Antidepressants anxiolitics anti psychiotrics.pptx

Anti depressants

1. Antidepressant, Anti-anxiety Drugs

2. Classification of Major Affective Disorders

3. Episodal (reactive) Depression Adverse life events. Physical illness. Drugs. Other psychiatric disorders.

4. Reactive (episodal) Depression More than 60% of all depressions. Core depressive syndrome: feelings of misery, apathy, inadequacy, pessimism, anxiety, tension, guilt. Ugliness, Low self –esteem, Bodily complaints

5. Withdrawn. Loss of interest in pleasurable activities. Indecisiveness, loss of motivation. Retardation of thought and action. Sleep disturbance

6. In severe cases, it is accompanied by hallucinations and delusions. Recurrent suicidal ideation, a suicide attempt or a specific suicide plan. significant weight change (without dieting ) Psychomotor agitation or retardation.

7. 1. Has a genetic component. 2. Depression can be drug-induced. 3. Depression can be drug-repressed. 4. Depression can be treated with drugs. 5. Depression can be treated with Electroconvulsive Therapy (ECT).

8. Mania Mania alone is rare (10%) and most frequently cycles with Major/endogenous depression (Manic-Depressive Disease, Bipolar Disorder). Core Symptoms: Characterized by an elevated “high” mood. Talkative, go on-and-on about the things they will do. Increased self-esteem. Auditory hallucinations. Decrease need to sleep. Expensiveness, unnecessary buying. Lack judgment, Supermen

9. The precise cause of affective disorders remains elusive. Evidence implicates alterations in the firing patterns of a subset of biogenic amines in the CNS, Norepinephrine (NE) and Serotonin (5-HT).  Activity of NE and 5 -HT systems ? .

10. Amost all NE pathways in the brain originate from the cell bodies of neuronal cells in the locus coereleus in the midbrain, which send their axons diffusely to the cortex, cerebellum and limbic areas (hippocampus, amygdala , hypothalamus, thalamus). Mood : -- higher functions performed by the cortex. Cognitive function : -- function of cortex. Drive and motivation : -- function of brainstem Memory and emotion : -- function of the hippocampus and amygdala . Endocrine response : -- function of hypothalamus.

11. Serotonin System As with the NE system, serotonin neurons located in the pons and midbrain (in groups known as raphe nuclei) send their projections diffusely to the cortex, hippocampus, amygdala , hypothalamus, thalamus, etc. --same areas implicated in depression . This system is also involved in: Anxiety. Sleep. Sexual behavior. Temperature regulation. CSF production.

12. Serotonin receptors 5–HT 1 subtypes 5–HT 1A , 5–HT 1B , 5–HT 1D , 5–HT 1E , 5–HT 1F primarily responsible for the therapeutic (antidepressant) effects of increased intrasynaptic serotonin 5–HT 2 subtypes 5–HT 2A , 5–HT 2B , 5–HT 2C primarily responsible for the toxic effects of increased intrasynaptic serotonin

13. Serotonin receptors Over all 14 types divided in to 1, 2, 3, and 4-7 family All are G-protein coupled receptors except 3 1- decreases cAMP while 4-7 increase 3- ligand gated cation channel

14. Alternative Therapies No way of a priori knowing which therapy will be best for a patient. Light Therapy Psychological Treatment ECT (patients with suicidal tendency and for quick action) St. John’s Wort (Plant)

15. Antidepressants TCAs MAOIs SSRIs TCAs TCAs TCAs TCAs SSRIs SSRIs SSRIs SSRIs MAOIs MAOIs MAOIs MAOIs MAOIs MAOIs Venflaxine Venflaxine Venflaxine MAOIs MAOIs maprotiline Amoxepine doxepin isocarboxazide Nortriptyline

