Drugs for Hyperlipoproteinemia PDF

Treatment of Hyperlipidemias Risk factors for coronary heart disease (CHD): 1. High LDL cholesterol and TG 2. low HDL cholesterol. 3. cigarette smoking 4. Hypertension 5. Obesity 6. diabetes  Elevated cholesterol can be due to: 1. Lifestyle: lack of exercise and consu...

Treatment of Hyperlipidemias Risk factors for coronary heart disease (CHD): 1. High LDL cholesterol and TG 2. low HDL cholesterol. 3. cigarette smoking 4. Hypertension 5. Obesity 6. diabetes  Elevated cholesterol can be due to: 1. Lifestyle: lack of exercise and consumption of a diet containing excess saturated fatty acids 2. a single inherited gene defect in lipoprotein metabolism 3. combination of genetic and lifestyle factors.  TREATMENT GOALS The primary goal: Reduction of the LDL level Recommendations for the reduction of LDL cholesterol to specific target levels are influenced by – Coexistence of CHD – number of other cardiac risk factors The higher the overall risk of heart disease, the more aggressive the recommended LDL-lowering therapy.  ATHEROSCLEROSIS A. Significance: Major cause of death in the U.S. (heart attacks and strokes) B. Risk Factors: Hypertension, age, obesity, diabetes, high fat diet, smoking, stress, low HDL, lack of exercise, family history and high plasma lipoproteins (VLDL, IDL and LDL).  ATHEROSCLEROSIS C. Pathogenesis: - Elevated plasma lipoproteins such as VLDL, IDL and LDL are a major risk factor in atherosclerosis - Endothelium of blood vessel is injured and blood components (LDL and platelets) infiltrate injured area. - Growth factors cause proliferation of cells and plaque starts to form at site of injury.  ATHEROSCLEROSIS C. Pathogenesis: (Continue) - Cells internalize LDL (oxidized) and form foam cells (saturated with fat). - Cells die and plaque is formed. - Narrowed vessel gets clogged by blood clot and stroke or heart attack is the consequence.  ATHEROSCLEROSIS D. Rationale of treatment: Studies have clearly demonstrated that appropriate diet and drugs reduces atherosclerosis- induced mortality 20 to 40%. Lipoprotein Structure  Classification of Lipoproteins 1. Chylomicrons - carry triacylglycerol from the intestines to the liver and adipose tissue. 2. Very low density lipoproteins (VLDL) - carry triacylglycerol from the liver to adipose tissue. 3. Low density lipoprotein (LDL) - carry cholesterol from the liver to the tissues. “Bad cholesterol“ 4. High density lipoprotein (HDL) - collects cholesterol from the tissues, and transport it back to the liver. “Good cholesterol“ Classification of Lipoproteins Composition of Lipoproteins  Hyperlipoproteinemia Lipoproteins Normal Values mg/dl Total Cholesterol < 200 LDL 100 HDL 40-50 Triglycerides 150 Hyperlipoproteinemia Fredrickson Classification of Hyperlipoproteinemia Type Serum Lipoprotein Disease Main cause elevation elevation I Familal Triglycerides Lipoprotein lipase Chylomicrons hyperchylomicronemia deficiency IIa Familal Cholesterol Defect in LDL receptors LDL hypercholesterolemia IIb Familal mixed Cholesterol and Overproduction of VLDL LDL, VLDL hyperlipidemia triglycerides by liver III Familal Cholesterol and Overproduction or IDL dysbetalipoproteinemia triglycerides underutilization of IDL (mutant apolipoprotien E) IV Familal Triglycerides Overproduction or VLDL hypertriglyceridemia decrease removal of serum VLDL & TG V Familal mixed Cholesterol and Overproduction or VLDL, hypertriglyceridemia triglycerides decrease clearance of chylomicrons VLDL & chylomicrons Lipoprotein metabolism LCAT: lecithin:cholesterol acyl transferase, CETP: cholesteryl ester transfer protein FFA: free fatty acid A. Treatment options for hypercholesterolemia Moderate hyperlipidemia: – Lifestyle changes, such as diet, exercise, and weight reduction, can lead to modest decreases in LDL levels and increases in HDL levels. – Patients who are unwilling to modify their lifestyle drug therapy may be required. Drug therapy: A. Patients with – LDL levels >160 mg/dL – one other major risk