Lipid drugs Flashcards
Niacin (Niaspan)
Class: Nicotinic acid
Mech: 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)
Thera: BEST AGENT to increase HDL (30-40%); as good as fibrates and statins at lowering triglycerides (35-45%); lowers LDL (20-30%); hypertriglyceridemia and low HDL
Important SE’s: Flushing, pruritis of face and upper trunk, rashes, acanthosis nigricans (hyperpigmentation)
Other SE’s: Hepatotoxicity, hyperuricemia, hyperglycemia; dyspepsia/reactivation of peptic ulcer disease; rarely, toxic ambylopia, tachyarrhythmias, a-fib (in elderly) and myopathy
Misc: Water soluble B vitamin complex at [low]; hypolipidemic at [high]; side effects limit compliance (<50% eligible patients follow on it); contraindicated in DM and gout patients; prevent flushing and pruritus with ASA
Clofibrate (Atromid-S)
Class: Fibric Acid Derivatives (Fibrates)
Mech: Unknown; may interact w/peroxisome proliferator-activated receptor (esp. PPARα) to stimulate LPL synthesis (enhance TG-rich lipoprotein clearance); inhibit apoC III expression (enhance VLDL clearance); stimulation of apoAI and apoAII (increase HDL)
Thera: Marked reduction in VLDL (thus, triglycerides); variable and small effect on LDL; small increase in HDL (10%); severe hypertriglyceridemia
Important SE’s: Potentiate oral anticoagulants (displace from albumin), increase bile lithogenicity; myositis flu-like syndrome in 5%, other effects in 10% (not serious)
Misc: Combination w/statin inadvisable due to higher myositis risk
Gemfibrozil (Lopid)
Class: Gemfibrozil (Lopid)
Mech: Unknown; may interact w/peroxisome proliferator-activated receptor (esp. PPARα) to stimulate LPL synthesis (enhance TG-rich lipoprotein clearance); inhibit apoC III expression (enhance VLDL clearance); stimulation of apoAI and apoAII (increase HDL)
Thera: Marked reduction in VLDL (thus, triglycerides); variable and small effect on LDL; small increase in HDL (10%); severe hypertriglyceridemia
Important SE’s: Potentiate oral anticoagulants (displace from albumin), increase bile lithogenicity (less than clofibrate); myositis flu-like syndrome in 5%, other effects in 10% (not serious)
Misc: Combination w/statin inadvisable due to higher myositis risk
Fenofibrate (Tricor)
Class: Fibric Acid Derivatives (Fibrates)
Mech: Unknown; may interact w/peroxisome proliferator-activated receptor (esp. PPARα) to stimulate LPL synthesis (enhance TG-rich lipoprotein clearance); inhibit apoC III expression (enhance VLDL clearance); stimulation of apoAI and apoAII (increase HDL)
Thera: Marked reduction in VLDL (thus, triglycerides); variable and small effect on LDL; small increase in HDL (10%); severe hypertriglyceridemia
Important SE’s: Potentiate oral anticoagulants (displace from albumin), increase bile lithogenicity (less than clofibrate); myositis flu-like syndrome in 5%, other effects in 10% (not serious)
Misc: Combination w/statin inadvisable due to higher myositis risk
Colestipol (Colestid); Cholestyramine (Questran); Colesevelam (Welchol)
Class: Bile acid sequestrants
Mech: Very positively charged resins 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
Thera: Decrease LDL (25%), but slight increase (5%) in TG and HDL
Important SE’s: Very safe (only hypolipidemic indicated for children) because not systematically absorbed; impairs fat soluble vitamin absorption, binds other drugs (e.g., cardiac glycosides, coumarins)
Other SE’s: Bloating, dyspepsia, constipation, gritty/unpleasant taste
Misc: Standard treatment in combo w/statin; contraindicated in hypertriglyceridemia
Lovastatin (Mevacor)
Class: HMG-CoA reductase Inhibitors (statins)
Mech: Inhibits HMG-CoA reductase formation of mevalonate; leads to activation of SREBP, a membrane-bound transcription factor that increases LDL-R synthesis and lessens degradation; reduction in cholesterol decreases VLDL synthesis, lowering TG
Thera: 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%)
Important SE’s: Very few; hepatic dysfunction in 1% (serious hepatotoxicity rare); myopathy/rhabdomyolysis (reduced if factors inhibiting statin catabolism lacking)
Misc: Lactone prodrug (modified in liver to hydroxy acid form); must be taken in evening; Advicor = niacin + lovastatin; 1. reduces susceptibility to LDL-C oxidation 2. cardioprotective effects 3. counters osteoporosis
Differences between lovastatin and Simvastatin (Zocor)
Pravastatin (Pravachol); Fluvastatin (Lescol)
Atorvastatin (Lipitor); Rosuvastatin (Crestor); Pitavastatin (Livalo)?