16. Mechanism of Action 1. Inhibition of MAO enzymes. (MAOIs). 2. Inhibition of NE and 5-HT reuptake. (TCAs, SSRIs, Newer TCAs). 3. Prominent alpha blocking and weak 5-HT antagonists. (Nefazodone, trazodone,) 4. Serotonin and noradrenalin reuptake inhibitor (SNRIs) (venlafaxine, duloxetine) 5. Noradrenergic and specific serotonergic antidepressants (NaSSA ) (Mirtazapine) 6. Inhibitor of Dopamine and Noradrenalin (Bupropion) 7. Blockade of pre-synaptic alpha 2 receptors (Mianserin) 8. Increases rather than inhibiting 5-HT uptake (Tianeptine, Amineptine) ATYPICAL

17. MAO ( monoamine oxidase) an enzyme Two types MAO – A -Peripheral adrenergic nerve endings -Intestinal mucosa -Human placenta -Liver -Serotonin , Noradrenalin and dopamine -Inhibited by moclobemide and clorgyline MAO-B -brain ( basal ganglia) -Platelets -Liver -Deaminates dopamine -Inhibeted by selegiline (deprenyl) Isoniazide, iproniazide, phenelzine, isocarboxazide,tranylcypromine were non selective and irreversible inhibitors (Hit and run drugs) used previously but not used now due to drug drug and drug food interactions. Linezolide (new drug against MRSA) Cheese and serotonin syndrome A-B C-D

18. Nonselective MAOIs not favorable Cheese Reaction Cheese, beer, wine, meat, fish, yeast, (contain large amount of tyrammine and other indirectly acting amines) Due to irreversible block of MAO These escape degradation in intestinal wall and liver Hypertensive crises , CVA Medical Emergency Reach to circulation Displace large amount of noradrenalin from loaded nerves Tt. I.V. Phentolamine, Prazosin

19. Nonselective MAOIs not favorable Cold and Cough medicines contain Ephedrine (Same result as cheese reaction) Levodopa- excitement and hypertension Tricyclic antidepressants- excitement, rise in BP, temperature

20. Reversible inhibitor of MAO-A (RIMAs) Moclobemide- Reversible and selective MAO-A inhibitor Short duration of action Competitive enzyme inhibition Tyramine is able to displace it Cheese reaction is less likely Devoid of anticholenergic, sedative, cognitive, cardiovascular effects Good for elderly with heart diseases

21. Tricyclic Antidepressants (TCAs) Imipramine represents the class (Prototype) Inhibit monoamine reuptake (serotonin and noradrenalin) Increase the concentration of Serotonin and NA at synapse and potentiate the action (therapeutic effects) Other receptors acted (Adverse effects) Muscarinic- Anticholinergic side effects (dryness etc.) # Alpha- alpha blocking actions (postural hypotension etc.) # Histamine-Antihistaminic (sedation) # Dopamine- antipsychotic (amoxapine, maprotiline)

22. TCAs actions (CNS) In Normal person Tiredness Light-headedness Sleepiness Difficulty in thinking Difficulty in concentration, Gait disturbances Provoke anxiety Unpleasant In Depressed -Sedation immediately -Elevation of mood (2-4Weeks) -Suppresses REM prolongs total sleep duration Lower seizure threshold and produce convulsions in overdose Don’t carry abuse potential, Development of dependence is less

23. TCAs uptake blockade is not directly responsible for antidepressant action? Uptake blockade occurs quickly but antidepressant action occurs after months Initially Pre synaptic alpha 2 and 5-HT1 auto receptors are activated by increased amount of NA and Serotonin in synaptic cleft resulting in decreased firing But on long term desensitize and down regulation of these receptors and induce adaptive changes in the number and sensitivity of receptors and amine turnover leading to enhanced NA and Serotonin transmission required for antidepressant action.

