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Drug
Interactions in Primary Care Geriatrics -
Part one of a two-part
review
by
Anne Hume, Pharm.D.,FCCP, BCPS, Professor
of Pharmacy Practice and Department Chair,
URI College of Pharmacy; Adjunct Professor
of Family Medicine, Brown University
School of Medicine; RIGEC Faculty
Member
Recently,
adverse drug events have received
considerable attention due to their
associated morbidity, mortality and costs.
Estimates of the costs of drug-related
morbidity and mortality have ranged
between $30 and 136 billion. While many
factors influence the development and
severity of an adverse drug event,
unrecognized drug interactions may be a
particularly important determinant
especially in older persons. Fortunately,
a key to preventing and detecting drug
interactions is a thorough medication
history that includes prescription drugs,
nonprescription and natural products. The
purpose of this two-part review is to
highlight practical issues with drug
interactions in primary care geriatrics.
In the first part, an evolving case of a
potential drug interaction will be
presented, followed by a brief overview of
issues with drug interactions. In the
second part, more information about the
case will be provided, as well as a list
of selected key drug interactions in
primary care geriatrics and Internet
resources on drug interactions.
Case
Study
A
74 year old man was admitted to the
hospital on 12/18/1999 for septic
arthritis of the left knee. Fluid drained
from the knee grew methicillin-resistant
Staphylococcus aureus (MRSA) and the
Infectious Disease team prescribed a six
week course of vancomycin and rifampin.
The patient initially had a drain placed
in the knee and was confined to bed for 7
- 10 days. Although he was on SQ heparin
as prophylaxis, he clinically developed a
deep venous thrombosis (DVT) in his left
leg that was confirmed by Doppler on
12/28/1999. Subsequently, he was started
on enoxaparin (Lovenox) and warfarin
(Coumadin). A hypercoagulability work up
was not performed because the orthopedist
felt that stasis was the cause of the DVT.
His PMH is significant for CAD (stent
placed 12/7/99), type 2 diabetes mellitus,
hypertension, and a poorly understood skin
rash. His medications include vancomycin,
rifampin, enoxaparin, warfarin, glipizide,
vitamin E, aspirin, clopidogrel,
diltiazem, and isotretinoin (2 days per
week).
A
therapeutic International Normalized Ratio
(INR) has not yet been achieved. The
patient's daily dose of warfarin (and INR)
are as
follows:
|
12/28
- 5mg
|
1
/ 1 - 20mg (1.3)
|
|
12/29
- 10mg (1.1)
|
1
/ 2 - 20mg (1.4)
|
|
12/30
- 10mg (1.1)
|
1
/ 3 - 20mg (1.3)
|
|
12/31
- 15mg (1.2)
|
1
/ 4 &endash; 20mg
(1.3)
|
The tentative plan on January 5th is to
increase the dose of warfarin to 25mg per
day. Most clinicians, however, would be
reluctant to increase the warfarin dose in
this 74 year old man, yet his INR remains
subtherapeutic. Among the ideas concerning
his failure to achieve a therapeutic INR
is whether or not a significant drug
interaction is present. What potential
drug interaction may be present and how
might it best be managed ?
Overview
Many
drug-drug interactions are recognized to
exist. Their actual clinical significance
is frequently difficult for the healthcare
professional to determine. Information on
some drug interactions have been based on
animal studies, anecdotal case reports (eg
influenza vaccine and warfarin), and
single dose studies in healthy volunteers.
Frequently, only limited information on
drug interactions is available when the
FDA first approves new drugs for use. In
addition, many simple factors will effect
whether or not a given interaction will be
important in a specific patient. For
example, order of administration may be
quite important. A patient taking
cimetidine (Tagamet) who is prescribed
warfarin may not have a significant
interaction because the anticoagulant is
gradually titrated upwards. However, a
patient maintained on a stable dose of
warfarin may experience bleeding if they
start self-treating with nonprescription
cimetidine because the drug will inhibit
the metabolism of warfarin. Selected other
factors include the dose of the drugs, the
duration of therapy, the specific dosage
form, pre-existing diseases, and
age-related physiologic
changes.
Drug
interactions are generally classified as
being either pharmacokinetic or
pharmacodynamic in nature. Pharmacokinetic
interactions occur when the administration
of one drug alters the absorption,
distribution, metabolism or renal
elimination of a second medication.
Pharmacodynamic interactions are those in
which the administration of a drug results
in a change in an individual's response to
another drug without a change in the
concentration of the latter medication.
For most patients, clinically significant
interactions involve hepatic metabolism
through the cytochrome P450 enzyme system.
Cytochrome enzymes are identified by "CYP"
followed by a number, a letter and another
number that designate the family,
subfamily and specific enzyme. As an
example, the following represents the four
common CYP enzymes, a few substrates
(drugs that are metabolized through the
enzyme), inducers and inhibitors of the
enzyme:
|
Enzyme
|
Substrates
|
Inducers
|
Inhibitors
|
|
1A2
|
acetaminophen,
olanzapine, warfarin,
propranolol, theophylline,
imipramine
|
|
ciprofloxacin,
erythromycin, tacrine,
fluvoxamine
|
|
2C9
|
diclofenac,
tolbutamide, warfarin
|
Certain
anticonvulsants
|
amiodarone,
fluoxetine, fluvastatin,
metronidazole
|
|
2D6
|
chlorpheniramine,
codeine, fluoxetine, haloperidol,
metoprolol, propafenone,
risperidone
|
|
amiodarone,
cimetidine, propoxyphene,
quinidine, ritonavir,
SSRIs
|
|
3A4
|
Many
drug classes!
|
Certain
anticonvulsants, rifampin,
etc.
|
grapefruit
juice, diltiazem, ketoconazole,
macrolides, metronidazole,
quinidine
|
copyright
2002
Go
to Part II of this
review.
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