Simvastatin

Simvastatin or simvastatin is a drug from the statin family used to lower blood cholesterol levels. Its importance is great, given the importance of cholesterol as a cardiovascular risk factor.

History

It was obtained synthetically from a fermentation product of Aspergillus terreus. Together with the rest of the drugs in the group, it is one of the most beautiful manifestations of modern pharmacology, since they were sought after exactly defining the therapeutic target where they wanted to act. Once it was known, the search for substances that met the requirements for receptor blockade began until the first molecules were found, which were refined until the current statins were achieved.

Description

Simvastatin is a white, crystalline powder that is practically insoluble in water and soluble in chloroform, methanol, and ethanol. It is actually a lactone, and it is its β-hydroxylated metabolite (simvastatin β-hydroxy acid or simvastatin acid) that exhibits pharmacological activity.

Pharmacokinetics

Routes of administration (forms of use)

Orally.

Absorption

It is absorbed orally, without being interfered with this absorption by food. After administration of a single dose, the maximum plasma concentration is reached after two hours.

In elderly patients, the maximum plasma concentration levels are elevated by 45%, which, although it does not have clinical repercussions in usual doses, can be significant with doses close to the maximum studied (120 mg in doses only). The administration of multiple doses does not produce accumulation of the product, therefore a single dose is recommended.

Distribution

Both simvastatin and its β-hydroxy acid metabolite are highly bound to plasma proteins (approximately 95%). It crosses the blood-brain barrier, as well as the placenta, and it is unknown if it appears in the milk of lactating mothers who take the drug.

Metabolism and metabolites

Simvastatin undergoes a strong hepatic first-pass effect, so bioavailability is low (<5%). The major active metabolites of simvastatin present in human plasma are simvastatin β-hydroxy acid and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives. Simvastatin is a CYP3A4 substrate, although it does not seem to act as an inhibitor of it. Thus, its plasma levels can be modified by other CYP3A4 substrate drugs, while the effect is not in the opposite direction. This is very interesting when it comes to understanding some of their interactions.

Co-administration with gemfibrozil increases maximum plasma levels of simvastatin by up to 185%, while co-administration with fenofibrate did not produce changes in them.

Excretion

13% of the dose is excreted in the urine and 60% in the feces.

Pharmacodynamics

Via de la HMG CoA reductasa.

Mechanism of action

Simvastatin β-hydroxy acid is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is a key metabolite in cholesterol biosynthesis. The attached diagram shows the blocking level of statins as well as other substances in the biosynthesis of cholesterol.

The concrete reaction would be

In which an HMG-CoA molecule is reduced by the action of HMG-CoA reductase and the coenzyme NADPH, resulting in mevalonate and CoA. The inhibition of the enzyme is carried out in a competitive, partial and reversible way.

The blockade of the hepatic synthesis of cholesterol causes an activation of the regulatory proteins SREBP (sterol regulatory elements-binding proteins), which activate the transcription of proteins and, therefore, they produce increased expression of the LDL receptor gene and an increase in the number of functional receptors in the hepatocyte.

Effects

As a consequence of HMG-CoA inhibition, total and LDL cholesterol levels decrease, substances closely related to atherosclerosis and increased cardiovascular risk. Apolipoprotein B is also substantially decreased during treatment with simvastatin. In addition, it moderately increases HDL-C and reduces plasma triglycerides. As a result of these changes, the ratio of total cholesterol to HDL cholesterol as well as the ratio of LDL cholesterol to HDL cholesterol are reduced. These effects, as well as their impact on the reduction of cardiovascular risk in general of statins, have been extensively studied through clinical trials:

• Study WOSCOPS (WOSCOPS)West of Scotland Coronary Prevention Study), in 6695 male patients and performed with pravastatin.
• AFCAPS StudyAir Force Coronary Atherosclerosis Prevention Study), with 6605 patients and performed with lovastatin.
• Heart protection study (heart protection study)HPS by heart protection study acronym, with 20,536 patients included.
• Scandinavian Simvastatin Survival Study (4S), with 4,444 patients with coronary heart disease and hypercholesterolemia.^,
• Lower Dose Simvastatine Comparative Studywith 230 patients,
• Upper Dose Simvastatine Comparative Studywith 1097 patients,
• Multi-Center Combined Hyperlipidemia Studywith 372 patients.

Interactions

Pharmacodynamic interactions

As previously discussed, both fibrates and niacin (nicotinic acid) increase the risk of myopathy associated with simvastatin. This is especially important in the case of gemfibrozil, which also interferes with hepatic metabolism at the CYP3A4 level. The studies carried out with fenofibrate suggest that this association would be free of such risk, and no studies have been carried out with other fibrates.

