Initial
Physical Exam
Blood pressure
(BP): 140/100 mm Hg
Pulse: 100 bpm
Respirations: 18 rpm
Loud fourth heart sound at apex 1+ left femoral
bruit
Electrocardiogram (EKG): 1-mm
horizontal ST elevations in inferior leads
Rest of exam: unremarkable
Initial Laboratory
Values
Complete blood count:
normal
Urinalysis: normal
Electrolytes: normal
Creatine kinase: CK-MB 825 U/L
Creatinine: 1.9 mg/dL
Blood urea nitrogen (BUN): 24 mg/dL
Fasting blood glucose (FBG): 152
mg/dL
HbA1c:
8.8%
TC: 236 mg/dL
LDL-C: 153 mg/dL
HDL-C: 39 mg/dL
TG: 153 mg/dL
Follow-Up Findings
(2 weeks)
BP: 118/72
mm Hg
Pulse: 60 bpm
FBG: 85 mg/dL
TC: 170 mg/dL
LDL-C: 90 mg/dL
HDL-C: 42 mg/dL
TG: 190 mg/dL
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| Related
information on this website: |
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 In
the Slide Library section:
Statin
Advisory: Risk Factors for Statin-Associated Myopathy
Statin
Advisory: Conclusions
In
the Current Literature section:
Therapy
With Hydroxymethylglutaryl Coenzyme A Reductase
Inhibitors (Statins) and Associated Risk of Incident
Cardiovascular Events in Older Adults—Evidence
From the Cardiovascular Health Study
Lemaitre RN, Psaty BM, Heckbert SR, Kronmal RA,
Newman AB, Burke GL.
Arch Intern Med. 2002;162:1395-1400.
Inhibitors
of hydroxymethylglutaryl-coenzyme A reductase and
Risk of Fracture Among Older Women
Chan KA, Andrade SE, Boles M, et al.
Lancet. 2000;355:2185-2188.
Tolerability of Statin-Fibrate and Statin-Niacin Combination Therapy in Dyslipidemic Patients at High Risk for Cardiovascular Events
Taher TH, Dzavik V, Reteff EM, Pearson GJ, Woloschuk BL, Francis GA.
Am J Cardiol. 2002;89:390-394.
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Polypharmacy and Drug-Induced Myotoxicity in an Elderly
Female
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John
A. Farmer, MD |
The following case was provided by NLEC Faculty Member
John A. Farmer, MD, Associate Professor, Department of Medicine,
Division of Cardiology and Clinical Atherosclerosis, Baylor
College of Medicine, Houston, Texas.
Disclosure Information for Dr Farmer: Retained consultant: Merck & Co., Inc.,
Pfizer Inc
A 72-year-old woman with a 9-year history of diet-controlled
type 2 diabetes was admitted to the Coronary Care Unit following
2 days of intermittent lower-substernal and mid-epigastric
pain, which did not radiate to the arm, back, or jaw. The
pain varied in intensity but became constant 8 hours before
admission and was accompanied by mild nausea. The patient
had previously self-administered oral antacids without significant
relief. It was noted that she had not seen a doctor in the
past 5 years.
During this initial visit (see column for
exam findings), the patient was administered aspirin,
ß-blockers, clopidogrel, angiotensin-converting enzyme
(ACE) inhibitors, and oxygen, resulting in the relief of chest
pain. Thrombolytic therapy was not administered owing to the
duration of the pain and because the patient no longer had
angina.
Pertinent laboratory findings (see
column) revealed elevated levels of CK, which was obtained
in the emergency room and trended downward to normal over
24 hours. The EKG evolved over 3 days with generation of Q
waves in the inferior leads.
The patient remained angina-free on medical
therapy and was transferred to the general medical floor for
cardiac rehabilitation. BP had decreased to 110/70 mm Hg on
medical treatment. She declined coronary angiography. A submaximal
treadmill test obtained on day 7 revealed no ischemia. The
next day she was discharged on lovastatin 40 mg/d, aspirin 81 mg/d, clopidogrel 75 mg/d, enalapril 10
mg q12h, and extended-release metoprolol 50 mg/d. The patient
received dietary instruction for diabetic dyslipidemia and
was begun on glipizide 10 mg/d.
At her 2-week follow-up visit, she was
active and remained angina-free (see column for findings).
The patient noted mild intermittent myalgias in the thighs
bilaterally, which made it somewhat difficult to rise out
of a chair. Physical examination of the lower extremities
revealed no tenderness, swelling, or discoloration. The left
femoral bruit was unchanged, and distal peripheral pulses
were full and intact. Aldolase, CK, and erythrocyte sedimentation
rates were within normal limits. She was continued on her
medical regimen. Later, she saw a dermatologist for diffuse
inguinal scaly cutaneous lesions. A diagnosis of tinea cruris
was made and 200 mg of itraconazole in divided doses was administered.
One week later, she experienced progressive
pain and weakness in the lower extremities and could not rise
from a chair without assistance. The patient also noted a
discoloration of her urine. She went to the emergency room,
where a urinalysis was brown, cloudy, and strongly positive
for heme. CK-MM was 1,246 U/L. Myoglobin was confirmed in
the urine. The patient’s creatinine on admission was
2.1 mg/dL. She was given intravenous fluids, and her phosphorus,
magnesium, and potassium levels were maintained within a normal
range. The patient did not become significantly acidotic,
and her CK and renal function gradually returned to baseline
over 3 days.
