lectuer

1. Lipid-lowering drugsLipid-lowering drugs

2. Introduction:Introduction:
Atheromatous disease is ubiquitous and underlies
the commonest causes of death (e.g. myocardial
infarction) and disability (e.g. stroke) in industrial
countries
Hypertension and dyslipidemia are ones of the
most important risk factors, amenable to drug
therapy
Atheroma is a focal disease of the intima of large
and medium-sized arteries

4. A t h e r o g e n e s i s involves several
stages:
Endothelial dysfunction with altered PGI2 and
NO synthesis
Monocyte attachment
Endothelial cells bind LDL
Oxidatively modified LDL is taken up by
macrophages then (now foam cells) migrate
subendothelially
Atheromatous plaque formation
Rupture of the plaque

5. Lipids, including cholesterol (Cho) and triglycerides (Tg),
are transported in the plasma as lipoproteins, of which
there are four classes:
 Chylomicrons transport Tg and Cho from the gut to
the tissues, where they are split by lipase, releasing
free fatty acids.there are taken up in muscle and
adipose tissue. chylomicron remnants are taken up in
the liver
 Very low density lipoproteins (VLDL), which
transport cho and newly synthetised tg to the tissues,
where tgs are removed as before, leaving:

6. Low lipoproteins (LDL) with a large
comdensity ponent of CHO, some of which is
taken up by the tissues and some by the liver,
by endocytosis via specific LDL receptors
High density lipoproteins (HDL).which
absorb CHO derived from cell breakdown in
tissues and transfer it to VLDL and LDL

7. There are two different pathways for
exogenous and endogenous lipids:
The Exogenous Pathway: CHO + TGCHO + TG
absorbed from the GIT are transported in
the lymph and than in the plasma as
ChylomicronsChylomicrons to capillaries in muscle and
adipose tissues.
Here the core TRIGLTRIGL are hydrolysed by
lipoprotein lipase, and the tissues take up
the resulting Free Fatty AcidsFree Fatty Acids

8. CHOCHO is liberated within the liver cells and
may be stored, oxidised to bile aids or
secreted in the bile unaltered
Alternatively it may enter the endogenous
pathway of lipid transpor in VLDLVLDL

9. The Endogenous Pathway:
CHO and newly synthetised TG are
transported from the liver as VLDL to muscle
and adipose tissue, the TG are hydrolysed and
the resulting FATTY ACIDS enter the tissues
The lipoprotein particles become smaller and
ultimetaly become LDL, which provides the
source of CHO for incorporation into cell
membranes, for synthesis of steroids, and bile
acids

10. Cells take up LDL by endocytosis via LDL receptors that
recognise LDL apolipoproteins
CHOCHO can return to plasma from the tissues in
HDLHDL particles and the resulting cholesteryl
esters are subsequently transferred to VLDVLDLL
or LDLLDL
One species of LDL – lipoprotein - is
associated with atherosclerosis (localised in
atherosclerotic lesions). LDL can also activate
platelets, constituting a further thrombogenic
effect

11. DyslipidemiaDyslipidemia::
The normal range of plasma total CHOtotal CHO
concentrationconcentration < 6.5 mmol/L.
There are smooth gradations of increased risk with
elevated LDL CHO concLDL CHO conc, and with reduced HDLHDL
CHO concCHO conc.
Dyslipidemia can be primary or secondary.

12. The primary forms are genetically
determined
Secondary forms are a consequence of other
conditions such as diabetes mellitus,
alcoholism, nephrotic sy, chronic renal
failure, administration of drug…

14. Lipid-lowering drugsLipid-lowering drugs
 Several drugs are used to decrease plasma
LDL-CHO
 Drug therapy to lower plasma lipids is only
one approach to treatment
 And is used in addition to dietary
management and correction of other
modifiable cardiovascular risk factors

15. Fibrates
Others
Resins
Statins
LIPID-
LOWERING
DRUGS

16. StatinsStatins::
MOA
 HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A)
reductase inhibitors.
The reductase catalyses the conversion of HMG-CoA to
mevalonic acid
Simvastatin + pravastatin + atorvastatin
 decrease hepatic CHO synthesis
up regulates LDL receptor synthesis, increasing
and LDL clearance from plasma into liver cells
Atorvastatin and rosuvastatin are long-
lasting inhibitors.

