Arteriosclerosis= hardening of the arteries.

1. Atherosclerosis & Lipoprotein Metabolism • Arteriosclerosis= hardening of the arteries.

2. ↑Serum cholesterol (above 4mmol/L)  ↑risk of coronary heart disease • <4mmol/L level of plasma cholesterol is considered to be safe • ↑LDL  ↑risk of coronary heart disease while, • ↑HDL  ↓risk of coronary heart disease Dyslipidemia vs. hyperlipidemia Dyslipidemia: increase or decrease in specific types of lipoproteins. Hyperlipidemia: increase in level of plasma lipid in general.

3. Classification of lipoproteins

4. If a drug acts on TAG then it affects VLDL Drugs acts on cholesterol it affects LDL

5. Lipoprotein Metabolism • Lipids & cholesterol are transported in the plasma as lipoproteins. Lipophilic components (cholesterol ester and TG) inside the core of lipoprotein Hydrophilic components are on the lipoprotein’s surface

6. Functions of Lipoproteins • Chylomicron:- transport of exogenous dietary TG • VLDL:- transport of endogenous dietary TG from liver to tissue • LDL:- transport of cholesterol to tissues • HDL:- transport of cholesterol out of the tissues to the liver.

7. Atherogenesis

9. Dyslipidemia

10. Primary dyslipidemia

11. Type I has no pharmacologic treatment (only dietetic treatment). • The most severe type is type II (whether IIa or IIb). • Type IIb is mixed or combined (VLDL& LDL). • Type III has abnormal elevated lipid (β VLDL) • Both types IV&V have modest risk for atherosclerosis.

14. Secondary Hyperlipidemia • 1-Hypertriglyceridemia Diabetes mellitus, obesity ,alcoholism (release VLDL), estrogens (e.g.oral contraceptives), chronic renal & liver failure • 2-Hypertriglyceridemia with hypercholesterolemia Diabetes mellitus, renal transplantation, nephrotic syndrome • 3-Hypertriglyceridemia with reduced HDL Drug-induced like: Non- selective β-blockers, isoretinoin(derivative of Vit A) and norgestrel (contraceptive).

15. Classification of Cholesterol levels

16. Classification of drugs used in hyperlipidemia

17. Dietary Management of hyperlipidemia For managing patients with no need for pharmacologic therapy. • Cholesterol, saturated fats and trans fats→↑ LDL and (decrease HDL trans particularly) • Acute ↑ in carbohydrates intake →↑ VLDL. • Alcohol  ↑triglycerides by inducing the secretion of VLDL from the liver. • Some forms of dietary fiber reduce LDL modestly. • Cis bond can converted to trans bond by increasing temperature trans cis

18. Cont’d • Omega-3 fatty acids found in fish oils  ↓triglycerides in patients with endogenous or mixed lipidemia. • Supplementation with antioxidant vitamins such as ascorbic acid (250 mg) and vit.E (50 IU on alternate days) may be beneficial. • ↓Calories & loss of weight →↓LDL & VLDL.

19. Cigarette smoking • Cigarette smoking is a major risk factor for coronary disease. • It is associated with reduced levels of HDL, • impairment of cholesterol retrieval, • Cytotoxic effects on the endothelium, • Increased oxidation of lipoproteins, • Stimulation of thrombogenesis.

20. Before getting to drugs, here’s a revision about lipoprotein and lipid metabolism Lipids are digested and absorbed in the small intestine to simple fats carried as chylomicron Peripheral tissues take up fats from chylomicron via the enzyme lipoprotein lipasewhich converts TAGs to fatty acids leaving cholesterol in chylomicron Chylomicron now is called chylomicron remnant is absorbed by the liver

22. Cont’d The liver distributes TAGs to different tissues in the form of VLDL VLDL is digested by tissues with the help of lipoprotein lipase IDL Then it’s called LDL which transports cholesterol to the tissues and liver (bad cholesterol)

24. Enterohepatic circulation The liver synthesizes bile from cholestrol Bile is secreted in the duodenum to help fat digestion 85-95% of the bile returns to the liver to be modified and released again

25. Drugs used for the treatment of hyperlipidemia1- Nicotinic Acid Nicotinic acid is not related to nicotine, yet it was first synthesized from it. Nicotinic acid(niacin) is vit.B3 Niacin nicotinacidvitamin

26. Nicotinic Acid • Mechanism of action:-Niacin inhibits VLDL’s secretion from the liver, thus concomitantly decreasing circulating LDL & hence ↑ HDL. • Converted in the body to nicotinamide. • Excreted in the urine as nicotinamide. Nicotinamide has no antihyperlipidimic activity, yet it retains its vitamin’s physiologic activity.

