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Back to Basics Practical Pharmacology – part 3

Back to Basics Practical Pharmacology – part 3. Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2013 rhalil@bruyere.org. Objectives.

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Back to Basics Practical Pharmacology – part 3

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  1. Back to BasicsPractical Pharmacology – part 3 Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2013 rhalil@bruyere.org

  2. Objectives • List the 4 steps in rationalizing drug therapy choices using evidence based medicine. • List the important parameters in choosing anti-thrombotic and psychiatric drugs in a clinical setting. • Identify clinically important differences in the efficacy, toxicity, cost and convenience of these different drugs. • Recognize the inherent weaknesses of current guidelines.

  3. Topics • Anti-Thrombotics • Anti-platelets • Anti-coagulants • Psychiatric Medications • Anti-depressants • Anxiolytics • Anti-psychotics

  4. Oral Anti-Thrombotics Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2013 rhalil@bruyere.org

  5. Anti-Thrombotics From: http://en.wikipedia.org/wiki/Direct_thrombin_inhibitor

  6. Oral Anti-thrombotics Antiplatelets • ASA • ASA + Dipyridamole MR • (Aggrenox®) • Thienopyridines: • Clopidogrel • Ticlopidine • Prasugrel • Ticagrelor Anticoagulants • Warfarin • Dabigatran • Rivaroxaban • Apixaban

  7. Antiplatelets Indications • Primary prevention MI • ASA • Clopidogrel • Ticlopidine • Secondary prevention MI • ASA • Clopidogrel • Ticlopidine • Prasugrel • Ticagrelor Indications • Primary prevention CVA • ASA • Clopidogrel • Ticlopidine • Secondary prevention CVA • ASA • Clopidogrel • Ticlopidine • ASA + Dipyridamole MR

  8. Mechanisms of Action ASA • Irreversible inh of COX-1 • (thromboxane reduction) • Platelet lifespan: 7-10 days Dipyridamole MR • inh the uptake of adenosine & breakdown of cGMP Ticagrelor • Reversible inhibition of ADP platelet receptor subtype P2Y12 Thienopyridines • Clopidogrel & Ticlopidine • Prodrugsactivated by P450-2C19 • N.B. 2% - 14% of population are poor metabolizers • Prasugrel • Prodrug activated by ester bond hydrolysis via: • Irreversible inhibition of ADP platelet receptor subtype P2Y12

  9. How to Choose?(if only there was a process…) • Efficacy • Toxicity • Cost • Convenience

  10. Primary Prevention – MI & CVA 1) Efficacy (all ~ equivalent) • ASA(++ evidence) • 75mg = 325mg daily • “For older patients with risk factors” • CHEST’12: >50yrs consider risk vs benefit • CCS’11: not recommended • AHA’10: if 10yr CAD risk ≥10% • USPSTF’09: men 45‐79 yrs if low bleed risk • Diabetes: men≥45yr/women≥50yr; & ≥1 risk factor (smoking,↑BP, ↑ lipids, history of young parenteral MI, albuminuria) • Clopidogrel & Ticlopidine • Little direct evidence • Only for ASA allergy or intolerance 2) Toxicity (bleeding ~ same) • ASA • NNH 125; major bleeds (WHS trial) • Any GI bleed ~ 2.7% (severe 0.7%) • Dyspepsia ~ 5% • Clopidogrel (C) & Ticlopidine(T) • Bleed: • Any GI bleed 2% (severe 0.5%) (C) • Rash: • 6% (C) / 12% (3% severe) (T) • TTP: • >20/3 million (C) / >1/5000 (T) • Neutropenia: • <1% (C) / 2.4% (T) !! From: www.Rxfiles.caORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

  11. Primary Prevention – MI & CVA 3) Cost • ASA • Pennies! • 81mg costs > 325mg • Can cut 325mg in 1/4th • Clopidogrel • ~ $95/mo • Ticlopidine • ~ $35/mo 4) Convenience • ASA • 75-325mg once daily • Clopidogrel • 75mg once daily • Ticlopidine • 250mg BIDpo • Requires regular monitoring of CBC, LFTs From: www.Rxfiles.caORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

  12. Bottom Line – 1o Prevention MI & CVA • ASA. • Most evidence, well tolerated, cheap cheap!, QD • Consider bleed risks, even with “baby” ASA (81mg) • RISK FACTORS FOR BLEEDING: • Age >75 yrs, DM, elevated INR warfarin, female, ↓ hematocrit, HF/MI, ↑HR, length of antithrombotic tx, liver dx, ↑↓ systolic BP, medications (e.g. anticoagulants, antiplatelets, NSAIDs), previous GI bleed or stroke noncardioembolic, ↑Scr, ↓ wt. • Clopidogrel only if ASA allergic / severe intolerance • Ignore ticlopidine: • Little evidence, serious toxicities, BID dosing plus regular blood work! • No evidence for Aggrenox® in primary prevention From: www.Rxfiles.caORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

  13. Secondary Prevention – MIEfficacy From: www.Rxfiles.caORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013 From: Antiplatelettreatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13 From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.

