Transcript No Slide Title

Antidyslipidemic drugs
(Summary)
Assoc. Prof. Iv. Lambev
E-mail: [email protected]
www.medpharm-sofia.eu
• 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.
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Mortality in 100 000 population
(men 39 – 74 year of age)
CVD and CHD mortality rates
International Cardiovascular Disease Statistics 2003; American Heart
Heart Association
Structure of lipoproteins
Free cholesterol
Phospholipids
Apolipoproteins
Triglycerides
Cholesterol esthers
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)
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
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 independently to HDL.
Fredrickson classification
of dyslipidemias (WHO)
Phenotype
Lipoprotein
increased
I
Chylomicrons
IIa
LDL
IIb
Plasma
cholesterol
Plasma
Atherogenity
triglycerides
Normal to
Rate
NO
Low
+++
High
LDL and VLDL
+++
High
III
IDL
+++
Medium
IV
VLDL
Normal to
+
High
V
VLDL and
Chylomicrons
Normal to
+
Low
Normal
Adapted from Yeshurun D, Gotto AM. Southern Med J 1995; 88 (4): 379–391
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
 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
As a result of meta-analyses of many years of clinical
studies on statins FDA (2012) makes the following
findings:
(1) 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.
(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.
 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 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
Arachidonic
acid
5 g/12 h p.o. ( A&D)
Eicosapentanoic
acid
Escimo-3®
Omacor®
TxA2: potent
trombocyte
antiaggregant
Potent
inflammatory LTs
PGI2: potent
trombocyte
antiaggregant
TxA3: week
trombocyte
aggregant
Week
inflammatory LTs
PGI3: potent
trombocyte
antiaggregant
Control of total serum cholesterol
< 5,2 mM
5,2–6,2 mM
 6,2 mM
Normal
levels
•Control in 5 years
Bordeline
levels
•Control in 12 months + diet
•In CHD or/and risk factors –
lipid status analysis, diet,
and antidyslipidemic treatment
High
levels
•Control in 6 months with
lipid status analysis, diet,
and antidyslipidemic treatment

•Smoking
•Lipid status
2/3
of the
risk
Risk factor for CVD
•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
 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
Patients with hypertension
and concomitant CVD have
< 1,3 mmol/l in women
increased risk for diabetes
•Arterial hypertension
mellitus.
> 130/85 mm Hg
•Glucose ≥ 6,1 mmol/l
Caffeine > 300 mg/d:
5–6 coffee cups daily
(–)
ATP
AC
cAMP
3’, 5’-AMP
Hypercholesterolemia
(+)
Lipolysis
PD
(+)
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
