Review Article
From the Departments of Internal Medicine and Pharmacology, King Faisal
University, College of Medicine, Dammam, Saudi Arabia.
Dr. Larbi: Departments of Medicine and Pharmacology, King Faisal University,
College of Medicine, P.O. Box 2114, Dammam, Saudi Arabia.
Accepted for publication 20 July 1998. Received 22 March 1998.

DRUG-INDUCED RHABDOMYOLYSIS

E.B. Larbi, MB, PhD, FRCP

The syndrome of rhabdomyolysis is the result of skeletal muscle injury that
alters the integrity of the sarcolemma and leads to the eventual release of
intracellular contents into the plasma. The causes are diverse, and include
muscle trauma (for instance, from vigorous exercise, crush injuries,
battering, or seizures), inadequate blood perfusion, heat stroke,
electrolyte imbalance, hereditary enzyme deficiencies, infections and
ingestion of drugs and toxins. Various serious medical disorders,
particularly those resulting in states of disordered energy production, are
also associated with rhabdomyolysis.

In general, drug toxicity involves organs, such as the kidney, liver,
gastrointestinal tract and the central nervous system, with skeletal muscle
being usually less readily affected. Although drug-induced rhabdomyolysis
was uncommon in the past, it is no longer rare, due to the introduction of
more and increasingly potent drugs into clinical practice.

The incidence of drug-induced rhabdomyolysis is uncertain, largely because
most of it is unreported. Similarly, the mortality rates are unknown.
However, it has been suggested that rhabdomyolysis from all causes leads to
5%-25% of cases of acute renal failure. Furthermore, about 10%-40% of
patients with rhabdomyolysis develop acute renal failure.

Rhabdomyolysis can result from direct muscle injury by myotoxic drugs, such
as cocaine and alcohol. This mechanism must be distinguished from
rhabdomyolysis that develops secondarily from muscle ischemia due to
prolonged seizures or local muscle compression in comatose states following
drug overdosage.

Mechanisms

A large number of drugs can cause rhabdomyolysis through various mechanisms,
which are probably multifactorial (Table 1). Any drug which directly or
indirectly impairs the production or use of adenosine triphosphate (ATP) by
skeletal muscle, or increases energy requirements so as to exceed ATP
production, can cause rhabdomyolysis. The processes include ischemia as a
result of prolonged immobilization from drug overdosage with CNS
depressants, thus impairing the delivery of oxygen and nutrients,
drug-induced delirium, choreoathetosis, dystonic reactions and seizures
(which increase muscle activity and the demand for ATP). Drugs can also be
directly toxic to muscle cells, interfering with the production or use of
ATP.

The potential mechanisms of drug-induced sarcolemmal injury, as reviewed by
Knochel and Armstrong et al., are as follows. A change in the viscosity of
sarcolemma is caused by activation of phospholipase A. It results in
increased permeability of the sarcolemma, permitting leakage of
intracellular contents, as well as an increase in the entry of sodium ions
into the cell. The increased intracellular sodium ion concentration
activates Na+,K+-ATPase, a process which requires energy. This eventually
exhausts the supplies of ATP and thus impairs cellular transport. The
increase in cellular sodium ion concentration also leads to an accumulation
of intracellular calcium ion concentration, which activates neutral
proteases within the cell, causing further cellular injury. However, it has
been suggested that, irrespective of the mechanisms involved, there is a
final common pathway, namely, there is an increase in the intracellular
concentration of sodium ion, which in turn leads to an increase in the
concentration of intracellular calcium ion. This enhances the activity of
the intracellular proteolytic enzymes, leading to further destruction of
intracellular structures.

There is another mechanism peculiar to the 3-hydroxy-3-methyl glutaryl
coenzyme A (HMG-Co A) reductase inhibitors, which inhibit cholesterol
synthesis. They reduce serum levels of coenzyme Q, a component of the
electron transport chain. This affects oxidative phosphorylation. The HMG-Co
A reductase inhibitors inhibit the synthesis of mevalonate, the reduced
supplies of which inhibit the formation of coenzyme Q.

Severe hypokalemia, especially that associated with significant reduction in
intracellular muscle potassium content, has also been implicated in the
pathogenesis of rhabdomyolysis. Glycogen synthesis is impaired in
hypokalemic states, leading to a reduction in energy production during
sustained muscle contraction. Hypokalemia has been shown experimentally to
reduce muscle cell transmembrane voltage and to cause muscle damage.
Contraction of muscle leads to the release of potassium ions into
intracellular space. Concentrations as high as 15 mEq/L can be attained.
This has a vasodilator effect, which thus enhances the increase in muscle
blood flow during exercise. In hypokalemic states there is no release of
potassium from the contracting muscles, and so blood flow is not increased.
Continued muscle contraction, therefore, leads to ischemia and muscle
necrosis.

