Dyslipidaemia Dr.Mohmmed Daoud Normal physiology:

The clinically important lipids in the blood {unesterified and esterified cholesterol and triglycerides (TGs) }

are not readily soluble in serum and are rendered miscible by incorporation into lipoproteins. There are six

main classes of lipoproteins: Chylomicrons (mainly TGs + cholesterol), chylomicron remnants ( mainly

cholesterol), Very low-density lipoproteins (VLDL) {mainly TGs + cholesterol}, Intermediate-density

lipoproteins (IDL) { 50% TGs + 50% cholesterol}, low-density lipoproteins (LDL) {mainly cholesterol)

and high-density lipoproteins (HDL) { unesterified cholesterol and phospholipid removed from peripheral

tissues and the surface of triglyceride-rich proteins }.

The protein components of lipoproteins are known as apoproteins (apo), of which apoproteins A, B & C are

the most important. Apoprotein A exists in two forms: A-I & A-II which are present mainly in HDL;

Apoprotein B exists in two forms: B-48, which is present in chylomicrons & chylomicron remnants and

associated with the transport of ingested lipids to the liver, and B-100, which is found in the hepatically

secreted VLDL and associated with the transport of lipids from the liver to periphery, on IDL & LDL and

associated with the transport of ingested lipids to the liver; Apoprotein C exists in two forms: C-I &C-II; C-II

is present in chylomicrons & VLDL . (Fig);

Note: Apoproteins act as transporters, key for recognition by receptors & activators of enzymes.

External source: Step1-When dietary cholesterol and triglycerides are absorbed from the intestine they are

transported in the intestinal lymphatics as chylomicrons. These are the largest of the lipoprotein particles of

which triglycerides normally constitute approximately 80% of the lipid core. The chylomicrons pass through

blood capillaries in adipose tissue and skeletal muscle where the enzyme lipoprotein lipase is located, bound

to the endothelium. Lipoprotein lipase is activated by apoprotein C-II on the surface of the chylomicron. The

lipase catalyses the breakdown of the triglyceride in the chylomicron to free fatty acid and glycerol, which

then enter adipose tissue and muscle. In this way most dietary TGs are cleared from the circulation.

Step2-The cholesterol-rich chylomicron remnant is taken up by receptors on hepatocyte membranes (by

recognition of B-48), and in this way dietary cholesterol is delivered to the liver and cleared from the

circulation.

Intrinsic source: Step1-VLDL is formed in the liver transporting Triglycerides (which make up

approximately 80% of its lipid core), to the periphery. The triglyceride content of VLDL is removed by

lipoprotein lipase in a similar manner to that described for chylomicrons above, and VLDL remnants connect

with HDL to forms IDL particles.

Step2-The core of IDL particles is roughly 50% triglyceride and 50% cholesterol esters, acquired from HDL

under the influence of the enzyme lecithin-cholesterol acyltransferase (LCAT).

Approximately half of the body's IDL particles are cleared from serum by the liver. The other half of IDL are

modified to become LDL particles (major cholesterol-carrying particle in serum). LDL in turn either go to

the liver or to the extra hepatic tissues & if excess oxidized , engulfed by macrophages then embedded on

blood wall.

*While VLDL and LDL are considered the ‘bad’ lipoproteins, HDL is often considered to be the ‘good’

antiatherogenic lipoprotein.

Pathology:Primary dyslipidaemia (Genitic)

Caused by genetically (familial) mediated defects, e.g. lipoprotein receptor defieciency, Excessive synthesis

of lipoproteins , lipoprotein lipase deficiency or apoprotein deficiency (to be discussed in details in applied

therapeutics at class 5 ); all of these defects causes disturbances in lipoprotein profile (dyslipidaemia).

-Familial hypercholesterolemia: cholesterol per se &/or LDL increased.

-familial hypertryglyceridemia: TGs per se &/or VLDL increased.

-familial mixed hyperlipidemia: all above increased .

Secondary dyslipidaemia: Obesity, Diabetes mellitus, Hypothyroidism, renal failure, Drugs (e.g: Diuretics,

ß-Blockers, Corticosteroids, Oral contraceptives), Alcohol.

