Drugs for Hyperlipidemia Ass.Prof. Dr. Naza M. Ali Lec. 9-10 G2 18 May 2019 G1 22 May 2019

Cigarette smoking, Hypertension, Obesity, Diabetes Coronary Heart Disease (CHD) is the leading cause of death worldwide CHD is correlated with: Elevated levels of LDL-C Elevated level of TG Low levels of HDL-C Other risk factors for CHD include: Cigarette smoking, Hypertension, Obesity, Diabetes

Hyperlipidemias can also result from an inherited defect in lipoprotein metabolism or, from a combination of genetic and life- style factors. Appropriate lifestyle changes, along with drug therapy, can lead to a 30% to 40% reduction in CHD mortality.

TREATMENT GOALS Plasma lipids consist mostly of lipoproteins, which are spherical complexes of lipids and specific proteins (apolipoproteins). Clinically important lipoproteins, listed in decreasing order of atherogenicity, are: LDL, VLDL , chylomicrons, HDL. The occurrence of CHD is positively associated with high total cholesterol and with elevated LDL-C.

Total cholesterol is the sum of LDL-C, VLDL-C, and HDL-C. high levels of HDL-C have been associated with a decreased risk for heart disease. Reduction of LDL-C is the primary goal of cholesterol- lowering therapy.

Adult Treatment Guidelines (2001) National Cholesterol Education Program Adult Treatment Guidelines (2001)

Recent cholesterol guidelines do not recommend targets but instead emphasize high-intensity or moderate-intensity statin therapy in defined populations with risk for atherosclerotic cardiovascular disease (ASCVD). Higher-intensity therapy is recommended in those with established ASCVD or in those with a higher overall risk of heart disease

 Chylomicrons carry triglycerides  from the intestines   to the  liver, to skeletal muscle, and to adipose tissue. VLDL carry (newly synthesized) triglycerides from the liver to adipose tissue. IDL are intermediate between VLDL and LDL. They are not usually detectable in the blood when fasting.

LDL carry 3,000 to 6,000 fat molecules (phospholipids, cholesterol, TG, etc.) around the body. LDL are referred to as "bad" lipoprotein because concentrations, dose related, correlate with atherosclerosis progression. HDL collect fat molecules (phospholipids, cholesterol, TG) from the body's cells/tissues, and take it back to the liver. HDLs are referred to as "good" lipoprotein because higher concentrations correlate with low rates of atherosclerosis progression.

Metabolism of lipoproteins of hepatic origin. The heavy arrows show the primary pathways. Nascent VLDL are secreted via the Golgi apparatus. They acquire additional apo C lipoproteins and apo E from HDL. VLDL are converted to VLDL remnants (IDL) by lipolysis via lipoprotein lipase in the vessels of peripheral tissues. In the process, C apolipoproteins and a portion of the apo E are given back to HDL. Some of the VLDL remnants are converted to LDL by further loss of triglycerides and loss of apo E. A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver and the peripheral tissues, for which apo B-100 is the ligand. Dark color denotes cholesteryl esters; light color denotes triglycerides; the asterisk denotes a functional ligand for LDL receptors; triangles indicate apo E; circles and squares represent C apolipoproteins. RER, rough endoplasmic reticulum.

Metabolism of plasma lipoproteins

Treatment options for hypercholesterolemia Lifestyle changes ( diet, exercise, weight reduction) can lead to modest decreases in LDL-C and increases in HDL-C. Most patients are unable to achieve significant LDL-C reductions with lifestyle modifications alone, and drug therapy may be required. Treatment with statins is the primary treatment option for hypercholesterolemia. Statin therapy is recommended for four major groups as outlined

Treatment options for hypertriglyceridemia Elevated TG are independently associated with increased risk of CHD. Diet and exercise are the primary modes . Niacin & fibric acid derivatives are most efficacious in lowering TG. Omega-3 fatty acids in adequate doses may also be beneficial. TG reduction is a secondary benefit of the statins, with the primary benefit being reduction of LDL-C.

Effect of circulating LDL and HDL on the risk of coronary heart disease

Antihyperlipidemic drugs Statins Niacin Fibrates Bile acid– binding resins Ezetimibe Omega-3 fatty acids. PSC9 inhibitor Drug therapy should always be accompanied by lifestyle modifications, (exercise and a diet low in saturated fats) .

Lovastatin, Simvastatin, Pravastatin, Statins / HMG CoA reductase inhibitors 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lower elevated LDL-C, Lovastatin, Simvastatin, Pravastatin, Atorvastatin, Fluvastatin, Pitavastatin , Rosuvastatin

Mechanism of Action The rate limiting step in hepatic cholesterol synthesis is conversion of hydroxy-methyl-glutaryl coenzyme A to mevalonate by HMG-CoA reductase. The statins are structural analogs of HMG-CoA that competitively inhibit the enzyme . They will fit into the enzyme's active site and compete with the native substrate (HMG-CoA).

