Drug Therapy for Hyperlipidemia Flashcards
Plasma Levels
Acceptable levels of cholesterol: 240
Acceptable levels of LDL-C: 200
Primary and Secondary Hyperlipidemia
Primary: attributed to diet or genetic defect
Secondary: associated with use of drug or presence of disease
First Line of therapy for hyperlipidemia
Diet, decrease fat intake, if there are hypertriglycerides restrict alcohol and/or carbohydrate intake, exercise
Bile Acid Resins - Cholestyramine, Colesevelam, and Colestipol
Mechanism: bind bile acids in the GI tract, DO NOT ENTER SYSTEMIC CIRCULATION, increases fecal bile acid excretion and diminishes bile acid enterohepatic recirculation, enhances hepatic conversion of cholesterol to bile acids (bile acids have negative feedback on 7a-hydroxylase), increases number of hepatic LDL receptors
Uses: lowers only cholesterol, takes 4 weeks of treatment, powder must be taken with liquid, Colesnvelam is a capsule
Adverse effects: GI - constipation, bloating, and abdominal pain; Interferes with absorption of fat soluble vitamins and/or drugs (stagger drugs 1 hour before or 4 hours after taking)
CAN BE USED DURING PREGNANCY and children over 6
HMG-CoA Reductase Inhibitors (Statins)
Mechanism: competitive inhibitor of HMG-CoA reductase, inhibiting endogenous cholesterol synthesis, increase hepatic LDL receptors, site of action is the liver
Uses: all can be used to lower cholesterol but only Atorvastatin and Rosuvastatin can be used to lower cholesterol and lower TGs
Adverse Effects:
- elevate serum transaminases so monitor liver enzymes (increased risk with concurrent use of cyclosporine, azole antifungals, gemfibrozil, nicotinic acid, erythromycin)
- muscle weakness, myalgia and/or dark brown urine (associated with elevated CPK, stop if CPK is 10x higher than normal, this is lowest with fluvastatin and pravastatin)
Contraindications:
PREGNANCY!!!, nursing mothers, and acute liver disease
Comparing Statins
Potency LDL-C: Rosuvastatin > Atorvastatin > Lovastatin > Simvastatin = Pitavastatin > Pravastatin > Fluvastatin
Atorvastatin and Rosuvastatin have longest half life
Low bioavailability but good absorption
Max effect in less than 2 weeks
Max endogenous cholesterol synthesis occurs at night so only take Fluvastatin, Lovastatin, and Simvastatin at night
Atorvastatin, Pravastatin, and Rosuvastatin can be taken anytime of the day
Pediatric patients can take which statins?
Pravastatin if over 8
but all others if at least 10
Effects of food on statins
Lovastatin absorption is increased by food
Pravastatin and Pitavastatin absorption is decreased by food (Don’t take statins with your Ps!)
Biotransformation considerations of statins
Lovastatin and Simvastatin are prodrugs metabolized by intestinal carboxyesterase to active metabolite and by CYP3A4
CYP3A4 most important for atorvastatin, lovastatin, and simvastatin (therefore… avoid grapefruit juice)
CYP2C9 important for rosuvastatin and fluvastatin
Pravastatin is excreted unchanged
Simvastatin minor CYP2D6 metabolism
Myopathy risk is increased by CYP2D6*4 allele and SCLO1B1 SNP
Ezetimibe
Mechanism: inhibits cholesterol absorption at the enterocytes of the small intestine
Uses: reduce cholesterol, when combined with statins will lower LDL-C more than high dose statin
Adverse Effects: diarrhea and myalgia when combined with statins
Contraindications: Liver Disease
Proprotein Converts Subtilisin/ Kevin 9 (PCSK 9) Inhibitors
Alirocumab and Evolocumab
Mechanism: Inhibit PCSK9 by binding, increases hepatocyte LDL receptor number, lower LDL levels, PCSK9 binds LDL receptor on hepatocytes to promote receptor degradation
Uses: lower cholesterol, used with statins
Adverse Effects: Hypersensitivity
Fibrates
Gemfibrozil, Fenofibrate, and Clofibrate
Mechanism: decreases hepatic VLDL TG production, increases LPL activity, mediated by binding to PPARalpha which stimulates LPL synthesis, diminishes expression of Apo CIII, and increases Apo I and II expression which increases HDL-C
Uses: Hypertriglyceridemia, lower TG by 40%, also increases HDL
Fenofibrate and Gemfibrozil are more effective
Adverse Effects: Clofibrate increases risk of gallstones, Myopathy increased with statins and worst with clofibrate because it inhibits OATP2 (Fenofibrate best choice with a statin)
Contraindications: Liver dysfunction or preexisting gallbladder disease, Severe renal impairment
Niacin or Nicotinic Acid
Mechanism: decreases TG synthesis, lower delivery of FFA to liver, diminish hepatic VLDL and LDL production, increase LPL activity and HSL, does not interact with PPARalpha
Uses: Lowers TGs, Lowers cholesterol, increases HDL, must taper dose over 4 week period
Extended release and regular dose are not interchangeable
Adverse Effects: Flushing (premedicate with Aspirin), Precipitate peptic ulcers, induce hyperuricemia, worsen glucose intolerance, *severe itching, myalgia (when combined with statin), liver enzymes and damage occur
Contraindications: acute liver disease, active peptic ulcer, bleeding disorder
DO NOT USE IN SOMEONE WITH GOUT and DIABETES
Familial Lipoprotein Lipase Deficiency (Type I)
elevated chylomicrons after 12 hr fast, high TGs, defect in LPL or apo C-II, no increased risk of heart disease, DIET therapy critical
can also treat with vibrates and nicotinic acid
Familial Hypercholesterolemia (Type IIa)
elevated cholesterol and LDL, marked increased risk of cardiovascular disease, decreased plasma clearance of LDL, deficiency of LDL receptors
Tx: statins, ezetimibe, and resins
