Arteriosclerosis hardening of the arteries Serum cholesterol above

Arteriosclerosis= hardening of the arteries.

• ↑Serum cholesterol (above 4 mmol/L) ↑risk of coronary heart disease • <4 mmol/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.

Classification of lipoproteins Fraction %Protein cholesterol Triacylglycerol (TG) PL HDL, αlipoproteins 45 21 8 26 LDL, βlipoproteins 21 51 10 18 VLDL, pre βlipoproteins 1 21 9 Chylomicron 2 6 54 (TG carrier) 85 (TG carrier) (cholesterol carrier) 7

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

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

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.

Lipoproteins are oxidized by free radicals They bind to scavenger cells Endocytosis of oxidized lipoproteins Formation of foam cells Foam cells + fibrin + calcium = atheroma

Dyslipidemia Primary (genetic) 6 phenotypes (according to the type of lipoprotein elevated) Secondary (caused by acquired conditions)

• 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.

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).

Classification of Cholesterol levels Desirable Borderline high High Total Cholesterol mmol/l <5. 2 LDL cholesterol mmol/l <3. 4 >5. 2 <6. 2 >3. 4<4. 1 >6. 2 >4. 1

drugs Sequestering bile acid in the intestine Exchange Resins (Polymeric&HMW) Altering lipoproteins levels Inhibiting cholesterol synthesis Ezetimibe Nicotinic acid HMG-Co. A reductase inhibitors fibrates Inhibiting cholesterol absorption from the intestine

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

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.

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.

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 lipase which converts TAGs to fatty acids leaving cholesterol in chylomicron Chylomicron now is called chylomicron remnant is absorbed by the liver

Cont’d The liver distributes TAGs to different tissues in the form of 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)

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

Drugs used for the treatment of hyperlipidemia 1 - Nicotinic Acid Nicotinic acid is not related to nicotine, yet it was first synthesized from it. Nicotinic acid(niacin) is vit. B 3 Ni ac in nicotin acid vitamin

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.

Therapeutic uses of niacin In type IIa ↓LDL In type IIb ↓TAG Has a slow onset of action (2 months)

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

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

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 T 1/2 = 1. 5 hr

Fenofibrate Is a methyl ester that is hydrolyzed completely in the intestine. T 1/2 = 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.

Mechanism of action Fibrates bind to peroxisome proliferatoractivated receptor-alpha (PPAR-α ) receptor ↑synthesis of lipoprotein lipase ↓ serum TAG So it stimulate gene expression of lipoprotein lipase. Effect on chylomicron & VLDL chylomicron remnant LDL

rash ↑aminotransferase and alkaline phosphatase They have toxic effect on the liver GI symptoms Toxic effect hypokalemia Myopathy (most important) arrhythmia They potentiate the action of coumarins (e. g. warfarin)

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 Those with mixed dyslipidamia Those with low HDL and at risk of atherma (e. g. type II diabetes)

This group is not first line treatment. They are polymers. They bind bile acids in the intestine preventing their absorption. In hypercholesterolemia it →↓LDL cholesterol, If used to ↓ LDL in patients with combined (mixed) hyperlipidemia →↑VLDL.

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

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)

As monotherapy when statins are contraindicated (e. g. allergies to ) statins In type IIa with statin if they are not enough for treatment uses Digitalis poisoning (As antidote) Relieves Pruritus resulting from partial biliary obstruction

IV- HMG-Co. A reductase Inhibito They are structural analogs of HMG-Co. A reductase enzyme. e. g. Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin, & rosuvastatin.

HMG-Co. A reductase mediates the first step in steroid genesis. They are most effective in reducing LDL. They decrease oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions.

Mechanism of action Decrease hepatic synthesis of cholesterol Decrease cholesterol in liver Increase receptors for LDL ↓release of VLDL ↓LDL in plasma

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).

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.

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. T 1/2 range from 1 hour to 3 hours except for atorvastatin, which has a t 1/2 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.

catabolism of lovastatin, simvastatin, and atorvastatin → cytochrome P 450 3 A 4 fluvastatin and rosuvastatin → CYP 2 C 9. Pravastatin is catabolized through other pathways, including sulfation.

Drug interactions: Plasma levels of lovastatin, simvastatin, and atorvastatin may be elevated in patients ingesting more than 1 liter of grapefruit juice daily. inhibit P 450 3 A 4

Therapeutic uses

Secondary prevention of MI or stroke in patient with atherosclerosis uses Primary prevention of arterial disease in patient who have high cholesterol level Atorvastatin is used in homozygous familial hypercholestrolemia Resins are added with statin in drug-induced dyslipidemia

Adverse effect ↑level of serum transaminase, may produce liver toxicity in patient with liver disease or a history of alcohol abuse. Minor increases in creatine kinase activity in plasma. Myopathy may occur when used in combination with fibrates. Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy. ↑Lenticular opacity

Ezetimibe inhibits intestinal absorption of cholesterol and phytosterols (plant sterols). Reduces LDL Ezetimibe is readily absorbed and conjugated in the intestine to an active glucuronide, reaching peak blood levels in 12– 14 hours.

It undergoes enterohepatic circulation. t 1/2 = 22 hours 80% excreted in feces Plasma ezetimibe concentrations are substantially increased when it is administered with fibrates and reduced when it is given with cholestyramine.

Therapeutic Uses Primary hypercholesterolemia, effective in patients with phytosterolemia. ADR Reversible impaired hepatic function

Up regulation of LDL receptor

VLDL (VLDL)