Alcohol directly injures the sarcolemma and increases sodium permeability.
This in turn increases the activity of the Na+,K+-ATPase pump, with the
eventual exhaustion of energy stores. Increased cytosolic Na+ enhances the
accumulation of cytosolic Ca++, which in addition to increased mitochondrial
Ca++ causes cellular injury. Analysis of skeletal muscle from chronic
alcoholics and experimental animals fed ethanol shows a marked depletion of
potassium, phosphorus, and magnesium, and elevated sodium, chloride, calcium
and water content. Acute hypophosphatemia would shut off ATP synthesis.
Uniform muscle necrosis, leukocyte and macrophage invasion of degenerated
muscle fibers are observed with light microscopy, and ultrastructural
changes include the separation of myofibrils and other cellular elements by
clear spaces.

Acute alcohol-induced rhabdomyolysis can occur after binge drinking or a
sustained period of alcohol abuse, and is associated with pain and swelling
of muscles, particularly the quadriceps. Symptoms resolve if the patient
abstains from alcohol use.

Serious drug poisoning is frequently associated with rhabdomyolysis,
although the incidence is uncertain. The mechanisms involved vary with the
drug. General anesthetic agents and overdosage with central nervous system
drugs, such as narcotics, cyclic antidepressants, benzodiazepines,
antihistamines and barbiturates, cause rhabdomyolysis by pressure-induced
ischemia due to prolonged immobilization. Drugs such as LSD,
sympathomimetics and phencyclidine, which induce delirium or agitation, and
those which cause prolonged involuntary muscle contraction (e.g.,
phenothiazines and butyrophenones), lead to increased ATP demand and
eventual exhaustion of its stores.

Hyperthermia also increases the energy requirements of muscle and
contributes to its damage. Cocaine and salicylate intoxication-induced
rhabdomyolysis is due partly to the associated hyperthermia. Cocaine, in
addition, produces a syndrome similar to neuroleptic malignant syndrome
associated with intermittent dystonia, alternating with substantial
agitation, thus further increasing the ATP requirement. Halothane-induced
rhabdomyolysis results from the production of malignant hyperthermia (in
predisposed patients) and a resultant increase in ATP requirement.

The frequent causative agents include psychotropic and central nervous
system depressant drugs, as well as alcohol. The occurrence of
rhabdomyolysis is further enhanced in the presence of predisposing factors,
namely, hypokalemia, hyponatremia, hypernatremia, magnesium and phosphorus
depletion, hypothermia or hyperthermia, diabetic ketoacidosis or hypertonic
states.

TABLE 1. Drugs which can cause rhabdomyolisis.

Antipsychotics and antidepressants
Amitriptyline
Amoxapine
Doxepine
Fluoxetine
Fluphenazine
Haloperidol
Lithium
Protriptyline
Phenelzine
Perphenazine
Promethazine
Chlorpromazine
Loxapine
Promazine
Trifluoperazine

Sedative hypnotics
Benzodiazepines:
-Diazepam
-Nitrazepam
-Flunitrazepam
-Lorazepam
-Triazolam
Barbiturates
Gluthetimide

Antilipemic agents
Lovastatin
Pravastatin
Simvastatin
Bezafibrate
Clozafibrate
Ciprofibrate
Clofibrate

Drugs of addiction
Heroin
Cocaine
Amphetamine
Methadone

Antihistamines
Diphenhydramine
Doxylamine

Others
Alcohol
Amphotericin B
Azathioprine
Butyrophenones
Emetics
Epsilon-aminocaproic acid
Halothane
Laxatives
Moxalactam
Narcotics
Oxprenolol
Paracetamol
Penicillamine
Pentamidine
Phencyclidine
Phenytoin
Phenylpropanolamine
Quinidine
Salicylates
Strychnine
Succinylcholine
Theophyline
Terbutaline
Thiazides
Vasopressin

Biochemical Features and Basis for Diagnosis

Injury to the sarcolemma and skeletal muscle cell results in the release of
myoglobin, creatinine phosphokinase (CK), as well as other protein and
nonprotein cellular contents into plasma. Among others, there occurs an
increase of serum myoglobin, CK, aldolase, lactic dehydrogenase, potassium,
phosphates, purines, uric acid, aspartate aminotransferase (AST), carbonic
anhydrase III, as well as myosin heavy-chain fragments.

