Agents Used To Treat Hyperlipidemia

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lipoprotein shell components

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phospholipids, free cholesterol, apolipoproteins

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purpose of lipoproteins

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transport lipids from tissue to tissue

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lipoprotein core

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triglycerides and cholesterol esters

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VLDL

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core lipid = triglycerides

Apo B-100, E

delivers TG to nonhepatic tissues

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VLDL & health

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major risk of pancreatitis

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LDL

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core lipid =cholesterol

Apo B-100

delivers ch to nonhepatic tissues

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HDL

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core lipid = cholesterol

Apo A-I, A-II, A-IV

transport CH from nonhepatic tissues back to the liver

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Familial combined hyperlipidemia (type IIb)

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underproduction of LDL-R and overproduction of ApoB-100 => increase in LDL and VLDL

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Familial hypertriglyceridemia (type IV)

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deficit in lipoprotein lipase = can't cleave chylomicrons, transfer FAs to tissues => increase in VLDLs and TGs

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Remnant Removal disease/Familial dysbetalipoproteinemia

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Deficiency in ApoE = can't recycle remnants => increase in VLDLs, IDLs, and chylomicron remnants

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Familial hypercholesteroleia

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decreased LDL-R = increase in LDLs

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Nicotinic acid (niacin/vitamin B3) MOA

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decreases release of free fatty acids by inhibiting hormone sensitive lipase => decreased synthesis of VLDL, decreasing LDL, increasing HDL

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Nicotinic acid overall effect

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decreases VLDL and triglycerides

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nicotinic acid indication

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drug of choice for patients at risk of pancreatitis (lower VLDL levels)

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best formulation of nicotinic acid

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niaspan - extended release form

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Nicotinic acid S/E

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dyspepsia (indigestion), skin flushing, itching, hepatotoxicity (less likely in extended formulas)

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nicotinic acid contraindications

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atrial arrhythmias, peptic ulcers, gout, diabetes, gallbladder dz

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Fibric acid derivatives

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Gemfibrozil and fenofibrate

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Fibrate MOA

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increase peroxisome proliferator activator receptor-alpha (PPAR-alpha) =>incr. metabolism of carbs and fat => incr. lipoprotein lipase => reduce rate of lipogenesis in liver => increase HDL and decrease VLDL

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Fibrate overall effects

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enhance oxidation of FA in liver and muscle, reduce rate of lipogenesis in liver, increase Apo I and II for more HDL, increase size of LDL

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Fibrates chemistry

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small carboxylic acids tightly bound to plasma proteins

eliminated as glucuronide conjugate thru kidney

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Fibrates indications

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decrease VLDL levels and raise HDL-cholesterol levels

patients with elevated plasma triglycerides (VLDLs)

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S/E fibrates

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GI, hepatotoxic, gallstones, displaces warfarin from plasma albumin, incr. risk of statin-induced myopathy (esp. gemfibrozil)

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gemfibrozil issues

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more drug-drug reactions because interferes with glucuronidation of statins

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fenofibrate pros

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longer half life, no statin interaction

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contraindications of fibrates

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preexisting gallstones, renal failure, hepatic dysfxn, hypersensitivity

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Bile Acid-Binding Resins

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Cholestyramine, colestipol, colesevelam

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resin MOA

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prevents reabsorption of bile, so there is an increased demand for cholesterol in liver = increase in LDL-R = decreases LDL and cholesterol in blood

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resins indication

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lowering elevated levels of LDL (15-20% reduction), good combo w/ statins

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resins S/E

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slight increase in triglyceride synthesis

cholestyramine and colestipol = constipation, bloating, decr. uptake of fat soluble vitamins, warfarin, statins and folic acid

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colesevelam S/E

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few GI effects, doesn't interfere w/ vitamin or drug absorption!!

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Statins

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lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, pitavastatin

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structure of statins

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resembles HMG CoA (hydroxymethylglutaryl CoA)

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statin MOA

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inhibit the rate limiting step in cholesterol synthesis = increase LDL receptors in liver = incr. removal of LDL

reduce inflammation (reducing C-reactive protein)

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drug-drug interactions with statins

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simvastatin and lovastatin are metabolized by CYP3A4 - inhibited by azole-antifungal, erythro/clarithromycin

metabolism accelerated with rifampin

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statins with fewer drug-drug interactions?

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fluvastatin, rosuvastatin, pitavastatin, pravastatin

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Asian patients and statins

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rosuvastatin reaches higher plasma levels

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statin indications

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hyperlipidemia, hypertriglyceridemia, lower LDL

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combo therapy

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statins + cholestyramine or colestipol (if drug withdrawn, LDL levels return to previous levels)

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statin + aspirin

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appear to lower the risk of colon cancer and osteoporosis

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statin S/E

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h/a, rash, GI, cognitive changes, hyperglycemia, hepatotoxicity, myopathy

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myopathy S/E

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statins + gemfibrozil or niacin

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statins are..

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teratogens (no for preggers)

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statins given only at bedtime...

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fluvastatin, lovastatin, pravastatin, simvastatin

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treat homozygous familial hypercholesterolemia

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mipomersen, lomitapide, alirocumab, evolocumab

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mipomersen MOA

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binds apoB-100 mRNA, degrades mRNA, prevents apoB-100 synthesis = decrease LDL

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lomitapide MOA

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inhibits microsomal triglyceride transfer protein (MTP), prevents assembly of apo-B100 containing lipoproteins (chylomicrons, VLDL, LDL)

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alirocumamb and evolocumab MOA

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binds and inhibits PCSK9 = allows LDL receptors to remain on the surface and incr. hepatic uptake of LDLs

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PCSK9

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binds LDL-R, promotes receptor recycling and degradation, prevents LDL clearance from the blood

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Cholesterol absorption inhibitor

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ezetimibe

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Ezetimibe MOA

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inhibits intestinal absorption of dietary and biliary cholesterol at the brush border of the small intestine = reduce cholesterol levels in liver, increase LDL-R = reduce plasma LDL

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ezetimibe contraindications

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patients w/ moderate to severe hepatotoxicity, gall bladder disease

absorption interfered with by cholestyramine and colestipol

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ezetimibe often combined with

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statins