Download B2B Basics Pharmacology Review

Back to Basics
Practical Pharmacology
Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Assistant Professor, Dept of Family Medicine, University of Ottawa
Clinical Pharmacist, Bruyere Academic Family Health Team
March 2017
[email protected]
Objectives
• Review all pharmacology in an abnormally short
amount of time in preparation for LMCC
• Apply knowledge of pharmacology to rationalize
the application of therapeutics
• List the four steps of rational prescribing
• Understand the pharmacological classes, generic
examples and mechanisms of action of important
tools in the practice of medicine.
• Understand how the pharmaco-kinetics and
dynamics of these agents can affect their use
• Highlight clinical pearls in the proper use of these
agents in practice.
Adding Pharmacology to your
Knowledge Base
(Pharmacology Informs Therapeutics)
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
Objectives
• To promote an efficient process for
incorporating pharmacology into your body of
knowledge
• To promote the creation of a “personal
formulary” during your residency.
Pharmacology
Therapeutics
=
Mechanism of Action
+
Pharmacokinetics
+
Pharmacodynamics
=
Pharmacology
+
Pathophysiology
Pharmacology
• Impossible to know during clerkship
– Every drug in every specialty? Get real.
• Possible to know during residency!
– Build your Personal Formulary
• Drugs that will be bread & butter during your career.
– How?
Personal Formulary
Pharmacology
• Pick one drug per class to become the
workhorse in your personal formulary.
– Need help? Ask a Pharmacist:
• What is your favourite member of any drug class?
• Why?
• Knows the in’s and out’s of that drug:
– Learn its Pharmacology
• (Pharmacology = M.O.A. + PK + PD)
+
– Dosing range, Cost / Drug coverage status, Dosage
forms available
Learning Pharmacology
Open a Drug
Database Software
Review Pharmaco-Kinetics
• Half-Life (t ½) – Long or Short?
• Clearance: Renal or Hepatic?
• If Hepatic: CYP-450?
Total:
3 min
Review
Mechanism of
Action
Review Pharmaco-Dynamics
(ie. Top 3 Side Effects)
• Rare & Severe
• Common & Bothersome
Pharmacology
• Learn the drugs that will be part of your
personal formulary.
– Build your formulary wisely.
• Brief & regular review will help you own it!
– Patients are treated more optimally
– Fewer side effects
– Less risk of litigation
– Better use of health care dollars
– Better likelihood of compliance
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
A Process for
Rational Prescribing
(your new best friend)
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
Objectives
• To promote an efficient process for selecting
optimal drug therapy for patients
• To promote a process for applying populationlevel EBM to individual patients.
Michael J. Mauboussin
Adjunct professor of finance at Columbia Business School
Managing Director and Head of Global Financial Strategies at Credit Suisse
• Prescribing is a probabilistic field
– Eg. investing, poker, baseball etc.
• Probabilistic players focus on:
1.
2.
3.
4.
Process versus outcome
A constant search for favorable odds
An understanding of the role of time
Weighing probabilities and outcomes
• i.e. an expected value mindset.
5. Awareness of factors that distort
judgment
• i.e. cognitive biases
Mauboussin, M. Decision-Making for Investors: Theory, Practice & Pitfalls. May 24, 2004 http://www.retailinvestor.org/pdf/decisionmaking.pdf Accessed Mar 7/16
Process
Process vs Outcome
Tragic / Malpractice
Skill
Skill & luck
Luck
Role of Time:
Michael Lewis makes this point convincingly using statistics from major
league baseball: “Over a long season the luck evens out, and skill shines through.”
Mauboussin, M. Decision-Making for Investors: Theory, Practice & Pitfalls. May 24, 2004 http://www.retailinvestor.org/pdf/decisionmaking.pdf Accessed Mar 7/16
Dr. Daniel Kahneman
Eugene Higgins Professor of Psychology Emeritus
Nobel Prize in Economic Sciences in 2002
• Success in prescribing
requires objective,
counter-intuitive
thinking
• We must set aside
our rapid heuristics
and Think Slow.
Dr. Keith Stanovich
Professor Emeritus of Applied Psychology and Human Development, University of Toronto
Rational and Irrational Thought:
The Thinking That IQ Tests Miss
Why smart people sometimes do dumb things
By Keith E. Stanovich
“No doubt you know several folks with perfectly
respectable IQs who repeatedly make poor decisions.
The behavior of such people tells us that we are missing
something important by treating intelligence as if it
encompassed all cognitive abilities.”
http://www.keithstanovich.com/Site/Research_on_Reasoning.html
Stanovich, K. E. (2015, Winter). Rational and Irrational Thought: The Thinking that IQ Tests Miss. Scientific
American Mind Special Collector’s Edition, 23(4), 12-17. Stanovich_Sci_American_2015.pdf
A Method of Prioritization
• Scarce resources:
– Your time
– Our money
• Resource allocation is
central to decisionmaking in any health
care system.
K C Calman. The ethics of allocation of scarce health care resources: a view from the centre. J Med Ethics. 1994 Jun; 20(2): 71–74.
PMCID: PMC1376429 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1376429/
ETHICS IN MEDICINE University of Washington School of Medicine https://depts.washington.edu/bioethx/topics/resall.html Accessed
Mar 7/16.
A Structure Requires Process
To prescribe or not to prescribe?
(That is the question…)
•
Rational prescribing requires a process for
selecting therapy: (in order)
1.
2.
3.
4.
Benefit
Harm
Cost
Convenience
Step 1: Benefit
How good is good?
aka
“Take this drug, it doesn’t do anything,
but it’s totally safe”
Benefit
1. Type of intervention:
What will reduce:
1. Mortality
2. Morbidity
3. Surrogate markers
4. Symptoms
Palliative Care
Disease management
“Do you want the drug that prevents death from stroke and lowers
your cholesterol…or the one that lowers your cholesterol?”
Benefit
2. Quality of evidence? (Hierarchy of evidence)
“Take this drug, it’ll
reduce the risk of
death, because my
grandma said so”
Robert Yokl. Good Evidence: The Missing Link. Apr 08, 2013. http://valueanalysismag.com/good-evidence-the-missing-link/
Benefit
“Take this drug, it’ll reduce mortality, as per 5 well designed RCTs,
by 0.001%.”
3. Quantity of evidence? (ie. effect size)
a) Absolute is more important than relative
– Eg. 2%  1%
= 1% absolute risk reduction (i.e. 50% relative risk reduction)
b) Number-needed to treat (NNT)
– The inverse of the ARR. (NNT = 100)(=1/0.01)
– Useful for the shepherd (population health)
c) Converse informs patients better than inverse
– Eg. Without treatment, 98% will be unaffected
– With treatment, 99% will be unaffected
– Useful for the flock (individual health)
Number Needed to Treat http://www.med.uottawa.ca/sim/data/Number_Needed_to_Treat_e.htm Accessed Nov 2/14
Benefit
Quantity
4. Time to benefit?
– The fourth dimension
Quality
Type
“Take this drug, it’ll
reduce mortality by 50%
as per many RCTs,
but you need to be on it
for 20 years to see a
benefit.”
Benefit
Four Priorities
• The key is the prioritization of:
• Benefit before harm
• Efficacy endpoints,
– ↓Mortality before ↓ symptoms
• Evidence quality and
• Evidence quantity
– Big before small
• Time to benefit
– Acute before chronic
– Sooner before later!
Benefit
• If there is no benefit, why waste your time on
the potential harm, cost and inconvenience of
a drug?
• If there is efficacy, it is usually proven in
populations. Balance this against the potential
toxicity to the individual.
Primum non nocere
• When EBM is strong:
– Benefit easily
outweighs Harm
– Only very specific
contraindications to
pursuing therapy
• When EBM is weak
– It is easy for Harm to
outweigh Benefit
– First, do no harm
Step 2: Harm
How bad is bad?
aka
“Take this drug, it’s free! …and most people won’t die”
Harm
Same 4 Priorities
Prioritization of:
A. Toxicity endpoints,
i.
ii.
iii.
iv.
What will kill me?
…Maim me?
…Worsen a surrogate marker?
…Make me feel lousy?
(bothersome side effects)
B. Evidence quality and
C. Evidence quantity
–
% risk
D. Time to harm
Harm
Likelihood
Common
Rare
Not legal
Who cares
Bothersome
Severity
Severe
Harm
Time: The 4th parameter
• Most drugs are approved based on their benefit
against nothing
– (ie. placebo, not the current gold-standard)
• Studies are usually powered for efficacy, not
toxicity
– (eg. Phase III study)
• Tox data is accumulated over time
– (eg. Phase IV, post-marketing surveillance study)
– Slower than accumulation of efficacy data
• Time lag!
Harm
Age Before Beauty
Prexige®
Prepulsid®
Arcoxia®
Meridia®
Vioxx®
Baycol®
Bextra®
Avandia®
Zelnorm®
Actos ®
Newer agents
Older agents
=
=
Less Safety Data
More Safety Data
Benefit: a population-based parameter
Harm: an individual risk
Robust EBM
• Eg. ACE-inh post MI
– Clear mortality benefit in
secondary prevention as
per many RCTs
– Patient A: K+ = 4.0 mmol/L
– Patient B: K+ = 6.0 mmol/L
• Will both get an ACEinh?
Weak EBM
• Eg. Anti-seizure meds
for migraine prophylaxis
– Questionable reduction
in severity & frequency
– Risk of:
• Hepatitis
• blood dyscrasias
• strong drug interactions
etc.
Step 3: Cost
Who pays the piper?
aka
“Take this life-saving therapy; it has no risks, but it’ll cost you
$1 million and you’ll need blood tests twice daily”
Cost ($) – Ask…
Patient cost vs Societal cost
• Rx cost?
– Out of pocket
• Provincial plan?
– Tax dollars
• Private plan?
– Insurance premiums
A simple example: Cost
Choosing an ACEinh
• Efficacy: equivalent
• Toxicity: equivalent
• Cost: all cheap,
generic
– Except: trandolapril
& perindopril
• Convenience:
all once daily
– Except: captopril TID
ACE INHIBITOR (ACEI) / ANGIOTENSIN II RECEPTOR BLOCKER (ARB): Jul
2015 Comparison Chart
http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/document
s/members/CHT-HTN-ace-arb.pdf Accessed Mar 8/16
Step 4: Convenience
(How much work is this?)
Convenience
How much work is this drug?
1. How often to take?
– QD vs QID
2. Special restrictions?
–
–
–
eg. Bisphosphonates
PO vs SC/IV
Home vs Office vs Hospital therapy
3. Many potential interactions?
–
eg. Rifampin
4. Special monitoring requirements?
–
eg. Amiodarone
Knowledge translation
Your agenda
Patient agenda
A Process for Rational Prescribing
Summary
1. Prioritize Benefit
– Improve mortality, morbidity, surrogate markers, sxs
– Consider quantity, quality and time to benefit
2. Prioritize Harm
– Minimize mortality, morbidity, surrogate markers, sxs
Consider quantity, quality, and time to harm
3. Minimize Costs
4. Maximize Convenience
– (Else they affect compliance)
Summary
• Practicing this process can be clunky at first.
– Think Slow!
• But with practice:
– You will internalize this process
– You will get faster
– You will prescribe with greater confidence
– You will sleep better at night
• …and that is priceless!
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
Antibiotic Review
(80% of the knowledge, 80% of the time)
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
Objectives
• Review clinically relevant pathogens in human
disease in an ambulatory care setting
• Review antibiotic classes and spectra of
activity
– Focus on bread and butter examples of each
• Review treatment recommendations for
common infections in primary care
Process
1. Map the Bugs
– “Know your enemy”
2. Map the Drugs
– “Save your ammo”
3. Map the Battlefield
Part 1 - Map the (Clinically Important) Bugs
“Know your enemy”
Gram Negative
Aerobic
β-Lactamase Negative
Cocci (spheres)
Bacilli (rods)
Gram Positive
Anaerobic
β-Lactamase Positive
Map the Bugs
Aerobes
Anaerobes
Gram Positive Gram Negative
Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli
Cocci Bacilli Cocci Bacilli
b-L[+] b-L[-]
b-L[+] b-L[-]
1 2 3
4
b-L[+] b-L[-] b-L[+] b-L[-]
5 6
7 8
b-L[+] b-L[-] b-L[+] b-L[-]
b-L[+] b-L[-] b-L[+] b-L[-]
9 10 11 12 13 14 15 16
Anaerobes
Above & below the diaphragm
Oral
•Simple organisms
•Easily handled by
penicillins (beta-lactams)
Gut
•Approx the same, except:
– Eg. Actinomyces
Bifidobacterium
Fusobacterium
Lactobacillus
Peptococcus
Peptostreptococcus
Propionibacterium
etc
• Bacteroides fragilis
(B.frag)
• Clostridium difficile
(C.diff)
•Human pathogens:
–More virulent bugs
requiring ‘bigger guns’…
Map the Bugs
Anaerobes
Aerobes
Gram Positive
Gram Negative
Cocci
Cocci
Bacilli
Above & Below
diaphragm
Bacilli
B.Frag
C.Diff
b-L[+] b-L[-]
b-L[+] b-L[-]
1 2
3 4
b-L[+] b-L[-]
5
6
b-L[+] b-L[-]
7 8
9
.
Map the Bugs
Anaerobes
Aerobes
Gram Positive
Gram Negative
Cocci
Cocci
Bacilli
Below
diaphragm
Bacilli
B.Frag
C.Diff
b-L[+] b-L[-]
b-L[+] b-L[-]
1 2
3 4
b-L[+] b-L[-]
5
6
b-L[+] b-L[-]
7 8
9
.
Gram[+] Bacilli
• Not usually pathogenic
– Major Exception: Listeria monocytogenes
• Listeriosis – enteritis, sepsis, meningitis +/- encephalitis
Map the Bugs
Anaerobes
Aerobes
Gram Positive
Gram Negative
Cocci
Cocci
Bacilli
Below
diaphragm
Bacilli
B.Frag
C.Diff
(Listeria)
β-L[+] β-L[-]
1 2
b-L[+] b-L[-]
3
4
β-L[+]
β-L[-]
5 6
7
.
Gm[-] Cocci
• Not usually pathogenic
– Major Exceptions:
• Neisseria gonorrhea
• Neisseria meningitidis
and
• Moraxella catarrhalis
– (formerly thought to be a type of Neisseria)
Map the Bugs
Anaerobes
Aerobes
Gram Positive
Gram Negative
Cocci
Cocci
(Neisseria &
Moraxella)
β-L[+] β-L[-]
1 2
Bacilli
(Listeria)
Below
diaphragm
Bacilli
B.Frag
C.Diff
β-L[+]
3
β-L[-]
4
5
.
β-Lactamase Enzymes
• First penicillinase described in 1940’s even
before penicillin was clinically available.
• Most bugs produce some type of β-lactamase
enzyme that destroys β-lactam antibiotics
(pen’s, ceph’s, carbapenems)
– Gm[+] cocci & β-lactamase [-]: Group A & B streps
give Penicillin
Map the Bugs
Anaerobes
Aerobes
Gram Positive
Gram Negative
Cocci
Cocci
(Neisseria &
Moraxella)
Bacilli
(Listeria)
β-L[+] β-L[-]
1
(G.A.S.)
Bacilli
B.Frag
C.Diff
β-L[+]
2
Below
diaphragm
3
β-L[-]
4
.
Map the Bugs
Anaerobes
Aerobes
Gram Positive
Gram Negative
Cocci
Below
diaphragm
Bacilli
B.Frag
C.Diff
β-L[+]
1
both β-L[+]&[-]
2
3
.
Map the Clinically Important Bugs
Atypicals
Aerobes
Gram [+]
Gram [-]
Cocci
Bacilli
1
2
1.Legionella
pneumonia
2.Chlamydia
pneumonia
3.Mycoplasma
pneumonia
3
.
Anaerobes
(esp. Gut
organisms)
Eg. C-Diff
& B-frag
4
.
1 - Gram [+] Cocci
Staphylococcus
•S. aureus
– Methicillin resistant (MRSA)
– Methicillin sensitive (MSSA)
•S. epidermidis
– Methicillin resistant (MRSE)
– Methicillin sensitive (MSSE)
– Skin commensal
– Rarely pathogenic
Streptococcus
•Group A (pyogenes) (β-Lact[-])
•Group B (agalactiae) (β-Lact[-])
•
Neonates, v. elderly, obstetrics
•S. pneumonia
etc. etc.
Enterococcus
•(Formerly thought to be ‘Strep D’)
•E. faecalis
•E. faecium
• A “mean” hospital organism 
2 - Gram [-] Bacilli
“Easy” to Kill
•Proteus mirabilis
•Escherichia coli
•Klebsiella pneumonia
•Salmonella
•Shigella
•Haemophilus influenza
“Hard” to Kill
•Serratia
•Pseudomonas
•Acinetobacter
•Citrobacter
•Enterobacter
– (Moraxella catarrhalis)
(actually a Gm[-] coccus)
PEcKSS-HiM
SPACE bugs
2.5 - Gram [-] Bacilli
“Easy” to Kill
•Proteus mirabilis
•Escherichia coli
•Klebsiella pneumonia
•Salmonella
•Shigella
PEcKSS bugs
“Hard” to Kill
•Serratia
•Pseudomonas
•Acinetobacter
•Citrobacter
•Enterobacter
SPACE bugs
?“Moderate” To Kill
• Haemophilus influenza
–(Moraxella catarrhalis) (actually a Gm[-] coccus)
HiM bugs
Gram Negative vs Gram Positive
Gm[-]: red on stain. (ie. Don’t retain stain)
Gm[+]: blue-purple on stain;
Gm[-]: must pass through pores
Gm[+]: molecules < 100kDa pass easily.
