CVS - Lipid Lowering Drugs Flashcards
Classes of lipid lowering drugs used & examples
- HMG-CoA Reductase Inhibitors (Statins - Simvastatin)
- Fibrates (Gemfibrozil, Fenofibrate)
- Niacin (Nicotinic acid, Vitamin B3)
- Bile Acid Sequestrants (Bile Acid-Binding Resins - Colestipol, Cholestyramine)
+ Diet, Exercise
Mechanism of action of statins
Reduces cholesterol synthesis + increases peripheral clearance of cholesterol
- Competitive inhibition of HMG-CoA reductase (rate limiting step in cholesterol synthesis)
- Depletion of intracellular cholesterol - increased number of LDL receptors - increased LDL uptake - lowers plasma LDL
Uses of statins (2)
- Hyperlipidemia - lowers plasma cholesterol levels
2. Ischemic Heart Disease - reduces risk of coronary events & mortality
Toxicity of statins (3+3)
Most common
- GIT-related (cramps, dyspepsia, flatulence, constipation)
- Headache
- Rash
Serious but rare
- Myotoxicity
- Hepatotoxicity
- Lenticular Opacities - Cataracts
Contraindications of statins (3)
- Drug Interactions
- CYP3A4 Inhibitors (eg erythromycin) - increases blood levels of simvastatin
- Amlodipine (CCB, anti-HTN) - increases risk of simvastatin toxicity - should reduce dose
- Fibrates - increased incidence/severity of muscle/liver injury & renal damage - Pregnant/lactating mothers - can enter breast milk
- Children/teenagers - HMG-CoA reductase is important for development - morphological defects
Mechanism of action of fibrates
Increases peripheral clearance of VLDL
- Binds to nuclear PPAR-α (mainly in liver & brown adipose tissue)
- Enhances synthesis & activity of endothelial LPL - increased breakdown of plasma TGs + clearance of VLDL
- Induces increased apolipoproteins I & II production - facilitates hepatic production of HDL - increases HDL
Uses of fibrates (1)
Hypertriglyceridemia associated with VLDL elevation, esp dysbetalipoproteinemia
Toxicity of fibrates (6) + Contraindications (1)
- GIT-related (nausea, abdominal pain)
- Musculoskeletal (backache)
- Skin Rash
- Rhabdomyolysis/Myositis - tender, weak muscles
- Hepatotoxicity - Gemfibrozil
- Gall Stones - long term
- Warfarin - displaced from plasma protein binding - bleeding
Mechanism of action of niacin
Reduces VLDL production
- Reduces hepatic lipase activity - decreased liver VLDL production - decreased IDL - decreased LDL
- Inhibits lipolysis in adipose tissue + enhances LPL activity (increased TG breakdown) - lowers plasma TG & LDL
- Increases HDL-cholesterol levels
- Decreases circulating fibrinogen & increases tissue plasminogen activator - less risk of thrombosis (associated with hypercholesterolemia & atherosclerosis)
Uses of niacin (2)
- Hyperlipoproteinemia type IIb & type IV
2. Thrombosis associated with hypercholesterolemia & atherosclerosis
Toxicity of niacin (4) + Contraindications (3)
- Intense (facial) cutaneous flush + Pruritus (esp with immediate release prep) - mediated by PGs, minimise by pre-treating with aspirin
- GIT-related (nausea, vomiting, diarrhea)
- Hepatotoxicity - more with long acting prep Niaspan
- Metabolic disorders (hyperuricemia & gout, hyperglycemia) - rare
- Hepatic Disease
- Gout/Hyperuricemia
- Diabetes Mellitus
Mechanism of action of resins
Decreases fat absorption
- Cationic resins bind to negatively charged bile acids/salts in the small intestine - prevents reabsorption into hepatocytes
- Hepatocytes generate more bile acid via hydroxylation of cholesterol - depletes intracellular cholesterol conc
- Compensatory upregulation of LDL receptors - increased hepatic uptake of cholesterol-containing LDL - decreased plasma LDL
Uses of resins (2)
- Primary Hypercholesterolemia (type IIa)
2. Combined Hyperlipoproteinemia (type IIb) (+niacin)
Toxicity of resins (2)
- GIT-related (constipation, abdominal discomfort, nausea, vomiting, flatulence)
- Impaired absorption of fat soluble vitamins A, D, E, K and folic acid
