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

Published in: Health & Medicine
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  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