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phants

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phants

  1. 1. Pharmacology of Antidepressants Douglas L. Geenens, D.O. The University of Health Sciences
  2. 4. Classes of Antidepressants Tricyclic-tertiary amines <ul><li>amitriptyline (Elavil) </li></ul><ul><li>imipramine (Tofranil) </li></ul><ul><li>doxepin (Sinequan) </li></ul><ul><li>clomipramine (Anafranil) </li></ul><ul><li>trimipramine (Surmontil) </li></ul>
  3. 5. Classes of Antidepressants Tricyclic-secondary amines <ul><li>desipramine (Norpramin) </li></ul><ul><li>nortriptyline (Pamelor) </li></ul><ul><li>protriptyline (Vivactyl) </li></ul><ul><li>amoxapine (Ascendin) </li></ul>
  4. 6. Classes of Antidepressants Atypical (non-tricyclic) <ul><li>maprotiline (Ludiomil) </li></ul><ul><li>trazodone (Desyrel) </li></ul><ul><li>bupropion (Wellbutrin) </li></ul><ul><li>venlafaxine (Effexor) </li></ul><ul><li>nefazodone (Serzone) </li></ul><ul><li>mirtazapine (Remeron) </li></ul>
  5. 7. Classes of Antidepressants Specific serotonin reuptake inhibitors (SSRIs) <ul><li>fluoxetine (Prozac) </li></ul><ul><li>sertraline (Zoloft) </li></ul><ul><li>paroxetine (Paxil) </li></ul><ul><li>fluvoxamine (Luvox) </li></ul><ul><li>citalopram (Celexa) </li></ul>
  6. 8. Classes of Antidepressants Monoamine oxidase inhibitors (MAOIs) <ul><li>phenelzine (Nardil) </li></ul><ul><li>isocarboxazid (Marplan) </li></ul><ul><li>tranylcypromine (Parnate) </li></ul><ul><li>selegiline (Deprenyl) </li></ul>
  7. 9. Classes of Antidepressants Psychostimulants <ul><li>methylphenidate (Ritalin) </li></ul><ul><li>dextro-amphetamine (Dexedrine) </li></ul><ul><li>magnesium pemoline (Cylert) </li></ul><ul><li>dex + amphetamine (Adderall) </li></ul><ul><li>methamphetamine (Desoxyn) </li></ul><ul><li>modafinil (Provigil) </li></ul>
  8. 10. Evaluation of the depressed patient Goals of the evaluation <ul><li>Establish a diagnosis </li></ul><ul><li>Identify specific target symptoms </li></ul><ul><li>Consider comorbidity </li></ul><ul><li>Quantify depression and/or specific symptoms </li></ul>
  9. 11. Evaluation of the depressed patient <ul><li>Obtain psychiatric history and perform mental status exam </li></ul><ul><li>Identify and r/o underlying medical problems </li></ul><ul><li>Physical exam in the past year </li></ul>
  10. 12. Evaluation of the depressed patient <ul><li>Optional exams: </li></ul><ul><ul><li>Laboratory </li></ul></ul><ul><ul><li>Neurological exam </li></ul></ul><ul><ul><li>Dexamethasone suppression test </li></ul></ul><ul><ul><li>TRH test </li></ul></ul>
  11. 13. Is an antidepressant indicated? <ul><li>The decision to treat a patient with antidepressants should be based on the following: </li></ul><ul><ul><li>Severity of symptoms and ability to identify target symptoms </li></ul></ul><ul><ul><li>Impairment of functioning </li></ul></ul><ul><ul><li>Patient’s view of medication </li></ul></ul><ul><ul><li>Not necessarily the specific diagnosis </li></ul></ul>
  12. 14. Predictors of antidepressant response. <ul><li>Acute onset </li></ul><ul><li>Severe depressive symptoms </li></ul><ul><li>Positive previous response to medication </li></ul><ul><li>Patient’s willingness to accept medication as an aid to successful treatment </li></ul>
  13. 15. How to start antidepressants? <ul><li>Start low to assess tolerance of side effects </li></ul><ul><li>Increase dosage rapidly as tolerated </li></ul><ul><li>Maintain typical dose for at least 4 to 8 weeks </li></ul>
  14. 16. Most common reasons antidepressants fail <ul><li>Dosage too low </li></ul><ul><li>Duration of trial to short </li></ul><ul><li>Poor compliance </li></ul><ul><li>Intolerable side effects </li></ul>
  15. 17. What is an adequate trial? <ul><li>Adequate dose: </li></ul><ul><ul><li>5 mg/kg/d </li></ul></ul><ul><ul><li>Nortriptyline 100 to 150/d (therapeutic window) </li></ul></ul><ul><ul><li>Fluoxetine 20 mg/d </li></ul></ul><ul><li>Adequate duration: </li></ul><ul><ul><li>4 – 8 weeks </li></ul></ul>
  16. 19. Indications for serum levels <ul><li>Unequivocally useful for: </li></ul><ul><ul><li>Patients who are not responding to usual doses </li></ul></ul><ul><ul><li>Patients who are at increased risk for toxicity, e.g. cardiac patients </li></ul></ul><ul><li>May be useful for: </li></ul><ul><ul><li>Patients where prompt response is critical </li></ul></ul><ul><ul><li>Determining compliance and metabolic availability </li></ul></ul>
