Dyslipidaemia and Antihyperlipidemic Agents

Dyslipidaemia and Antihyperlipidemic Agents Summer 2020 Antihyperlipidemic Agents Classes of Hyperlipidemia Medications: 1. HMG-CoA Reductase Inhibitors (Statins). 2. Bile Acid Sequestrants (Resins). 3. Niacin (Nicotinic acid or Vitamin B3). 4. Fibric Acid Derivatives (Fibrates). 5. Cholesterol Absorption Inhibitors (Ezetimibe). 6. Omega- 3 Fatty Acids 7. Other agents HMG-CoA Reductase Inhibitors (Statins) Atorvastation (Lipitor) Fluvastatin (Lescol XL) Lovastatin (lipdip) Pravastatin (lipostat) Rosuvastatin (Crestor) Simvastatin (Zocor) Pitavastatin (livalo) ❑ 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (commonly known a as statins) lower elevated LDL-C, resulting in a substantial reduction in coronary events and death from coronary heart disease (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. Pharmacokinetics Bioavailability (%) Half-life (h) Metabolism Prodrug Solubility Atorvastation 12 14 3A4 NO Lipophilic Fluvastatin 24 1 2C9 NO Hydrophilic Lovastatin <5 2-3 3A4 YES Lipophilic Pravastatin 17 1.5-2 Non CYP NO Hydrophilic Rosuvastatin 20 20 2C19 NO Hydrophilic Simvastatin <5 2 3A4 YES Lipophilic Pitavastatin 51 12 2C9.2C8 YES Lipophilic Mechanism of action Therapeutic uses ❑ Pitavastatin, Rosuvastatin and Atorvastatin are the most potent LDL cholesterol lowering statins, followed by Simvastatin and Pravastatin then Lovastatin and Fluvastatin. ❑ Statins are useful alone or with resins, niacin or ezetimibe in reducing levels of LDL. ❑ Because cholesterol synthesis occurs predominantly at night, statins except atorvastatin and rosuvastatin should be given in the evening if a single daily dose is used . ❖ Use in children is restricted to selected patients with familial hypercholesterolemia or familial combined hyperlipidemia. ❖ Women with hyperlipidemia who are pregnant, lactating or likely to become pregnant should not be given these agents, Efficacy Reduce LDL-C by 24-60% Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin 55% 24% 34% 43% 34% 60% 41% Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin 29% 10% 16% 18% 24% 18% 18% Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin 6% 8% 9% 8% 12% 8% 12% Reduce TGs by 10-29% Raise HDL-C by 6-12% ❖ Reduce major coronary events ❖ Reduce CHD mortality. ❖ Reduce coronary procedures (PCI or CABG) ❖ Reduce stroke by 17% ❖ Reduce total mortality. Side effects ❑ Hepatic; ✓ Elevated liver enzymes up to 3 times normal in some patients. ✓ Monitoring is usually needed (liver function test); at 1-2 months, and then every 6-12 months (if stable). ✓ Statins should be discontinued in patients whose liver enzymes activity is persistently elevated to more than three times the upper limit of normal. ❑ Muscle; ✓ The most common statin side effect is muscle pain (10-15%). ✓ Rare reactions statins can cause myopathy (inflammation of the muscles). ✓ very rarely, stats can cause life-threatening muscle damage called rhabdomyolysis, severe muscle pain, liver damage, kidney failure and death. ✓ Monitoring, check creatine kinase (CK) at baseline and then only if muscle symptoms occur, no regular monitoring. The risk of statin-induced rhabdomyolysis increases with older age, use of interacting medications such as fibrates and hypothyroidism. ❖ Coenzyme Q10 supplements are sometimes used to treat statin-associated myopathy. ❖ CoQ10 (is a cofactor for mitochondrial energy production) levels are decreased in statin use Side effects Digestive: • Some people taking a statin may develop nausea, gas, diarrhea or constipation after taking a Statin. Neurological • Meta-analysis reported cognitive impairment (memory loss) from statin use for several years. “FDA Warning” (Last Updated January 31, 2014) 1) FDA has found that liver injury associated with statin use is rare but can occur. 2) Some drugs interact with statins in a way that increases the risk of muscle injury called myopathy, characterized by unexplained muscle weakness or pain. FDA is revising the drug lable for lovastatin to clarify the risk of myopathy 3) FDA has been investigating reports of cognitive impairment (memory loss) from statin use for several years. 