003 Antihyperlipidemic.pdf

Treatment of Hyperlipidemia o These drugs should be avoided in pregnant and lactating women and those likely to become pregnant. o All drugs that alter plasma lipoprotein concentrations may require adjustment of doses of warfarin (?!) o Children with heterozygous familial hyperchol...

Treatment of Hyperlipidemia o These drugs should be avoided in pregnant and lactating women and those likely to become pregnant. o All drugs that alter plasma lipoprotein concentrations may require adjustment of doses of warfarin (?!) o Children with heterozygous familial hypercholesterolemia may be treated with a resin or statins, usually after 7 or 8 years of age, when myelination of the CNS is complete. o The decision to treat a child should be based on the level of LDL, other risk factors, the family history, and the child's age. o Drugs are rarely indicated before age 16.  Hypolipidemic agents I. HMG-CoA Reductase Inhibitors (Statins) Lovastatin, simvastatin, pravastatin, atorvastatin and fluvastatin Mechanism of action Inhibit the synthesis/activity of HMG-CoA reductase (3-hydroxy-3- methylglutaryl-coenzyme A), a rate-limiting step in the hepatic synthesis of cholesterol   intracellular cholesterol which will lead to: 1. The liver compensates by LDL receptors amounts of LDL removed from circulation 2. Secretion of VLDL I. HMG-CoA Reductase Inhibitors (Statins) Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed.  I. HMG CoA Reductase Inhibitors (Statins) Clinical effects  LDL cholesterol by 30-40%.  plasma triglycerides (10-30%). (through inhibition of VLDL synthesis)  The average HDL cholesterol by 5-15%. Atorvastatin is the most potent.  I. HMG CoA Reductase Inhibitors (Statins) Therapeutic uses 1) Familial and non-familial hypercholesterolemias. o Many patients have mutations in the LDLR gene that encodes the LDL receptors o Heterozygous FH is normally treated with statins, bile acid sequestrants or other hypolipidemic agents. o Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation. Familial Hypercholesterolemia  I. HMG CoA Reductase Inhibitors (Statins) Therapeutic uses 2)Statins may interfere with osteoclast-mediated bone resorption and may reduce osteoporosis 3) Statins may reduce the incidence of some cancers 4) They also have weak anti-inflammatory activity  I. HMG CoA Reductase Inhibitors (Statins) Adverse Effects Nausea, epigastric fullness, distension, constipation or loose bowel actions, and headache. Mild  of transaminases is common Myositis (inflammation and degeneration of muscle tissue) : 0.1- 0.2%  ↑creatine kinase (CK) Rarely rhabdomyolysis (destruction of muscle cells)  due to synthesis of Coenzyme Q10 (ubiquinone), which plays an important role in muscle cell energy production and changes in the cell-membrane permeability Myoglobinuria which may cause kidney damage. Hypotension Statin blood levels increase when administered concurrently with erythromycin, cyclosporin, gemfibrozil and niacin.  I. HMG CoA Reductase Inhibitors (Statins) Combination Regimens Statins/bile acid sequestrants combination exerts an additive effect on LDL cholesterol. The combination of statins/gemfibrozil is associated with an increased risk of myopathy. All statins except pravastatin undergo metabolism via the cytochrome P450 enzyme system. Other pharmacologic agents that are also metabolized via this pathway may interact with the statins and cause rhabdomyolysis. The risk of statin-induced rhabdomyolysis is increased significantly when statins are used concomitantly with such drugs as fibrates, cyclosporine, macrolide antibiotics, and azole antifungals  II. Bile Acid Sequestrants Cholestyramine (Questran®), Colestipol (Colestid®) Mode of action Bind bile acids forming unabsorble complex that is excreted in the faeces preventing enterohepatic recycling of bile acids. The liver must increase the synthesis of bile acids, using endogenous cholesterol as the substrate. Decreased bile acids decreases lipids absorption  II. Bile Acid Sequestrants Clinical Effect Decrease LDL cholesterol by 10 to 30% in patients with some normal LDL receptors. This excludes patients who completely lack functional LDL receptors because of a genetic defect (homozygous familial hypercholesterolemia). HDL cholesterol levels are usually not affected Main use is as additive therapy with statin  II. Bile Acid Sequestrants Dosage and Administration Powder which is usually taken with water or fruit juice Start with one sachet daily and gradually increase to maximum tolerated dose. Timing of the dose in relation to meals is not important Adverse effects Constipation, heartburn, abdominal pain, bloating and nausea. Impair the absorption of fat-soluble vitamins (A,D,E and K), and other substances such as iron and folate (Vitamin supplement is advised for patients on long term high-dose therapy). Bind other fat soluble drugs - anticoagulants, cardiac glycosides and thyroid hormone. Bind other acidic drugs such as naproxen and thiazide diuretics  III. Fibrates (Fibric acid derivaties) Gemfibrozil, clofibrate, bezafibrate, fenofibrate Mode of Action Stimulate the activity of peroxisome proliferating activating receptors alpha (PPARα, a class of nuclear receptor) altering the transcription of a number of genes involved in triglyceride metabolism including lipoprotein lipase (They induce this enzyme) and apolipoprotein CIII (a protein component of VLDL that inhibit lipoprotein lipase). 