Misc for simvastatin: Lactone prodrug (modified in liver to hydroxy acid form); must be taken in evening; Vytorin = ezetemibe + simvastatin;
Misc for pravastatin and fluvastatin: Must be taken in evening;
Misc for last three: Due to longer half-life, can be taken anytime per day
Ezetimbe (Zetia)
Class: Inhibits enterocyte absorption of cholesterol in intestine
Mech: Decreases LDL-C alone (15-20%) or in combination w/statin (60%)
Thera: 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)
Important SE’s: None (rare allergies)
Misc: Long-term decrease in endpoints not seen yet (questionable effectiveness); combine with statin = Vytorin;
Lipoproteins contain ____ that provide
apolipoproteins;
- structural stability to the lipoprotein particle
- needed for assembly and secretion
- act as ligands for specific cell surface receptors or as cofactors in enzymatic reactions
What combines with what to get chylomicrons? What is the liver doing? What is reverse cholesterol transport?
- Cholesterol and triglycerides can combine with proteins to form chylomicrons in the gut wall; go into circulation and send TG’s to adipose and muscle tissue with LPL in vascular endothelial cells; remnant sends cholesterol to liver
- Liver makes VLDL from same components, and these send TG’s to adipose and fat, same manner as chylomicrons, but are converted to IDL and cholesterol-rich LDL; LDL can send cholesterol to atheromas and they are oxidized and eaten by macrophages and you get foam cells (LDL goes to liver, binds LDL receptors, and lipoprotein particle broken down into aa’s and free cholesterol, and cholesterol decrease HMG-CoA reductase activity, the rate-limiting enzyme in cholesterol synthesis, then cholesterol activates ACAT which esterifies free cholesterol into cholesterol ester for storage; then cholesterol inhibits transcription of gene encoding LDL-R to decrease uptake of cholesterol
- HDL particles made by gut and liver to use plasma LCAT to take cholesterol from tissues and atheromas to send to liver
Atherosclerosis process
- endothelial injury
- LDL accumulation and oxidation
- blood monocytes adhere, becoming macrophages
- macrophages phagocytose oxidized LDL to become foam cells
- Platelets then adhere
- smooth muscle cells migrate and deposit collagen
- get necrosis and plaque lysis
Some secondary causes of hyperlipidemia; polygenic-environ hyperlipidemia?
- Hypothyroidism
- Cholestasis
- Hypopituitarism
- Anorexia, early nephrosis, corticosteroid excess others;
serum LDL cholesterol, HTN, AGE!!!, smoking (risk goes up as serum cholesterol passes 200 mg/dL)
As we age, lipid levels; therapeutic strategies include
go up…;
- Diet (get normal body weight and minimize plasma lipids)
- Other lifestyle changes: HDL is anti-atherogenic (it is involved in reverse cholesterol transport to remove cholesterol from artery walls; protects against endothelial dysfunction; inhibits oxidation of atherogenic lipoproteins)
How can HDL go up? go down?
- estrogens 2. exercise 3. leanness 4. alcohol 5. familial hyperalphaproteinemia 6. antihyperlipidemic drugs;
- androgens 2. puberty for males 3. obesity 4. cig smoking 5. familial HDL deficiency 6. type II diabetes mellitus 7. hypertriglyceridemia
