Pharmacology Lec13 (Dyslipidemia) Dr.Yassir PDF

1/15/2022 drugs for hyperlipidemia 22 OVERVIEW: Coronary heart disease (CHD) is the leading cause of death worldwide. CHD is correlated with elevated levels of low-density lipoprotein cholesterol (LDL-C; bad cholesterol) and triglycerides and low leve...

1/15/2022 drugs for hyperlipidemia 22 OVERVIEW: Coronary heart disease (CHD) is the leading cause of death worldwide. CHD is correlated with elevated levels of low-density lipoprotein cholesterol (LDL-C; bad cholesterol) and triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C; good cholesterol ). Other risk factors for CHD include: cigarette smoking, hypertension, obesity, and diabetes. Cholesterol levels may be elevated due to lifestyle factors (for example, lack of exercise or diet containing excess saturated fats). Hyperlipidemias can also result from an inherited defect in lipoprotein metabolism or, more commonly, from a combination of genetic and lifestyle factors. Appropriate lifestyle changes, along with drug therapy, can lead to a (30-40) % reduction in CHD mortality. Antihyperlipidemic drugs (Figure 23.1) are often taken indefinitely to control plasma lipid levels. 1  1/15/2022 Drugs for hyperlipidemia: 1. HMG CoA REDUCTASE INHIBITORS (STATINS) Atorvastatin LIPITOR Fluvastatin LESCOL Lovastatin MEVACOR Pitavastatin LIVALO Pravastatin PRAVACHOL Rosuvastatin CRESTOR Simvastatin ZOCOR 2. FIBRATES Gemfibrosil LOPID Fenofibrate TRICOR, LOFIBRA, TRIGLIDE 3. NIACIN Niacin NIASPAN, SLO-NIACIN 4. CHOLESTEROL ABSORPTION INHIBITOR Ezetimibe ZETIA 5. BILE ACID SEQUESTRANTS Colesevelam WELCHOL Colestipol COLESTID Cholestyramine QUESTRAN, PREVALITE 6. OMEGA-3 FATTY ACIDS Docosahexaenoic and eicosapentaenoic acids LOVAZA, various OTC preparations Icosapent ethyl VASCEPA Figure 23.2 illustrates the normal metabolism of serum lipoproteins and the characteristics of the major genetic hyperlipidemias. 2  1/15/2022 most patients are unable to achieve significant LDL-C reductions with lifestyle modifications alone, and drug therapy may be required Treatment with HMG CoA reductase inhibitors (statins) is the primary treatment option for hypercholesterolemia. Statin therapy is recommended for four major groups as outlined in Figure 23.4) B. Treatment options for hypertriglyceridemia Elevated triglycerides are independently associated with increased risk of CHD Diet and exercise are the primary modes of treating hypertriglyceridemia. Drugs: niacin and fibric acid derivatives are the most efficacious in lowering triglycerides Omega 3 fatty acids (fish oil in adequate doses may also be beneficial Triglyceride reduction is a secondary benefit of the statins, with the primary benefit being reduction of LDL-C 3  1/15/2022 II. DRUGS FOR HYPERLIPIDEMIA A. HMG CoA reductase inhibitors 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (commonly known as statins) lower elevated LDL-C, resulting in a substantial reduction in coronary events and death from CHD. They are considered first-line treatment for patients with elevated risk of atherosclerotic cardiovascular disease (ASCVD). Therapeutic benefits include plaque stabilization, improvement of coronary endothelial function, inhibition of platelet thrombus formation, and anti-inflammatory activity. The value of lowering LDL-C with statins has been demonstrated in patients with and without established CHD. 1. Mechanism of action: Lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, pitavastatin and rosuvastatin are competitive inhibitors of HMG CoA reductase, the rate-limiting step in cholesterol synthesis. By inhibiting de novo cholesterol synthesis, they deplete the intracellular supply of cholesterol (Figure 23.5). Depletion of intracellular cholesterol causes the cell to increase the number of cell surface LDL receptors that can bind and internalize circulating LDLs. Thus, 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. [Note: 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. 4  1/15/2022 2. Therapeutic uses: These drugs are effective in lowering plasma cholesterol levels in all types of hyperlipidemias. However, patients who are homozygous for familial hypercholesterolemia lack LDL receptors and, therefore, benefit much less from treatment with these drugs. 3. 