DANGEROUS DRUGS AND
HOW TO MINIMIZE THE
DANGERS
April 17, 2014
Adapted from:
American College of Physicians
Internal Medicine 2012
Dangerous Drugs and How to Minimize Their
Dangers
Douglas S. Paauw, MD, MACP
And...
Assessing Medication
Appropriateness
in the Elderly:
Using Beers
& STOPP START
Criteria
Julia Bareham
BSc, BSP, MSc Candidate
julia@rxfiles.ca
RxFiles Academic Detailing
Program
Disclosures

Dr. Anthony Weaver has no relationships to
disclose.
Objectives
Review some of the most dangerous drugs used
in general medicine practice (emphasizing drugdrug interactions).
Discuss ways to prescribe these drugs safely.
1.
2.
1.
2.
3.
4.
3.
Beers Criteria
STOPP Criteria
Most dangerous drug
CYP 3A4 Interactions
Evaluate the interactions that make certain drugs
dangerous.




Over 2 million serious ADRs annually
100,000 deaths annually
Fourth leading cause of death
Ambulatory patient’s ADR rate is unknown
Institute of Medicine. To err is human: building a safer health system. Washington, D.C.:
National Academy Press; 2000.
2Lazarou J, Pomeranz B, Corey PN. Incidence of adverse drug reactions in hospitalized
patients: A meta-analysis of prospective studies. JAMA 1998;279:1200–1205.
3Gurwitz JH, Field TS, Avorn J, McCormick D, Jain S, Eckler M, et al. Incidence and
preventability of adverse drug events in nursing homes. Am J Med 2000;109(2):87–94.
Medication Related Problems


Seniors = 12.9% of U.S. population, but 34% of
total prescriptions.
> 65
 40%
take 5-9 medications per year
 18% take 10 or more



ADRs among the top five threats to seniors’ health.
28% of hospitalizations among seniors due to
ADRs.
32,000 seniors suffer hip fractures/yr due to falls
caused by medication-related problems.
American Society of Consultant Pharmacists
Medication Related Problems



Drug related admissions for aged 65-84 increased
by 96% from 1997 to 2008
Half of ADR hospitalizations occur in > 80 yo
Rapidly growing senior population will magnify the
problem
Shepherd G et al. Ann Pharmacother 2012;46:169-175
Figure 2. Adverse drug reaction death rates by state (1999–2006).
Shepherd G et al. Ann Pharmacother 2012;46:169-175
Medication Related Problems
Estimated Annual Cost

