Download Basics Pharmacology Review Part 2 - Dr. Halil

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Practical Pharmacology – part deux
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 2013
[email protected]
(Partially adapted from slides by Marc Riachi, R.Ph.)
Anti-Dyslipidemic Drugs
(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 2013
Objectives
• List the 4 steps in rationalizing drug therapy
choices using evidence based medicine.
• 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.
Rational Prescribing Process
•
FOUR steps to Rational Prescribing:
1. EFFICACY
2. TOXICITY
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
•
(Inhibits absorption of cholesterol at the brush border of the small
intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1)).
4. Niacin
5. Cholestyramine
•
(Bile acid sequestrant)
Efficacy – Endpoints?
• Hard Endpoints
– Reduction in mortality
• Fatal MI, Fatal stroke
– Reduction in morbidity
• Non-fatal MI, non-fatal stroke, reduction in hospitalization
• Soft Endpoints
– Reduction in plaque size
– Reduction in lipid panel values
– etc
Efficacy
• Only statins have any proven reduction in hard
endpoints.
The End.
Who cares about lipid panel numbers going up
and down if they don’t affect morbidity or
mortality?
So….why bother with the
Toxicity,
Cost or
Inconvenience of any others?
Can J Cardiol Vol 25 No 10 October 2009
Cdn Dyslipidemia Guidelines 2009
Can J Cardiol Vol 25 No 10 October 2009
Cdn Dyslipidemia Guidelines 2009
Can J Cardiol Vol 25 No 10 October 2009
Pharmacotherapy
• “The majority of patients will be able to
achieve target LDL-C levels on statin
monotherapy.”
• “Clinical outcome data on the incremental
benefit of combination therapy with statin
plus ezetimibe, niacin or fibrate, versus statin
monotherapy are lacking, although clinical
trials are underway to examine this issue.”
Can J Cardiol Vol 25 No 10 October 2009
Correlation versus Causation
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.
So?
• So….
• If equivalent LDL lowering with non-statin
drugs have no effect on morbidity or mortality
then LDL may only be a surrogate marker of
the pleiotrophic effects of statins.
Bottom Line
• Being on any statin at any dose is the most
important thing.
• Being on the highest dose of statin that a
patient can tolerate is secondary.
– Doubling the statin dose only lowers LDL by 6%
– Pushing the statin dose to levels that result in side
effects is just not worth it. Non-compliance will
result.
• The LDL target is just your guide.
Exceptions
• Gemfibrozil
– Two trials that show reduction in CVD events
• Helsinki Heart Study (HHS)
• Veterans Administration HDL Intervention Trial (VA-HIT)
– Never combine it with statins
• Serious risk of rhabdomyolysis
• N.B. Fenofibrate
– No effect on CVD events
• Fibrates for high TGs – reduce risk of pancreatitis
• Fibrates for high TGs – treatment of gout
Statin + Fibrate
(ACCORD-Lipid Trial)
• No difference in vascular (hard) outcomes.
– Almost a difference in lipids values (ie. soft outcomes)
– ?Possible vascular harm in women? [9.1% vs 6.6%]
Rxfiles.ca ACCORD Lipid & BP Trial Overview Sept 2010. Accessed Apr 26/12.
Statin + Ezetimibe
(Lipid-ENHANCE Trial)
• No hard endpoints reported.
• Even intima-media thickness non-significant
– IMPROVE-IT Trial still ongoing (expected 2013)
– “Dr Steven Nissen (Cleveland Clinic, OH) questioned whether
the trial would be completed because more than 5000 hard
clinical end points are needed for the study to reach statistical
significance, an unusually high number given that past studies
required a few hundred events.” (see: http://www.theheart.org/article/1064755.do )
Rxfiles.ca. ENHANCE Trial Summary, June 2008. Accessed Apr 26/12.
Statin + Niacin
(AIM-HIGH Trial)
• “ …stopped early for futility.”
– 3414 patients
• Earlier Statin + Niacin studies had only showed reduction in soft endpoints.
– Eg. Regression of carotid atherosclerosis
Rxfiles.ca. AIM-HIGH Trial Summary, Dec 2011. Accessed Apr 29/12.
Michael O'Riordan. AIM-HIGH fell short, leaving experts looking for reasons in new review. Heart.org APR 19, 2012. Accessed Apr 25/12
Treatment Populations
• Who gets statins?
– Secondary prevention
– Primary prevention?
– Moderate risk??
– Put it in the water???
Secondary Prevention
• Clear efficacy
• Reduction of
mortality
• Reduction of
morbidity
• Benefit in as
little as one
year
– (usually 4-5
years)
Primary Prevention
• Clear efficacy
in High Risk
Framingham
• Reduction in
morbidity
• No effect on
mortality
Primary Prevention
(never had an MI or Stroke)
• High risk Framingham patients with history of:
– Diabetes
– CKD
– CHF
– Angina
– PVD
– CABG or PCI
– Metabolic syndrome
– Score > 20%
Moderate Risk
• Likely not worthwhile…
• BUT, the JUPITER trial = reduction in hard
endpoints!