Discussion
Pharmacologic agents that lower serum cholesterol by partial
inhibition of the limiting enzyme in cholesterol synthesis
have revolutionized the clinician’s ability to optimize
the lipid profile in dyslipidemic patients. Along with their
benefits proven over the past 15 years, however, a large database
has accrued concerning the clinical risks of statins (HMG-CoA
reductase inhibitors). Myotoxicity was among the first major
adverse effects associated with statin toxicity, although
the precise pathogenetic mechanism still remains controversial.
Statin-associated myotoxicity ranges from mild myalgias to
life-threatening rhabdomyolysis (see Figure below).
Myalgias
With Normal CK Levels
Uncomplicated myalgias are generally reversible following
statin discontinuation. The causative mechanism is unknown,
but has been proposed as a direct myotoxic effect that does
not reach the threshold required for membrane disruption and
release of specific muscle enzymes into the circulation. However,
this hypothesis had not been previously supported with histopathologic
data.
A small study recently evaluated individuals
who developed symptoms of myalgia with normal CK levels while
on statin therapy. Symptoms resolved following discontinuation
of the medication and recurred following reinstitution. Subsequent
serial muscle strength evaluation documented reduced performance
with adduction and flexion of the hip. Histopathologic examination
from biopsies documented lipid droplet accumulation and cytochrome
oxidase negative fibers, which were consistent with a statin-related
myopathy. CK and statin levels remained normal during the
trial. Despite its limitations—it was not blinded, was
small (N=4), and lacked appropriate controls—the study
provides quantitative evidence for the pathologic abnormality
in statin-associated myalgia. This important observation may
provide insight into the future elaboration of the underlying
mechanism.
Myalgias
With Elevated CK Levels
Statin myotoxicity associated with elevated CK in combination
with a compatible symptom complex also has an obscure mechanism.
However, genetic enzyme defects, intrinsic pharmacologic properties
of the statins, and potential interactions with coadministered
drugs that share metabolic pathways have been causally implicated.
Pharmacologic
Properties. The relative lipophilic characteristics
of statins determine, to a degree, the level of tissue penetration;
theoretically, they have the potential to increase the risk
of muscle toxicity if a subsequent increase in intracellular
levels determines the degree of induced myocyte damage. Additionally,
statins inhibit an early step in the synthesis of cholesterol
and thus are associated with a secondary intracellular depletion
of metabolic intermediates. It has been suggested that key
intermediates such as geranylgeraniol, farnesol, and ubiquinone
(coenzyme Q) reduce the capacity for posttranslational modification
of a variety of regulatory proteins and may play a role in
myocyte damage.
Drug Interaction.
The interactions due to coadministration of drugs that utilize
the cytochrome P450 enzyme system play a significant role
in statin myotoxicity. The cytochrome P450 system represents
a group of enzymes that oxidatively modifies drugs and converts
them to water-soluble metabolic intermediates that facilitate
renal excretion. The cytochrome P450 3A4 isoform accounts
for approximately 50% of the metabolism of all commonly used
drugs. (See Box in the left column for statin-specific
metabolism features.)
Statin-associated myotoxicity is significantly
increased when the statin is coadministered with a drug that
either inhibits the components of the P450 enzyme system or
competes for a common (eg, 3A4) enzyme system. The combination
of statin and fibric-acid derivatives has been scrutinized,
for instance, because of the definite increased risk of myositis.
The metabolism of fibric-acid derivatives is complex and not
clearly delineated. Fibrates are thought to utilize the P450
3A4 pathway; however, this is not universally accepted and
the exact mechanisms involved in the catabolism remain controversial.
The risk of rhabdomyolysis with statin–fibrate combinations
ranges from 1% to 5% and may be due to a noncytochrome P450
mechanism.
Rhabdomyolysis
Rhabdomyolysis is a rare (<1/103) but life-threatening
complication of statin therapy. It can be precipitated by
trauma, infection, toxins, and genetically mediated enzyme
deficiencies. The clinical manifestations of rhabdomyolysis
share a common path resulting from widespread myocyte sarcolemmal
destruction and resultant cell lysis. Myonecrosis is characterized
by the release of a variety of intracellular constituents
and enzymes into the circulation. Myoglobin is released into
the plasma compartment and cleared by the kidney with the
potential for tubular obstruction. Additionally, intense renal
vasoconstriction occurs, which is at least partially secondary
to inhibition of nitric-oxide synthase in the endothelial
cells. Plasma CK levels in excess of 5,000 IU have more than
a 50% risk for the development of irreversible renal failure.
Conclusion
The patient in question had multiple factors predisposing
her to statin-associated myotoxicity by demographic analysis:
elderly, diabetes, renal insufficiency. She had symptoms compatible
with statin-associated myopathy, although this was discounted
because of the lack of clinical evidence marked by elevated
CK levels. The addition of a second medication (itraconazole),
which shares the cytochrome P450 metabolism, significantly
increased the risk for statin-associated myositis and the
potential for renal failure. Prompt recognition of discolored
urine and institution and management of volume and electrolyte
status allowed her to preserve her renal function.
This case points out the clinical pitfalls
associated with evaluation of symptoms suggestive of a drug-induced
myopathy in the elderly, and the potential complications associated
with polypharmacy.
*For
complete bibliography listing, please click here.
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