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
• 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 2013
rhalil@bruyere.org
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
Antiplatelets
Indications
• Primary prevention MI
– ASA
– Clopidogrel
– Ticlopidine
Indications
• Primary prevention CVA
– ASA
– Clopidogrel
– Ticlopidine
• Secondary prevention MI
–
–
–
–
–
ASA
Clopidogrel
Ticlopidine
Prasugrel
Ticagrelor
• Secondary prevention CVA
–
–
–
–
ASA
Clopidogrel
Ticlopidine
ASA + Dipyridamole MR
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
–
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.
2.
3.
4.
Efficacy
Toxicity
Cost
Convenience
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.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013
Primary Prevention – MI & CVA
3) Cost
4) Convenience
– ASA
– ASA
• Pennies!
• 81mg costs > 325mg
– Can cut 325mg in
1/4th
– Clopidogrel
• ~ $95/mo
– Ticlopidine
• ~ $35/mo
• 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 – MI
Efficacy
Agent
ASA
Monotherapy
Combo w/ ASA
Excellent evidence for NSTEMI,
STEMI, CABG, PCI (low NNTs)
--
Clopidogrel ~ equivalent to ASA (small
Clopidogrel + ASA > ASA
Prasugrel
Prasugrel + ASA > Clop + ASA
absolute improvement per CAPRIE 3-12 mo (CURE trial))
trial)
(ACS, PCI various durations)
Ticagrelor
untested
(ACS + PCI) x12 mo (TRITON-TIMI
38 trial)
Ticagrelor + ASA > Clop + ASA
untested
(ACS + PCI +/- CABG) x12mo
(PLATO trial)
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013
From: Antiplatelet treatment 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.
Secondary Prevention – MI
Toxicity
Agent
ASA
Clopidogrel
Prasugrel
Monotherapy
Combo w/ ASA
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)
--
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)
untested
More fatal and lifethreatening bleeds vs
clopid + ASA
untested
More major and minor
bleeds vs clopid + ASA
More dyspnea, & incr
UA
Ticagrelor
Secondary Prevention – MI
Toxicity
Agent
ASA
Monotherapy
Combo w/ ASA
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 sense
Slightly less GI bleed & GI events except
diarrhea; More Rash
Prasugrel
More major bleeding
vs ASA alone
untested
More fatal and lifethreatening bleeds vs
Clopid + ASA
untested
More major and
minor bleeds vs
Clopid + ASA
More dyspnea &
increased urate
Ticagrelor
Secondary Prevention – MI
3) Cost
– ASA
• Pennies! (only 325mg covered)
– Clopidogrel
• ~ $95/mo
• LU code for MI
– Prasugrel
• ~ $95/mo; not covered
– Ticagrelor
4) Convenience
– ASA
• 75-325mg once daily
– Clopidogrel
• 75mg once daily
– Prasugrel
• 10mg once daily
– Tigagrelor
• 90mg BID po
• ~ $105/mo; not covered
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 – CVA
Efficacy
Agent
ASA
Ticlopidine
Monotherapy
Combo w/ ASA
ASA ~23% RRR > placebo
NNT ~ 50-100 x1 year to prevent
any vascular event. (50-325mg)
(CAST, IST, SALT, Dutch-TIA trials)
--
Superior to ASA
(CATS & TASS trials)
Clopidogrel Equivalent to ASA
(extremely small absolute
improvement per CAPRIE trial)
Aggrenox®
unknown
Possible improvement for 1st 21 days
post CVA (CHANCE trial)
No benefit long term (CHARISMA,
MATCH trials)
Superior to ASA (ESPRIT & ESPS2
trials), but Equivalent to
Clopidogrel (PRoFESS trial) whaa?
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013
From: Antiplatelet treatment 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.
--
Secondary Prevention – CVA
Toxicity
Agent
ASA
Monotherapy
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
Aggrenox®
Combo w/ ASA
More headache, diarrhea, GI upset,
dizziness, & early D/C vs ASA or Clopidogrel
More intracranial bleed vs Clopidogrel
-More bleeding vs
ASA alone
(CHARISMA & MATCH
trials)
--
Secondary Prevention – CVA
3) Cost
– ASA
• Pennies!
– Clopidogrel
• ~ $95/mo
• LU code for ASA
intolerance only
– Aggrenox®
4) Convenience
– ASA
• 75-325mg once daily
– Clopidogrel
• 75mg once daily
– Aggrenox®
• 200/25mg BID po
• ~ $61/mo
• LU code for CVA
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
Warfarin
Efficacy
Toxicity
Excellent vs placebo or ASA
1.3% - 3.5% -- major bleed
< 0.25% - 0.5%/yr -- ICH
~ same
Dabigatran
Rivaroxaban
N.B. (~1% absolute difference)
(RE-LY trial - industry funded)
~ same
N.B. (<1% absolute difference)
(ROCKET-AF trial – industry funded)
~ same
Apixaban
N.B. (<1% absolute difference)
(ARISTOTLE trial – industry
funded)
Less intracranial & More GI
bleeds; ?More MI?
Untested > 79y.o. or CrCL < 30
NO reversal agent
Less intracranial & More GI
bleeds
Untested > 79y.o. or CrCL < 30
NO reversal agent
Less intracranial bleeds
GI bleeding – no difference
Untested > 77y.o. or CrCL < 30
NO reversal agent
Rxfiles.ca Comparison of Warfarin & New Oral Anticoagulants (NOACs) in Non-Valvular Atrial Fibrillation 07/03/2013
Anticoagulants
(VTE, Afib, Valve disease)
Agent
Warfarin
Dabigatran
Cost
Convenience
~ $40/mo
(with INR monitoring)
QD po
INR q3d – q1mo
$110/mo
Rivaroxaban
$100/mo
Apixaban
$140/mo
(ODB covered)
BID po
(ODB w/ LU code 431 for
AFib)
QD with food
(ODB w/ LU code post-op
TRK/THA)
BID po
No 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 2013
rhalil@bruyere.org
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 overestimation 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, antihistaminergic & weight
gain effects often go handin-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
• Convenience
– 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
– 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 2013
rhalil@bruyere.org
Anti-psychotics
Typical (1st gen / conventional)
(Relative terms)
• Butyrophenones
– Haloperidol & Droperidol
• Phenothiazines
–
–
–
–
–
–
–
Chlorpromazine & Fluphenazine
Perphenazine & Prochlorperazine
Thioridazine & Trifluoperazine
Mesoridazine & Periciazine
Promazine & Triflupromazine
Levomepromazine & Promethazine
Pimozide
• Thioxanthenes
– Chlorprothixene & Clopenthixol
– Flupenthixol & Thiothixene
– Zuclopenthixol
Atypical (2nd gen)
• Clozapine
• Olanzapine
• Quetiapine
• Risperidone
• Aripiprazole
• Ziprasidone
• Paliperidone
• Asenapine
etc.
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?
• rhalil@bruyere.org
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @Roland Halil, PharmD