Lipid Lowering Drugs

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Drug class of Cholestryamine

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bile acid sequestrant

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Cholestyramine

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Questran, colestipol

bile acid sequestrant

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Therapeutic class of Cholestryamine

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cholesterol lowering agent

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Pharmacodynamics of Cholestryamine

(bile acid sequestrant)

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forms a non-absorbable complex with bile acids in small bowel (releasing Cl)

inhibits enterohepatic reuptake of intestinal bile salts

increases fecal loss of bile acids --> increases bile synthesis --> increases cholesterol synthesis --> increases expression of LDL receptors on cell surface of hepatocytes!!!!!! --> reduces LDL cholesterol by 10-20%

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Pharmacokinetics of Cholestryamine

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virtually no absorption

excreted in feces

peak effect noted in about 3 weeks

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Toxicity of Cholestryamine

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greater than 10% of patients have GI problems including gas, bloating, diarrhea

may interfere with absorption of fat-soluble vitamins

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Drug interactions with Cholestryamine

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may diminish absorption of statins, steroids, digoxin, warfarin

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Special issues of Cholestryamine

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provided as a powder for oral suspension

be sure to drink liquids of it

(this can cause low compliance)

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Dose of cholestryamine

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4 grams once a day, up to 6 times per day

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Nicotinic acid

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Niacor

cholesterol lowering agent

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Pharmacologic class of Nicotinic acid

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its a vitamin

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Therapeutic class of nicotinic acid

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its a cholesterol lowering agent

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Pharmacodynamics of Nicotinic Acid

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lowers both TG and LDL cholesterol

decreases the production of VLDL --> decreases production of LDL --> INCREASES LDL RECEPTOR IN THE LIVER


modestly effective as a single agent, usually used in combination

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Pharmacokinetics of Nicotinic Acid

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Nicotinic acid (a vitamin) is well absorbed

Has a large first pass effect (to nicotinamide)

Tmax: 45 minutes

Half life: 45 minutes

Urinary excretion of unchanged drug and metabolite

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Toxicity of Nicotinic acid

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many patients develop skin flushing...this skin flushing can be lessened by taking aspirin

Some patients even develop hepatitis (think first pass effect)

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Interactions with other drugs using Nicotinic Acid

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the absorption is decreased by cholestryamine

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Interactions of nicotinic acid with other drugs

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absorption decreased by cholestryamine

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Special issues with nicotinic acid

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in 1930's found to be a vitamin (B3) that cured pellegra; renamed niacin in 1940s;

partically converted in the body to nicotinamide, which is NOT active in lowering lipids, but is active in forming NAD

avoid in patients with CAD and heavy ethanol use

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Dose of nicotinic acid

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pellegra use 100mg tid

hyperlipidemia use 0.5-2 gm tid after meals

realize that you use A LOT more for hyperlipidemia

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Gemfibrozil

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Lopid, Clofibrate, Atromid

fibric acid derivative

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Drug class of Gemfibrozil

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Pharm: fibric acid der.

Therapeutic: lipid lowering agent

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Pharmacodynamics of Gemfibrozil

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cellular mechanism remains unclear (probably related to inhibiting lipolysis and decrease hepatic fatty acid uptake, inhibits hepatic secretion of VLDL)

produces slight reduction in LDL-cholesterol leves (~4%)

MOST USEFUL in treatment of hypertriglyceridemia in types IV and V hyperlipidemia (31%)

may increase HDL-chol (6%)

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Pharmacokinetics of Gemfibrozil

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well absorbed

oxidized in liver to two inactive metabolites

half life is 1-2 hours

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Toxicity of Gemfibrozil

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elevation of LFTs

myositis

GI distress

Avoid in patients with renal, hepatic, or biliary tract disease

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Interactions of Gemfibrozil and other drugs

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effects increased with statins, buy may potential toxicity (liver, muscle) as well

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Indications and dose/route of Gemfibrozil

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600 mg po twice daily

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Lovastatin

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Mevacor

Atorvastatin (Lipitor)

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Drug class of Lovastatin

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Pharm: LACTONE

Therapeutic class: cholesterol lowering drug

primary and secondary prevention of CAD

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Pharmacodynamics of Lovastatin

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parent drug is transformed to an active metabolite, which inhibits HMG-CoA reductase, the early and rate-limiting step in the synthesis of cholesterol

Inhibition is not complete...LEADS TO UP-REGULATION OF LDL RECEPTORS ON HEPATOCYTES

leads to reduction in LDL-chol (10-50%), increase in HDL (small)

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Pharmacokinetics of Lovastatin

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about 30% absorbed

onset of action is 3 days

Peak effects in several weeks

Excreted in feces

Metabolized primarly by CYP 3A4 (which is used to metabolize a LOT of things)

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Toxicity of Lovastatin

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check LFTs and CPK during first year of use, because of risk of hepatitis, myopathy, myositis

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Lovastatin and its interactions with other drugs

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additive effects with cholestryamine, nicotinic acid, ezetimibe

Gemfibrozil and niacin may increase risk of myopathy

Erythromycin and others may inhibit CYP 3A4 metabolism, thereby causing increased accumulation and toxicity

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Special consideration of Lovastatin

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avoid in patients with pre-existing hepatitis, muscle disease, and PREGNANCY (X)!!!!

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Indications and dose/route of Lovastatin

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20 mg po daily, with dinner, may increase to 80 mg po daily, or switch to more potent statin

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Ezetimibe

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Zetia

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Drug class of Ezetimibe

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Pharm class: 2 azetidinone compound

Ther class: cholesterol absorption inhibitor

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Pharmacodynamics of Ezetimibe

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selectively blocks the intestinal absorption of cholesterol and related phytosterols, by acting at the level of the small bowel brush border

causes reduction of hepatic cholesterol stores and INCREASE IN THE BLOOD CLEARANCE OF CHOLESTEROL
(upregulates the LDL receptors in hepatocytes)

when used as monotherapy, can lower LDL-chol by up to 18%

often used with statin

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Pharmacokinetics of Ezetimibe

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given orally

Tmax 4-12 hours

extensively metabolized to the glucoronide

F 35-60%

diarrhea in about 4%

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Toxicity of Ezetimibe

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HA in about 8%

diarrhea in about 4%

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Interactions with Ezetimibe
and other drugs

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use in combo with dietary therapy, as monotherapy, or in combo with a statin

Bile acid sequestrants may decrease F

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Vitorin

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ezetimibe + simvastatin

the ezetimibe in combo with a statin

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Special considerations of Ezetimibe

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use with caution in patients with hepatic or renal impairment

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Indications and dose/route of Ezetimibe

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10 mg po daily