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R Hawa MD FRCPC DABPN SABSM Deputy Psychiatrist in Chief- UHN Director, C/L Service, TWH

Psychopharmacology in the Psychiatric Patient with Co-Morbid Medical Illness- The Heart, The lung & The Gut Clinical Pearls for the General Adult Psychiatrist/ GPs. R Hawa MD FRCPC DABPN SABSM Deputy Psychiatrist in Chief- UHN Director, C/L Service, TWH Deputy Clerkship Director

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R Hawa MD FRCPC DABPN SABSM Deputy Psychiatrist in Chief- UHN Director, C/L Service, TWH

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  1. Psychopharmacology in the Psychiatric Patient with Co-Morbid Medical Illness- The Heart, The lung & The Gut Clinical Pearls for the General Adult Psychiatrist/ GPs R Hawa MD FRCPC DABPN SABSM Deputy Psychiatrist in Chief- UHN Director, C/L Service, TWH Deputy Clerkship Director Director Psychiatry UME University of Toronto

  2. Disclosure • No financial disclosures or conflict of interest to be declared for the development and presentation of this session

  3. Learning Objectives At the end of this course the participant will be able to: • Describe an organized approach to the psychopharmacological management of the psychiatric patient with co-morbid medical illness • List sources of information to help navigate clinically challenging situations • List drugs that require modification in use (e.g. dosing, dosing timing, etc.) because of co-morbid medical conditions

  4. Outline General Approach to Psychopharmacology in the Patient with Co-Morbid Medical Illness: Heart Failure COPD Bariatric Surgery Q & A

  5. Basic Principles of Psychopharmacology in the Medically Ill KUWAIT CONFERENCE

  6. The Context: Increasing Rates of Polypharmacy in Mental Health Care

  7. An Approach to Psychopharmacology in the Medically Ill • Diagnostic clarity is paramount • Identify target symptoms • Consider drug-drug interactions • Practice pharmacological parsimony when possible • Start low & go slow – BUT give it a “good” trial • Consult available psychopharmacology resources when challenged Sockalingam, S, Tan A, Abbey S. Chapter 4 in Psychopharmacology in the Medically Ill 2010

  8. Principles of Psychopharmacology • Pharmacodynamics • Pharmacokinetics

  9. Pharmacokinetics & Pharmacodynamics Pharmacokinetics: What the body is doing to the drug Pharmacodynamics: What the drug is doing to the body Drug in tissues of distribution Drug at site of action Drug in systemic circulation Dose of drug administered Pharmacological Effect Drug metabolized or excreted Adapted from Ferrando SJ et al. 2010

  10. Proportion of Drugs Metabolized by Phase I Enzymes (CYP450) Wynn GH. Clinical Manual of Drug Interaction Principles for Medical Practice 2009

  11. Pathways of Metabolism and Excretion Ferrando SJ et al. 2010

  12. P-glycoprotein Pump– Efflux Transporters • Can be inhibited or induced • If inhibit or induce CYP3A4, in most cases will do the same for p-gp • Examples: MDR1sub-type (intestine), Blood-brain-barrier Adapted from Ferrando S et al. 2011

  13. Potential Drug-Drug Interactions Among 1st-Line Antidepressants Cytochrome P450 isoenzyme or p-glycoprotein inhibition noted in brackets CANMAT 2009 Guidelines for Major Depressive Disorder. J Affect Disord 2009.

  14. Harnessing Antidepressant Profiles: Prescribing Parsimony • Pain –TCA, duloxetine, venlafaxine (desvenlafaxine) • Sleep – mirtazapine, TCA, trazodone • Nausea / poor appetite – mirtazapine, olanzapine • Constipation – SSRIs • Fatigue – Bupropion, SNRI

  15. Cardiac Disease and Psychopharmacology

  16. Cardiovascular Disease and Depression • Leading health problems • 85 % of cardiac deaths occur in >65 yrs • Bidirectional relationship • Depression + 1 or more chronic diseases= worst functional health score across all disease states across 20 countries

  17. Depression in Cardiac Disease • 3x risk of depression in cardiac disease • 15-20% at any one time have MDD • 17-36% of hospitalized CAD patients (HF higher) • 2.0-2.5 RR of poor cardiac outcome if depressed (esp. in first 30 days)

  18. Depression and Heart Failure • Heart Failure: 10 per 1000 >65 yrs • Depression: 20 % of Heart failure patients • HF Mortality 2X if depressed • Increases incident HF, worsens quality of life and functional status • Outpatients = inpatients