Gm[-]: b-lactamases concentrated in periplasmic space
Gm[+]: b-lactamases diffuse outside cell;
Atypicals:
• Mycoplasma pneumo
• Chlamydia pneumo
• Legionella pneumo
Map the Bugs
• Gram positive aerobes:
– Cocci
Summary
Anaerobes:
• Oral
• Gut – Bfrag & Cdiff
• Gram negative aerobes:
– Bacilli
• Staph
– Aureus
» MRSA (~8-10%)
» MSSA
– Epiderimidis
» MRSE (~65%)
» MSSE
• Easy to Kill
– PEcKSS (Proteus, Ecoli,
Klebsiella, Salmonella, Shigella)
– HiM (H.flu and Moraxella
(actually a Gm[-]coccus))
• Hard to Kill
– SPACE bugs (Serratia,
Pseudomonas, Acinetobacter,
Citrobacter, Enterobacter)
• Strep
–
–
–
–
Group A strep (pyogenes)
Group B strep (agalactiae)
Strep Viridans
Strep pneumo etc.
• Enterococcus
– Faecalis
– Faecium
– Bacilli
• Listeria
– Cocci
• Neisseria
– gonorrhaea
– meningitidis
• Moraxella catarhallis
Map the Bugs - Summary
Otitis media: S.pneumo, Hi,M
Conjunctivitis: viral
Sinusitis: viral
AECOPD: S.pneumo, Hi,M
Oral abscess: oral anaerobes
C.A.P: S.pneumo, atypicals –
CAP+comorb./risk factors, or
NHAP: also HiM bugs
Pharyngitis: viral
(Group A Strep)
Bronchitis: viral
Skin abscess:
anaerobes, staph,
strep
N.B. Boils = Staph
Cellulitis: MSSA, GAS, GBS
Pyelonephritis: PEcK
H.pylori:
Cdiff / Bfrag:
UTI (Cystitis): PEcK
Traveller’s Diarrhea: (80% bacterial): EcSS,
(camphlyobacter)
Part 2 - Map the Drugs
(Save your Ammo)
Map the Drugs
• Arms race!
– Remember: “Bigger guns
breed higher walls”
• Older drugs tend to be
simpler drugs
– More narrow spectrum
– Broad spectrum drugs
breed resistance
– Superbugs develop
• MRSA, VRE, ESBL, etc
• Older drugs have more
safety data
– Tend to be less toxic
– Learn their history
– Learn their
pharmacology
Part 2 - Map the Drugs
“Save your Ammo”
Fluoroquinolones
Penicillins
Tetracyclines
Aminoglycosides
Vancomycin
Macrolides
Carbapenems
Cephalosporins
Clindamycin
Metronidazole
Antibiotics – Mechanisms of Action
From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12
Beta-Lactams - Penicillins
Penicillin
Anti-Staph
Anti-Strep
Amoxicillin / Ampicillin
(po)
(iv)
Amox + Clavulanic acid
Increasing Gram[-] coverage
Cloxacillin / Methicillin
(clinic)
(lab)
Beta-Lactams - Cephalosporins
– Cephalexin (Keflex™)(or Cefadroxil) (po)
– Cefazolin (Ancef™) (iv)
• 2nd Generation
– Cefuroxime (po & iv)
• 3rd Generation
– Ceftriaxone, Cefotaxime, Ceftazidime (iv)
– Cefixime (Suprax™) (po)
• 4th Generation
– Cefepime (iv)
Increasing Gram[-] coverage
• 1st Generation
Beta-Lactams – Other (FYI)
(IV only, inpatient use only)
• Piperacillin (plus tazobactam)
– big gun, tazo = suicide substrate, like clavulanic acid
• Carbapenems
– Meropenem
– Imipenem
– Ertapenem
• Monobactams
– Aztreonam
Broad spectrum, big gun antibiotics
that cover Gm[+], both easy and hard
to kill Gm[-] bugs, even some
anaerobes.
Antibiotics – Mechanisms of Action
From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12
Fluoroquinolones
• 2nd generation
– Ofloxacin
– Ciprofloxacin
– Norfloxacin
• 3rd generation
– Levofloxacin
• 4th generation
– Moxifloxacin
• Covers: Gm[-]’s
– PEcKSS-HiM & SPACE bugs
– 3rd and 4th gen. FQs cover
strep pneumo. well too
• Ofloxacin
• Ciprofloxacin
– Anti-pseudomonal – the
only PO option!
– Norfloxacin
• Same spectrum as Cipro
(even anti-Pseudomonal) –
but only for cystitis UTI.
• Concentrates in the G.U.
system only
• N.B. Not good enough for
pyelonephritis or systemic
infection
N.B. New FDA warnings on FQ safety (neuropathies, tendon rupture, hallucinations etc)
By Kristin J. Kelley. FDA Calls for More Restrictions on Fluoroquinolone Use. NJEM Journal Watch. May 16, 2016.
http://www.jwatch.org/fw111568/2016/05/16/fda-calls-more-restrictions-fluoroquinolone-use?query=pfw&jwd=000013533416&jspc=
Fluoroquinolones
• The “Respiratory FQs”
– Concentrate in alveolar
macrophages
– Greater than serum concn
1. Levofloxacin
– the more active Lenantiomer of Ofloxacin
– Renal clearance
2. Moxifloxacin
– Hepatic clearance
• Enhanced coverage of:
1. Strep pneumo
2. Oral Anaerobes
3. Atypicals
– N.B. only Moxi cover B.frag
– Neither covers C.diff
• (Both will cover Clostrium
non-difficile strains)
• Both have 100% oral
bioavailability
– Therefore PO = IV dose
Antibiotics – Mechanisms of Action
From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12
Macrolides
• Coverage of:
– Atypicals, Strep pneumo, &
Hi.M. (Hflu & Mcat)
• So, good for respiratory
infections!
– N.B. But doesn’t cover
PEcKSS or SPACE bugs
• Erythromycin
– Efficacy: Poorer coverage of
H.flu, MSSA
– Toxicity:
• Prokinetic = diarrhea!
• Worse for QTc prolongation
– Convenience: QID dosing
• Clarithromycin
– Better Hflu &MSSA coverage
– Less QTc prolongation vs E
– Shorter half-life vs Azithro
• BID dosing x 7-10days
• New daily ‘XL’ formulation
• Azithromycin
– An azalide, (not a macrolide)
• Same spectrum of activity
• Less QTc prolongation vs E & C!
– Long t1/2 – QD dosing x 5d
• BUT can breed resistant
S.pneumo (since below [MIC]
for long periods of time)
Antibiotics – Mechanisms of Action
From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12
Aminoglycosides
1. Gentamicin
2. Tobramycin
– Reserved for Pseudomonas
aeruginosa
3. Amikacin
• Efficacy: excellent Gm[-]
• Toxicity:
– Nephrotoxicity
– Ototoxicity
– Less now with daily dosing
• Cost:
• All excellent Gram[-]
coverage:
– PEcKSS-HiM and SPACE
bugs
– Cheap, old meds
• Convenience
– Now Once daily IV/IM
Pharmacodynamics
Relationship between Abx Concentration & Effect
Concentration Dependent
Killing
• Higher the peak, better the
kill
• i.e. Ratio of peak drug
concentration and M.I.C.
determines rate of kill.
• Eg. FQs, AGs
Log
[Conc]
Time Dependent Killing
• Time over MIC matters
• i.e. Independent of peak
concentration. Determined
by length of time over MIC
• Eg. B-lactams (Pen, Ceph etc)
Log
[Conc]
Peak
MIC
MIC
Time (h)
Time (h)
Pharmacodynamics
Relationship between Abx Concentration & Effect
Concentration Dependent
Killing
• With renal impairment:
– Maintain the peak,
lengthen the interval
– This ensures good rate of
killing while allowing
enough time to eliminate
the drug and avoid
toxicities
– For eg:
• Higher the peak, better the
kill
• i.e. Ratio of peak drug
concentration and M.I.C.
determines rate of kill.
• Eg. FQs, AGs
Log
[Conc]
Peak
Log
[Conc]
Peak
MIC
Time (h)
MIC
Time (h)
• If CrCL = 90mL/min Levofloxacin 750mg q24h po
• If CrCL = 30mL/min –
Levofloxacin 750mg q48h po
Pharmacodymamics
Bactericidal vs Bacteriostatic
• Bactericidal Abx
–
–
–
–
–
–
B-lactams (Pen, Ceph)
Aminoglycosides (AGs)
Fluoroquinolones (FQs)
Rifampin
Metronidazole
Vancomycin
• Bacteriostatic Abx
–
–
–
–
Tetracyclines
Macrolides
Clindamycin
Chloramphenicol
Rarely a clinically important characteristic, unless the
patient is immunocompromised or the risk of death with
delayed/incorrect therapy is high.
Combination Therapy
• Why?
– Broaden spectrum
• (eg. Mixed infection)
– Synergistic activity for hard to kill bugs
• (eg. Enterococcus or pseudomonas)
– Prevent resistance
• (eg. TB)
– Reduce dose and side effects
Map the Drugs
Pharmacology Summary
• Many antibiotic classes
– Beta-lactams generally safest agents.
• Even at high doses
– Some have overlapping mechanisms of action
– Avoid combining similar mechanisms of action
• Competing effects may reduce effectiveness of one agent
• Eg. Penicillins + vancomycin – cell wall synthesis inhibitors
• Eg. Tetracyclines + aminoglycosides –protein synthesis
inhibitors via 30-S subunit of the ribosome
Map the Drugs – Summary
For: TB, MRSA
For: skin,
dental
infx
(staph,
strep, &
anaerobes)
From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12
Part 3 – Map the Battlefield
Map the Battlefield
Rational Prescribing
Individual
Population
1. Efficacy
1.Efficacy
– Could be reduced, BUT:
– Empiric tx still effective if
it is well chosen
– Maintained long term with
lower resistance rates
2.Toxicity
• (Lower risk infections,
properly dosed, clinically
stable, true indication etc.)
– Reduced since lifespan of
older drugs is maintained
3.Cost
2. Toxicity
– Reduced with narrow
spectrum tx
3. Cost
– Reduced with older tx
4. Convenience
– Usually less convenient
VS.
– Reduced insurance costs,
economic losses, hospital
costs dealing with
superbugs
4.Convenience
Map the Battlefield
Map the Bugs - Summary
Otitis media: S.pneumo, Hi,M
Conjunctivitis: viral
Sinusitis: viral
AECOPD: S.pneumo, Hi,M
C.A.P: S.pneumo, atypicals –
CAP+comorb./risk factors, or
NHAP: also HiM bugs
Oral abscess: oral anaerobes
Pharyngitis: viral
(Group A Strep)
Bronchitis: viral
Skin abscess:
Cellulitis: MSSA, GAS, GBS
Pyelonephritis: PEcK
Cdiff / Bfrag:
anaerobes, staph,
strep (GAS, GBS)
N.B. boils = staph
H.pylori:
UTI (Cystitis): PEcK
Traveller’s Diarrhea: (80% bacterial): EcSS, (campylobacter)
Map the Bugs - Summary
Otitis media: S.pneumo, Hi,M
Conjunctivitis: viral – no tx
(Amox +/- Clav, Cef2, Septra)
Sinusitis: viral – no tx
AECOPD: S.pneumo, Hi,M
Oral anaerobes: abscess
drainage +/- tx
(Amox +/- Clav, Cef2, Septra)
(Amox 2g – pre dental sx?)
C.A.P: S.pneumo, atypicals –
(Amox, Macrolides (Clarithro/Azithro))
Pharyngitis: viral – no tx
CAP+comorb./risk factors, or
NHAP: also HiM bugs (Combine
(Group A Strep – Pen VK)
AmoxClav or Cef2 + Macrolide (or use
FQ))
Bronchitis: viral – no tx
Skin abscess:
drainage +/- tx
Cellulitis: MSSA, GAS, GBS (Clox, Cef1, & Clinda (more resistant)
H.pylori: triple po tx
PPI + (Clarithro +/Amox +/- Metro)
Pyelonephritis: PEcK –
(Septra, Amox-Clav, FQ (not Norflox)
Cdiff / Bfrag: Metro / po Vanco
UTI (Cystitis): PEcK – (Septra,
Traveller’s Diarrhea: (80% bacterial): EcSS, (campylobacter)
Macrobid, Amox+/-Clav, Norflox)
- Septra, FQ, (Azithro)
Map the Battlefield
Penicillin
(Group A Strep, oral anaerobes, Neisseria)
Amoxicillin / Ampicillin
(Strep & Enterococcus plus
Easy-to-Kill Gm[-](ie. PEcKSS))
Cloxacillin
(Staph aureus, Staph epi)
Amox/Clav
(Vancomycin)
(for Strep & Entero & PEcKSS-HiM)
(H.flu & Moraxella can be ~35% amox resistant)
(for MRSA / MRSE)
(~8-10% / ~ 65% resistant)
Beta-Lactams - Cephalosporins
– Cephalexin (Keflex™) or Cefadroxil (po)
– Cefazolin (Ancef™) (iv)
• 2nd Generation
– Cefuroxime (po & iv)
• 3rd Generation
To boost: for PEcKSS-HiM
(same as Amox/Clav)
SPACE bugs: The Big Guns
– Ceftriaxone, Cefotaxime, Ceftazidime (iv)
– Cefixime (Suprax™) (po)
• 4th Generation
– Cefipime (iv)
Increasing Gram[-] coverage
• 1st Generation
MSSA and Strep & PEcKSS
(same as Amox)
N.B. never Enterococcus!
SPACE bugs
• The Big Guns:
– 3rd and 4th generation Cephalosporins
– Carbapenems (Meropenem)
– Piperacillin/Tazobactam
– Aminoglycosides (Gentamicin, Tobramicin)
– Fluoroquinolones (Levofloxacin, Moxi, Cipro)
Reserved for Pseudomonas
• Ciprofloxacin (FQ)
– The only PO agent!
– (Use Norfloxacin for UTI if a FQ is needed)(3rd line)
•
•
•
•
•
Ceftazidime (Cef3)
Cefipime (Cef4)
Tobramycin (AG)
Piperacillin/Tazobactam
Meropenem
Need for Bigger guns
• There is a higher risk of Gram negative SPACE bugs
with:
– More risk factors / comorbidities
– COPD, HIV, Diabetes, CKD etc
– More institutionalized settings
• Community  Retirement Home  Nursing Home 
Hospital ward  ICU  ventilated pt in ICU.
Map the Battlefield
• PEN – for b-lact[-] Gm[+] cocci (GAS, GBS), oral anaerobes, Neisseria (meningitidis)
• ?What to do for Strep pneumo /Enterococcus?
– Amox po / Amp iv (also good for PEcKSS)
– How to boost? Amox/Clav (for HiM-PEcKSS)
• ?What to do for Staph?
– Clox (MSSA, MSSE); Else Vanco (MRSA, MRSE)
• What about Cef1? (cephalexin / cefadroxil po or cefazolin iv)
– Maps to Amox/Amp for PEcKSS and strep
• N.B. NOT Enterococcus (Cef’s never cover enterococcus!)
– How to boost? Cef2 (cefuroxime) for HiM-PEcKSS
• What about SPACE bugs?
– FQs, AGs, Cef3, Cef4, Pip/Tazo, Meropenem)
– Reserved for Ps aureginosa:(cipro, tobra, ceftazidime, cefipime, pip/tazo, meropenem)
• What about gut anaerobes? (Metro/PO Vanco)
• What about atypicals? (Macrolides, Tetracyclines (doxy))
• Where does Septra fit? (analogous with Amox/Clav and Cef2)
Summary
• This is far from an exhaustive review
• Some parts have been highly simplified for use
in clinical practice
• Some memorization is needed with regular
review of the material to retain this
knowledge
• Doing so will allow you to choose empiric
antibiotics with greater comfort in difficult
situations and unfamiliar settings.
Case 1
• Mr. PT
• 68 y.o. smoker with AE-COPD
–
–
–
–
Vitals stable; ambulatory; fever, productive cough, phlegm is green
PMHx: HTN, COPD
Allergies: penicillin
Meds: Tiotropium 18mcg qd, Ramipril 10mg qd
– Expected pathogens?
– Rx options?
– Management of allergy status?
• Rx: ________ ?
Allergy status
1. Severe diarrhea, pain
2. Rash at age of 5 y.o.
3. Rash 2 weeks post Rx
–
allergic to penicillin 10 years after their
initial allergic reaction if they are not
exposed to it again during this time period”
10% report allergy to penicillin (~90% not
true allergy)
involved hives (raised, intensely itchy spots
that come and go over hours), with
wheezing & swelling of the skin & throat
4. Major rash 3 yrs ago
–
1. = side effect, not allergy
2. “Only about 20 percent of people will be
3. = delayed hypersensitivity not true
allergy (IgE mediated)
flat, blotchy, spread over days but did not
change by the hour
5. Anaphylaxis
–
4. .