– Patients with low/normal cholesterol and high CRP
– Relative Risk Reduction ~ 50%!
– But the Absolute Risk Reduction was tiny!
– hsCRP can differentiate between higher- and lowerrisk Moderate Category Framingham patients
Ridker PM, et al. the JUPITER Study Group. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N
Engl J Med. 2008 Nov 9.
Rosuvastatin:
22/8901 (0.28%)
of non-fatal MI
JUPITER trial
N Engl J Med 2008;359:2195-207.
Placebo:
62/8901 (0.70%)
of non-fatal MI
Relative vs Absolute Risk
Time to Benefit
• How old is too old to start therapy?
– Upper ages of trials ~ 80-83 yrs old.
– …Add time to divergence of survival curves
• ~ 4 to 6 years…
plus
• ?Prognosis
• Older than 85y.o, don’t start?
– Already on it, don’t stop, but don’t bother
checking LDL either.
Pharmacotherapy
• “The majority of patients will be able to
achieve target LDL-C levels on statin
monotherapy.”
• “Clinical outcome data on the incremental
benefit of combination therapy with statin
plus ezetimibe, niacin or fibrate, versus statin
monotherapy are lacking, although clinical
trials are underway to examine this issue.”
Can J Cardiol Vol 25 No 10 October 2009
“…Trials (were) Underway…”
• Statin + Niacin trials:
• AIM-HIGH trial
– Stopped early. No benefit from niacin in HDL
raising.
• See: http://www.theheart.org/article/1231453.do
– Known risk of hepatotoxicty with Niacin and
significant flushing.
• HPS2-THRIVE trial (statin + ER Niacin/Laropiprant)
– No benefit (n = 25673)
• See: http://www.theheart.org/article/1515533.do
Toxicity
• Statin
– Rare/Severe:
• Myopathy, even
Myositis/Rhabdomyolysis
• Hepatotoxicty
• Memory impairment
• ?Diabetes??
– discuss
– Common/Bothersome:
• Myalgias
• Fibrates
– Same as above
• Ezetimibe
– Same as above
• Niacin
– +++ flushing
– Hepatotoxicity (esp with
long acting form –
Niaspan)
Cost
• All statins covered under ODB
• All statins are generic
Convenience
• Older statins require QHS dosing
– 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: @Roland Halil, PharmD
GI Meds
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2013
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
– 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 magnesium, 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 2013
Objectives
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 - 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 – 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
OR =13.5
Multiple NSAID
OR = 9
High dose NSAID
OR = 7
Concomitant anticoagulant
OR = 6.4
Age≥70
OR = 5.6
Age ≥60
OR = 3.1
Concomitant steroid
OR = 2.2
Hx heart dx
OR = 1.8
NSAID comparison chart. p69 Oct 11 – Access Nov 11/11 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 - Cardiac
• COX-2 selectivity increases 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
Toxicity - Cardiac
(incl. PGI2)
Toxicity - Cardiac
• However, 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
Cost
• Cheapest = older & generic ($/30 days)
– Naproxen
$17
– Ibuprofen
$12
– ASA
$19
– Meloxicam $19
– Indomethacin $17
– Celecoxib
$54 - $99
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 / Meloxicam?
?Safer with Naproxen / 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
– PO:IV = 2:1
• Toxicity: (many!)
– Constipation: ~ equivalent
(no tolerance)
• (?codeine more than others)
– Respiratory depression: equivalent
– Sedation: equivalent
– Pruritis / Histamine release:
(rapid tolerance)
(rapid tolerance)
(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: @Roland Halil, PharmD
Drug-Drug Interactions
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2013
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
- SNRIs
– TCAs
- MAOinh’s
– Triptans
- St John’s Wort
– Opioids (incl. DM syrup)
- 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.torsades.org or www.qtdrugs.org
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
- Hypokalemia
– Elderly
- Hypothyroidism
– Myocarditis
- Hypomagnesemia
– Bradycardia
- Hypothermia
– Myocardial infarction
- Hypocalcemia
– Stroke
- Hypoglycemia
– Long QT Syndrome (congenital form)
– Syncope of unknown cause
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 P450):
2. Get a good EMR
– Most have interactions checkers – active while Rx’ing
3. Get a good drug database
– (All have better interactions 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
- Atenolol 25mg
– HCTZ 12.5mg
- ASA 81mg
– Amitriptyline 25mg - Trazodone 50mg
– Insulin NPH & R
- Glycopyrrolate 2mg
– Haloperidol 1mg
- 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: @Roland Halil, PharmD