FORMULARY FORUM
SIMVASTATIN: A REVIEW OF ITS PHARMACOLOGY AND CLINICAL USE Vincent F. Mauro and Joanne L. MacDonald
Simvastatin,a chemical derivative of lovastatin, is an antihyperlipidemicmedication that inhibits hydroxymethylglutaryl coenzyme A reductase, Animal and clinical data suggest simvastatin is twice as potent as lovastatin. It lowers serum cholesterol by inhibitinghepatic synthesisof cholesterol and, more importantly,by increasingthe number of low-densitylipoprotein (LOL) receptors present on hepatic cellular membranes. Simvastatin,when used at doses of 40 mg/d in patients with heterozygousfamilial hypercholesterolemia, significantlyreduces total cholesterol (>30 percent)and LOL cholesterol (35-45 percent) and tends to reduce triglyceridesand raise high-densitylipoprotein (HOL) cholesterol. The agent is also effective in patients with polygenic hypercholesterolemia, familialdysbetalipoproteinemia, and nephrotic syndrome. Addition of cholestyramineto simvastatinenhances the LOL cholesterol-lowering effect to approximately 55 percent. Common clinical adverse effects reported with simvastatin use include headaches and gastrointestinal complaints. Transient elevations in serum transaminases and creatine phosphokinasehave also been seen. Based on data currently available,the drug's clinical activity and adverse-effectprofile are similar to those of lovastatin. Therefore, there is no need for formularies to contain both medications.To choose between the two, one needs to consider the incidenceof adverse effects and the daily cost of each product when used at equally effective doses. That information is now now available and, until it is, a clear recommendationcannot be made. Simvastatin, presently marketed in several countries, is investigational in the U.S. but is expected to be available soon. ABSTRACT:
DICP Ann Pharmacorher 1991;25:257-64. UNTIL A FEW YEARS AGO, medications available for the treatment of hypercholesterolemia worked by inhibiting the synthesis of lipoproteins or enhancing the clearance of lipids or lipoproteins. t In 1987, lovastatin became available for use in the U.S. Lovastatin's pharmacology is unique compared with prior anti hyperlipidemic medications because it inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme responsible for cholesterol synthesis.' Simvastatin, previously known as synvinolin or MK-733, is also an HMG-CoA reductase inhibitor currently available in several European countries (Belgium, Denmark, France, Germany, Great Britain, Greece, Holland, Ireland, Italy, Luxembourg, Sweden, and Switzerland), Brazil, Mexico, New Zealand, and VINCENT F. MAURO, Phann.D., is an Associate Professor of Clinical Pharmacy, College of Pharmacy, University of Toledo, and a Clinical Pharmacist, Department ofPhannacy, Medical College Hospitals, Toledo; JOANNE L. MACDONALD was a B.S.Phann. student at the time of writing, and is now a Phann.D. student, College of Pharmacy, University of Toledo. Toledo, OH. Reprints: Vincent F. Mauro, Phann.D., College of Pharmacy, University of Toledo. 2801 W. Bancroft St., Toledo, OH43606.
This article is approved forcontinuing education credit.
B
A
Figure I. Graphic formulas of simvastatin (A) and lovastatin (B).