27. Has a slow onset of action (2 months)

28. Adverse effects • Harmless cutaneous flush due to vasodilatation resulting from the release of PG. • Pruritus, rash, and dry skin. • Impairment of glucose tolerance in patients with latent diabetes. Thus, niacin is used with caution in diabetic patients. This phenomenon is less seen in long-term use of niacin. This manifestation can be alleviated by taking aspirin.

29. Cont’d • Nausea & abdominal discomfort. • Reversible elevations in aminotransferases (liver toxicity). • Hyperuricemia, thus contraindicated in gout patients.

30. II- Fibrates(gemfibrozil & fenofibrate) gemfibrozil • Supplied as the free acid form • Undergoes enterohepatic circulation • Tightly bound to plasma albumin • Readily passes the placenta (thus contraindicated in pregnant women) • 70% is excreted unchanged in the urine • T1/2 = 1.5 hr

31. Fenofibrate • Is a methylethyl ester that is hydrolyzed completely in the intestine. • T1/2 = 20 hr • 60% is excreted in the urine as a glucuronide conjugate and about 25% in feces. Fenofibrate is uricosuric (decreases uric acid in the blood by increasing the excretion of uric acid in the urine)  used with gout patients accompanied with dyslipidemia.

32. Mechanism of action So it stimulate gene expression of lipoprotein lipase. Effect on chylomicron & VLDL chylomicron remnant LDL

33. They have toxic effect on the liver They potentiate the action of coumarins (e.g. warfarin)

34. The risk of myopathy increases when fibrates are given along with statins. • ↑ risk of cholesterol gallstone formation  taken carfully in patients with biliary tract diseases. Clinical uses

35. III- Bile Acid binding resins (colestipol & cholestyramine) • This group is not first line treatment. • They are polymers. • Theybind bile acids in the intestine preventing their absorption. • In hypercholesterolemia it →↓LDL cholesterol, • If used to ↓ LDL in patients with combined (mixed) hyperlipidemia →↑VLDL .

36. Mechanism of action The liver needs more cholesterol for bile synthesis They increase bile acid excretion Little bile goes back to the liver The liver increases LDL receptors in order to get more cholesterol from the plasma ↓LDL in plasma Resins should be taken in two or three doses with meals, where they are ineffective when taken between meals.

38. Toxicity • They are devoid of systemic side effects. • Common complaints are constipation & bloating sensation. • Heart burn • Malabsorption of vit. A,D,E,K (lipid soluble vitamins) • Dry flaking skin • Lead to ↓ Absorption of thiazides, tetracyclines, & folic acid • Formation of gallstone (less than fibrates)

40. IV- HMG-CoAreductase Inhibitors • They are structural analogs of HMG-CoA reductase enzyme. • e.g. Lovastatin, atorvastatin, fluvastatin, pravastatin,simvastatin, & rosuvastatin.

42. HMG-CoA reductase mediates the firststep in steroid genesis. • They are most effective in reducing LDL. • They decrease oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions.

43. Mechanism of action

44. Pharmacokinetics • Lovastatin and simvastatin are prodrugs, due to the inactive closed lactone ring. • The closed ring is opened, becoming active, when drugs are passing through the GIT. • Atorvastatin, fluvastatin, and rosuvastatin are fluorine-containing congeners that are active as given (due to the already open lactone ring).

45. Abosorption of statins is 40% to 75% with the exception of fluvastatin 100%. • Absorption of statins are enhanced when taken with food with the exception of pravastatin.

46. All have high first-pass metabolism in the liver. • Most of the absorbed dose is excreted in the bile; about 5–20% is excreted in the urine. • T1/2 range from 1 hour to 3 hours except for atorvastatin, which has a t1/2 of 14 hours, and rosuvastatin, 19 hours. • Because cholesterol occurs predominantly at night, reductase inhibitors-except atorvastatin and rosuvastatin- should be given in the evening.

47. catabolism of lovastatin, simvastatin, and atorvastatin → cytochrome P450 3A4 • fluvastatin and rosuvastatin → CYP2C9. • Pravastatin is catabolized through other pathways, including sulfation.

48. Drug interactions:- • Plasma levels of lovastatin, simvastatin, and atorvastatin may be elevated in patients ingesting more than 1 liter of grapefruit juice daily. inhibit P450 3A4

49. Therapeutic uses