lipid-lowering drugs. atherosclerosis and lipoprotein metabolism atheromatous disease is ubiquitous...

Lipid-lowering drugsLipid-lowering drugs

Atherosclerosis and lipoprotein metabolismAtherosclerosis and lipoprotein metabolism

Atheromatous disease is ubiquitous and underlies the commonest causes of death (e.g. myocardial infarction) and disability (e.g. stroke) in industrialcountriesHypertension 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


LIPIDSLIPIDS, including , including CHOLESTEROLCHOLESTEROL (CHO)(CHO) and and TRIGLYCERIDES (TG),TRIGLYCERIDES (TG), are are transported in the plasma as lipoproteins, of which there are four classes: transported in the plasma as lipoproteins, of which there are four classes:

- - chylomicronschylomicrons transport TG and CHO from the GIT to the tissues, where 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 they are split by lipase, releasing free fatty acids.There are taken up in muscle and adipose tissue. and adipose tissue. Chylomicron remnantsChylomicron remnants are taken up in the liver are taken up in the liver

- - very low density lipoproteinsvery low density lipoproteins (VLDL), which transport CHO and newly (VLDL), which transport CHO and newly synthetised TG to the tissues, where TGs are removed as before, leaving:synthetised TG to the tissues, where TGs are removed as before, leaving:

- - low density lipoproteinslow density lipoproteins (LDL) with a large component of CHO, some of (LDL) with a large component of CHO, some of which is taken up by the tissues and some by the liver, by endocytosis via which is taken up by the tissues and some by the liver, by endocytosis via specific specific

LDL receptorsLDL receptors

- - high density lipoproteinshigh density lipoproteins (HDL).which absorb CHO derived from cell (HDL).which absorb CHO derived from cell breakdown in tissues and transfer it to VLDL and LDLbreakdown in tissues and transfer it to VLDL and LDL


There are two different pathways for exogenous and endogenous There are two different pathways for exogenous and endogenous lipids:lipids:

THE EXOGENOUS PATHWAYTHE EXOGENOUS PATHWAY:: CHO + TGCHO + TG absorbed from the GIT are absorbed from the GIT are transported in the lymph and than in the plasma as transported in the lymph and than in the plasma as CHYLOMICRONSCHYLOMICRONS to capillaries in muscle and adipose tissues. Here to capillaries in muscle and adipose tissues. Here the core the core TRIGL TRIGL are hydrolysed by lipoprotein lipase, and the are hydrolysed by lipoprotein lipase, and the tissues take up the resulting tissues take up the resulting FREE FATTY ACIDSFREE FATTY ACIDS

CHOCHO is liberated within the liver cells and may be stored, is liberated within the liver cells and may be stored, oxidised to bile aids or secreted in the bile unaltered oxidised to bile aids or secreted in the bile unaltered

Alternatively it may enter the endogenous pathway of lipid Alternatively it may enter the endogenous pathway of lipid transpor in transpor in VLDLVLDL


CHO

may be stored

oxidised to

bile acids

secretedin

the bileunaltered

ENDOGENOUS PATHWAY

EXOGENOUS PATHWAY

(According to Rang, Dale 1999)

CHO Bile duct

v.portae

GIT

bile acids

ENDOGENOUS PATHWAY for lipids

EXOGENOUS PATHWAY for lipids

chylomicrTG CHO

chylomicrremn

bile acids CHO

Fig.1a

Peripheral tissues

ENDOGENOUSPARTHWAY

Fat+ CHO

+ fatty acids

HEPATOCYTE

CHO TG

Fatty acids


THE ENDOGENOUS PATHWAYTHE ENDOGENOUS PATHWAY

CHO CHO and newly synthetised and newly synthetised TGTG are transported from the liver as are transported from the liver as VLDL VLDL to to muscle and adipose tissue, there muscle and adipose tissue, there TGTG are hydrolysed and the resulting are hydrolysed and the resulting

FATTY ACIDSFATTY ACIDS enter the tissues enter the tissues

The lipoprotein particlesThe lipoprotein particles become smaller and ultimetaly become become smaller and ultimetaly become LDLLDL , ,

which provides the source of which provides the source of CHOCHO for incorporation into cell membranes, for for incorporation into cell membranes, for synthesis of steroids, and bile acidssynthesis of steroids, and bile acids

Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins

CHOCHO can return to plasma from the tissues in can return to plasma from the tissues in HDLHDL particles and the resulting particles and the resulting cholesteryl esters are subsequently transferred to cholesteryl esters are subsequently transferred to VLDLVLDL or or LDLLDL

One species of One species of LDLLDL – – lipoproteinlipoprotein - is associated with atherosclerosis - is associated with atherosclerosis (localised in atherosclerotic lesions). LDL can also activate platelets, (localised in atherosclerotic lesions). LDL can also activate platelets, constituting a further thrombogenic effect constituting a further thrombogenic effect


CHOBile duct

v.portae

GIT

bile acids



bile acids CHO

Fig.1b

Peripheral tissues

HEPATOCYTE

ACoA

MVA

LDLreceptors

VLDL

TG CHO

lipase

CHO

CHO

CHOLDLHDL

CHO

Uptakeof CHO

Fattyacids

CHO

from cells

CHO

DyslipidemiaDyslipidemiaThe normal range of plasma The normal range of plasma total CHO concentrationtotal CHO concentration << 6.5 mmol/L. 6.5 mmol/L.

There are smooth gradations of increased risk with There are smooth gradations of increased risk with

elevated elevated LDL CHO concLDL CHO conc, and with reduced , and with reduced HDL CHO concHDL CHO conc..

DyslipidemiaDyslipidemia can be primary or secondary. can be primary or secondary.

The primary formsThe primary forms are genetically determined are genetically determined

Secondary formsSecondary forms are a consequence of other conditions are a consequence of other conditions

such assuch as diabetes mellitus, alcoholism, nephrotic sy, diabetes mellitus, alcoholism, nephrotic sy,

chronic renal failure, administration of drug… chronic renal failure, administration of drug…

Lipid-lowering drugsLipid-lowering drugs Several drugs are used to decrease plasma Several drugs are used to decrease plasma

LDL-CHOLDL-CHO Drug therapy to lower plasma lipids is Drug therapy to lower plasma lipids is

only one approach to treatment only one approach to treatment andand is used in addition to dietary is used in addition to dietary

management management andand correction of other modifiable correction of other modifiable

cardiovascular risk factorscardiovascular risk factors

Fibrates

Others

Resins

Statins

LIPID-LOWERING DRUGS


CHO

Bile duct

v.portae

GIT

bile acids



bile acids CHO

Fig.1c

Peripheral tissues

fat+ CHO+ fatty acids

HEPATOCYTE

ACoA

MVA

LDLreceptors

VLDL

TG CHO

lipase

CHO

CHO

CHOLDL

HDL

CHO

Uptakeof CHO

Fattyacids

Fattyacids

CHO

from cells

Chylomikr

TG CHO

GIT

Chylomikr remn

CHO TG

STATINS

STATINSFIBRATES

FIBRATES

FIBRATES

RESINS

LIPID-LOWERING DRUGSLIPID-LOWERING DRUGS

StatinsStatinsHMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase

inhibitorsinhibitors. The reductase catalyses the conversion of . The reductase catalyses the conversion of HMG-CoAHMG-CoA to to mevalonic acidmevalonic acid

Simvastatin + pravastatin + atorvastatinSimvastatin + pravastatin + atorvastatin

decrease hepatic CHO synthesisdecrease hepatic CHO synthesis

increase in synthesis of CHO receptors increase in synthesis of CHO receptors

+ increased clearance of LDL+ increased clearance of LDL

Several studies demonstrated positive effects on morbidity and mortality


StatinsStatins

Promising pharmacodynamic actionsPromising pharmacodynamic actions:: improved endothelial functionimproved endothelial function reduced vascular inflammation and platelet aggregabilityreduced vascular inflammation and platelet aggregability antithrombotic actionantithrombotic action stabilisation of atherosclerotic plaquesstabilisation of atherosclerotic plaques increased neovascularisation of ischaemic tissueincreased neovascularisation of ischaemic tissue enhanced fibrinolysisenhanced fibrinolysis immune suppressionimmune suppression osteoclast apoptosis and increased synthetic activity in osteoclast apoptosis and increased synthetic activity in

