ANTIDEPRESSANTS <ul><li>Tricyclic Antidepressants  </li></ul><ul><li>Selective Seratonin Reuptake Inhibitors </li></ul>
Definitions <ul><li>Affective disorders   -  mental illnesses characterized by pathological changes in   mood  (not though...
Depression <ul><li>common mental disorder that presents with depressed mood, loss of interest or pleasure, feelings of gui...
Neurobiological theory of depression <ul><li>Monoamine (catecholamine) theory (1965)  = the underlying biological or neuro...
Therapy of depression <ul><li>Pharmacotherapy/Mood Elevators </li></ul><ul><ul><li>Tricyclic antidepressants (TCA)   </li>...
 
<ul><li>Chemical structure with characteristic </li></ul><ul><li>three - ring nucleus – lipophilic nature </li></ul><ul><l...
Mode of action <ul><li>Block reuptake of NE,Serotonin and Dopamine at nerve terminal,thus increasing the NE,5HT or DA at t...
 
Pharmacological action <ul><li>CNS-mood elevation in depress patient,can cause ataxia,epilepsy,seizures and coma. </li></u...
Classification <ul><li>A.  Tertiary Amines :  Amitriptyline, Butriptyline, Clomipramine, Dosulepin, Doxepin, Imipramine, L...
Classification <ul><li>A. NA and 5HT reuptake inhibitors </li></ul><ul><li>Imipramine,Amitryptaline,Clomipramine </li></ul...
Most important TCAs <ul><li>imipramine </li></ul><ul><li>desimipramine </li></ul><ul><ul><li>demethylated form, the   acti...
INDICATIONS <ul><li>Clinical depression </li></ul><ul><li>Neuropathic pain-Diabetic neuropathy/Analgesia </li></ul><ul><li...
<ul><li>Agranulocytosis </li></ul><ul><li>Severe liver damage </li></ul><ul><li>Glaucoma </li></ul><ul><li>Prostatic hyper...
Pharmacokinetics <ul><li>Administered  orally  – rapid absorption, however extensive first pass effect    low and inconsi...
Drug interaction <ul><li>Tricyclic interaction includes additive depression of the CNS with other antidepressents include ...
Drug Dose <ul><li>It takes about 2-3 weeks before tricyclic antidepressents has any evident action on depression( although...
<ul><li>When starting the drug start with a low dose and gradually increase it to prevent the side-effects. </li></ul><ul>...
Adverse Effects Pharmacological Action Adverse Effect Muscarinic receptor Blockage/ Anticholinergic <ul><li>Dry mouth, tac...
Teratogenic effects <ul><li>Have not been proved but it should be used cautiously in the first trimester of pregnancy. </l...
Toxic Effects <ul><li>CVS : Ventricular fibrillation, Conduction disturbances, Low BP, --- ecg shows prolong PR and QT int...
Management of toxicity <ul><li>Supportive care </li></ul><ul><li>Cardiac monitoring---if arrythmia, ICU </li></ul><ul><li>...
Newer Drugs <ul><li>Lofepramine -Has strong anti-cholinergic side-effect than amitriptyline and is less sedating; however,...
 
II.  Selective Serotonin Re-uptake Inhibito r s (SSRI) <ul><li>More modern (1 st  drug fluoxetine available in 1988) and s...
 
Most important SSRI <ul><li>(10-60mg/day) Fluoxetine   (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR), Fluox (N...
Pharmacokinetics <ul><li>Good absorption  after oral administration </li></ul><ul><li>Important biotransformation  in the ...
 
Adverse effects <ul><li>Relative improvement to other antidepressants  (mostly mild) </li></ul><ul><li>Less Cardiotoxic co...
Serotonin Syndrome <ul><li>SSRIs are contraindicated with concomitant use of MAOIs ( monoamine oxidase inhibitors ). This ...
SSRI discontinuation syndrome <ul><li>not as significant as  benzodiazepines </li></ul><ul><li>little to no abuse potentia...