  14. Secondary Prevention – MIToxicity

  15. Secondary Prevention – MIToxicity

  16. Secondary Prevention – MI 3) Cost • ASA • Pennies! (only 325mg covered) • Clopidogrel • ~ $95/mo • LU code for MI • Prasugrel • ~ $95/mo; not covered • Ticagrelor • ~ $105/mo; not covered 4) Convenience • ASA • 75-325mg once daily • Clopidogrel • 75mg once daily • Prasugrel • 10mg once daily • Tigagrelor • 90mg BIDpo From: www.Rxfiles.caORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

  17. Bottom Line: 2o Prevention MI • ASA + Clopidogrelx 3- 12 mo, then ASA alone • Clopidogrel alone if ASA allergy • Prasugrel only in cardiac centres post ACS + PCI & if no excess bleed risks

  18. Secondary Prevention – CVAEfficacy From: www.Rxfiles.caORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013 From: Antiplatelettreatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13 From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.

  19. Secondary Prevention – CVAToxicity

  20. Secondary Prevention – CVA 3) Cost • ASA • Pennies! • Clopidogrel • ~ $95/mo • LU code for ASA intolerance only • Aggrenox® • ~ $61/mo • LU code for CVA 4) Convenience • ASA • 75-325mg once daily • Clopidogrel • 75mg once daily • Aggrenox® • 200/25mg BIDpo From: www.Rxfiles.caORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

  21. Bottom Line 2o Prevention CVA • ASA or Clopidogrel or Aggrenox® • Any will do, until tie breaker trial between these agents. • Aggrenox® might be more efficacious, but with more side effects and less convenience.

  22. Anticoagulants • Warfarin • Vitamin K antagonist • (clotting factors 2,7,9,10, protein C & S) • For: Afib, VTE prophylaxis & tx, valvular disease • Dabigatran • Direct thrombin inhibitor (factor 2) • For: Afib, VTE prophylaxis post-op TKR/THA • (N.B. Ximelagatran – withdrawan due to hepatotoxicity) • Rivaroxaban • Factor Xa inhibitor • For: Afib, VTE prophylaxis post-op TKR/THA, DVT tx • Apixaban • Factor Xa inhibitor • For: Afib, VTE prophylaxis post-op TKR/THA

  23. Anticoagulants (VTE, Afib, Valve disease)

  24. Rxfiles.caComparison of Warfarin & New Oral Anticoagulants (NOACs) in Non-ValvularAtrial Fibrillation07/03/2013

  25. Anticoagulants (VTE, Afib, Valve disease)

  26. Summary • Antiplatelets • Small differences in efficacy or toxicity, dictate that cost will drive selection. • = ASA • Combination therapy where indicated • Anticoagulants • Small differences in efficacy and important unknowns in newer agents (age effects, renal dysfunction, lack of antidotes) dictate selection of warfarin except for carefully selected patients with significant compliance barriers due to the inconvenience of INR testing.

  27. Anti-depressants & Anxiolytics Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2013 rhalil@bruyere.org

  28. Anti-depressants & Anxiolytics • Selection of therapy: • Efficacy: All equivalent! • N.B. Wouldn’t use Bupropion for anxiety • Therefore, tailor therapy based on potential toxicities! • Meta-analyses that include grey literature trials show an over-estimation of efficacy and an under-appreciation of toxicity. • SSRI’s: • Fluoxetine, sertraline, (es)citalopram, fluvoxamine, paroxetine • SNRI’s: • (des)venlafaxine, duloxetine • Mirtazapine • Bupropion • TCA’s: • Amitriptyline, nortriptyline, despramine, imipramine, clomipramine, doxepin • MAOi’s: (+++ types) • Moclobemide (reversible) • Phenelzine (irreversible) etc. etc.

  29. Toxicities • Anti-cholinergic effects • Paroxetine • Mirtazipine • (des)Venlafaxine • TCAs: • amitriptyline > nortriptyline > desipramine • N.B. Anti-cholinergic, anti-histaminergic & weight gain effects often go hand-in-hand. • Wt gain is usually minimal • Some subpopulations gain++ • Sedation • TCAs • Fluvoxamine • Paroxetine (less extent) • Mirtazapine • Trazodone • Activation • Fluoxetine • Bupropion • (des)Venlafaxine • Moclobemide

  30. Toxicities • GI side effects • Nausea - SSRIs • Constipation - TCAs • Diarrhea - sertraline, fluoxetine, paroxetine, duloxetine • QTc prolongation (TdP) • TCA’s • Citalopram > 40mg/day • Escitalopram > 20mg/day • Sexual dysfunction • SSRIs (>30% !) • TCAs • N.B. More serotonin = less libido • More dopamine = more libido • Drug/disease interactions • Least with: (es)citalopram, mirtazapine, moclobemide, sertraline, (des)venlafaxine • Moclobemide: • no tyramine restrictions (unlike irrevMAOi’s!)