$76.6 billion among ambulatory population

$20 billion in acute-care facilities

$7.6 billion in nursing facilities

Total annual direct medical cost in the US:
$104.2 billion
American Society of Consultant Pharmacists
AGS UPDATED 2012 BEERS CRITERIA
FOR POTENTIALLY INAPPROPRIATE
MEDICATION USE IN OLDER ADULTS
Mark H Beers, MD 1954-2009
 MD, Univ of Vermont
 First med student to do a geriatrics
elective at Harvard‘s Division on Aging
 Geriatric Fellowship, Harvard
 Faculty, UCLA/RAND
 Co-editor, Merck Manual of Geriatrics
 Editor in Chief, Merck Manuals
“A ballet-dancing opera
critic who hiked the Alps
and took up rowing after
diabetes cost him his legs”
Original Purpose
1991 Original Beers Criteria
 Evaluate inappropriate Rx used in NH residents in
“common” situations, but under “certain
circumstances” might be appropriate
 Clinical research on use of Potentially Inappropriate
medications (PIMs)
 QA/QI
 Education
Not included in Beer’s List
 Drugs with risks not unique to elderly
• Purpose is for PIMs specific to elderly
 Drug-drug interactions
• Not unique to elderly
 List of alternatives
• Too complex, requires patient specific judgment
2012 AGS Beers Criteria - Categories
1st Category
2nd Category
PIMs for older people:
PIMs for older people:
• Pose high risks of
adverse effects OR
• Who have certain
diseases/disorders
• Appear to have limited
effectiveness in older pts
– b/c these drugs may
exacerbate the specified
health problems
AND
• There are alternatives
to these medications
• 53 medications or medication classes that should
be avoided in older adults
3rd Category
Use with caution in older
adults
• May be associated with
more risks than benefits
in general
– However, may be the
best choice for a
particular individual if
administered with caution
• 14 that should be used
with caution
FREE Beers Criteria Apps
Print off the Pocket Card
www.americangeriatrics.org/files/documents/
beers/PrintableBeersPocketCard.pdf
Or, search “Beers pocket card”
Open access, available for free.
Drugs to Avoid (except if….)
• Table 1 in the pocket guide
Table 1. Drugs to Avoid (except if…)
Organ System or
TC or Drug
Rationale
Recommend.
Quality of
Evidence
Strength of
Recommend.
Nitrofurantoin
Pulmonary tox
Alternatives
Lack of efficacy
<60 mL/min
Avoid long
term
suppression;
avoid if CrCl
<60 mL/min
Moderate
Strong
Antipsychotics
(conventional or
atypical)
Increase CVA
Avoid unless
Moderate
and CV mortality danger to
in dementia
self/others and
non pharm has
failed
Strong
Insulin, sliding
scale
Hypoglycemia
risk
Avoid
Moderate
Strong
Chlorpropamide
Glyburide
Hypoglycemia
risk
Avoid
High
Strong
Table 1. Drugs to Avoid (except if…)
Organ System or
TC or Drug
Rationale
Recommend.
Quality of
Evidence
Strength of
Recommend.
Benzodiazepines
Short and long
acting
Risk cognitive
effects and injury
(fall/MVA); rare
use appropriate
eg benzo
withdrawal
Avoid for
treatment of
insomnia,
agitation, or
delirium
High
Strong
Megestrol
Minimal effect on Avoid
weight; risk of
thrombotic events
and death
Moderate
Strong
Metclopramide
EPS and TD
Avoid, unless
gastroparesis
Moderate
Strong
Non-COX NSAIDs, GI bleeding;
Avoid chronic
oral
Protection w/ PPIs use
or misoprostol
Moderate
Strong
Table 1. Drugs to Avoid (except if…)
Organ System or
TC or Drug
Rationale
Recommend.
Quality of
Evidence
Strength of
Recommend.
Non
Benzodiazepines
Hypnotic s
(“z” drugs)
Risk cognitive
effects and injury
(fall/MVA); same
ADE as benzo’s
Avoid chronic
use, >90 days
Moderate
Strong
Estrogens with or Carcinogenic
w/o progestin
potential, lack of
efficacy in
dementia/CV dz
prevention
Avoid oral and
topical patch.
Topical cream
safe and
effective for
vaginal
symptoms
High
Strong
Muscle Relaxants Ineffective at
tolerated doses,
antichol, falls
Avoid
Moderate
Strong
Use of Caveats
 “Z” drugs for sleep: avoid chronic use
 Testosterone: avoid unless indicated for moderate
to severe hypogonadism
 Topical vaginal estrogen: acceptable low dose use
for specific conditions
 Spironolactone: avoid >25 mg/day in pts with
heart failure or CrCl <30
 Antipsychotics: avoid unless nonpharm treatment
has failed or threat to self/others
Table 2. Drug-disease/syndrome
Interactions
Disease or Drug
Syndrome
Rationale
Rec.
Quality of
Evidence
Strength of
Rec.
Syncope
Orthostatic
hypotension
or
bradycardia
Avoid
α- blockers:
High
TCAs, AChEIs,
antipsych:
Moderate
AChEIs, TCAs:
Strong
CNS
stimulant
effects
Avoid
Moderate
Strong
AChEIs
Peripheral αblockers
Tert. TCAs
Chlorpromazine
Thioridazine
Olanzapine
Insomnia
Oral
decongestants
Stimulants
Theobromines
α- blockers,
antipsych.:
Weak
Drug-disease/syndrome Interactions
• Table 2 in the pocket guide
Table 3. Use with Caution
Drug
Rationale
Recommend
Quality of
Evidence
Strength of
Recommend
Dabigatran
Risk of bleeding;
lack of evidence if
CrCl < 30mL/min
Use with
caution if >75
or if CrCl <
30mL/min
Moderate
Weak
Drugs linked to
SIADH/
Hyponatremia (eg
SSRI, TCA, CBZ,
antipsychotics)
May exacerbate or
cause SIADH/
hyponatremia;
monitor
Use with
caution
Moderate
Strong
Use with Caution
• Table 3 in the pocket guide
Non-Drug Approaches
Targeting Behavior and Symptoms
 Dementia
 “T A DA” VA Health
 Tolerate, Anticipate,
don’t aggravate




Resistive Behaviors
Needs Based Approach
Sleep
Cardiovascular
Educational Interventions
 AGS Website
Materials
 Interprofessional
 Use of EHR/CDSS
 Target Groups
 Consumers
Alternate Plan
Target the sickest patients, use Beers criteria
JAGS July 2013; 61 (7)
Introduction


PIM: potentially inappropriate medication.
Pharmacological effects potentially harmful to an
elderly adult
AIM: actually inappropriate medication.
Risk of harm outweighs benefit
of elderly adults discharged on ≥ 1 PIM
 85% of ICU survivors discharged on ≥ 1 PIM
 80% of elderly adults discharged on ≥ 1 AIM
 50% of ICU survivors discharged on ≥ 1 AIM
 50% of PIMs and 59% of AIMs rx’d in ICU
 50%
Hypothesis


Opiates, sedatives, and antipsychotics are the PIMs
most often AIMs in older ICU survivors
Older adults with delirium are at highest risk for
discharge on PIMs and AIMs
Methods






Prospective nested cohort study
Critically ill patients with respiratory failure or
shock admitted to Vanderbilt ICU
Age ≥60, discharged alive
Not hospice
PIM determined by using 2003 Beers criteria
AIM by chart review by a hospitalist, geriatrician,
and clinical pharmacist (2/3 wins)
Drug Categories






Benzodiazepines
Non-BZD sedatives
Typical antipsychotics
Atypical
antipsychotics
Opioids
Anticholinergics






Antidepressants
Drugs causing orthostasis
NSAIDs
Antiarrhythmics
Muscle relaxants
other


Results:
PIMs
250 PIMs at discharge
4 most common PIMs
 Opioids
 Anticholinergics
 Antidepressants
 Drugs
causing orthostasis
Results: AIMs