Estimation of myoglobin in the serum and urine is useful for the diagnosis
of rhabdomyolysis, particularly in the early phases of the disease.
Myoglobin is filtered by the kidney and appears in the urine when the plasma
concentration exceeds 1.5 mg/dl. It imparts a dark red brown color to urine
when urine concentration exceeds 100 mg/dl. Myoglobin has a short half-life
(2-3 hours), and is rapidly cleared by both renal excretion and metabolism
to bilirubin. Serum myoglobin levels, therefore, return to normal in about
6-8 hours, following cessation of muscle injury. Owing to its rapid
clearance from plasma, its absence does not exclude the diagnosis of
rhabdomyolysis.

Elevated creatinine phosphokinase is the hallmark of rhabdomyolysis. It
rises within 12 hours of the onset of muscle injury, peaks in 1-3 days, and
declines 3-5 days after cessation of muscle injury. The half-life of CK is
1.5 days and so it remains elevated longer than serum myoglobin levels.

Hyperkalemia increases the risk of cardiac dysrrhythmia. The release of
organic and inorganic phosphates from the injured muscles causes an increase
in serum phosphate levels, which may elevate calcium phosphate product
resulting in deposition of calcium salts in muscle and other tissues.
Hypocalcemia then ensues. However, in late stages of the disease,
mobilization of calcium from damaged muscle results in hypercalcemia. The
released purine precursors are converted to uric acid, thus increasing its
levels.

Carbonic anhydrase III is present in skeletal muscles but not in myocardium.
An increase in its levels is thus more specific for skeletal muscle injury
than CK. Increase in myosin heavy-chain fragments is also more specific in
skeletal than myocardial muscle injury. The levels increase in about 4 to 7
days after muscle injury, and remain so even until after day 12. Measurement
of myosin heavy-chain fragments is particularly useful for the late
diagnosis of rhabdomyolysis. Unfortunately, these tests are not readily
available. Other biochemical abnormalities include increased serum levels of
creatinine, hydroxybutyrate and lactic acid, thrombocytopenia, increased
fibrinogen degradation products, prolonged prothrombin time and proteinuria.

Clinical Manifestations

There is wide variation in the clinical presentation of rhabdomyolysis. The
classical triad of symptoms are muscle pain, weakness and dark urine. The
muscles can be tender and swollen, and there can be skin changes indicating
pressure necrosis. However, these classical features are seen in less than
10% of patients. Over 50% of patients may not complain of muscle pain or
weakness. Diagnosis becomes even more difficult in patients with altered
mental state or levels of consciousness, who are unable to give a coherent
history. Features related to the effects of drug poisoning can also
predominate and the possibility of rhabdomyolysis can be missed. A high
index of suspicion of rhabdomyolysis is thus necessary for early diagnosis.

Rhabdomyolysis should be suspected in patients presenting with drug
poisoning, altered levels of consciousness, severe fluid and electrolyte
abnormality, hyperthermia, hypotension, hypoxia, and states of increased
muscular activity, such as seizures, agitation, strenuous muscle exercise or
dystonia, particularly in patients with alcohol or substance abuse. Patients
who have ingested neuroleptic drugs can present initially with dystonia,
hyperthermia, or neuroleptic malignant syndrome characterized by fever,
muscle rigidity, autonomic dysfunction and altered consciousness.

Acute Renal Failure

Acute renal failure, oliguric or nonoliguric, is the most common
complication of rhabdomyolysis. It occurs in 10%-40% of patients.
Rhabdomyolysis also accounts for 5%-25% of all cases of acute renal failure.
The causes of the renal injury include direct nephrotoxicity of ferrihemate
produced by the dissociation of myoglobin at pH 5.6 or less, tubular
obstruction due to protein, uric acid crystals and precipitates of myoglobin
(myoglobin casts), and reduction in renal blood flow as a result of renal
vasoconstriction.

Intracellular iron is an important mediator of tissue damage. As a
transition metal it can donate and accept electrons, and its toxicity is due
to its ability to catalyze oxygen- and non-oxygen-based free radical
reactions. In rhabdomyolysis, the cytotoxic iron moiety is derived from
heme, a product of myoglobin metabolism. In the renal tubules the iron so
derived catalyzes free radical reactions, which are associated with lipid
peroxidation. The major mechanism of renal tubular damage in rhabdomyolysis
is the mitochondrial free radical production which induces lipid
peroxidation. Procedures which chelate iron, or prevent or reduce the
release of free iron, have been shown to have a protective effect, thus
demonstrating the important role of iron in tubular damage in
rhabdomyolysis.

