantages: – No sedation, so no cognitive or psychomotor function interference – No anicholinergic effects – No alpha-blocking action, so no postural hypotension and suits for elderly – No seizure induction – No arrhythmia  Drawbacks: – Nausea is common – Interfere with ejaculation – Insomnia, dyskinesia, headache and diarrhoea – Impairment of platelet function – epistaxis – Serotonin Syndrome: Mental confusion, hallucinations, sweating, hyperthermia, twitching of muscle, clonus and convulsion.
    42. 42. SELECTIVE SEROTONIN REUPTAKE INHIBITORS  Fluoxetine: – Prototype of SSRIs – Slow action and not used for rapid effects – Longest acting – 2 days, t1/2 = 2 days – Used in depression and OCDs in adult and children
    43. 43. SSRIs – Pharmacokinetic comparison Dose mg/day Drug interaction Half life Steady state (Days) Fluoxetine 5-20 high 2-4 days 30-60 Sertraline 50 low 26 Hrs 7-14 Paroxetime 20 high 20 Hrs 10-14 Citalopram 20-40 low 35 Hrs 7
    44. 44. Atypical Antidepressants 1. Trazodone:  Weak 5-HT uptake block, α – block, 5-HT2 antagonist  No anticholinergic action  No arrhythmia  No seizure  ADRs: Priapism, Postural Hypotension 2. Venlafaxine:  SNRI (Serotonin and NA uptake inhibitor)  Fast in action  No cholinergic, adrenergic and histaminic interference  Raising of BP
    45. 45. Atypical Antidepressants – contd. 3. Mirtazapine:  NaSSA action (Noradrenaergic and specific serotonergic antidepressant) – enhancement of NA release and specific 5- HT1 receptor action  Blockade of 5-HT2 and 5-HT3  No anticholinergic or antidopaminergic action 4. Bupropion:  Inhibitor of DA and NA uptake (NDRI)  Non-sedative but excitant property  Used in depression and cessation of smoking  Seizure may precipitated
    46. 46. Antidepressants - Uses 1. Endogenous Major Depression:  Aim: Relieve symptoms of depression and restore Normal social Behavior  1st choice – SSRI (atypical ones also may be considered)  TCAs – in non-responsive cases (TCAs have to be used in severe depression in adults)  MAO –A inhibitors in mild and moderate cases  Maintenance – by TCAs (Imipramine 100 mg)  Combined with Lithium in Bipolar disorder  Newer ones are not recommended in children – suicide chance
    47. 47. Antidepressants (Uses) – contd. 2. Obsessive Compulsive Disorder (OCD) and Phobic states: (SSRIs are useful) – Compulsive eating in Bulimia – Body dysmorphic disorder – Compulsive buying – Kleptomania 3. Anxiety Disorders: BZD 4. Neuropathic pain: Imipramine, Amitriptyline – post herpetic neuralgia 4. Attention Deficit Hyperactivity Disorder: TCAs 5. Enuresis 6. Migraine: Amitryptiline as prophylactic
    48. 48. Antianxiety Drugs
    49. 49. What is anxiety?  Anxiety is a normal reaction to stress  It helps one deal with a tense situation in the office, study harder for an exam, keep focused on an important speech  In general, it helps one cope  But when anxiety becomes an excessive, irrational dread of everyday situations, it has become a disabling disorder
    50. 50. Antianxiety Drugs – contd.  Five major types of anxiety disorders are: – Generalized Anxiety Disorder (GAD) – Obsessive-Compulsive Disorder (OCD) – Panic Disorder – Post-Traumatic Stress Disorder (PTSD) – Social Phobia (or Social Anxiety Disorder)  GAD: – Excessive, exaggerated anxiety and worry about everyday life events with no obvious reasons for worry – always expect disaster and can't stop worrying about health, money, family, work, or school – interferes with daily functioning, including work, school, social activities, and relationships.
    51. 51. Antianxiety Drugs – contd.
    52. 52. What are the Drugs?  Benzodiazepines: Alprazolam, Diazepam, Chlordiazepoxide, Oxazepam and Lorazepam  Older Drugs: Barbiturates, Chloral hydrate and Meprobamate  Azapirones: Buspirone, Gepirone and Isapirone  Others: Propranolol, Imipramine Fluoxetine and Zolpidem etc.
    53. 53. Antianxiety Drugs – BZDs  High potency BZDs are useful  Slow and Long duration of action  Relieve anxiety at low doses – no generalized CNS depression  Prescribed for short period – especially for alcohol and drug abuse persons  Less cognitive impairment  At low dose – CVS and Respiratory side effects are less  Withdrawal syndrome – tapering of Doses  Clonazepam - social phobia and GAD  Lorazepam - panic disorder  Alprazolam - panic disorder and GAD  Diazepam – acute panic state and organic disease anxiety
    54. 54. Antianxiety Drugs – Buspirone  No marked sedation and euphoria  No direct effect on GABA or BZD receptors  No physical dependence or tolerance  No muscle relaxant, no anticonvulsant or no extra pyramidal effects  No functional and cognitive impairment  No cross tolerance to other anxiolytics and little abuse potential
    55. 55. Buspirone – contd.  Partial agonist action on presynaptic auto receptor 5- HT1A – reduces serotonergic activity in dorsal raphe  Antagonist of certain 5-HT1A post synaptic receptors  Weak D2 action but no antipsychotic effect  Adaptive changes after chronic treatment – reduction in 5-HT2 receptors in cortex  Given orally, absorbed rapidly – high 1st pass metabolism, active metabolite – urine and faeces  Dose: 5-15 mg dose
    56. 56. Antianxiety Drugs - Propranolol  Reduces symptoms of anxiety  Symptoms: Sympathetic overactivity – palpitation, tachycardia, rise in BP, sweating, tremor, GIT hurrying etc  No action on psychological symptoms – fear, tension etc.  Useful in examination fear, public appearance etc.
    57. 57. Pharmacotherapy of Anxiety  Anxiety is a Physiological phenomenon  Start medication only when marked impairment of performance  Start with a BZD according to the type of disorder at smallest dose possible  Doses are found out by titrating with the symptoms  Usually start with ½ or 2/3rd of the normal dose at bed time  If required the rest of the doses be given at day time  Simultaneously treat the primary cause – hypertension, Peptic ulcer etc.  SSRIs and Buspirone may be used in severe cases but not in acute cases
    58. 58. Pharmacotherapy of Anxiety – contd.  Beta-blockers may be given as adjuncts  Withdraw anxiolytics, if required in tapering doses  Lifelong therapy may be required for some patients but avoid short acting drugs for long therapy  Monitor for Drug interactions  In GAD – counseling, mental relaxations and Behavioural therapy  Avoid: – Excess of Cola or Coffee (stimulants) – Combination of alcohol, antihistamines, anticholinergics
    59. 59. Thank you / Khublei

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