Lec 1. Hyperlipidemia PDF

Al- Kut university collage Pharmacology Lectures 2024 Fourth stage By Dr. Taif M Maruish BSc Pharm., MSc.(Pharmacology& Toxicology), Ph.D. Pharmacology &Toxicology  Drugs for H...

Al- Kut university collage Pharmacology Lectures 2024 Fourth stage By Dr. Taif M Maruish BSc Pharm., MSc.(Pharmacology& Toxicology), Ph.D. Pharmacology &Toxicology  Drugs for Hyperlipidemia Lec 1 9/23/2024 2  Drugs for Hyperlipidemia Hyperlipidemia is abnormally elevated levels of one or all lipids (cholesterol, triglyceride) or lipoproteins (VLDL, LDL) in the blood. Hyperlipidemia as are divided into primary I and secondary subtypes. Primary hyperlipidemia is usually due to genetic causes (such as a mutation in a receptor protein). Secondary hyperlipidemia arises due to other underlying causes such as diabetes. Lipid and lipoprotein abnormalities are common in the general population and are regarded as modifiable risk factors for cardiovascular disease due to their influence on atherosclerosis. In addition, some forms may predispose to acute pancreatitis. 3 4 5 6 7  Treatment goals Plasma lipids consist mostly of lipoproteins, which are spherical complexes of lipids and specific proteins (apolipoproteins). The clinically important lipoproteins are LDL, VLDL, chylomicrons and HDL. The occurrence of coronary heart disease is positively associated with high total cholesterol and more strongly with elevated LDL, meanwhile, high levels of HDL have been associated with a decreased risk for heart disease. Reduction of LDL is the primary goal of cholesterol-lowering therapy. ) 8 IS.im work HMG hydroxy methyl Glutarin vitamin show In B www 9 10 Treatment options for hypercholesterolemia  Lifestyle changes, such as diet, exercise, and weight reduction, can lead to modest decreases in LDL and increases in HDL.  However most patients are unable to achieve significant LDL 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. 11 Treatment options for hypercholesterolemia  Patients with LDL levels higher than 160 mg/dL and with one other major risk factor, such as hypertension, diabetes, smoking, or a family history of early CHD, are candidates for drug therapy. Patients with two or more additional risk factors should be treated aggressively, with the aim of reducing their LDL level to less than 100 mg/dL and, in some patients, to as low as 70 mg/dL 12 Treatment options for hypertriglyceridemia  Elevated triglycerides are independently associated with increased risk of CHD.  Diet and exercise are the primary modes of treating hypertriglyceridemia. If indicated, 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.  [Note: The major lipid component of VLDL is composed of triacylglycerol.] 13 Drugs for hyperlipidemia Antihyperlipidemic drugs include the statins, niacin, fibrates, bile acid– binding resins, a cholesterol absorption inhibitor, and omega-3 fatty acids. These agents may be used alone or in combination. However, drug therapy should always be accompanied by lifestyle modifications, such as exercise and a diet low in saturated fats. 14 HMG-CoA reductase inhibitors Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (commonly known as statins) This group of antihyperlipidemic agents inhibits the first enzymatic step of cholesterol synthesis, and they are the first-line and more effective treatment for patients with elevated LDL cholesterol, resulting in a substantial reduction in coronary events and death from coronary heart disease. They are considered first-line treatment for patients with elevated risk of atherosclerosis. 15  Therapeutic benefits of statins include:  plaque stabilization,  improvement of coronary endothelial function  inhibition of platelet thrombus formation  Anti-inflammatory activity. The value of lowering LDL with statins has been demonstrated in patients with and without established CHD. 16 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.  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. 17 18 Mechanism of action:  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. 19  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. 20 21  Adverse effects: It is noteworthy that during the 5-year trials of simvastatin and lovastatin, only a few adverse effects, related to liver and muscle function, were reported 1- Liver: Biochemical abnormalities in liver function have occurred with the HMG CoA reductase inhibitors. Therefore, it is prudent to evaluate liver function and measure serum transaminase levels periodically. These return to normal on suspension of the drug. [Note: Hepatic insufficiency can cause drug accumulation.]. 22.  Adverse effects: 2-Muscle: Myopathy and rhabdomyolysis (disintegration or dissolution of muscle) have been reported only rarely. In most of these cases, patients usually suffered from renal insufficiency or were taking drugs such as cyclosporine, itraconazole, erythromycin, gemfibrozil, or niacin. Plasma creatine kinase levels should be determined regularly. 3-Drug interactions: The HMG CoA reductase inhibitors may also increase warfarin levels. Thus, it is important to evaluate INR times frequently. 4 -Contraindications: These drugs are contraindicated during pregnancy and in nursing mothers. They should not be used in children or teenagers. 