6anti hyperlipidemic drugs

Hyperlipidemia

• Lipids of human plasma are transported as complexes with proteins, such macromolecular complexes are termed lipoproteins; except fatty acids which are bound to albumin.

• Any metabolic disorders involving the elevations in plasma concentrations of any lipoprotein species known as hyperlipoproteinemias or hyperlipidemias.

• Hyperlipidemia is generally restricted to conditions that involve increased level of triglycerides in plasma.

• The major complications are acute pancreatitis and atherosclerosis

• Those which contain apolipoprotein (apo) B100 act as vehicles by which cholesterol are transported into artery wall.

• Those are low-density (LDL), intermediate density (IDL), very low density (VLDL) and Lp(a) lipoproteins.

• Cellular components in atherosclerotic plaque are foam cells, derived form macrophages and smooth muscle cells filled with cholesteryl esters.

• The atheromatous plaque grows over time with the accumulation of increased no. of foam cells and of collagen and fibrin.

• High-density lipoproteins (HDL) exert anti-atherogenic effects.

RISK FACTORS

1) Cigarette is a major risk factor for coronary disease– Associated with reduced HDL levels– Impaired cholesterol level– Cytotoxic effects on endothelium– Increased oxidation of atherogenic lipoproteins– Stimulates thrombogenesis2) Hypertension3) Diabetes4) LDL levels

• Normally EDRF, nitric oxide are responsible for vessels regulation but it is impaired in hyperlipidemia.

• So natural antioxidants such as tocopherol and ascorbic acid can reduce such impairment.

Pathophysiology of hyperlipoproteinemia

• Major lipoproteins are:1. Cholesteryl esters and2. Triglycerides• A monolayer of unesterified cholesterol and phospholipids

surrounds the hydrophobic core of above lipoproteins.• Specific proteins (apolipoproteins) are located on the surface.• Also certain lipoproteins contain large mol. wt

apolipoproteins(B lipoproteins) which don’t migrate like smaller ones.

• Subtypes of B apolipoproteins:– B-48 formed in intestine with chylomicrons– B100 synthesized in liver and found in VLDL, VLDL remnants,LDL

and the Lp(a) lipoproteins.

• Chylomicrons:– Lagest type;formed in intestine and carry dietary lipids –

triglycerides– Responsible for transport of lipids

• Very low density lipoproteins (VLDL) :– Secreted by liver; means for transporting triglycerides to

peripheral tissues– Hydrolyzed by lipoprotein lipase yielding free fatty acids for

oxidation and storage.– Intermediate particles called IDL are formed after the VLDL

is depleted of triglycerides.

• Low density lipoproteins:– Further removal of triglycerides by hepatic

lipaseresults in its formation.– Hepatocytes play a major role for its catabolic

activity.• Lp(a) lipoprotein:– Formed form an LDL-like moiety– The Lp(a) lipoprotein complex can be found in

atherosclerotic plaques and contribute to coronary disease by inhibiting thrombolysis.

• High density lipoproteins:– Secreted by the liver and intestine– Comes from surface of chylomicrons and VLDL

during lipolysis.

• Atherosclerosis: It is a disease which affects large and medium size arteries, and a leading cause of death.

• consists of localized plaque in the intima, and is composed of cholesterol esters, proliferation of smooth muscle, deposition of fibrous proteins and calcifications.

• Effects: – Narrowing of the arterial lumen– Ulceration of arterial lumen and thrombosis of artery and

embolization.– Weakens arterial wall and formation of aneurysms.

Classification of anti-hyperlipidemics:

• HMG-CoA reductase inhibitors ( statins)– Lovastatin– Atorvastatin– Simvastatin– Pravastatin– Rosuvastatin

• Bile acid sequestrants (resins):– Cholestyramine– Colestipol

• lipoprotein lipase inducers (fibric acid derivative)– Clofibrate– Gemfibrozil– Benzafibrate

• Inhibit lipolysis and triglycerides synthesis– Nicotinic acid ( niacin)

• Inhibit intestinal cholesterol absorption– Ezetimibe

• Others – Probucol– gugulipid

HMG-CoA reductase inhibitors

• Mechanism of action The de novo synthesis of cholesterol involves a pathway in

which mevalonic acid is formed and by the enzyme hydroxymethylglutaryl co-enzyme reductase (HMG-Co A reductase); the statins inhibits this step resulting in decrease hepatic cholesterol synthesis.