90 AIMs
Three most common (36%)
 Anticholinergics
 Histamine
blockers 61%
 Promethazine 15%
 Non-BZD
 Opioids
hypnotics
PIMs transitioning to AIMs

Three least common PIM-AIM
Opioids (16% likelihood)
 Antidepressants (23% likelihood)
 Orthostatic drugs (10% likelihood)


Three most common PIM-AIM
Anticholinergics (55% likelihood)
 Non-BZD hypnotics (67% likelihood)
 Benzodiazepines (67% likelihood)
 Atypical psychotics (71% likelihood)
 Muscle relaxants (100% likelihood)

Results




67% of anticholinergic AIMs started in ICU
46% of non-BZD hypnotics started in ICU
73% of AIM opioids started in ICU
80% of atypical antipsychotics started in ICU
 1%
on atypical anti-psychotic on admission
 12% on atypical antipsychotic on discharge
Discussion





3 of the most commonly prescribed PIMs (opioids,
antidepressants, and orthostatic drugs) were often
appropriate for condition
Risk factors for PIMs did not predict AIMs
We should (move beyond) labeling medicines as
“potentially inappropriate”
Clinicians must actively determine which PIMs can be
discontinued at discharge/followup
Screening tools using [Beers] PIMs to generate alerts
could lead to inappropriate discontinuation, and
possibly more harmful alternatives
More Discussion

