Lipid-Lowering Drugs. What are lipoproteins? Lipoproteins are protein-lipid complexes.

Lipid-Lowering Drugs

What are lipoproteins?• Lipoproteins are protein-lipid complexes.

The Players – Lipids

Triacylglycerol

Phospholipids

CholesterolCholesteryl esters

The Players - Apolipoproteins

• Apo AI (liver, small intestine)– Structural; activator of lecithin:cholesterol acyltransferase (LCAT)

• Apo AII (liver)– Structural; inhibitor of hepatic lipase; component of ligand for HDL

binding

• Apo A-IV (small intestine)– Activator of LCAT; modulator of lipoprotein lipase (LPL)

• Apo A-V (liver)– Direct functional role is unknown; regulates TG levels.

Apolipoproteins

• Apo B-100 (liver)– Structural; synthesis of VLDL; ligand for LDL-receptor

• Apo B-48 (small intestine)– Structural; synthesis of chylomicrons; derived from apo B-

100 mRNA following specific mRNA editing

• Apo E (liver, macrophages, brain)– Ligand for apoE receptor; mobilization of cellular

cholesterol

Apolipoproteins

• Apo C-I (liver)– Activator of LCAT, inhibitor of hepatic TGRL uptake

• Apo C-II (liver)– Activator of LPL, inhibitor of hepatic TGRL uptake

• Apo C-III (liver)– Inhibitor of LPL, inhibitor of hepatic TGRL uptake

Amphipathic HelicesLipoprotein Surface

Lipoprotein Classes

Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000;149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.

HDLLDLChylomicrons,VLDL, and their catabolic remnants

> 30 nm 20–22 nm 9–15 nm

D<1.006 g/ml D=1.019-1.063g/ml D=1.063-1.21 g/ml

Lipids Online

Lipoprotein Metabolism

• Exogenous/chylomicron pathway (dietary fat)• Endogenous pathway (lipids synthesized by

the liver)• HDL metabolism (apolipoprotein transfer,

cholesteryl ester transfer, reverse cholesterol transport

Surface Monolayer Phospholipids (12%)Free Cholesterol (14%)Protein (4%)

Hydrophobic CoreTriglyceride (65%) Cholesteryl Esters (8%)

TG Rich: VLDL

Cholesterol and Atherosclerosis, Grundy)

VLDL Metabolism


Apo C’s and apoE and cholesteryl ester are acquired from HDL in circulation

Fatty Acid Transport


ApoC-II activates lipoprotein lipase which catalyses the hydrolysis of TG

VLDL Conversion to

LDL


Further action on IDL by hepatic lipase loses additional apolipoproteins (apoE) becomes and is converted to LDL



CE Rich: LDL


LDL Metabolism


Hepatic LipaseCholesteryl ester transfer protein

LDL is removed by apoB100 receptors which are mainly expressed in the liver

LDL Uptake by Tissues


Defects in the LDL receptor leads to familial hypercholesterolemia

X X



CE Rich: HDL


HDL MetabolismNascent HDL (lipid-poor apoA-I) is produced by the liver and intestine

Hepatic Cholesterol Metabolism

Hepatic Cholesterol Synthesis

Cholesterol and Atherosaclerosis, Grundy)

Rate LimitingOnly pathway for cholesterol degradation

Energetically expensive; prefer to conserve what is already made/acquired – LDL receptor pathway

LDL Cellular Metabolism

Cholesterol and Atherosaclerosis, Grundy)

LDL are taken up by the LDL Receptor into clathrin-coated pits

Endothelial Dysfunction

• Increased endothelial permeability to lipoproteins and plasma constituents mediated by NO, PDGF, AG-II, endothelin.

• Up-regulation of leukocyte adhesion molecules (L-selectin, integrins, etc).

• Up-regulation of endothelial adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1).

• Migration of leukocytes into artery wall mediated by oxLDL, MCP-1, IL-8, PDGF, M-CSF.

Ross, NEJM; 1999

Formation of Fatty Streak

• SMC migration stimulated by PDGF, FGF-2, TGF-B

• T-Cell activation mediated by TNF-a, IL-2, GM-CSF.

• Foam-cell formation mediated by oxLDL, TNF-a, IL-1,and M-CSF.

• Platelet adherence and aggregation stimulated by integrins, P-selectin, fibrin, TXA2, and TF.

Ross, NEJM; 1999

Formation of Advanced, Complicated Lesion

• Fibrous cap forms in response to injury to wall off lesion from lumen.

• Fibrous cap covers a mixture of leukocytes, lipid and debris which may form a necrotic core.

• Lesions expand at shoulders by means of continued leukocyte adhesion and entry.

• Necrotic core results from apoptosis and necrosis, increased proteolytic activity and lipid accumulation.

Ross, NEJM; 1999

Development of Unstable Fibrous Plaque

• Rupture or ulceration of fibrous cap rapidly leads to thrombosis.

• Occurs primarily at sites of thinning of the fibrous cap.

