Antidyslipidemic drugsAntidyslipidemic drugs((SummarySummary))

Assoc. Prof. Iv. Lambev E-mail: itlambev@mail.bgwww.medpharm-sofia.eu

• CVD (cardiovascular disease)CVD (cardiovascular disease)

is the leading cause of death ais the leading cause of death ammongong

the adult population in the world.the adult population in the world.

• CHD (coronary heart disease) is the mainCHD (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 levelsTotal plasma cholesterol, high plasma levels

of LDL, low levels of HDL are importantof LDL, low levels of HDL are important

risk factors for CHD.risk factors for CHD.

0

500

1000

mortality ( CVD)

mortality ( CHD)

Mo

rta

lity

in

10

0 0

00

po

pu

lati

on

Mo

rta

lity

in

10

0 0

00

po

pu

lati

on

(me

n 3

9

(me

n 3

9 ––

74

ye

ar

of

ag

e)

74

ye

ar

of

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e)

I nternational Cardiovascular Disease S tatistics 2003; American HI nternational Cardiovascular Disease S tatistics 2003; American H eart Associationeart Association

CVD and CHD mortality ratesCVD and CHD mortality rates

Free cholesterol

Phospholipids Triglycerides

Cholesterol esthersApolipoproteins

Structure of lipoproteins

Chylomicrons

Very low density lipoproteins (VLDL)

Intermediate density lipoproteins (IDL)

Low density lipoproteins (LDL)

High density lipoproteins (HDL)

Classification of lipoproteinsClassification of lipoproteins

according to their densityaccording to their density

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

ApolipoproteinsApolipoproteins

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 Lipoproteins rich in triglyceridestriglycerides

Hypertriglyceridemia can predict

CHD risk independently to HDL.

Phenotype

I

IIa

IIb

III

IV

V

Lipoproteinincreased

Chylomicrons

LDL

LDL and VLDL

IDL

VLDL

VLDL andChylomicrons

Atherogenity

NO

+++

+++

+++

+

+

Rate

Low

High

High

Medium

High

Low

Plasmacholesterol

Normal to

Normal to

Normal to

Plasmatriglycerides

Normal

Adapted from Yeshurun D, Gotto AM. Southern Med J 1995; 88 (4): 379–391

Fredrickson classification of dyslipidemias (WHO)

Notes

1. The Fredrickson classification does not take into account HDL-C (cholesterol in HDL), 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.

I. Drugs inhibiting cholesterol and lipoprotein synthesis

• Statins• Fibrates• Nicotinic acids

StatinsHMG-CoA reductaseinhibitors) – p.o.

CYP 3A4 substrates• Atorvastatin• Lovastatin • Simvastatin

CYP 2C9 substrates• Fluvastatin• Rosuvastatin

CYP450 substrate•Pravastatin

ARs: CPK, myositis,rabdomyolysis,hepatotoxicity

As a result of meta-analyses of many years of clinicalstudies on statins FDA (2012) makes the followingfindings:

(1) Due to the their extremely rare hepatotoxicity it does not recommend frequent routinemonitoring of liver enzymes. (2) Long-term therapy with statins is associated withincreases in fasting serum glucose levels and glycosylated hemoglobin and increses te risk forincident DN in 9 to 13%; in rosuvastatin-treatetedpatients this risk is higher.

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

Fibrates – p.o. (inhibit lipolysis in adipocytes)

– Ciprofibrate – Clofibrate – Fenofibrate

Nicotinic acid inhibits secretion of VLDL and reduces production of LDL:

– Niacin (Vitamin B3)

II. Drugs enhancing cholesteroland 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)

Arachidonic acid

Cod-liver oil

Eicosapentanoicacid

TxA3: weektrombocyteaggregant

PGI3: potenttrombocyteantiaggregant

Weekinflamma-tory LTs

Potentinflamma-tory LTs

PGI2: potenttrombocyteantiaggregant

TxA2: potenttrombocyteantiaggregant

5 g/12 h p.o. ( A&D)

Escimo-3®

Omacor®

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

Normallevels

Bordelinelevels

Highlevels

•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

•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 ofpresence of ≥≥ 3 3 risk factorsrisk factors::

••Waist > 102 cm in men and > 85 cmWaist > 102 cm in men and > 85 cm in womenin women••TriglyceridesTriglycerides ≥ 1,7 ≥ 1,7 mmol/lmmol/l ••HDL-cholesterolHDL-cholesterol < 1 mmol/l< 1 mmol/l in men orin men or < 1< 1,3,3 mmol/l in women mmol/l in women••Arterial hypertensionArterial hypertension >> 130/85 130/85 mm Hgmm Hg••GlucoseGlucose ≥ 6,1 ≥ 6,1 mmol/lmmol/l

Patients with hypertensionand concomitant CVD haveincreased risk for diabetes

mellitus.

ATP 3’, 5’-AMPcAMP

Lipolysis

(–)

AC PD

Cholesterol synthesis

Caffeine > 300 mg/d:5–6 coffee cups daily

(+)

(+)

Hypercholesterolemia

Patient’s compliance

200

ml/2

4 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