Screening tools should consider positive predictive
value, highest in:
 Atypical
antipsychotics (71%)
 Non-BZD hypnotics (67%)
 Benzodiazepines (67%)
 Anticholinergics (55%)
 Muscle relaxants (100%)
STOPP Criteria
Screening Tool of Older Persons’ potentially
inappropriate Prescriptions
65 rules relating to the most common and the most
potentially dangerous instances of inappropriate
prescribing in older people
O’Mahony D, Gallagher P, Ryan C, Byrne S, Hamilton H, Barry P, O’Connor M, Kennedy J. STOPP & START criteria: A new
approach to detecting potentially inappropriate prescribing in old age. European Geriatric Medicine. 2010 Jan 6; 1(1):45-51.
Hamilton H, Gallagher P, Ryan C, Byrne S, O'Mahony D. Potentially inappropriate medications defined by STOPP criteria and the risk
of adverse drug events in older hospitalized patients. Arch Intern Med. 2011 Jun 13;171(11):1013-9.
A. Cardiovascular System
1. Digoxin at a long-term dose > 125µg/day with impaired renal function *
(increased risk of toxicity). * estimated GFR <50ml/min
2. Loop diuretics:
• for dependent ankle oedema only i.e. no clinical signs of heart failure (no
evidence of efficacy, compression hosiery usually more appropriate).
• as first-line monotherapy for hypertension (safer, more effective alternatives
available).
3. Thiazide diuretic with a history of gout (may exacerbate gout).
4. Beta-blockers:
• with Chronic Obstructive Pulmonary Disease (COPD) (risk of increased
bronchospasm).
• in combination with verapamil (risk of symptomatic heart block).
5. Use of diltiazem or verapamil with NYHA Class III or IV heart failure (may
worsen heart failure).
6. Calcium channel blockers with chronic constipation (may exacerbate
constipation).
7. Dipyridamole as monotherapy for cardiovascular secondary prevention (no
evidence for efficacy).
8. Aspirin:
•
with a past history of peptic ulcer disease without histamine H2 receptor
antagonist or
•
Proton Pump Inhibitor (risk of bleeding).
•
at dose > 150mg day (increased bleeding risk, no evidence for increased efficacy).
•
with no history of coronary, cerebral or peripheral vascular symptoms or
occlusive event (not indicated).
•
to treat dizziness not clearly attributable to cerebrovascular disease (not
indicated).
9. Warfarin:
•
for first, uncomplicated deep venous thrombosis for longer than 6 months
duration (no proven added benefit).
•
for first uncomplicated pulmonary embolus for longer than 12 months duration
(no proven benefit).
10. Use of aspirin and warfarin in combination without histamine H2 receptor
antagonist (except cimetidine because of interaction with warfarin) or proton
pump inhibitor (high risk of gastrointestinal bleeding).
11. Aspirin, clopidogrel, dipyridamole or warfarin with concurrent bleeding
disorder (high risk of bleeding).
B. Central Nervous System and Psychotropic
Drugs
1. Tricyclic antidepressants (TCA’s):
• with dementia (risk of worsening cognitive impairment).
• with glaucoma (likely to exacerbate glaucoma).
• with cardiac conductive abnormalities (pro-arrhythmic effects).
• with constipation (likely to worsen constipation).
• with an opiate or calcium channel blocker (risk of severe
constipation).
• with prostatism or prior history of urinary retention (risk of
urinary retention).
2. Long-term (i.e. > 1 month)
•
long-acting benzodiazepines e.g. chlordiazepoxide, fluazepam,
nitrazepam, chlorazepate and benzodiazepines with long-acting
metabolites e.g. diazepam (risk of prolonged sedation, confusion, impaired
balance, falls).
•
neuroleptics as long-term hypnotics (risk of confusion, hypotension,
extra-pyramidal side effects, falls).
•
neuroleptics in those with parkinsonism (likely to worsen extrapyramidal symptoms)
3. Phenothiazines in patients with epilepsy (may lower seizure threshold).
4. Anticholinergics to treat extra-pyramidal side-effects of neuroleptic
medications (risk of anticholinergic toxicity).
5. Selective serotonin re-uptake inhibitors (SSRI’s) with a history of
clinically significant hyponatraemia (non-iatrogenic hyponatraemia
<130mmol/l within the previous 2 months).
6. Prolonged use (> 1 week) of first generation antihistamines i.e.
diphenhydramine, chlorpheniramine, cyclizine, promethazine (risk of
sedation and anti-cholinergic side effects).
C. Gastrointestinal System
1. Diphenoxylate, loperamide or codeine phosphate for treatment of:
•
diarrhea of unknown cause (risk of delayed diagnosis, may exacerbate
constipation with overflow diarrhoea, may precipitate toxic megacolon in
inflammatory bowel disease, may delay recovery in unrecognised
gastroenteritis).
•
infective gastroenteritis i.e. bloody diarrhea, high fever or severe
systemic toxicity (risk of exacerbation or protraction of infection)
2. Prochlorperazine or metoclopramide with Parkinsonism (risk of
exacerbating Parkinsonism).
3. PPI for peptic ulcer disease at full therapeutic dosage for > 8 weeks
(dose reduction or earlier discontinuation indicated).
4. Anticholinergic antispasmodic drugs with chronic constipation (risk of
exacerbation of constipation).
D. Respiratory System
1. Theophylline as monotherapy for COPD (safer, more effective
alternative; risk of adverse effects due to narrow therapeutic index)
2. Systemic corticosteroids instead of inhaled corticosteroids for
maintenance therapy in moderate to severe COPD (unnecessary
exposure to long-term side-effects of systemic steroids).
3. Nebulized ipratropium with glaucoma (may exacerbate
glaucoma).
E. Musculoskeletal System
1. Non-steroidal anti-inflammatory drug (NSAID):
•
with history of peptic ulcer disease or gastrointestinal bleeding, unless with
concurrent histamine H2 receptor antagonist, PPI or misoprostol (risk of peptic
ulcer relapse).
•
with moderate-severe hypertension (moderate: 160/100mmHg – 179/109mmHg;
severe: ≥180/110mmHg) (risk of exacerbation of hypertension).
•
with heart failure (risk of exacerbation of heart failure).
•
long-term use of NSAID (>3 months) for relief of mild joint pain in osteoarthritis
(simple analgesics preferable and usually as effective for pain relief)
•
warfarin and NSAID together (risk of gastrointestinal bleeding).
•
with chronic renal failure * (risk of deterioration in renal function). * estimated GFR
20-50ml/min.
2. Long-term corticosteroids (>3 months) as monotherapy for rheumatoid arthritis
or osteoarthritis (risk of major systemic corticosteroid side-effects).
3. Long-term NSAID or colchicine for chronic treatment of gout where there is no
contraindication to allopurinol (allopurinol first choice prophylactic drug in gout)
F. Urogenital System
1. Bladder antimuscarinic drugs:
• with dementia (risk of increased confusion, agitation).
• with chronic glaucoma (risk of acute exacerbation of glaucoma).
• with chronic constipation (risk of exacerbation of constipation).
• with chronic prostatism (risk of urinary retention).
2. Alpha-blockers:
• in males with frequent incontinence i.e. one or more episodes
of incontinence daily (risk of urinary frequency and worsening of
incontinence).
• with long-term urinary catheter in situ i.e. more than 2 months
(drug not indicated).
G. Endocrine System
1. Glibenclamide or chlorpropamide with type 2 diabetes mellitus
(risk of prolonged hypoglycemia).
2. Beta-blockers in those with diabetes mellitus and frequent
hypoglycaemic episodes i.e. ≥ 1 episode per month (risk of
masking hypoglycemic symptoms).
3. Estrogens:
• with a history of breast cancer or venous thromboembolism
(increased risk of recurrence)
• without progestogen in patients with intact uterus (risk of
endometrial cancer).
H. Drugs that adversely affect those prone to
falls (≥ 1 fall in past three months)
1. Benzodiazepines (sedative, may cause reduced sensorium, impair
balance).
2. Neuroleptic drugs (may cause gait dyspraxia, Parkinsonism).
3. First generation antihistamines (sedative, may impair sensorium).
4. Vasodilator drugs known to cause hypotension in those with
persistent postural hypotension i.e. recurrent > 20mmHg drop
in systolic blood pressure (risk of syncope, falls).
5. Long-term opiates in those with recurrent falls (risk of
drowsiness, postural hypotension, vertigo).
I. Analgesic Drugs
1. Use of long-term powerful opiates e.g. morphine or fentanyl as
first line therapy for mild-moderate pain (WHO analgesic ladder
not observed).
2. Regular opiates for more than 2 weeks in those with chronic
constipation without concurrent use of laxatives (risk of severe
constipation).
3. Long-term opiates in those with dementia unless indicted for
palliative care or management of moderate/severe chronic pain
syndrome (risk of exacerbation of cognitive impairment).
J. Duplicate Drug Classes
Any duplicate drug class prescription e.g. two concurrent opiates,
NSAID’s, SSRI’s, loop diuretics, ACE inhibitors (optimisation of
monotherapy within a single drug class should be observed prior to
considering a new class of drug).
Medication Appropriateness Index
1. Is there an indication for the drug?
2. Is the medication effective for the condition?
3. Is the dosage correct?
4. Are the directions correct?
5. Are the directions practical?
6. Are there clinically significant drug-drug interactions?
7. Are there clinically significant drug-disease/condition interactions?
8. Is there unnecessary duplication with other drugs?
9. Is the duration of therapy acceptable?
10. Is this drug the least expensive alternative compared with others of
equal usefulness?
Arch Intern Med. Vol 166, March 27, 2006
What about targeting the most
dangerous drug?
N Engl J Med
2011;365:2002-12
Emergency Hospitalizations for Adverse Drug
Events in Older Americans