Resultantly synthesis of high affinity LDL receptors on the liver occurs and increased clearance of plasma LDL.

• Decrease liver cholesterol• Increase LDL gene expression• Decrease plasma LDL• Decrease VLDL synthesis • Decrease TGLs

• Pharmacokinetics:– Given orally except fluvastatin– Upto 90% available– Undergoes first pass metabolism and secreted in

bile– 5-10% excreted in urine

• Adverse effects:– Headache, nausea, bowel upsets, rashes– Sleep disturbances– Rhabdomyolysis – Myalgia , myopathy – Rise in LFTs particularly serum transaminases– Muscle weakness

• Indications:– Hyperlipidemia with raised LDL and Cholesterol level– Progression of atherosclerotic lesion– Ischemic heart disease of elderly

• Drug interactions :– Gemfibrogil– Cyt P450 enzymes

Cholestyramine

• Also known as bile acid binding resin.• Bile acid binding resins are cholesterol lowering

drugs that are man made resins. They are gritty, insoluble granules which are available in the form of a bar that has to be chewed thoroughly or comes in the form of a powder and needs to be mixed with a liquid.

• These prevent re-absorption of cholesterol into the body when they bind with the cholesterol-rich bile acids secreted by the liver.

• Resulting in decreased enterohepatic circulation of causing the liver to increase production of bile acids utilizing cholesterol

• Decrease LDL levels• Increase LDL receptor gene expression.• It significant effect on LDL levels by utilizing

the LDL receptors but no effect on the HDL levels.

• Pharmacokinetics:– Orally (chewed)– No systemic effects as it is retained in the GI tract– Usual dose of 12-36g of resin per day in divided

doses with meals.

• Side-effects:– Increased VLDL and triglycerides– Usually causes GI symptoms like constipation and

flatulence.– May interfere with the absorption of fat-soluble vitamins

and may bind with other drugs if taken concurrently.Drug interactions – Orally administered drugsContraindication:– Hypertriglyceridemia

Nicotinic acid

• Inhibition of VLDL synthesis( inhibiting ApoB100 gene expression and resulting in:– Decreased plasma VLDL– Decreased plasma LDL– Increased plasma HDL

Side effects :– Flushing , pruritus , rashes – hepatotoxicity

Fibric acid derivatives• Prototype: Gemfibrozil• Others : clofibrate , benzafibrate • Mechanism of action:

– Induction of lipoprotein lipase– Activation of the nuclear transcription receptor “peroxisome

proliferator - activated receptor alpha” (PPAR-α). –mediate effects of insulin

– class of intracellular receptors that modulate carbohydrate and fat metabolism and adipose tissue differentiation.

– PPAR-α activation by fibrates results in numerous changes in lipid metabolism that act together to decrease plasma triglyceride levels & increase plasma HDL.

– Decrease VLDL and IDL

• Indications: – Hypertriglyceridemias in which VLDL predominate

& in dysbetalipoproteinemia. – Treatment of hypertriglyceridemia resulting from

treatment with viral protease inhibitors.Contraindication: Hypercholesteremia

• Pharmacokinetics: – absorbed from the GI tract & undergoes

enterohepatic circulation– most (70%) is eliminated unchanged through the

kidneys– half life : 1.5 hrs.

• Side Effects: – rare cases of rash– GI symptoms– Gall stones – Myositis – Myopathy– Arrhythmias – Hypokalemia &– High aminotransferase or alkaline phosphatase levels,

risk of cholesterol gallstones.

Lab findings Drugs

Hypercholesteremia Cholestyramine , colestipol, ezetimibe

Hypertriglyceridemia Gemfibrozil

Combined hyperlipidemia (Statins and niacin) + ezetimibe