Antidislipidemic drugs ( Summary ) © Dr Ivan Lambev, PhD Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology

CVD (cardiovascular disease) CVD (cardiovascular disease) is the leading cause of death among is the leading cause of death among the adult population in the world. the adult population in the world. CHD (coronary heart disease) is the main CHD (coronary heart disease) is the main cause of death in patients with CVD. cause of death in patients with CVD. Total plasma cholesterol, high plasma levels Total plasma cholesterol, high plasma levels of LDL, low levels of HDL are important of LDL, low levels of HDL are important risk factors for CHD. risk factors for CHD.

Free cholesterol Phospholipids Triglycerides Cholesterol esthers Apolipoproteins Structure of lipoproteins

Chylomicrones Very low density lipoproteins (VLDL) Intermediate density lipoproteins (IDL) Low density lipoproteins (LDL) High density lipoproteins (HDL) Classification of lipoproteins according to theirs density

They are the main protein ingredient of lipoproteins with the follow functions: (1) Facilitate lipid transportation (2) Activate main enzymes in lipid metabolism – lecithin cholesterol acetyltransferase – lipoprotein lipase – liver triglyceride lipase (3) Connect to receptors on the cell surface Apolipoproteins

After LDL oxidation free radicals and active oxygen species are formed and they activate macrophages.

Activated macrophages produce inflammatory cytokines (IL-6, TNF alpha), which damage endothelium and initiate atherogenesis.

Hypertriglyceridemia can predict CHD risk in independent to HDL way.

Phenotype I IIa IIb III IV V Lipoprotein increased Chylomicrones LDL LDL and VLDL IDL VLDL VLDL and Chylomicrones Atherogenity NO Rate Low High Medium High Low Plasma cholesterol Norma to Plasma triglycerides Norma Adapted from Yeshurun D, Gotto AM. Southern Med J 1995; 88 (4): 379–391 Fredrickson classification of dislipidemias (WHO)

Notes 1. Fredrickson classification does not take in account HDL-C (cholesterol in HDL), whose low plasma level have significant atherogenic role. 2. Homocysteine (norm 5–15 mmol/l) is produced in methionine metabolism. Increased plasma levels of homocysteine is an independent risk factor for the development of atherosclerosis and CVD, even in normal lipid status. High homocysteine plasma levels are reduced by folic acid (vitamin B 3 ), pyridoxine (vitamin B 6 ) and vitamin B 12.

I.Drugs, inhibiting cholesterol and lipoprotein synthesis Statins Fibrates Nicotinic acids

 Statins HMG-CoA reductase inhibitors) – p.o. CYP 3A4 substrates Atorvastatin Lovastatin Simvastatin CYP 2C9 substrates Fluvastatin Rosuvastatin CYP450 substrate Pravastatin ARs: CPK, myositis, rabdomyolysis, hepatotoxicity

 Fibrates – p.o. (inhibit lipolysis in adipocytes) – Ciprofibrate – Clofibrate – Fenofibrate  Nicotinic acid inhibits secretion of VLDL and reduce production of LDL: – Niacin (Vitamin B 3 )

II. Drugs enhancing cholesterol and lipid metabolism (ARs: constipation, decreased GI absorption of many other drugs)  Bile acid sequestrants inhibit bile acid enterohepatic recirculation – p.o. : Colestipol, Colestyramine  Phytoproducts (p.o.): Pectin Pectivit C ® (pectin/vitamin C)

III. Drug, inhibiting intestinal cholesterol absorption: Ezetimibe – p.o. IV. Drugs, containing polyunsaturated essential omega-3-fatty acids: Escimo-3 ® Omacor ®

Control of total serum cholesterol < 5,2 mM 5,2–6,2 mM  6,2 mM Normal levels Bordeline levels High levels Control in 5 years Control in 12 months + diet In CHD or/and risk factors – lipid status analysis, diet and antidislipidemic treatment Control in 6 months with lipid status analysis, diet and antidislipidemic treatment

BMI >30: >>> saturated fatty acids > >>salt and >>> sugar >>> (or <<<) alcohol <<< fruits and vegetables Smoking Lipid status Stress Diabetes mellitus Metabolic syndrome Sedentary life style 2/3 of the risk Risk factor for CVD Homocysteine >15 mmol/l 

Metabolic syndrome – high risk for CVD (European Guidelines, 2003) presence of ≥ 3 risk factors: Waist > 102 cm in men and > 85 cm in women Triglycerides ≥ 1,7 mmol/lTriglycerides ≥ 1,7 mmol/lHDL-cholesterol < 1 mmol/l in men or < 1 mmol/l in men or < 1,3 mmol/l in women < 1,3 mmol/l in women Arterial hypertension > 130/85 mm Hg > 130/85 mm Hg Glucose ≥ 6,1 mmol/l Patients with hypertension and concomitant CVD have increased risk for diabetes mellitus. 

ATP3’, 5’-AMP cAMP Lipolysis (–) ACPD Cholesterol synthesis Caffeine > 300 mg/d: 5–6 coffee cups daily (+) Hypercholesterolemia

Patient’s compliance 200 ml/24 h Quantum therapy device  treatment (+ 1 to 2 measure of BP) non-pharmacological treatment physical activity dietary regimen 8–9 h of sleep avoidance of risk factors