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Antidepressants Tca Ssri

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Antidepressants Tca Ssri Psychiatry Tricyclic Antidepressants Selective Serotonin Reputake inhibitors

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Antidepressants Tca Ssri

  1. 1. ANTIDEPRESSANTS <ul><li>Tricyclic Antidepressants </li></ul><ul><li>Selective Seratonin Reuptake Inhibitors </li></ul>
  2. 2. Definitions <ul><li>Affective disorders - mental illnesses characterized by pathological changes in mood (not thought – compare with schizophrenia) </li></ul><ul><ul><li>Unipolar disorders </li></ul></ul><ul><ul><ul><li>Depression – pathologically depressed mood (life time prevalence up to 17%) </li></ul></ul></ul><ul><ul><ul><li>Mania – excessive elation and accelerated psychomotoric activity (rare) </li></ul></ul></ul><ul><ul><li>Bipolar disorder (manic-depressive illness) – „cycling mood“ </li></ul></ul><ul><ul><ul><li>= severe highs (mania, event. hypomania) and lows (major depressive episodes) </li></ul></ul></ul><ul><ul><ul><li>prevalence 1-5%, life-time illness, stronger genetic background </li></ul></ul></ul>
  3. 3. Depression <ul><li>common mental disorder that presents with depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration (WHO def.) </li></ul><ul><li>Major Depressive Episode Criteria/Core symptoms </li></ul><ul><ul><li>Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure . </li></ul></ul><ul><ul><ul><li>depressed mood most of the day … </li></ul></ul></ul><ul><ul><ul><li>markedly diminished interest or pleasure </li></ul></ul></ul><ul><ul><ul><li>significant weight loss /gain </li></ul></ul></ul><ul><ul><ul><li>insomnia or hypersomnia </li></ul></ul></ul><ul><ul><ul><li>psychomotor agitation or retardation , fatigue or loss of energy </li></ul></ul></ul><ul><ul><ul><li>feelings of worthlessness or excessive or inappropriate guilt </li></ul></ul></ul><ul><ul><ul><li>diminished ability to think or concentrate, or indecisiveness </li></ul></ul></ul><ul><ul><ul><li>recurrent thoughts of death or suicidal ideation without a specific plan or a suicide attempt (!) </li></ul></ul></ul>
  4. 4. Neurobiological theory of depression <ul><li>Monoamine (catecholamine) theory (1965) = the underlying biological or neuroanatomical basis for depression is a deficiency of central noradrenergic and/or serotonergic transmission in the CNS </li></ul><ul><li>Supported by: </li></ul><ul><ul><ul><li>pharmacological effect of antidepressants (TCA, MAO I ) </li></ul></ul></ul><ul><ul><ul><li>In the past , medication of hypertension with reserpine induced depression </li></ul></ul></ul><ul><li>Contradiction : </li></ul><ul><ul><ul><li>several drugs (e.g. cocaine) increase the amount of these neurotransmitters in the CNS but are unable to treat depression </li></ul></ul></ul><ul><ul><ul><li>the effect of antidepressants on neurotransmitter levels is relatively quick but onset of antidepressant action is significantly delayed </li></ul></ul></ul><ul><li>„ Receptor theory“ = the problem is in up-regulation of post-synaptic receptors and alterations in their sensitivity </li></ul><ul><li>The antidepressant treatment increases the amount of monoamines in CNS and thereby gradually normalize the density/sensitivity of their receptors </li></ul><ul><li>The precise pathophysiology of depression remains unsolved </li></ul>
