Agents used in dyslipidemia Dr. Madonna Vida R. Quinagon LIPOPROTEIN METABOLISM Structure of lipoprotein INTEGRAL APOPROTEINS CHOLESTEROL ESTERS MONOLAYER OF PHOSPHOLIPID AND CHOLESTERLOL CORE TRIGLYCERIDES PERIPHERAL APOPROTEINS The content Synthesis and Catabolism • Chylomicrons • formed in the intestine and carry • triglycerides of dietary origin, • unesterified cholesterol, • cholesteryl esters • transit the thoracic duct to the bloodstream • Contribute TG to peripheral tissues Lipid metabolism Synthesis and catabolism • Very low density lipoproteins • secreted by liver • carry TG to peripheral tissues • which are hydrolyzed by LPL, for storage in adipose tissue and for oxidation in cardiac and skeletal muscle. • remnants (IDL) undergo endocytosis by liver • converted to LDL by further removal of triglycerides mediated by hepatic lipase. Lipid metabolism Synthesis and catabolism • Low density lipoprotein • catabolized chiefly in hepatocytes and other cells by receptormediated endocytosis. • • Cholesteryl esters from LDL are hydrolyzed, yielding free cholesterol for the synthesis of cell membranes. • • 70% of LDL is removed from plasma by hepatocytes. • • Even more cholesterol is delivered to the liver via IDL and chylomicrons. Lipid metabolism Synthesis and catabolism • Lp(a) lipoprotein • • formed from LDL and the (a) protein, linked by a disulfide bridge • • found in atherosclerotic plaques and may also contribute to coronary disease by inhibiting thrombolysis • • Levels are elevated in certain inflammatory states Lipid metabolism Synthesis and catabolism • High density lipoproteins • secreted by the liver and intestine. • • Much of the lipid comes from the surface monolayers of chylomicrons and VLDL • • acquires cholesterol from peripheral tissues • • Free cholesterol is transported from the cell membrane by a transporter, ABCA1, and then esterified by lecithin:cholesterol acyltransferase (LCAT) • Lipid metabolism Synthesis and catabolism • High density lipoprotein • Cholesterol is also exported from macrophages by the ABCA1 transporter • • The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP) • These cholester esters are then carried to the liver Lipoproteins Lipoprotein Apoproteins Function Chylomicron apoB-48, apoC, apoE Transport TGs form intestine to liver/ other tissues VLDL apoB-100, apoC, apoE Transport TGs from liver to adipose/ muscles. IDL apoB-48, apoC, apoE Intermediary between VLDL and LDL LDL apoB-48 Transport cholesterol to peripheral tissues. HDL apoA, apoC, apoE, apoD •Absorb cholesterol form peripheral tissues and transport it to liver •Reservoir for exchange of lipoproteins in VLDL and Chylomicron metabolism Lipid metabolism LIPOPROTEIN DISORDERS Lipoprotein measurement • detected by measuring lipids in serum after a 10-hour fast. The primary hypertriglyceridemia • • • • Familial chylomicronemia Familial hypertriglyceridemia Familial combined hyperlipoproteinemia Familial dysbetlipoproteinemia Primary hyperchylomicronemia • deficiency of LPL or its cofactor, apo C-II • eruptive xanthomas, hepatosplenomegaly, hypersplenism, and lipid-laden foam cells in bone marrow, liver, and spleen • The lipemia is aggravated by estrogens because they stimulate VLDL production • predominant chylomicronemia, moderately elevated VLDL FamiliaL hypertriglyceridemia • impaired removal of triglyceride- rich lipoproteins • Factors that increase VLDL production aggravate the lipemia because VLDL and chylomicrons compete for LPL • centripetal obesity with insulin resistance, eruptive xanthomas, lipemia retinalis, epigastric pain, and pancreatitis Familial combined hyperlipoproteinemia • Elevated levels of VLDL, LDL, or both • Doubling of VLDL secretion • Elevations of cholesterol and triglycerides are generally moderate • xanthomas are usually absent • Reductase inhibitor alone or with niacin or fenofibrate Familial dysbetalipoproteinemia • remnants of chylomicrons and VLDL accumulate and levels of LDL are decreased • remnants are rich in cholesteryl esters • xanthomas of the palmar creases, obesity, and impaired glucose tolerance, coronary and peripheral atherosclerosis The primary hypercholesterolemia 1. Familial hypercholesterolemia 2. Familial ligand defective apolipoprotein B-100 3. Familial combined hyperlipoproteinemia 4. Lp(a) hyperlipoproteinemia 5. HDL deficiency Familial hypercholesterolemia • • • • autosomal dominant trait