Hypolipidemic Drugs and plasma expanders Dr Rishi Pal

Hypolipidemic Drugs and plasma expanders Dr. Rishi Pal Assistant Prof. Deptt. of Pharmacology

29 -2 Cholesterol • Critical substrate for the body: – Fundamental building block of steroid hormones – Essential for building cell membranes, the myelin sheath, and the brain – Core component of bile salts, which helps in digest dietary fats

29 -3 Lipoproteins • There are several different lipoproteins: – Low-density lipoprotein (LDL) – Very-low-density lipoprotein (VLDL) – High-density lipoprotein (HDL)

29 -4 Triglycerides • Main form of fat from diet • Provide body with energy • Chylomicrons: – Very large lipoproteins that deliver triglycerides to muscle and fat tissue

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29 -7 Hypolipidemic Drugs • There are five groups of drugs used in the management of hyperlipidemia: – HMG-Co. A reductase inhibitors – Cholesterol absorption inhibitors – Bile acid sequestrants – Fibric acid derivatives – Nicotinic acid

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29 -9 Atherosclerosis • Atherosclerosis is a progressive condition that leads to CAD and PAD. • Fat buildup inside the arteries—plaque • CAD—coronary artery disease • PAD—peripheral artery disease © 2012 The Mc. Graw-Hill Companies, Inc. All rights reserved.

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29 -11 Atherosclerosis • There are two types • of plaque buildup: – Stable – Unstable Plaque buildup can block arteries, causing: – Angina – TIA – Stroke – Intermittent claudication © 2012 The Mc. Graw-Hill Companies, Inc. All rights reserved.

29 -12 Monitoring the Disease • Risk factors for atherosclerosis – Age – History of smoking – Hypertension – Premature menopause – Obesity – Diabetes mellitus – Hyperthyroidism

29 -13 Monitoring the Disease • The goals of treatment are: – Lowering LDL cholesterol – Reducing total serum cholesterol and triglycerides – Increasing HDL cholesterol

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HMG-Co. A Reductase inhibitors • • • Atorvasatatin Simvastatin Lovastatin Pravastatin Fluavastatin Rosuvastatin

Bile acid binding resins • Cholestyramine • Colestipol • Colesevelam

Intestinal cholesterol absorption inhibitors • Stanol esters • Ezetimibe

Activators of lipoprotein lipase (Fibrates) • • Gemfibrozil Benafibrate Fenofibrate Ciprofibrate

Inhibitor of VLDL secretion and lipolysis • Niacin (Nicotinic acid) Miscellaneous: Gugulipid and fish oil derivatives

Statins Fibrates LIPID-LOWERING DRUGS Resins Others © 2012 The Mc. Graw-Hill Companies, Inc. All rights reserved.

29 -21 HMG-Co. A Reductase Inhibitors • Also referred to as statins • MOA—inhibit enzyme that causes cholesterol synthesis • IND—adjunct to dietary treatment to decrease total serum and LDL cholesterol: – Reduce LDL level up to 30% – Raise HDL level up to 20%

1 -22 HMG-Co. A Reductase Inhibitors • An early, very important step in this process is the conversion of acetyl-Co. A molecules into HMG-Co. A, which is then converted to mevalonic acid by HMG-Co. A reductase. Mevalonic acid is a rate-limiting pivotal step in steroid and cholesterol biosynthesis • The liver makes two-thirds cholesterol requirement. of the daily

1 -23 HMG-Co. A Reductase Inhibitor • All of the statins reduce LDL up to 30 percent. When a greater reduction of LDL is required, simvastatin (Zocor), atorvastatin (Lipitor), and rosuvastatin (Crestor) reduce more than 45 percent; in fact, rosuvastatin and atorvastatin have been demonstrated to reduce up to 60 percent. • All of the statins raise the HDL level up to 20 percent. Again, simvastatin (Zocor), atorvastatin (Lipitor), and rosuvastatin (Crestor) increase HDL more than 30 percent.

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29 -25 HMG-Co. A Reductase Inhibitors • Adverse effects: – Headache, dizziness, alteration of taste, insomnia, abdominal cramping and photosensitivity • May cause myalgias, leg ache, and muscle weakness • Contraindicated during pregancy

29 -26 Cholesterol Absorption Inhibitors • Ezetimibe: – MOA—blocks absorption of cholesterol in the intestines • Decreases VLDL • Decreases circulating LDL cholesterol – IND—treatment of hyperlipidemia in conjunction with diet alteration

29 -27 Cholesterol Absorption Inhibitors • Ezetimibe: – Modestly reduces total cholesterol, LDL, and triglyceride blood levels – Ideal to combine with other hypolipidemic drugs – Adverse effects—abdominal pain, fatigue, coughing, diarrhea, back pain, and arthralgia

29 -28 Bile Acid Sequestrants • MOA—bind bile salts and cholesterol in the GI tract, preventing absorption of both • IND—hyperlipidemia: – Increased elimination of bile salts, cholesterol, and other fats in the faeces. – Adverse effects include GI disturbances, severe constipation, and fecal impaction. – Most serious adverse effect is intestinal obstruction.