• Thinning is a result of continuing influx of and activation of macrophages which release metalloproteinases and other proteolytic enzymes.

• These enzymes degrade the matrix which can lead to hemorrhage and thrombus formation

Ross, NEJM; 1999

Role of LDL in Atherosclerosis

Steinberg D et al. N Engl J Med 1989;320:915-924.

Endothelium

Vessel LumenLDL

LDL Readily Enter the Artery Wall Where They May be Modified

LDL

Intima

Modified LDL

Modified LDL are Proinflammatory

Hydrolysis of Phosphatidylcholineto Lysophosphatidylcholine

Other Chemical Modifications

Oxidation of Lipidsand ApoB

Aggregation

Lipids Online

Role of LDL in Atherosclerosis

Endothelium

Vessel LumenMonocyte

Macrophage

MCP-1AdhesionMolecules

Foam Cell

IntimaModifiedRemnantsCytokines

Cell ProliferationMatrix Degradation

Doi H et al. Circulation 2000;102:670-676.

Growth FactorsMetalloproteinases

Remnant Lipoproteins

Remnants

Lipids Online

HDL Prevent Foam Cell Formation

LDL

LDL

Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80.

Endothelium

Vessel LumenMonocyte

Modified LDL

Macrophage

MCP-1AdhesionMolecules

Cytokines

IntimaHDL Promote Cholesterol Efflux

Foam Cell

Lipids Online

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 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


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


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


EXOGENOUS PATHWAY


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

DyslipidemiaThe 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.

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…

Lipid-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

LIPID-LOWERING DRUGS: StatinsHMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase

inhibitors. The reductase catalyses the conversion of HMG-CoA to mevalonic acid; blocks the synthesis of CHO in the liver:

Simvastatin + pravastatin + atorvastatin

decrease hepatic CHO synthesis: lowers total and LDL

increase in synthesis of CHO receptors + increased clearance of LDL

Stimulates the exprssion of more enzyme restores CHO synthesis to normal.Several studies demonstrated positive effects on morbidity and mortality.Reltatively few side-effects...However, adverse effects: myopathy (incr in pts given combined therapy with nicotinic acid or fibrates. Should not be given during pregnancy.

LIPID-LOWERING DRUGS Statins

Promising pharmacodynamic 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

LIPID-LOWERING DRUGStatins

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

extensive presystemic biotransformation

Simvastatin is an inactive pro-drug


C 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


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)

LIPID-LOWERING DRUGS: Fibrates

- stimulate the β-oxidative degradation of fatty acids - liberate free fatty acids for storage in fat or for metabolism in striated muscle- Are ligands for nuclear txn receptor, peroxisome proliferator-activated recptor-α (PARP-α)- 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.- Produce a modest decrease in LDL (~ 10%) and increase in

HDL (~ 10%).- But, a marked decrease in TGs (~ 30%).

LIPID-LOWERING DRUGS Fibrates

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 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

LIPID-LOWERING DRUGS

Fibrates

1st-line defense for:

*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).* Indicated in patients with VERY HIGH [TG]s who are at risk for pancreatitis


Bile acid binding resins (Anion-exchange 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)

Anion-exchange Resins

• Increase the excretion of bile acids, causing more CHO to be converted to BAs.

• The decr in hepatocyte [CHO] compenatory incr in HMG CoA reductase activity and the number of LDLRs.

• Because these resins don’t work in patients with homozygous familial hypercholesterolemia, increased expression of hepatic LDLRs is the main mechanism by which resins lower plasma CHO.


Bile acid binding resins

Colestyramin colestipolanion 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)


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, bec resins not absorbed. resins are unappetizing. 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


Others

Nicotinic acid inhibits hepatic TG production and VLDL Secretion (by ~ 30-50%) modest reduction in LDL and increase in HDL.

Nicotinic acid was the 1st lipid-lowering drug to decr overall mortality in patients with CAD.But its use is limited by the desirable

A d v e r s e e f f e c t s:flushing, palpitations , GIT disturbances.

Currently, nicotinic acid is rarely used.


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)


Others

Inhibitors of Intestinal CHO Absorption: Ezetimibe:

Reduces CHO and phytosterol absorption and decreases LDL CHP by ~18%, but with little change in HDL CHO.

May be synergistic with statins: so good for combination therapy.

Drug Combinations• Severe hyperlipidemia often requires multiple LLDs

to get the job done.• As usual, combinations should involve drugs with

different mechanisms of action (e.g., statins with fibrates).

• Even though some combinations (foregoing) may increase risk of, say, myopathy, the benefits of lowering LDL CHO outweigh the small incr in adverse effects.

• Recent trial with gemfibrozil (fibrate) decr myocardial infarction, stroke, and overall mortality in men with CAD assoc with low HDL (this drug inc HDL CHO w/o decr LDL CHO).

Lipid-Lowering Drugs. What are lipoproteins? Lipoproteins are protein-lipid complexes.

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