Atorvastatin

HMG-CoA reductase inhibitor (statin). Therapeutic class: Antihyperlipidemic

Atorvastatin competitively inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis. This inhibition reduces cholesterol synthesis in the liver, leading to an increase in LDL receptor expression on hepatocyte surfaces. Increased LDL receptors enhance the uptake of LDL cholesterol from the bloodstream, thus lowering LDL-C levels. Atorvastatin also modestly reduces triglycerides and increases HDL-C. The pleiotropic effects are believed to be mediated by improved endothelial function, decreased oxidative stress, and stabilization of atherosclerotic plaques, independent of lipid lowering.

Absorption: Approximately 12% of an oral dose is absorbed. Absorption is influenced by first-pass metabolism in the gut wall and liver. Food decreases the rate, but not the extent of absorption. Distribution: Atorvastatin is highly bound (approximately 98%) to plasma proteins, primarily albumin. It exhibits a large volume of distribution, indicating extensive tissue distribution. Metabolism: Atorvastatin undergoes extensive first-pass metabolism in the liver and gut wall. It is metabolized by cytochrome P450 3A4 (CYP3A4) to active metabolites, including ortho- and para-hydroxylated forms. These metabolites also exhibit HMG-CoA reductase inhibitory activity. Excretion: Approximately 72% of the drug is excreted in feces, primarily as metabolites. Only a small amount (less than 6%) is excreted unchanged in urine. Half-life: The terminal elimination half-life of atorvastatin is approximately 14 hours, but the half-life of its active metabolites is longer, around 20-30 hours. This contributes to its sustained effect.

Atorvastatin reduces total cholesterol, LDL-C, apolipoprotein B, and triglycerides, while increasing HDL-C. The magnitude of these effects is dose-dependent. Beyond lipid effects, atorvastatin can reduce markers of inflammation (e.g., C-reactive protein) and improve endothelial function. It also demonstrates anti-thrombotic effects, potentially reducing the risk of cardiovascular events. The primary pharmacodynamic effect is the reduction in hepatic cholesterol synthesis, leading to decreased circulating LDL-C levels.

• Hyperlipidemia: As an adjunct to diet restrictions to reduce elevated total cholesterol, LDL-C, apolipoprotein B, and triglycerides, and to increase HDL-C. • Primary Prevention of Cardiovascular Disease: To reduce the risk of stroke and myocardial infarction in patients without clinically evident coronary heart disease but with multiple risk factors (e.g., dyslipidemia, age, smoking, hypertension, family history). • Secondary Prevention of Cardiovascular Disease: To reduce the risk of nonfatal myocardial infarction, stroke, and revascularization procedures in patients with established coronary heart disease. • Familial Hypercholesteremia: To reduce total cholesterol and LDL-C in patients with primary (heterozygous) familial hypercholesteremia.

Absolute: • Active liver disease or unexplained persistent elevations in serum transaminases. • Hypersensitivity to atorvastatin or any component of the formulation. Relative: • Conditions predisposing to rhabdomyolysis (e.g., renal impairment, hypothyroidism, advanced age, concomitant use of fibrates). • History of statin intolerance.

Hyperlipidemia: Initial dose is typically 10-20 mg once daily. Dosage adjustments are made based on LDL-C levels and response, up to a maximum of 80 mg daily. Primary Prevention of Cardiovascular Disease: 20-40 mg once daily, based on individual risk profile. Secondary Prevention of Cardiovascular Disease: 40-80 mg once daily, particularly in patients with high-risk features. Familial Hypercholesteremia: Higher starting doses (e.g., 40-80 mg daily) are often required, with titration based on LDL-C response.

Pediatric: Safety and efficacy in children with heterozygous familial hypercholesteremia have been established. Dosing is weight-based and adjusted based on LDL-C response. Geriatric: No dosage adjustment is typically required, but lower starting doses may be considered due to increased risk of adverse effects. Renal impairment: Dose adjustments are generally not necessary in mild to moderate renal impairment. Caution is advised in severe renal impairment, and lower doses should be considered. Hepatic impairment: Contraindicated in active liver disease. Caution and lower doses are recommended in patients with a history of liver disease.

Common (>10%): • Myalgia (muscle pain) - most common; often mild and transient. • Nasopharyngitis (common cold) • Diarrhea • Headache • Arthralgia (joint pain) Serious (<1%): • Rhabdomyolysis - rare but potentially life-threatening muscle breakdown. • Liver enzyme elevations - can indicate hepatotoxicity. • New-onset diabetes mellitus – increased risk observed in some studies.

• Gemfibrozil/Fibrates: Increased risk of myopathy and rhabdomyolysis. • Cyclosporine: Significantly increases atorvastatin exposure, increasing risk of myopathy. • Erythromycin/Clarithromycin: Inhibits CYP3A4, increasing atorvastatin levels. • Azole antifungals (e.g., ketoconazole, itraconazole): Inhibits CYP3A4, increasing atorvastatin levels. • Grapefruit juice: Inhibits CYP3A4, increasing atorvastatin levels. • Warfarin: May increase INR and bleeding risk (monitor INR closely).

• Myopathy/Rhabdomyolysis: Monitor for muscle pain, tenderness, or weakness, especially in patients with risk factors. Discontinue if myopathy is suspected. • Liver Enzyme Elevations: Monitor liver function tests periodically, especially during the first few months of therapy. • New-Onset Diabetes: Monitor for signs and symptoms of hyperglycemia, particularly in patients with risk factors for diabetes. • Cognitive Impairment: There have been reports of memory loss and cognitive dysfunction, although a causal relationship has not been definitively established.

Pregnancy: Atorvastatin is contraindicated during pregnancy (FDA Pregnancy Category X) due to potential harm to the fetus. It can cause birth defects. Lactation: Atorvastatin is excreted in human breast milk. It is not recommended during breastfeeding.

• Lipid panel (total cholesterol, LDL-C, HDL-C, triglycerides): Monitor at baseline and periodically to assess treatment efficacy. • Liver function tests (ALT, AST): Monitor at baseline and periodically, especially during the first few months of therapy. • Creatine Kinase (CK): Monitor if patients report muscle symptoms. • Fasting blood glucose/HbA1c: Monitor for signs of new-onset diabetes.

• Explain the importance of adhering to diet and lifestyle recommendations in conjunction with atorvastatin therapy. • Instruct patients to report any muscle pain, tenderness, or weakness immediately. • Advise patients to inform their healthcare provider of all medications they are taking, including over-the-counter drugs and supplements. • Counsel patients about the potential for liver enzyme elevations and the importance of periodic monitoring. • Explain that atorvastatin is a long-term medication and requires consistent use to achieve its benefits.

Store at room temperature (15-30°C, 59-86°F) away from light and moisture. Keep out of reach of children.

• Consider genetic testing for variations in SLCO1B1 gene, which can influence atorvastatin metabolism and risk of myopathy. • In patients with high triglyceride levels (>500 mg/dL), consider initiating therapy with a fibrate or omega-3 fatty acids *before* starting atorvastatin to reduce the risk of pancreatitis. • Ensure patients understand the difference between statin intolerance (true allergic reaction) and statin-associated muscle symptoms (SAMS).

• Rosenson RS, et al. 2019 AHA/ACC Guideline on the Management of Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):3235-3271. • National Center for Biotechnology Information. PubChem Compound Summary for CID 6627. https://pubchem.ncbi.nlm.nih.gov/compound/Atorvastatin. • Lipitor [package insert]. New York, NY: Pfizer; 2023.