elevated umbilical cord blood cholesterol Tendon xanthomas, coronary artery disease, Defects of LDL receptors Familial Ligand-Defective Apolipoprotein B-100 • Defects in the domain of apo B-100 that binds to the LDL receptor impair the endocytosis of LDL, leading to hypercholes- terolemia of moderate severity. Lp(a) Hyperlipoproteinemia • increased atherogen-esis • determined chiefly by alleles that dictate increased production of the (a) protein moiety • Lp(a) can be secondarily elevated in patients with severe nephrosis and certain other inflammatory states • Niacin reduces levels of Lp(a) in many patients. Lipid metabolism PHARMACOLOGY Agents used in dyslipidemia • • • • • HMG-CoA Reductase inhibitors Niacin Fibric Acid Derivatives or Fibrates Bile acid binding resin Inhibitors of intestinal sterol absorption Reductase inhibitors -Harmacokinetics • structural analogs of HMG-CoA (3-hydroxy- 3-methylglutarylcoenzyme A • Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin, rosuvastatin, and pitavastatin • Lovastatin and simvastatin are inactive prodrugs that are hydrolyzed in the gastrointestinal tract to the active derivatives • pravastatin has an open, active lactone ring • Atorvastatin, fluvastatin, and rosuvastatin are active as given Reductase inhibitors -Pharmacokinetics • Absorption varies from 40% to 75% except fluvastatin, which is almost completely absorbed • All have high first-pass extraction by the liver • Most of the absorbed dose is excreted in the bile • Plasma half- lives of these drugs range from 1 to 3 hours except for atorvastatin (14 hours), pitavastatin (12 hours), and rosuvastatin (19 hours) Reductase inhibitors - MOA • Inhibits HMG-CoA reductase • induce an increase in high-affinity LDL receptors • Increases both the catabolic rate of LDL and the liver’s extraction of LDL precursors (VLDL remnants) from the blood, thus reducing LDL • Modest decreases in plasma triglycerides • small increases in HDL also occur Reductase inhibitors pharmacodynamics • Not given to pregnants, lactating mothers, and those who are likely to become pregnant • Should be given in the evening except atorvastatin and rosuvastatin • Rosuvastatin, the most efficacious agent for severe hypercholesterolemia • Absorption generally is enhanced by food, except for pravastatin Reductase inhibitors - toxicity • Elevated serum aminostransferases, may continue statins • Discontinue in patients with liver disease and history of alcohol abuse and elevated aminostransferases • Discontinue if serum aminotransferases are 3x the upper limit of normal • Aminotransferase should be measured at baseline, at 1–2 months, and every 6–12 months (if stable). Reductase inhibitors - toxicity • Minor increases in creatine kinase (CK) associated with heavy physical activity • Generalized discomfort or weakness in skeletal muscles • If the drug is not discontinued, myoglobinuria can occur, leading to renal injury Niacin (nicotinic acid) • Converted to the amide, which is incorporated into niacinamide adenine dinucleotide (NAD) • It is excreted in the urine unmodified • inhibits VLDL secretion, decreasing production of LDL • no effect on bile acid production • catabolic rate for HDL is decreased • Inhibits the intracellular lipase of adipose tissue, possibly reducing VLDL production by decreasing the flux of free fatty acids to the liver. Niacin • most effective agent for increasing HDL • only agent that may reduce Lp(a) • Given in divided doses with meals, starting with 100 mg two or three times daily and increasing gradually. Niacin - toxicity • harmless cutaneous vasodilation, flushing, and sensation of warmth after each dose when niacin is started or the dose increased. • aspirin one half hour before- hand blunts this prostaglandinmediated effect • Pruritus, rashes, dry skin or mucous membranes, and acanthosis nigricans, nausea, abdominal discomfort • Acanthosis nigricans –contraindicated use of niacin Niacin - toxicity • • • • • • • • Reversible elevation of aminotransferases May be given to diabetics on insulin Hyperuricemia Red cell macrocytosis Significant platelet deficiency Arrhythmias, mostly atrial macular edema. May potentiate the action of antihypertensive agents Fibrates or fibric acid derivatives • Gemfibrozil and fenofibrate bezafibrate • Gemfibrozil • absorbed quantitatively from the intestine • tightly bound to plasma proteins • undergoes enterohepatic