South Africa, and is expected to be released soon in the U.S. The following is a review of the pharmacology and clinical use of simvastatin,
Pharmacotherapeutic Rationale An adult on a low-cholesterol diet synthesizes, mostly by the liver, approximately 800 mg of cholesterol per day.' Moderate dietary intake of cholesterol reduces the endogenous production of cholesterol to maintain cholesterol homeostasis.' Cholesterol is used by the body as a component of cellular membranes and for the synthesis of steroid hormones, bile acids, and vitamin D. Cholesterol, itself insoluble in water, is transported through the blood combined with proteins, triglycerides, and phospholipids to form lipoproteins, and it leaves the body through fecal excretion as bile acids (40 percent) or neutral sterols (60 percent).' Elevated serum cholesterol concentrations may occur because of genetic lipid disorders, systemic diseases, medications, or a diet excessively high in cholesterol. t Elevated serum cholesterol, most specifically low-density lipoprotein (LDL) cholesterol, is associated with the development of coronary artery disease.s Studies have shown that the lowering of total serum cholesterol by diet and medication can reduce the incidence of morbidity and mortality associated with coronary artery disease'" and can even lead to the regression of atherosclerotic plaque.t-" Chemistry Sirnvastatin is a lactone and pharmacologically inactive. It is chemically derived from lovastatin and differs in structure by an additional methyl group on the ester side chain (Figure I) that allows sirnvastatin to be approximately twice as potent as lovastatin based on ability to inhibit
DICP, The Annals ofPharmacotherapy Downloaded from aop.sagepub.com at University of Sussex Library on September 14, 2015
•
1991 March, Volume 25
•
257
rat liver HMG-CoA reductase." A white crystalline powder, simvastatin is soluble in chloroform, methanol, and ethanol but insoluble in water. Its empiric formula is C 2sHJ8 0 s and the molecular weight is 418.57. Simvastatin is known chemically as 11S-[la,3a,7~,8B(2S*,4S*), 8a~] }- I ,2,3,7 ,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-I-naphthalenyl 2,2 dimethylbutanoate.P Pharmacology MECHANISM OF ACTION
The biosynthesis of cholesterol and other compounds dependent on HMG-CoA reductase for synthesis is shown in Figure 2. The mechanism by which HMG-CoA reductase inhibitors reduce plasma cholesterol, most specifically LDL cholesterol, has been discussed in detail elsewhere.' Briefly, these reductase inhibitors restrict the conversion of HMG-CoA to mevalonic acid by competitively inhibiting HMG-CoA reductase." The affmity of HMG-CoA reductase for simvastatin is 13 ()()() times greater than for HMGCoA.2 Inhibiting HMG-CoA reductase lowers plasma cholesterol by moderately reducing the body's endogenous production of cholesterol'! and, more importantly, increasing the number of LDL receptors present on the cellular membrane of the liver and extrahepatic tissues, thus allowing for greater removal of LDL from the plasma.IS In addition, because LDL is derived from very-low-density lipoprotein (VLDL) and VLDL remnants, the increase in LDL receptors may decrease the production of LDL through increased VLDL and VLDL remnant removal by the LDL receptors."
••
AcetylCoA
HMGCoA
+*
Mevalonic Acid
+ +
Isopentenyl Pyrophosphate ~ ~ ~ Isopentenyl tRNA
Geranyl
T"Phale
Ubiquinone ~ ~ ~ Farnesyl Pyrophosphate
~~~
Dolichol
+
Toxic intermediate compounds resulting from inhibiting the conversion of HMG-CoA to mevalonic acid are not known to appear and are not expected to occur because HMG-CoA can easily be converted back to acetyl coenzyme A.17 Theoretically, HMG-CoA reductase inhibitors could significantly inhibit the production of compounds dependent on mevalonic acid for synthesis; however, clinical trials have yet to document this. Simvastatin has not been shown to interfere with the 24-hour urinary excretion of cortisol, 17-hydroxysteroids, or 17-ketosteroids'" or with the response of the adrenal glands to adrenocorticotropic hormone (ACTH).18,19 Additionally, this agent was not shown to increase the risk of gallstone formation.w Experience with 10vastatin indicates it also does not cause a marked reduction in steroid hormone or bile acid secretion.' Mevastatin, another HMG-CoA reductase inhibitor, was observed not to lower ubiquinone concentrations in patients with familial hypercholesterolemia (FH).21 The effects of HMG-CoA reductase inhibitors on the synthesis of dolichol and isopentenyl transfer ribonucleic acid (tRNA) are not fully known.' PHARMACOKINETICS