29 -29 Nicotinic Acid • MOA—affects cholesterol synthesis through a G proteins coupled receptor: – Inhibits triglyceride lipase – Stimulates lipoprotein lipase – Decreases free fatty acid release and removes triglycerides • IND—hyperlipidemia • Adverse effects—flushing, nausea, vomiting, and diarrhea

29 -30 Fibric Acid Derivatives (Fibrates) • Gemfibrozil: – MOA—inhibits breakdown of fat into triglycerides, and limits liver production of triglycerides – IND—to decrease triglycerides – Adverse effects—nausea, vomiting, diarrhea, and flatulence

Gugulipid • Consists of Z and E gugulsterone • Inhibit cholestrol biosynthesis and also enhance rate of cholesterol excretion • Dose 25 mg 3 times a day • Reduced total CH, LDL-C with an elevation of HDL-C • It is well tolerated, no side effect, except loose stool

Fish oil derivative • Omega-3 -fatty acids • Eicosa-pentanoic and docosa-hexanoic acid • Prophylaxis use in high risk patient of CAD • Usually formulated with vit. E

Combination drug therapy • • Bile acid binding resins+Fibrates Bile acid binding resins+Niacin Bile acid binding resins+Statins Bile acid binding resins+Niacin+ Statins Niacin+Statin (Atorva 10+ Nia 500) Statins+Ezetimibe Statins+Fibrate

29 -34 Hypolipidemic Drugs

29 -35 Preferred Therapy • All hypolipidemic drugs are indicated as adjunctive therapy to reduce elevated cholesterol levels. • HMG-Co. A reductase inhibitors are the most prescribed. • Cholestyramine can also be used in the treatment of partial biliary obstruction.

29 -36 Contraindications • Systemic hypolipidemic drugs should not be used in patients with liver dysfunction. • Bile acid sequestrants should not be used in patients with biliary obstruction. • Statins should not be used in pregnant women.

29 -37 Drug Interactions

New drugs • Cholesteryl ester transfer protein (CETP) • Torcetrapib • Anacetrapib

Blood substitutes and plasma expenders

Hypovolaemia • Shock is a state of acute circulatory failure • So, it is essential to restore intravascular blood volume as quickly as possible • Intravenous fluid therapy

Types of fluid used for replacement • Whole blood and plasma • Plasma substitute: • a) Colloidal: Dextran, hydroxyethyl starch polyvenyl pyrrolidone, oxypolygelatin. b) crystalline: Na. Cl, dextrose solution

Desirable properties of plasma expenders 1. Should exert oncotic pressure comparable to plasma. 2. Should retain in circulation and not leak out in tissues or too rapidly disposed. 3. Should be pharmacodynamically inert. 4. Should not be pyrogenic or antigenic 5. Should not interfere with grouping and cross matching of blood. 6. Should be stable and easily sterilizable and cheap.

Substance employed are • • Human albumin Dextran Polygeline Hetastarch

Albumin • 100 ml of 20% human albumin solution is osmotic equivalent of about 400 ml of fresh frozen plasma or 800 ml of whole blood. • Not interfere with blood group and coagulation process. • Crystalloid solutions must be infused concurrently for optimum benefit. • It is expensive.

Dextran • Dextran-40: 10% in dextrose or in Na. Cl • Dextran-70, expends plasma volume for 24 hr. • 500 -1000 ml in 30 min. and 100 ml by continuous infusion for 2 -3 days. • Be careful in patients of Renal impairment, CHF or Polycythaemia. • Dextran-70 & dextran 110: 6% in dextrose or in Na. Cl, used for hypovolaemic or haemorrhagic shock

Polyvenylpyrrolidone • It is synthetic water soluble preparation with MW 35, 000 -40, 000. • It is sterile solution in buffered physiological saline • It has tendency to bind with insulin and penicillin

Gelatin • MW 30, 000 • 500 -1000 ml of 3. 5 -4% used in low blood volume • Expends plasma volume for 12 hr • More expensive than dextran

Contraindications • • • Severe anemia Cardiac failure Pulmonary edema Liver disease Renal insufficiency

Electrolyte and water replacement • Normal saline (0. 9%) • Dextrose 5%