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Drugs for Hyperlipoproteinemia.ppt

This document discusses the treatment of hyperlipidemias. It outlines the main risk factors for coronary heart disease including high LDL cholesterol, low HDL cholesterol, smoking, hypertension, obesity and diabetes. The primary treatment goal is reduction of LDL levels through lifestyle changes and medication. Main drug classes for treatment include statins, bile acid sequestrants, cholesterol absorption inhibitors, niacin, and fibric acid derivatives. The document provides details on the mechanisms of action, pharmacokinetics, therapeutic uses and adverse effects of these drug classes.

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Treatment of Hyperlipidemias Pharmacology Team Ansam Sawalha, Adham Abu Taha, Suhaib Hattab, Naim Kittana and Waleed Sweileh An-Najah National University Faculty of Medicine and Health Sciences Department of Biomedical Sciences 1
Risk factors for coronary heart disease (CHD): 1. High LDL cholesterol and TG 2. low HDL cholesterol. 3. Cigarette smoking 4. Hypertension 5. Obesity 6. Diabetes 2
• Elevated cholesterol can be due to: 1. Lifestyle: lack of exercise and consumption of a diet containing excess saturated fatty acids 2. A single inherited gene defect in lipoprotein metabolism 3. A combination of genetic and lifestyle factors. 3
TREATMENT GOALS • The primary goal: Reduction of the LDL level • Recommendations for the reduction of LDL cholesterol to specific target levels are influenced by – Coexistence of CHD – number of other cardiac risk factors • The higher the overall risk of heart disease, the more aggressive the recommended LDL-lowering therapy. 4
ATHEROSCLEROSIS A. Significance: Major cause of death in the U.S. (heart attacks and strokes) B. Risk Factors: Hypertension, age, obesity, diabetes, high fat diet, smoking, stress, low HDL, lack of exercise, family history and high plasma lipoproteins (VLDL, IDL and LDL). 5
ATHEROSCLEROSIS C. Pathogenesis: - Elevated plasma lipoproteins such as VLDL, IDL and LDL are a major risk factor in atherosclerosis - Endothelium of blood vessel is injured and blood components (LDL and platelets) infiltrate injured area. - Growth factors cause proliferation of cells and plaque starts to form at site of injury. 6
ATHEROSCLEROSIS C. Pathogenesis: (Continue) - Cells internalize LDL (oxidized) and form foam cells (saturated with fat). - Cells die and plaque is formed. - Narrowed vessel gets clogged by blood clot and stroke or heart attack is the consequence. 7
D. Rationale of treatment: Studies have clearly demonstrated that appropriate diet and drugs reduces atherosclerosis- induced mortality 20 to 40%. ATHEROSCLEROSIS 8
Lipoprotein Structure 9
Classification of Lipoproteins 1. Chylomicrons - carry triacylglycerol from the intestines to the liver and adipose tissue. 2. Very low density lipoproteins (VLDL) - carry triacylglycerol from the liver to adipose tissue. 3. Low density lipoprotein (LDL) - carry cholesterol from the liver to the tissues. “Bad cholesterol“ 4. High density lipoprotein (HDL) - collects cholesterol from the tissues, and transport it back to the liver. “Good cholesterol“ 10
Classification of Lipoproteins 11
Composition of Lipoproteins 12
Hyperlipoproteinemia Lipoproteins Normal Values mg/dl Total Cholesterol < 200 LDL 100 HDL 40-50 Triglycerides 150 13
Hyperlipoproteinemia 14
Lipoprotein metabolism 15
LCAT: lecithin:cholesterol acyl transferase, CETP: cholesteryl ester transfer protein FFA: free fatty acid 16
Fredrickson Classification of Hyperlipoproteinemia Lipoprotein elevation Main cause Serum elevation Disease Type Chylomicrons Lipoprotein lipase deficiency Triglycerides Familal hyperchylomicronemia I LDL Defect in LDL receptors Cholesterol Familal hypercholesterolemia IIa LDL, VLDL Overproduction of VLDL by liver Cholesterol and triglycerides Familal mixed hyperlipidemia IIb IDL Overproduction or underutilization of IDL (mutant apolipoprotien E) Cholesterol and triglycerides Familal dysbetalipoproteinemia III VLDL Overproduction or decrease removal of serum VLDL & TG Triglycerides Familal hypertriglyceridemia IV VLDL, chylomicrons Overproduction or decrease clearance of VLDL & chylomicrons Cholesterol and triglycerides Familal mixed hypertriglyceridemia V 17
Treatment options for hypercholesterolemia • Moderate hyperlipidemia: – Lifestyle changes, such as diet, exercise, and weight reduction, can lead to modest decreases in LDL levels and increases in HDL levels. – Patients who are unwilling to modify their lifestyle drug therapy may be required. 18