4) A Small increased risk of raised blood sugar levels and the development of type 2 diabetes have been reported with the use of statin. Drug interactions ❑ Fibrates: Increase risk of myopathy and rhabdomyolysis when coadministered with statins. (Gemfibrozil greater than Fenofibrate). ❑ Niacin: Doses greater than 1 g/day increase the risk of myopathy and rhabdomyolysis when used concomitantly with statins: Risk is lower than with fibrates; when statins and niacin are used together monitor for muscle pain. ❑ Amiodarone, Verapamil and Diltiazem also causes an increased risk of myopathy when used with lovastatin and simvastatin (dose monitoring is needed). ❑ Inhibitors of CYP3A4 such as Macrolide antibiotics, cyclosporine, ketoconazole (and other azoles), some HIV protease inhibitors, Tacrolimus and Nefazodone may increase plasma levels of CYP3A4- dependent reductase inhibitors (Lovastatin, Simvastatin, and Atorvastatin). ❑ Grapefruit juice Plasma levels. of Lovastatin, Simvastatin and Atorvastatin may be elevated in patients ingesting more than 1 liter of grapefruit juice daily. Contraindications ➢ Active liver dsease, unexplained persistent elevations in liver enzymes. ➢ Pregnnancy (FDA Pregnancy Category X) ➢ Lactating women (Nursing mothers) Bile Acid sequestrants (Resins) Cholestyramine (questran) Colesevelam (Cholestagel) Colestipol (Colestid) Bile salts (-ve charge) is manufactured and secreted by the liver and stored in the gallbladder responsible for emulsifies fat and lipids to facilitate absorption in the intestine. Pharmacokinetics and Mechanism of action ❑ Bile acid sequestrants are insoluble in water and have large Mwt. ❑ After oral administration, they are not absorbed and not metabolically altered by the intestine. ❑ They are totally excreted in feces ----------------------------------------------------------------------------------------------------------------------❑ Bile acid sequestrants are anion-exchange resins that bind negatively charged bile acids in the small intestine. ❑ Resin/bile acid complex is excreted in the feces – lowering bile acid concentration – this causes hepatocytes to increase conversion of cholesterol to bile acids. ❑ Consequently; ✓ Decrease intracellular cholesterol concentrations ✓ Increase hepatic uptake of LDL-C ✓ Decrease in plasma LDL-C. ❑ Efficacy ✓ Reduce LDL-C by 15-26% ✓ Raise HDL-C BY 3-6% ✓ May increase TG concentrations. ✓ Reduce major coronary events ✓ Reduce CHD mortality ❑ Therapeutic Uses ✓ Resins are also used in combination with other drags to achieve further hypocholesterolemia effect in patients with primary hypercholesterolemia and treating type IIA and type IIB hyperlipidemias. ✓ Cholestyramine can also relieve pruritus caused by accumulation of bile acids in patients with biliary stasis. ✓ Because the resins bind finials glycosides, they may be useful in digitalis, toxicity. ✓ Colesevelam is also indicated for type 2 diabetes due to its glucose lowering effects. Side effects ❑ GI disturbances: Such as: constipation, nausea and flatulence Colesevelam has fewer GI side effects ❑ Malabsorption of fat soluble vitamins (A, D,E and K) may occur; Usually not used with pregnant women due to vitamin deficiencies that may affect the fetus. Drug interactions ❑ Absorption of certain drugs. including those with neutral or cationic charge as well as anions, may be impaired by the resins. These include • Digitalis glycosides, Thiazides, Warfarin, Tetracycline, thyroxine, Iron salts, Pravastatin, Fluvastatin, Ezetimibe, Folic acid, Phenylbutazone, Aspirin, and Ascorbic acid, among others. • Colesevelam does not bind Digoxin, Warfarin or Statins. In general additional medication (except Niacin) should be given at least 1 to 2 hours before or 4 to 6 hours after, the bile acid binding resins. Contraindications: these agents may raise triglyceride levels and are contraindicated patients with significant hypertrighyceridemia (> 400 mg/dL) Niacin (Nicotinic Acid or Vitamin B3) Niacin or Nicotinic acid (not Niacinamide) is a Vitamin B3, it is primarily used to treat hypercholesterolemia and pellagra (niacin deficiency). - It occurs naturally in plants and animals and is also added to many foods as a vitamin supplement. It is also present in many multiple vitamins and nutritional supplements. ❑ Pharmacokinetics - Niacin is administered orally. - It is converted in the body to nicotinamide, which is incorporated into the cofactor nicotinamide adenine dinucleotide (NAD+) - Niacin and its other derivative metabolites are excreted in the urine. N.B Nicotinamide alone does not decrease plasma lipid levels. ❑ Mechanism of action ✓ 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. - Reduces liver triglyceride levels. Decrease hepatic VLDL Production Reduces LDL-C plasma concentration ❑ Therapeutic uses ✓ Niacin often