National Electronic Injury Surveillance
System–Cooperative Adverse Drug Event
Surveillance project (2007 through 2009) was
used to estimate the frequency of emergency
hospitalization for adverse drug events in
patients >65
100,000 admissions annually due to adverse
drug events occurred during the study period
N Engl J Med 2011;365:2002-2012.
Emergency Hospitalizations for Adverse Drug
Events in Older Americans


Four drug classes caused 67% of admissions
 Warfarin
33%,
 Insulins
13.9%,
 Oral antiplatelet drugs
13.3%
 Oral hypoglycemics
10.7%.
Potentially inappropriate medications were
implicated in only 3.6% of emergency
department visits
N Engl J Med 2011;365:2002-2012.
Warfarin Interactions
Case 3
A 72 y.o. male S/P AVR replacement two years ago
for aortic stenosis presents with wide spread
bruising on his back/legs and some bruising on the
back of both hands. His last INR was three weeks
ago and was 3.0. He states he saw an M.D. six
days ago for a cough and was put on a medication
described as a “white tablet.”
His chronic medications include: Coumadin 5 mg
qd, Albuterol inhaler 2 puffs 4 times a day and
Nortryptiline 25 mg qhs.
What medication was he placed on?
a) Amoxicillin
b) Codeine
c) Cefixime
d) Azithromycin
e) TMP/Sulfa
Warfarin Interactions
Decrease metabolism (increase PT)
Most Severe
 TMP/Sulfa
 Erythromycin
 Amiodarone
 Propafenone
 Ketoconazole
 fluconazole
 Itraconazole
 Metronidazole
Possible*
 Quinolones
 Omeprazole
 Clarithromycin
 Azithromycin
* Especially in elderly
and polypharmacy
Antibiotics and Warfarin


104 patients on stable warfarin therapy. Effect on
INR of Terazosin (control), Azithromycin (32
patients), Levofloxacin (27) and TMP/Sulfa (16)
Mean change in INR:





Terazosin
Azithromycin
Levofloxacin
Sulfa
-.15,
+.51 ,
+ .85,
+1.76
Percent patients having a INR > 4:




Terazosin
Azithromycin
Levofloxacin
TMP/Sulfa
5%,
31%,
33%,
69%
JGIM 2005;20 (7);653-6.
Risk of UGI Hemorrhage in Warfarin
Treated Patients Receiving Antibiotics
Antibiotic
 TMP-Sulfa
 Ciprofloxacin
 Amoxicillin
 Nitrofurantoin
Odds Ratio
3.84 (CI 2.33-6.33)
1.94 (CI 1.28-2.95)
1.37 (CI .92-2.05)
1.40 (CI .71-2.75)
Arch Intern Med 2010; 170(7):617-621)
Warfarin Interactions With Antibiotics in the Ambulatory Care Setting
Thirty-Day Outcomes by Antibiotic and Interaction Mechanism
JAMA Intern Med. 2014;():. doi:10.1001/jamainternmed.2013.13957
Antibiotics for UTI in Patients on
Warfarin




Penicillins/cephalosporins
ok
Nitrofurantoin
ok
Quinolones
be worried
TMP/Sulfa
don’t use
Case 4
A 39 y.o. woman with a prosthetic aortic valve
presents with bruising. Her last INR 6 weeks ago
was 2.4, today’s INR is 6.5. She has not taken any
extra Coumadin. Which of the following when taken
on a daily basis could explain her increased INR?
a) Acetaminophen
b) Calcium carbonate
c) OCP
d) Ranitidine
e) DOSS
Warfarin and Acetaminophen
3 studies suggest increased INR with
Acetaminophen + Warfarin
1
 > 9100 mg/week led to 10 x risk of having INR > 6
 In double blind crossover trial patients on Warfarin + 4
g/d of Acetaminophen had PT 1.75 x control2
 Patients received 2 gm or 4 gm acetaminophen or
placebo with warfarin, 54% of those receiving
acetaminophen overshot INR goal vs 17% of placebo3
1. JAMA 1998;279:657-662
2. Clin Res 1984;32:698a
3. Pharmacotherapy 2007; 27 (5):675-83.
Case 5
A 76 yo man is admitted with increasing SOB. He has
a long history of COPD and has had a recent
productive cough. He is admitted to the hospital and
treated with amoxicillin, prednisone, codeine, and
albuterol.
PMH: A fib, Hypertension, COPD, GERD.
Outpatient meds: Metoprolol, coumadin, pantoprazole,
lisinopril. His recent INR 2 weeks ago was 2.2, on
hospital day 6 it is 4.3. What is the most likely
interaction with coumadin?
A) Prednisone
B) Amoxicillin
C) Codeine
D) Amoxicillin + Pantoprazole
Effect of Oral Corticosteroids On
Warfarin Therapy