5.
http://www.uptodate.com/contents/allergy-to-penicillin-and-relatedantibiotics-beyond-the-basics
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255391/
(up to 21 days later)
Est freq of anaphylaxis at 1-5 per 10 000 cases of
penicillin therapy. The major determinant in the
immunological reaction is the similarity between
the side chain of 1st generation ceph & penicillins,
rather than the ß-lactam structure. This means
that the risk of an allergic reaction to ceph in those
with an established IgE-mediated allergy to
penicillin may be low or non-existent. Avoid Cef1;
?ok with Cef2, Cef3, Cef4
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
Hypertension and BP Meds
(The ABCD’s of HTN)
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
Objectives
• List first line classes of medication for the
treatment of essential hypertension
• Explain how co-morbid indications may
change your choice in therapy
• Apply a rational approach in selecting therapy
• Understand the dosing, monitoring and
titration of key examples from each class of
medication
Vascular
Disease
CAD /
ACS
CVA
Hypertension
CKD
CHF
PVD
Rational Prescribing
•
Rational prescribing requires a process for
selecting therapy: (in order)
1.
2.
3.
4.
Benefit
Harm
Cost
Convenience
Essential Hypertension
A
A
B
C
ACEinh
ARB
(B-bl) betablockers
DHP-CCB
(dihydropyridine)
"-pril"
"-sartan"
"-olol"
"-dipine"
enalapril
lisinopril
ramipril
valsartan
irbesartan
candesartan
bisoprolol
metoprolol
propranolol
nifedipine
amlodipine
felodipine
Blocks conversion of AT1 to ATII
(ACEinh) or blocks ATII receptors
(ARB) =
Inhibition of vasoconstriction,
aldosterone, catecholamine, and
arginine vasopressin release, water
intake, and hypertrophic responses
1st line
1st line
D
Thiazide Diuretic
hydrochlorothiazide
chlorthalidone
indapamide
Reduces
Reduction in
sympathetic
Relaxes
systemic vascular
outflow & heart
peripheral
resistance (not
rate & renal smooth muscle
diuresis)
AT2 production
1st line
(if < 60y.o.)
1st line
1st line
Essential Hypertension
Efficacy
Toxicity
Monitor
Cost
Convenience
(eg.)
A (ACEinh)
A (ARB)
B
C
D
1st line
1st line
1st line
1st line
1st line
Hypotension
Hypotension
hyperK+
hyperK+
(< 60yo)
Hypotension Hypotension
Hypotension
Orthostatic
Bradycardia
hypoK+, hypoNa+
hypotension
Acute renal
failure
(ARF)
ARF
Bronchoconstric
tion in brittle
asthmatics
(esp high dose,
esp non-cardioselective)
BP, SCr, K+
BP, SCr, K+
BP, HR, RR
Edema
ARF
BP, OH,
edema
BP, SCr, K+, Na+
cheap, generic
still expensive,
Cheap &
expensive,
(except Coversyl
new generics,
generic,
generics,
& Mavik),
ODB covered ODB covered ODB covered
ODB covered
QD
Ramipril
2.5mg - 10mg
QD
Losartan
25mg - 100mg
QD
Bisoprolol
2.5mg - 10mg
QD
Amlodipine
2.5mg - 10mg
VERY cheap,
generic,
ODB covered
QAM
Chlorthalidone
25mg
Choosing Therapy
• If benefit (#1), cost (#3) and convenience (#4) are all
more or less equivalent:
– Choose based on potential Harm (#2)
– Tailor the meds to the individual patient!
• Benefit is population based
• Harms are individual
• Additive vs Synergistic BP lowering
– Can choose between groups A or B plus C or D
(synergistic)
• Rarely clinically relevant
• N.B. Choice will also be guided by various
comorbidites
Hypertension with Comorbidities
A (ACEinh)
A (ARB)
B
D
(ALLHAT)
HTN
MI
(HOPE)
CHF
(CONSENSUS,
SOLVD, ATLAS)
DM2
(HOPE)
(IDNT, IRMA-2,
RENAAL)
CVA
(HOPE,
PROGRESS)
(LIFE, SCOPE,
MOSES)
PVD
(HOPE)
Angina
C
(VALIANT)
(CAPRICORN,
BHAT)
(MERIT-HF,
CIBIS II,
COPERNICUS)
(ALLHAT,
PROGRESS)
RAASystem
Pharmacology of ACEinh / ARBs
Second Line Therapy
• What if you have used all
available 1st line options?
• 2nd line options:
–
–
–
–
–
–
–
Alpha blockers
Spironolactone
Hydralazine
Nitrates
Clonidine
Beta-blockers (> 60 y.o.)
etc.
• ~ Equivalent benefit –
choose based on potential
harm, cost or convenience
factors.
• Ensure that you balance
these factors in their order
of importance.
Second Line Therapy
• Alpha blockers
– Eg. Terazosin, Prazosin, Doxazosin
– Harm: Risk of orthostatic
hypotension
– Cost: cheap, generic
– Convenience: only QD
• Good 1st choice of 2nd line tx
• Dual treatment of BPH & BP if
also needed in male patients
• Spironolactone
– Benefit: mortality benefit in
late stage CHF (NYHA class III or IV)
– Harm: risk of hyperK+
• esp with ARBs or ACEinh’s
– Cost: cheap generic
– Convenience: only QD
• Hydralazine
– MOA: direct vasodilation of
arteries
– Harm: orthostatic
hypotension
– Cost: cheap, generic
– Convenience: QID dosing
• Nitrates
– eg. ISDN, ISMN, NTG
– MOA: smooth muscle
vasodilation of vasculature
(veins > arteries);
– Harm: headache, orthostatic
hypotension, dizziness
– Cost: cheap/ generic
– Convenience: BID- QID dosing;
Process
1. Start first drug
2. Increase to moderate
dose
3. Monitor for efficacy
(BP) and toxicity
• If close to target:
• Dose response curves
– Flatten at top half
– Less bang for your buck
BP
– increase dose
• If far from target:
– start new drug
mg
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
Dyslipidemia
(So simple it hurts)
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
Objectives
• List the important parameters in choosing
anti-dyslipidemia drugs in a clinical setting.
• Identify clinically important differences in the
efficacy, toxicity, cost and convenience of
different anti-dyslipidemics.
• Recognize the inherent weaknesses of current
guidelines.
Dyslipidemia
• Never forget your 4 Steps of Rational
Prescribing!
It will save you a LOT of time.
1 Benefit
2 Harm
3 Cost
4 Convenience
Choosing Anti-dyslipidemics
• First, define your options:
1.
Statins (HMG-CoA Reductase inhibitors)
• Prava-, Fluva-, Simva-, Atorva-, Rosuva-statin
2.
Fibrates
•
(The exact mechanism of action of gemfibrozil is unknown; Theories re: the VLDL
effect; it can inhibit lipolysis and decrease subsequent hepatic fatty acid uptake as well
as inhibit hepatic secretion of VLDL; together these actions decrease serum VLDL
levels; increases HDL-cholesterol; the mechanism behind HDL elevation is currently
unknown)
• Feno-, Beza-, Clo-fibrate, & Gemfibrozil
3.
Ezetimibe
•
4.
5.
(Inhibits absorption of cholesterol at the brush border of the small intestine via the
sterol transporter, Niemann-Pick C1-Like1 (NPC1L1)).
Niacin (raises HDL)
Cholestyramine
•
6.
(Bile acid sequestrant)
Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor
•
Increases LDL-receptors to reduce serum LDL
Dyslipidemia
•
•
•
•
•
•
Statins
Fibrates
Niacin
Ezetimibe
Cholestyramine
PCSK9 inhibitor
1. Efficacy:
1. Mortality Benefit
2. Morbidity Benefit
• (reduction in non-fatal
MI, CVA, hospitalizations
etc)
3. Reduction in Surrogate
Markers
•
Eg. LDL
*
Bottom Line: Statins.
Only statins have clear reduction in mortality.
• High Risk Framingham patients:
– Primary prevention – morbidity reduction
– Secondary prevention – mortality reduction
• Moderate Risk Framingham patients:
– Tiny absolute risk reduction
– Not usually clinically relevant
(*) Some evidence with Gemfibrozil (VA-HIT, HHS trials) but ++ GI side effects
The End.
Exception #1
• Gemfibrozil
– Two trials that show reduction in CVD events
• Helsinki Heart Study (HHS)
• Veterans Administration HDL Intervention Trial (VA-HIT)
– Performed before widespread adoption of ACEinh, statins, etc
– Never combine it with statins
• Serious risk of rhabdomyolysis
• N.B. Fenofibrate
– No effect on CVD events
• Fibrates for high TGs – risk of pancreatitis
– ?inferior to statins in outcomes?
–
See: David Preiss, et al. Lipid-Modifying Therapies and Risk of Pancreatitis: A Meta-analysis. JAMA. 2012;308(8):804-811. (see:
http://jama.jamanetwork.com/article.aspx?articleid=1352090 )
• Fibrates for high TGs – treatment of gout risk factors
Exception #2
• Evolucumab
– Benefit: New study showing less CV events
• Adjunct therapy to statins
• FOURIER trial - Publication pending
– Quality of / Quantity of / Time to Benefit – UNKNOWN
– Harm: ??? Too new!
• New reassuring data on neurocognitive effects (EBBINGHAUS trial)
– Cost : $$$ (thousands per month)
– Convenience: sc injection every 2 - 4 weeks
– N.B. Alirocumab – No evidence of benefit
Patrice Wendling. Evolocumab Scores in Long-Awaited FOURIER Outcomes Trial: Top-line Results. February 03, 2017. http://www.medscape.com/viewarticle/875364
Accessed Feb 27/17
Patrice Wendling. Pooled Safety Data 'Reassuring' for Very Low LDL on Alirocumab. February 03, 2017
http://www.medscape.com/viewarticle/875381?nlid=112592_3864&src=WNL_mdplsfeat_170207_mscpedit_card&uac=181662FG&spon=2&impID=1286061&faf=1
Accessed Feb 27/17
What about Ezetimibe?
• Many negative trials for efficacy
–
–
–
–
–
ENHANCE
SEAS
ARBITER-HALTS 6
SHARP
AIM-HIGH, etc.
Lots of evidence of no benefit
No evidence for benefit
1) Table summary of clinical trials for ezetimibe. http://www.trialresultscenter.org/DR-ezetimibe%20clinical%20trials.htm Accessed Feb 23/16
2) Doggrell SA. Expert Opin Pharmacother. 2012 Jul;13(10):1469-80. http://www.ncbi.nlm.nih.gov/pubmed/22725704 Accessed Feb 23/16
3) Battaggia A et al. Clinical efficacy and safety of Ezetimibe on major cardiovascular endpoints: systematic review and meta-analysis of randomized
controlled trials. PLoS One. 2015 Apr 27;10(4):e0124587 http://www.ncbi.nlm.nih.gov/pubmed/25915909 Accessed Mar 7/16
What about Ezetimibe?
• The IMPROVE-IT trial
– Type: Reduction in cardiac mortality & morbidity
– Quality: Well designed RCT
– Quantity: 2% ARR…
• [34.7% down to 32.7%]
– i.e. 65.3% improved to 67.3%
– Time: 7 years to benefit…
• $185 million spent in 2013 (up 6.4% from 2012)
1) Rxfiles. IMPROVE-IT trial summary. http://www.rxfiles.ca/rxfiles/uploads/documents/Lipid-IMPROVE-IT-Trial-SummaryQandA.pdf Accessed Feb 23/16
2) IMS Health Pharmafocus 2018; Table 7. https://www.ic.gc.ca/eic/site/lsg-pdsv.nsf/eng/h_hn01703.html Accessed Feb 23/16
Why statins?
• Lipid lowering effects
vs
• Pleiotrophic effects
– Plaque stabilizing
– Anti-inflammatory
– Improved endothelial cell function
– Inhibition of thrombogenic response
Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118.
see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694580/?tool=pubmed Accessed Apr 25/12.
Correlation
versus
Causation
Bottom Line
• Priority #1 = any statin at any dose
• Priority #2 = highest dose of the highest potency
statin you can tolerate.
– Push the dose too hard = Side effects = Noncompliance
• Doubling the statin dose only lowers LDL by 6%
• The LDL target is just your guide
– A marker of the statin’s pleiotrophic effects
– (Or a compliance check)
Time to Benefit
• How old is too old to start statin therapy?
– Upper ages of trials ~ 80-83 yrs old.
– …Add time to divergence of survival curves
• ~ 4 to 6 years…
plus
• ?Prognosis
• If a patient is already on it, with an indication,
don’t stop, but don’t bother checking LDL
either.
Toxicity
• Statin
• Fibrates
– Rare/Severe:
• Myopathy, even
Myositis/Rhabdomyolysis
• Hepatotoxicty
• Memory impairment
• ?Diabetes??
– discuss
– Common/Bothersome:
• Myalgias
– Same as statins (Additive)
• Ezetimibe
– Same as statins (Additive)
• Niacin
– +++ flushing
– Hepatotoxicity (esp with
long acting form –
Niaspan)
• PCSK9 inhibitor
– ?????
Cost
• All statins covered under ODB
• All statins are generic
Convenience
• Older statins require QHS dosing
– Shorter half-life vs newer, more potent statins
– Cholesterol synthesis mostly occurs late at night
• New statins last long enough to be dosed daily
at any time
• Lacking grapefruit juice interaction:
– Rosuvastatin, fluvastatin, pravastatin
• (non 3A4 P450 metabolism)
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
Coronary Artery Disease &
Acute Coronary Syndromes
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
CAD / ACS
• All on a spectrum of
ischemic damage:
•
•
•
•
Stable Angina
Unstable Angina
NSTEMI
STEMI
• Basic Principles:
1. BP control
2. Plaque
stabilization
3. Clot prevention
CAD / ACS
1) BP control
Mortality benefit with:
– ACEinh or ARB
2) Plaque Control
Mortality benefit with:
– Statin
plus
– Beta-blocker*
N.B. HTN accelerates atherosclerosis!
(see: HTN section)
(see: Dyslipidemia section)
(*) b-blocker benefit may end between 1 month to 3 years post-MI
Anthony G. Nappi, William E. Boden. Should Beta-Blockers Continue to Be Used in Post-Percutaneous Coronary Intervention Patients Without Myocardial
Infarction? JACC: Cardiovascular Interventions Aug 2016, 9 (16) 1649-1651; http://www.interventions.onlinejacc.org/content/9/16/1649 Accessed Feb 27/16
Bangalore S. et al. Clinical outcomes with β-blockers for myocardial infarction: a meta-analysis of randomized trials. Am J Med. 2014 Oct;127(10):939-53. doi:
10.1016/j.amjmed.2014.05.032. PMID: 24927909 https://www.ncbi.nlm.nih.gov/pubmed/?term=24927909
CAD / ACS
3) Clot Prevention
Anti-Thrombotics – lots!
From: http://en.wikipedia.org/wiki/Direct_thrombin_inhibitor
Antiplatelets
Options
• Primary prevention ACS
– ASA
– Clopidogrel
• Primary prevention CVA
– ASA
– Clopidogrel
• Secondary prevention ACS • Secondary prevention CVA
– ASA
+
– Clopidogrel
– Prasugrel
– Ticagrelor
or
or
– ASA (Aspirin®)
– Clopidogrel (Plavix®)
– ASA + Dipyridamole MR
(Aggrenox®)
Mechanisms of Action
ASA
• Irreversible inh of COX-1
•
– (thromboxane reduction)
– Platelet lifespan: 7-10 days
Dipyridamole MR
• inhibits the uptake of
adenosine & breakdown of
cGMP
Ticagrelor
• Reversible inhibition of
ADP platelet receptor
subtype P2Y12
•
Thienopyridines
Clopidogrel
–
Prodrug 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.
Benefit
Harm
Cost
Convenience
Primary Prevention – ACS & 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’15: if 10yr CAD risk ≥10%
USPSTF’16: men 50‐69 yrs if low bleed risk
Diabetes: CDA’13: not rec ; age & ≥1 risk factor,
ADA’16: 1RF & >50yr & 10yr risk >10%.
–
RF = smoking,BP,  lipids, history of young
parenteral MI, albuminuria
– Clopidogrel
• Little direct evidence
• Only for ASA allergic or
intolerant
2) Toxicity
(bleeding ~ same)
• ASA
– NNH 125; major bleeds (WHS trial)
– Bleed:
• Any GI bleed 2.7%
• (severe 0.7%)
– Dyspepsia ~ 5%
• Clopidogrel
– Bleed:
• Any GI bleed 2%
• (severe 0.5%)
– Rash: 6%
– TTP: >20/3 million
– Neutropenia: <1%
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2017
Primary Prevention – ACS & CVA
3) Cost
4) Convenience
– ASA
– ASA
• Pennies! ($4/mo)
• 81mg costs > 325mg
– Can cut 325mg in
1/4th
• 75-325mg once daily
– Clopidogrel
• 75mg once daily
– Clopidogrel
• ~ $26/mo
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2017
Bottom Line: 1o Prevention ACS & CVA
• ASA.