  17. 20. Therapeutic Blood Levels for antidepressants <ul><li>Known: </li></ul><ul><ul><li>imipramine </li></ul></ul><ul><ul><li>desipramine </li></ul></ul><ul><ul><li>nortriptyline </li></ul></ul><ul><li>Possibly known: </li></ul><ul><ul><li>amitriptyline </li></ul></ul><ul><li>Under assessment: </li></ul><ul><ul><li>All other antidepressants </li></ul></ul>
  18. 21. How Antidepressants Work <ul><li>Most of the important clinical actions of antidepressant drugs cannot be fully accounted for on the basis of “synaptic pharmacology”. </li></ul><ul><li>There are two important observations that contribute to this rationale. </li></ul>
  19. 22. How Antidepressants Work <ul><li>Many drugs require long term administration to be effective. </li></ul><ul><li>Drugs of abuse require repeated administration to produce tolerance and physical dependence. </li></ul>
  20. 23. How Antidepressants Work <ul><li>Clinical effects would appear to result from the slow onset adaptive changes that occur within neurons, not within the synapse. </li></ul><ul><li>That is, activation of intraneuronal messenger pathway and regulation of neural gene expression play a central role. (drug-induced neural plasticity). </li></ul>
  21. 24. “Synaptic Pharmacology” of antidepressants <ul><li>Acute: </li></ul><ul><ul><li>Block reuptake or degradation of monoamines and post-synaptic alpha-1 receptor. </li></ul></ul><ul><li>Chronic: </li></ul><ul><ul><li>Down regulation of the post-synaptic receptors </li></ul></ul><ul><ul><li>Alteration of second messenger systems </li></ul></ul><ul><ul><li>Alteration of protein synthesis. </li></ul></ul>
  22. 25. After Dosing Antidepressants (days) Series 1 Synaptic effects: hours to days Side effects: hours to days Therapeutic effect: 1 to 6 weeks
  23. 26. Pharmacokinetics of Antidepressants <ul><li>Absorption is rapid </li></ul><ul><li>Metabolism: extensive 1 st pass </li></ul><ul><li>Oxidation, hydroxylation, demethylation </li></ul><ul><li>5% = “slow acetylators” </li></ul><ul><li>Protein bound: 90 – 95% </li></ul>
  24. 28. Antidepressant half-lives (hrs)
  25. 29. Cardiac Side-effects of tricyclic antidepressants <ul><li>Cardiac conduction delay </li></ul><ul><li>Anti-arrhythmic at therapeutic doses </li></ul><ul><li>Arrhythmigenic at toxic doses </li></ul><ul><li>Minimal effects on cardiac output </li></ul>
  26. 30. Cardiac Side-effects of tricyclic antidepressants <ul><li>Monitoring EKG parameters: </li></ul><ul><li>QTc = 450 msec </li></ul><ul><li>PR = 210 msec </li></ul><ul><li>QRS - >30% above baseline </li></ul>
  27. 32. How to choose an antidepressant <ul><li>Rationale should be based on side effects, not efficacy </li></ul><ul><li>The SSRIs, secondary amines, and atypical antidepressants, are generally better choices. </li></ul><ul><ul><li>Why? </li></ul></ul>
  28. 33. Norepinephrine uptake blockade Possible clinical consequences <ul><li>Tremors </li></ul><ul><li>Tachycardia </li></ul>
  29. 34. Norepinephrine uptake blockade (potency)
  30. 35. Serotonin reuptake blockade Possible clinical consequences <ul><li>Gastrointestinal disturbances </li></ul><ul><li>Anxiety (dose – dependent) </li></ul><ul><li>Sexual dysfunction </li></ul>
  31. 36. Serotonin uptake blockade (potency)
  32. 37. Blocking selectivity 5-HT vs. NE
  33. 39. Dopaminergic uptake blockade Possible clinical consequences <ul><li>Psychomotor activation </li></ul><ul><li>Antiparkinsonian effects </li></ul><ul><li>Psychoses </li></ul><ul><li>Increased attention/concentration </li></ul>
  34. 40. Dopamine uptake blockade (potency)
  35. 41. Histamine H 1 blockade Possible clinical consequences <ul><li>Sedation, drowsiness </li></ul><ul><li>Weight gain </li></ul><ul><li>hypotension </li></ul>
  36. 42. Histamine H 1 receptor blockade (affinity)
  37. 43. Muscarinic receptor blockade possible clinical consequences <ul><li>Blurred vision </li></ul><ul><li>Dry mouth </li></ul><ul><li>Sinus tachycardia </li></ul><ul><li>Constipation </li></ul><ul><li>Urinary retention </li></ul><ul><li>Memory dysfunction </li></ul>
  38. 44. Muscarinic receptor blockade (affinity)
  39. 45. alpha – 1 receptor blockade possible clinical consequences <ul><li>Postural hypotension </li></ul><ul><li>Reflex tachycardia </li></ul><ul><li>Dizziness </li></ul>
  40. 46. alpha-1 receptor blockade (affinity)
  41. 48. imipramine (Tofranil) receptor affinities
  42. 49. fluoxetine (Prozac) receptor affinities

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