Back to Basics Practical Pharmacology – part 3 Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD...
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Transcript of Back to Basics Practical Pharmacology – part 3 Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD...
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 [email protected]
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.
Topics
• Anti-Thrombotics– Anti-platelets– Anti-coagulants
• Psychiatric Medications– Anti-depressants– Anxiolytics– Anti-psychotics
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 [email protected]
Anti-Thrombotics
From: http://en.wikipedia.org/wiki/Direct_thrombin_inhibitor
Oral Anti-thrombotics
Antiplatelets• ASA• ASA + Dipyridamole MR– (Aggrenox®)
• Thienopyridines:– Clopidogrel– Ticlopidine– Prasugrel
• Ticagrelor
Anticoagulants• Warfarin• Dabigatran• Rivaroxaban• Apixaban
AntiplateletsIndications
• 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
Mechanisms of ActionASA
• 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
– 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 P2Y12
How to Choose?(if only there was a process…)
1. Efficacy2. Toxicity3. Cost4. Convenience
Primary Prevention – MI & CVA1) 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.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013
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 BID po• Requires regular
monitoring of CBC, LFTs
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013
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.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013
Secondary Prevention – MIEfficacy
Agent Monotherapy Combo w/ ASAASA 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)
Prasugreluntested
Prasugrel + ASA > Clop + ASA (ACS + PCI) x12 mo (TRITON-TIMI 38 trial)
Ticagreloruntested
Ticagrelor + ASA > Clop + ASA (ACS + PCI +/- CABG) x12mo (PLATO trial)
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.
Secondary Prevention – MIToxicity
Agent Monotherapy Combo w/ ASAASA w/ ASA: rate of hemorrhagic events = 5.58 (95% CI, 5.39-5.77) /
1000 pt-yrs VS. w/o ASA: 3.60 (95% CI, 3.48-3.72) Incidence rate ratio: 1.55; (95% CI, 1.48-1.63)
--
Clopidogrel Less GI bleed - clopidogrel < ASA (1.99% vs 2.66% p < 0.002) (Less severe GI bleed - 0.49 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)
Prasugreluntested
More fatal and life-threatening bleeds vs clopid + ASA
Ticagreloruntested
More major and minor bleeds vs clopid + ASAMore dyspnea, & incr UA
Secondary Prevention – MIToxicity
Agent Monotherapy Combo w/ ASAASA w/ ASA: rate of hemorrhagic events = 5.58 (95%
CI, 5.39-5.77) / 1000 pt-yrs VS. w/o ASA: 3.60 (95% CI, 3.48-3.72)
Incidence rate ratio: 1.55; (95% CI, 1.48-1.63)
--
Clopidogrel ~ equivalent in absolute senseSlightly less GI bleed & GI events except diarrhea; More Rash
More major bleeding vs ASA alone
Prasugreluntested
More fatal and life-threatening bleeds vs Clopid + ASA
Ticagrelor
untested
More major and minor bleeds vs Clopid + ASAMore dyspnea & increased urate
Secondary Prevention – MI3) 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 BID po
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013
Bottom Line: 2o Prevention MI
• ASA + Clopidogrel x 3- 12 mo, then ASA alone– Clopidogrel alone if ASA allergy– Prasugrel only in cardiac centres post ACS + PCI &
if no excess bleed risks
Secondary Prevention – CVAEfficacy
Agent Monotherapy Combo w/ ASAASA ASA ~23% RRR > placebo
NNT ~ 50-100 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 1st 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: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.
Secondary Prevention – CVAToxicity
Agent Monotherapy Combo w/ ASAASA 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 senseSlightly 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--
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 BID po
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013
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.
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
Anticoagulants (VTE, Afib, Valve disease)
Agent Efficacy Toxicity
Warfarin Excellent 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 < 30NO reversal agent
Rivaroxaban~ same
N.B. (<1% absolute difference)(ROCKET-AF trial – industry funded)
Less intracranial & More GI bleedsUntested > 79y.o. or CrCL < 30NO reversal agent
Apixaban~ same
N.B. (<1% absolute difference)(ARISTOTLE trial – industry
funded)
Less intracranial bleedsGI bleeding – no differenceUntested > 77y.o. or CrCL < 30NO reversal agent
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Anticoagulants (VTE, Afib, Valve disease)
Agent Cost Convenience
Warfarin ~ $40/mo (with INR monitoring)
QD poINR q3d – q1mo
(ODB covered)
Dabigatran $110/moBID po
(ODB w/ LU code 431 for AFib)
Rivaroxaban $100/moQD with food
(ODB w/ LU code post-op TRK/THA)
Apixaban $140/mo BID poNo coverage yet
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.
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 [email protected]
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.
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
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!)
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
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
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.
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 [email protected]
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• Asenapineetc.
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
Anti-psychotics
• Toxicities:– Clozapine: • Agranulocytosis (10x higher risk vs other antipsychotics)• Hence, mandatory CBC q2-4weeks• Therefore, last line therapy, despite superior efficacy
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
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
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)
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/do
cuments/members/Cht-Psyc-Neuroleptics.pdf
Comments, Questions & Requests?
• [email protected]• Monday & Fridays: – 613-230-7788 ext 238
• Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327
• Twitter: @Roland Halil, PharmD