1. Induction of lipoprotein lipase increases the clearance of triglycerides 2. Induction of hepatic fatty acids uptake and reduction of hepatic triglyceride production 3. Increased removal of LDL by LDL receptor 4. Increase in HDL production (Fibrates increase the production of apoA in liver) 5. Increase the peripheral catabolism of VLDL and chylomicrons  III. Fibrates (Fibric acid derivaties) Therapeutic uses Treatment of hyperlipidemia of several etiologies, especially hypertriglyceridemia due to dys-beta-lipoproteinemia, a defect in apolipoprotein E that impairs clearance of chylomicron remnants and VLDL. Contraindicated in hypercholesterolemia due to defects in LDL receptors as they will further elevate the plasma level of LDL (Possibly as a result of an accelerated fibrate-induced catabolism of triglyceride-rich lipoproteins).  III. Fibrates (Fibric acid derivaties) Clinical Effects  plasma triglycerides by 20-30%.  plasma total cholesterol 5-10 %  HDL-cholesterol by 5-10% Result in approximately 20% reduction in cardiac events Increased risk of malignancy with clofibrate Adverse Effects Cholelithiasis and cholecystitis, abdominal discomfort, epigastric fullness, nausea and mild diarrhoea. Weight gain, fluid retention, and impotence Liver enzymes are sometimes slightly elevated Muscle tenderness with a raised serum creatine phosphokinase (CPK) Displacement of sulphonylureas and warfarin from albumen  IV. Probucol Mechanism of Action Increases LDL catabolism Inhibits cholesterol synthesis and delay its absorption Strong antioxidant properties (inhibit formation of foam cells). Pharmacokinetics Probucol is lipid soluble and concentrates in adipose tissue Excreted slowly with a half-life of between 20 and 50 days Plasma drug concentration rise slowly to a plateau level after 3-4 months  IV. Probucol Clinical Effects  total serum cholesterol and LDL-C levels by about 10-20% No change in triglyceride levels There are no large-scale trials demonstrating a reduction in cardiovascular disease events with probucol, and its clinical use is therefore, controversial. Adverse Effects Diarrhoea, bloating, indigestion, heartburn Headache, arthralgia  serum HDL-cholesterol concentrations (by 15-20%) Increases the QT interval on the electrocardiogram (i.e delayed repolarization)  IV. Nicotinic Acid (Niacin, B3) Mode of Action Nicotinic acid can exert cholesterol- and triglyceride-lowering effects at high concentrations (nicotinamide cannot do this). Reduces VLDL synthesis in the liver and hence LDL by: 1. Inhibiting the synthesis and esterification of fatty acids in the liver 2. Reducing lipolysis in adipose tissue by inhibiting adipose tissue lipase In much smaller doses, nicotinic acid can also be used as a vitamin supplement in the treatment of pellagra. In this case nicotinic acid is converted to nicotinamide which is used for biosynthesis of the cofactors NAD and NADP  IV. Nicotinic Acid (Niacin, B3) Pharmacokinetics Nicotinic acid is a water soluble vitamin Clinical Effects At high doses (1.5-3.0 grams), it affects all plasma lipid subtypes, lowers plasma total and LDL cholesterol by 10-25%  Triglycerides by 5-30%  plasma HDL cholesterol by 10-20% (by decreasing HDL catabolism)  IV. Nicotinic Acid (Niacin, B3) Adverse Effects Flushing, tingling and headache (prostaglandin-induced effects)  Aspirin (325mg) taken 30 minutes before the drug decreases it Nausea, flatulence and diarrhea are also common. May exacerbate peptic ulceration and gout Relatively contraindicated in gout and in diabetics (induce insulin resistance) Hepatotoxicity  IV. Nicotinic Acid (Niacin, B3) niacin-extended-release and lovastatin tablets reduces LDL-C, TC, TG and increases HDL-C available as 500/20, 750/20 and 1000/20 mg tablets Advicor®  V. Inhibitors of Intestinal Sterol Absorption Ezetimibe (Zetia) Acts within the intestine to reduce cholesterol absorption. Blocks one or more of cholesterol transporters. Used alone or combined with a statin. Well tolerated, may cause fatigue, abdominal pain, and diarrhea  Summary Case Drugs ↑ Cholesterol Cholestyramine, colestipol, Ezetimibe ↑Triglycerides Gemfibrozil ↑Cholesterol and Trigelycerides Statins and Niacin, ezetimibe  Thankyou Reference Lippincott Illustrated Reviews: Pharmacology 6th edition (Lippincott Illustrated Reviews Series), Ed. K. Whalen, 6th Edition, 2014, Pub. Lippincott Williams & Wilkins, Philadelphia, ISBN-13: 978-1451191776 Basic & Clinical Pharmacology. Ed. B.G. Katzung & A. J. Trevor, 14th Edition, 2017, Pub. McGraw-Hill, New York City, ISBN-13: 978-1259641152.