  19. Anxiety and Cardiac Disease • 25-30% of cardiac patients have anxiety symptoms • GAD and PTSD (more common if depressed) • Increased risk of cardiac mortality in anxious medically healthy individuals • Anxiety and depression in cardiac disease additive • 1= 2X mortality 2= 3X mortality

  20. Depression and cardiovascular disease Links • Inflammation (CRP, TNF-α, IL-6, IL-1) • Endothelial dysfunction and atherogenesis • Platelet activation and aggregation • HPA axis (HR, HRV, cortisol, epi.) • Behavioral (diet, exercise, cardiac rehab.)

  21. Neurotransmitter effects on cardiovascular function • NE- binds to peripheral α and β adreneric receptors: orthostatic hypotension, hypertension, conduction abnormalities, increased HR and contractility and conduction velocity (ischemia, cp, bp, arrhythmias) • DA (converted to NE) • 5-HT- platelet aggregation, vasodilatation vasoconstriction

  22. SSRIs- cardiac trials

  23. SSRIs- Cardiac trials

  24. SSRIs- CYP450 • SSRIs inhibit P450 (CYP1A2, CYP3A4, CYP 2D6) • Can increase levels of antiarrhythmics, β-blockers, antihistamines, and Ca2+ channel blockers • e.g. CYP2D6 inhibition by fluoxetine, paroxetine, sertraline (weak) may cause metoprolol and carvediolol accumulation and bradycardia • e.g. CYP2C19 inhibition by fluoxetine inhibits clopidogrel’s effect by inhibiting conversion to active metabolite • Escitalopram and citalopram (1A2,2D6,2C19) weak inhibitors

  25. SSRIs • Increased risk of G.I. bleeding through antiplatelet activity and increased gastric acidity • Hazard Ratio of combining SSRI with: • aspirin- 1.42 clopidogrel 1.54 aspirin and clopidogrel-2.35 • Use PPI to decrease bleeding risk • Note PPI inhibition of CYP2C19 (clopidogrel)- avoid omeprazole and esomeprazole • Pantoprazole is weak inhibitor • Note other medications can affect INR through P450 (2C9 most significant; 1A2, 3A4): reduce dose by ~ 25 %

  26. SSRIs and QT interval • Health Canada- don’t Rx above 40mg • Citalopram (20mg- 8.5ms; 40mg- 12.6ms; 60mg- 18.5ms). • Dose max >65yrs: 20mg <65: 40mg • Escitalopram (10mg- 4.3ms; 30mg- 10.7ms) • Dose max >65 yrs: 10mg • note tdp associated qt>60msΔ

  27. TCAs • Orthostatic hypotension (20%) and tachycardia • Nortriptyline most favorable cardiac profile • Act as class I antiarrhythmic- prolong interventricular conduction; prolong QT • Can cause heart block, asystole, **lethal in overdose • *Avoid- many other options*

  28. Mixed action agents • Limited studies • Venlafaxine: dose dependent BP and HRV; minimal interaction potential (weak 2D6) • Duloxetine: possible hypertension; moderate CYP 2D6 • Mirtazapine: weight and body mass. MIND- IT (negative): no significant changes in cardiovascular indices; minimal interaction potential (weak 1A2, 2D6, 3A4) • Bupropion: May  HR (higher doses). Used widely in smoking cessation in this population with no adverse cardiac events. Moderate interaction (2D6)

  29. QT and Torsades de Pointes • QT modestly associated with TdP (syncope, seizure, sudden death) • Health QTc 400ms, Upper M=450ms F=460ms • >500ms or Δ60ms risk for TdP • RFs: Congenital long QT (1/1000), fam. Hx of sudden death, structural heart disease, bradycardia, reduced renal function, potassium/magnesium/calcium, proarrhythmic agents, reduced renal/hepatic

  30. Benzodiazepines • Generally safe at therapeutic doses • Can cause BP and HR • Hepatic and renal impairment can affect clearance- increasing BP and HR effects (reduce dose in these groups) • Elderly at higher risk

  31. Typical Antipsychotics • Low potency typicals (chlorpromazine)- significant orthostatic hypotension, QT, HR • avoid where possible • High potency typicals (haloperidol)- QT prolongation (esp. IV); moderated 2D6 inhibitor

  32. Atypical Antipsychotics • 2-3 x mortality from CV disease; risk of stroke (role of glucose and lipids?) • Increased risk of venous thromboembolism • Orthostatic hypotension (worse in vol) • Tachycardia (olanzapine least) • QTc prolongation: • ziprasidone>quetiapine/risperidone>aripiprazole (not assoc.)