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Retrospective review of patients in ACC who
received oral corticosteroids. Patients were
excluded if they were treated with any drug with a
known interaction with warfarin.
Mean difference between pre steroid INR and the
INR when patients on steroids was 1.24, p<.001.
62% of the patients had an INR above their
targeted range.
Mean time to INR elevation was 6.7 days after
starting steroids.
Ann Pharmacother 2006;40:2101-6.
Warfarin –Simvastatin Interaction

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Study looking at average warfarin dose needed in
patients on simvastatin and warfarin, compared to
warfarin alone.
56 patients in each group, matched by age, body
size, and gender.
Mean warfarin dose was 3.3 for those taking
simvastatin vs 4.0 for those not taking simvastatin
Etiology of the need for less warfarin was likely
P450 inhibition of CYP3A4 and CYP2C9 subunits
J Thromb Heamost 2006;4 (6): 1422-4.
Dabigatran: Safer???



In 2011, the FDA received more adverse event reports
related to dabigatran than for any other drug.
3,800 serious adverse events, 542 deaths, 2,367
reports of hemorrhage, 291 acute renal failure and
644 strokes
Warfarin #2: 1,106 serious adverse events, 72 deaths.
ISMP
Quarterwatch
Oct 2013
CYP450 enzyme CYP3A4

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CYP3A4 metabolizes about half of all drugs on the
market
many other common drugs are moderate-to-potent
inhibitors of CYP3A4
a number of drugs are known to be CYP3A4 inducers
http://www.pharmacytimes.com/publications/issue/2
008/2008-09/2008-09-8687#sthash.uQjlfuF1.dpuf
CYP3A4 Inhibitors
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Clarithromycin
Erythromycin
Conazole’s—Flu, Itra,
Keto, Mi, Vori
Diltiazem
Verapamil
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Amiodarone
Fluoxetine
Grapefruit juice
Nefazodone
Tamoxifen
Cyclosporine
CYP3A4 Inducers
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Carbamazepine
Dexamethasone
Efavirenz
Fosphenytoin
Griseofulvin
Modafinil
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Nafcillin
Phenobarbital
Phenytoin
Primidone
Rifampin
St. John's wort
CYP3A4 and Statins
Case 6
A 70 yo man with atrial fibrillation presents for followup
after an MI. He reports that he has medicare part D and
is concerned about the cost of his meds.
Current medications : Metoprolol, amiodarone,
nitroglycerin, ASA. His lipid panel shows an LDL
cholesterol of 120. What would you recommend?
A) No treatment
B) Atorvastatin
C) Simvastatin
D) Lovastatin
E) Pravastatin
Simvastatin and Amiodarone



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Amiodarone is a potent inhbitor of CYP3A subunit
of the P450 system, which metabolizes
simvastatin.
Multiple case reports of severe rhabdomyolysis in
patients treated with simvastatin and amiodarone
In the SEARCH trial, those receiving amiodarone
and 80 mg of simvastatin had an 8.8 RR of
myopathy
Lovastatin shares the same metabolism, so would
avoid it
Disposition Kinetics with Amiodarone
/Simvastatin vs Pravastatin