Lipid-lowering therapy:

The choice among the anti -dyslipidemic drugs depend on the degree and the type of the lipoproteins

disturbed.

There are five main classes of lipid-lowering agents available:

1- Statin: inhibit cholesterol synthesis.

2- Nicotinic acid and derivatives: inhibit TGs lipolysis..

3- Fibrates: Activates lipoprotein lipase.

4-Bile acid binding agents : inhibit cholesterol synthesis.

5- Cholesterol absorption inhibitors: inhibit cholesterol synthesis.

*Agents such as soluble fiber and fish oils have also been used to reduce lipid levels.

1-Statins: (Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin,Rosuvastatin, Simvastatin)

Mechanism of action:

(Inhibition of HMG CoA reductase); These drugs are analogs of HMG {3-Hydroxy-3-methylglutaryl

(HMG)} coenzyme A (CoA), the precursor of cholesterol. Because of their strong affinity for the enzyme, all

compete effectively to inhibit HMG CoA reductase, the rate-limiting step in cholesterol synthesis. So by

inhibiting cholesterol synthesis, they deplete the intracellular supply of cholesterol. Depletion of intracellular

cholesterol causes the cell to increase the number of specific cell-surface LDL receptors (upregulation) that

can bind and inactivate circulating LDLs. Thus, the end result is a reduction in plasma cholesterol, both by

lowered cholesterol synthesis and by increased catabolism of LDL. In addition , Low intracellular cholesterol

decreases the secretion of VLDL which in turn reduce TGs level. FIG;

Therapeutic uses: These drugs are effective in lowering plasma cholesterol levels in all types of

hyperlipidemias . However, familial hypercholesterolemia due to lack of LDL receptors benefit much less

from treatment with these drugs.

Pharmacokinetics: Pravastatin and fluvastatin are almost completely absorbed after oral administration. Oral

doses of lovastatin and simvastatin are from 30 to 50 percent absorbed. Similarly, pravastatin and fluvastatin

are active as such, whereas lovastatin and simvastatin must be hydrolyzed to their acid forms. All are

biotransformed, with some of the products retaining activity. Excretion takes place principally through bile

and feces, but some urinary elimination also occurs.

Adverse effects:

a. Liver: Biochemical abnormalities in liver function have occurred with the HMG CoA reductase inhibitors.

Therefore, it is prudent to evaluate liver function and measure serum transaminase levels periodically. These

return to normal on suspension of the drug.

[Note: Hepatic insufficiency can cause drug accumulation.]

b. Muscle: Myopathy and rhabdomyolysis (disintegration or dissolution of muscle) have been reported only

rarely.

Drug interactions: The HMG CoA reductase inhibitors may also increase warfarin levels.

Contraindications: These drugs are contraindicated during pregnancy and in nursing mothers. They should

not be used in children or teenagers.

2- Nicotinic acid and derivatives.: Niacin (nicotinic acid)

Mechanism of action: Niacin strongly inhibits lipolysis in adipose tissue, the primary producer of circulating

free fatty acids. The liver normally uses these circulating fatty acids as a major precursor for TGs synthesis

followed by secretion as VLDL. Depletion of free fatty acids,Therefore, causes a reduction in the VLDL

concentration. Depletion of VLDL blood concentration in turn results in a decreased plasma LDL

concentration. Thus, both plasma TGs (in VLDL) and cholesterol (LDL) are lowered(Figure).

Therapeutic uses: Niacin lowers plasma levels of both cholesterol and triacylglycerol. Therefore, it is

particularly useful in the treatment of familial mixed hyperlipidemia.

Pharmacokinetics: Niacin is administered orally. Niacin, its nicotinamide derivative, and other metabolites

are excreted in the urine.

Adverse effects:

-The most common side effects of niacin therapy are an intense cutaneous flush (accompanied by an

uncomfortable feeling of warmth) and pruritus. Administration of aspirin prior to taking niacin decreases the

flush, which is prostaglandin mediated.

Some patients also experience nausea and abdominal pain.

Niacin inhibits tubular secretion of uric acid and, thus, predisposes to hyperuricemia and gout.

3- Fibrates (Gemfibrozil,Fenofibrate)

Mechanism of action: These drugs act by :

1- Activating lipoprotein lipase {through activating peroxisome activator & proliferator response

elements(PPARs)} thus increasing the breakdown of the TGs in the chylomicron & VLDL .