  5. 5. Therapy of depression <ul><li>Pharmacotherapy/Mood Elevators </li></ul><ul><ul><li>Tricyclic antidepressants (TCA) </li></ul></ul><ul><ul><li>Monoamine oxidase inhibitors (MAOI) </li></ul></ul><ul><ul><li>Selective Serotonin Re-uptake Inhibitors (SSRI) </li></ul></ul><ul><ul><li>Other and atypical antidepressant </li></ul></ul><ul><ul><ul><li>Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) </li></ul></ul></ul><ul><ul><ul><li>Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) </li></ul></ul></ul><ul><ul><ul><li>Noradrenaline and Dopamine Reuptake Inhibitors (NDRI) </li></ul></ul></ul><ul><ul><ul><li>Noradrenaline Reuptake Inhibitors (NaRI) </li></ul></ul></ul><ul><ul><ul><li>Noradrenergic/Specific Serotonergic Antidepressants (NaSSA) </li></ul></ul></ul><ul><ul><ul><li>Duration of treatment – 6 months after recovery (1st epizode), may be even life-long treatment in recurrent depression </li></ul></ul></ul><ul><li>Non-pharmacological treatment </li></ul><ul><ul><li>Psychotherapy </li></ul></ul><ul><ul><li>Light therapy </li></ul></ul><ul><ul><li>Electroconvulsive therapy (ECT) </li></ul></ul>
  6. 7. <ul><li>Chemical structure with characteristic </li></ul><ul><li>three - ring nucleus – lipophilic nature </li></ul><ul><li>Originally developed as antipsychotic s </li></ul><ul><li>(1949), but were found to have no effect in </li></ul><ul><li>this indication. </li></ul><ul><li>Principal mechanism of action : </li></ul><ul><ul><li>blockade of re-uptake of monoamine neurotransmitters noradrenaline (NA) and serotonin (5-HT) by competition for binding site of the carrier protein . 5HT and NA neurotransmission is similarly affected but the effect on the dopamine system is much less important (compare with cocaine) </li></ul></ul><ul><ul><li>in most TCA , other receptors (incl. those outside the CNS) are also affected: blockade of H1-receptor,  -receptors, M-receptors </li></ul></ul>I. Tricyclic Antidepressants (TCAs) imipramine
  7. 8. Mode of action <ul><li>Block reuptake of NE,Serotonin and Dopamine at nerve terminal,thus increasing the NE,5HT or DA at the extracellular and more of its action on at receptor site. </li></ul><ul><li>Down regulation of Beta-adregernic receptors </li></ul><ul><ul><li>in most TCA , other receptors (incl. those outside the CNS) are also affected: blockade of H1-receptor,  -receptors, M-receptors </li></ul></ul>
  8. 10. Pharmacological action <ul><li>CNS-mood elevation in depress patient,can cause ataxia,epilepsy,seizures and coma. </li></ul><ul><li>CVS-orthostatic hypotension </li></ul><ul><li>ANS-anticholinergic effects.Most potent anticholinergic action </li></ul>
  9. 11. Classification <ul><li>A. Tertiary Amines : Amitriptyline, Butriptyline, Clomipramine, Dosulepin, Doxepin, Imipramine, Lofepramine, Trimipramine </li></ul><ul><li>B. Secondary Amines : Desipramine, Nortriptyline, Protriptyline </li></ul><ul><li>C. Others/Dibenzodiazepine derivitive : Dibenzepin </li></ul>
  10. 12. Classification <ul><li>A. NA and 5HT reuptake inhibitors </li></ul><ul><li>Imipramine,Amitryptaline,Clomipramine </li></ul><ul><li>B. Predominantly NA reuptake inhibitor </li></ul><ul><li>Desipramine,Nortriptyline,Amoxapine </li></ul>
  11. 13. Most important TCAs <ul><li>imipramine </li></ul><ul><li>desimipramine </li></ul><ul><ul><li>demethylated form, the active metabolite of imipramine </li></ul></ul><ul><li>amitriptyline </li></ul><ul><li>nortriptyline </li></ul><ul><ul><li>demethylated form, the active metabolite of amitriptyline) </li></ul></ul><ul><li>Clinical use and efficacy is relatively close within the group the more significant difference is in their adverse effects </li></ul>
  12. 14. INDICATIONS <ul><li>Clinical depression </li></ul><ul><li>Neuropathic pain-Diabetic neuropathy/Analgesia </li></ul><ul><li>ADHD </li></ul><ul><li>Nocturnal Enuresis (Imipramine) </li></ul><ul><li>Panic disorder(Imipramine) </li></ul><ul><li>OCD(Clomipramine) </li></ul><ul><li>Others like eating disorder,narcolepsy </li></ul>
  13. 15. <ul><li>Agranulocytosis </li></ul><ul><li>Severe liver damage </li></ul><ul><li>Glaucoma </li></ul><ul><li>Prostatic hyperplasia </li></ul><ul><li>Epilepsy </li></ul><ul><li>lactation </li></ul>Contraindication