– Most evidence, well tolerated, cheap cheap!, QD
• Ongoing efficacy studies for primary prevention (eg . ASPREE)
– http://www.ahrq.gov/professionals/clinicians-providers/resources/aspprovider.html
– 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®, ticagrelor, prasugrel in primary
prevention
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2015
Secondary Prevention – ACS
Efficacy
Agent
Monotherapy
Combo 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
x3-12 mo
Prasugrel
untested
(CURE trial) (ACS, PCI various durations)
Prasugrel + ASA > Clop + ASA
(ACS + PCI) x12 mo
(TRITON-TIMI 38 trial)
Ticagrelor
equivalent
(for post-stroke CVA events)
Ticagrelor + ASA > Clop + ASA
(ACS + PCI +/- CABG) x12mo
(PLATO trial)
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2017
From: Claiborne Johnston, S. et al. SOCRATES trial. N Engl J Med 2016;375:35-43. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1603060 Accessed Feb 27/17
Secondary Prevention – ACS
Toxicity
Agent
ASA
Clopidogrel
Prasugrel
Ticagrelor
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)
--
~ equivalent in absolute sense
Slightly less GI bleed & GI events except
diarrhea; More Rash
More major bleeding
vs ASA alone
untested
More fatal & lifethreatening bleeds vs
Clopid + ASA
More minor bleeding & dyspnea vs ASA
More major & minor
bleeds vs C + ASA
More dyspnea &
increased urate
Secondary Prevention – ACS
Toxicity
Agent
Monotherapy
Combo w/ ASA
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
Less GI bleeding: 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)
Prasugrel
Ticagrelor
untested
More minor bleeding & dyspnea vs ASA
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)
More fatal and lifethreatening bleeds vs
clopid + ASA
More major and minor
bleeds vs clopid + ASA
More dyspnea, & incr UA
Secondary Prevention – ACS
3) Cost
– ASA
• Pennies! (only 325mg covered)
– Clopidogrel
• ~ $26/mo
• No LU code required
– Prasugrel
• ~ $100/mo; covered w/ LU code
– Ticagrelor
4) Convenience
– ASA
• 75-325mg once daily
– Clopidogrel
• 75mg once daily
– Prasugrel
• 10mg once daily
– Tigagrelor
• 90mg BID
• ~ $109/mo; covered w/ LU code
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2017
Bottom Line: 2o Prevention ACS
• ASA + Clopidogrel x 3- 12 mo, then ASA alone
– Clopidogrel alone if ASA allergy
– Ticagrelor/Prasugrel + ASA only in cardiac centres
post ACS + PCI & if no excess bleed risks
Always assess risk of clotting vs risk of bleeding!
Secondary Prevention – CVA
Efficacy
Agent
ASA
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)
Clopidogrel
Equivalent to ASA
(extremely small absolute improvement per
CAPRIE trial)
Aggrenox®
Superior to ASA (ESPRIT & ESPS2 trials), but
Equivalent to Clopidogrel (PRoFESS trial)
whaaa…??
Ticagrelor
Equivalent to ASA
N.B. (for post-stroke CV events)
Possible improvement for 1st 21
days post CVA (CHANCE trial)
No benefit long term (CHARISMA,
MATCH trials)
--
--
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2017
From: Claiborne Johnston, S. et al. SOCRATES trial. N Engl J Med 2016;375:35-43. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1603060 Accessed Feb 27/17
Secondary Prevention – CVA
Toxicity
Agent
Monotherapy
Combo w/ ASA
Low, but look at additive bleeding risk factors:
ASA
(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.)
--
~ 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
--
Ticagrelor
More minor bleeding and dyspnea vs ASA
--
Clopidogrel
N.B. (for post-stroke CV events)
Secondary Prevention – CVA
3) Cost
– ASA
• Pennies! ($4/mo)
– Clopidogrel
• ~ $26/mo
• LU code for ASA
intolerance only
– Aggrenox®
4) Convenience
– ASA
• 75-325mg once daily
– Clopidogrel
• 75mg once daily
– Aggrenox®
• 200/25mg BID po
• ~ $66/mo
• LU code for CVA
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2017
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.
Summary – CAD / ACS
• N.B. Remember which modifiable risk factors
need management
– Remember which medications offer a mortality
benefit in treated those risk factors; Use them 1st!
• BP control with ACEinh (or ARB) + b-blocker
– (For stroke: ACEinh (or ARB) + Thiazide)
• Plaque stabilization with statin
• Clot prevention with ASA (+/- Clopidogrel)
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
(Congestive) Heart Failure (CHF)
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
Heart Failure
• Several types:
– Left vs Right sided
– Systolic vs Diastolic
– Preserved ejection
fraction vs not
• Basic Principles:
1. BP control
2. Plaque
stabilization
3. Clot prevention
CHF – Systolic, Poor LVEF
1) BP control
Mortality benefit with:
– ACEinh or ARB
2) Plaque Control
Mortality benefit with:
– Statin
plus
– Beta-blocker
(see: HTN section)
(see: Dyslipidemia section)
CHF – Systolic, Poor LVEF
3) Clot Prevention
• Mortality Benefit with:
– ASA 81mg qd
– If ASA allergic:
• Clopidogrel 75mg qd
(see: Primary prevention of
ACS & CVA section)
• Other forms of CHF less
well studied.
• Benefits of these
interventions are not as
clear
– But offered anyway.
– Pay closer attention to
benefit/risk ratio since
benefit is smaller /
unknown
CHF – other interventions
• Spironolactone
– Mortality benefit in NYHA
Class III & IV
– N.B. Increased harm in
NYHA Class I or II
• Risk of hyperK+ !
• Furosemide
– Reduction in CHF
symptoms
– No morbidity nor mortality
benefit (chronically).
Rxfiles.ca HEART FAILURE: Drug & Dosage Considerations. Feb 2017
• Digoxin
– Morbidity benefit with
low LVEF
– (See DIG trial, PROVED trial)
– Reduction in
hospitalizations due to CHF
• Not seen with preserved
ejection fraction
– Reduction in sxs of CHF
• For patients in sinus
rhythm with moderatesevere persistent sxs
despite optimized CHF Rx
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
CKD & PVD
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
Chronic Kidney Disease (CKD)
• Vascular damage to renal beds
– Is BP control required?
• If so, what is the best agent?
• ACEinh or ARB first!
– Is prevention of atherosclerosis required?
• If so, what is the best agent?
• Statin at any dose tolerated
– Is CKD a vascular risk?
• If so, are anti-platelets required?
• ASA (low dose, every day)
Peripheral Vascular Disease (PVD)
• Vascular damage to peripheral beds
– Is BP control required?
• If so, what is the best agent?
– Is prevention of atherosclerosis required?
• If so, what is the best agent?
– Is PVD a vascular risk?
• If so, are anti-platelets required?
(Same)
Overall Summary
• Vascular problems throughout the body require similar
approaches to management.
• Understanding the pathophysiology and pharmacology
of preferred agents will inform your therapeutics.
– ACEinh
• Anti-inflammatory and modulation of RAAS
– Statin
• Anti-inflammatory and other pleiotrophic effects
– ASA
• Anti-inflammatory and anti-platelet
– Beta-blocker
• (If cardiac involvement) – to reduce MVO2
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
Hypoglycemic Drugs
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
Objectives
• List the classes of oral antihyperglycemic agents and
understand their place in therapy.
– Determine the relative efficacy, toxicity, cost and
convenience of these agents before choosing therapy
– Rationalize prescribing of oral hypoglycemics
• Describe the current approach to pharmacologic
management of type 2 diabetes.
Diabetes: complications
MACROvascular
Stroke
Heart disease
&
hypertension
MICROvascular
Diabetic eye
disease
(retinopathy &
cataracts)
Nephropathy
Peripheral
vascular disease
Neuropathy
Foot problems
Foot problems
Kumamoto Study – HbA1c & Complications
• Intensive vs. conventional insulin therapy (N=110)
• Median A1c - 7.1% vs. 9.4%
16
14
Retinopathy
16
14
12
Nephropathy
12
10
10
8
6
4
2
0
8
6
7%
5
6
7
7%
4
2
0
8
9
HbA1c (%)
10 11
5
6
7
8
9
HbA1c (%)
10 11
Prevention of Diabetes in IGT
• Lifestyle modification
– (see Finnish Diabetes Trial)
– Moderate weight loss (5%) (esp. abd fat)
– Regular physical activity
• > 150 minutes per week
– 58% RRR for type 2 Diabetes at four years
• Pharmacotherapy
– Multiple effective trials
• Eg. LIFE trial - Losartan  onset of new DM2
Can J Diabetes 2003;27(2);S12
Pharmacological Prevention Studies
Study
Drug
DPP
Metformin
850mg BID
2.8
31
STOPNIDDM
Acarbose 100mg
TID
3.3
30
DREAM
Rosiglitazone
8mg daily
3.0
55
Orlistat 120mg
TID
4.0
37
XENDOS
Duration
(years)
RRR (%)
Non-Pharmacologic Tx
Mainstay of therapy!
• Nutrition therapy
– ↓ A1c 1-2%
– CDA recommends counseling by a dietician for
all type 2 diabetics
– www.cvtoolbox.com diet for Type 2 diabetes
Can J Diabetes 2003;27(2);S27
Pharmacotherapy
Comparison of antihyperglycemics
Drug Classes
Sensitizers
Secretagogues
Other
Drug Classes
Sensitizers
Secretagogues
• Metformin
• Glitazones
• Sulfonylureas
– Eg. Glyburide, Gliclazide
• Meglitinides
– Rosiglitazone (AVANDIA)
– Pioglitazone (ACTOS)
– Eg Repaglinide (GLUCONORM)
Other
• Alpha glucosidase inhibitors (Acarbose)
SGLT2 inhibitors (Cana-, Dapa, Empa-gliflozin)
• DPP4 inhibitors (Gliptins)
Incretin (GLP1) Analogues
• Sitagliptin,
Linagliptin
• Saxagliptin,
Alogliptin
* Liraglutide
(VICTOZA) (sc inj)
* Exenatide
(BYETTA) (sc inj)
Drug Classes
Sensitizers
• Metformin
• Glitazones
– Rosiglitazone (AVANDIA)
– Pioglitazone (ACTOS)
• Sensitizers – reduce
insulin resistance
• Increase glucose uptake &
utilization in muscle and
adipose tissue
• Reduce hepatic glucose
output
Drug Classes
• ↑Basal & prandial insulin
secretion, ↓hepatic
gluconeogenesis
• Doesn’t correct impaired
1st phase insulin
secretion; primarily
affects 2nd phase
• Beta-cell sensitizer –
primes glucose mediated
insulin secretion (1st
phase)
Secretagogues
• Sulfonylureas
– Eg. Glyburide, Gliclazide
• Meglitinides
– Eg Repaglinide
(GLUCONORM)
Drug Classes: Other
• Alpha glucosidase inhibitors (Acarbose)
• Competitive inhibitor of pancreatic α-amylase and intestinal brush border α-glucosidases,
resulting in delayed hydrolysis of ingested complex carbohydrates and disaccharides and
absorption of glucose; Dose-dependent reduction in postprandial serum insulin and
glucose peaks; inhibits the metabolism of sucrose to glucose and fructose
• SGLT2 inhibitors (Canagliflozin, Dapagliflozin, Empagliflozin)
– Inhibits sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, reducing
reabsorption of filtered glucose from the tubular lumen and lowering the renal threshold for
glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered
glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose,
thereby reducing plasma glucose concentrations.
• DPP4 inhibitors (Gliptins) – (Sitagliptin, Lingliptin, Saxagliptin, Alogliptin)
• Prolongs the action of endogenous incretin hormones by blocking their breakdown by the
enzyme, dipeptidyl peptidase-4 (DPP-4). This leads to more insulin release after eating.
• Incretin (GLP1) Analogues – (Liraglutide (Victoza®), Exenatide (Byetta®))
– sc injection
– mimic endogenous incretin hormones
Benefit– Prioritize:
1. HARD Outcomes
a) Any mortality benefit?
b) Any morbidity benefit?
Then,
2. SURROGATE Outcomes
a) Clinically relevant?
Benefit
1. HARD Outcomes
– Mortality benefit
– Metformin – UKPDS-34 trial
– Liraglutide – LEADER trial
– Empagliflozin – EMPA-REG OUTCOME trial
– Morbidity
–
Reduction in microvascular complications (nephropathy,
retinopathy, neuropathy)
2. SURROGATE Outcomes
a) Hgb-A1c reduction
•
Blood glucose level reduction
– Fasting or Prandial
b) Insulin Sparing Effects
Benefit
A) Surrogate Outcome - Hgb-A1c
–
–
~ 1% to 2%
•
•
•
•
•
Metformin
Sulfonylureas
Repaglinide
Glitazones (TZDs)
Canagliflozin
(1% - 2%)
•
Liraglutide / Exanatide
(1% - 2%)
(1% - 2%)
(1% - 1.5%)
(0.4% - 1.5%)
(0.8 – 1%)
~ 0.5% to 0.9%
•
•
•
•
Acarbose
DPP4 inhibitors (‘Gliptins)
Dapagliflozin, Empagliflozin
Nateglinide
Nathan DM, et al. Diabetes Care 2008 (Dec);31:1-11.
Benefit
B) Surrogate Outcome - Insulin Sparing Effect
– METFORMIN
– ACARBOSE
– TZD’s (GLITAZONE’s)
– DPP4 inh (‘gliptins)
– Incretin Analogues (Liraglutide, Exenatide)
– SGLT2 inh (Canagliflozin, Dapagliflozin,Empagliflozin)
= Weight neutral or weight negative
= Reduction of hyperinsulinemia
Harm – Prioritize:
1. Serious / Rare Side Effects
2. Bothersome / Common s.e.
3. Age?
•
•
Newer agents = Less Safety Data
Older agents = More Safety Data
Harm – Serious / Rare
•
Glitazones
–
–
–
–
• Secretatgogues
CHF
Fractures
M.I.
(Sulfonylureas &
Meglitinides)
•
– Severe Hypoglycemia
(rosiglitazone)
Bladder Cancer
•
(pioglitazone)
Harm – Serious / Rare
•
SGLT2 inhibitors
• Incretin Analogues –
(Liraglutide, Exenatide (sc inj))
(Cana-, Dapa, Empa-gliflozin)
–
?DKA
•
•
–
“March 2013 to June 6, 2014, 20
cases of acidosis — diabetic
ketoacidosis, ketoacidosis or ketosis
— were recorded in the FDA Adverse
Event Reporting System in patients
treated with SGLT2 inhibitors. All
patients required emergency room
visits or hospitalization to treat the
ketoacidosis.”
http://www.fda.gov/Drugs/DrugSafety/ucm446845.
htm
Bone fracture as soon as
12 weeks
•
(Canagliflozin) see: here
= Unknown - too new
&
• DPP4 inhibitors (‘gliptins)
•
?Heart failure
– Sitagliptin - Yes, per lower quality data
[2014 post
hoc pooled analysis of 25 RCTs (n = 1261)]
• No, per 2015 TECOS trial (n = 14,671)
– Saxoglitpin – Yes? (SAVOR-TIMI 53 trial)
– Alogliptin - Yes? (EXAMINE trial)
•
?Pancreatitis
–
–
Yes: Faillie 2014 (PMID: 2435244)
No: Chou 2014 (PMID: 24859164); Thomsen 2015(PMID:
25633664)
= Unknown - too new
Harm – Serious / Rare
• Metformin
• ?Risk of Lactic Acidosis
– 0.03 to 0.06 cases / 1000 pt-yrs
– ~ 50% fatal
– When implicated:
• Metformin plasma levels are usually >5 μg/mL
• Cases - primarily diabetics w/ significant renal
insufficiency, both intrinsic renal disease and renal
hypoperfusion, w/ multiple medical/surgical problems
and multiple medications.
Metformin Dosing
• Dosing recommendations with renal insufficiency:
– (CONTROVERSIAL)
• CrCl 60ml/min→
– 1700 mg/day (Rxfiles)
– 2.5g/day (Roland)
• CrCl 30ml/min→
– 850mg/day (Rxfiles)
– 2.5g/day (Roland)
• CrCl < 30ml/min→
– Contraindicated (Rxfiles)
– 1g/day (>20mL/min) (Roland) If NO other risk factors, else D/C.
– Take home: assess OTHER RISK FACTORS for L.A.
1) Salpeter SR, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database of Systematic Reviews
2010, Issue 4. Art. No.: CD002967. http://www.cochrane.org/CD002967/ENDOC_risk-of-fatal-and-nonfatal-lactic-acidosis-with-metformin-use-in-type-2diabetes-mellitus Accessed Sept 24, 2015
2) Nasri, H. et al. Metformin: Current knowledge. J Res Med Sci. 2014 Jul; 19(7): 658–664. PMCID: PMC4214027
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214027/ Accessed Sept 24, 2015
3) A A Tahrani, et al. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? BMJ. 2007 Sep 8; 335(7618): 508–512. PMCID:
PMC1971167. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1971167/ Accessed Sept 24, 2015
4) Lalau JD. Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf. 2010 Sep 1;33(9):727-40. PMID: 20701406
Risk Factors - Lactic Acidosis
• Severe renal impairment
– (caution if CrCl < 30ml/min)
and
•
•
•
•
•
•
•
Hepatic disease
alcoholism
CHF
COPD
CRF
Pneumonia
Ongoing acidosis
– Lactic, keto etc.
Harm – Common / Bothersome
1) METFORMIN
– GI upset / diarrhea – Start low, go slow!