used in combination with a Resin or Statins, it normalizes LDL in most patents with familial hypercholesterolemia and other forms of hypercholesterolemia, ✓ Used in niacin deficiency (pellagra). ✓ Niacin or Nicotinanide used topically for many skin problems. ❑ Efficacy ✓ ✓ ✓ ✓ ✓ Lowers TG by 20-50% Raises HDL-C by 15-26% Lowers LDL-C by 15 -26% Reduces major coronary events Lowers lipoprotein ❑ Side effects 1) Niacin flush (Facial Flushing): The most common side effects of niacin are an intense cutaneous flush (accompanied by an uncomfortable feeling of warmth) and pruritus, due to prostaglandin mediated vasodilation effect. • Symptoms occurred in up to 78% of patients and usually resolved after 2 weeks of continued therapy. • Flushing usually lasts for about 15 to 30 minutes. Flushing can be minimized by: 1- taking aspirin 325 mg or ibuprofen 200 mg 30-60 minutes before niacin. 2- use of an extended release form of the drug. 3- gradual dosage titration (over 2 to 3 months) 4- administering the dose during or within 30min after meals. 5- taking Niacin at bedtime with food and avoiding hot beverages, spicy foods and hot showers around the time of administration. Side effects 2) Upper GI Distress Some patients experience nausea and dyspepsia (indigestion), 3) Hepatic ✓ Reversible elevations in liver enzymes up to twice normal may occur, usually not associated with liver toxicity. ✓ Monitor liver enzymes level, every 6-12 weeks and then yearly. 4) Metabolic; ✓ Hyperuricemia; due to niacin inhibits tubular secretion of uric acid, more common in men. Allopurinal can be given with niacin if needed. ✓ Carbohydrate tolerance (hyperglycemia) may be moderately impaired, especially in obese patients, but this is usually reversible. 5) Other: ✓ Rarely, niacin is associated with arrhythmias. Fibric Acid Derivatives (Fibrates) Fenofibrate (lipanthyl) Gemfibrozil (lopid) The most common fibrates used are fenofibrate and Gemfibrozil another fibrate such as, Bezafibrate, is not yet available in the USA ❑ Pharmacokinetics - Fenofibrate: -It is a pro-drug of active chemical moiety Fenofibric acid. - Completely absorbed after oral administration, distribute widely and bound to plasma proteins. - Plasma half-life is 20 hours. - 60 % Is excreted in the urine as the glucuronide and 25% in feces Gemfibrozil: - Completely absorbed after oral administration , distribute widely and bound to plasma proteins. - Plasma half life is 1.5 hours. - 70% is excreted in the urine as the glucuronide. ❑ Mechanism of action Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor supergene family that regulates lipid metabolism. Upon binding to their natural ligands (fatty acids or eicosanoids) PPARs are activated. Fibrates function primarily as ligands for the nuclear transcription receptor (PPAR-a) activate PPAR-A: ✓ Decreased triglyceride concentrations by increasing the expression of lipoprotein lipase and decreasing Apo-CIII concentration (an inhibitor of lipolysis) ✓ Increase the level of HDL-C by increasing the expression of Apo-AI and Apo-AII. ✓ Levels of VLDL decrease, in part as a result of decreased secretion by the liver; only modest reductions of LDL occur in most patients Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor- ,lareves fo noisserpxe eht setaludom hcihw , α LPL .snietorp snietorpopil ytisned-wol-yrev ,LDLV ;esapil nietorpopil ❑ Efficacy ➢ ➢ ➢ ➢ ➢ Lowers LDL-C by 5 -20% (with normal TGs) May raise LDL-C by 45% (with very high TGs) Lowers TG by 30-55%. Raises HDL-C by 18-22% Reduces progression of coronary lesions. ❑ Therapeutic uses ✓ ✓ ✓ ✓ They are useful in severe hypertriglyceridemia. They are useful in hypertriglyceridemia in which VLDL predominate. They are useful in dysbetalipoproteinemia (Type IV hyperlipidemia). They also may be of benefit in treating the hypertriglyceridemia that results from treatment with viral protease inhibitors. ❑ Side Effects Mild GI disturbances; Mild GI disturbances are the most common. Gallstones; Gallstones may occur due to biliary cholesterol excretion. Myositis: Muscle inflammation and pain can occur. Myopathy and rhabdomyolysis have been reported in patients taking Gemfibrozil and Statins together. The use of Gemfibrozil is contraindicated with Simvastatin. Fenofibrate is the fibrate of choice for use in combination with a statins. Hepatic: Elevated liver enzymes may occur in some patients (monitor liver enzymes every 3 months during first year). Pregnancy: category C. ❑ Contraindications: severe renal