24. TCAs on other systems ANS Potent anticholinergic (dry mouth, blurring of vision,, constipation, urinary hesitancy) Weak alpha 1 blocking (postural hypotension, impairment of ejaculation,) H1 antihistaminic (sedation) CVS Tachycardia Postural hypotension Cardiac arrhythmias (T wave suppression or inversion) due to intra ventricular conduction interference due to NA and Anti cholinergic actions Tolerance to Anticholinergic and hypotensive actions develop latter on

25. TCAs (Pharmacokinetics) Good oral absorption Highly bound to Proteins (plasma and tissue) Metabolized in liver (oxidation, glucuronide conjugation and CYP2D6, CYP3A4, CYP1A2 Many active metabolites may be produced Mostly can be given once a day (at bed) Have Therapeutic Window phenomenon (50-200ng/ml of imipramin)

26. TCAs Adverse effects Anticholinergic - dry moth, bad taste, constipation, epigastric fullness, urinary retention (more common in elderly male), blurred vision, palpitation Sedation , mental confusion, weakness Increased appetite and weight Sweating, fine tremors Precipitation of seizures Postural hypotension Cardiac arrhythmias Rashes and jaundice

27. TCAs (Acute Poisoning) Usually suicidal attempt Presents as Excitement delirium, Anticholinergic symptoms like atropine poisoning Muscle spasm Convulsions Respiratory depression Coma Treatment Gastric lavage I.V. line Oxygen Maintenance of BP and Temperature Diazepam iv Propranolol / lignocain

28. TCAs (Interactions) Potentiation of sympathomimetics (direct acting) Reduce action of sympathomimetics (indirect acting) Reduce antihypertensive action of guanethidine and clonidine ( by preventing their transport in to neurons) Potentiate other CNS sedatives SSRIs inhibit metabolism of TCAs With MAO inhibitors dangerous hypertensive crisis with excitement and hallucinations Retard the absorption of other drugs Phenytoin, phenylbutazone , chlorpromazine, aspirin, displace TCAs and produce toxicity Phenobarbitone induce metabolism and inhibit the effect of the drug

29. Miscellaneous Amoxapine Tetra cyclic compound Blocks D2 reuptake also Has mixed antidepressant and neuroleptic effects Good for psychotic depression Reboxetine Selective NA reuptake blocker Weak action on 5-HT mechanism Anticholinergic effects are minimal

30. Selective Serotonin Reuptake Inhibitors (SSRIs) Limitations of TCAs Anticholinergic effects Alpha blocking action Cardio toxicity Sedation, seizures ppt Low safety margin Weight gain Therapeutic window Overdose poisoning common Lag of 1 month period Incomplete response to Tt Answers may be given by SSRIs Selectively inhibit membrane associated SERT (serotonin transporter) More tolerability and better acceptability Used in depression as well as in OCD, phobias No sedation, No seizure ppt No alpha blocking action Less chances of arrhythmia No weight gain Now 1 st choice for OCD, Panic disorders, Social Phobia, Eating disorders, Premenstrual syndrome, Post traumatic stress

31. Important points TCAs have slightly more efficacy Some patients not responding to TCAs may respond to SSRIs, SSRIs preferred in prophylaxis of recurrent depression In severe depression TCAs appear to be more efficacious

32. Individual compounds Fluoxetine Prototype of SSRIs Longest acting Fluvoxamine Short acting Commonly used in indoor patients Paroxetine Short acting More GI side effects Sertraline Less chances of drug interactions due to low potency to cause cytochrome enzyme depression Citalopram Similar to sertraline but should be avoided in patients attempting suicide Escitalopram Active enantiomer of citalopram side effects are less

33. SSRIs Side effects Gastric upset Nausea Interfere with ejaculation Nervousness Restlessness Insomnia Anorexia Headache Diarrhea Epistaxis Ecchymosis Others Inhibit cytochrome enzymes and elevate the plasma level of other drugs Other serotonergic drug ( MAOIs) is taken may precipitate Serotonin Syndrome manifesting as agitation, restlessness, sweating, twitching, convulsions

34. Atypical Antidepressants Mianserin Unique not inhibit NA and 5-HT uptake Blocks pre-synaptic alpha 2 receptors increases release and turnover of NA Antagonist at serotonin 2, 1c, and H1 receptors Has sedative effect Damages liver and bone marrow (Reserve drug) Trazodone Blocks 5-HT uptake Has prominenent alpha blocking Weak 5-HT2 antagonistic No anticholinergic effect Bradycardia Has anxiolytic action also Prolonged and painful penile erection (priaprism)

