Anti Hyper Lip i de Mics

Antihyperlipedemics

S. Aravinth Vijay Jesuraj;Senior Lecturer,

AUCMS

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Learning Objectives

• Introduction to hyperlipidemia• Useful terms• Drug classification• Individual drug of specific category with MOA,

clinical use and toxicity.• Combination therapy

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Introduction• Atherosclerosis is the leading cause of death in the

Western world. • Plasma lipids are transported in complexes called

lipoproteins.• Metabolic disorders that involve elevations in any

lipoprotein species are termed hyperlipoproteinemias or hyperlipidemias. Hyperlipemia denotes increased levels of triglycerides.

• The two major clinical sequelae of hyperlipidemias are acute pancreatitis and atherosclerosis

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Important terms

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Classification of drugs

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HMG CoA reductase InhibitorsMOA: The rate-limiting step in hepatic cholesterol synthesis is conversion of hydroxymethylglutaryl coenzyme A ( HMG-CoA) to mevalonate by HMG-CoA reductase. The statins are structural analogs of HMG-CoA that competitively inhibit the enzyme. Lovastatin and simvastatin are prodrugs, whereas the other HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, pravastatin, and rosuvastatin) are active as given.

• Although the inhibition of hepatic cholesterol synthesis contributes a small amount to the total serum cholesterol-lowering effect of these drugs, a much greater effect derives from the response to a reduction in a tightly regulated hepatic pool of cholesterol.

• The liver compensates by increasing the number of high-affinity LDL receptors, which clear LDL and VLDL remnants from the blood.

• HMG-CoA reductase inhibitors also have direct anti-atherosclerotic effects, and have been shown to prevent bone loss.

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HMG Co A reductase inhibitors- toxicity• Mild elevations of serum aminotransferases are common but are not

often associated with hepatic damage. • An increase in creatine kinase (released from skeletal muscle) is noted in

about 10% of patients; in a few, severe muscle pain and even rhabdomyolysis may occur.

• HGM-CoA reductase inhibitors are metabolized by the cytochrome P450 system; drugs or foods (eg, grapefruit juice) that inhibit cytochrome P450 activity increase the risk of hepatotoxicity and myopathy.

• Because of evidence that the HMG-CoA reductase inhibitors are teratogenic, these drugs should be avoided in pregnancy.

HMG CoA RI Dosage RemarksLovastatin 20 to max. 80 mg/day in 3 to 6 weeks Effective if it is taken in eve. meal than at bedtimeSimvastatin In most patients is 20 mg at bedtime. Max. 80 mg/day should be taken at bedtime

Pravastatin started with a 20- or 40-mg dose. Max. 80 mg/day -do-

fluvastatin 20 or 40 mg, and the maximum is 80 mg/day -do-

Atrovastatin Starting dose is 10 mg, and the max. is 80 mg/day long t1/2, - allows dosing at any time of the day

Rosuvastatin 5 to 40 mg -do-

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Resins• Normally, over 90% of bile acids, metabolites of cholesterol,

are reabsorbed in the gastrointestinal tract and returned to the liver for reuse.

• Bile acid-binding resins (cholestyramine, colestipol, and colesevelam ) are large nonabsorbable polymers that bind bile acids and similar steroids in the intestine and prevent their absorption.

• By preventing the recycling of bile acids, bile acid-binding resins divert hepatic cholesterol to synthesis of new bile acids, thereby reducing the amount of cholesterol in a tightly regulated pool. A compensatory increase in the synthesis of high-affinity LDL receptors increases the removal of LDL lipoproteins from the blood.

• The resins cause a modest reduction in LDL cholesterol but have little effect on HDL cholesterol or triglycerides.

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Resins-Clinical Use & Toxicity• The resins are used in patients with hypercholesterolemia.

They have also been used to reduce pruritus in patients with cholestasis and bile salt accumulation.

• Adverse effects from resins include bloating, constipation, and an unpleasant gritty taste. Absorption of vitamins (eg, vitamin K, dietary folates) and drugs (eg, thiazide diuretics, warfarin, pravastatin, fluvastatin) is impaired by the resins.