osteoblastsosteoblasts

LIPID-LOWERING DRUGLIPID-LOWERING DRUGStatinsStatins

PharmacokineticsPharmacokinetics- well absorbed when given orallywell absorbed when given orally- extracted by the liver (target tissue), undergo extracted by the liver (target tissue), undergo

extensive presystemic biotransformationextensive presystemic biotransformation

Simvastatin is Simvastatin is an inactive pro-drugan inactive pro-drug


C l i n i c a l u s e sC l i n i c a l u s e s Secondary preventionSecondary prevention of myocardial infarction and of myocardial infarction and

stroke in patients who have symptomatic atherosclerotic disease stroke in patients who have symptomatic atherosclerotic disease (angina, transient ischemic attacks) (angina, transient ischemic attacks) following acute myocardial following acute myocardial infarction or strokeinfarction or stroke

Primary preventionPrimary prevention of arterial disease in patients who of arterial disease in patients who are at high risk because of elevated serum CHO concentration, are at high risk because of elevated serum CHO concentration, especially it there are other risk factors for atherosclerosisespecially it there are other risk factors for atherosclerosis

AtorvastatinAtorvastatin lowers serum CHO in patients with lowers serum CHO in patients with homozygous familiar hypercholesterolemiahomozygous familiar hypercholesterolemia


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 disturbancesmild gastrointestinal disturbances

- increased plasma activities in liver enzymesincreased plasma activities in liver enzymes

- severe myositis (rhabdomyolysis) severe myositis (rhabdomyolysis)

andand angio-oedema (rare) angio-oedema (rare)


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

LIPID-LOWERING DRUGSLIPID-LOWERING DRUGS FibratesFibrates

O t h e r e f f e c t s : improve glucose tolerance inhibit vascular smooth muscle inflammation

fenofibrate clofibrate gemfibrozil ciprofibrate

LIPID-LOWERING DRUGSLIPID-LOWERING DRUGS FibratesFibrates

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) in patients with renal impairment myositis (rhabdomyolysis)

myoglobulinuria, acute renal failure myoglobulinuria, acute renal failure

Fibrates should be avoided in such patients and also in alcoholics)Fibrates should be avoided in such patients and also in alcoholics)

mild GIT symptoms


FibratesFibrates

C l i n i c a l u s e sC l i n i c a l u s e s

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

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

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


Bile acid bindingBile acid binding resinsresins 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)


Bile acid binding resinsBile acid binding resins

Colestyramin colestipolanion exchange resins

C l i n i c a l u s e s:C l i n i c a l u s e s: heterozygous familiar hypercholesterolemiaheterozygous familiar hypercholesterolemia an addition to a statin if response has been inadequatean addition to a statin if response has been inadequate

hypercholesterolemiahypercholesterolemia when a statin is when a statin is contraindicatedcontraindicated

uses unrelateduses unrelated to atherosclerosis, including: to atherosclerosis, including: pruritus pruritus in patients with partial biliary obstructionin patients with partial biliary obstruction bile acid diarrheabile acid diarrhea (diabetic neuropathy) (diabetic neuropathy)


Bile acid binding resinsBile acid binding resins

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::

GITGIT symptoms symptoms - - nauzea, abdominal bloating, nauzea, abdominal bloating, constipation or diarrheaconstipation or diarrhea

resins are resins are unappetisingunappetising. This can be minimized by . This can be minimized by suspending them in fruit juicesuspending them in fruit juice interfere with the absorption of fat-soluble vitamins interfere with the absorption of fat-soluble vitamins andand drugs (chlorothiazide, digoxin, warfarin) drugs (chlorothiazide, digoxin, warfarin)

These drugs should be given at last 1 hour before or 4-6 hours after a resin These drugs should be given at last 1 hour before or 4-6 hours after a resin


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


OthersOthers 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

lipid-lowering drugs. atherosclerosis and lipoprotein metabolism atheromatous disease is ubiquitous...

Documents

cho tg

lipoprotein metabolism

bile unaltered cho

cholesterol cho

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large component of cho

low density lipoproteins