| Drug ID: | D320 |
| Drug Name: | Atorvastatin |
| Synonyms: |
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| Type: | small molecule |
| DrugBank ID: |
DB01076
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| DrugBank Description: |
Atorvastatin, also known as the brand name product Lipitor, is a lipid-lowering drug belonging to the statin class of medications. By inhibiting the endogenous production of cholesterol within the liver, statins lower abnormal cholesterol and lipid levels and ultimately reduce the risk of cardiovascular disease. More specifically, statin medications competitively inhibit the enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) Reductase,[A181421] which catalyzes the conversion of HMG-CoA to mevalonic acid. This is the third step in a sequence of metabolic reactions involved in the production of several compounds involved in lipid metabolism and transport including cholesterol, low-density lipoprotein (LDL) (sometimes referred to as "bad cholesterol"), and very low-density lipoprotein (VLDL). Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD, such as those with Type 2 Diabetes. The clear evidence of the benefit of statin use coupled with very minimal side effects or long term effects has resulted in this class becoming one of the most widely prescribed medications in North America.[A181087, A181406]
Atorvastatin and other drugs from the statin class of medications including [lovastatin], [pravastatin], [rosuvastatin], [fluvastatin], and [simvastatin] are considered first-line options for the treatment of dyslipidemia.[A181087, A181406] Increasing use of the statin class of drugs is largely due to the fact that cardiovascular disease (CVD), which includes heart attack, atherosclerosis, angina, peripheral artery disease, and stroke, has become a leading cause of death in high-income countries and a major cause of morbidity around the world.[A181084] Elevated cholesterol levels, and in particular, elevated low-density lipoprotein (LDL) levels, are an important risk factor for the development of CVD.[A181087,A181553] Use of statins to target and reduce LDL levels has been shown in a number of landmark studies to significantly reduce the risk of development of CVD and all-cause mortality.[A181090,A181093,A181096,A181427,A181475,A181538] Statins are considered a cost-effective treatment option for CVD due to their evidence of reducing all-cause mortality including fatal and non-fatal CVD as well as the need for surgical revascularization or angioplasty following a heart attack.[A181087, A181406] Evidence has shown that even for low-risk individuals (with <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks.[A181397, A181403]
While all statin medications are considered equally effective from a clinical standpoint, [rosuvastatin] is considered the most potent; doses of 10 to 40mg [rosuvastatin] per day were found in clinical studies to result in a 45.8% to 54.6% decrease in LDL cholesterol levels, while atorvastatin has been found to have about one-third of that potency.[A174580,A181409,A181535,A181538,A1793] Potency is thought to correlate to tissue permeability as the more lipophilic statins such as atorvastatin are thought to enter endothelial cells by passive diffusion, as opposed to hydrophilic statins such as [pravastatin] and [rosuvastatin] which are taken up into hepatocytes through OATP1B1 (organic anion transporter protein 1B1)-mediated transport.[A181424,A181460] Despite these differences in potency, several trials have demonstrated only minimal differences in terms of clinical outcomes between statins.[A181438, A181427]
Atorvastatin was first synthesized in 1985 by Dr. Bruce Roth and approved by the FDA in 1996.[T568] It is a pentasubstituted pyrrole[A177415] formed by two contrasting moieties with an achiral heterocyclic core unit and a 3,5-dihydroxypentanoyl side chain identical to its parent compound.[T571] Unlike other members of the statin group, atorvastatin is an active compound and therefore does not require activation.[A177436]
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| PubChem ID: |
60823
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| CasNo: |
134523-00-5
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| Repositioning for NAFLD: |
Yes
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| SMILES: |
CC(C)C1=C(C(=O)NC2=CC=CC=C2)C(=C(N1CC[C@@H](O)C[C@@H](O)CC(O)=O)C1=CC=C(F)C=C1)C1=CC=CC=C1
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| Structure: |
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| InChiKey: |
XUKUURHRXDUEBC-KAYWLYCHSA-N
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| Molecular Weight: |
558.6398
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| DrugBank Targets: |
3-hydroxy-3-methylglutaryl-coenzyme A reductase; Dipeptidyl peptidase 4; Aryl hydrocarbon receptor; Histone deacetylase 2; Nuclear receptor subfamily 1 group I member 3
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| DrugBank MoA: |
Atorvastatin is a statin medication and a competitive inhibitor of the enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis.[A177388,A181421] Atorvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Atorvastatin also reduces Very Low Density Lipoprotein-Cholesterol (VLDL-C), serum triglycerides (TG) and Intermediate Density Lipoproteins (IDL), as well as the number of apolipoprotein B (apo B) containing particles, but increases High Density Lipoprotein Cholesterol (HDL-C).
In vitro and in vivo animal studies also demonstrate that atorvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins.[A181424] This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response.
Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation.[A181559]
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| DrugBank Pharmacology: |
Atorvastatin is an oral antilipemic agent which reversibly inhibits HMG-CoA reductase. It is used to lower total cholesterol, low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), non-high density lipoprotein-cholesterol (non-HDL-C), and trigleride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, atorvastatin reduces the risk of cardiovascular morbidity and mortality.[A174580,A181087,A181406,A181925]
Elevated cholesterol levels, and in particular, elevated low-density lipoprotein (LDL) levels, are an important risk factor for the development of CVD.[A181087] Use of statins to target and reduce LDL levels has been shown in a number of landmark studies to significantly reduce the risk of development of CVD and all-cause mortality.[A181090,A181093,A181096,A181427,A181475] Statins are considered a cost-effective treatment option for CVD due to their evidence of reducing all-cause mortality including fatal and non-fatal CVD as well as the need for surgical revascularization or angioplasty following a heart attack.[A181087, A181406] Evidence has shown that even for low-risk individuals (with <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks.[A174580,A181397,A181403] Clinical studies have shown that atorvastatin reduces LDL-C and total cholesterol by 36-53%.[A177415]
In patients with dysbetalipoproteinemia, atorvastatin has been shown to reduce the intermediate-density lipoprotein cholesterol.[A177397] It has also been suggested that atorvastatin can reduce angiogenesis which can be useful in the treatment of chronic subdural hematoma.[A177388]
**Myopathy/Rhabdomyolysis**
Atorvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is dose-related and is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Chinese patients may also be at increased risk for myopathy. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued.
The risk of myopathy during treatment with lovastatin may be increased with concurrent administration of interacting drugs such as [fenofibrate], [niacin], [gemfibrozil], [cyclosporine], and strong inhibitors of the CYP3A4 enzyme. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with [colchicine], and caution should therefore be exercised when prescribing these two medications together.[F4670,F4673]
Real-world data from observational studies has suggested that 10-15% of people taking statins may experience muscle aches at some point during treatment.[A182258]
**Liver Dysfunction**
Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (> 3 times the upper limit of normal [ULN] occurring on two or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. This effect appears to be dose-related.[F4670,F4673]
**Endocrine Effects**
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.
An in vitro study found that atorvastatin, [pravastatin], [rosuvastatin], and [pitavastatin] exhibited a dose-dependent cytotoxic effect on human pancreas islet β cells, with reductions in cell viability of 32, 41, 34 and 29%, respectively, versus control]. Moreover, insulin secretion rates were decreased by 34, 30, 27 and 19%, respectively, relative to control.[A182012]
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Clinical studies with atorvastatin and other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma cortisol concentration or impair adrenal reserve and do not reduce basal plasma testosterone concentration. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.[F4673]
**Cardiovascular**
Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.[F4673]
**Lipoprotein A**
In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in Lp(a) lipoprotein concentrations. Present knowledge suggests the importance of high Lp(a) levels as an emerging risk factor for coronary heart disease.[F4673] Further studies have demonstrated statins affect Lp(a) levels differently in patients with dyslipidemia depending on their apo(a) phenotype; statins increase Lp(a) levels exclusively in patients with the low molecular weight apo(a) phenotype.[A181418]
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| DrugBank Indication: |
Atorvastatin is approved for the treatment of several types of dyslipidemias including:
- Primary hyperlipidemia and mixed dyslipidemia in adults.
- Hypertriglyceridemia.
- Primary dysbetalipoproteinemia.
- Homozygous familial hypercholesterolemia.
- Heterozygous familial hypercholesterolemia in adolescent patients with failed dietary modifications.[A177397]
Dyslipidemia is defined as an elevation of plasma cholesterol, triglycerides or both as well as to the presence of low levels of high-density lipoprotein. This condition represents an increased risk for the development of atherosclerosis.[L6025]
Atorvastatin is indicated, in combination with dietary modifications, to prevent cardiovascular events in patients with cardiac risk factors and/or abnormal lipid profiles.[A177397]
Atorvastatin can be used as a preventive agent for myocardial infarction, stroke, revascularization, and angina, in patients without coronary heart disease but with multiple risk factors, and in patients with type 2 diabetes without coronary heart disease but multiple risk factors.[A177397]
Atorvastatin can also be used as a preventive agent for non-fatal myocardial infarction, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure and angina in patients with coronary heart disease.[A177397]
Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD. Statin-indicated conditions include diabetes mellitus, clinical atherosclerosis (including myocardial infarction, acute coronary syndromes, stable angina, documented coronary artery disease, stroke, trans ischemic attack (TIA), documented carotid disease, peripheral artery disease, and claudication), abdominal aortic aneurysm, chronic kidney disease, and severely elevated LDL-C levels.[A181087, A181406]
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