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

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
Learning Outcomes
29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis.

3. Lipoproteins There are several different lipoproteins:
Low-density lipoprotein (LDL)
Very-low-density lipoprotein (VLDL)
High-density lipoprotein (HDL)
Learning Outcomes
29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis.

4. Triglycerides Main form of fat from diet Provide body with energy
Chylomicrons:
Very large lipoproteins that deliver triglycerides to muscle and fat tissue
Learning Outcomes
29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis.

7. Hypolipidemic Drugs
HMG-CoA reductase inhibitors
Cholesterol absorption inhibitors
Bile acid sequestrants
Fibric acid derivatives
Nicotinic acid
There are five groups of drugs used in the management of hyperlipidemia:
Learning Outcomes
29.2 Discuss the treatment of hyperlipidemia.
29.3 Explain the mechanism of action of five different hypolipidemic drugs.
There are five groups of drugs that are used alone or as adjunctive treatment to diet: in the management of hyperlipidemias, for the prevention of coronary events in patients at risk, for the treatment of clinically evident coronary heart disease, to slow the progression of atherosclerosis. The groups are the HMG-CoA reductase inhibitors (known as the statins), cholesterol absorption inhibitors, bile acid sequestrants, fibric acid derivatives, and nicotinic acid.

9. 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
Learning Outcomes
29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis.
Atherosclerosis is a progressive condition that leads to coronary artery disease (CAD) and peripheral artery disease (PAD). It is the leading cause of illness and death in the United States.
Atherosclerosis is a disease that begins in early adulthood, even childhood, in which fat builds up inside the smooth lining of the arteries. This accumulated fat, called plaque, is mostly cholesterol with calcium, cell debris, and other substances found in the blood. 9

10. 1-10

11. Atherosclerosis There are two types of plaque buildup: Stable Unstable
29-11
Atherosclerosis
There are two types of plaque buildup:
Stable
Unstable
Plaque buildup can block arteries, causing:
Angina
TIA
Stroke
Intermittent claudication
Learning Outcomes
29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis. 11

12. Monitoring the Disease
Age
History of smoking
Hypertension
Premature menopause
Obesity
Diabetes mellitus
Hyperthyroidism
Risk factors for atherosclerosis
Learning Outcomes
29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis.

13. Monitoring the Disease
The goals of treatment are:
Lowering LDL cholesterol
Reducing total serum cholesterol and triglycerides
Increasing HDL cholesterol
Learning Outcomes
29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis.

15. HMG-CoA Reductase inhibitors
Atorvasatatin
Simvastatin
Lovastatin
Pravastatin
Fluavastatin
Rosuvastatin

16. Bile acid binding resins
Cholestyramine
Colestipol
Colesevelam

17. Intestinal cholesterol absorption inhibitors
Stanol esters
Ezetimibe

18. Activators of lipoprotein lipase (Fibrates)
Gemfibrozil
Benafibrate
Fenofibrate
Ciprofibrate

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

20. LIPID-LOWERING
DRUGS

21. HMG-CoA 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%
Learning Outcomes
29.3 Explain the mechanism of action of five different hypolipidemic drugs.
29.4 Explain why the HMG-CoA inhibitors are more effective than other hypolipidemic drugs.

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

23. HMG-CoA 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.

25. HMG-CoA 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
Learning Outcomes
29.3 Explain the mechanism of action of five different hypolipidemic drugs.
29.4 Explain why the HMG-CoA inhibitors are more effective than other hypolipidemic drugs.

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
Learning Outcomes
29.2 Discuss the treatment of hyperlipidemia.
29.3 Explain the mechanism of action of five different hypolipidemic drugs.
29.6 Explain the essential terminology associated with atherosclerosis and hypolipidemic drugs.

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
Learning Outcomes
29.2 Discuss the treatment of hyperlipidemia.
29.3 Explain the mechanism of action of five different hypolipidemic drugs.
29.6 Explain the essential terminology associated with atherosclerosis and hypolipidemic drugs.

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.
Learning Outcomes
29.2 Discuss the treatment of hyperlipidemia.
29.3 Explain the mechanism of action of five different hypolipidemic drugs.

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
Learning Outcomes
29.2 Discuss the treatment of hyperlipidemia.
29.3 Explain the mechanism of action of five different hypolipidemic drugs.

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
Learning Outcomes
29.2 Discuss the treatment of hyperlipidemia.
29.3 Explain the mechanism of action of five different hypolipidemic drugs.

31. 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

32. 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

33. 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

34. Hypolipidemic Drugs

35. Preferred Therapy
All hypolipidemic drugs are indicated as adjunctive therapy to reduce elevated cholesterol levels.
HMG-CoA reductase inhibitors are the most prescribed.
Cholestyramine can also be used in the treatment of partial biliary obstruction.
Learning Outcomes
29.2 Discuss the treatment of hyperlipidemia.
29.3 Explain the mechanism of action of five different hypolipidemic drugs.

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.
Learning Outcomes
29.2 Discuss the treatment of hyperlipidemia.
29.3 Explain the mechanism of action of five different hypolipidemic drugs.

37. Drug Interactions Learning Outcomes
29.6 Explain the essential terminology associated with atherosclerosis and hypolipidemic drugs.
The bile acid sequestrants stay in the lumen of the intestine and trap other subtances during transit through the intestine. Cholestyramine binds with fat-soluble vitamins (A, D, and K), folic acid, and many drugs, thus reducing their GI absorption. Supplementation at time intervals when the bile acids are no longer in the absorption area may be necessary to avoid vitamin deficiencies.
Taking some medication in the presence of grapefruit juice can significantly decrease drug metabolism at the intestinal wall and increase its bioavailability. Increasing a drug’s bioavailability will increase risk of developing adverse effects. Grapefruit juice interacts only with drugs that are administered orally.
Atorvastatin, lovastatin, and simvastatin are definitely affected by grapefruit. Although the studies concerning grapefruit interactions with pravastatin, fluvastatin, or rosuvastatin were not as significant, it probably would be prudent not to consume grapefruit a few hours before or after taking these medications. Orange juice does not have any effect on absorption of these drugs.
Drugs that are potent inhibitors of CYP3A4 and also cause an increase in statin blood levels include cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, and HIV protease inhibitors. For patients who require antifungal therapy, the statins should be stopped until the fungal treatment is discontinued.

38. New drugs Cholesteryl ester transfer protein (CETP) Torcetrapib
Anacetrapib

39. Blood substitutes and plasma expenders

40. 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

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

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

43. Substance employed are
Human albumin
Dextran
Polygeline
Hetastarch

44. Albumin
100ml of 20% human albumin solution is osmotic equivalent of about 400ml 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.

45. Dextran Dextran-40: 10% in dextrose or in NaCl
Dextran-70, expends plasma volume for 24 hr.
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 NaCl, used for hypovolaemic or haemorrhagic shock

46. 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

47. 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

48. Contraindications Severe anemia Cardiac failure Pulmonary edema
Liver disease
Renal insufficiency

49. Electrolyte and water replacement
Normal saline (0.9%)
Dextrose 5%