• Initial dose 250mg QDaily to BID
– B12 / folate deficiency / anemia (6 - 8/100)
• Reduced absorption – so, supplement
– Anorexia – usually transient
– Metallic taste
Harm – Common / Bothersome
2) Sulfonylureas:
– Sulfa skin reactions
• Rash / photosensitivity ~1%
– Weight gain (2-3kg)
– Mild Hypoglycemia:
• Most with glyburide. Least w/ glimepiride & gliclazide
• Requires consistent food intake
• Major episodes 1-2% (esp. in elderly)
Harm – Common / Bothersome
3) Glitazones:
–
Edema
4) Meglitinides:
–
Hypoglycemia
5) Acarbose:
–
GI upset / diarrhea /
bloating
7) Incretin analogues
–
8) SGLT2 inhibitors
–
–
–
6) Gliptins:
–
GI upset, edema,
?infection
N/V/D, ?infection
HyperK+, ARF (AKI)
UTI (includes bacteriuria [asymptomatic],
cystitis: 9%; females: 4%-18%;
males: 4%),
Genitourinary fungal infection
(4%; females: 5% to 11% [includes
bacterial vaginosis, cervicitis, vulvitis,
vulvovaginal candidiasis, vulvovaginal
infection, vulvovaginitis];
–
males: 2% to 3% [includes balanitis,
balanoposthitis, genitourinary fungal
infection, penile infection, scrotal abscess])
Cost
• From Rxfiles Mar 2017
– Cost per 100 days therapy (in
Sask.)
• Alternatively, check ODB eformulary
– N.B. Not true pt costs
– Only comparative costs
Rxfiles.ca ANTI‐HYPERGLYCEMIC AGENTS (AHA): Comparison Chart. Mar 2017
http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/documents/member
s/cht-diabetes.pdf
Cost
• From Rxfiles Mar 2017
– Cost per 100 days therapy (in
Sask.)
• Alternatively, check ODB eformulary
– N.B. Not true pt costs
– Only comparative costs
Rxfiles.ca ANTI‐HYPERGLYCEMIC AGENTS (AHA): Comparison Chart. Mar 2017
http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/documents/member
s/cht-diabetes.pdf
Convenience
•
•
•
•
•
•
•
•
•
Gliptin’s
Glitazones
SGLT2 inh
DPP-4 inhibitors
GLP-1 analogs
Sulfonylureas
Metformin
Meglitinides
Acarbose
- QD
- QD
- QD
- QD
- QD sc inj
– QD to BID
- QD to TID
– QD to TID
– QD to TID
with meals
• 1st line – METFORMIN
• 2nd line - SULFONYLUREA or INSULIN
– Meglitinide – if poor CrCL or irregular eating
• 3rd line – any other hypoglycemic if patients
absolutely REFUSE insulin
NEVER USE GLITAZONEs!
Did I say, never? I meant NEVER!
Individualization of Drug Therapy
Patient Factor
Renal Failure
Hepatic Disease
Hyoglycemia
Consider→ Possibly preferred drugs
Repaglinide, Acarbose, ‘Gliptins
Also: insulin
Insulin, repaglinide, acarbose,
Caution: glyburide, metformin, glitazones
Metformin, Acarbose, (DPP4 inh),(SGLT2 inh)
Also, repaglinide, gliclazide
Obese
Metformin, Acarbose, Liraglutide
Irregular Mealtimes
Repaglinide, DPP4-inh
Rxfiles.ca ANTI‐HYPERGLYCEMIC AGENTS (AHA): Comparison Chart. Mar 2017
http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/documents/members/cht-diabetes.pdf
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
Insulins
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
New Drugs/Drug News vol 24 (3):
May/June 2006
Insulins - Simplified
• Long = Basal
• Short = Prandial
– NPH, (Humulin N®)
– Glargine (Lantus)
– Detemir (Levemir)
– Short
• Regular (Humulin R®)
• Toronto
– Rapid
• Lispro (Humalog)
• Aspart (NovoRapid)
• Glulisine (Apidra)
• Premixed
• 30/70 (and 40/60, 50/50)
• HumalogMix-25, NovoMix-30
Which to choose?
Basic Concepts
• Hyperglycemia = Chronic
Hypoglycemia = Acute
– So, go after Hypo’s first!
• Fed: 6h/24h = 25%
• Fasting: 18h/24h = 75%
– So, go after Fastings first!
• AM affects PM & HS
– So, go after AM first!
1. ?Any hypo’s?- fix ‘em!
then,
2. FBS AM
3. FBS Noon
4. FBS PM
5. FBS HS
then,
6. 2h PPG AM
7. 2h PPG Noon
8. 2h PPG PM
Insulins
• Long – Basal
– NPH, (N)
– Glargine (Lantus)
– Detemir (Levemir)
• Short – Prandial
– Short
• Regular (R)
• Toronto
– Rapid
• Lispro (Humalog)
• Aspart (NovoRapid)
• Glulisine (Apidra)
• Premixed
• 30/70 (and 10/90, 20/80, 40/60, 50/50)
• Humalog Mix-25, NovoMix-30
(R + NPH)
(Rapid + NPH)
Now, which to choose?
Rational Prescribing
•
FOUR steps to Rational Prescribing:
1. Benefit
2. Harm
3. Cost
4. Convenience
Long – Basal Insulins
• Benefit:
– NPH = Lantus = Levemir = NPH
– Equivalent
• Morbidity benefits, A1c lowering effect
– Despite the marketing:
• Kinetics don’t affect overall efficacy:
– Slowest absorption: Thigh (best for basal insulins)
– Fastest absorption: Abdomen (best for prandial insulins)
• Lots of Lantus is injected BID
• NPH can be used QHS for some (esp w/ CKD)
Long – Basal Insulins
• Harm:
– All:
• Hypoglycemia
– NPH:
• Peak effect at ~ 8hrs (4-10hrs)
– Risk of hypoglycemia (~ 5%? vs “peakless” insulins)
– Lantus / Levemir:
• Insulin analogues
• Increased breast cancer risk?
– more research needed
Long – Basal Insulins
• Cost:
– All: covered under ODB
• N.B. No Rx required for any insulins – all “Schedule 2”
– NPH: ~ $45
– Lantus: ~ $110
– Levemir: ~ $115
• Convenience:
– All sc injections, via penfills
– All QD – BID
– All stable at room temp x 30 days
Bottom Line – Basal Insulins
• All equivalent
• Choose therapy based on cost (NPH)
– For the very small proportion suffering from
hypoglycemia due to the peak effect of NPH or
lamenting BID dosing, consider Lantus or Levemir.
Starting Basal Insulin
• Fancy Way:
– calculate unit/kg dose = 0.1 - 0.2u/kg/day sc
• Risk hypoglycemia on first dose – lose your patient’s buy-in
forever.
• Primary Care Method:
– Initiate 5u or 10u qhs sc
– Titrate by 1-2u q3-4d until AM FBS = 4 - 7 mmol/L
• 10% titrations
– If dose = 30’s – increase by 3 units
– If dose = 40’s – increase by 4 units
– etc. etc.
Rx
1. NPH
– Sig: 5u qhs sc or ud
– M: 1 box penfills
– Repeat x 12
2. Needle tips – 28G - 6mm
– Sig: ud
– M: 1 box
– r x 12
•
N.B. (Please teach pt pen
technique)
Insulins
• Long = Basal
• Short = Prandial
– NPH, (N)
– Glargine (Lantus)
– Detemir (Levemir)
– Short
• Regular (R)
• Toronto
– Rapid
• Lispro (Humalog)
• Aspart (NovoRapid)
• Glulisine (Apidra)
• Premixed
• 30/70 (and 40/60, 50/50)
• Humalog Mix-25, NovoMix-30
(R + NPH)
(Rapid + NPH)
Short – Prandial Insulins
• Efficacy
– Equivalent reduction in morbidity, HgbA1c
Short – Prandial Insulins
• Toxicity
– Hypoglycemia
– Rapid insulins
better reflect
physiological
effect of
pancreatic insulin
(vs Regular insulin)
• More important
in CKD (=longer
insulin t½ )
Short – Prandial Insulins
• Cost
– All covered under ODB (all Schedule 2 drugs)
•
•
•
•
Regular (R) / Toronto ~ $45
NovoRapid (aspart) ~ $56
Humalog (lispro) ~ $58
Apidra (glulisine) ~ $48
• Convenience
– All injected with meals
– Regular insulin injected 30-45 min before meal
– Rapid insulin can be taken with meal
• Reduced risk of hypo if pt injects, then forgets to eat
Bottom Line – Prandial Insulins
• All equivalent
• Choose therapy based on cost / familiarity
– Rapid insulins reflect pancreatic insulin release
better than [R]/Toronto.
– The worse the CrCL, the more important this fact
becomes.
Starting Prandial Insulin
• Fancy Way:
– Total dose: 0.5u/kg
– 40% of total dose - basal insulin qHS
– 20% of total dose TID with meals (60%) – prandial insulin 1530 min before meals
• Eg. 80kg pt – 0.5u/kg = 16u basal (40%); 8u TID (20% x 3 = 60%)
• Primary Care Method:
– Start 5u sc with meals
• Titrate AM to HS to target
– Monitor 2h PPG
• Start injection TID or only single meal as required
– If poor control: inj TID sc; If mediocre control: inj qAM sc
• Still aim for ~ 2/3rds split (40% basal / 60% prandial)
Insulins
• Long = Basal
– NPH, (N)
– Glargine (Lantus)
– Detemir (Levemir)
• Short = Prandial
– Short
• Regular (R)
• Toronto
– Rapid
• Lispro (Humalog)
• Aspart (NovoRapid)
• Glulisine (Apidra)
• Premixed
• 30/70 (and 40/60, 50/50) (Reg + NPH)
• Humalog Mix-25, NovoMix-30
(Rapid + NPH)
Pre-mixed Insulins
• NovoMix-30 = Humalog Mix25 (equivalent)
• Efficacy
– All ~ 30% short / 70% long
• Toxicity
– Hypoglycemia (less with Rapid vs Regular insulin)
• Cost: ~$63 (Rapids) ~$47 (Regular 30/70)
• Convenience ~ Rapids can be injected with meal
Starting Pre-mixed Insulins
• Fancy Way:
– Estimate total starting daily dose
• (0.3-0.6 units/kg)
– Divide daily dose:
• 2/3 before breakfast; 1/3 before supper
• Primary Care Method:
– From scratch: Start 5-10u QD-BID and titrate
– From other insulins: Calculate approximate
amount of basal and prandial units and divide
2/3rd - 1/3rd AM and PM
Pearls
• Insulin is 2nd line after metformin
– No need to save it for last!
• Better than adding a 3rd PO drug
– Better efficacy, lower toxicity, better studied
• Improve buy-in from patient:
– “Natural” supplement
– Only BID glucochecking at alternating times required:
•
•
•
•
•
•
•
FBS AM + PPG breakfast, then
FBS AM + FBS lunch, then
FBS AM + PPG lunch, then
FBS AM + FBS supper, then
FBS AM + PPG supper, then
FBS AM + FBS HS
repeat
Pearls (cont’d)
• D/C secretagogues after starting insulin to
reduce risk of hypo’s.
– Eg. Sulfonylureas, meglitinides
– Black box warning against combo with glitizones!
(Actos, Avandia)
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
GI Meds
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
Objectives
• Describe the utility of step up or step down
approach to therapy in the treatment of GI
problems
• List classes of medications used in common GI
complaints and understand differences in
their pharmacology
• Choose therapy using a process for rational
prescribing
Dyspepsia, GERD, PUD:
• Buffer antacids
– MOA: raise gastric pH
• Immediate effect, short lived
– Efficacy: relieves mild
GERD sxs in ~20% of
patients
– Calcium carbonate:
• Eg. TUMS, Rolaids
• most potent, chew 2-3 tabs prn,
• Tox: constipation
– Sodium bicarb
• Eg. Alka-Seltzer
• Tox: flatulence, belching. C.I. in CHF,
edema, renal dysfunction
– Magnesium/Aluminum
hydroxide
• Eg. Gelusil, Maalox liquid
• Tox: diarrhea . C.I. in CKD, ARF
Options
• H2 receptor blocker (H2RA)
– Eg. Ranitidine, Famotidine,
Nizatidine, Cimetidine
– MOA: competitively inhibit
histamine H2 receptors on
parietal cells thereby decrease
gastric acid secretion
– Efficacy: all equivalent
• useful in
treatment/prevention of mild
GERD
• Not effective enough for
NSAID prophylaxis of PUD
– Toxicity: well tolerated
• Cimetidine: ++ interactions
– Cost: Cheap, generic, OTC
– Convenience: BID dosing
• Eg. Ranitidine 75-150mg QD-BID
Dyspepsia, GERD, PUD:
• Proton Pump Inhibitors
(PPI)
– Eg. Omeprazole 20mg,
(esomeprazole 20mg),
rabeprazole 20mg,
pantoprazole 40mg,
lansoprazole 30mg,
(dexlansoprazole 30mg)
Options
• Efficacy: (all equivalent)
– Superior to H2RAs for dyspepsia,
GERD, & PUD (esp meal-induced
acid secretion)
– QD vs BID dosing – no difference
• BID for severe, persistent sxs
• Toxicity:
–
–
–
–
–
Rebound hypersecretion – taper!
Reduced calcium absorption – hip#
?Elevated risk of VIT B12 deficiency
?Elevated risk of C-Diff infection?
?Elevated risk of pneumonia?
– MOA: suppresses gastric
basal and stimulated
acid secretion by
• Cost: generic, ODB and OTC
– Tecta (pantoprazole magnesium)
inhibiting the parietal
and Pariet (rabeprazole) – ODB
cell H+/K+ ATP pump
coverage, no LU code required
• Convenience: all QD or BID
– Eg. Pantoprazole magnesium
(Tecta®) 40mg once daily
Dyspepsia & GERD
• Step-up Therapy:
– Find minimally effective, safest dose
Vs
• Step-down Therapy:
– Immediate relief first, then reduce
• Hiatus Hernia with symptoms: PPI QD-BID for
prevention of Barrett’s esophagus
Peptic Ulcer Disease
NSAID-Induced
H.pylori-Induced
• Cause most H.pylori• 90% of DU, 70% of GU
negative PUD
• Once diagnosed, treat
with at least triple therapy • Assess risk factors!
– Single and dual therapy are
not effective enough
– 14 day tx more effective
than 7-10 day tx
Rxfiles Comparison Charts. p40 Aug 2012. Accessed Mar 2013
–
–
–
–
–
–
–
Previous Hx (OR=13.5x)
High dose NSAID (OR=7x)
Anticoagulants (OR=6.4x)
Age > 70y.o. (OR=5.6x)
SSRI use (OR=4.8x)
Age > 60y.o. (OR=3.1x)
Steroids (OR=2.2x)
Helicobacter pylori
• 1-2-3: “one week, twice daily, 3 drugs”
– 14d versus 7-10d Rx:
• Superior efficacy, but elevated toxicity & cost
• Triple therapy (all BID):
– PPI + Clarithromycin + Amoxicillin
– PPI + Clarithromcyin + Metronidazole
– N.B. PPI + Amox + Metro – inferior regimen
• Quadruple therapy: (also 1st line)
– PPI BID plus Metronidazole + Tetracyline +
Bismuth subsalicylate (PeptoBismol®) all QID
NSAID-induced Peptic Ulcer Disease
• PPI superior to H2RA or Misoprostol (PG analog)
• PPI QD = PPI BID
– BID only for symptomatic control
• Misoprostol 200mcg TID-QID
– Effective, but intolerable! (mucho diarrhea)
– Arthrotec® usually only BID dosing, so, under-dosed.
• GU: PPI QD x 8 weeks
• DU: PPI QD x 4 weeks
Laxatives
1. Stool Softeners
–
–
Eg. Docusate sodium
Not a laxative: “All mush, no push”
2. Bulk laxatives:
–
–
Water absorption; peristalsis
Eg. Psyllium, fibre, calcium
polycarbophil (Prodiem®)
3. Osmotic laxatives
–
–
Osmotic + colonic acidification
Eg. Milk of magnesia, mag
citrate, sorbitol, lactulose, PEG
solution, sodium phosphate,
glycerin suppositories
4. Stimulant laxatives
–
–
Direct effect on mucosa
Bisacodyl, sennosides
Increasing potency =
– Increasing efficacy and
– Increasing side effects
– Cramps, pain, diarrhea
Narcotic induced
constipation requires at
least an osmotic laxative,
(usually stimulant
laxative)
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @Roland Halil, PharmD
Analgesics
Dr Roland Halil, BSc(Hon), BScPharm, ACPR,
PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
Objectives
• Compare and contrast somatic and
neuropathic pain
• List the relative efficacy and toxicities of
analgesics
• Develop a step-wise approach to treating
chronic, non-malignant pain
Pain:
Somatic vs Neuropathic
Somatic
• WHO Pain Ladder:
1. Acetaminophen
2. NSAID
3. Acetaminophen or NSAID +
“weak” opioid (eg. Codeine)
•
Eg. Tylenol #2, Tyl#3, 222’s,
4. Pure “strong” opioid
•
•
•
•
Hydromorphone
Oxycodone
Morphine
Codeine
Neuropathic
• TCA
– Nortriptyline
– Amitriptyline
• Gabapentin
• Pregabalin
• Anti-epileptics
– CBZ
– VPA
– Phenytoin
Acetaminophen
• MOA: unknown
– (NAPQI metabolite may interfere w/ TRPA1 mediated pain transmission in the spine)
• Efficacy
– Equivalent analgesia and antipyresis to NSAIDs
• Eg. OA, non-inflammatory pain
• Toxicity
– Much less GI upset vs NSAIDs, no PUD, no ARF
– Liver toxicity in overdose – N.B. combo OTC products!
• Cost
– Cheap!