Acute renal failure is associated in the early phases with a marked rise in
uric acid and hypocalcemia. The raised uric acid is due to rapid metabolism
of muscle purines. Binding of calcium by damaged muscle and decreased levels
of serum dihydroxycholecalciferol account for the observed hypocalcemia. The
combination of hypocalcemia and hyperkalemia can result in ventricular
dysrrhythmia and possible cardiac arrest. Acute renal failure is also
associated with a disproportionate increase in serum creatinine levels as a
result of the release of preformed creatinine from the damaged muscle into
plasma. Currently there is no reliable factor of predictive value in those
likely to develop acute renal failure. Involvement of myocardium and
intercostal muscles and diaphragm can lead to acute cardiomyopathy and acute
respiratory failure.

Compartment syndrome is not unusual in drug-induced rhabdomyolysis. The
compartments containing anterior tibial, peroneal, lateral thigh, soleus,
gluteal, deltoid and forearm muscles may be affected. There is increased
swelling and tenderness of the involved muscle, and the increased pressure
in the compartment can be associated with decreased pulse and neuropathy in
the affected limb. Re-elevation of CK levels can herald the onset of
compartment syndrome. Immediate fasciotomy is required if intracompartment
pressure exceeds 30-50 mm Hg, in order to prevent the sequelae of limb
contracture, ischemia and possible amputation.

Management

The treatment of rhabdomyolysis consists of: 1) general measures; 2)
attempts to prevent acute renal failure; 3) hemodialysis; and 4) other
measures.

General measures

General management of drug overdosage includes termination of further
exposure, reduction of absorption, enhancement of metabolism and excretion
of the offending drug as appropriate. Features of drug overdosage,
particularly in comatose patients, namely, hypothermia, hyperthermia,
hypoxia, hypovolemia and hypotension, should be identified and treated.
Measures should also be taken to stop further muscle damage. These include
control of excessive muscle activity, such as in severe agitation and
convulsions and abnormal posturing in unconscious patients. Sedatives, or in
some cases anticonvulsants, may be required to control convulsions.
Overdosage with phenothiazines may require the administration of
anticholinergic agents to control dystonic reactions.

Attempts to prevent acute Renal failure

Early correction of hypovolemia reduces the incidence of renal failure.
Various types of fluid composition and infusion regimes have been suggested.
Other additional measures include continued infusion of 0.9% saline and the
administration of mannitol following correction of hypovolemia in order to
induce diuresis. Although it may be difficult, it is essential to maintain a
urine output of 300 cc/hour or more. Alkalinization of urine prevents the
dissociation of myoglobulin into globin and ferrihemate, which are toxic to
the renal tubules. The possibility of aggravation of hypocalcemia by large
doses of bicarbonate should be borne in mind, although this is rather
uncommon, especially if hypovolemia is corrected. The administration of
mannitol also reduces intracompartment pressure and its attendant
complications.

Hemodialysis

The indications for hemodialysis are standard and include failure of
conservative measures in the management of acute tubular necrosis, severe
acidosis, rapid increase in serum potassium levels, and hypocalcemia.

Other Measures

Supplement of calcium in hypocalcemia is rarely required. Its administration
may not only enhance the deposition of calcium in damaged muscles and lead
to further muscle damage, but may also increase the level of hypercalcemia
during the recovery phase. Hyperkalemia may require treatment with sodium
bicarbonate (usually 50-100 mmol), glucose (50 mL of 50% dextrose) and
insulin (10 units regular), resin preparation, such as sodium polystyrene
sulphonate (25-50 g resin mixed with 100 mL of 20% sorbitol given orally, or
50 g of resin and 50 mL of 70% sorbitol, mixed in 150 mL of tap water, given
as a retention enema), or as indicated above by dialysis.

Prognosis

The prognosis depends on the underlying drug toxicity, which may contribute
to the reported mortality of about 5% observed in serious rhabdomyolysis.
Most cases are, however, mild. If there are no other underlying
complications, acute renal failure in rhabdomyolysis is reversible and has
an excellent prognosis, although recovery may be delayed. Early recognition
and treatment of compartment syndrome prevents permanent disability.

Most cases of drug intoxication may be associated with rhabdomyolysis. It is
thus fairly common. In a majority of cases, however, symptoms may be absent
or mild. Its recognition and diagnosis, therefore, depend on a high index of
clinical suspicion. The prognosis depends on the other effects of the
offending drug, complications and severity of rhabdomyolysis. However, with
appropriate treatment, the outcome is generally good.