factor, such as hypertension, diabetes, smoking, or a family history of early CHD B. Aggressive treatment: – Patients with two or more additional risk factors should be treated aggressively – Aim: reducing LDL level to less than 100 mg/dL and, in some patients, to as low as 70 mg/dL. B. Treatment options for hypertriacylglycerolemia Primary modes of treating hypertriacylglycerolemia: – Diet – Exercise Efficacious drugs in lowering TG: 1. Niacin 2. Fibric acid derivatives HMG CoA reductase Inhibitors : Most efficacious and well tolerated. They act by competitive inhibition of HMG CoA reductase – the rate limiting step in cholesterol synthesis. HMG CoA reductase Inhibitors  Statins Atorvastatin Fluvastatin Lovastatin Mevastatin Pravastatin Rosuvastatin Simvastatin Simvastatin+Ezetimibe Lovastatin+Niacin extended-release Atorvastatin+Amlodipine Besylate Simvastatin+Niacin extended-release HMG CoA reductase Inhibitors: 1. Reduced cholesterol synthesis results in a compensatory increase in the hepatic uptake of plasma cholesterol mediated by an increase in the number of LDL receptors. 2. Hepatic synthesis of VLDL is reduced 3. There is an increase in HDL levels HMG CoA reductase Inhibition  HMG CoA reductase Inhibitors Lovastatin and Simvastatin: – Prodrugs, have to be hydrolyzed to be activated. – Cross the BBB and can cause sleep disturbances Fluvastatin – Less myopathy Atorvastatin and rosuvastatin are long acting – Rosuvastatin, Pitavastatin, & Atorvastatin are the most potent in decreasing LDL cholesterol. – Atorvastatin (Lipitor) – antioxidant effect  Pharmacokinetics: Absorption after oral administration: – Pravastatin and fuvastatin: complete – Lovastatin and simvastatin: 30 -50% Pravastatin and fuvastatin are active as such Lovastatin and simvastatin must be hydrolyzed to their acid (active) forms.  Pharmacokinetics: All are metabolized in the liver and excreted through bile and feces, but there is also some urinary elimination Their half-lives range from 1.5 to 2 hours. Comparison of some pharmacokinetic parameters for some HMG-CoA reductase inhibitors  Therapeutic uses of HMG-CoA reductase inhibitors : Lowering plasma cholesterol levels in all types of hyperlipidemias Patients who are homozygous for familial hypercholesterolemia lack LDL receptors and, therefore, benefit much less from treatment with these drugs. Adverse effects of HMG CoA reductase Inhibitors: Headache Sleep disturbances Hepatotoxicity Myopathy (muscle tenderness) and rhabdomyolysis Drug interactions: – May increase Warfarin levels Contraindications: During pregnancy and in nursing mothers. In children or teenagers.  Bile acid–binding resins Ø Cholestyramine Ø Colestipol Ø Colesevelam These are bile acid binding resins They are neither digested nor absorbed in the gut These interrupt enterohepatic circulation of bile salts and increase fecal excretion of bile salts and cholesterol Increase in LDL receptor in the liver Effect of bile-acid binding resins  Effect of bile-acid binding resins Compensatory increase in the activity of HMG CoA reductase results in increased cholesterol synthesis and thus increased VLDL secretion – blunting the long term effectiveness of monotherapy Mild increase in triglycerides can be seen. Therapeutic uses of bile-acid binding resins: These are the drugs of choice (often in combination with diet or niacin) in treating Type IIA and Type IIB hyperlipidemias [Note: In those rare individuals who are homozygous for Type IIA, that is, for whom functional LDL receptors are totally lacking, these drugs have little effect on plasma LDL levels] Cholestyramine can also relieve pruritus caused by accumulation of bile acids in patients with biliary obstruction It is also used to treat diarrhea Adverse effects GI disturbances, such as constipation, nausea, and flatulence. Colesevelam has fewer GI side effects than other bile acid sequestrants. At high doses, cholestyramine and colestipol (but not colesevelam) impair the absorption of the fat-soluble vitamins (A, D, E, and K). Drug interactions: Cholestyramine and colestipol interfere with the intestinal absorption of many drugs (for example, tetracycline, phenobarbital, digoxin, warfarin, pravastatin, fuvastatin, aspirin, and thiazide diuretics). Therefore, drugs should be taken at least 1–2 hours before, or 4–6 hours after, the bile acid–binding resins. Cholesterol uptake inhibitor: Ezetimibe It decrease cholesterol absorption by localizing at the brush border of the small intestine. In addition to this direct effect, decreased cholesterol absorption leads to an increase in LDL-cholesterol uptake into cells, thus decreasing levels in the plasma. Can be used in combination with Simvastatin (Vytorin®)  Pharmacokinetics of Ezetimibe Ezetimibe is metabolized in the small intestine and liver via glucuronide conjugation, with subsequent biliary and renal excretion. half-life of approximately 22 hours. Patients with moderate to severe hepatic insufficiency should not be treated with ezetimibe.  Niacin (nicotinic acid) The most rapid effect of nicotinic acid on lipid metabolism is a decrease in plasma levels of free fatty acid , which can be observed within minutes upon administration of the drug. After a few hours, the plasma VLDL and TG levels are reduced, whereas the LDL and HDL cholesterol levels are changed only after several days of treatment. It reduces VLDL and TG production The most effective in increasing HDL Effective in reducing LDL Therapeutic uses of niacin: Niacin lowers both cholesterol and triacylglycerol. So it is useful in the treatment of familial hyperlipidemias. Used in treating severe hypercholesterolemias It is the most potent anti-hyperlipidemic agent for raising plasma HDL levels, which is the most common indication for its clinical use. Adverse effects of Niacin Cutaneous dilator – flushing, itching Liver dysfunction Hyperglycemia Potentiates gout (decrease uric acid secretion), diabetes and peptic ulcers  Fibric acid derivatives Drugs: § Fenofibrate (a prodrug for the active metabolite fenofibric acid) § Gemfibrozil § Clofibrate They lower serum triacylglycerol and increase HDL levels  Mechanism of action of Fibric acid derivatives They interact with the peroxisome proliferator activated receptor alpha (PPARα) which regulates gene expression of enzymes involved in fatty acid oxidation. They increase expression of lipoprotein lipase, which enhances clearance of triglyceride rich lipoproteins. Fibrates also increase the level of HDL cholesterol by increasing the expression of apo AI and apo AII.  Therapeutic uses: Treatment of hyper triacylglycerolemias, causing a significant decrease in plasma triacylglycerol levels. Treatment of Type III hyperlipidemia (dysbetalipo proteinemia), in which intermediate-density lipoprotein particles accumulate. Patients with hypertriacylglycerolemia (Type IV [elevated VLDL] or Type V [elevated VLDL plus chylomicron] disease) who do not respond to diet or other drugs may also benefit from treatment with these agents. Adverse effects : Gall stones with clofibrate Myopathy (Myositis): - Inflammation of skeletal muscles) causing muscle weakness and tenderness - Rhabdomyolysis can occur - Risk is greatly increased in combination with statins (contraindicated) Nausea Skin Rash Drug interactions: Fibrates compete with the coumarin anticoagulants for binding sites on plasma proteins (monitor INR frequently) They may transiently elevate the levels of sulfonylureas. Drugs for Hyperlipoproteinemia Drugs for Hyperlipoproteinemia Drugs Indication Effects On Adverse Lipid Profile Effects Cholestyramine Elevated LDL ↓ LDL(20%) GI problems Colistipol Pregnancy and ↑ TGs (~5%) (bloating, Colesevelam Children constipation) Niacin Elevated LDL, ↓ TG (40%) Flushing of face Low H D L and ↓ LDL (15%) & Pruritus Elevated TG ↑ H D L (25%) Hyperglycemia Gemfibrozil Elevated TG ↓ TG (50%) Myositis ↓ LDL (10%) Gall stones ↑ H D L (15%) HMG- C o A Elevated LDL ↓ LDL (30%) Hepatotoxicity Reductase ↑ H D L (8%) Myositis Inhibitors ↓ TG (20%)