Antihyperlipidemic Agents

Antihyperlipidemic Agents

Antihyperlipidemic agents are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidemias.

What’s Hyperlipidemia?

Hyperlipidemia is the condition of abnormally elevated levels of any or all lipids and/or lipoproteins in the blood (serum)

Normal Lipid profile(in mg/dl):

Cholesterol < 200

Triglycerides < 150

HDL (High-Density Lipoprotein) > 60 LDL (Low-Density Lipoprotein) < 130

Cholesterol to HDL Ratio < 3.4 (no unit)

There are five types of Hyperlipidemia(hyperlipoproteinemia), each with a different profile of blood fat and a different set of associated risks of heart disease.

V IV III IIb IIa I TypeFamilial mixed hypertriglyceridemia

Familial hypertriglyceridemia

Familial dysbetalipoproteinemia

Familial mixed hyperlipidemia

Familial hypercholesterolemia

Familial Hyperchylomicronemia

Scientific Name

VLDL,Chylomiron

VLDL IDL VLDL,LDL LDL Chylomicron Increased Lipoprotein Class

Increased production of decreased clearance of VLDL and Chylomicrons

Overproduction or decreased removal of VLDL TG in serum

Overproduction or underutilization of IDL

Overproduction of VLDL by liver

Defect in synthesis or processing of LDL receptors

Deficiency of lipoprotein lipase or apolipoprotein CII

Cause

Nacin, fibrate,statin

Niacin,fibrate


Bile acid-sequestrantand niacin or statin


Low fat diet intake

Treatment

V IV III IIb IIa I TypeFamilial mixed hypertriglyceridemia

Familial hypertriglyceridemia

Familial dysbetalipoproteinemia

Familial mixed hyperlipidemia

Familial hypercholesterolemia

Familial Hyperchylomicronemia

Scientific Name

VLDL,Chylomiron

VLDL IDL VLDL,LDL LDL Chylomicron Increased Lipoprotein Class

Increased production of decreased clearance of VLDL and Chylomicrons

Overproduction or decreased removal of VLDL TG in serum

Overproduction or underutilization of IDL

Overproduction of VLDL by liver

Defect in synthesis or processing of LDL receptors

Deficiency of lipoprotein lipase or apolipoprotein CII

Cause


Niacin,fibrate




Low fat diet intake

Treatment

All types require low fat diet intake

Antihyperlipidemic drugs include:

• Statins• Fibrates• Bile Acid Sequestrants• Nicotinic Acid• Ezetimibe

Serum Cholesterol Cellular Cholesterol

Diet Biosynthesis

Bile Acids

Intestine

Feces

Re-absorption

Lipoproteincatabolism


Diet Biosynthesis

Bile Acids

Intestine

Feces

Re-absorption


STATINS


Diet Biosynthesis

Bile Acids

Intestine

Feces

Re-absorption


Ezetimibe


Diet Biosynthesis

Bile Acids

Intestine

Feces

Re-absorption


FIBRATES


Diet Biosynthesis

Bile Acids

Intestine

Feces

Re-absorption

LipoproteincatabolismBILE ACID

SEQUESTRANTS


Diet Biosynthesis

Bile Acids

Intestine

Feces

Re-absorption


NicotinicAcid


Diet Biosynthesis

Bile Acids

Intestine

Feces

Re-absorption


STATINS

NicotinicAcid

BILE ACIDSEQUESTRANTS

FIBRATES

Ezetimibe

STATINS(ex:Atorvastatin,Cerivastatin,Fluvastatin,Lovast

atin,Pravastatin,Simvastatin,Mevastatin…etc)

Statins are used to treat Type II,III and V of

hyperlipidemia.

How do they work?

1. Inhibiting cholesterol synthesis by inhibiting HMG-CoA reductase,which plays a central role in the production of cholesterol in the liver, statins block the pathway for synthesizing cholesterol in the liver.

This is significant because most circulating cholesterol comes from internal manufacture rather than the diet. When the liver can no longer produce cholesterol, levels of cholesterol in the blood will fall.

2.Increasing LDL uptakeLiver cells sense the reduced levels of liver cholesterol since the intracellular synthesis of cholesterol is inhibited and cells are therefore dependent on extracellular sources of cholesterol and seek to compensate by synthesizing LDL receptors to draw cholesterol out of the circulation.

LDL and VLDL are drawn out of circulation into the liver where the cholesterol is reprocessed into bile salts.

Adverse effect:

• Liver: Changes in liver function occur in a small fraction of people,withdraw of the drug The liver is expected to return to normal function.

• Muscle:“Myopathy" involving actual damage to muscle tissue, can be very serious, if myopathy occurs and the drugs are not stopped a condition, called “rhabdomyolysis”(is the rapid breakdown (lysis) of skeletal muscle)can be fetal.

Myopathy and rhabdomyolysis are more common if people are on other cholesterol lowering drugs, particularly niacin or fibrates as well as a statin.

Drug interaction:

• They increase effect of Warfarin.

• Grapefruit juice increases simvastatin levels, so should be avoided.

• Patients started on some macrolide antibiotics, such as erythromycin, or azole antifungals should stop the statin for the duration of the course or should have an alternative antibiotic prescribed.

FIBRATES(ex:Bezafibrate,Ciprofibrate,

Clofibrate,Gemfibrozil,Fenofibrate…etc)

Fibrates are used to treat Type III,IV and V of

hyperlipidemia.

How do they work?

Fibrates are agonists of the PPAR-α receptor in muscle, liver, and other tissues.

