Lipid Drugs Flashcards
What is Cholestyramine (Questran™, colestipol)?
Cholestyramine is a bile acid sequestrate and removes bile acids from the body by forming insoluble complexes with bile acids in the intestine, which are then excreted in the feces.
As a result of this loss of bile acids, more plasma cholesterol is converted to bile acids in the liver to normalize levels. This conversion of cholesterol into bile acids lowers plasma cholesterol levels.
- Not used much due to adverse drug effects
To what drug class does Cholestyramine belong?
Pharmacologic => bile acid sequestrate
Therapeutic class => cholesterol-lowering agent
Describe the pharmacodynamics of Cholestyramine.
- Cholestyramine 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 acid synthesis –> increases cholesterol synthesis –> increases expression of LDL receptors on cell surface of hepatocytes
- Reduces LDL chol by 10-20% (maximum)
Describe the pharmacokinetics of Cholestyramine.
- Virtually no absorption
- Excreted in feces
- Peak effect 3 weeks
What toxicity is associated with Cholestyramine?
> 10% of patients have GI problems
- Gas, bloating, diarrhea, constipation
- May interfere with absorption of fat-soluble vitamins, and drugs including digoxin, warfarin, thyroxine
What interactions should be considered for patients on Cholestyramine?
- May diminish absorption of statins, steroids, digoxin, warfarin
What special considerations are made with Cholestyramine?
- Provided as a powder for oral suspension
- Be sure to drink liquids with it
What is the dose for Cholestyramine?
4 gm once a day, up to 6 times per day
What is Nicotinic Acid (niacin/Vit B3, Niacor™, others)?
Niacin has been used for over 50 years to increase levels of HDL in the blood and has been found to decrease the risk of cardiovascular events modestly
To what drug class does Nicotinic Acid belong?
Pharmacologic class => vitamin
Therapeutic class=> cholesterol-lowering agent
Describe the pharmacodynamics of Nicotinic Acid.
- Lowers BOTH TG and LDL-cholesterol
- Decreased production of VLDL –> decreased production of LDL –> increase in LDL receptor in liver
- Modestly effective as single agent, usually used in combination
- Can also raise HDL
Describe the pharmacokinetics of Nicotinic Acid.
- Well absorbed, large first pass effect (to nicotinamide)
- Tmax 45 min
- Half-life 45 min
- Urinary excretion of unchanged drug and metabolite
What toxicity is associated with Nicotinic Acid?
- Many patients develop skin flushing, which can be lessened by taking aspirin
- Some patients develop hepatitis
What interactions should be considered for patients on Nicotinic Acid?
Absorption is decreased by cholestyramine
What special considerations should be made for patients on Nicotinic Acid?
Avoid in patients with CAD and avoid heavy ethanol use
What dose should Nicotinic Acid be given in?
Pellagra 100 mg tid
Hyperlipidemia 0.5-2 gm tid after meals
What is the clinical importance of Nicotinic Acid?
Although Nicotinic Acid improves all three lipid levels more than placebo, there is no incremental clinical benefit from the addition of niacin to statin therapy
To what drug class does Gemfibrozil (Lopid™, fenofibrate) belong?
Pharmacologic–>Fibric acid derivative
Therapeutic–>Lipid-lower agent
Describe the pharmacodynamics of Gemifibrozil.
- Produces slight reduction in LDL-chol levels (-4%)
- Most useful in treatment of hypertriglyceridemia in types IV and V hyperlipidemia (-31%); may increase HDL-chol (+6%)
Describe the pharmacokinetics of Gemifibrozil.
- Well absorbed
- Oxidized in liver to two inactive metabolites
- Half-life 1-2 h
What toxicity is associated with Gemifibrozil?
- Elevation of liver function tests
- Myositis (muscle inflammation)
- GI distress
- Avoid in patients with renal, hepatic, or biliary tract disease
What drug-drug interactions are present with Gemifibrozil?
- Therapeutic effects increased with statins, but may potentially increase toxicity (liver, muscle)
What special considerations should be made with patients on Gemifibrozil?
Contraindicated in patients with renal or liver disease
What are the indications/dose/route for Gemifibrozil?
600 mg po twice daily
What is Atorvastatin/Lipitor™ ?
Like all statins, atorvastatin works by inhibiting HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body.
- $30 per month for atorvastatin, $340 per month for branded Lipitor™
To what drug class does atorvastatin belong?
Pharmacologic class => HMG-CoA reductase inhibitor
Therapeutic class => cholesterol-lowering drug; primary and secondary prevention of CAD
Describe the pharmacodynamics of atorvastatin.
- Parent drug (lactone) is transformed to an active metabolite => inhibits HMG-CoA reductase
- Inhibition is not complete.
- Leads to up-regulation of LDL receptors on hepatocytes, so that liver cells can import more cholesterol.
- Leads to reduction in LDL-chol (-10-65%), increase in HDL (small)
Describe the pharmacokinetics of Atorvastatin.
- Rapidly absorbed
- Extensively metabolized, likley mostly by CPY 3A4
- Metabolites account for most of its activity
- Active metabolites have half-life of 20-30 h
What toxicity is associated with Atorvastatin?
Check liver function tests and creatinine phosphokinase (CPK) during first year of use
- Be ware of risk of hepatitis, myopathy, myositis, and even rhabdomyolysis (rare!!!)
What drug-drug interactions are associated with Atorvastatin?
- Additive effects with cholestyramine, nicotinic acid, ezetimibe
- Gemfibrozil and niacin may increase risk of myopathy
- Erythromycin, cyclosporine, fluconazole, and others may inhibit CYP 3A4 metabolism, thereby causing increased accumulation and increasing toxicity
What special considerations should be made for patients on Atorvastatin?
Avoid in patients with pre-existing hepatitis, muscle disease, and pregnancy (X)
What are the indications/dose/route for Atorvastatin?
10-20-40-80 mg po once daily
What is Ezetimibe (Zetia™)?
Ezetimibe is a plasma cholesterol lowering drug that acts by decreasing cholesterol absorption in the small intestine.
To what drug class does Ezetimibe belong?
Pharmacologic class–>2-azetidinone compound
Therapeutic class–> cholesterol absorption inhibitor
Describe the pharmacodynamics of Ezetimibe.
- 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 an increase in the blood clearance of cholesterol
- When used as monotherapy, can lower LDL-chol by up to 18%; often used with a statin
Describe the pharmacokinetics of Ezetimibe.
- Given orally
- Tmax 4-12h
- Extensively metabolized to glucoronide
- F 35-60%
- T 1/2 = 22 h
What toxicity is associated with Ezetimibe?
HA in about 8%, diarrhea in about 4%
What are the drug-drug interactions of Ezetimibe?
- Use in combination with dietary therapy, as monotherapy, or in combination with a statin (is available as Vitorin, ezetimibe + simvastatin)
- Bile acid sequestrants may decrease bioavailability (F)
What special considerations should be made in patients on Ezetimibe?
Use with caution in patients with hepatic or renal impairment
What is the dose/route of Ezetimibe?
10 mg po daily