35. Atypical Antidepressants Tianeptine / and Amineptine Increases rather inhibiting 5-HT uptake Neither sedative nor stimulant Effective in anxiodepressive states Venlafaxine / Duloxetine SNRI selective in action Faster onset of action Increases BP Duloxetine increases uretheral tone used in urinary incontinence ( over active bladder) Mirtazapine ( NaSSA ) Noradrenergic and specific serotonergic antidepressant Blocks alpha 2 auto receptor (on NA neuron) and hetero- (on 5-HT neuron) receptors increasing both NA and serotonin release. Bupropion Inhibits DA and NA uptake has excitant effect Used to reduce smoking

36. Antidepressant uses Depression ( ECT may be needed in severely depressed and patients having suicidal tendency) Bipolar affective disorders TCAs and lithium or SSRIs with lithium or valporate/ lamotrigine SSRIs with atypical antipsychotic in psychotic depression Obsessive compulsive disorders (SSRI and Clomipramine) Eating disorders

37. I have a presentation I have a tough exam I have an important interview

38. Common Emotional Symptoms of anxiety irrational and excessive fear and worry Irritability Restlessness Trouble concentrating Feeling tense

39. Common Physical Symptoms of Anxiety Sweating Tachycardia Stomach upset Shortness of breath Frequent urination or diarrhea Sleep disturbances (Insomnia) Fatigue

40. Types of anxiety Generalized anxiety disorder Post-traumatic stress disorder (PTSD). Obsessive-compulsive disorder (OCD). Panic disorder Phobia

41. Generalized Anxiety Disorder (GAD) Patients are usually and constantly worried about health, money, work with no apparent reasons.

42. Obsessive-Compulsive Disorder (OCD) An anxiety disorder in which people cannot prevent themselves from unwanted thoughts or behaviors that seem impossible to stop as Washing their hands

43. Panic disorder An disorder in which people have sudden and intense attacks of anxiety in certain situations.

44. Post-traumatic stress disorder (PTSD ) An anxiety disorder that affects people who have experienced a severe emotional trauma, such as rape or dramatic car accident, or even war.

45. Phobia An intense, uncontrolled fear of a specific situation such as open spaces & heights

46. Treatment of anxiety Psychotherapy (cognitive behavioral therapy). Anxiolytics

47. Classification of anxiolytic drugs: Benzodiazepines ( BDZ ). 5HT 1A agonists. 5HT reuptake inhibitors. Antidepressants beta-adrenergic blockers MAO inhibitors

48. Classifications of Benzodiazepines -  Short acting: (3-5 hours): tria zolam -  Intermediate: (6-24 hours) Alpra zolam Lora zepam Oxa zepam Esta zolam Tema zepam

49. Classifications of Benzodiazepines -  Long acting: ( 24-72 hours) Clona zepam Chlordiazepoxide Dia zepam Flura zepam

50. Mechanism of Action Benzodiazepines act by binding to BZ receptors in the brain  enhance GABA action on brain  chloride channels opening   chloride influx to the cell  hyper- polarization  inhibition of brain. GABA ( γ -aminobutyric acid): is an inhibitory neurotransmitter

51. PHARMACOKINETICS are lipid soluble well absorbed orally, can be given parenterally Chlordiazepoxide- Diazepam (IV only NOT IM) widely distributed. cross placental barrier (Fetal depression). excreted in milk (neonatal depression).

52. metabolized in the liver to active metabolites ( long duration of action- cumulative effect ). Redistribution from CNS to skeletal muscles, adipose tissue) (termination of action).

53. Pharmacological Actions Anxiolytic action. Depression of cognitive and psychomotor function Sedative & hypnotic actions Anterograde amnesia.

54. Pharmacological Actions Minimal depressant effects on Cardiovascular system Respiratory system Some have anticonvulsant effect: clonazepam, diazepam.