  14. 16. Pharmacokinetics <ul><li>Administered orally – rapid absorption, however extensive first pass effect  low and inconsistent BAV </li></ul><ul><li>Strong binding to plasma proteins (90-95% bound). They are also bound in tissues + wide distribution (high lipophilicity) = large distribution volumes (ineffectiveness of dialysis in acute intoxications). </li></ul><ul><li>Biotransformation – in the liver ( CYP450 , N-demethylation and tricyclic ring hydroxylation) – most of these metabolites are active! CYP450 polymorphisms ! Glucuronidation  inactive metabolites excreted in the urine. </li></ul><ul><li>Elimination half-lives - generally LONG ( T1/2 =10-80h). Elderly patients – even longer T1/2, risk of accumulation. </li></ul>
  15. 17. Drug interaction <ul><li>Tricyclic interaction includes additive depression of the CNS with other antidepressents include ethanol, barbiturates, benzodiazipines, and opioids. </li></ul><ul><li>Tricyclic may also cause reversal of the anti-hypertensive action of guanethidine by blocking its transport into sympathetic nerve endings. </li></ul><ul><li>Less commonly, tricyclics may interfere with the anti-hypertensive actions of methylnorepinephrine( the active metabolite of methyldopa) and clonidine. </li></ul><ul><li>Tricyclics also share metabolic pathways with phenytoin, hence it may increase concentrations of phenytoin. </li></ul><ul><li>Tricyclics also potentiate the pressor effects of adrenaline and noradrenaline, so that there is a potantial hazard when a local anaesthetic is used with a pressor amine. </li></ul>
  16. 18. Drug Dose <ul><li>It takes about 2-3 weeks before tricyclic antidepressents has any evident action on depression( although sleep and agitation may respond earlier). </li></ul><ul><li>Hence, it is useless to give it as per needed only.They must be administred regularly in sufficient doses to achieve the desired effect. </li></ul><ul><li>After remission of symptoms, it is essential to continue the anti-depressents for 6-12 months in the 1 st episode and longer duration in subsequent episodes to prevent reccurence of symptoms. </li></ul><ul><li>A drug, e.g. imipramine is given in sufficient doses(100-300 mg) for 6 weeks, can it be called as ineffective for a particular patient. </li></ul>
  17. 19. <ul><li>When starting the drug start with a low dose and gradually increase it to prevent the side-effects. </li></ul><ul><li>When stopping the drug, taper the dose over 2-3 weeks period. As if you were to stop it abruptly, it will cause withdrawal symptoms such as: </li></ul><ul><li>-Nausea </li></ul><ul><li>-Tremor </li></ul><ul><li>-Headache </li></ul><ul><li>-Insomnia </li></ul>
  18. 20. Adverse Effects Pharmacological Action Adverse Effect Muscarinic receptor Blockage/ Anticholinergic <ul><li>Dry mouth, tachycardia, blurred vision, glaucoma </li></ul><ul><li>Constipation, Urinary retention, Sexual dysfunction </li></ul><ul><li>Cognitive impairement </li></ul>ᾴ1 Adrenoceptor blockade <ul><li>Drowsiness, Postural Hypotension, Sexual dysfunction (loss of libido, impaired erection) </li></ul><ul><li>Cognitive Impairement </li></ul>Histamine H1 receptor Blockade Drowsiness, Weight Gain Membrane stabilizing properties Cardiac conduction defects, Cardiac arrythmia, Seizures Others Rash, Oedema, Leukopenia, Elevated liver enzymes
  19. 21. Teratogenic effects <ul><li>Have not been proved but it should be used cautiously in the first trimester of pregnancy. </li></ul>
  20. 22. Toxic Effects <ul><li>CVS : Ventricular fibrillation, Conduction disturbances, Low BP, --- ecg shows prolong PR and QT intervals, depressed ST, flattened T waves. Heartblock occasionally </li></ul><ul><li>RS : Respiratory depression -> Hypoxia, Aspiration pneumonia </li></ul><ul><li>CNS : Agitation, twitching, convulsions, hallucinations, delerium, coma. Parasympathetic dry mouth, dilated pupil, blurred vision, urine retention, pyrexia </li></ul>
