Society of Cardiovascular Anesthesiologists

Rhabdomyolysis and Cerivastatin

Reviewers: Patrick Breen, MD and Kyung W. Park, MD
Beth Israel Deaconess Medical Center
Boston, MA

Manufacturer's voluntary withdrawal of cerivastatin for the management of hypercholesterolaemia in August 2001 was linked to the occurrence of rhabdomyolysis and over 40 deaths worldwide.¹ In a typical case report, a patient who has recently been placed on cerivastatin presents with general malaise, muscle pain, and muscle weakness and is found to have an elevated level of creatine kinase and myoglobinuria. The patient may go on to develop acute renal failure, which usually resolves with discontinuance of the statin, but may not. If renal failure worsens, the patient may suffer a fatality.²

Cerivastatin (Baycol), along with atorvastatin, are third-generation inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme in cholesterol synthesis. Cholesterol is synthesized from acetyl-CoA in virtually all human cells, but primarily in hepatocytes. During cholesterol synthesis, the conversion of HMG-CoA to mevalonic acid is catalyzed by HMG-CoA reductase and is the rate-limiting step in the process. Three generations of HMG-CoA reductase inhibitors are available. Each generation has slight differences, but all are selectively targeted to HMG-CoA reductase in the liver. Simvastatin (Zocor), lovastatin (Mevacor) and pravastatin (Pravachol) are first-generation HMG-CoA reductase inhibitors. Simvastatin and lovastatin are administered as prodrugs and are hydrophobic, whereas pravastatin is administered in an active form and is hydrophilic. Fluvastatin (Lescol) is a second-generation HMG-CoA reductase inhibitor. It is a synthetic compound, administered as an active drug and is more hydrophilic than other reductase inhibitors. Cerivastatin and atorvastatin (Lipitor) are third-generation synthetic HMG-CoA reductase inhibitors. Metabolites of these 2 drugs also have HMG-CoA reductase inhibitory activity. All HMG-CoA reductase inhibitors competitively inhibit HMG-CoA reductase, primarily in the liver.

The cytochrome P450 (CYP) system is largely responsible for the metabolism of HMG-CoA reductase inhibitors. The CYP 3A4 subfamily is thought to be responsible for the metabolism of simvastatin, atorvastatin, lovastatin and cerivastatin. The CYP 2C8 subfamily is also involved in cerivastatin metabolism. Fluvastatin has several metabolic pathways involving the CYP mechanism. Pravastain does not appear to be significantly metabolized by this enzyme system.³ The CYP 3A4 isoenzyme is also responsible for the metabolism of several other compounds. These include azole antifungal agents, calcium channel blockers, cyclosporine, macrolide antibiotics and certain antihistamines. Diltiazem, cyclosprine, erythromycin, and grapefruit juice may also inhibit CYP 3A4 enzymatic activity. Plasma concentrations of HMG-CoA reductase inhibitors metabolized by CYP 3A4 may be considerably increased with coadministration of these inhibitors or competing substrates. Because cerivastatin has a secondary metabolic pathway via CYP 2C8 in addition to CYP 3A4, the potential for inordinate rise in its serum level may be less, at least in theory.⁴

Intermittent ophthalmological examinations were required by the US Food and Drug Administration when HMG-CoA reductase inhibitors were first introduced. Because agents that interrupted cholesterol synthesis downstream of mevalonic acid have been shown to cause lens opacification in experimental animals and humans, HMG-CoA reductase inhibitors have also been scrutinized for such complications.⁴However, several clinical trials have failed to demonstrate ophthalmological toxicity with the initial HMG-CoA reductase inhibitors (pravastatin, lovastatin, and simvastatin), and such examinations have been discontinued.^5,6

HMG-CoA reductase inhibitors are metabolized within the liver and thus may affect hepatic function. Their use is associated with mild elevations of circulating aminotransfereases in approximately 1 to 3% of patients receiving these agents, when the abnormality is defined as 3 times the upper limit of normal on two successive readings. Alterations in hepatic transaminases appear to be dose-related and generally reversible with discontinuation of the agent. HMG-CoA reductase inhibitors have not definitely been correlated with severe alterations in hepatic function. ⁴

The side effect that prompted the voluntary recall of cerivastatin was rhabdomyolysis. But rhabdomyolysis has been reported with variable frequency not only in patients on cerivastatin, but also in patients receiving other HMG-CoA reductase inhibitors.^7-11Mevalonic acid, whose synthesis is blocked by HMG-CoA reductase inhibitors, is important not only in cholesterol synthesis, but also in production of ubiquinone or coenzyme Q 10 in the muscle cell. Ubiquinone is utilized by the electron transport chain for ATP synthesis. Thus, HMG-CoA reductase inhibitors can lead to interference with ATP synthesis and this may be the mechanism of muscle injury. The myotoxicity is a drug-class effect and is dose-dependent. The risk of rhabdomyolysis appears to be increased by concomitant administration of fibrates (e.g., gemfibrozil given for refractory hypercholesterolemia), cyclosporine (given to heart or kidney transplant recipients), niacin, erythromycin or warfarin. In addition, manufacturers warn against the use of an HMG-CoA reductase inhibitor in situations that may be associated with an increased risk of rhabdomyolysis such as sepsis, major surgery, trauma and uncontrolled seizures.¹¹ An important factor in determining myotoxicity of statins may be their tissue selectivity for the peripheral tissues vs. the liver; the more selective a statin is for the liver, the less likely it may be myotoxic.