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, with some metabolites retaining activity. Excretion takes place principally through bile and feces, but some urinary elimination also occurs. Their half-lives are variable. Figure 23.6 4. Adverse effects: Elevated liver enzymes may occur with statin therapy. Therefore, liver function should be evaluated prior to starting therapy and if a patient has symptoms consistent with liver dysfunction. [Note: Hepatic insufficiency can cause drug accumulation.] 5  1/15/2022 Myopathy and rhabdomyolysis (disintegration of skeletal muscle; rare) have been reported. In most of these cases, patients usually had renal insufficiency or were taking drugs such as erythromycin, gemfibrozil, or niacin. Simvastatin is metabolized by cytochrome P450 3A4, and inhibitors of this enzyme may increase the risk of rhabdomyolysis. Plasma creatine kinase CK levels should be determined in patients with muscle complaints. The HMG CoA reductase inhibitors may also increase the effect of warfarin. Thus, it is important to evaluate international normalized ratio (INR) frequently. These drugs are contraindicated during pregnancy and lactation. B. Niacin (nicotinic acid) Niacin can reduce LDL-C by (10-20) % and is the most effective agent for increasing HDL-C. It also lowers triglycerides by (20-35) % at typical doses of 1.5-3 g/d. Niacin can be used in combination with statins, and a fixed-dose combination of lovastatin and long-acting niacin is available. 1. Mechanism of action: At gram doses, niacin strongly inhibits lipolysis in adipose tissue, thereby reducing production of free fatty acids (Figure 23.8). The liver normally uses circulating free fatty acids as a major precursor for triglyceride synthesis. Reduced liver triglyceride levels decrease hepatic VLDL production, which in turn reduces LDL-C plasma concentrations. 6  1/15/2022 2. Therapeutic uses: Since niacin lowers plasma levels of both cholesterol and triglycerides, it is useful in the treatment of familial hyperlipidemias. It is also used to treat other severe hypercholesterolemias, often in combination with other agents. 3. Pharmacokinetics: Niacin is administered orally. It is converted in the body to nicotinamide, which is incorporated into the cofactor nicotinamide adenine dinucleotide (NAD+). Niacin, its nicotinamide derivative, and other metabolites are excreted in the urine. [Note: Nicotinamide alone does not decrease plasma lipid levels.] 4. Adverse effects: The most common side effects of niacin are an intense cutaneous flush (accompanied by an uncomfortable feeling of warmth) and pruritus. Administration of aspirin prior to taking niacin decreases the flush, which is prostaglandin mediated. Some patients also experience nausea and abdominal pain. Slow titration of the dosage or usage of the sustained-release formulation of niacin reduces bothersome initial adverse effects. Niacin inhibits tubular secretion of uric acid and, thus, predisposes to hyperuricemia and gout. Impaired glucose tolerance and hepatotoxicity have also been reported. The drug should be avoided in hepatic disease. 7  1/15/2022 C. Fibrates Fenofibrate and gemfibrozil are derivatives of fibric acid that lower serum triglycerides and increase HDL levels. 1. Mechanism of action: The peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor family that regulates lipid metabolism. PPARs function as ligand-activated transcription factors. 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 triglyceride concentrations through increased expression of lipoprotein lipase (Figure 23.9) and decreasing apolipoprotein (apo) CII concentration. Fenofibrate is more effective than gemfibrozil in lowering triglyceride levels. Fibrates also increase the level of HDL cholesterol by increasing the expression of apo AI and apo AII. 2. Therapeutic uses: The fibrates are used in the treatment of hypertriglyceridemias. They are particularly useful in treating type III hyperlipidemia (dysbetalipoproteinemia), in which intermediate density lipoprotein particles accumulate. 3. 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. Both drugs undergo extensive biotransformation and are excreted in the urine as glucuronide conjugates. 