Antidyslipidemic drugs ( Summary )

1. Antidyslipidemic drugs (Summary) Assoc. Prof. Iv. Lambev E-mail: itlambev@mail.bg www.medpharm-sofia.eu

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

4. Structure of lipoproteins Free cholesterol Phospholipids Triglycerides Apolipoproteins Cholesterol esthers

5. Classification of lipoproteins according to their density • Chylomicrons • Very low density lipoproteins (VLDL) • Intermediate density lipoproteins(IDL) • Low density lipoproteins (LDL) • High density lipoproteins(HDL)

6. Apolipoproteins They are the main protein ingredient of lipoproteins with the following 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

7. AfterLDL oxidation free radicals and active oxygen species are formed and they activate macrophages.

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

9. Hypertriglyceridemia can predict CHD risk independently to HDL.

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

11. Notes 1.The Fredricksonclassification does not take into account HDL-C (cholesterol inHDL), whose low plasma level has a significant atherogenic role. 2.Homocysteine(normal 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 B3), pyridoxine (vitamin B6), and vitamin B12.

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

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

14. As a result of meta-analyses of many years of clinical • studies on statins FDA (2012) makes the following • findings: • Due to the their extremely rare hepatotoxicity • it does not recommend frequent routine • monitoring of liver enzymes.  • (2) Long-term therapy with statins is associated with • increases in fasting serum glucose levels and • glycosylated hemoglobin and increses te risk for • incident DN in 9 to 13%; in rosuvastatin-treateted • patients this risk is higher.

15. (3) Statins, though rare, can cause reversible symptoms of cognitive impairment (memory loss, amnesia, some confusion) requiring discontinuation of therapy.  (4) Lovastatinat is a substrate of P450 3A4 with proven in vivo sensitivity to this class isoenzymes. Comedication with strong inhibitors of P450 3A4 (anti-retroviral drugs, etc.) significantly increases the risk of serious ADRs (myopathy and/or rhabdomyolysis) in therapy with lovastatin.  This may require its replacement with another statin or reduce DD.The risk is much greater in liver function and alcoholism.

16. Fibrates– p.o. • (inhibit lipolysis in adipocytes) • – Ciprofibrate • – Clofibrate • –Fenofibrate • Nicotinic acid • inhibits secretion of VLDL and • reduces production of LDL: • – Niacin (Vitamin B3)

17. 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)

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

19. Control of total serum cholesterol 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 antidyslipidemic treatment • Control in 6 months with • lipid status analysis, diet, • and antidyslipidemic treatment < 5,2 mM 5,2–6,2 mM  6,2 mM

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

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

22. Caffeine >300 mg/d: 5–6 coffee cups daily (–) AC PD cAMP ATP 3’, 5’-AMP Hypercholesterolemia (+) (+) Cholesterol synthesis Lipolysis

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