Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology

Antidislipidemic drugs

(Summary) © Dr Ivan Lambev, PhD E-mail: [email protected]

•

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.

1000 mortality (CVD) mortality (CHD) 500 0 Roma ni a Pol an d Sc ot la nd US A Ge rma ny Sw ed en Ne th er la nd s Au st ra lia Ja pa n

International Cardiovascular Disease Statistics 2003; American H eart Association

Structure of lipoproteins

Free cholesterol Phospholipids Triglycerides Apolipoproteins Cholesterol esthers

Classification of lipoproteins according to theirs density



Chylomicrones



Very low density lipoproteins (VLDL)



Intermediate density lipoproteins (IDL)



Low density lipoproteins (LDL)



High density lipoproteins (HDL)

Apolipoproteins

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

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.

Lipoproteins rich in triglycerides Hypertriglyceridemia can predict CHD risk in independent to HDL way.

Fredrickson classification of dislipidemias (WHO)

Phenotype I IIa IIb III IV V Lipoprotein increased Chylomicrones LDL Plasma cholesterol Norma to LDL and VLDL IDL VLDL Norma to VLDL and Chylomicrones Norma to Plasma triglycerides Atherogenity Norma NO +++ +++ +++ + + Rate Low High High Medium High Low Adapted

from Yeshurun D, Gotto AM.

Southern Med J

1995;

88 (4)

: 379–391

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



S

tatins

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 ® Cod-liver oil 5 g/12 h p.o. ( A&D) Arachidonic acid Eicosapentanoic acid Potent TxA trombocyte antiaggregant inflamma tory LTs 2 : potent PGI 2 Escimo-3 ® Omacor ® : potent trombocyte antiaggregant Week inflamma tory LTs TxA 3 : week trombocyte aggregant PGI 3 : potent trombocyte antiaggregant

Control of total serum cholesterol

< 5,2 mM 5,2–6,2 mM Normal levels Bordeline levels

•Control in 5 years •Control in 12 months + diet •In CHD or/and risk factors –

lipid status analysis, diet and antidislipidemic treatment



6,2 mM High levels

•Control in 6 months with

lipid status analysis, diet and antidislipidemic treatment

 •Smoking •Lipid status •Stress

2/3 of the risk

•Homocysteine >15 mmol/l •Diabetes mellitus •Metabolic syndrome •Sedentary life style •BMI >30:

>>> saturated fatty acids > >>salt and >>> sugar >>> (or <<<) alcohol <<< fruits and vegetables

Risk factor for CVD



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/l •HDL-cholesterol < 1 mmol/l in men or < 1,3 mmol/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.

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

• treatment (+ 1 to 2

measure of BP)

• non-pharmacological

treatment

• physical activity • dietary regimen • 8–9 h of sleep • avoidance of risk factors

Patient’s compliance



Quantum therapy device