• Convenience
– Q4h dosing, same as NSAIDs
Choosing NSAIDs
As ever, work through the 4 steps:
1. EFFICACY: What are the endpoints of interest?
1. Analgesia
2. Anti-inflammation
3. Antipyresis
•
All NSAIDs are generally considered
equivalent for each endpoint.
•
Few useful comparative trials published
Efficacy - Analgesia
• Efficacy vs placebo
– Clearly beneficial
– Lots of evidence (RCTs, meta-analyses etc)
• Efficacy vs other NSAIDs
– Indirect evidence of differences in analgesia.
• Single dose studies only
• Acute pain only
• Limited number of indications & comparators
– Ass-u-me-s we are able to extrapolate data
• See Oxford League Table (Table 1)
– here: http://www.clinmedres.org/content/5/1/19.long
– N.B. ONLY compares EFFICACY
Ong CKS et al. An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs. ClinMedRes 2007;5(1):19-34
see: http://www.clinmedres.org/content/5/1/19.long Accessed Oct 31, /11
Oxford League Table
Ong CKS et al. An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs. ClinMedRes 2007;5(1):19-34
see: http://www.clinmedres.org/content/5/1/19.long Accessed Oct 31, /11
Toxicity – 1) Renal
• Additive pharmacodynamic
effects on renal vasculature
–
–
–
–
–
ACEinh
ARBs
Aliskiren
Diuretics
NSAIDs
• NSAIDs equivalent
• Direct nephrotoxicity
– Antibiotics – Aminoglycosides,
Sulfonamides, Amphotericin B,
Foscarnet, Fluoroquinolones,
Rifampin, Tetracycline, Acyclovir
(only IV), Pentamidine,
Vancomycin
– Immunosuppressants – Cisplatin,
Methotrexate, Mitomycin,
Cyclosporine, Ifosphamide
– Heavy Metal Poisoning – Mercury,
Lead, Arsenic, Bismuth
– Lithium
Toxicity – Renal Triple Whammy!
1) Diuretics
reduce
forward
flow into
kidney
2) NSAIDs
vasoconstrict
afferent arterioles
(inh of PG
synthesis)
3) ACEinh / ARBs vasodilate
efferent arterioles (blockade of
ATii effects)
Result:
Reduced
GFR &
Acute
Renal
Failure!
Katarzyna K Loboz and Gillian M Shenfield. Drug combinations and impaired renal function – the ‘triple whammy’. Br J Clin
Pharmacol. 2005 February; 59(2): 239–243. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/ Accessed Oct 31/11
Toxicity – 2) Gastrointestinal
Mechanism
• Direct (local)
–
–
–
–
Contact with GI mucosa
Acidic
Toxic to epithelia
Reduction of mucus and
bicarb secretion
– Enterohepatic circulation
of some NSAIDs (repeated
exposure)
• Indirect (systemic)
– Inhibition of PG synthesis
JOHN L. WALLACE Physiol Rev 88: 1547–1565, 2008 Accessed Nov 11/11 http://physrev.physiology.org/content/88/4/1547.full.pdf+html
Toxicity – Gastrointestinal
Relative
Toxicity - Gastrointestinal
• In general:
– LOW Risk:
– INTERMEDIATE Risk:
– HIGH Risk:
Ibuprofen
Naproxen, Diclofenac
Ketorolac, Piroxicam
Toxicity - Gastrointestinal
• Risk Factors:
–
–
–
–
–
–
–
Age > 60
Hx of PUD
GI cancer
GERD
esophageal varices
liver disease
recent MI or CVA
• Drugs:
–
–
–
–
–
Antiplatelets
Anticoagulants
Corticosteroids
Alcohol
ASA 81mg too!
N.B. There is no correlation between symptoms of dyspepsia
and GI mucosal damage as seen on endoscope.
Toxicity - Gastrointestinal
• GI ULCER Risk: ~annual risk 1-4%
• Elevated odds ratio (OR) with: (Consider adding PPI)
–
–
–
–
–
–
–
–
–
Hx of ulcer complication
Multiple NSAID
High dose NSAID
Concomitant anticoagulant
Age≥70
SSRI use
Age ≥60
Concomitant steroid
Hx heart dx
OR =13.5
OR = 9
OR = 7
OR = 6.4
OR = 5.6
OR = 4.8
OR = 3.1
OR = 2.2
OR = 1.8
Rxfiles. NSAID comparison chart. Feb 2017 – Accessed Feb 27/17 www.Rxfiles.ca
Toxicity – GI – COX-2 inhibitors
• The sole COX-2 inhibitor on the market is
Celecoxib (Celebrex®).
• SUCCESS-I trial – RCT showed celecoxib was
?“safer”.
– celecoxib 100 mg bid (n=4393)
– celecoxib 200 mg bid (n=4407)
– naproxen 500 mg bid (n=905)
– diclofenac 50 mg bid (n=3489)
Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I study. Am J Med 2006; 119:255-266
Landmark CLASS trial
(Celebrex® / Celecoxib)
12 mo
16 mo
6 mo
• “… an interim report of the first 6 months of data from
2 trials that lasted 12 and 16 months.”
– “… at …16 months there was no difference in GI adverse
effects between celecoxib and traditional NSAID groups.”
• Discovered because crucial info was posted on FDA
website
– Not included in Canadian disclosures.
1) Lexhin, J et al. CMAJ • NOV. 23, 2004; 171 (11)
2) Silverstein FE, et al. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284(10):1247-55
Toxicity – 3) Cardiac
• COX-2 selectivity seems to increase cardiac risk
– Dose and duration dependent
• Ratio of COX-2 : COX-1 inhibition:
– Rofecoxib
– Celecoxib
– Ibuprofen
– Naproxen
80 : 1
9:1
0.4 : 1
0.3 : 1
Somatic:
NSAID Toxicity: Cardiac
Celebrex™ (Celecoxib)
• “Pfizer announced Dec 17, 2004, just 11 weeks
after the Vioxx recall, that the National Cancer
Institute suspended a trial after finding patients
in the cancer study taking 400 to 800 mg of
Celebrex daily had 2-3 times the cardiovascular
risk than those taking a placebo.”
Celebrex Safety. http://www.adrugrecall.com/celebrex/safety.html Accessed Feb 10/08
Toxicity - Cardiac
(incl. PGI2)
(Also involved in renal function,
tissue repair and reproduction).
Toxicity - Cardiac
• Higher cardiac risk might also occur in
traditional NSAIDs
– ?that are more COX-2 selective?
– Diclofenac
– Meloxicam
– ?Indomethacin
• Based on observational studies only
• “Safer” = Naproxen, ?ibuprofen
Health Canada. Summary Safety Review - Diclofenac - Risk of Major Heart and Stroke Related Adverse Events. October 6, 2014 - updated October 14, 2014.
See: http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/diclofenac-eng.php Accessed Mar 10/15
Pawlosky, N. Cardiovascular risk: Are all NSAIDs alike? Can Pharm J (Ott). 2013 Mar; 146(2): 80–83. see:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676195/ Accessed Mar 10/15
Cost
• Cheapest = older & generic ($/30 days)
– Naproxen
$8 - $20
– Ibuprofen
$15
– ASA
$18
– Meloxicam $20
– Indomethacin $19
– Celecoxib
$54 - $100
Rxfiles. NSAID comparison chart. Feb 2017 – Accessed Feb 27/17 www.Rxfiles.ca
Convenience
• All po
– Some IV, some PR
• Shorter effect (q4-6h)
– Ibuprofen
– Indomethacin
– ASA
• Longer effect (q8-12h)
– Naproxen
– Diclofenac
Summary
1. Efficacy – equivalent at equipotent doses
2. Toxicity – Renal – equivalent risk
– GI – dose and duration dependent
•
•
Higher with some NSAIDs (eg. Ketorolac)
With more risk factors – add a PPI or Misoprostol
– CV - COX-2 inhibitors > NSAIDs
•
•
•
AVOID COX-2 inh.
Higher risk with Diclofenac (?and Meloxicam?)
Safer with Naproxen (?and Ibuprofen?)
3. Cost – cheap & generic!
4. Convenience
– Naproxen for BID convenience
– Ibuprofen for short half-life
•
•
(faster onset and offset)(eg. Gout tx)
Remember: time to steady state = time to exit system = 3-5 half-lives
Opioids
• Efficacy:
– All equivalent analgesia at equipotent doses
– Bioavailability PO:IV = 2:1
• Toxicity: (many!)
– Constipation: ~ equivalent
(no tolerance)
• (?codeine more than others)
– Respiratory depression: ~ equivalent (rapid tolerance)
– Sedation: ~ equivalent
(rapid tolerance)
– Pruritis / Histamine release:
(slow tolerance)
• Morphine > Hydromorphone > Fentanyl
• Cost:
– all have generic forms, short and long acting forms.
– Codeine, morphine, hydromorphone, oxycodone, fentanyl all
ODB covered +/- LU code
• Convenience: all po q4h (long acting versions all q12h)
Rxfiles.ca – Opioid Comparison Chart
Opioids
• Bottom line: all about the same.
– Choose one or two and learn them well
•
•
•
•
Hydromorphone
1mg
Oxycodone
~ 2.5mg
Morphine
~ 5mg
Codeine
~ 60mg
~ 5:1
~ 2:1
~ 12:1
• N.B. conversion requires calculation that takes
into account possible incomplete cross tolerance
Neuropathic Agents
• Efficacy: ~ the same; but additive
– Presumed inhibition of fast, neuronal Na+ channels
1. Antidepressants
– TCAs: Nortriptyline, Amitriptyline, etc.
– SNRIs: Duloxetine, Venlafaxine
2. Anticonvulsants
– Gabapentin, Pregabalin, VPA, CBZ, phenytoin,
topiramate
3. Topicals
– Lidocaine 5%, capscaicin, NSAIDs, compounded
agents above etc.
Neuropathic Agents
• If Efficacy is ~ equivalent; choose based on potential
toxicity, cost, and convenience factors
• Toxicity:
–
–
–
–
TCA’s: anticholinergic, sedation, QTc prolongation
Gabapentin & Pregabalin: sedation, edema, dizziness
Duloxetine & Venlafaxine : CNS effects, GI effects
Anti-epileptics: hepatitis, GI effects, CBC alterations, drug
interactions
• Cost:
– Pregabalin & duloxetine – pricey, (since no generics)
• Convenience: all ~ qhs or BID
Rxfiles.ca - Neuropathic Agents
Rxfiles.ca Table 2: Overview of Drugs Used in Treatment of Chronic Non‐Cancer Pain (CNCP) Feb 2013. pg 67 Accessed Mar 24/13
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
Drug-Drug Interactions
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2017
Objectives
• List the mechanism of various pharmacodynamic
and pharmacokinetic drug-drug interactions
• Define clinically relevant interactions
• List common red-flag interactions that all
practitioners should be aware of in primary care
• Learn useful resources for finding accurate and
timely information regarding drug interactions
Outline
• Intro
• Mechanisms
– Outline bread & butter examples for each type
– Summarize and underscore mains types
– Outline rare & severe examples
• (5HT syndrome, QTc prolongation, prescribing cascades,
renal triple whammy)
• Future support
– Tricks for clinical context
Introduction
Things will only get worse….
• Wide spectrum of cases in Family Practice
– Cradle to grave
– 2/3rds of MD office visits result in a prescription
• Aging population
– Multiple disease states
– Multiple caregivers
– Self Treatment
• An increasing armamentum of drugs
– Rx / OTC / herbal / homeopathic
Jaski M.E. et al. Effective Clinical Practice, ACP Internal Medicine Jan/Feb 2000. http://www.acponline.org/journals/ecp/janfeb00/jaski.htm Accessed April
17/12.
Drug Interactions
• Nature
– Synergistic
– Additive
– Antagonistic
• Consequence
– Beneficial
• Increased therapeutic effect
• Reduced toxicity
– Adverse
• Reduced therapeutic effect
• Increased toxicity
Drug Interactions – Mechanism
1. Pharmacokinetic (PK)
– What the body does to the drug
1.
2.
3.
4.
Absorption
Distribution
Metabolism
Excretion
2. Pharmacodynamic (PD)
– What the drug does to the body
PK – 1) Absorption Interactions
• Important in family practice:
– Chelation (binding interactions)
• Less commonly clinically relevant:
– Alteration of gastric pH
– Alteration of GI motility
1.
2.
3.
Aymard JP et al. Med Toxicol Adverse Drug Exp 1988;3:430-48.
Murray J.J. et al. JAMDA 1991;1:p.
Lomaestro BM et al. Drug Intell Clin Pharm 1991;25: 1249-58.
PK – 1) Absorption Interactions
Chelation
1. Fluoroquinolones or Tetracyclines plus minerals
[Minerals = calcium (Ca2+) , magnesium (Mg2+) , iron (Fe3+) , aluminum (Al3+)]
[Almost all buffering antacids (TUMS, Gaviscon, Milk of Magnesia, Rolaids, etc.), as well as
MVITs, iron tabs etc.]
– Risk of treatment failure!
2. Bisphosphonates plus minerals
– Risk of osteoporotic fracture
3. Phenytoin plus minerals
– Potential loss of seizure control
Separate administration by 2 hours
PK – 1) Absorption Interactions
• Alteration of gastric pH
– Increased pH
• Eg. Iron / Ketoconazole / Vit B12 absorption is reduced
• Administer with OJ or Coca-cola
• Alteration of GI motility
– Decreased motility
• Eg. Decreased absorption of Levodopa
– Increased metabolism at intestinal brush border
– Increased motility
• Eg. Decreased absorption of Digoxin
PK – 2) Distribution Interactions
• Displacement Reaction
– (from protein binding sites)
– Rarely significant
– Often need:
• Highly bound drug
– (98% bound to 96% bound = 100% increase in free concentration)
• PLUS, you often need inhibition of metabolism (or
elimination) to allow enough time for these effects before
redistribution to a new steady state.
PK – 2) Distribution Interactions
• Eg. Warfarin + Septra
– Displacement of warfarin off protein binding sites
• (plus inhibition of metabolism
and Vitamin K synthesis by gut flora)
• Eg. Phenytoin + Valproic acid
– Displacement of phenytoin off binding sites
• (plus inhibition of metabolism
and zero order kinetics (enzyme saturation kinetics) of
phenytoin)
Hogan M.J. et al. DNS Aug. 30, 1999 http://www.findarticles.com/p/articles/mi_m3374/is_13_21/ai_55693815/pg_4 Accessed Apr 18/12
PK – 3) Metabolism Interactions
• Metabolism occurs in many places
– Skin, lung, intestine, serum, kidney, liver
– Most metabolism occurs in the liver
• Few interactions with non-oxidative metabolism –
(ubiquitous enzymes)
– Not everything is P450
• P-glycoprotein poorly understood so far
– Genetic variability becoming more important
• Isoniazid, codeine
PK – 3) Metabolism Interactions
• Cytochrome P450 isoforms – so many!
• Family - Subfamily - Genotype (eg. 2-C-19)
(18)
(42)
(60)
– Substrates, inhibitors, & inducers for each isoform!
– 3A4 - most common
PK – 3) Metabolism Interactions
• Inducers:
• Substrates:
• Ask: Time to effect?
– ~ 2 weeks to kick in
– ~ 2 weeks to fade out
Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.
– Ask: Consequences of
sub-therapeutic doses?
PK – 3) Metabolism Interactions
• Inducers of 3A4:
–
–
–
–
–
–
–
–
• Substrates of 3A4:
Rifampin / Rifabutin
Efavirenz / Nevirapine
Glucocorticoids
Phenytoin
Carbamazepine
Barbiturates
St. John's Wort
Pioglitazone
etc
–
–
–
–
–
–
–
–
Clarithro / Erythromycin
Alpraz / Diaz / Midazolam
CSA / Tacrolimus
Indinavir / Nelfinavir
Ritonavir / Saquinavir
Amlodipine / Felodipine
Nifedipine / Verap / Dilt
Atorva / Simvastatin
Estrogen
Carbamazepine
etc
Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.
PK – 3) Metabolism Interactions
Clinical Scenarios
• 50 y.o. male - PMHx of
HTN, MI x3, COPD on:
– Ramipril 10mg daily
– HCTZ 25mg qAM
– Amlodipine 10mg daily
– BP control borderline/high
– COPD exacerbation
• Rx: PREDNISONE 25mg qAM
for 7 days
• 50 y.o. female – PMHx of
DM2, renal transplant on:
–
–
–
–
Ramipril 10mg daily
Amlodipine 10mg daily
Tacrolimus 10mg BID
Cyclosporine 15mg BID
– Endo Rx: ACTOS 30mg qd
– N.D.: St John’s Wort i qd
• Issues?
• Issues?
» NO!
» YES!
PK – 3) Metabolism Interactions
Pearl
• Inducers of 1A2:
• Substrates of 1A2:
– Nicotine
– Caffeine
– Smoking cessation…
– Sweaty, anxious,
nauseous, sleepless…
– Nicotine withdrawal?
– No! Caffeine overdose!
Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.
PK – 3) Metabolism Interactions
• Inhibitors:
• Substrates:
• Ask: Time to effect?
– Immediate effect
– Hours/days to fade
Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.
– Ask: Consequences of
supra-therapeutic doses?
PK – 3) Metabolism Interactions
• Inhibitors of 3A4:
• Substrates of 3A4:
–
–
–
–
–
–
Clarithro / Erythro
Ciprofloxacin
Fluco / Itra / Ketoconazole
Grapefruit juice
Amiodarone
Indinavir / Nelfinavir
Ritonavir /Saquinavir
Delaviridine
– Verapamil / Diltiazem
– Cimetidine
Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.
