Lipid-lowering drugsLipid-lowering drugs

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

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 attachmentEndothelial cells bind LDLOxidatively modified LDL is taken up

by macrophages then (now foam cells) migrate subendothelially

Atheromatous plaque formationRupture 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 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:

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

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 TRIGL TRIGL are hydrolysed by lipoprotein lipase, and the tissues take up the resulting Free Fatty AcidsFree Fatty Acids

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

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

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 VLDVLDL L 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

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 HDL CHO concHDL 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 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

Fibrates

Others

Resins

Statins

LIPID-LOWERING DRUGS

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.

Promising Promising pharmacodynamic actionspharmacodynamic actions of statins: of statins: Improved endothelial functionReduced vascular inflammation and

platelet aggregabilityAntithrombotic actionStabilisation of atherosclerotic

plaquesIncreased neovascularisation of

ischaemic tissueEnhanced fibrinolysisImmune suppressionOsteoclast apoptosis and increased

synthetic activity in osteoblasts

PharmacokineticsPharmacokinetics of of StatintsStatints- 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 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

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)

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

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

inflammation

Fenofibrate Clofibrate Gemfibrozil Ciprofibrate

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

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

Bile acid bindingBile acid binding resinsresins:: ((Colestyramin colestipolColestyramin colestipol)) sequester bile acids in the GIT prevent

their reabsorption and enterohepatic recirculationThe 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)

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 contraindicatedUses unrelated to

atherosclerosis, including:pruritus in patients with partial

biliary obstructionbile acid diarrhea (diabetic

neuropathy)

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

OthersOthersNicotinic 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

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)

Cardiovascular Disease (CVD)Cardiovascular Disease (CVD)Main type of CVD is Atherosclerosis (AS)Endothelial dysfunction is one of earliest

changes in ASMechanical, chemical, inflammatory

mediators can trigger endothelial dysfunction:◦High blood pressure ◦Smoking (free radicals that oxidatively

damage endothelium)◦Elevated homocysteine◦Inflammatory stimuli◦Hyperlipidemia

A Healthy Endotheliumproduces: PGI2

NO

Maintaining ananti-coagulant, anti-thrombotic surface

A Dysfunctional Endotheliumhas decreased: PGI2

NO

Shifting to apro-coagulant, pro-thrombotic surface

Increased:pro-inflammatory

molecules:MCP-1TNF

VCAM-1

Pro-Inflammatory MoleculesPro-Inflammatory MoleculesChemokines = monocyte

chemoattractant protein 1 (MCP-1)Inflammatory cytokines = tumor necrosis

factor (TNF)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.

Endothelial DysfunctionEndothelial Dysfunction( endothelial activation, impaired endothelial-dependent ( endothelial activation, impaired endothelial-dependent vasodilation)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

Oxidation of LDL (oxLDL)Oxidation of LDL (oxLDL)Oxidation = process by which free radicals (oxidants)

attack and damage target molecules / tissuesTargets 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

Atherosclerotic PlaqueAtherosclerotic PlaqueContinued 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

Know Your Lipid ProfileKnow Your 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