2- Fibrates also increase the level of HDL cholesterol by increasing the expression of apo AI and apo AII .

Therapeutic uses: The fibrates are used in the treatment of hypertriglyceridemia, causing a significant

decrease in plasma TGs levels.

Pharmacokinetics: Both drugs are completely absorbed after an oral dose. Gemfibrozil and fenofibrate

distribute widely, bound to albumin. Both drugs undergo extensive biotransformation and are excreted in

urine as their glucuronide conjugates.

Adverse effects:

a. Gastrointestinal effects: The most common adverse effects are mild gastrointestinal (GI) disturbances.

b. Lithiasis: Because these drugs increase biliary cholesterol excretion (why?), there is a predisposition to the

formation of gallstones.

c. Muscle: Myositis (inflammation of a voluntary muscle) can occur with both drugs, and muscle weakness or

tenderness should be evaluated. Patients with renal insufficiency may be at risk (why?).

Drug interactions: Both fibrates compete with the warfarine for binding sites on plasma proteins, thus

potentiating anticoagulant activity. INR should, therefore, be monitored when a patient is taking both drugs.

Similarly, these drugs may elevate the levels of sulfonylureas.

Contraindications: The safety of these agents in pregnant or lactating women has not been established. They

should not be used in patients with severe hepatic and renal dysfunction or in patients with preexisting

gallbladder disease.

4-Bile acid–binding resins (Colesevelam, Colestipol , Cholestyramine)

Mechanism of action: These drugs are anion exchange resins that bind negatively charged bile acids and bile

salts in the small intestine (Figure). The resin/bile acid complex is excreted in feces, thus preventing the bile

acids from returning to the liver by the enterohepatic circulation. Lowering the bile acid concentration causes

hepatocytes to increase conversion of cholesterol to bile acids. Consequently, the intracellular cholesterol

concentration decreases, which causes the cell to increase the number of specific cell-surface LDL receptors

(upregulation) that can bind and inactivate circulating LDL. Thus, the end result is a reduction in plasma

cholesterol, both by increased conversion of cholesterol to bile acids and by increased catabolism of LDL. In

addition , Low intracellular cholesterol decreases the secretion of VLDL which in turn reduce TGs level.

Therapeutic uses: The bile acid–binding resins are the drugs of choice (often in combination with diet or

niacin) in treating all types of hyperlipidemias. Cholestyramine can also relieve pruritus caused by

accumulation of bile acids in patients with biliary obstruction.

Pharmacokinetics: Cholestyramine, colestipol, and colesevelam are taken orally. Because they are insoluble

in water and are very large (molecular weights are greater than 106), they are neither absorbed

nor metabolically altered by the intestine. Instead, they are totally excreted in feces.

Adverse effects:

a. GI effects: The most common side effects are GI disturbances, such as constipation, nausea, and flatulence.

Colesevelam has fewer GI side effects than other bile acid sequestrants.

b. Impaired absorptions: At high doses, cholestyramine and colestipol (but not colesevelam) impair the

absorption of the fat soluble vitamins (A, D, E, and K).

Drug interactions: These drugs interfere with the intestinal absorption of many drugs (for example,

tetracycline, phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin,

and thiazide diuretics). Therefore, drugs should be taken at least 1–2 hours before, or 4–6 hours after, the bile

acid–binding resins.

5-Cholesterol absorption inhibitor: Ezetimibe

Mechanism of action: selectively inhibits absorption of dietary and biliary cholesterol in the small intestine,

leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic

cholesterol stores and an increase in clearance of cholesterol from the blood (LDL receptors up regulation).

Pharmacokinetics: Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide

conjugation, with subsequent biliary and renal excretion. Both ezetimibe and ezetimibe-glucuronide are

slowly eliminated from plasma, with a half-life of approximately 22 hours.

Adverse effects:

Experience to date reveals a low incidence of reversible impaired hepatic function with a small increase in

incidence when given with a reductase inhibitor. Myositis has been reported rarely.

Contraindications: Patients with moderate to severe hepatic insufficiency should not be treated with

ezetimibe.