– Alpraz / Diaz / Midazolam
– CSA / Tacrolimus
– Amlodipine / Felodipine
Nifedipine / Verap / Dilt
– Atorva / Simvastatin
– Clarithro / Erythromycin
– Indinavir / Nelfinavir
Ritonavir / Saquinavir
– Estrogen
– Carbamazepine
etc
PK – 3) Metabolism Interactions
Clinical Scenarios
• 60 y.o. female – PMHx of
HTN on:
– Nifedipine XL 60mg qd
– BP: 105/60
– Enjoys a fresh grapefruit
when in season.
• 60 y.o. male – PMHx of
NSTEMI, CHF on:
–
–
–
–
Lipitor 80mg qd
Ramipril 10mg qd
ASA 81mg qd
Bisoprolol 5mg qd
– New onset Afib – Cardio Rx:
Amiodarone 200mg daily
• Issues?
• Issues?
» No!
» Yes, two!
PK – 3) Metabolism Interactions
Pearl
• Inhibitor of 2C19:
• Substrates of 2C19:
– Omeprazole
– Clopidogrel
• ?All PPI’s
– Time to effect is
immediate
Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.
– Lack of metabolism from
pro-drug to active form
– Sub-therapeutic effect!
PK – 3) Metabolism
Summary
• Inducers
– Remember: time to effect ~
2 weeks
• Longer treatments will
result in more significant
interactions
• Harder to see the
temporal correlation
– Lower doses of affected
substrate need to be
clinically relevant
• Inhibitors
– Remember: time to effect
is immediate
• Shorter treatments will
result in more significant
interactions
• N.B. Drugs with long halflives will take longer to
show their effect!
– Higher doses of affected
substrate need to be
clinically relevant
PK – 4) Excretion Interactions
• Rarely significant, but…
– Enterohepatic circulation:
• Bile acid sequestrants + Warfarin or L-T4 or Estrogen
– Alteration in urine pH
• Ion trapping
– Eg. Management of ASA overdose with bicarb
– Eg. Methamphetamine overdose with Vit C / NH4Cl
– Competition for tubular transporters
• Anion: Probenecid + beta-lactams (osteomyelitis)
• Cation: Itraconazole /cimetidine + digoxin / quinidine
Pharmacodynamic (PD) Interactions
• Think: Review of Systems
– Head to Toe
• Bottom Line:
– The molecular mechanism is
irrelevant.
– The physiological effect is
important.
• These effects are additive.
– (or synergistic or antagonistic)
PD - CNS
• Eg. CNS depression
– Alcohol
– Opioids
– Benzodiazepines
– Antihistamines
• Diphenydramine, hydroxyzine, etc
– Antipsychotics (typical & atypical)
– Antidepressants (TCAs, SSRIs etc)
– Barbiturates
– Etc.
What to do?
• Monitor more closely for tolerance
– Temporal correlations will be helpful
• Other classic pearls of prescribing:
– Avoid the combo if possible
• Explore alternatives using the 4 steps of rational
prescribing
– Use the lowest effective dose
– Limit duration of treatment
– Start low, go slow
PD - CV
• Bradycardia
–
–
–
–
Beta blockers
Diltiazem, Verapamil
Digoxin
Amiodarone
• Hypertension
–
–
–
–
–
–
NSAIDs & COX-2 inh
Corticosteroids
EPO
Estrogens
Cyclosporine
Sympathomimetics
• phenylephrine
• caffeine
• pseudoephedrine
PD
• Respiratory Depression
–
–
–
–
Opioids
Barbiturates
Benzodiazepines
Alcohol
PD interactions are
common and best
prevented by
understanding the
MOA of drugs used in
practice.
• Constipation
•
•
•
•
•
•
Loperamide
Opioids
Calcium / antacids
Anticholinergics
Metamucil
Etc
• Diarrhea
•
•
•
•
•
Laxatives
Erythromcyin
Antibiotics
Magnesium
So many more!
Prescribing Cascades
• Very common in primary care
• Unrecognized side effects of one drug lead to
prescribing of another to compensate.
– Chain linked pharmacodynamic interactions!
– Have seen up to 20 drugs in elderly patients
accumulate over the years!
Renal Triple Whammy
• Commonly overlooked in Primary Care
• ACEinh (or ARB) + diuretic + NSAID
Katarzyna K Loboz et al. Drug combinations and impaired renal function – the ‘triple whammy’. Br J Clin Pharmacol.
2005 February; 59(2): 239–243. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/pdf/bcp0059-0239.pdf
Accessed Apr 18/12
1)
Diuretics
reduce
forward
flow into
kidney
3) ACEinh / ARBs vasodilate
efferent arterioles (blockade of
ATii effects)
Result:
2) NSAIDs
vasoconstrict
afferent
arterioles (inh of
PG synthesis)
Reduced
GFR &
Acute
Renal
Failure!
Katarzyna K Loboz and Gillian M Shenfield. Drug combinations and impaired renal function – the ‘triple whammy’. Br J Clin Pharmacol. 2005
February; 59(2): 239–243. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/ Accessed Oct 31/11
Rarities
(that never seem rare enough)
Serotonin Syndrome
– Hyperstimulation of 5-HT 1A & 2A receptors
• Peripherally and centrally
– Concentration dependent symptoms
• Mild - tremors and diarrhea
• Severe – hyperthermia and rigidity, even death.
– Rare in monotherapy
• Usually with polypharmacy
Rastogi, Rahul et al. Case Scenario: Opioid Association with Serotonin Syndrome: Implications to the Practitioners. Anesthesiology: December
2011 - Volume 115 - Issue 6 - p 1291–1298
see: http://journals.lww.com/anesthesiology/Fulltext/2011/12000/Case_Scenario___Opioid_Association_with_Serotonin.24.aspx Accessed Apr 18/12.
Serotonin Syndrome
• Important Meds:
–
–
–
–
SSRIs
TCAs
Triptans
Opioids (incl. DM syrup)
- SNRIs
- MAOinh’s
- St John’s Wort
- MDMA (ecstasy)
• Opioids may affect serotonin levels
– Tramadol, fentanyl, methadone, meperidine, dextromethorphan
• Weak SSRI’s and also increase release of 5HT into the synapse
• Possibly also morphine, hydromorphone, oxycodone and buprenorphine
(which lack SSRI activity)
Joel Lamoure. How Common or Significant Is Serotonin Syndrome? Medscape 11/10/2008 http://www.medscape.com/viewarticle/582862
Accessed Apr 18/12.
Serotonin Syndrome
• Predisposing factors:
– Serotonergic Load
• Consider all potentially offending drugs
• Gauge the load by dose and frequency of use.
– P450-2D6 and -3A4 mutations (polymorphisms)
– P450-2D6 and -3A4 inhibitors
– Inhibitors of: NE reuptake, GABA, NMDA, and 5HT3
Clinical Scenario
• 39 year old male on:
– Citalopram 10mg qd for depression
– Nortriptyline 75mg qhs for neuropathy
– Ibuprofen 400mg prn for migraine
• He is asking about a triptan for his migraines.
They were effective back home in Lebanon.
– Considerations? (five of them)
QTc Prolongation
• Also rare, but with serious potential
outcomes.
– Torsades (TdP), death
• Hard to predict
• Long list of meds that prolong the QTc
– See: www.crediblemeds.org (free registration)
Common Culprits
• Recent cases:
– Domperidone, Citalopram, Escitalopram
• Macrolides
– Erythromycin > Clarithromycin > Azithromycin
• Fluoroquinolones
– Ciprofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin
• Miscellaneous
– Clindamycin, Trimethoprim/Sulfamethoxazole
• Azole Antifungals
– Fluconazole, Itraconazole, Ketoconazole
• Antipsychotics
• SSRI’s
• TCAs
Etc.
Risk factors for QTc Prolongation
–
–
–
–
–
–
–
–
Female
Elderly
Myocarditis
Bradycardia
Myocardial infarction
Stroke
Long QT Syndrome (congenital form)
Syncope of unknown cause
- Hypokalemia
- Hypothyroidism
-Hypomagnesemia
- Hypothermia
- Hypocalcemia
- Hypoglycemia
QTc Prolongation
Clinical Scenario
• 66 y.o. female with
PMHx of Long QT
Syndrome
– Normal EKG 3 months
ago
– Labs normal
• New UTI; No C&S yet
– Options?
– Macrobid, Amox – avoid
macrolides, septra,
cipro!
• 66 y.o. male with PMHx
of bipolar on:
– Quetiapine 400mg qd
– Citalopram 20mg qd
– Labs normal
• New pneumonia (CAP)
– Options?
– Any will do, preferrably
Azithro, Clavulin, Doxy
Summary - Resources
1. Learn the basic mechanism of action of the drugs in
your personal formulary
– Most interactions you’ll see are pharmacodynamic
For pharmacokinetic interactions (usu CYP-P450):
2. Get a good EMR
– Most have interactions checkers – active while Rx’ing
3. Get a good drug database
– (All have superior interaction checkers in them!)
• Eg. Micromedex or Lexi-Comp
4. Get a good pharmacist 
– They are well positioned to help manage these cases
Clinical Scenario 1
• H.R. - 66y.o. male with hypothyroidism, HTN
and OP
• Meds:
– Synthroid 100mcg qAM
– Altace 5mg qPM
– Triamterene 100mg qAM
– Actonel 35mg/wk
– Calcium/Vitamin D 1000mg/1000iu qAM
• Three potential issues!
Clinical Scenario 1 - answer
• 1) ? Ca2+ & Synthroid co-administration?
• 2) ? Ca2+ & Actonel co-administration?
• 3) ? Hyperkalemia with ACEi & K+sparing
diuretic?
Clinical Scenario 2
• J.K. - 29y.o. female from Sudan
• Meds:
– Rifampin 600mg
– Isoniazid 300mg
– Pyrazinamide 2g
– Ethambutol 1.6g
– Alesse 21
Clinical Scenario 2 - answer
•
•
•
•
Rifampin induction of P450 3A4
Risk of OCP failure
(When? Within 2 weeks)
Management:
– Barrier method until 2 weeks post RIF
– INH 3A4 DI, not significant here
Clinical Scenario 3
• T.Y. 83 y.o. female with DM2, HTN, delirium
and recent fall
• Meds:
– Altace 5mg
– HCTZ 12.5mg
– Amitriptyline 25mg
– Insulin NPH & R
– Haloperidol 1mg
- Atenolol 25mg
- ASA 81mg
- Trazodone 50mg
- Glycopyrrolate 2mg
- Demerol 50mg
Clinical Scenario 3 - answer
• Delirium:
– Additive anticholinergic fx in elderly
• Glycopyrrolate, trazodone, amitriptyline, haloperidol
• Fall:
– Additive sedative fx in elderly
• Haloperidol, demerol, trazodone, amitriptyline
– Additive dizziness
• Atenolol, altace, HCTZ, demerol, trazodone
Summary
• The more meds patients take, the greater the risk
of drug interactions (DI)
– The nature and mechanism of DI’s can have beneficial
or adverse consequences
• Pharmacokinetic DI - alter drug levels
– Most commonly metabolic DI (P450)
• We’ll never know them all; get good software!
• Pharmacodynamic DI - alter responses
– Additive, synergistic or antagonistic effects occur
regardless of the mechanism – most common DI’s!
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
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
Mar 2017
[email protected]
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)
• Apixaban
• Rivaroxaban
• Edoxaban (new)
– Factor Xa inhibitor
– For:
• Afib (all)
• Recurrent VTE (all)
• VTE prophylaxis post-op
TKR/THA
– N.B. Edoxaban not indicated
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
Less intracranial & More GI bleeds vs Warf
?More MI? More GI upset
(~1% absolute
difference) (RE-LY trial - Untested > 79y.o. or CrCL < 30
NO reversal agent (Idarucizumab pending)
industry funded)
~ same
(<1% abs diff)
(ROCKET-AF trial – industry)
Apixaban
Edoxaban
Less intracranial & More GI bleeds vs Warf
Untested > 79y.o. or CrCL < 30
NO reversal agent (Andexanet pending)
Less intracranial bleeds
~ same
GI bleeding – no difference vs Warf
(<1% abs diff) (ARISTOTLE
Untested > 77y.o. or CrCL < 30
trial – industry)
NO reversal agent (Andexanet pending)
~ same
(ENGAGE-AF trial)
More GI bleeds vs Warf
(VTE, Afib, Valve disease)
Agent
Warfarin
Cost
Convenience
~ $40/mo
QD po
INR q3d – q1mo
(with INR monitoring)
Dabigatran
$116/mo
Rivaroxaban
$104/mo
Apixaban
$116/mo
Edoxaban
$109/mo
(ODB covered)
BID po
(ODB w/ LU code 431 for Afib or VTE)
QD with food
(ODB w/ LU codes for Afib or VTE)
BID po
(ODB w/ LU code for Afib or VTE)
QD po
(No ODB coverage)
Rxfiles.ca Comparison of Warfarin & New Oral Anticoagulants (NOACs) in Non-Valvular Atrial Fibrillation. Oct 2014c
Anticoagulants
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.
– With time, more safety data may make DOACs 1st line
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
Mar 2017
[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 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
– $30-$47/mo
• Escitalopram
– $65/mo
– New generics; price is
dropping
• Paroxetine CR
– $69-$75/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 ‘70’s.
– In 1975 – 100 million Rxs written in USA alone
– Efficacy – excellent SHORT term efficacy
• Sedation & anxiolysis
• Rapid tolerance is developed + Dependence – insidious combo!
– Toxicity – addictive!
• D/C’ing is VERY hard
• Long term risk of dementia, falls, and memory impairment
• Severe withdrawal can be fatal (seizures)
– Cost & Convenience – Who cares?; Fuggetabout-it!
•
•
•
•
http://www.youtube.com/watch?v=tfGYSHy1jQs
http://www.youtube.com/watch?v=Zf0ZyoUn7Vk
http://www.youtube.com/watch?v=J5Xu9UcOdj0
Maximum supply: Mitte: single digits! No refills.
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
– 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
Mar 2017
[email protected]
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:
– ($60-$160/month)
•
•
•
•
Aripiprazole
Ziprasidone
Paliperidone
Asenapine
– Clozapine
– Quetiapine (XR)
– Olanzapine (Zydis)
• Convenience
–
–
–
–
Most BID po
Olanzapine Zydis (melts)
Risperidone M-tab (melts)
Some I.M. long acting forms:
•
•
•
•
•
•
Risperidone q2wk
Paliperidone q4wk
Flupentixol q2wk
Fluphenazine q4wk
Zuclopenthixol q3wk
Haloperidol q4wk
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.ca – 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: @RolandHalil
Gout
(Get Out the Gout)
Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Assistant Professor, Dept of Family Medicine, University of Ottawa
Clinical Pharmacist, Bruyere Academic Family Health Team
Mar 2017
[email protected]
Pathophysiology
• Precipitation of monosodium urate crystals in
avascular tissues
– (cartilage, epiphyseal bone, periarticular bone)
– Hyperuricemia likely asymptomatic for years
• The acute attack:
– Crystals activate plasma proteases
– Can activate factor XII & C5
– Can adsorb opsonins in area, attracting phagocytes!
Pathophysiology – Acute Attack
Inflammation lowers
pH in the joint
Urate precipitates
out of solution = tophi
Phagocytosis fails.
Crystals lyse
phagocytes.
Tophi are released
MORE PHAGOCYTES
ARRIVE - Lactic acid
is a byproduct
of phagocytosis
Enzymes released
into synovial fluid
Damage tissue,
activate
complement etc
Pathophysiology – Acute Attack
A vicious cycle.
• Acute attacks probably self-limited due to heat of
inflammation re-dissolving the crystals
Principles of Management
1. Terminate acute attacks
2. Prevent recurrence
–
Eliminate urate crystals from joints & tissues
3. Address co-morbidities
–
–
–
–
–
Obesity
Hypertriglyceridemia
Hypertension
Diabetes mellitus
Excessive alcohol
1) Treatment of Acute Attacks
• Directed at WBC inflammatory response
Options:
1. NSAIDs
2. Colchicine
3. Corticosteroids
• Choice depends on toxicity, cost & convenience since
efficacy is ~ equivalent
– More importantly – rapidity of treatment selection!
– Keep agent close at all times; start PRN A.S.A.P.
• Especially with poor renal function:
• N.B. A slower response = increased drug exposure over
the course of a flare
Colchicine vs NSAIDs
1.
Untreated

2.
Aliern et al.(1987);
Indomethacin

1)
2)
Ahern el al. (1987);
Colchicine

4.
2
Placebo group

3.
Bellainy et al. (1987);
Ruotsi Vainio (1978);
Management of Gout With Colchicine http://www.theberries.ns.ca/Archives/colchicine.html Accessed Nov 1/07
Ahern MJ, et al. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med 1987;17:301-4.
NSAIDs
No difference in Efficacy
• Choose based on: Toxicity, Cost, Convenience
– Toxicity:
• N/V/D, GI bleeding, fluid retention, ARF, etc
• So: avoid in PUD/GERD, CHF, peripheral edema, CKD etc
– Cost
• Rx vs OTC
– Convenience
• Choose NSAID with a shorter half-life (t½) (ss = 3 - 5 t½’s!)
