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Back to Basics Practical Pharmacology – part 3 Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University.

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Presentation on theme: "Back to Basics Practical Pharmacology – part 3 Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University."— Presentation transcript:

1 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

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

5 Anti-Thrombotics From:

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 P2Y 12 Thienopyridines Clopidogrel & Ticlopidine – Prodrugs activated 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 P2Y 12

9 How to Choose? (if only there was a process…) 1.Efficacy 2.Toxicity 3.Cost 4.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: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013www.Rxfiles.ca

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

12 Bottom Line – 1 o 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: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013www.Rxfiles.ca

13 Secondary Prevention – MI Efficacy AgentMonotherapyCombo w/ ASA ASA Excellent evidence for NSTEMI, STEMI, CABG, PCI (low NNTs) -- Clopidogrel ~ equivalent to ASA (small absolute improvement per CAPRIE trial) Clopidogrel + ASA > ASA 3-12 mo (CURE trial)) (ACS, PCI various durations) Prasugrel untested Prasugrel + ASA > Clop + ASA (ACS + PCI) x12 mo (TRITON-TIMI 38 trial) Ticagrelor untested Ticagrelor + ASA > Clop + ASA (ACS + PCI +/- CABG) x12mo (PLATO trial) From: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013www.Rxfiles.ca From: Antiplatelet treatment Accessed Apr 4/13http://cks.nice.org.uk/antiplatelet-treatment#!management From: Accessed Apr 4/13.http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf

14 Secondary Prevention – MI Toxicity AgentMonotherapyC ombo w/ ASA ASA w/ ASA: rate of hemorrhagic events = 5.58 (95% CI, ) / 1000 pt-yrs VS. w/o ASA: 3.60 (95% CI, ) Incidence rate ratio: 1.55; (95% CI, ) -- Clopidogrel Less GI bleed - clopidogrel < ASA (1.99% vs 2.66% p < 0.002) (Less severe GI bleed vs 0.71%; p < 0.05) Less GI events - clopidogrel < ASA (27.1 vs 29.8%; p < 0.001) More Diarrhea clopidogrel > ASA (4.46 vs 3.36%; p < 0.001) More Rash – clopidogrel > ASA (6.0% vs 4.6% p < 0.001) No difference in: Early D/C, Neutropenia, Thrombocytopenia & Intracranial bleed. (per CAPRIE) Major bleeding – clop + ASA > ASA (3.7% vs. 2.7%; RR = 1.38; P=0.001), Life-threatening bleeding - no diff (2.1 percent vs. 1.8 percent, P=0.13) Hemorrhagic strokes – no diff (per CURE trial) Prasugrel untested More fatal and life- threatening bleeds vs clopid + ASA Ticagrelor untested More major and minor bleeds vs clopid + ASA More dyspnea, & incr UA

15 Secondary Prevention – MI Toxicity AgentMonotherapyC ombo w/ ASA ASA w/ ASA: rate of hemorrhagic events = 5.58 (95% CI, ) / 1000 pt-yrs VS. w/o ASA: 3.60 (95% CI, ) Incidence rate ratio: 1.55; (95% CI, ) -- Clopidogrel ~ equivalent in absolute sense Slightly less GI bleed & GI events except diarrhea; More Rash More major bleeding vs ASA alone Prasugrel untested More fatal and life- threatening bleeds vs Clopid + ASA Ticagrelor untested More major and minor bleeds vs Clopid + ASA More dyspnea & increased urate

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 mg once daily – Clopidogrel 75mg once daily – Prasugrel 10mg once daily – Tigagrelor 90mg BID po From: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013www.Rxfiles.ca

17 Bottom Line: 2 o Prevention MI ASA + Clopidogrel x 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 – CVA Efficacy AgentMonotherapyCombo w/ ASA ASA ASA ~23% RRR > placebo NNT ~ x1 year to prevent any vascular event. (50-325mg) (CAST, IST, SALT, Dutch-TIA trials) -- Ticlopidine Superior to ASA (CATS & TASS trials) unknown Clopidogrel Equivalent to ASA (extremely small absolute improvement per CAPRIE trial) Possible improvement for 1 st 21 days post CVA (CHANCE trial) No benefit long term (CHARISMA, MATCH trials) Aggrenox® Superior to ASA (ESPRIT & ESPS2 trials), but Equivalent to Clopidogrel (PRoFESS trial) whaa? -- From: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013www.Rxfiles.ca From: Antiplatelet treatment Accessed Apr 4/13http://cks.nice.org.uk/antiplatelet-treatment#!management From: Accessed Apr 4/13.http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf

19 Secondary Prevention – CVA Toxicity AgentMonotherapyC ombo w/ ASA ASA Low, but look at additive bleeding risk factors: ( 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 ~ equivalent in absolute sense Slightly less GI bleed & GI events except diarrhea; More Rash More bleeding vs ASA alone (CHARISMA & MATCH trials) Aggrenox ® More headache, diarrhea, GI upset, dizziness, & early D/C vs ASA or Clopidogrel More intracranial bleed vs Clopidogrel --

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 mg once daily – Clopidogrel 75mg once daily – Aggrenox® 200/25mg BID po From: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013www.Rxfiles.ca

21 Bottom Line 2 o 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) AgentEfficacyToxicity WarfarinExcellent vs placebo or ASA 1.3% - 3.5% -- major bleed < 0.25% - 0.5%/yr -- ICH Dabigatran ~ same N.B. (~1% absolute difference) (RE-LY trial - industry funded) Less intracranial & More GI bleeds; ?More MI? Untested > 79y.o. or CrCL < 30 NO reversal agent Rivaroxaban ~ same N.B. (<1% absolute difference) (ROCKET-AF trial – industry funded) Less intracranial & More GI bleeds Untested > 79y.o. or CrCL < 30 NO reversal agent Apixaban ~ same N.B. (<1% absolute difference) (ARISTOTLE trial – industry funded) Less intracranial bleeds GI bleeding – no difference Untested > 77y.o. or CrCL < 30 NO reversal agent

24 Rxfiles.ca Comparison of Warfarin & New Oral Anticoagulants (NOACs) in Non-Valvular Atrial Fibrillation 07/03/2013

25 Anticoagulants (VTE, Afib, Valve disease) Agent CostConvenience Warfarin ~ $40/mo (with INR monitoring) QD po INR q3d – q1mo (ODB covered) Dabigatran$110/mo BID po (ODB w/ LU code 431 for AFib) Rivaroxaban$100/mo QD with food (ODB w/ LU code post-op TRK/THA) Apixaban$140/mo BID po No coverage yet

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

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 irrev MAOi’s!)

31 Anti-depressants & Anxiolytics Cost – All ~ $25 - $35 / month – Newest agents, without generics cost more. Bupropion XL – $45/mo Escitalopram – $65/mo Paroxetine CR – $60/mo – Not covered under ODB Desvenlafaxine – $85/mo – Not covered under ODB Convenience – Most once daily – Bupropion SR – BID Bupropion XL – 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 !

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

35 Anti-psychotics Typical (1 st gen / conventional) (Relative terms) Atypical (2 nd 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? Tardive Dyskinesia – 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 – Olanzapine Zydis (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 – cuments/members/Cht-Psyc-Neuroleptics.pdf cuments/members/Cht-Psyc-Neuroleptics.pdf

42 Comments, Questions & Requests? Monday & Fridays: – ext 238 Tuesday, Wednesday, Thursday: – ext 327 Halil, PharmD


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