Lipid Lowering Drugs

Dr. Hiwa K. Saaed, Ph.D.

Drugs used to lower lipid levels

HMG-CoA reductase inhibitors (HMGs or statins)

Fibric acid derivatives Niacin (nicotinic acid) Bile acid sequestrants Cholesterol absorption inhibitors

Atherosclerosis and lipoprotein metabolism

Major plasma lipids

Cholesterol ‘Chol’ (free & esterified), Phospholipids (pl), Triacylglycerols (TG), and

Free fatty acids (FFA)

LIPIDS, (Chol) and (TG), are transported in the plasma as lipoproteins, of which there are four classes:

- chylomicrons transport TG and Chol from the GIT to the tissues, Where they are split by lipase, releasing FFAs FFAs are taken up in muscle and adipose tissue. Chylomicron remnants are taken up in the liver

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

- low density lipoproteins (LDL) with a large component of Chol, 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 Chol derived from cell breakdown in tissues and transfer it to VLDL and LDL

Atherosclerosis and lipoprotein metabolism

Atherosclerosis and lipoprotein metabolism

There are two different pathways for exogenous and endogenous lipids:

THE EXOGENOUS PATHWAY:

Chol + 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 TG are hydrolysed by lipoprotein lipase, and the tissues take up the resulting FREE FATTY ACIDS (FFA)

Chol 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 transport in VLDL

Atherosclerosis and lipoprotein metabolism

cholesterol

may be stored

oxidised to

bile acids

secretedin

the bileunaltered

ENDOGENOUS PATHWAY

EXOGENOUS PATHWAY

Atherosclerosis and lipoprotein metabolismTHE ENDOGENOUS PATHWAY

Chol 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 Chol 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

Chol 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

Atherosclerosis and lipoprotein metabolism

LIPID + PROTEIN (LIPOPROTEIN) Lipids are insoluble in plasma, combine with specific

proteins (apolipoproteins):

Soluble lipoproteins are classified:

1. Chylomicrons (CM): v rich in TG, v low APOL

2. Very low density lipoproteins (VLDL): same as CM

3. Low density lipoproteins (LDL): v rich in cholesterol-atherosclerosis-CHD-CVA

4. High density lipoproteins (HDL): good cholesterol

5. Intermediate density lipoproteins (IDL)

Types of Lipoproteins

Lipid Protein Content Lipoprotein ClassificationContent

Most chylomicron Least

é very-low density lipoprotein

(VLDL) ê

é Intermediate-density lipoprotein

(IDL) êLeast High-density lipoprotein (HDL) Most

Clinical squelae of the hyperlipoproteinemia

The 2 major clinical squelae of the hyperlipoproteinemia are: Acute pancreatitis: occurs in pts w marked hyperlipidemia Atherosclerosis: certain plasma lipoptns play an essential

role in atherogenesis “LDL, IDL, HDL” those that contain lipoptn (apo) B100

The characteristic cellular components in atherosclerotic plaques are foam cells which are transformed macrophages & smooth muscle cells that has become filled with cholesterol esters “endocytosis”.

Coronary Heart Disease (CHD) CHD is the cause of about half of all deaths in

the United States. The incidence of CHD is correlated with:

1. elevated levels of LDL cholesterol and TGs

2. low levels of HDL cholesterol.The risk of CHD in patients with cholesterol levels of 300

mg/dL is 3 to 4 times greater than that in patients with levels less than 300 mg/dL

Other risk factors: smoking, HTN, obesity and DM

HMG-CoA REDUCTASE INHIBITORS ("statins") block cholesterol synthesis at the rate-limiting

step; Inhibit HMG-CoA reductase, which is used by the liver to produce cholesterol

increase uptake of LDL from circulation by inducing LDL receptor expression

most effective drugs at reducing circulating LDL most significant side effects are myopathies,

changes in liver enzymes and drug-drug interactions

Hepatic Cholesterol Synthesis

Rate LimitingOnly pathway for cholesterol degradation

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

Inhibition of HMG CoA reductase by the statin drugs.

Summary of 3-hydroxy-3-methylglutaryl coenzyme (HMG CoA) reductase inhibitors.

Adverse effects of statins Mild, transient GI disturbances Rash Headache Myopathy (muscle pain) Elevations in liver enzymes

LIPID-LOWERING DRUGS- StatinsPromising pharmacodynamic actions: 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

Activation of lipoprotein lipase by fibrates: Clofibrate, gemfibrozil, (Lopid), fenofibrate

• Ligand for peroxisome proliferator activated receptors (PPARs) increase expression of Lipase

activating lipase, hence increasing hydrolysis of TG in chylomicrons and VLDL particles.

reduce hepatic VLDL production increase hepatic LDL uptake. Also suppress release of FFA from the adipose

tissue, inhibit synthesis of TGs in the liver, and increase the secretion of cholesterol in the

bile

Produce a modest decrease in LDL (~ 10%) and increase in HDL (~ 10%).But, a marked decrease in TGs (~ 30%).

Fibrates-Side Effects

Abdominal discomfort Diarrhea Nausea Blurred vision Increased risk of gallstones, because? Prolonged prothrombin time Liver studies may show increased function

CHOLESTEROL ABSORPTION INHIBITOR (EZETIMIBE) selectively inhibits the cholesterol transporter in

the intestine - reduces absorption by ~50% induces LDL receptor expression a synergistic

with statins potentiates side effects of statins (including

myopathies)

Bile acid binding resins (Anion-exchange resins)cholestyramine, colestipol, colesevelam

sequester bile acids in the GIT

prevent their reabsorption and enterohepatic recirculation

The result 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 plasm(while an unwanted increase in TG)

Bile acids are necessary for absorption of cholesterol

decreases absorption of fat-soluble vitamins and other drugs

Therapeutic Uses Type II hyperlipoproteinemia Relief of pruritus associated with partial biliary

obstruction (cholestyramine)Side Effects:

Constipation, Heartburn, nausea, belching, bloating

NIACIN (NICOTINIC ACID)/VIT B3 Vitamin B3

Lipid-lowering properties require much higher doses than when used as a vitamin

vitamin dose ~15-35 mg/day; antihyperlipidemic activity 1-2 g, 3x day

Effective, inexpensive, often used in combination with other lipid-lowering agents

Niacin- mechanism of action: stimulation of a nicotinic acid receptor

(discovered in 2003) that is found on adipocytes decreases the release of FFAs from adipocytes

a decreased synthesis of TG and VLDL in the liver à decrease in circulating VLDL and LDL levels

nicotinic acid is the most potent drug for increasing HDL levels

Niacin inhibits lipolysis in adipose tissue, resulting in decreased hepatic VLDL synthesis and production of LDLs in the plasma.

adverse effects of Niacin

Flushing (due to histamine release) Pruritusan intense cutaneous flush and pruritus, which

decreases after several days but is severe enough to decrease compliance

GI distress

Niacin

To minimize side effects of niacin, start on low initial dose and gradually increase it, and take with meals.

Small doses of aspirin or NSAIDs may be taken 30 minutes before niacin to minimize cutaneous flushing.

Thank you