Limited pharmacokinetic data are currently available for simvastatin. The following is a summary of information made available by the manufacturer.P After oral absorption, inactive simvastatin is highly extracted by the liver and hydrolyzed to the active beta-hydroxy acid form of the drug known as L-654,969. Other minor active and inactive metabolites may also be formed. For the most part, the metabolites are subsequently excreted in the bile. In radioactive studies, 60 percent of the radioactivity was recovered in the feces (which also included unabsorbed parent drug) and 13 percent was recovered in the urine (of which
SIMVASTATIN: A REVIEW OF ITS PHARMACOLOGY AND CLINICAL USE Vincent F. Mauro and Joanne L. MacDonald
Simvastatin,a chemical derivative of lovastatin, is an antihyperlipidemicmedication that inhibits hydroxymethylglutaryl coenzyme A reductase, Animal and clinical data suggest simvastatin is twice as potent as lovastatin. It lowers serum cholesterol by inhibitinghepatic synthesisof cholesterol and, more importantly,by increasingthe number of low-densitylipoprotein (LOL) receptors present on hepatic cellular membranes. Simvastatin,when used at doses of 40 mg/d in patients with heterozygousfamilial hypercholesterolemia, significantlyreduces total cholesterol (>30 percent)and LOL cholesterol (35-45 percent) and tends to reduce triglyceridesand raise high-densitylipoprotein (HOL) cholesterol. The agent is also effective in patients with polygenic hypercholesterolemia, familialdysbetalipoproteinemia, and nephrotic syndrome. Addition of cholestyramineto simvastatinenhances the LOL cholesterol-lowering effect to approximately 55 percent. Common clinical adverse effects reported with simvastatin use include headaches and gastrointestinal complaints. Transient elevations in serum transaminases and creatine phosphokinasehave also been seen. Based on data currently available,the drug's clinical activity and adverse-effectprofile are similar to those of lovastatin. Therefore, there is no need for formularies to contain both medications.To choose between the two, one needs to consider the incidenceof adverse effects and the daily cost of each product when used at equally effective doses. That information is now now available and, until it is, a clear recommendationcannot be made. Simvastatin, presently marketed in several countries, is investigational in the U.S. but is expected to be available soon. ABSTRACT:
DICP Ann Pharmacorher 1991;25:257-64. UNTIL A FEW YEARS AGO, medications available for the treatment of hypercholesterolemia worked by inhibiting the synthesis of lipoproteins or enhancing the clearance of lipids or lipoproteins. t In 1987, lovastatin became available for use in the U.S. Lovastatin's pharmacology is unique compared with prior anti hyperlipidemic medications because it inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme responsible for cholesterol synthesis.' Simvastatin, previously known as synvinolin or MK-733, is also an HMG-CoA reductase inhibitor currently available in several European countries (Belgium, Denmark, France, Germany, Great Britain, Greece, Holland, Ireland, Italy, Luxembourg, Sweden, and Switzerland), Brazil, Mexico, New Zealand, and VINCENT F. MAURO, Phann.D., is an Associate Professor of Clinical Pharmacy, College of Pharmacy, University of Toledo, and a Clinical Pharmacist, Department ofPhannacy, Medical College Hospitals, Toledo; JOANNE L. MACDONALD was a B.S.Phann. student at the time of writing, and is now a Phann.D. student, College of Pharmacy, University of Toledo. Toledo, OH. Reprints: Vincent F. Mauro, Phann.D., College of Pharmacy, University of Toledo. 2801 W. Bancroft St., Toledo, OH43606.
This article is approved forcontinuing education credit.
B
A
Figure I. Graphic formulas of simvastatin (A) and lovastatin (B).
