Pharmacology of Agents Used in Hyperlipidemia

1. Pharmacology of Agents Used in Hyperlipidemia Dr. Thomas Abraham PHAR417: Fall 2005

2. Development of Atherosclerosis Early plaque formation Clot formation Advanced Plaque

3. Treatment Options in Heart Disease Balloon Angioplasty Stent Coronary Artery Bypass Graft

4. Potential Role of Cholesterol in Heart disease Normal Coronary Artery Atherosclerotic Coronary Artery Cholesterol contributes to atherosclerosis and may make the disease worse by the development of unstable or fragile atheromas. Atherosclerotic plaques promote thrombotic events that can lead to cardiac tissue ischemia and death.

5. Endogenous Lipid Transport System • Very low density lipoproteins (VLDL) composed of mostly triglycerides, cholesterol ester and ApoB-100. Formed in the liver and metabolized in the peripheral circulation by lipoprotein lipase to Intermediate density lipoprotein (IDL, VLDL remnant). • IDL returns to liver where it is metabolized to LDL (released into general circulation) or taken up into liver cells. LDL removed from plasma by cells (hepatic and non-hepatic) that express the LDL receptor. • High circulating LDL may be due to increased metabolism of IDL to LDL (by liver) or due to decreased LDL receptors on peripheral tissues

6. Endogenous Lipid Transport System • High density lipoproteins (HDL) carries lipids from the peripheral cells to the liver and transfers lipids between lipoproteins. Anti-atherogenic actions due to ability to carry cholesterol away from vasculature. • Dietary triglycerides and cholesterol incorporated into chylomicrons which carry lipids via the lymphatic system and the blood to the liver.

7. Bile Acid binding Resins Cholestyramine (Questran®) • Basic anion exchange resin of trimethylbenzylammonium in large copolymer of styrene and divinylbenzene. • Water-insoluble, hygroscopic. Cholestipol HCl (Colestid®) • Copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane; water insoluble and very hygroscopic. • Colesevelam (Welchol®) • Anion-exchange resin in a tablet gel formulation

8. Bile Acid binding Resins • 97% of bile acids reabsorbed via enterohepatic circulation. • Anion exchange resins bind negatively charged bile acids in place of Cl- to decrease bile acid reabsorption. • Decreased bile acid reabsorption …… Increased cholesterol conversion to bile acid ……. Increased LDL uptake……..Decreased Plasma cholesterol.

9. Bile Acid binding Resins • Also increased hepatic LDL receptors enhance LDL uptake; and increased HMG CoA reductase activity increases cholesterol biosynthesis. • VLDL levels not significantly altered by resin therapy; LDL cholesterol decreases by 10-35%, mostly in first 2 weeks of therapy. • Adverse effects: bloating, abdominal cramps, constipation. Can interfere with absorption of anions; decreases absorption of thyroxine, digitalis, anticoagulants.

10. Fibric Acid derivatives • Gemfibrozil: non-halogenated derivative. • Well absorbed from GI tract esp. with meal; ester derivatives are metabolized to acid form in liver. • Highly protein bound in plasma. Up to 90% metabolized to glucuronide conjugate and excreted in urine.

11. Fibric Acid derivatives • Mechanism of action to decrease VLDL and increase HDL may be related to increased lipoprotein lipase activity; has variable effects on LDL levels • May increase gene transcription of apolipoprotein AI and AII via activation of peroxisome proliferator-activated receptor a (PPARa): Apo AI and AII are components of HDL-C • May decrease VLDL by up to 50% and increase HDL by 10-30% and indirectly decrease LDL by 10-20% • Adverse effects: skin rash, GI disturbances, myopathy (increased risk when combined with high dose HMG CoA reductase inhibitors), arryhthmias, hypokalemia, impotence and liver toxicity.

12. HMG CoA Reductase inhibitors • Mevastatin isolated from Penicillium cultures (1976); Lovastatin isolated from Aspergillus species. • Lovastatin and simvastatin administered in lactone ring form which is hydrolyzed to acid (active) form. Pravastatin and fluvastatin already in acid form; fluvastatin supplied as sodium salt. • Oral bioavailability of 30-80%; high first-pass metabolism – only about 5% of ingested dose reaches blood. Predominant liver metabolism and excretion for statins but some urine excretion occurs (esp. pravastatin).

13. HMG CoA Reductase inhibitors • Inhibits cholesterol synthesis by competing with hydroxymethylglutaryl (HMG)-CoA for the reductase enzyme. Cholesterol • Decreases cholesterol biosynthesis to decrease LDL levels (25-55%); atorvastatin appears more efficacious than other statins.

14. HMG CoA Reductase inhibitors • Inhibition of HMG CoA reductase causes increased reductase protein synthesis, which tends to restore cholesterol biosynthesis toward pretreatment levels. Also increases LDL receptor expression which increases plasma clearance of LDL, IDL and VLDL. • Adverse effects (relatively rare): increases heptic transaminase levels in serum; myopathies (with increases in creatine phosphokinase). • Rhabdomyolysis occurs more often when combined with gemfibrozil, cyclosporine or azole fungal drugs

15. Miscellaneous Agents • Ezetimibe (Zetia®) • Is rapidly absorbed into intestinal cells where it is metabolized to the glucuronide conjugate. Glucuronide form is eliminated from liver by the biliary route into small intestines. • Glucuronide form of the drug binds the cholesterol transport protein to prevent absorption of dietary cholesterol into the intestinal cells. • Ezetimibe can lower LDL-C by up to 20% after about 2 week treatment and has some effect to increased HDL-C and lower triglycerides. • Combination with statins or fenofibrate results in additive lowering in LDL-C.

16. Miscellaneous Agents • Ezetimibe (Zetia®) • Chronic therapy with ezetimibe alone results in enhanced cholesterol biosynthesis in the liver. • Cholestyramine decreases absorption of ezetimibe; cyclosporine and renal failure may elevated ezetimibe blood levels. • Adverse effects are generally minor or rare: chest pains, arthralgia, diarrhea, dizziness, headache, sinusitis, pharyngitis, upper respiratory infection.

17. Miscellaneous Agents • Nicotinic acid (Niacin, Niaspan ®) • Pyridine 3-carboxylic acid; water-soluble vitamin B. • Lipid-lowering activity is unrelated to vitamin function. • Good oral bioavailability; excreted unchanged in urine. • Decreases VLDL production by: (a) decreased lipolysis and delivery of FFA to liver; (b) decreased triglyceride synthesis; (c) increased VLDL clearance by liver. • LDL is lowered secondary to VLDL lowering; HDL levels increased (perhaps by decreasing HDL metabolism). Decreases LDL by 20-30% (3-5 wks.) and VLDL by 35-45%.

18. Miscellaneous Agents Nicotinic Acid (Niaspan®) • Adverse effects: flushing, pruritis (face, upper body), dyspepsia, vomiting, diarrhea, peptic ulcers, dry skin, increased AST/ALT (liver enzymes), jaundice, hepatic failure, increased plasma glucose, increased uric acid levels (gout). • Cutaneous flush may be decreased by aspirin or ibuprofen since this a prostaglandin-mediated event.