  31. Anti-depressants & Anxiolytics • Cost • All ~ $25 - $35 / month • Newest agents, without generics cost more. • BupropionXL • $45/mo • Escitalopram • $65/mo • ParoxetineCR • $60/mo • Not covered under ODB • Desvenlafaxine • $85/mo • Not covered under ODB • Convenience • Most once daily • BupropionSR – BID • BupropionXL – QD • Moclobemide - BID

  32. The Evils of Benzodiazepines(Yes, this includes “z-drug, non-benzo alternatives” Eg. Zopiclone) • Formerly one of the most commonly prescribed drug families of the 1960’s and 1970’s. • In 1975 – 100 million Rxs written in USA alone • Efficacy – excellent SHORT term efficacy • Sedation & anxiolysis • Rapid tolerance is developed • Toxicity – addictive! • D/C’ing after tolerance develops is VERY hard • Long term risk of dementia, falls, and memory impairment • Withdrawal can be fatal • Cost & Convenience – Hey!, Fuggetabout-it! • http://www.youtube.com/watch?v=tfGYSHy1jQs • http://www.youtube.com/watch?v=Zf0ZyoUn7Vk • http://www.youtube.com/watch?v=J5Xu9UcOdj0

  33. Summary • Highly variable response in efficacy • All ~ equivalent in efficacy • Trial and error • Tailor to potential toxicities to maintain compliance • Focus on relative toxicities! • Efficacy often overestimated and toxicity often underestimated • Avoid Benzodiazepines and Zopiclone (addictive) • Even Rx’s for 10 tabs often snowball into chronic use.

  34. Anti-psychotics Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2013 rhalil@bruyere.org

  35. Anti-psychoticsTypical (1st gen / conventional) (Relative terms)Atypical (2nd gen) • Butyrophenones • Haloperidol & Droperidol • Phenothiazines • Chlorpromazine & Fluphenazine • Perphenazine & Prochlorperazine • Thioridazine & Trifluoperazine • Mesoridazine & Periciazine • Promazine & Triflupromazine • Levomepromazine & Promethazine • Pimozide • Thioxanthenes • Chlorprothixene & Clopenthixol • Flupenthixol & Thiothixene • Zuclopenthixol • Clozapine • Olanzapine • Quetiapine • Risperidone • Aripiprazole • Ziprasidone • Paliperidone • Asenapine etc.

  36. Anti-psychotics • Efficacy • No clinically relevant differences (variable responses) • ?Olanzapine superiority? • See CATIE trial • Exception: Clozapine – clearly superior • As ever, when efficacy is ~ equivalent, choose therapy based on potential toxicities

  37. Anti-psychotics • Toxicities: • Clozapine: • Agranulocytosis (10x higher risk vs other antipsychotics) • Hence, mandatory CBC q2-4weeks • Therefore, last line therapy, despite superior efficacy

  38. Toxicities • Sedation • Quetiapine • Olanzapine • Clozapine • Typicals • Least: haloperidol, risperidone, aripiprazole?, ziprasidone? • Weight gain • Clozapine • Olanzapine • Quetiapine • Least: haloperidol, risperidone, aripiprazole?, ziprasidone? • TardiveDyskinesia • Typicals • Least: Clozapine (esp), all atypicals • Anticholinergic effects • Clozapine • Typicals • Least: risperidone, quetiapine, haloperidol

  39. Toxicities • EPS • Typicals • Least: atypicals • QTc prolongation • Clozapine • Paliperidone • Ziprasidone • Pimozide • Asenapine • Thioridazine • Least: Risperidone, haloperidol, aripiprazole, olanzapine, low dose quetiapine • Hypotension • Clozapine • Risperidone • Typicals • Least: olanzapine, haloperidol, ziprasidone, paliperidone

  40. Antipsychotics • Cost • ~ $20 - $40/month • More expensive: • Newest agents: • Aripiprazole • Ziprasidone • Paliperidone • Asenapine • Clozapine • Quetiapine (XR) • Olanzapine (Zydis) • Convenience • Most BID po • Some injectable, long acting forms • Risperidone • Paliperidone • Flupentixol • Pipotiazine • Fluphenazine • Zuclopenthixol • Haloperidol • OlanzapineZydis (melts) • Risperidone M-tab (melts)

  41. Summary • Choose anti-psychotics based on potential toxicities • Learn two or three very well that complement each other. • Low threshold to confer with psychiatry or pharmacy • Rxfiles – excellent comparison charts to help guide therapy • http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/documents/members/Cht-Psyc-Neuroleptics.pdf

  42. Comments, Questions & Requests? • rhalil@bruyere.org • Monday & Fridays: • 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: • 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD

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