1. Antidyslipidemic drugs
(Summary)
Assoc. Prof. Iv. Lambev

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.

3. Atherosclerosis eventually leads to cardiovascular disease (CVD), resulting in a variety of clinical manifestations including; coronary heart disease (CHD) (angina pectoris, MI, and sudden cardiac death), cerebrovascular disease (transient ischaemic attacks [TIA] and stroke) and peripheral vascular disease (PVD) (intermittent claudication and gangrene).
The most significant clinical manifestation, in terms of morbidity and mortality, is CHD. This slide shows that the death rates in selected countries resulting from CVD and CHD vary greatly in different countries, with the highest rates in Romania and the lowest in Japan.1
According to WHO estimates, 16.6 million people around the globe die of CVD each year, contributing to nearly one-third of global deaths.2 In 2001 there were 7.2 million deaths from heart disease and 5.5 million from stroke.2 Another 15 million each year survive minor strokes and 600 million people with high blood pressure are at risk of heart attack, stroke and cardiac failure.3
CVD is the leading cause of death in Europe, accounting for over 4 million deaths a year.4 Nearly half (49%) of all deaths are from CVD (55% of deaths in women and 43% of deaths in men).
References
1. The World Health Organisation Web page,
2. The World Health Report, 2002.
3. Cardiovascular diseases – Prevention and Control. WHO CVD strategy, 2001/2002.
4. European Cardiovascular Disease Statistics 2000 Edition, British Heart Foundation.

4. Structure of lipoproteins
Free cholesterol
Phospholipids
Triglycerides
Lipoproteins are macromolecular aggregates of lipids and apolipoproteins. Lipids can be divided into two main groups, simple and complex. The two most important simple lipids are cholesterol and fatty acids. Lipids become complex lipids when fatty acids undergo esterification to produce esters.1-3
Simple lipids Cholesterol is a soft waxy substance present in all cells of the body. Most tissues can produce cholesterol, but it is synthesised primarily in the liver and small intestine. Approximately 50% of the cholesterol requirement is synthesised, whilst the rest is obtained from animal produce in the diet. Cholesterol is important in the repair of cell membranes and in the synthesis of steroid hormones, vitamin D and bile acids. Fatty acids are the simplest form of lipid found in the body and are an important energy source. They exist as saturated, monounsaturated and polyunsaturated forms, distinguished by the number of bonds between the hydrocarbon chain and carbon atoms. The most common fatty acids in the body are stearic and palmitic (saturated), and oleic (monounsaturated). Fatty acids exist freely in the plasma mostly bound to albumin, but are stored in adipose tissue as triglycerides.1-3
Complex lipids Triglycerides are mainly stored in adipose tissue and are the main lipid currency of the body. Phospholipids are glycerol esters containing two fatty acids. They have a water-soluble and a lipid-soluble surface and are an important component of the cell membrane. Cholesterol esters, oleate and linoleate, are the storage molecules of cholesterol in cells.1-3
Apolipoproteins In order for these water-insoluble lipids to be transported around the body in the the aqueous medium, blood, they are aggregated with apolipoproteins to form lipoproteins. These multimolecular packages consist of a hydrophobic core containing cholesteryl esters and triglyceride, surrounded by a hydrophilic surface layer of phospholipids, proteins and some free cholesterol. While structurally similar, lipoproteins vary in their proportions of component molecules and the type of proteins present.1-3
References
1. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A. Health Press Ltd, Oxford, –17.
2. In: Manual of Lipid Disorders, 2nd Edition. Eds Gotto A, Pownall H. Williams & Wilkins, US,
3. In: Statins - The HMG-CoA Reductase Inhibitors in Perspective. Eds Gaw A, Packard CJ, Shepherd J. Martin Dunitz 2000, 1-19.
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)
There are five major classes of lipoproteins based on their density. The degree to which lipoproteins cause atherosclerosis depends to some extent on their size, and thus their ability to enter and form deposits within the arterial wall. Thus, smaller VLDL, IDL and LDL are all atherogenic, whereas large VLDL and chylomicrons are not. HDL, largely by its ability to carry cholesterol away from the arterial wall, is anti-atherogenic.
Chylomicrons are the largest in size, lowest in density and are not associated with atherosclerosis. They are synthesised in the intestinal mucosal cells after a fatty meal. They transport dietary triglyceride from the intestine to the sites of use and storage, and are cleared rapidly from the bloodstream, generally being undetectable 12 hours after a meal.1,2
VLDL are similar in structure to chylomicrons but are smaller. They are produced in the liver and are the main carriers of endogenous (synthesised in the liver rather then dietary) triglycerides and cholesterol to sites for use or storage. As they are also involved in the synthesis of LDL, VLDL are implicated in atherosclerosis development.1,2
IDL are highly atherogenic. They are formed during the breakdown of VLDL and chylomicrons and are also implicated in atherosclerosis development. They contain less triglyceride and more cholesterol than VLDL, and are involved in the recycling of cholesterol by the liver as well as formation of LDL in the blood.1,2
LDL are generated from IDL in the circulation and are the principal lipoproteins involved in atherosclerosis. Oxidised LDL is the most atherogenic form of LDL. They are the main carriers of cholesterol, accounting for 60–70% of plasma cholesterol. They comprise four main subtypes: LDL I, II, III and IV, of which LDL-III is the most atherogenic subclass.1,2
HDL are the smallest but most abundant of the lipoproteins. They do not cause atherosclerosis, but actually protect against its development. This is because they return about 20–30% of cholesterol in the blood to the liver from peripheral tissue for excretion. They also inhibit the oxidation of LDL and they decrease the attraction of macrophages to the artery wall. There are two main subtypes: HDL2 and HDL3.1,2
References
1. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A. Health Press Ltd, Oxford, –17.
2. In: Manual of Lipid Disorders, 2nd Edition. Eds Gotto A, Pownall H. Williams & Wilkins, US, –10.