17. Promising pharmacodynamicPromising pharmacodynamic
actionsactions of statins:of statins:
Improved endothelial function
Reduced vascular inflammation and platelet
aggregability
Antithrombotic action
Stabilisation of atherosclerotic plaques
Increased neovascularisation of ischaemic
tissue
Enhanced fibrinolysis
Immune suppression
Osteoclast apoptosis and increased synthetic
activity in osteoblasts

18. PharmacokineticsPharmacokinetics of Statintsof Statints
- well absorbed when given orally
- extracted by the liver (target tissue),
undergo extensive presystemic
biotransformation
Simvastatin is an inactive pro-drug

19. C l i n i c a l u s e sC l i n i c a l u s e s::
 Secondary prevention of myocardial infarction and
stroke in patients who have symptomatic
atherosclerotic disease (angina, transient ischemic
attacks) following acute myocardial infarction or
stroke
 Primary prevention of arterial disease in patients
who are at high risk because of elevated serum
CHO concentration, especially it there are other
risk factors for atherosclerosis
 Atorvastatin lowers serum CHO in patients with
homozygous familiar hypercholesterolemia

20. A d v e r s e e f f e c t s:A d v e r s e e f f e c t s:
mild gastrointestinal disturbances
 Raised concentrations of liver enzymes in
plasma
 Severe myositis (rhabdomyolysis)
Angio-oedema (rare)

21. 2-2- FibratesFibrates::
stimulate the beta-oxidative degradation of
fatty acids
- liberate free fatty acids for storage in fat or for
metabolism in striated muscle
 increase the activity of lipoprotein lipase,
 hence increasing hydrolysis of triglyceride in
chylomicrons and VLDL particles
reduce hepatic VLDL production and increase
hepatic LDL uptake

22. O t h e r e f f e c t s :
 improve glucose tolerance
 inhibit vascular smooth muscle inflammation
Fenofibrate
 Clofibrate
Gemfibrozil
 Ciprofibrate

23. A d v e r s e e f f e c t s:A d v e r s e e f f e c t s:
In patients with renal impairment
 myositis (rhabdomyolysis)
 myoglobulinuria, acute renal failure
 Fibrates should be avoided in such patients.
Mild GIT symptoms

24. C l i n i c a l u s e sC l i n i c a l u s e s::
Mixed dyslipidaemia (i.e. raised serum
triglyceride as well as cholesterol)
In patients with low high-density lipoprotein
and high risk of atheromatous disease (often
type 2 diabetic patients
Combined with other lipid-lowering drugs in
patients with severe treatment-resistant
dyslipidaemia

25. Bile acid bindingBile acid binding resinsresins::
((Colestyramin colestipolColestyramin colestipol))
 sequester bile acids in the GIT prevent their
reabsorption and enterohepatic recirculation
The r e s u l t is:
decreased absorption of exogenous CHO and increased
metabolism of endogenous CHO into bile acid acids
increased expression of LDL receptors on liver cells
increased removal of LDL from the blood
reduced concentration of LDL CHO in plasma
(while an unwanted increase in TG)

26. C l i n i c a l u s e s:C l i n i c a l u s e s:
an addition to a statin if response has
been inadequate
for Hypercholesterolemia when a statin
is contraindicated
Uses unrelated to atherosclerosis,
including:
pruritus in patients with partial biliary
obstruction
bile acid diarrhea (diabetic neuropathy)

27. A d v e r s e e f f e c t sA d v e r s e e f f e c t s::
GIT symptoms - nauzea, abdominal bloating,
constipation or diarrhea
 Resins are unappetising. This can be minimized
by suspending them in fruit juice
 Interfere with the absorption of fat-soluble
vitamins and drugs (chlorothiazide, digoxin,
warfarin)
 These drugs should be given at last 1 hour before or 4-6 hours
after a resin