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Ezetimibe• Ezetimibe is a prodrug that is converted in the liver to the active

glucuronide form. This active metabolite inhibits a transporter that mediates gastrointestinal uptake of cholesterol and phytosterols.

• By preventing absorption of dietary cholesterol and cholesterol that is excreted in bile, ezetimibe reduces the cholesterol in the tightly regulated hepatic pool. A compensatory increase in the synthesis of high-affinity LDL receptors increases the removal of LDL lipoproteins from the blood.

• As monotherapy, ezetimibe reduces LDL cholesterol by about 18%. When combined with an HMG-CoA reductase inhibitor, it is even more effective.

• Ezetimibe is used for treatment of hypercholesterolemia and phytosterolemia, a rare genetic disorder that results from impaired export of phytosterols.

• Ezetimibe is well tolerated. When combined with HMG-CoA reductase inhibitors, it may increase the risk of hepatic toxicity.

• Serum concentrations of the glucuronide form are increased by fibrates and reduced by cholestyramine

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Niacin (Nicotinic Acid)• Through multiple actions, niacin (but not nicotinamide) reduces LDL

cholesterol, triglycerides, and VLDL and also often increases HDL cholesterol.

• In the liver, niacin reduces VLDL synthesis, which in turn reduces LDL levels.

• In adipose tissue, niacin appears to activate a signaling pathway that reduces hormone-sensitive lipase activity and thus decreases plasma fatty acid and triglyceride levels. Consequently, LDL formation is reduced, and there is a decrease in LDL cholesterol.

• Increased clearance of VLDL by the lipoprotein lipase associated with capillary endothelial cells has also been demonstrated and probably accounts for the reduction in plasma triglyceride concentrations.

• Niacin reduces the catabolic rate for HDL. Finally, niacin decreases circulating fibrinogen and increases tissue plasminogen activator.

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Clinical Use & Toxicity• Because it lowers serum LDL cholesterol and triglyceride

concentrations and increases HDL cholesterol concentrations, niacin has wide clinical usefulness in the treatment of hypercholesterolemia, hypertriglyceridemia, and low levels of HDL cholesterol.

• Cutaneous flushing is a common adverse effect of niacin. Pretreatment with aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the intensity of this flushing, suggesting that it is mediated by prostaglandin release. Dose-dependent nausea and abdominal discomfort often occur. Pruritus and other skin conditions are reported. Moderate elevations of liver enzymes and even severe hepatotoxicity may occur. Severe liver dysfunction has been associated with an extended-release preparation, which is not the same as the sustained-release formulation. Hyperuricemia occurs in about 20% of patients, and carbohydrate tolerance may be moderately impaired.

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Fibric Acid Derivatives• Fibric acid derivatives (eg, gemfibrozil, fenofibrate) are ligands for the

peroxisome proliferator-activated receptor-alpha (PPAR-α) protein, a receptor that regulates transcription of genes involved in lipid metabolism.

• This interaction with PPAR-α results in increased synthesis by adipose tissue of lipoprotein lipase, which associates with capillary endothelial cells and enhances clearance of triglyceride-rich lipoproteins.

• In the liver, fibrates stimulate fatty acid oxidation, which limits the supply of triglycerides and decreases VLDL synthesis. They also decrease expression of apoC-III, which impedes the clearance of VLDL, and increase the expression of apoA-I and apoA-II, which in turn increases HDL levels. In most patients, fibrates have little or no effect on LDL concentrations.

• However, fibrates can increase LDL cholesterol in patients with a genetic condition called familial combined hyperlipoproteinemia, which is associated with a combined increase in VLDL and LDL.

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Combination Therapy

• All patients with hyperlipidemia are treated first with dietary modification, but this is often insufficient and drugs must be added.

• Drug combinations are often required to achieve the maximum lowering possible with minimum toxicity and to achieve the desired effect on the various lipoproteins (LDL, VLDL, and HDL).

• Because resins interfere with the absorption of certain HMG-CoA reductase inhibitors (pravastatin, cerivastatin, atorvastatin, and fluvastatin), these must be given at least 1 h before or 4 h after the resins. The combination of reductase inhibitors with either fibrates or niacin increases the risk of myopathy.

Thank you…

Anti Hyper Lip i de Mics

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