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Prospective, cross over, randomized , open label
study in 12 healthy volunteers
All received Simvastatin alone and after 3 days of
400 mg amiodarone, and pravastatin alone and
after 3 days of amiodarone
Amiodarone increased simvastatin AUC by 73%,
peak plasma concentration by 100%, and t ½ by
48%.
There was no effect on pravastatin.
Clin Pharmacol Ther 2007; 81 (5): 679-684
Case 7
A 65 yo man presents with cough and fever. He has had severe
diarrhea for 2 days. He was on a cruise with a friend who was
diagnosed with Legionella yesterday.
PMH – diabetes, hyperlipidemia, hypertension.
Meds: Lisinopril, simvastatin, amlodipine, gemfibrozil,
metformin.
Chest XRay shows patchy bilateral infiltrates. WBC 17,000
Na 125. What is the most appropriate treatment?
A) Amoxicillin/clavulanate
B) Clarithromycin
C) Levofloxacin
D) Cefuroxime
E) Trimethoprim/sulfa
Drugs That Increase Risk of
Statin Toxicity
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Fibrates (Gemfibrozil 15X >> Fenofibrate)
Azole antifungals
Amiodarone
Erythromycin/Clarithromycin
Protease inhibitors
Verapamil/Diltiazem
Least drug interactions with pravastatin,
most with simvastatin and lovastatin
What Should You Worry About
When Prescribing Simvastatin?
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Mild interaction with warfarin
Major interaction with grapefruit juice
Major interaction with amiodarone
Usual statin concern with fibrates, clarithromycin,
azoles
Red flags should go off when prescribing for A fib
patients, where they might be on both warfarin
and amiodarone (and a Ca channel blocker)
June 2011 FDA advisory to not put new patients
on 80mg of simvastatin
Lovastatin Dose Limitations 2/28/12
Previous lovastatin label
Avoid lovastatin with:
•Itraconazole
•Ketoconazole
•Erythromycin
•Clarithromycin
•Telithromycin
•HIV protease inhibitors
•Nefazodone
New lovastatin label
Contraindicated with lovastatin:
•Itraconazole /Ketoconazole
•Posaconazole
•Erythromycin /Clarithromycin
/Telithromycin
•HIV protease inhibitors
•Boceprevir
•Telaprevir
•Nefazodone
Do not exceed 20 mg lovastatin daily with: Avoid with lovastatin:
•Gemfibrozil /Other fibrates
•Cyclosporine
•Lipid-lowering doses (≥1 g/day) of niacin •Gemfibrozil
•Cyclosporine
Do not exceed 20 mg lovastatin daily with:
•Danazol
•Danazol
•Diltiazem
•Verapamil
Do not exceed 40 mg lovastatin daily with: Do not exceed 40 mg lovastatin daily with:
•Amiodarone
•Amiodarone
•Verapamil
Avoid large quantities of grapefruit juice (>1 Avoid large quantities of grapefruit juice (>1
quart daily)
quart daily)
Case 10
A 36 yo man with a history of gout returns for follow up.
He has had a 2 day history cough and today fevers.
Chest xray shows a RLL infiltrate.
PMH: CRI baseline Cr 2.0.
Meds : Allopurinol 200 mg a day, colchicine .6 mg a
day, citalopram 20 mg a day. Which drug would be
most dangerous to prescribe?
A) Azithromycin
B) Clarithromycin
C) Levofloxacin
D) Erythromycin
E) Chloramphenicol
Colchicine Drug Interactions
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
Higher risk in patients with renal
insufficiency
Many (over 100) reports of death with
interaction with clarithromycin, a strong
CYP3A4 inhibitor
Avoid clarithromycin, protease inhibitors,
itraconazole and ketoconazole
Case 12
78 yo man is brought to the ED with hypotension.
His BP is 70/50. He has a history of atrial fibrillation
and CAD and was diagnosed with pneumonia 3
days ago. Medications: Isosorbide mononitrate,
Lisinopril, Diltiazem, clarithromycin and linezolid.
What is the most likely cause of his hypotension?
A) Isosorbide-clarithromycin interaction
B) Lisinopril-clarithromycin interaction
C) Diltiazem-clarithromycin interaction
D) Linezolid- clarithromycin interaction
E) Linezolid- isosorbide interaction
Hypotension Related to MacrolideCa Channel Blocker Interaction
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Nested, case-crossover study of patients age
66 and older prescribed a CCB over a 15 year
period.
Study group was those admitted to the
hospital with hypotension/shock
Compared risk of exposure to macrolide in 7
days before hospitalization with 7 day control
interval the month prior
RR of hypotension 5.8 for erythromycin, 3.7 for
clarithromycin. Azithromycin was not
associated with hypotension
CMAJ 2011;183 (3):303-307.
JAMA. 2013;310(23):2544-2553. doi:10.1001/jama.2013.282426
Published online November 9, 2013.
Beware of Clarithromycin
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Major statin interaction (especially
simvastatin/lovastatin)
Major interaction with CCB
Increase levels of glypizide/glyburide
(hypoglycemia)
Major interaction with colchicine
82 Major drug interactions reported!
Miscellaneous Effects of Common Drugs
Case 11
A 85 yo man is brought to the ED for evaluation of
weakness and nausea. He was diagnosed 10 days ago
with prostatitis. His other problems include hypertension,
CHF and CRI.
Meds: Carvedilol, furosemide, TMP/Sulfa, verapamil,
digoxin. Exam- BP 100/60 P-100 T 36.9 cardiac- grade
2/6 SEM lower extremity edema present. Lab: Na- 132 K
-6.8 BUN 37 Cr- 2.3.
What is the most likely cause of his hyperkalemia?
A) Chronic renal insufficiency
B) Carvedilol
C) TMP/Sulfa
D) Verapamil
E) Digoxin
Trimethoprim-Sulfamethoxazole
and Hyperkalemia
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Population based, nested case-control study of patients
66 or older who were receiving and ACEI or ARB (14
years)
Case patients were those who had hyperkalemia within
14 days of receiving TMP-sulfa, amoxicillin,ciprofloxacin,
norfloxacin or nitrofurantoin. For each case patient 4
controls were matched.
4148 admissions due to hyperkalemia, 371 within 14 days
of antibiotic exposure. Compared to amoxicillin the
relative risk for hyperkalemia with TMP-sulfa was 6.7 (CI
4.5-10) . No other antibiotic posed a significant risk for
hyperkalemia.
Arch Intern Med 2010; 170(12): 1045-1049.
Effect of Standard Dose TMP-Sulfa
on Potassium in Elderly Men
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Thirty-three patients who received standard-dose
TMP/SMX for 3 or more days comprised the study
group.
Twenty patients who received oral cephradine or
amoxicillin for 3 or more days comprised the control
group.
Patients taking ACEI, NSAIDS,B Blockers or who had
CRI were excluded
The serum potassium concentration in the study
group was 4.22 ± 0.40 mmol/L and increased by 0.31
± 0.38 mmol/L at the end of therapy (p < 0.001).
Ann of Pharm 1996;30(4):347-350.
Trimethoprim Induced
Hyperkalemia
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More common in elderly and patients with
renal impairment
More likely if patient is on an ACEI or ARB
More likely if patient is receiving high doses of
steroids
Trimethoprim acts like amiloride, a potassium
sparing diuretic, and reduces urinary
potassium excretion by 40%
When Not to Use TMP/Sulfa
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Patient taking warfarin
Patient taking methotrexate
Allergy
Elderly patients with renal insufficiency
Case 14
A 66 yo woman presents with hypotension and confusion.
She was in her usual state of health until 4 hours prior
when she felt ill and vomited a small amount of bloody
material. She did not seek medical attention for 2
additional hours . She had another episode of emesis this
time of a large amount of bloody material. She has also
had one episode of maroon stool.
PMH HTN, Osteoporosis and depression.
Meds: fluoxetine, benazapril, hydrochlorathiazide,
acetominophen, and estrogen/progestin.
Which has the strongest association with UGI bleeding?
A) Fluoxetine
B) Benazapril
C) Hydrochlorothiazide
D) Acetaminophen
E) Estrogen
SSRI’S and GI Bleeding
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Multiple retrospective studies show relative risk for UGI
bleeding of 3-4 with the use of SSRI’s
Risk is further increased with concurrent use of a NSAID
Odds ratio 6.33 if SSRI combined with NSAID
Risk is highest in the elderly
Strongly consider gastroprotection if combination used in
patients with history of UGI bleeding, in patients taking
NSAIDS or the elderly
Arch Intern Med 2003;163:59-64
BMJ 1999; 319 (7217):1106-9.
Aliment Pharmacol Ther 2008; 27: 31-40.
Meta-analysis
Clin Gastroenterol Hepatol. 2009
Dec;7(12):1314-21.
Case 15
A 66 yo woman presents with fatigue. She has a history
of bipolar disorder and reflux disease. She has felt well
the past few months until the last few weeks.
Medications: Rabeprazole, lithium, paroxetine, calcium.
Physical exam is normal. As part of her workup she is
found to have the following labs: Na 120, K 3.6 Bun 3
Cr 0.7 What is the most likely cause of her low sodium?
A) Hyperlipidemia
B) Lithium
C) Acute psychosis
D) Rabeprazole
E) Paroxetine
SSRI’s AND Hyponatremia
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Older age
Female
Concomitant diuretic use
Low body weight
Citalopram and QT
Prolongation

