Simvastatin is used to lower the cholesterol level in the blood such as the low-density lipoprotein (LDL) and triglycerides and to raise the high-density lipoprotein (HDL), It decreases the risk of heart diseases and helps to prevent the heart attacks and strokes by reducing the amount of cholesterol that is made by the liver (Raleys.com, 2015).
Chemical structure and functional groups
Simvastatin is one of the statins derivatives that is synthesised from a fermentation product of Aspergillus terreus. The simvastatin is an inactive lactone which is hydrolysed to the ??-hydroxyacid form when it is taken orally. ??-hydroxyacid form is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA) reductase. This enzyme catalyses the conversion of HMG-CoA to mevalonate. Mevalonate is an early step in the biosynthesis of cholesterol.
Simvastatin is butanoic acid. Its molecular weight is 418.57g/mol; its molecular structure is C25H38O5 as it is shown in figure1.The functional group in Simvastatin are ester, secondary alcohol and lactone groups.
IUPAC name of simvastatin is 2,2-dimethyl-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester,[1S-[1??,3??,7??,8??(2S*,4S*),-8a??]] (Pubchem.ncbi.nlm.nih.gov, 2015).
Figure1: The chemical structure of simvastatin.
The mode of action
Statins are competitive inhibitors HMG-CoA reductase, it has been considered as a first line for the treatment of hypercholesterolemia. Their mode of action is by mimicking the substrate molecule HMG-CoA and competes for binding to the HMGCR enzyme. It works by slowing the production rate of mevalonate which responsible for the production of cholesterol molecule.
Most of the cholesterol synthesis in the body is done by internal mechanism through the liver cells particularly at night during fasting; it is taken at night to inhibit the cholesterol production. It maximizes its inhibitory effect and the data shows a significant fall in the LDL and a fall in the total cholesterol level in the blood.
Simvastatin can have different pharmacological effects from other statins groups due to different ring structures and chemical side groups such as different affinity toward the receptors, different rates of connection to liver cells from non-liver cells, different bioavailability and biochemical metabolism and execration. All these factors affect its half-life which is short (Anon, 2015).
Statins are selective towards the hepatic cells because of their lipophilic properties. It passes through the membrane towards the cell type.
In recent years many data has shown that simvastatin binds reversibly to HMGCR enzyme because its affinity can be considered as nano-molar range. However, its affinity shows approximately 10,000 times higher for the natural substrate molecule within the micro-molar range. The affinity is encountered due to the bonding interactions between the statin and the HMGCR enzyme at the active site (Atrainceu.com, 2015).
Pharmacodynamic and pharmacokinetic
The pharmacogenomics of statins medicine is presented by gene involvement in mediating the pharmacodynamic effects of statins on plasma lipoprotein metabolism and pharmacokinetics effects of the drug transport and metabolism.
The pharmacodynamic of statin drugs is by inhibition of the enzyme HMG CoA reductase of cholesterol metabolism in the liver, it works by selecting gene that can modify the statin effect on metabolism and transport of the lipoprotein in the plasma. The general research shows the elevated levels of LDL and the decreased levels of HDL are associated with the development of atherosclerosis and the increase of cardiovascular diseases risks. By lowering the LDL levels decreases these risks (RxList, 2015).
The pharmacokinetic of statin drugs is by taking the dose orally then the drug enters the systemic circulation from the intestinal cells by both passive and active transport via ABC (ATP Binding Cassette) and SLC (Solute Carrier) gene family transporters. The hydrophobicity of each individual statins affects the pharmacokinetic pathway. The more hydrophilic compounds, it moves via active transport to the liver, the lesser metabolized by CYP (Cytochrome p450) and the more excreted via the kidney. While the hydrophobic compounds such as simvastatin diffuses by passive pathway and it is the substrate for CYP enzymes and transported in the bile excretion (PharmGKB, 2015).