8  1/15/2022 4. Adverse effects: The most common adverse effects are mild gastrointestinal (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. Patients with renal insufficiency may be at risk. Myopathy and rhabdomyolysis have been reported in patients taking gemfibrozil and statins together. The use of gemfibrozil is contraindicated with simvastatin. Both fibrates may increase the effects of warfarin. INR should, therefore, be monitored more frequently when a patient is taking both drugs. Fibrates should not be used in patients with severe hepatic or renal dysfunction or in patients with preexisting gallbladder disease. D. Bile acid binding resins Bile acid sequestrants (resins) have significant LDL cholesterol lowering effects, although the benefits are less than those observed with statins. 1. Mechanism of action: Cholestyramine, colestipol and colesevelam are anion- exchange resins that bind negatively charged bile acids and bile salts in the small intestine (Figure 23.10). 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. Consequently, 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 surfaceLDL receptors.] 9  1/15/2022 2. Therapeutic uses: The bile acid binding resins are useful (often in combination with diet or niacin) for treating type IIA and type IIB hyperlipidemias. [Note: In those rare individuals who are homozygous for type IIA and 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 stasis. Colesevelam is also indicated for type 2 diabetes due to its glucose-lowering effects. 3. 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. Instead, they are totally excreted in feces. 4. Adverse effects: The most common side effects are GI disturbances, such as constipation, nausea, and flatulence. Colesevelam has fewer GI side effects than other bile acid sequestrants. 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 (for example, digoxin, warfarin, and thyroid hormone). Therefore, other drugs should be taken at least 1 to 2 hours before, or 4 to 6 hours after, the bile acid binding resins. These agents may raise triglyceride levels and are contraindicated in patients with significant hypertriglyceridemia ( 400 mg/dL). E. 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. Modest LDL-C effects by approximately 17%. Often used as an adjunct to statin therapy or in statin-intolerant patients. Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation, with subsequent biliary and renal excretion. Patients with moderate to severe hepatic insufficiency should not be treated with ezetimibe. Adverse effects are uncommon. 10  1/15/2022 F. Omega-3 fatty acids: Omega-3 polyunsaturated fatty acids (PUFAs) are essential fatty acids that are predominately used for triglyceride lowering. Essential fatty acids inhibit VLDL and triglyceride synthesis in the liver. The omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in marine sources such as tuna, halibut, and salmon. Approximately 4 g of marine-derived omega-3 PUFAs daily decreases serum triglyceride concentrations by (25-30) %, with small increases in LDL-C and HDL-C. Over-the-counter or prescription fish oil capsules (EPA/DHA) can be used for supplementation, as it is difficult to consume enough omega-3 PUFAs from dietary sources alone. Icosapent ethyl is a prescription product that contains only EPA and, unlike other fish oil supplements, does not significantly raise LDL-C. Omega-3 PUFAs can be considered as an adjunct to other lipid-lowering therapies for individuals with significantly elevated triglycerides ( 500 mg/dL). Although effective for triglyceride lowering, omega-3 PUFA supplementation has not been shown to reduce cardiovascular morbidity and mortality. The most common side effects: GI effects (abdominal pain, nausea, diarrhea) and a fishy aftertaste. Bleeding risk can be increased in those who are concomitantly taking anticoagulants or antiplatelets. G. 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 (Figure 23.11). Simvastatin and ezetimibe, as well as simvastatin and niacin, are currently available combined in one pill to treat elevated LDL cholesterol. There is uncertainty about the long-term benefits of combination therapy and the use of a high-dose statin. 11  1/15/2022 Many experts recommend maximizing statin dosages and adding niacin or fibrates only in those with persistently elevated triglycerides (greater than 500 mg/dL) or those with low HDL cholesterol levels (less than 40 mg/dL). Combination drug therapy is not without risks. Liver and muscle toxicity occurs more frequently with lipid-lowering drug combinations. 12