circulation • readily passes the placenta • half-life is 1.5 hours. • 70% eliminated through the kidneys, mostly unmodified fibrates • Fenofibrate • an isopropyl ester that is hydrolyzed completely in the intestine • half-life is 20 hours • 60% is excreted in the urine as the glucuronide, and about 25% in feces. Fibrates • ligands for the nuclear transcription receptor, PPAR-α. • transcriptionally up-regulate LPL, apo A-I and apo A-II, and down-regulate apo C-III, an inhibitor of lipolysis. • increase in oxidation of fatty acids in liver and striated muscle • Increase lipolysis of lipoprotein triglyceride via LP • Intracellular lipolysis in adipose tissue is decreased • Levels of VLDL decrease, in part as a result of decreased secretion by the liver fibrates • Useful in hypertriglyceridemias in which VLDL predominate and in dysbetalipoproteinemia • Gemfibrozil is 600 mg orally once or twice daily • Fenofibrate is one to three 48 mg tablets (or a single 145 mg tablet) daily. • Absorption of gemfibrozil is improved when the drug is taken with food. Fibrates - toxicity • rashes, gastrointestinal symptoms, myopathy, arrhythmias, hypokalemia, and high blood levels of aminotransferases or alkaline phosphatase • decreases in white blood count or hematocrit • Potentiate the action of coumarin and indanedione anticoagulants • Rhabdomyolysis Fibrates - toxicity • increase in the risk of cholesterol gallstones • use with caution in patients with biliary tract disease or in those at high risk such as women, obese patients, and Native Americans • Fenofibrate is the fibrate of choice for use in combination with a statin • Avoid in patients with renal or hepatic disease Bile acid binding resin • • • • • Colestipol, cholestyramine, and colesevelam useful only for isolated increases in LDL large polymeric cationic exchange resins insoluble in water bind bile acids in the intestinal lumen and prevent their reabsorption Bile acid binding resin • Excretion of bile acid is increased up to tenfold • Enhanced conversion of cholesterol to bile acids in liver via 7αhydroxylation • Increased uptake of LDL and IDL from plasma results from upregulation of LDL receptors, particularly in liver. Bile acid binding resin - use • treatment of patients with primary hypercholesterolemia, producing approximately 20% reduction in LDL cholesterol in maximal dosage • helpful in relieving pruritus in patients who have cholestasis and bile salt accumulation • bind digitalis glycosides Bile acid binding resin - use • • • • • • • Colestipol and cholestyramine are available as granular prepara- tions A gradual increase of dosage of granules Safe in children Mixed with juice or water and allowed to hydrate for 1 minute Colestipol must be swallowed whole Should be taken in two or three doses with meals Lack effect when taken between meals. Bile acid binding resin - toxicity • • • • • • Constipation and bloating Avoid in patients with diverticulitis. Heartburn and diarrhea Malabsorption of vitamin K Malabsorption of folic acid Increased formation of gallstones, particularly in obese persons Bile acid binding resin - toxicity • Impaired absorption of digitalis glycosides, thiazides, warfarin, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, ezetimibe, folic acid, phenylbutazone, aspirin, and ascorbic acid, • Colesevelam does not bind digoxin, warfarin, or reductase inhibitors. INHIBITORS OF INTESTINAL STEROL ABSORPTION • Ezetimibe is readily absorbed and conjugated in the intestine to an active glucuronide • peak blood levels in 12–14 hours • undergoes enterohepatic circulation • half-life is 22 hours • 80% excreted in feces • Plasma concentrations are when administered with fibrates and reduced when given with cholestyramine Ezetimibe • selective inhibitor of intestinal absorption of cholesterol and phytosterols • A transport protein, NPC1L1, appears to be the target of the drug • Average reduction in LDL cholesterol with ezetimibe alone in patients with primary hypercholesterolemia is about 18% • synergistic with reductase inhibitors, producing decrements as great as 25% in LDL cholesterol CETP inhibitors • Torcetrapib • Anacetrapib • Dalcetrapib THANK YOU GIVE THE MECHANISM OF ACTION OF EACH DRUG, AND GIVE AND EXAMPLE FROM EACH: (2 POINTS EACH) 1. HMG CoA inhibitors 2. Ezetimibe 3. Bile-acid binding resin 4. Niacin Give an adverse effect for each drug: •5. HMG CoA inhibitors •6. Niacin