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Dose dependent QT prolongation
Maximum dose recommended for citalopram
40 mg
Contraindicated in patients with congenital
long QT syndrome
Important interaction with CYP2C19 inhibitors
(fluvoaxamine-luvox, fluoxetine, PPI’s,
cimetidine, clopidogrel)
Avoid use with other QT prolonging drugs
FDA Drug Safety Communication:

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
Recognize that if citalopram must be used in patients with certain
conditions because of the risk of QT prolongation, ECG monitoring
and/or electrolyte monitoring should be performed.
Patients with congenital long QT syndrome are at particular risk of
Torsade de Pointes, ventricular tachycardia, and sudden death
when given drugs that prolong the QT interval. Nevertheless, the
labeling recommendation for patients with congenital long QT
syndrome has been changed from “contraindicated” to “not
recommended,” because it is recognized that there may be some
patients with this condition who could benefit from a low dose of
citalopram and who lack viable alternatives.
The maximum recommended dose of citalopram is 20 mg per day
for patients older than 60 years of age.
Citalopram should be discontinued in patients who are found to
have persistent QTc measurements greater than 500 ms.
Think Before Putting SSRI’S
in the Drinking Water

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Probable increased risk of UGI bleed
Often overlooked cause of hyponatremia
Sexual dysfunction (20-50%)
QT prolongation with citalopram
PPI’s and Recurrent C Difficile

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
Retrospective, cohort study of 1166 patients with
an initial diagnosis of C Difficile infection (CDI)
Patients who received a PPI within 14 days after
their C diff dx were defined as PPI exposed.
45% of patients with CDI were PPI exposed.
Recurrent CDI was more common in PPI exposed
patients (25% vs 18%) HR 1.42,95% CI 1.11-1.82
Arch Intern Med 2010;170:772-778.
 Also W J Gastroenterology 2010;16 (28):3573- 3577.

FDA Drug Safety Communication
•
•
•
A diagnosis of CDAD should be considered for PPI
users with diarrhea that does not improve.
Advise patients to seek immediate care from a
healthcare professional if they experience watery
stool that does not go away, abdominal pain, and
fever while taking PPIs.
Patients should use the lowest dose and shortest
duration of PPI therapy appropriate to the
condition being treated.
Problems With PPI’s


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Decreased Ca absorption
Increased fracture risk
Decreased iron absorption
Decreased thyroid absorption
Poor Magnesium absorption
Poor B12 absorption
Decreased Ketoconazole/Itraconazole absorption
Increased risk of C. difficile, and recurrent C Diff
and more severe C diff. (FDA warning 2/12)
What To Remember From This
Talk




Beers criteria are commonly used to identify
dangerous drugs, but may not be accurate
STOPP criteria have been tested to reduce
numbers of drugs
CYP3A4 interactions are a common source of
neurotoxicity
Watch carefully for side effects from
TMP/Sulfa, PPIs and SSRIs.