LipidLipid-lowering drugs

Prof. MUDr Ji ina Martnkov, PhD 2006/2007

Atherosclerosis and lipoprotein metabolism

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 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 - having taken up oxidised LDL, these macrophages (now foam cells) migrate subendothelially - atheromatous plaque formation - rupture of the plaque

Atherosclerosis and lipoprotein metabolism

LIPIDS, 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 GIT 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: - low density lipoproteins (LDL) with a large component 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

Atherosclerosis and lipoprotein metabolism

There are two different pathways for exogenous and endogenous lipids: THE EXOGENOUS PATHWAY: CHO + TG absorbed from the GIT are transported in the lymph and than in the plasma as CHYLOMICRONS to capillaries in muscle and adipose tissues. Here the core TRIGL are hydrolysed by lipoprotein lipase, and the tissues take up the resulting FREE FATTY ACIDS CHO 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 VLDL

Atherosclerosis and lipoprotein metabolism

EXOGENOUS PATHWAY

CHO ENDOGENOUS PATHWAY

may be stored

oxidised to bile acids

secreted in the bile unaltered

ENDOGENOUS PATHWAY for lipids

EXOGENOUS PATHWAY for lipids

HEPATOCYTE

Fig.1a

GIT

CHO

bile acids
CHO

Bile duct v.portae

bile acids

Fat + CHO + fatty acids

ENDOGENOUS PARTHWAY

chylomicr remn
CHO TG

chylomicr
TG CHO

Peripheral tissues Fatty acids

(According to Rang, Dale 1999)

Atherosclerosis and lipoprotein metabolism

THE ENDOGENOUS PATHWAY CHO and newly synthetised TG are transported from the liver as VLDL to muscle and adipose tissue, there 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
Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins

CHO can return to plasma from the tissues in HDL particles and the resulting cholesteryl esters are subsequently transferred to VLDL or LDL One species of LDL lipoprotein - is associated with atherosclerosis (localised in atherosclerotic lesions). LDL can also activate platelets, constituting a further thrombogenic effect

ENDOGENOUS PATHWAY for lipids

HEPATOCYTE ACoA
MVA

EXOGENOUS PATHWAY for lipids

Fig.1b

GIT

Bile duct CHO bile acids

CHO

bile acids v.portae

LDL receptors

CHO

VLDL CHO TG CHO

HDL CHO

CHO

LDL CHO

lipase

CHO

from cells

Uptake of CHO

Fatty acids

Peripheral tissues

(According to Rang, Dale 1999)

Dyslipidemia
The normal range of plasma total CHO concentration < 6.5 mmol/L. There are smooth gradations of increased risk with elevated LDL CHO conc, and with reduced HDL CHO conc. conc, conc.

Dyslipidemia can be primary or secondary.

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

LipidLipid-lowering drugs


Several drugs are used to decrease plasma LDLLDL-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

Statins

Fibrates

LIPID-LOWERING DRUGS

Resins

Others

ENDOGENOUS PATHWAY for lipids

HEPATOCYTE ACoA
MVA

EXOGENOUS PATHWAY for lipids

Fig.1c GIT GIT

STATINS

Bile duct CHO bile acids

CHO

STATINS FIBRATES

bile acids v.portae

FIBRATES

LDL receptors

RESINS fat + CHO + fatty acids

CHO

VLDL Chylomikr remn TG CHO FIBRATES CHO TG

Chylomikr TG CHO

HDL CHO

CHO

LDL CHO

lipase

CHO

from cells

Uptake of CHO

Fatty acids

Fatty acids

Peripheral tissues

(According to Rang, Dale 1999)

LIPIDLIPID-LOWERING DRUGS

Statins
HMGHMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (3-hydroxy- methylglutarylinhibitors. inhibitors. The reductase catalyses the conversion of HMG-CoA to HMGmevalonic acid

Simvastatin + pravastatin + atorvastatin

decrease hepatic CHO synthesis increase in synthesis of CHO receptors + increased clearance of LDL Several studies demonstrated positive effects on morbidity and mortality

LIPIDLIPID-LOWERING DRUGS
Statins

Promising pharmacodynamic actions: actions:

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


LIPIDLIPID-LOWERING DRUG
Statins

Pharmacokinetics
-

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

LIPIDLIPID-LOWERING DRUG
Statins

Clinical uses  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

LIPIDLIPID-LOWERING DRUG
Statins

A d v e r s e e f f e c t s:
-

mild gastrointestinal disturbances increased plasma activities in liver enzymes severe myositis (rhabdomyolysis) and angio-oedema (rare) angio-

LIPIDLIPID-LOWERING DRUGS

Fibrates
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

LIPIDLIPID-LOWERING DRUGS
Fibrates Other effects: improve glucose tolerance inhibit vascular smooth muscle inflammation

fenofibrate clofibrate gemfibrozil ciprofibrate

LIPIDLIPID-LOWERING DRUGS
Fibrates

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 and also in alcoholics) mild GIT symptoms

LIPIDLIPID-LOWERING DRUGS
Fibrates

Clinical uses mixed dyslipidemia (i.e. raised serum TG and CHO)

patients with low HDL and high disease (often type 2 diabetic patients)

risk of atheromatous

patients with severe treatment- resistant dyslipidemia (combination with other lipid-lowering drugs)

LIPID-LOWERING DRUGS

Bile acid binding resins

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)

LIPIDLIPID-LOWERING DRUGS
Bile acid binding resins

Colestyramin colestipol
anion exchange resins

C l i n i c a l u s e s: heterozygous familiar hypercholesterolemia

an addition to a statin if response has been inadequate

hypercholesterolemia

when a statin is contraindicated

uses unrelated to atherosclerosis, including:

pruritus in patients with partial biliary obstruction bile acid diarrhea (diabetic neuropathy)

LIPIDLIPID-LOWERING DRUGS
Bile acid binding resins

A 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 fatand drugs (chlorothiazide, digoxin, warfarin)
These drugs should be given at last 1 hour before or 4-6 hours after a resin 4-

LIPID-LOWERING DRUGS

Others
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

LIPID-LOWERING DRUGS

Others
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)

Lipid-lowering drugs