By inhibiting de novo cholesterol synthesis, they deplete the intracellular supply of cholesterol Depletion of intracellular cholesterol causes the cell to increase the number of cell surface LDL receptors that can bind and internalize circulating LDLs. Plasma cholesterol is reduced, by both decreased cholesterol synthesis and increased LDL catabolism.

Pitavastatin, rosuvastatin, and atorvastatin are the most potent LDL cholesterol–lowering statins, followed by simvastatin, pravastatin, and then lovastatin and fluvastatin.

Because these agents undergo a marked first-pass extraction by the liver, their dominant effect is on that organ. The HMG CoA reductase inhibitors also decrease triglyceride levels and may increase HDL cholesterol levels in some patients.

Therapeutic uses: are effective in 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.

Pharmacokinetics: Lovastatin and simvastatin are lactones that are hydrolyzed to the active drug. The remaining statins are all administered in their active form. Absorption of the statins is variable (30% - 85%) following oral administration. All statins are metabolized in the liver Excretion takes place principally through bile and feces, but some urinary elimination also occurs.

Adverse effects: Elevated liver enzymes may occur with statin therapy. liver function should be evaluated prior to starting therapy and if a patient has symptoms consistent with liver dysfunction. 2.Myopathy and rhabdomyolysis have been reported.

Simvastatin is metabolized by cytochrome P450 3A4, and inhibitors of this enzyme may increase the risk of rhabdomyolysis. Plasma creatine kinase levels should be determined in patients with muscle complaints. They increase the effect of warfarin. They are contraindicated during pregnancy and lactation.

2. Niacin (nicotinic acid) Reduce LDL-C by 10% - 20% is the most effective agent for increasing HDL-C. also lowers TG by 20% - 35%

Mechanism of action: At gram doses, niacin strongly inhibits lipolysis in adipose tissue, thereby reducing production of FFA The liver normally uses circulating FFA as a major precursor for TG synthesis. Reduced liver TG levels decrease hepatic VLDL production, which in turn reduces LDL-C plasma concentrations.

Niacin inhibits lipolysis in adipose tissue

Therapeutic uses: Niacin lowers plasma levels of both cholesterol and TG, it is useful in the treatment of familial hyperlipidemias. used in combination with other agents.

Pharmacokinetics Administered orally. It is converted in the body to nicotinamide Adverse effects: an intense cutaneous flush and pruritus. Administration of aspirin prior to taking niacin decreases the flush, Slow titration of the dosage

3. Fibrates Fenofibrate Gemfibrozil, Benzafibrate are derivatives of fibric acid that lower serum TG and increase HDL levels.

Bezafibrate  is the first agonist that affects all three peroxisome proliferator-activated receptors (PPARs) subtypes, PPARα, PPARγ, and PPARδ. Activation of PPARα reduces triglycerides, Activation of PPARγ causes insulin sensitization & increases glucose metabolism Activation of PPARδ enhances fatty acid metabolism. 

Mechanism of Action: The PPARs are members of the nuclear receptor family that regulates lipid metabolism. Upon binding to their natural ligands (fatty acids or eicosanoids) or antihyperlipidemic drugs, PPARs are activated. They then bind to peroxisome proliferator response elements, which ultimately leads to decreased TG concentrations through increased expression of lipoprotein lipase

Activation of lipoprotein lipase by gemfibrozil.

Therapeutic uses: in the treatment of hypertriglyceridemias. Pharmacokinetics: Gemfibrozil and fenofibrate are completely absorbed after oral administration and distribute widely, bound to albumin. Fenofibrate is a prodrug, which is converted to the active moiety fenofibric acid.

Adverse effects: mild GI disturbances. These lessen as the therapy progresses. Because these drugs increase biliary cholesterol excretion, there is a predisposition to form gallstones. Myositis (inflammation of a voluntary muscle) can occur, and muscle weakness or tenderness should be evaluated. may increase the effects of warfarin. Fibrates should not be used in patients with severe hepatic or renal dysfunction or in patients with preexisting gallbladder disease.

4. Bile acid–binding resins have significant LDL cholesterol– lowering effects, Cholestyramine, Colestipol Colesevelam

Mechanism of action: are anion-exchange resins that bind negatively charged bile acids and bile salts in the small intestine. The resin/bile acid complex is excreted in the feces, thus lowering the bile acid concentration. This causes hepatocytes to increase conversion of cholesterol to bile acids, which are essential components of the bile.