The large number of adverse reactions to cerivastatin is interesting for three reasons. First, the drug has two described pathways of metabolism (i.e. via CYP 3A4 and CYP 2C8). Second, cerivastatin has less affinity for CYP 3A4 than lovastatin and simvastatin. Third, the systemic bioavailability of cerivastatin is also greater than lovastatin and simvastatin. These three factors should make it less influenced by CYP 3A4 inhibitors. This may imply a more direct mechanism of muscle damage, rather than via less metabolism by the cytochrome P 450 enzyme system. Dividing myoblasts are known to be affected by HMG-CoA reductase inhibitors. Statins can cause intracellular calcium elevation, which may account for myotoxicity. ¹²

High plasma levels of total cholesterol and LDL-cholesterol are risk factors for coronary artery disease (CAD) and reductions in their levels by long-term treatment with HMG-CoA reductase inhibitors have been shown to reduce the risk of CAD.^13-14 As hypercholesterolemia is a relatively common comorbidity in patients presenting for cardiovascular surgery, HMG-CoA reductase inhibitors are often encountered by anesthesiologists in the perioperative setting. As practicing cardiovascular anesthesiologists, we will need to be aware of (a) drug interactions that may cause rhabdomyolysis, as already listed above, (b) patient factors that may increase the risk of rhabdomyolysis such as advanced age, female gender, renal or liver disease, diabetes, hypothyroidism, and debilitated status, and (c) other drugs that may independently cause myotoxicity, such as corticosteroids, beta-blockers, diuretics through hypokalemia, cimetidine and barbiturates. The anesthesiologist may also encounter patients with electrolyte disturbances, major trauma, seizures, hypothermia, metabolic acidosis, hypoxia and drugs of abuse (alcohol, amphetamines, cocaine and ecstasy), which may predispose to myopathy and rhabdomyolysis. Thus far, there is no report of any danger of using a depolarizing muscle relaxant in the setting of a clinical or subclinical rhabdomyolysis due to a statin.

References

1. http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01095.html

2. Bermingham RP, Whitsitt TB, Smart ML, Nowak DP, Scalley RD. Rhabdomyolysis in a patient receiving the combination of cerivastatin and gemfibrozil. Am J Health-Syst Pharm 2000; 57:461-4

3. Ucar M, Mjorndal T and Dahlqvist, R. HMG-CoA Reductase Inhibitors and Myotoxicity. Drug Safety 2000; 22 (6): 441-57.

4. Farmer JA and Torre-Amione G. Comparative Tolerability of the HMG-CoA Reductase Inhibitors. Drug Safety 2000; 23 (3): 197-213.

5. Laties AM, Shear CL, Leppa EA et al. Expanded clinical evaluation of lovastatin (Excel) study results. II. Assessment of the human lens after 48 weeks of treatment with lovastatin therapy. Am J Cardiol 1991; 67 (6): 447-53.

6. Harris ML, Bron AJ, Brown NA et al. Oxford Cholesterol Study Group. Absence of effect of simvastatin on the progression of lens opacities in a randomized, placebo-controlled study. Br J Ophthalmol 1995; 79 (11): 996-1002.

7. Ozdemir O, Boran M, Gokce V et al. A case with Severe Rhabdomyolysis and Renal failure Associated with Cerivastatin-Gemfibrozil Combination Therapy. Angiology 2000; 51(8): 695-97.

8. Alvarez JM, Rawdanowiz TJ and Goldstein J. Rhabdomyolysis After Coronary Artery Bypass Grafting In A Patient Receiving Simvastatin. J Thorac Cardiovasc Surg 1998; 116:654-5.

9. Maltz HC, Balog DL, Cheigh JS. Rhabdomyolysis with concomitant use of atorvastatin and cyclosporine. Annals Pharmacotherapy 1999; 33:1176-9

10. Zatarain GF, Navarro V, Garcia H, Villatoro J, Calvo C. Rhabdomyolysis and acute renal failure associated with lovastatin. Nephron 1994; 66:483-4

11. Rosenberg AD, Neuwirth MG, Kagen LJ, Singh K, Fischer HD, Bernstein RL. Intraoperative rhabdomyolysis in a patient receiving pravastatin, a 3-hydroxy-3-methylglutaryl Coenzyme A (HMG CoA) reductase inhibitor. Anesth Analg 1995; 81:1089-91

12. Gadbut AP, Caruso AP, Galper JB. Differential sensitivity of C2-C12 striated cells to lovastatin and pravastatin. J. Mol Cell Cardiol 1995; 27(10): 2397-402

13. Hunnington D. LDL-Cholesterol as a determinant of coronary heart disease. Clin Ther 1990; 12(5): 370-5.

14. Manninen V, Elo MO, Frick MH et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinke Heart Study. JAMA 1988; 260 ( 5): 641-51

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