Lipid Lowering Agents Flashcards
5 classes of lipid lowering agents?
Niacin, Fibric Acid Derivatives, Bile Acid Sequestrants, HMG-CoA Reductase Inhibitors, Ezetimbe (inhibits enterocyte absorption of cholesterol in intestine)
Nicotinic acid (niacin) class? MOA? Nicotine is the best agent to do what? It does what as effectively as fibrates as statins? Does it reduce LDL-C levels? So ultimately nicotinic acid is best used for? Side effects? Contraindications?
Water-soluble B complex vitamin (at low doses – lipid-lowering effects are only achieved at much higher levels); MOA: Reduction of liver triglyceride synthesis, leading to less hepatic VLDL (thus, LDL) production; decreases lipolysis in adipose tissue, leading to lowered FFA transport to liver (thus, less triglycerides); reduced hepatic clearance of ApoAI (raising HDL). Best agent to increase HDL (30-40%); as good as fibrates and statins at lowering triglycerides (35-45%); lowers LDL (20-30%); Thus, best used in patients with hypertriglyceridemia and low HDL. Side effects: Flushing, pruritis of face and upper trunk, rashes, acanthosis nigricans (hyperpigmentation), hepatotoxicity, hyperuricemia, hyperglycemia; dyspepsia/reactivation of peptic ulcer disease; rarely, toxic ambylopia, tachyarrhythmias, afib (in elderly) and myopathy – side effects limit compliance to less than 50%. Contraindications: gout, DM.
Fibric acid derivatives (fibrates)?
Clofibrate (no longer available), Fenofibrate, Ciprofibrate, Bezafibrate, Gemifbrozil
Fibrate MOA? Fibrates cause a greatest reduction in? What about the other two main parameters of lipids? As such, what are they best used for? Side effects? Can these be combined with statins?
MOA: Largely unknown – may interact w/peroxisome
proliferator-activated receptor (esp. PPARα) to stimulate LPL synthesis (enhance TGrich lipoprotein clearance); inhibit apoC III expression (enhance VLDL clearance); stimulation of apoAI and apoAII (increase HDL). Marked reduction in VLDL (thus, triglycerides); variable and small effect on LDL; small increase in HDL (10%). Mostly used for patients with severe hypertriglyceridemia. Side effects: Generally tolerated well – Potentiate oral anticoagulants (displace from albumin), increase bile lithogenicity (in older drugs, this caused gallstone formation, but the newer drugs result in much less gallstone formation); myositis flu-like syndrome in 5%, other effects in 10% (not serious). Combination w/statin inadvisable due to higher myositis risks.
Bile acid sequestrants?
Colestipol, Cholestyramine, Colesevelam
Bile acid sequestrats are? MOA? The greatest effect of bile acid sequestrants is to? But, they do this as well? Are these actually safe? What are side effects? These are standard treatment when? When are these contraindicated?
Bile acid sequestrants are very positively charged resins (anion-exchange resins). MOA: Binds negative charged bile acids, inhibiting reabsorption and increasing cholesterol loss –> leads to increase in LDL receptors in
liver (to make more cholesterol), decreasing LDL in blood.
Decrease LDL (25%), but slight increase (5%) in TG and HDL. Very safe (only hypolipidemic indicated for children) because not systematically absorbed!! Side effects: impairs fat soluble vitamin absorption, binds other drugs (e.g., cardiac glycosides, coumarins), bloating, dyspepsia, constipation, gritty/unpleasant taste. Standard treatment in combo w/statin. Contraindicated in
hypertriglyceridemia.
HMG-CoA reductase inhibitors? Which can be taken once a day? When must others be taken & why? Which are prodrugs? Which is combined with niacin (& what is this drug called?) Which is combined with ezetemibe (& what is this drug called?) These drugs cannot be given with? Why?
“statins” – Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin, Rosuvastatin, Pitavastatin (“ros lov sim, flu atorv pita pra”). Once a day: Atorvastatin, Rosuvastatin, Pitavastatin. All others must be taken in the evening b/c hepatic cholesterol synthesis is maximal between mignight and 2 am. Lovastatin & Simvastatin: Lactone prodrug (modified in liver to hydroxy acid form); must be taken in
evening. Advicor = niacin + lovastatin. Vytorin = ezetemibe + simvastatin. Never combine statin + fibrate b/c of increased risk of myositis.
HMG-CoA reductse inhibitors MOA? Uses? Side effects? What is the rule for combining these with other drugs that predispose for myopathy? Contraindicated in?
Inhibits HMG-CoA reductase formation of mevalonate from HMG-CoA; ultimately, leads to decreased cholesterol, which activates SREBP, a membrane-bound transcription factor that increases LDL-R synthesis and lessens degradation…increased LDL receptors allows for increased removal of LDL from the blood; reduction in cholesterol synthesis also decreases VLDL synthesis (cholesterol is needed for VLDL), lowering TG. Uses: Reduce LDL (20-55%) and TG (25%), while increasing HDL (5-10%); treatment of dyslipidemia (reduces fatal & nonfatal CHD, strokes; total mortality reduction is 20%). Side effects: Very few; hepatic dysfunction in 1% (serious hepatotoxicity rare); myopathy/rhabdomyolysis (reduced if factors inhibiting statin catabolism lacking). Combination with predisposing drugs is fine as long as statin is administered at no more than 25% its maximal dose. Contraindicated in pregnant women.
Ezetimibe MOA? Use? Side effects? Has this been studied long-term?
Inhibits enterocyte absorption of cholesterol in
intestine. Decreases LDL-C alone (15-20%) or in
combination w/statin (60%). Inhibits cholesterol absorption by enterocytes in jejunum (70% in mice),
leading to less cholesterol in chylomicrons; reduction in chylomicron remnant cholesterol delivery to liver; may also decrease atherogenesis directly (remnants very atherogenic). Side effects: None (rare allergies) —Long-term decrease in endpoints not seen yet (questionable
effect.