  21. 23. Management of toxicity <ul><li>Supportive care </li></ul><ul><li>Cardiac monitoring---if arrythmia, ICU </li></ul><ul><li>Plasma level monitoring: Shudn go above 450ng/ml or 300ng/ml if concomitant medical disorder </li></ul><ul><li>TCA has delayed gastric emptyin, do gastric lavage if several hours after overdose </li></ul><ul><ul><li>Activated Charcoal 1gm/kg PO/NG </li></ul></ul>
  22. 24. Newer Drugs <ul><li>Lofepramine -Has strong anti-cholinergic side-effect than amitriptyline and is less sedating; however, it may cause anxiety and insomnia.In overdose it is also less toxic than conventional tricyclics. </li></ul><ul><li>Trazodone -Also has few anti-cholinergic side effects, but has strong sedating properties. </li></ul>
  23. 26. II. Selective Serotonin Re-uptake Inhibito r s (SSRI) <ul><li>More modern (1 st drug fluoxetine available in 1988) and safe antidepressants </li></ul><ul><li>Principal mechanism of action : </li></ul><ul><ul><li>selective inhibition of 5-HT (sero to nin) reuptake  more extracellular seratonin -> More action on seratonin receptors on post synaptic -> more stimulation </li></ul></ul><ul><li>Other indications of SSRI - anxiety disorders : generalized anxiety, panic disorder, social anxiety disorder, obsessive-compulsive disorder </li></ul><ul><li>+ bulimia nervosa, gambling </li></ul>
  24. 28. Most important SSRI <ul><li>(10-60mg/day) Fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS) </li></ul><ul><li>(50-300mg/day) Fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox) </li></ul><ul><li>(10-40mg/day) Paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Rexetin, Xetanor, Paroxat) </li></ul><ul><li>(50-200mg/day) Sertraline (Zoloft, Lustral, Serlain) </li></ul><ul><li>(10-40mg/day) Citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox) </li></ul>
  25. 29. Pharmacokinetics <ul><li>Good absorption after oral administration </li></ul><ul><li>Important biotransformation in the liver </li></ul><ul><ul><li>CYP450 - 2D6 and 2C19 isoforms (polymorphism  interindividual variability in the clinical effect) and active metabolites (e.g. fluoxetine) </li></ul></ul><ul><li>Long half-lives of elimination(s) </li></ul><ul><ul><li>fluoxetine (T 1/2 =50h) + active metabolite (T 1/2 =240h) </li></ul></ul><ul><li>Drug interaction : based on plasma protein binding and CYP blockade </li></ul><ul><ul><li>increased effect of co-administered TCA but also  -blockers, benzodiazepines etc. </li></ul></ul>
  26. 31. Adverse effects <ul><li>Relative improvement to other antidepressants (mostly mild) </li></ul><ul><li>Less Cardiotoxic compared to TCA </li></ul><ul><li>Generally, much safer in overdose </li></ul><ul><li>Lack anticholinergic effects and are not Sedating </li></ul><ul><li>GIT – nausea, vomiting, diarrhea </li></ul><ul><li>Neuropsychiatry – Headache, Irritability, Restless (Akathisia)-EPS more common in SSRI than TCA, Agitation, Tremor, Insomnia and daytime somnolence, Seizures Mania </li></ul><ul><li>Sexual dysfunctions – Ejaculatory delay, anorgasmia </li></ul><ul><li>Suicidal Behavior </li></ul><ul><li>Serotonin syndrome upon intoxication or drug interactions </li></ul>
  27. 32. Serotonin Syndrome <ul><li>SSRIs are contraindicated with concomitant use of MAOIs ( monoamine oxidase inhibitors ). This can lead to increased serotonin levels which could cause a serotonin syndrome . </li></ul><ul><li>CF:- </li></ul><ul><ul><li>NEURO: Myoclonus, Nystagmus, Headache, Tremors, Rigidity, Seizures </li></ul></ul><ul><ul><li>MENTAL STATE: Irritability, Confusions, Agitations, Hypomania, Coma </li></ul></ul><ul><ul><li>OTHERS: Hyperpyrexia, sweating, diarrhea, cardiac arrythmia, death </li></ul></ul>
  28. 33. SSRI discontinuation syndrome <ul><li>not as significant as benzodiazepines </li></ul><ul><li>little to no abuse potential </li></ul><ul><li>Withdrawal symptoms: common descriptions include dizziness, electric shock-like sensations, sweating, nausea, insomnia, tremor, confusion, and vertigo </li></ul>
  29. 34. THANK YOU
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