Pravastatin and Statin Metabolism Quiz

Pravastatin Metabolism

• Pravastatin undergoes minimal first-pass metabolism, unlike lipophilic statins.
• First-pass metabolism reduces bioavailability of lipophilic statins.
• Rosuvastatin has minimal CYP metabolism and is primarily excreted unchanged.

Statin Interactions

• Atorvastatin is metabolized by CYP3A4, making it susceptible to grapefruit juice interactions.
• Lovastatin and simvastatin are prodrugs hydrolyzed to active beta-hydroxy acid forms in the liver.

Bile Acid Sequestrants

• Bind bile acids in the gut, preventing reabsorption.
• Force the liver to convert cholesterol to bile acids, reducing LDL-C.
• Common side effect is gastrointestinal discomfort, especially constipation.

Nicotinic Acid

• Decreases lipolysis in adipose tissue, reducing free fatty acid availability.
• Nicotinamide lacks lipid-modifying effects of nicotinic acid.
• Sustained-release niacin increases hepatotoxicity risk.

Flushing and Vasodilation

• Flushing is associated with prostaglandin-mediated vasodilation.
• Flushing occurs due to prostaglandin conjugation pathway to nicotinuric acid.
• Sustained-release niacin produces metabolites linked to hepatotoxicity.

Omega-3 Fatty Acids

• EPA reduces hepatic VLDL synthesis, lowering triglycerides effectively.
• Omega-3 fatty acids reduce triglycerides by decreasing hepatic VLDL production.

PCSK9 Inhibitors

• Indicate for patients with homozygous familial hypercholesterolemia or clinical ASCVD.
• Evolocumab is FDA approved for clinical ASCVD and familial hypercholesterolemia.
• PCSK9 inhibits LDL receptor degradation, increasing LDL-C clearance.
• Inclisiran reduces circulating PCSK9 by silencing PCSK9 production.

Bempedoic Acid

• Bempedoic acid is activated in the liver, reducing LDL-C without muscle activation.
• Avoids muscle-related side effects due to liver-specific activation and lack of muscle uptake.
• Phase I metabolism (oxidation, hydroxylation, or reduction) is often mediated by CYP450 enzymes.

Phase II Metabolism

• Phase II involves conjugation (glucuronidation or sulfation), making drugs more water-soluble for excretion.
• Rosuvastatin and fluvastatin primarily metabolized by CYP2C9.
• Ezetimibe undergoes glucuronidation in the intestinal wall and liver, forming an active metabolite.

Drug Contraindications and Risk Factors

• Statins and fibrates are contraindicated in pregnancy, lactation, and patients with active liver, gallbladder, or kidney disease.
• Gemfibrozil inhibits glucuronidation, increasing myopathy risk.
• Grapefruit juice inhibits CYP3A4, increasing plasma levels of lipophilic statins.
• Chronic kidney disease impairs drug clearance, increasing statin-induced myopathy risk.
• Primary prevention aims to reduce ASCVD risk in patients without established disease but with high LDL-C or risk factors.
• Secondary prevention involves managing patients with established ASCVD.
• Clinical ASCVD includes coronary artery disease, stroke, and peripheral artery disease not isolated hypertriglyceridemia.
• LDL-C reduction is the main focus in dyslipidemia treatment due to its strong correlation with ASCVD risk.

Statistical Data

• Studies show a 20% reduction in ASCVD risk for every 1 mmol/L (38.7 mg/dL) decrease in LDL-C.
• Patients with LDL-C ≥190 mg/dL fall into severe hypercholesterolemia and benefit from high-intensity statins regardless of ASCVD risk.

Study Recommendations

• Class I recommendations are supported by strong evidence, outweighing risks.
• Class C recommendations are based on limited data or consensus.
• High-risk ASCVD patients require LDL-C ≤70 mg/dL.
• Diabetic patients aged 40-75, with additional ASCVD risk factors, should receive high-intensity statin therapy.
• PCSK9 inhibitors are recommended for very high-risk ASCVD patients.
• Adding ezetimibe is recommended if LDL-C remains ≥100 mg/dL after high-intensity statin therapy.

Severe Hypertriglyceridemia

• Fibrates or omega-3 fatty acids are first-line options.
• In moderate hypertriglyceridemia, LDL-C reduction with statins are prioritized.
• Statin therapy effectiveness is monitored with liver function tests and CK levels when muscle symptoms are present.
• A ≥50% reduction in LDL-C indicates effective high-intensity statin therapy.
• Hydrophilic statins (pravastatin, rosuvastatin) have a lower muscle-related side effect risk.
• Soluble fiber improves lipid profiles by reducing LDL-C.