The liver organ is the major site for satins metabolism and elimination which is occurring by CYP and UGT (Glucuronosyl transferase) gene family enzymes and by biliary excretion (ABC transporter) respectively. In respect to the kidney and the elimination pathway, it has a much lesser extent.
The endogenous cholesterol synthesis is naturally a cyclical process and it is greatest during prolong fasting. The elimination half-life of statins is determined whether the dose should be taken at bed time. Simvastatin half-life is less than 5 hours. To maximize its effect, the night-time dose is better in lipid lowering because it allows the greatest drug concentration during the highest peak of endogenous cholesterol synthesis. However, the other statins derivatives with the long half-life are more flexibly in their administration time (Gpnotebook.co.uk, 2015) (Pharmacologyweekly.com, 2015).
Use in Practice
Simvastatin is used as a first line to treat Primary hypercholesterolemia, heterozygous or homozygous familial hypercholesterolemia or combined hyperlipidemia in individuals who are not responding to dietary changes, prevent of coronary events and its complications, slow the development of coronary atherosclerosis in individuals with coronary heart diseases (Statin Use Associated With Reduced Risk of Liver Cancer Among Those in the UK, 2015).
Who should take simvastatin
‘ Suffer from a history of CVD, include angina, acute myocardial infarction, acute coronary syndrome, stroke, transient ischemic attack (TIA) and peripheral arterial disease.
‘ suffer from a monogenic lipid disorder such as familial hypercholesterolemia (FH).
‘ Age up to 84 years and who have a 10 years risk of cardiovascular diseases of 10% or more as measured by the QRISK2 risk assessment tool.
‘Type1 diabetes mellitus, aged over 40 years or who have diabetes mellitus for more than 10 years suffer from nephropathy or who are in great risk to cardiovascular diseases.
However, in some clinical conditions statins should be indicated without the estimation to the cardiac risk factors which involve individuals who:
‘Have diabetes mellitus and additional risk factors such as hypertension, metabolic syndrome, total cholesterol level more than 6mmol/L and a strong family history.
‘Have renal dysfunction such as diabetic nephropathy.
‘Aged 40-74 years are under high risk (Raleys.com, 2015).
Major side effect
Rhabdomyolysis such as muscle damage or destruction, the outcome could lead to acute kidney failure and liver damage (RxList, 2015).
Common side effect
Nose bleeding, sore throat, runny or blocked nose, headache, feeling sick, digestive system problem such as (constipation, diarrhea, indigestion, hyperglycemia and increased risk of diabetes (Nhs.uk, 2015).
‘ Stop taking the medicine immediately if the patient felt one of these symptoms: muscle pain or tenderness or weakness especially if it combined with fever, tiredness and dark colored urine.
‘Taking simvastatin with the doctor instruction, because taking large doses of the medicine leads to life threating diseases from statins serious side effects.
‘ Statins interact with over the counter (OTC) medicines such as nexium (esomeprazole), vitamins and herbals.
‘The patients should consult their doctor before taking statins, if they suffer from: liver or kidney diseases, diabetes, thyroid disorder, and Chinese descent, drink more than 2 alcoholic beverages per day.
‘ Statins should be avoided for pregnant women and during lactation because it could harm the baby.
‘ Stains show an interaction with grapefruit juice which could lead to dangerous effects (RxList, 2015).
‘To make the medicine works much better should change the life style such as eating a low fat diet, exercise, try to lose weight for overweight patients and stop smoking and consumption of alcohol Dosage
‘The usual dose range from 5-40mg per day.
‘Patients with Coronary Heart Diseases (CHD), starting dose is 10-20mg per day at bed time.
‘Patients of high risk of CHD with diabetes, peripheral vessel disease, history of stroke and cerebrovascular diseases, starting dose is 40mg per day.
‘Dosing 80mg per day should be restricted due to statins serious side effects such as Rhabdomyolysis.
‘ Statins tolerance patients should be switched to an alternative statins which should be effective as lowering cholesterol agents (RxList, 2015).
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