Mechanism of bile acid–binding resins.

intracellular cholesterol concentrations decrease, which activates an increased hepatic uptake of cholesterol- containing LDL particles, leading to a fall in plasma LDL-C. Note: This increased uptake is mediated by an up- regulation of cell surface LDL receptors.

Therapeutic uses: are useful for treating type IIA and type IIB hyperlipidemias. Cholestyramine can also relieve pruritus caused by accumulation of bile acids in patients with biliary stasis. Colesevelam is also indicated for type 2 diabetes due to its glucose-lowering effects.

Pharmacokinetics: Bile acid sequestrants are insoluble in water and have large molecular weights. After oral administration, they are neither absorbed nor metabolically altered by the intestine. they are totally excreted in feces.

Adverse effects: GI disturbances( constipation, nausea, and flatulence). These agents may impair the absorption of the fat-soluble vitamins (A, D, E, and K), and they interfere with the absorption of many drugs ( digoxin, warfarin, and thyroid hormone). other drugs should be taken at least 1 to 2 hours before, or 4 to 6 hours after, the bile acid–binding resins.

5. Cholesterol absorption inhibitor Ezetimibe Selectively inhibits absorption of dietary and biliary cholesterol in the small intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood.

Ezetimibe lowers LDL cholesterol by approximately 17%. Is metabolized in the small intestine and liver via glucuronide conjugation, with subsequent biliary and renal excretion

Docosahexaenoic acid / DHA found in tuna and salmon 6. Omega-3 fatty acids Eicosapentaenoic acid / EPA Docosahexaenoic acid / DHA found in tuna and salmon Omega-3 PUFA are essential fatty acids used for TG lowering. Essential fatty acids inhibit VLDL and TG synthesis in the liver. Omega-3 can be used as an adjunct to other lipid-lowering therapies for individuals with significantly elevated TG (≥500 mg/dL). Omega-3 has not been shown to reduce CV morbidity & mortality.

Combination drug therapy It is often necessary to use two antihyperlipidemic drugs to achieve treatment goals in plasma lipid levels. The combination of an HMG CoA reductase inhibitor with a bile acid– binding agent has been shown to be very useful in lowering LDL-C levels Simvastatin and ezetimibe, as well as simvastatin and niacin, are available combined in one pill to treat elevated LDL cholesterol. Liver and muscle toxicity occurs more frequently with drug combinations.

HMG-CoA reductase inhibitor / In liver Elevated liver enzymes, Drug M.O.A Side effects Statins HMG-CoA reductase inhibitor / In liver Elevated liver enzymes, Myopathy Niacin strongly inhibits lipolysis / in adipose tissue intense cutaneous flush, pruritus Fibrate Bind to peroxisome proliferator activator response elements, increased expression of lipoprotein lipase GIT disturbance, Myositis Bile acid–binding resins The resin/bile acid complex lowering the bile acid concentration. increase conversion of cholesterol to bile acids GIT disturbance Ezetimibe Ezetimibe selectively inhibits absorption of dietary and biliary cholesterol in the small intestine tiredness or weakness PCSK9 inhibitors/ SC Alirocumab Monoclonal antibodies. inactivate a specific protein in the liver Hypersensitivity reactions

Which one of the following is the most common side effect of antihyperlipidemic drug therapy? A.Elevated blood pressure. B. Gastrointestinal disturbance. C. Neurologic problems. D. Heart palpitations. E. Migraine headaches.  Which one of the following hyperlipidemias is characterized by elevated plasma levels of chylomicrons and has no drug therapy available to lower the plasma lipoprotein levels? A. Type I. B. Type II. C. Type III. D. Type IV. E. Type V.  Which one of the following drugs decreases cholesterol synthesis by inhibiting the enzyme 3-hydroxy-3- methylglutaryl coenzyme A reductase? A.Fenofibrate. B. Niacin. C. Cholestyramine. D. Lovastatin. E. Gemfibrozil.

 Which one of the following drugs causes a decrease in liver triglyceride synthesis by limiting available free fatty acids needed as building blocks for this pathway? A. Niacin. B. Fenofibrate. C. Cholestyramine. D. Gemfibrozil. E. Lovastatin. Which one of the following drugs binds bile acids in the intestine, thus preventing their return to the liver via the enterohepatic circulation? D. Fluvastatin. E. Lovastatin.

https://www.youtube.com/watch?v=Of1Aewx-zRM Correct answer = B. Correct answer = A. Correct answer = D. Correct answer = C. https://www.youtube.com/watch?v=Of1Aewx-zRM