Drug therapy: Patients with – LDL levels >160 mg/dL – one other major risk factor, such as hypertension, diabetes, smoking, or a family history of early CHD Aggressive treatment: – Patients with two or more additional risk factors should be treated aggressively – Aim: • reducing LDL level to less than 100 mg/dL and, in some patients, to as low as 70 mg/dL. 19
Treatment options for hypertriacylglycerolemia • Primary modes of treating hypertriacylglycerolemia: – Diet – Exercise • Efficacious drugs in lowering TG: 1. Niacin 2. Fibric acid derivatives 20
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HMG CoA reductase Inhibitors (Statins) : • Most efficacious and well tolerated. • They act by competitive inhibition of HMG CoA reductase – the rate limiting step in cholesterol synthesis. 22
HMG CoA reductase Inhibitors 23
Statins Atorvastatin Fluvastatin Lovastatin Mevastatin Pravastatin Rosuvastatin Pitavastatin Simvastatin Simvastatin+Ezetimibe Lovastatin+Niacin extended-release Atorvastatin+Amlodipine Besylate 24
HMG CoA reductase Inhibitors (Statins): 1. Reduced cholesterol synthesis results in a compensatory increase in the hepatic uptake of plasma cholesterol mediated by an increase in the number of LDL receptors. 2. Hepatic synthesis of VLDL is reduced 3. There is an increase in HDL levels 25
HMG CoA reductase Inhibition 26
• Lovastatin and Simvastatin: – Prodrugs, have to be hydrolyzed to be activated. – Cross the BBB and can cause sleep disturbances • Fluvastatin – Less myopathy • Atorvastatin and rosuvastatin are long acting • Rosuvastatin, Pitavastatin, & Atorvastatin are the most potent in decreasing LDL cholesterol. • Atorvastatin (Lipitor®) – antioxidant effect HMG CoA reductase Inhibitors 27
Pharmacokinetics: • Absorption after oral administration: – Pravastatin and fluvastatin: complete – Lovastatin and simvastatin: 30 -50% • Pravastatin and fluvastatin are active as such • All are metabolized in the liver and excreted through bile and feces, but there is also some urinary elimination 28
Comparison of some pharmacokinetic parameters for some HMG-CoA reductase inhibitors 29
Therapeutic uses of HMG-CoA reductase inhibitors : • 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. 30
Adverse effects of HMG CoA reductase Inhibitors: • Headache • Sleep disturbances • Hepatotoxicity • Myopathy (muscle tenderness) and rhabdomyolysis 31
Drug interactions: – May increase Warfarin levels Contraindications: • During pregnancy and in nursing mothers. • In children or teenagers. 32
Bile acid–binding resins  Cholestyramine  Colestipol  Colesevelam • These are bile acid binding resins • They are neither digested nor absorbed in the gut • These interrupt enterohepatic circulation of bile salts and increase fecal excretion of bile salts and cholesterol • Increase in LDL receptor in the liver 33
Effect of bile-acid binding resins 34
• Compensatory increase in the activity of HMG CoA reductase results in increased cholesterol synthesis and thus increased VLDL secretion – blunting the long term effectiveness of monotherapy • Mild increase in triglycerides can be seen. Effect of bile-acid binding resins 35
Therapeutic uses of bile-acid binding resins: • These are the drugs of choice (often in combination with diet or niacin) in treating Type IIA and Type IIB hyperlipidemias  [Note: In those rare individuals who are homozygous for Type IIA, that is, for whom 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 obstruction • It is also used to treat diarrhea 36
Adverse effects • GI disturbances, such as constipation, nausea, and flatulence. • Colesevelam has fewer GI side effects than other bile acid sequestrants. • At high doses, cholestyramine and colestipol (but not colesevelam) impair the absorption of the fat-soluble vitamins (A, D, E, and K). 37
Drug interactions: • Cholestyramine and colestipol interfere with the intestinal absorption of many drugs (for example, tetracycline, phenobarbital, digoxin, warfarin, pravastatin, fuvastatin, aspirin, and thiazide diuretics). • Therefore, drugs should be taken at least 1–2 hours before, or 4–6 hours after, the bile acid–binding resins. 38
• It decrease cholesterol absorption by localizing at the brush border of the small intestine. • Leads to an increase in LDL-cholesterol uptake into cells, thus decreasing levels in the plasma. • Can be used in combination with Simvastatin Cholesterol uptake inhibitor: Ezetimibe 39
Pharmacokinetics of Ezetimibe • Ezetimibe is metabolized in the small intestine and liver via glucuronide conjugation, with subsequent biliary and renal excretion. • half-life of approximately 22 hours. • Patients with moderate to severe hepatic insufficiency should not be treated with ezetimibe. 40