55. Therapeutic Uses Anxiety disorders:   short term relief of severe anxiety General anxiety disorder Obsessive compulsive disorder Panic attack with depression Alprazolam (antidepressant effect) Sleep disorders (Insomnia). Triazolam , Lorazepam , Flurazepam

56. Therapeutic Uses Treatment of epilepsy Diazepam – Lorazepam In anesthesia Preanesthetic medication ( diazepam ). Induction of anesthesia ( Midazolam , IV )

57. Adverse Effects Ataxia (motor incoordination) Cognitive impairment. Hangover: (drowsiness, confusion) Tolerance & dependence Risk of withdrawal symptoms Rebound Insomnia, anorexia, anxiety, agitation, tremors and convulsion.

58. Adverse Effects Toxic effects: respiratory & cardiovascular depression in large doses.

59. Drug interactions Examples CNS depressants Alcohol & Antihistaminics of effect of benzodiazepines Cytochrome P450 (CYT P450) inhibitors Cimetidine & Erythromycin t ½ of benzodiazepines CYT P450 inducers Phenytoin & Rifampicin t 1/2 of benzodiazepines

60. Dose should be reduced in Liver disease Old people. Precaution Should not used in pregnant women or breast-feeding. People over 65.

61. 5HT 1A agonists Buspirone acts as agonist at brain 5HT 1A receptors rapidly absorbed orally. Slow onset of action (delayed effect) T½ : (2 – 4 h). liver dysfunction   its clearance. Drug Interactions with CYT P450 inducers and inhibitors.

62. Buspirone Only anxiolytic No hypnotic effect. Not muscle relaxant. Not anticonvulsant. No potentiation of other CNS depressants. Minimal psychomotor and cognitive dysfunctions. Does not affect driving skills. Minimal risk of dependence. No withdrawal signs.

63. Uses of buspirone As anxiolytic in mild anxiety & generalized anxiety disorders. Not effective in severe anxiety/panic disorder.

64. Beta Blockers Propranolol – atenolol act by blocking peripheral sympathetic system. Reduce somatic symptoms of anxiety. Decrease BP & slow HR. Used in social phobia. are less effective for other forms of anxiety

65. Tricyclic Antidepressants Doxepin- imipramine act by reducing uptake of 5HT & NA. Used for anxiety especially associated with depression. Effective for panic attacks. Delayed onset of action (weeks). dry mouth, postural hypotension, sexual dysfunction, weight gain.

66. Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine acts by blocking uptake of 5HT Orally Delayed onset of action (weeks). Used for panic disorder – OCD depression- Generalized anxiety disorders - phobia. Side Effects: Weight gain, sexual dysfunction, dry mouth

67. MONOAMINE OXIDASE INHIBITORS Phenelzine Acts by blocking the action of MAO enzymes. Used for panic attacks and phobia. Require dietary restriction Avoid wine, beer, fermented foods as old cheese that contain tyramine. Side effects Dry mouth, constipation, diarrhea, restlessness, dizziness.

68. Conclusion of anxiolytics CLASSES OF ANXIOLYTICS USES Benzodiazepines Generalized anxiety disorders, OCD, phobia, panic attack SSRIs (Fluoxetine) Generalized anxiety disorders, OCD, phobia, panic attack Tricyclic antidepressants (doxepin, imipramine ) anxiety with depression. panic attacks 5HT1A agonists ( Buspirone) Mild anxiety Not effective in panic attack Beta blockers ( propranolol , atenolol ) Phobia (social Phobia) MAO inhibitors Phenelzine Panic attack , phobia

69. Conclusion of anxiolytics CLASSES OF ANXIOLYTICS Adverse effects Benzodiazepines Ataxia, confusion, dependence, tolerance, withdrawal symptoms, SSRIs (Fluoxetine) weight gain, sexual dysfunction Dry mouth Tricyclic antidepressants (doxepin, imipramine ) weight gain, sexual dysfunction, atropine like actions 5HT1A agonists ( Buspirone) Minimal adverse effects Beta blockers ( propranolol, atenolol ) Hypotension