Pharmacokinetic interactions

A large part of the interactions of simvastatin, like the rest of the statins, will be determined by the fact that it is a substrate of CYP3A4. Thus, in relation to hepatic metabolism we can find:

Clinical use

Simvastatin is used to control hypercholesterolemia and to prevent cardiovascular disease. Its use seems to reduce the incidence of Parkinson's disease and dementia, although studies in this field are still incipient.^, Likewise, some authors are studying the usefulness of simvastatin to shorten the duration and intensity of septic shock by altering IL-6 levels. Its possible use in patients with osteoporosis is also being considered, a situation in which it seems that simvastatin improves the formation of new bone.

Clinical trials

Hundreds of studies have been carried out on simvastatin to confirm its efficacy in both primary and secondary prevention of cardiovascular disease, or even to compare it with other lipid-lowering drugs. Due to its statistical power or the quality of the design, we can highlight:

• Study 4S (Scandinavian Simvastatin Survival Study), with 4,444 patients with coronary heart disease and hypercholesterolemia. Where the effectiveness of simvastatin is demonstrated by lowering LDL cholesterol levels and secondary prevention of cardiovascular disease.^,
• Cardiac Protection Study or HPSHeart Protection Study), with 20,536 patients and study of simvastatin at doses of 40 mg/day in 5963 of them, in which it reduced the risk of coronary disease and total cardiovascular events both in diabetics with a history of coronary disease and in which they did not have the antecedent.
• Estudio CHESS (Study CHESS)Comparative HDL Efficacy and Safety Study), performed on 917 patients, comparing simvastatin to atorvastatin at high doses. In this study, better results appear to be found regarding the increase in HDL cholesterol levels with simvastatin than with atorvastatin, with less adverse reactions and a better economic balance for the first.
• Study 3T (Treat-To-Target Study), with 1087 patients with cardiovascular disease and dyslipemia, treated with atorvastatin or simvastatin.
• SCAT Study (SCAT)Simvastatin/Enalapril Coronary Atherosclerosis Trial).
• SEARCH Study (SEARCH Study)the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine tests), comparing low and high doses of simvastatin.
• IDEAL Studythe Incremental Decrease in Endpoints through Aggressive Lipid Lowering trial), comparing atorvastatin and simvastatin in 8888 patients over the age of 80.
• SAFARI study.

Indications

• Hypercholesterolemia.
  • Primary hypercholesterolemia or mixed dyslipidemia.
  • Family hypercholesterolemia homozigota.
• Cardiovascular prevention.
  • Reduction of cardiovascular morbidity in patients with manifest atherosclerotic cardiovascular disease.
  • Reduction of cardiovascular morbidity in patients with diabetes mellitus, with normal or high cholesterol levels.
  • Supplementary treatment to the correction of other risk factors and other cardioprotective treatments.

Adverse effects

For the assessment of adverse reactions (ADRs) the CIOSM criteria will be taken into account.

Contraindications

The following will be absolute contraindications:

• Hypersensitivity to simvastatin or any of the excipients.
• Active hepatopathy or persistent and inexplicable elevations of serum transaminates.
• Pregnancy and breastfeeding.
• Concomitant administration of CYP3A4 potent inhibitors (itraconazole, ketoconazole, HIV protease inhibitors, erythromicin, clarythromycin, telithhromycin and nephazodone).

These will be relative contraindications (it can be taken but special medical supervision will be necessary):

• Elders (age oriented 70 years).
• Kidney failure.
• Hypothyroidism.
• Personal or family history of inherited muscle disorders.
• History of muscle toxicity with a statin or fiberte.
• Alcoholism.
• Concomitant administration of CYP3A4 weak inhibitors.

Introductions

Tablets of 10, 20, 40 and 80 mg.

Among the usual excipients for this product we can find:

• Ascorbic acid. (E300)
• Hidroxibutilanisol.(E320)
• Cellulose microcrystalline. (E460 I)
• Titanium dioxide. (E171)
• Magnesium stearate. (E470 B)
• Hydroxypropylene. (E463)
• Hipromelosa.
• Talco.
• Monohydrate citric acid. (E330)
• Pregelatinized corn starch.
• Lactose monohydrate (anhydrous lactose).
• Red iron oxide. (E172)
• Yellow iron oxide. (E172)
• Glycerol tricetate.
• Crospovidona.