– Fast in = achieves steady state faster for acute pain,
– Fast out = smaller footprint on CrCL (renal strain)
– Eg. Ibuprofen (2-4hrs); Diclofenac (2hrs); Indomethacin (4.5hrs);
Colchicine
• Used for centuries
• Most specific agent in use
– Decreases leukocyte motility
• Binds to tubulin and inhibits microtubule
formation, arresting neutrophil motility
– Decreases phagocytosis in joints
• Decreases lactic acid production
• OVERALL EFFECT:
– Interruption of inflammatory process
– PO or IV
• Avoid IV - Potentially fatal if mis-dosed!
– Risk of arrhythmia
Colchicum autumnale
(autumn crocus)
(meadow saffron)
Colchicine
• Traditional dosing:
– 0.6mg q1-2hrs until:
• Improved sxs
OR
• GI distress
OR
• 10 doses with no effect
– Too rigourous for most patients!
• (Esp elderly) - GI distress in 50-80% of patients!
• Narrow therapeutic window
Colchicine
• 1 mg & 0.6 mg tablets - scored
• Alternative regimens
– 1mg loading dose, then 0.5mg q2-6hrs
OR
– 0.5 - 1mg TID
OR
– 1.2mg initially, then 0.6mg BID
• Most effective w/i first 12hrs of attack
• Dose low! Try TID dosing first
• D/C if GI distress develops
Corticosteroids
• Reserved for:
– Intolerant of NSAIDs or colchicine
– Co-morbidities that prohibit use of other meds
• Good alternative for elderly w/ poor renal function
– Few trials – choice is empiric
– Eg. Prednisone 20-60mg /day PO
• Lower doses may be less effective
– Flares noted in transplant patients on 7.5 mg - 15 mg/day
– Methylprednisolone 125mg/day IV or IM q1-4 days prn
• Can give intra-articular injection, but avoid if joint is septic!
Serum Urate
• Rising urate levels can provoke flare
– For reasons unknown, lowering serum urate can
as well.
• Worse with more rapid or severe changes in urate
• Occurs in ~ 25% of patients
• N.B. Do not alter existing gout meds during acute
flare! (ie. allopurinol)
Summary
Treatment of Acute Attacks
• Start treatment A.S.A.P.!
• Do not change doses of any med that can alter urate
levels when treating acute attacks (ie. allopurinol)
• Consider NSAIDs, colchicine, steroids at low doses and
in combination (different MOA’s; additive benefits)
• Avoid NSAIDs in CKD, CHF
• Avoid / Reduce colchicine dose in CKD, liver dz,
neutropenia, on diuretics, statins, or cyclosporin
2) Preventing Recurrence
• Eliminate excess body urate
– Else, tophi may continue to enlarge
– Result: chronic arthritis due to chronic inflammatory
response destroying cartilage & bone
– Target: Urate < 360 umol/L
• High likelihood of recurrence
– 62% w/i 1 yr
– 78% w/i 2 yrs
– 90% w/i 5 yrs
Preventing Recurrence
• Recall that: Lowering urate can precipitate a flare!
• Start 2-3 weeks after flare resolved
– Uricosuric agents – increase UA excretion
• Probenecid
• Sulfinpyrazone
– Xanthine Oxidase inhibitors – decrease UA production
• Allopurinol – agent of choice
• Febuxostat – new agent (ULORIC™)
• May consider prophylaxis before urate lowering
therapy (eg. low dose colchicine or NSAID daily)
– Continue 3-6 months and/or [urate] < 360 umol/L
Allopurinol
• Start Allopurinol at low dose and titrate up to
avoid precipitating event
– Eg. 100mg, increasing by 100mg q2-4 weeks to target
dose
– With renal dysfunction:
• 50mg initiation, increase by 50mg
Febuxostat (ULORIC™)
• A non-purine, selective xanthine oxidase inh.
• Efficacy vs Allopurinol:
– Similar frequency of gout flares
• N.B. Higher frequency of flare with initiation at higher
doses!
– More potent reduction of UA than Allopurinol
– Limited RCTs - need more evidence in:
• Renal dysfunction, concomitant use of urate raising drugs
(eg. ASA, thiazides), comparison against non-fixed doses of
Allopurinol
See: Gaffo LA et al. Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout. Core Evid. 2009; 4: 25–36.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2899777/?tool=pubmed Accessed Feb 7th, 2011.
Febuxostat (ULORIC™)
• Start 40mg daily (+/- food)
– Up to 80mg or 120mg qd
• after 2 weeks if UA > 360 umol/L
– CrCL > 30mL/min – no dose adjustment
– CrCL < 30 mL/min – unstudied – avoid
• Side effects:
– Rash (1% to 2%)
– Liver function abnormalities (5% to 7%)
• F/U LFTs in 2 & 4 months after starting tx
– Arthralgia (1%)
• Cost: 80mg tabs ~ $60/ month;
– (no ODB coverage)
• Treat the same as allopurinol
Note Bene (N.B.)
• No prophylaxis without urate lowering tx!
– Acute flare prevented but crystal deposition in tissue
continues!
– Hence no warning signs of continued cartilage and
bone damage and deposition in organs, especially
kidneys!
– Remember: Cochicine is NOT uricosuric!
Preventing Recurrence - Summary
• Allopurinol
– Most common
• Febuxostat
–
–
–
–
New kid on the block!
Improved efficacy
Lacking sufficient safety data for some populations
No ODB coverage
• Probenecid or Sulfinpyrazone: (unlikely)
– only if CrcL > 50mL/min
– No hx of kidney stones
– No ASA > 2g/day
• Interference with uricosuric effects
Preventing Recurrence -Allopurinol
• Dosing:
– 50mg to 800mg qd
(usually 300mg)
– N.B. Only 21-55% attain
urate < 360 umol/L on
“standard” dose
• Most insufficient doses –
main barrier to control
• N.B. Dose adjust for renal
function
– Dosing according to CrCL
may not attain control
• GOAL: lowest dose to
target urate < 360 umol/L
• ADRs: (well tolerated)
– Common:
• GI upset,
• Rash
– (esp if on Amox/Amp or
Cyclophosphamide)
– Rare:
•
•
•
•
Blood dyscrasias
Jaundice
TEN
Hypersensitivity Syndrome
(including rash)
– If mild rash occurs, hold
and re-challenge
Preventing Recurrence
Sulfinpyrazone:
– Up to 800mg /day
divided bid
– Start: 100mg BID
• Increase q1wk
– May decrease to
200mg/d once urate
controlled
– ADRs: GI upset, rash
Probenecid:
– 500mg to 3g /day
divided bid-tid
– Start: 250mg BID
• Increase by 500mg
q4wk
– May decrease by
500mg q6mo if stable >
6 mo till urate starts to
rise
– ADRs: GI upset, rash
Useless Trivia With Which To
Impress Your Patients
• Urate levels in humans are 10 times higher than other
mammals because we lack the enzyme uricase!
– PEGlyated-uricase (Pegloticase) (Krystexxa™)
• Only approved in USA for refractory gout
Summary of Gout Prevention
• High likelihood of recurrence
• Eliminate excess body urate to prevent chronic
destructive changes
– Colchicine is not uricosuric!
– No prophylaxis without urate lowering therapy!
• Manage risk factors
– Drugs, diet, co-morbidities
• Allopurinol – drug of choice
– Start low, go slow
– May have to push dose to attain control
• N.B. Must differentiate mild rash from a serious hypersensitivity
syndrome
3) Address Co-Morbid Conditions
•
•
•
•
Obesity
Hypertriglyceridemia
Hypertension and Diabetes Mellitus
Excessive Alcohol
Obesity & Hypertriglyceridemia
• Weight loss independently lowers urate levels
• Decreased alcohol consumption, regular
exercise and weight reduction will lower TGs
– Fibrates
• Especially fenofibrate – mild uricosuric effect
Diet Restriction
• Total diet restriction only lowers urate levels by
~ 52.9 umol/L (1mg/dL)
– Very unpalatable
– Poor compliance
• Purine sources matter
– Increase with meat & seafood
– Decrease with dairy
• Daily consumption lowers urate levels
– Oatmeal and purine rich vegetables do not increase
risk of gout
• Peas, mushrooms, lentils, spinach, cauliflower
Dietary sources
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
High-Purine Content
Anchovies
Beer
Bouillon (meat based)
Brains
Broth (meat based)
Clams
Consommé
Goose
Grain alcohol
Gravy
Heart
Herring
Kidney
Lobster
Mackerel
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Meat extracts
Mincemeat
Mussels
Oysters
Partridge
Roe (fish eggs)
Sardines
Scallops
Shrimp
Sweetbreads
Yeast (baker's and brewer's) taken as a
supplement
Moderate-Purine Content
Beans, dried
Fish (except those in the high-purine
content list)
Lentils
Meat (except those in the high-purine
content list)
Mushrooms
Hypertension
• ~ 1/3rd with gout have HTN
• Major cardiac risk factor
– Caution with thiazides and ASA!
– N.B. LOSARTAN – mild uricosuric effect!
Excessive alcohol
•
Mechanisms:
1. Purine content of beverage
•
BEER! (lots of guanosine)
2. Chronic alcohol stimulates de novo purine biosynthesis in
liver
3. Binge drinking results in lactic acidemia, lowering renal
urate excretion
•
Moderate wine ok, but any alcohol is a risk factor
–
–
–
RR 1.32 (10 - 15 g/day)
RR 1.49 (15 - 30 g/day)
RR 1.96 (30 - 50 g/day)
•
–
> 30g/d in females; > 45g/d in males ↑ risk of liver disease
RR 2.53 (> 50 g/day)
Summary of Lifestyle Modification
• Lose weight
• Lower TG’s (esp with Fenofibrate)
• Lower BP (esp with Losartan)
– Avoid diuretics and ASA if you can
• Elimination alcohol
• Avoid eating brainsssss
Patient Education
Urate crystals •
Gout attack •
Colchicine or NSAIDs •
Treatment delay •
Prophylactic colchicine •
Uricosuric agent (eg. Allopurinol) •
Matches
Matches catch fire
Put out the fire
More matches catch fire
Dampen matches
Eliminates matches
Questions?
TB drugs
Adapted from: Marc Riachi, RPh
Mycobacterium tuberculosis
The Consumption
• Mostly latent, asymptomatic infection (90-95%)
–
–
–
–
Activation risk ~ 10%
Usually pulmonary; can occur anywhere
Spreads via air droplet
One third of world population infected!
• Europe:, TB rates rose from 1600s to peak in the 1800s (caused ~25% of all deaths)
• Organism has "waxy" hard to penetrate cell wall
– Acid-fast bacilli
– Combinations of drugs needed to treat
• Slow growing
– Therefore requires extended treatment period
• Treatment:
– Multiple side effects = reduced compliance by patient = further emergence
of resistant strains
– MDR, XDR strains
Adapted from: Marc Riachi, RPh
Available antimycobacterials
• First-line:
– Isoniazid (INH)
– Rifampin (RIF) or Rifampicin (RMP)
– Pyrazinamide (PZA)
– Ethambutol (ETB)
• Second-line:
– Amikacin
– FQs (Ciprofloxacin / Levofloxacin / Moxifloxacin)
– Clarithromycin / Azithromycin
Ref: Marc Riachi, RPh
Treatment - Active Pulmonary TB
• “4 drugs x 2 months, then 2 drugs x 4 mo”
• (N.B. 3x/weekly dosing must be D.O.T.)
Ref: PHAC. Canadian Tuberuclosis Standards, 7th Ed. 2013 p. 37A http://www.respiratoryguidelines.ca/sites/all/files/Chapter%205_final1_0.pdf Accessed Dec 20, 2013
Treatment – Latent TB
•
SAP = self-administered prophylaxis, DOP = directly observed prophylaxis.
• INH – monitor LFTs
– Hepatitis (rare < 20y.o.; >2% in >50y.o.)
– Drug interactions!
• RIF – GI toxicities, major drug interactions!
– Huge inducer of cytochrome P450
Ref: PHAC. Canadian Tuberuclosis Standards, 7th Ed. 2013 p. 14 http://www.respiratoryguidelines.ca/sites/all/files/Chapter%206.pdf Accessed Dec 20, 2013
Which agents to use in active disease?
• Pulmonary or extrapulmonary disease:
– INH+RIF+PZA+ETB
• If resistant to INH:
– RIF+PZA+ETB (+FQ if severe)
• If resistant to RIF:
– INH+PZA+ETB+FQ
• if resistant to INH and RIF:
– PZA+ETB+FQ+amikacin
• If resistant to INH, RIF and PZA or ETB
– ETB (or PZA)+FQ+amikacin+two 2nd line agents
Ref: Marc Riachi, RPh
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
Anti-fungals
Adapted from: Marc Riachi, RPh
Drug info
•
•
INH (inhibits formation of fatty acids found in the
cell wall):
– Bactericidal; penetrates cavitations
– Hepatotoxicity (↑ with alcohol & rifampin)
 monitor LFTs
– peripheral neuropathy (give vit B6)
– GI symptoms, skin rash
– ↑ phenytoin, carbamazepine &
benzodiazepine blood levels
RIF (inhibits mRNA synthesis):
– Bactericidal; penetrates cavitations
– Hepatotoxicity (↑ with alcohol)  monitor
LFTs
– GI symptoms, skin rash
– Pancytopenia
– Colours urine, feces, saliva, tears orange 
may permanently stain contact lenses
– Induces CYP450
Ref: Marc Riachi, RPh
•
•
PZA (may inhibit mycobacterial
metabolism):
– Bactericidal in acid environment (in
macrophages)
– Hepatotoxicity (↑ with alcohol &
rifampin)  monitor LFTs
– Hyperuricemia  monitor uric acid
– GI symptoms and arthralgias
ETB (may inhibit cell wall synthesis):
– Bacteriostatic
– GI symptoms, hyperuricemia
– Ocular toxicity and change in color
perception  monitor at high doses
Antifungals
• Oral
– Azole anti-fungals
• Active vs. yeast and
dermatophytes
• Itra- (Sporanox),
• flu- (Diflucan),
• vori-,
• posa• ketoconazole (Nizoral)
– Terbinafine (Lamisil)
• Active vs. yeast and
dermatophytes
– Nystatin
• Active vs. yeast only
Ref: Marc Riachi, RPh
• Topical
– Ciclopirox
• (cream, lacquer, shampoo),
– nystatin
• (cream, pv, oral suspension),
– clotrimazole
• (cream, pv),
– miconazole
• (cream, pv),
– ketoconazole
• (cream shampoo),
– terbinafine
• (cream, spray),
– tolnaftate
• (powder  suitable for skin folds)
• Injectables
– usually require I.D. consult
Which agents to use?
• Onychomycosis:
– oral terbinafine, oral itraconazole, ciclopirox lacquer (use lacquer only for mild distal form;
expensive)
• Fungal skin:
– topical clotrimazole, topical miconazole, topical terbinafine, topical ketoconazole. Nystatin is
ineffective vs. dermatophytes. Candidal skin infections respond to nystatin. Use topical azoles
for tinea versicolor (not terbinafine).
• Seborrheic dermatitis:
– topical ciclopirox, ketoconazole
• Oral candidiasis:
– Oral nystatin swish and swallow (not absorbed from GI tract). Oral fluconazole.
• Vulvovaginal candidiasis:
– topical azoles, po fluconazole one dose (now available without a prescription), boric acid pv
suppositories (very irritative)
• Diaper rash:
– Topical nystatin, clotrimazole, miconazole, or ketoconazole.
Ref: Marc Riachi, RPh
•
•
Drug info
Terbinafine po:
– Very active vs dermatophytes
– headache, GI diarrhea, dyspepsia, abdominal pain
– taste disturbance (may persist post treatment)
– CYP2D6 inhibitor:
• Decreases formation of active metabolites of tamoxifen
• May ↓ breakdown of TCA’s, fluoxetine, paroxetine, fluvoxamine, sertraline,
tamsulosin, mirtazapine, haloperidol, some beta blockers
Azole antifungals po:
– Itraconazole and ketoconazole particularly are strong inhibitors of CYP3A4 and so
many drug interactions. Also hepatotoxic. Ketoconazole > itraconazole >
terbinafine wrt hepatic toxicity. Itra may worsen heart failure symptoms.
Ketoconazole is rarely used and is poorly tolerated; anorexia, nausea, vomiting
high doses, and effects sexual function/sex hormones and steroidogenesis.
– Fluconazole is considered a moderate inhibitor of CYP3A4 and so less clinically
important drug interactions. Strong CYP2C9, 2C19 inhibitor. QT prolongation with
amiodarone, clarithromycin, TCA’s. Bioavailability of PO similar to IV; use PO if
possible.
Ref: Marc Riachi, RPh
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil
Grande Finale
• Remember the Four Steps of Rational Prescribing!
– 1) Benefit, 2) Harm, 3) Cost, and 4) Convenience
– This will save you a LOT of time & confusion
• Your EBM skills will inform your Benefit
– When evidence is weak; First, Do No Harm
• ie. (Toxicity outweighs Efficacy)
• Study your Pharmacology!
– Pharmacology will inform your Therapeutics
– Mechanism of action and basic PK/PD data (P450 metabolism (Y/N)
and Top 3 side effects) will inform your monitoring & Toxicities
• Build your Personal Formulary in residency
– Focus your studying where it is needed!
• Eg. With equivalent efficacy – focus on learning the potential toxicities
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @RolandHalil