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
Apolipoproteins are the protein constituents of lipoproteins and they have three main functions:1
1. They facilitate lipid transport by stabilising the water-soluble lipids, cholesterol esters and triglycerides in aqueous plasma.
2. They regulate the interaction of these lipids with the enzymes lecithin cholesterol acyltransferase (LCAT), lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL).
3. They bind to cell surface receptors.
There are eight broad groups of apolipoproteins that have currently been identified. These are designated apo A to F, apo H and apo J. The form of apolipoprotein B that is made in the liver (apo B100) is associated with high levels of LDL and is an important marker for atherosclerosis.2
References
1. In: Statins - The HMG-CoA Reductase Inhibitors in Perspective. Eds Gaw A, Packard CJ, Shepherd J. Martin Dunitz 2000, 1–19.
2. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A. Health Press Ltd, Oxford, –17.  

7. After LDL oxidation free radicals and active oxygen
species are formed and they activate macrophages.
Figure 23 Atherogenic lipoproteins (LDL or other apo B-containing lipoproteins) penetrate the intima. This renders them susceptible to oxidation – the auto-oxidation lipid cycle. Oxidized LDL contains modified apo B which is not recognized by the normal receptors. Instead, it is recognized by the non-regulated scavenger receptor on the activated macrophage.

8. Activated macrophages produce inflammatory cytokines (IL-6,
TNF alpha), which damage endothelium and initiate atherogenesis.
Figure 24 Oxidized LDL contains large amounts of cholesterol ester (CE). When macrophages are full of CE they secrete cytokines (IL-6, CRP, TNFa) which, in turn, induce vascular inflammation, cell recruitment, and weakening of the fibrous cap.

9. Hypertriglyceridemia can predict
CHD risk independently to HDL.

10. Fredrickson classification of dyslipidemias (WHO)
Phenotype I
IIa
IIb
III IV V
Lipoprotein
increased
Chylomicrons
LDL
LDL and VLDL
IDL
VLDL
VLDL and
Plasma
cholesterol
Plasma
triglycerides
Atherogenity NO
+++ +
Rate
Low
High
Medium
Normal to
Normal
The Fredrickson classification was the first classification of dyslipidaemias. It was based on the analysis of plasma for various lipoprotein fractions, but took no account of the underlying aetiology of any of the dyslipidaemias. In addition, high-density lipoprotein (HDL) cholesterol levels are not considered in this classification.1 Today it is more common to identify the dyslipidaemias by the particular lipoprotein or apolipoprotein that is abnormal. Once dyslipidaemia has been identified it is important to determine the cause where possible. Dyslipidaemia may be secondary to other disorders or a primary abnormality. Common causes of secondary dyslipidaemia include: diabetes mellitus, the nephrotic syndrome, chronic renal failure, hepatobiliary disease (generally of the obstructive variety) and hypothyroidism. It should be recognised that these cause some but not all dyslipidaemias. For example, diabetes can lead to elevation of triglyceride-rich lipoproteins and reduction of HDL, but does not necessarily increase the levels of LDL. On the other hand, hepatobiliary disease is associated with an increase in the levels of LDL. Of the primary causes of dyslipidaemia, the most severe forms are caused by genetic disorders of lipoprotein metabolism. The most easily identifiable in clinical practice are familial hypercholesterolaemia (FH), polygenic hypercholesterolaemia and familial combined hypercholesterolaemia, all of which increase the risk of premature development of CHD. Patients presenting with severe forms of hypercholesterolaemia should undergo family screening to detect other family members for therapy.2
FH is an autosomal dominant disease with defects in the gene for the LDL receptor. In its heterozygous form, it is present in about 1/500 of the population. It is a highly variable disorder, with the age of onset of CHD ranging from 30–70 years for patients with the same LDL-cholesterol levels at diagnosis, and with a poor prognosis when using older lipid-modifying drugs. Women with FH tend to develop CHD 10–15 years later than male siblings with the identical LDL-receptor mutation.3
Therapy of these disorders is directed towards aggressive management of hypercholesterolaemia with a target LDL-cholesterol that depends on the overall coronary risk of the affected person.3
References
1. Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391.
2. National Cholesterol Education Program. Circulation 1994;98(3):1333–1445.
3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001:285;2486–2497.
Normal to
Normal to
Adapted from Yeshurun D, Gotto AM. Southern Med J 1995; 88 (4): 379–391

11. 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.

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

13.  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

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.  Nicotinic acid (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
High
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
< 5,2 mM
5,2–6,2 mM
 6,2 mM

20. Homocysteine >15 mmol/l
2/3
of the
risk
Risk factor for CVD
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  presence of ≥ 3 risk factors:
– 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.

22. Cholesterol synthesis
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
Patient’s compliance
Quantum therapy device 
200 ml/24 h