28. OthersOthers
Nicotinic acid inhibits hepatic TG
production and VLDL secretion
Modest reduction in LDL and increase in
HDL
A d v e r s e e f f e c t s:
flushing, palpitations , GIT disturbances

29. Fish oil (rich in highly unsaturated fatty acids)
the omega-3 marine TG
- reduce plasma TG but increase CHO (CHO is
more strongly associated wih coronary artery
disease)
- the effects on cardiac morbidity or mortality is
unproven
( although there is epidemiological evidence that
eating fish regularly does reduce ischemic heart
disease)

31. Cardiovascular Disease (CVD)Cardiovascular Disease (CVD)
Main type of CVD is Atherosclerosis (AS)
Endothelial dysfunction is one of earliest
changes in AS
Mechanical, chemical, inflammatory mediators
can trigger endothelial dysfunction:
◦ High blood pressure
◦ Smoking (free radicals that oxidatively damage
endothelium)
◦ Elevated homocysteine
◦ Inflammatory stimuli
◦ Hyperlipidemia

32. A Healthy Endothelium
produces:
 PGI2
 NO
Maintaining an
anti-coagulant,
anti-thrombotic
surface

33. A Dysfunctional Endothelium
has decreased:
 PGI2
 NO
Shifting to a
pro-coagulant, pro-
thrombotic surface
Increased:
pro-inflammatory
molecules:
MCP-1
TNFα
VCAM-1

34. Pro-Inflammatory MoleculesPro-Inflammatory Molecules
Chemokines = monocyte chemoattractant protein
1 (MCP-1)
Inflammatory cytokines = tumor necrosis factor α
(TNF α)
Adhesion molecules = intercellular adhesion
molecule 1 (ICAM-1), vascular cell adhesion
molecule 1 (VCAM-1)
Overexpression of all these inflammatory
mediators is commonly seen in atherosclerotic
lesions.

35. Endothelial DysfunctionEndothelial Dysfunction
( endothelial activation, impaired endothelial-dependent vasodilation)( endothelial activation, impaired endothelial-dependent vasodilation)
  endothelial synthesis of PGI2 (prostacylcin), & NO
(nitric oxide)
◦ PGI2 = vasodilator, platelet adhesion/aggregation
◦ NO = vasodilator, platelet & WBC (monocyte) adhesion
  Adhesion of monocytes onto endothelium -->
transmigration into subendothelial space (artery
wall) --> change to macrophages
Endothelial dysfunction --> increased flux of LDL into
artery wall

38. Oxidation of LDL (oxLDL)Oxidation of LDL (oxLDL)
 Oxidation = process by which free radicals (oxidants) attack and
damage target molecules / tissues
 Targets of free radical attack:
◦ DNA - carbohydrates
◦ Proteins - PUFA’s>>> MUFA’s>>>>> SFA’s
 LDL can be oxidatively damaged: PUFA’s are oxidized and
trigger oxidation of apoB100 protein --> oxLDL
 OxLDL is engulfed by macrophages in subendothelial space

41. Atherosclerotic PlaqueAtherosclerotic Plaque
 Continued endothelial dysfunction (inflammatory response)
 Accumulation of oxLDL in macrophages (= foam cells)
 Migration and accumulation of:
◦ smooth muscle cells,
◦ additional WBC’s (macrophages, T-lymphocytes)
◦ Calcific deposits
◦ Change in extracellular proteins, fibrous tissue formation
 High risk =  VLDL (TG)  LDL  HDL

42. KnowYour Lipid ProfileKnowYour Lipid Profile
Total Cholesterol < 200 mg/dl
LDL-Cholesterol < 100 mg/dl
HDL-Cholesterol ≥ 60 mg/dl
Triglycerides < 150 mg/dl
Fasting Blood Level Ideal, Healthy Level