South Africa, and is expected to be released soon in the U.S. The following is a review of the pharmacology and clinical use of simvastatin,
Pharmacotherapeutic Rationale An adult on a low-cholesterol diet synthesizes, mostly by the liver, approximately 800 mg of cholesterol per day.' Moderate dietary intake of cholesterol reduces the endogenous production of cholesterol to maintain cholesterol homeostasis.' Cholesterol is used by the body as a component of cellular membranes and for the synthesis of steroid hormones, bile acids, and vitamin D. Cholesterol, itself insoluble in water, is transported through the blood combined with proteins, triglycerides, and phospholipids to form lipoproteins, and it leaves the body through fecal excretion as bile acids (40 percent) or neutral sterols (60 percent).' Elevated serum cholesterol concentrations may occur because of genetic lipid disorders, systemic diseases, medications, or a diet excessively high in cholesterol. t Elevated serum cholesterol, most specifically low-density lipoprotein (LDL) cholesterol, is associated with the development of coronary artery disease.s Studies have shown that the lowering of total serum cholesterol by diet and medication can reduce the incidence of morbidity and mortality associated with coronary artery disease'" and can even lead to the regression of atherosclerotic plaque.t-" Chemistry Sirnvastatin is a lactone and pharmacologically inactive. It is chemically derived from lovastatin and differs in structure by an additional methyl group on the ester side chain (Figure I) that allows sirnvastatin to be approximately twice as potent as lovastatin based on ability to inhibit
DICP, The Annals ofPharmacotherapy Downloaded from aop.sagepub.com at University of Sussex Library on September 14, 2015
•
1991 March, Volume 25
•
257
rat liver HMG-CoA reductase." A white crystalline powder, simvastatin is soluble in chloroform, methanol, and ethanol but insoluble in water. Its empiric formula is C 2sHJ8 0 s and the molecular weight is 418.57. Simvastatin is known chemically as 11S-[la,3a,7~,8B(2S*,4S*), 8a~] }- I ,2,3,7 ,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-I-naphthalenyl 2,2 dimethylbutanoate.P Pharmacology MECHANISM OF ACTION
The biosynthesis of cholesterol and other compounds dependent on HMG-CoA reductase for synthesis is shown in Figure 2. The mechanism by which HMG-CoA reductase inhibitors reduce plasma cholesterol, most specifically LDL cholesterol, has been discussed in detail elsewhere.' Briefly, these reductase inhibitors restrict the conversion of HMG-CoA to mevalonic acid by competitively inhibiting HMG-CoA reductase." The affmity of HMG-CoA reductase for simvastatin is 13 ()()() times greater than for HMGCoA.2 Inhibiting HMG-CoA reductase lowers plasma cholesterol by moderately reducing the body's endogenous production of cholesterol'! and, more importantly, increasing the number of LDL receptors present on the cellular membrane of the liver and extrahepatic tissues, thus allowing for greater removal of LDL from the plasma.IS In addition, because LDL is derived from very-low-density lipoprotein (VLDL) and VLDL remnants, the increase in LDL receptors may decrease the production of LDL through increased VLDL and VLDL remnant removal by the LDL receptors."
••
AcetylCoA
HMGCoA
+*
Mevalonic Acid
+ +
Isopentenyl Pyrophosphate ~ ~ ~ Isopentenyl tRNA
Geranyl
T"Phale
Ubiquinone ~ ~ ~ Farnesyl Pyrophosphate
~~~
Dolichol
+
Toxic intermediate compounds resulting from inhibiting the conversion of HMG-CoA to mevalonic acid are not known to appear and are not expected to occur because HMG-CoA can easily be converted back to acetyl coenzyme A.17 Theoretically, HMG-CoA reductase inhibitors could significantly inhibit the production of compounds dependent on mevalonic acid for synthesis; however, clinical trials have yet to document this. Simvastatin has not been shown to interfere with the 24-hour urinary excretion of cortisol, 17-hydroxysteroids, or 17-ketosteroids'" or with the response of the adrenal glands to adrenocorticotropic hormone (ACTH).18,19 Additionally, this agent was not shown to increase the risk of gallstone formation.w Experience with 10vastatin indicates it also does not cause a marked reduction in steroid hormone or bile acid secretion.' Mevastatin, another HMG-CoA reductase inhibitor, was observed not to lower ubiquinone concentrations in patients with familial hypercholesterolemia (FH).21 The effects of HMG-CoA reductase inhibitors on the synthesis of dolichol and isopentenyl transfer ribonucleic acid (tRNA) are not fully known.' PHARMACOKINETICS
Limited pharmacokinetic data are currently available for simvastatin. The following is a summary of information made available by the manufacturer.P After oral absorption, inactive simvastatin is highly extracted by the liver and hydrolyzed to the active beta-hydroxy acid form of the drug known as L-654,969. Other minor active and inactive metabolites may also be formed. For the most part, the metabolites are subsequently excreted in the bile. In radioactive studies, 60 percent of the radioactivity was recovered in the feces (which also included unabsorbed parent drug) and 13 percent was recovered in the urine (of which