  33. Atypical antipsychotics • Interactions (Quetiapine best due to limited effect on hepatic oxidation) • Weight and WC- Histamine and Serotonin antagonism, increased leptin sectretion (Olanzapine,clozapine>quetiapine>risperidone> ziprasidone,aripiprazole) • Lipid Profile/Glucose (Olanzapine worst); disease vs. medication vs both? • Clozapine- cardiomyopathy, myocarditis (0.3%) • Avoid Ziprasidone in recent MI, QT, or uncompensated HF

  34. Mood stabilizers • Lithium- generally safe; interactions w. thiazide diuretics, ACE inhibitors, calcium channel blockers, NSAIDs- toxicity • Valproic acid- safe; rare peripheral edema • Carbamazepine- contraindicated in A/V block; hyponatremia; interaction with calcium channel blockers (inhibit metabolism)

  35. Sleep Medications • Zopiclone- generally safe; rare tachycardia or arrhythmia elderly • Trazodone- orthostatic hypotension; uncommon conduction abnormalities

  36. Psychotherapy • CBT • IPT • Collaborative supportive care f/u- eg. post cardiac event

  37. Exercise! ! ! • Exercise effective in depression in cardiac disease; also reduces relapse! • Benefits on cardiac health and metabolic profile • Reduces fatal cardiac events by 25% • Should be part of regimen for every depressed patient!

  38. Summary • Risk/benefit favors treatment • Consider interactions, comorbidities, age • Collaborate with cardiology, GP, pharmacy • Monitor metabolic, EKG, and bleeding profiles • Consider psychotherapy/supportive care • Exercise for all of our patients

  39. Breathless: Psychopharmacology in COPD

  40. COPD: The Context

  41. COPD • Largely caused by smoking • Persistent inflammation of airways, lung parenchyma, vasculature • Cardinal symptom = dyspnea • Associated medical comorbidity • Ischemic heart disease, osteopenia, cachexia and malnutrition, anemia, peripheral muscle dysfunction, cancer, metabolic syndrome

  42. COPD Management: CTS Guidelines O’Donnell et al., Can Resp J, 2008 15(SupplA)

  43. Psychopathology and COPD • Anxiety and depression most common • Depression and anxiety rates vary based on disease severity • 10% (stable disease) to 60-70% (severe disease) • Nicotine dependence, cognitive impairment, sleep disturbances • Maurer et al., 2008

  44. Psychiatric Side Effects of CommonDrugs used to treat COPD Drug Name(s) Bronchodilators Beta-agonists (e.g. short acting – salbutamol, long acting salmeterol) Anticholinergics (e.g. short acting- ipratropium, long-acting-tiotropium) Psychiatric Side Effects Anxiety, insomnia, tremor, palpitations, rare paranoia, hallucinations No significant psychiatric side-effects (vs. atropine), often given in combination with beta agonists

  45. Psychiatric Side Effects of Common Drugs used to treat COPD Drug Name Bronchodilators (cont’d) Theophylline Psychiatric Side Effects Anxiety, insomnia, tremor, restlessness, rare seizures Drug levels may require monitoring (narrow therapeutic window)

  46. Psychiatric Side Effects of Common Drugs used to treat COPD Drug Corticosteroids Inhaled Oral (systemic absorption) Psychiatric Side Effects Uncommon Depression, mania, mood lability, anxiety, insomnia, psychosis, personality changes

  47. Pharmacokinetic Considerations in COPD • Nil in general related to COPD • Consider co-morbidities (e.g. chronic renal failure) • Consider pharmacokinetic and pharmacodynamic changes with ongoing cigarette smoking • Bronchoconstriction • Induction of CYP1A2, 2B6, 2D6

  48. High Risk Drug Choices in COPD Drugs that decrease respiratory drive especially with CO2 retention • Barbiturates • Benzodiazepines with caution

  49. Dosage Alterations in COPD • No specific data • Start low, go slow • Parsimony in prescribing • Drug-drug interactions, patient reticence to take another medication

  50. Antidepressants • In general safe to use • Caution in combining sedating antidepressants with other sedative/hypnotic drugs due to additive potential for respiratory depression

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