Activation of PPAR-α signaling results in:

•Increased β-oxidation in the liver

•Decreased hepatic triglyceride secretion

•Increased lipoprotein lipase activity, and thus increased VLDL clearance

•Increased HDL

•Increased clearance of remnant particles

Adverse effect:

• Most fibrates can cause mild stomach upset and myopathy (muscle pain with CPK” creatine phosphokinase” elevations).

• Since fibrates increase the cholesterol content of bile, they increase the risk for gallstones.

Drug interaction:

• They compete with coumarin anticoagulant and some acidic drugs such as phenytoin and tolbutamide for binding with albumin and therefore increase their effect.

•In combination with statin drugs, fibrates cause an increased risk of rhabdomyolysis, idiosyncratic destruction of muscle tissue, leading to renal failure

•They also may increase the risk of cancer

Bile Acid Sequestrants

(ex: Cholestyramine,Colesevelam,Colestipol)

Bile acid sequestrants are used to treat Type IIa and

IIb of hyperlipidemia.

How do they work?

Bile acid sequestrants serve as ion exchange resins. They exchange anions such as chloride ions for bile acids. By doing so, they bind bile acids and sequester them from enterohepatic circulation.

• bile acid sequestrants, along with any bile acids bound to the drug, are excreted via the feces after passage through the gastrointestinal tract

• Since bile acids are biosynthesized from cholesterol, the disruption of bile acid reabsorption will decrease cholesterol levels, in particular LDL

Adverse effect:

constipation, diarrhea, and flatulence. Some patients complain of the bad taste.

Drug interaction:

• Interfere with intestinal absorption of some drugs such as (tetracycline,phenobarbital,digoxin,warfarin,statin,aspirin,thiazide diuretics)

•They may also bind fat-soluble vitamins, such as vitamin A, vitamin D, vitamin E, and vitamin K. This effect may result in a vitamin deficiency. Hence, vitamin supplementation may be warranted.

Nicotinic acid(also known as vitamin B3, niacin.Ex: : Nicolar and Niaspan…etc)

Nicotinic acids are used to treat Type II,III,IV and V of

hyperlipidemia.

How do they work?

Niacin blocks the breakdown of fats in adipose tissue. These fats are used to build VLDL in the liver, which are precursors of LDL or "bad" cholesterol.

Because niacin blocks the breakdown of fats, it causes a decrease in free fatty acids in the blood and, as a consequence, decreases the secretion of VLDL and cholesterol by the liver.

By lowering VLDL levels, niacin also increases the level of high-density lipoprotein (HDL) or "good" cholesterol in blood, and therefore it is sometimes prescribed for patients with low HDL, who are also at high risk of a heart attack.

Adverse effect:

• dermatological conditions such as skin flushing and itching, dry skin, and skin rashes.• Gastrointestinal complaints, such as

dyspepsia (indigestion), nausea and liver toxicity.

• High-dose niacin may also elevate blood sugar, thereby worsening diabetes mellitus.

• Hyperuricemia is another side effect of taking high-dose niacin, and may exacerbate gout.

• Extremely high doses of niacin can also cause niacin maculopathy, a thickening of the macula and retina, which leads to blurred vision and blindness. This maculopathy is reversible after stopping niacin intake.

• Side effects of hyperglycemia, cardiac arrhythmias and "birth defects in experimental animals" have also been reported.

Drug interaction:

• Alcohol (Ethanol) and Hot drinksConsuming alcohol or hot drinks along with niacin might make the flushing and itching worse. And also alcohol might increase the chance of having liver damage.

• Bile acid sequestrantsbile acid sequestrants can decrease how much niacin the body absorbs. This might reduce the effectiveness of niacin.Take niacin and the bile acid sequestrants at least 4-6 hours apart.

•StatinsNiacin can adversely affect the muscles.statins can also affect the muscles. Taking niacin along with these medications might increase the risk of muscle problems.

Ezetimibe(cholesterol absorption inhibitor,it is marketed as Zetia or Ezetrol)

Ezetimibe is used to treat Type II,III,IV and V of

hyperlipidemia.

How do they work?

Ezetimibe localises at the brush border of the small intestine, where it inhibits the absorption of cholesterol from the intestine. Specifically, it appears to bind to a critical mediator of cholesterol absorption, the Niemann-Pick C1-Like 1 (NPC1L1) protein on the gastrointestinal tract epithelial cells as well as in hepatocytes.

In addition to this direct effect, decreased cholesterol absorption leads to an upregulation of LDL-receptors on the surface of cells and an increased LDL-cholesterol uptake into cells, thus decreasing levels of LDL in the blood plasma which contribute to atherosclerosis and cardiovascular events.

Adverse effect:

• Headache and diarrhea.

• Infrequent adverse effects include: myalgia and raised liver function test (ALT/AST) results.

•Rarely hypersensitivity reactions (rash, angioedema) or myopathy may occur.

•Myalgia, rhabdomyolysis, hepatitis, pancreatitis, and thrombocytopenia were also noted.

Drug interaction:

• Fenofibratefenofibrate and ezetimibe together may increase the levels of ezetimibe in the blood and also cause problems in people with gallbladder disease.

• Cyclosporinecyclosporine together with ezetimibe may increasing the risk of developing myopathy.

• Warfarinlonger clotting times if the patient is currently on warfarin while on the cholesterol-lowering medication.

• Cholestyramine,Colestipol and Colesevelam These drugs bind to ezetimibe and reduce its absorption from the intestine by about 50%.

References:

• Lippincott’s Illustrated Reviews• Goodman and Gilman’s Pharmacological Basis of Therapeutics• Some websites

Prepared By:

• Brwa Dilshad• Hasan Mohammad• Sana Kawa• Nashmeel Dler

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Antihyperlipidemic Agents