23 Niacin (nicotinic acid) Niacin can reduce LDL by 10% to 20% and is the most effective agent for increasing HDL. It also lowers triglycerides by 20% to 35% at typical doses of 1.5 to 3 grams/day. Niacin can be used in combination with statins, and a fixed-dose combination of lovastatin and long-acting niacin is available. 24  Mechanism of action: At gram doses, niacin strongly inhibits lipolysis in adipose tissue, thereby reducing production of free fatty acids. 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 plasma concentrations 25 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.] 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. 26 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. sideeffect s e É the  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. 27 Fibrates Fenofibrate and gemfibrozil are derivatives of fibric acid that lower serum triglycerides and increase HDL levels. However, fenofibrate is ore effective than gemfibrozil in lowering plasma LDL cholesterol and triglyceride levels. 28  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. 29 They then bind to peroxisome proliferator response elements,which ultimately leads to decreased triglyceride concentrations through increased expression of lipoprotein lipase and decreasing apolipoprotein (apo) CII concentration. Fibrates also increase the level of HDL cholesterol by increasing the expression of apo AI and apo AII 30 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. Fibrates JI rise In. 1 actuatid of PPAR adf.tt i eum a p ef.fi 2 TO enhancing TG 6stimulatefattyacidmetabolism 8 catabolism secretion of VLDL 7 LDL A HDL 3 f inducingHDLlipoprotein II 8 Reversecholesterol s hÉti tryp 3 c 4 Activation of Lipoprotienlipase efflata the 31 Adverse effects: 1-Gastrointestinal effects: The most common adverse effects are mild gastrointestinal disturbances. These lessen as the therapy progresses. 2-Lithiasis: Because these drugs increase biliary cholesterol excretion, there is a predisposition to the formation of gallstones. 3-Muscle: Myositis (inflammation of a voluntary muscle) can occur with both drugs; thus, muscle weakness or tenderness should be evaluated. Patients with renal insufficiency may be at risk. Myopathy and rhabdomyolysis have been reported in a few patients taking gemfibrozil and lovastatin together. 1 Myopathy we ing risk. 2 Fox01 pathway 7 1 5is frjh 3 creatinekinase amigo assist 32 4 Rhabdomyolysis iha geyifib.se bld6 Drug interactions: Both fibrates compete with the coumarin anticoagulants for binding sites on plasma proteins, thus transiently potentiating anticoagulant activity. INR times should therefore be monitored when a patient is taking both drugs. Similarly, these drugs may transiently elevate the levels of sulfonylureas. time is t.IE se Contraindications: The safety of these agents in pregnant or lactating women has not been established. They should not be used in patients with severe hepatic and renal dysfunction or in patients with preexisting gallbladder disease. g INR International Normalized Ratio ma mean misato 4 in 33 Bile acid–binding resins Bile acid sequestrates (resins) have significant LDL cholesterol– lowering effects, although the benefits are less than those observed with statins. 34 Mechanism of action:  Cholestyramine , colestipol , and colesevelam 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. 35 Mechanism of action:  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 surface LDL receptors.] 36  Therapeutic uses:  The bile acid–binding resins are useful (often in combination with diet or niacin) for treating 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. 37 Adverse effects: Gastrointestinal effects: The most common side effects are gastrointestinal disturbances, such as constipation, nausea, and flatulence. Colesevelam has fewer gastrointestinal side effects than other bile acid sequestrants. Impaired absorptions: 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, fluvastatin, aspirin, and thiazide diuretics. Therefore, drugs should be taken at least 1 to 2 hours before, or 4 to 6 hours after, the bile acid “binding resins. 38 Cholesterol absorption inhibitor Ezetimibe selectively inhibits absorption of dietary and biliary cholesterol in we 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%. Due its modest LDL- lowering effects, ezetimibe is often used as an adjunct to statin therapy or in statin-intolerant patients. Patients with moderate to severe hepatic insufficiency should not be treated with ezetimibe. Adverse effects are uncommon with use of ezetimibe. 39 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% to 30%, with small increases in LDL-C and HDL-C. . 40  Omega-3 fatty acids  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 (eicosapentaenoic acid) 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 41 shown to reduce cardiovascular morbidity and mortality.  Omega-3 fatty acids  The most common side effects of omega-3 PUFAs include GI effects (abdominal pain, nausea, and diarrhea) and a fishy aftertaste.  Bleeding risk can be increased in those who are concomitantly taking anticoagulants or antiplatelets. 42 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 currently available combined in one pill to treat elevated LDL cholesterol. However, more clinical information is needed to determine whether combination therapy produces better long-term benefits than the use of a high-dose statin. 43 Combination drug therapy Until this uncertainty is resolved, 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. 44 45