or hepatic disease and patients with preexisting gallbladder disease Cholesterol Absorption inhibitors Ezetimibe is the first member of a group of drugs that inhibit intestinal absorption of cholesterol. ❑Pharmacokinetics • Absorption: it is absorbed and extensively - conjugated to. active a glucuronide (Ezetimibe-glucuronide). • Protein binding; Ezetimibe-glucuronide are highly bound (>90%) to plasma proteins. • Peak: plasma peak attained within 12-14 hours : Plasma concentrations are substantially increased when it is administered with Fibrates and reduced when it is given with Choleyramine. • Half life : 22 hours. • Excretion; approximately 80% of the drug Is excreted in feces. ❑ Mechanism of Action ✓ It acts by blocking a transporter protein, NPC1L1, in the brush border of enterocytes ✓ Is the first member of a group of drugs that selectively inhibits a transporter that mediates gastrointestinal uptake of cholesterol and phytosterols. ✓ Leading to a decrease in the delivery of intestinal cholesterol to the liver. ✓ Reduction of hepatic cholesterol stores, leading to an increase in clearance of cholesterol from the blood. ❑ Efficacy - Lowers LDL-C by 18-20% - May raise HDL-C by 1-5% - Lowers TG by 5-10 % Ezetimibe binds to the NPC1L1 protein on epithelial cells, blocking the absorption of cholesterol ❑ Therapeutic uses Ezetimibe is synergistic with Statins, so it is often used as an; ✓ Adjunct to statin therapy. ✓ Statin-intolerant patients Recent data, suggest that ezetimibe combination with simvastatin is superior than simvastatin alone in reducing cardiovascular event. ❑ Side effects Headache and rash (rare). ❑ Drug interaction : there are no significate interactions Effectofon LDL Effect onefficacy HDL Summary Antihyperlipidemic Drug Statins Fibrates Niacin Bile Acid Sequestrates (Resins) Cholesterol Absorption Inhibitors Effect on TGs Omega-3 Fatty Acids Omega -3 Fatty Acids (Lovaza®) (Vascepa®) Omega-3 Fatty Acids; are essential fatty acids, polyunsaturated fatty acids (PUFAs) with a double bond (C=C) at the third carbon atom from the end of the carbon chain. Essential fatty acids inhibit VLDL and triglyceride synthesis in the liver (Unknown mechanism). The three types of omega-3 fatty acids involved in human physiology are a-linolenic acid. (ALA) (found in plant oils), Elcosapentaenoic acid (EPA), and Docosahezaenoic acid (DHA) (both commonly found in marine oils). Efficacy (DHA and EPA) Lovaza®: ✓ Lowers TG by 26-45%. ✓ May raise in LDL-C to 45% when TG concentrations are very high. ✓ ✓ ✓ ✓ Lcosapent (vascepa) is a form of EPA, unlike other fish oil supplements, Does not significantly rais LDL-C lowers TG by 33%. Raises HDL-C by 11-14% N.B ❖ Omega-6 fatty acids; are essential fatty acids (polyunsaturated fat). ❖ Omega-9 fatty acids; are monounsaturated fats. ❖ Omega-3-6-9 fatty acids play specific roles in overall health; ➢ Prevent, coronary heart disease, stroke and diabetes. ➢ Promote; healthy nerve activity and cell development ➢ Maintain a healthy immune system. ❖ Omega-3-Carboxylic Acid (Epanova®); ❑ Efficacy: ✓ Lowers TG by 30%. ✓ May raise HDL-C by 5%. ✓ May raise LDL-C by 25%. ✓ Uses; treat hypertriglyceridemia as an adjunct to diet with TG conc. Of > 500 mg/dL. ❑ Side effects: ✓ Diarrhea. Red Yeast Rice (Cholestin®) (Statosan®) Red Yeast Rice (RYR) is made from yeast (Monascuspurpureus) grown on rice, It is a bright reddish purple colour. It is a dietary staple in some Asian countries (Japanese), going back to 300 BC. RYR contains several compounds known as Monacolins, which block cholesterol production. One of these, Mionacolin K, has the same structure as the drugs Lovastatin. It also contains Sterols, Isoflavones, and Monounsaturated Fatty Acids. Studies suggest that RYR may lead to ✓ 10-33% reduction in LDL-C ✓ Increase levels of HDL-C. RYR extract has been sold in supplements to lower cholesterol and may have benefits in diabetes and CHD, Side effects: elevated liver enzymes and GI symptoms. Garlic The results of research on garlic have been mixed, but it may: help. ✓ ✓ ✓ ✓ Lower blood pressure, Reduce blood cholesterol levels, and Slow the progress of atherosclerosis Can slightly lower blood cholesterol levels. For example, studies have shown positive effects for short-term use of one to three months. However, National Center for Complementary and Alternative Medicine (NCCAM) study on the safety and effectiveness of three garlic preparations found no long-term effect on lowering blood cholesterol levels.