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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
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(me
n 3
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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
Recommended