Niacin (nicotinic acid) • Within minutes upon administration: rapid reduction in plasma levels of free fatty acid • After a few hours, the plasma VLDL and TG levels are reduced • After several days of treatment: the LDL and HDL cholesterol levels are changed.  It reduces VLDL and TG production  The most effective in increasing HDL  Effective in reducing LDL 41
Therapeutic uses of niacin: • Niacin lowers both cholesterol and triacylglycerol. • It is useful in the treatment of familial hyperlipidemias. • Used in treating severe hypercholesterolemias • It is the most potent anti-hyperlipidemic agent for raising plasma HDL levels, which is the most common indication for its clinical use. 42
Adverse effects of Niacin • Cutaneous dilator – flushing, itching • Liver dysfunction • Hyperglycemia • Potentiates gout (decrease uric acid secretion), diabetes and peptic ulcers 43
Fibric acid derivatives • Drugs:  Fenofibrate (a prodrug for the active metabolite fenofibric acid)  Clofibrate  Gemfibrozil • They lower serum triacylglycerol and increase HDL levels 44
Mechanism of action of Fibric acid derivatives • They interact with the peroxisome proliferator activated receptor alpha (PPARα) which regulates gene expression of enzymes involved in fatty acid oxidation. • They increase expression of lipoprotein lipase, which enhances clearance of triglyceride rich lipoproteins. • Fibrates also increase the level of HDL cholesterol by increasing the expression of apo AI and apo AII. 45
Therapeutic uses: • Patients with hypertriacylglycerolemia (Type IV [elevated VLDL] or Type V [elevated VLDL plus chylomicron] disease) who do not respond to diet or other drugs may also benefit from treatment with these agents. • Treatment of Type III hyperlipidemia (dysbetalipo proteinemia), in which intermediate-density lipoprotein particles accumulate. 46
Adverse effects: • Gall stones with Clofibrate • Myopathy (Myositis): - Inflammation of skeletal muscles) causing muscle weakness and tenderness - Rhabdomyolysis can occur - Risk is greatly increased in combination with statins (contraindicated) • Nausea • Skin Rash 47
Drug interactions: • Fibrates compete with the coumarin anticoagulants for binding sites on plasma proteins (monitor INR frequently) • They may transiently elevate the levels of sulfonylureas. 48
PCSK9 inhibitor Alirocumab Evolocumab
Alirocumab Monoclonal Antibody - Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitor • PCSK9 is an enzyme that binds to an epidermal growth factor- like domain of the LDL receptor, and targets it for lysosomal degradation. • degradation of LDL receptors reduces the amount of LDL that can be cleared from the circulation – If PCSK9 is inhibited (and does not bind to the LDL receptor), the receptor can return to the surface of the liver cell and remove more cholesterol.
• Inhibiting PCSK9 prevents destruction of the LDL receptor & facilitates recycling of hepatic LDL receptors, which enhances removal of LDL from the blood • when added to patients taking statins, alirocumab produced an additional 36-59% mean reduction in LDL compared to those given a placebo
• Indications: – Adjunct therapy (e.g. if statins are not enough) to lower LDL in patients with • heterozygous hypercholesterolemia (HeFH) • atherosclerotic CV disease (e.g. myocardial infarction or stroke) – Used in combination with diet, exercise, and maximally tolerated doses of statins
• Pharmacokinetics: – subcutaneous injection – after sc injection, maximal suppression of PCSK9 occurs in 4-8 hours – half life 17-20 days • at low concentrations the antibody (drug) is eliminated by binding to its target • at higher concentrations the drug is eliminated by proteolytic degredation
• Side Effects: – ~2% estimated incidence (but its still a new drug) – itching, swelling, pain or bruising at the injection site – nasopharyngitis, flu – allergic reactions requiring hospitalization
Drugs for Hyperlipoproteinemia 55
Drugs for Hyperlipoproteinemia 56
Drugs Indication Effects On Lipid Profile Adverse Effects Cholestyramine Colistipol Colesevelam Elevated LDL Pregnancy and Children ↓ LDL(20%) ↑ TGs (~5%) GI problems (bloating, constipation) Niacin Elevated LDL, Low HDL and Elevated TG ↓ TG (40%) ↓ LDL (15%) ↑ HDL (25%) Flushing of face & Pruritus Hyperglycemia Gemfibrozil Elevated TG ↓ TG (50%) ↓ LDL (10%) ↑ HDL (15%) Myositis Gall stones HMG-CoA Reductase Inhibitors Elevated LDL ↓ LDL (30%) ↑ HDL (8%) ↓ TG (20%) Hepatotoxicity Myositis 57
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