Drug Profile of Ezetimibe- Patient Friendly Hypolipedaemic Agent

Mohamed iliyas

Hyperlipidaemia results from a disorder in the synthesis and degradation of plasma lipoproteins. Although the main concern has generally been the overall elevation of plasma lipids (hyperlipidaemia), it is now increasingly recognised that the balance of lipids in the plasma is also important, and the term dyslipidaemia is often used.

Dyslipidaemias have genetic and other causes, and are often associated with a high-fat diet. Although patients with hyperlipidaemia may have symptoms that require treatment, the major concern is their increased risk of ischaemic heart disease.
The principal groups of lipid regulating drugs (hypolipidaemic drugs) are the statins, fibric acid derivatives and related compounds, bile-acid binding resins, nicotinic acid and its derivatives, and the omega-3 marine triglycerides.(1,2,3)
Statins (HMG-CoA reductase inhibitors) reduce cholesterol by stimulating an increase in LDL-receptors on hepatocyte membranes, thereby increasing the clearance of LDL from the circulation. Their main effect is to reduce LDL-cholesterol, but they may also reduce triglycerides to a modest extent and increase HDL-cholesterol. They are generally considered to be the most effective lipid lowering drugs.
Fibrates inhibit the synthesis of cholesterol and bile acids, and enhance the secretion of cholesterol in bile. Their main effect is to reduce triglycerides by reducing the concentration of VLDL; they also increase HDL-cholesterol and have variable effects on LDL-cholesterol. They are used mainly in patients with hypertriglyceridaemia.
Bile-acid binding resins lower cholesterol by combining with bile acids in the gastrointestinal tract and preventing their reabsorption. This leads to an increased oxidation of cholesterol to replace the lost bile acids, and an increase in LDL-receptor synthesis on hepatocytes, resulting primarily in a reduction of LDL-cholesterol.
Nicotinic acid inhibits production of VLDL in the liver; it lowers LDL-cholesterol and triglycerides and increases HDL-cholesterol, but adverse effects may limit its use.
Omega-3 triglycerides primarily reduce triglycerides.
Other drugs that may be used include cholesterol absorption inhibitors(4). such as Ezetimibe dietary supplements containing soluble fibre, such as guar gum or ispaghula, or plant stanols or sterols, may also be used to reduce cholesterol absorption. In postmenopausal women, oestrogen therapy reduces lipid concentrations, but the adverse effects may outweigh any benefit soya protein may have a similar effect. Garlic supplements have also been promoted for hyperlipidaemia, although their effect appears to be modest.

Description

Ezetimibe is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related Phytosterols. It is a white, crystalline powder that is freely to very soluble in ethanol, Methanol, and acetone and practically insoluble in water. It has a melting point of about 163°C and is stable at ambient temperature(5).

Chemical name

(3R,4S)-1-(p-fluorophenyl)-3-[(3S)-3-(p-fluorophenyl)-3-hydroxypropyl]-4-(p-hydroxyphenyl)-2-azetidinone(6)

Molecular formula

C24H21F2NO3 =409.4

Structure

Chemical Structure of Ezetimibe

Mechanism of Action

Ezetimibe is the first new class of lipid-lowering compounds approved by the FDA, which works by selectively inhibiting the intestinal absorption of cholesterol and related phytosterols, with a resultant decreases in hepatic cholesterol storage and an increase in the clearance of cholesterol from the blood. It has demonstrated the ability to reduce the total cholesterol, LDL, apolipoprotien- B and triglycerides level which increases the HDL level in patients with hypercholesterolemia(7).
Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, it localizes and appears to act at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver as shown in figure-1. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of HMG-CoA reductase inhibitors.

Pharmacokinetics

After oral administration, Ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (Ezetimibe-glucuronide). After a single 10-mg dose of Ezetimibe to fasted adults, mean Ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of Ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. Ezetimibe has variable bioavailability; the coefficient of variation, based on inter-subject variability, was 35 to 60% for AUC values. Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins. It is primarily metabolized in the small intestine and liver via glucuronide conjugation. It is excreted primarily in the faeces via bile and undergoes enterohepatic recycling; following an oral dose, about 78% is excreted in the faeces, mainly as ezetimibe, and about 11% is excreted in the urine, mainly as the glucuronide. The elimination half-life for both ezetimibe and the glucuronide is about 22 hours(8).

Adverse Effects and Warnings

Ezetimibe is generally well tolerated. The most common adverse effects include headache, abdominal pain, and diarrhoea; other gastro-intestinal disorders, hypersensitivity reactions including rash and angioedema, fatigue, chest pain, and arthralgia have also been reported. Myalgia has occurred in patients taking ezetimibe either alone or when added to a statin.The manufacturers state that elevated creatine phosphokinase concentrations during ezetimibe therapy may be associated with a syndrome of myopathy, and rarely rhabdomyolysis; most cases of rhabdomyolysis were in patients also taking a statin. Upto August 2005, the Australian Adverse Drug Reactions Advisory Committee(9) had received 44 reports of muscle disorders with ezetimibe, including myalgia, muscle cramp, weakness and pain; in 5 of these cases a statin was also being taken. There have been 2 other cases reported(10) of symptoms starting after addition of ezetimibe to treatment with a statin; symptoms resolved after withdrawal of ezetimibe.
Ezetimibe should be avoided in patients with moderate or severe hepatic impairment.

Interactions

Cholestyramine reduces the absorption of ezetimibe and should not be given at the same time of day.
Ciclosporin has been reported to increase the plasma concentration of ezetimibe and patients receiving both drugs should be carefully monitored; the effect may be greater in patients with severe renal impairment.

Indication and Dosage:

Ezetimibe is an inhibitor of intestinal cholesterol absorption. It is used, alone or with statins, to reduce total cholesterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B in the management of hyperlipidaemias and to reduce sitosterol and camposterol in patients with homozygous familial sitosterolaemia. It is given by mouth in a usual dose of 10 mg once daily.

Dosage Form Available:

It is available as Tablets-10mg.

Contraindications:

Hypersensitivity to any component of this medication.
The combination of Ezetimibe with an HMG-CoA reductase inhibitor is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.
All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When Ezetimibe is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and product labeling for the HMG-CoA reductase inhibitor.

Marketing Distribution(11,12)

Conclusion:

Ezetimibe works by reducing the amount of cholesterol that the body absorbs from the food ingested.. Ezetimibe is added to the statin treatment because it works in a different way to statins (which lower cholesterol by preventing its production by the liver) and so it can boost their cholesterol lowering effect. There by lowering blood levels of cholesterol and fats which helps to prevent heart disease, angina (chest pain), strokes, and heart attacks.

References:

1. Chong PH, Bachenheimer BS. Current, new and future treatments in dyslipidaemia and atherosclerosis. Drugs 2000; 60: 55–93.
2. Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999; 341: 498–511.
3. Anonymous. Choice of lipid-regulating drugs. Med Lett Drugs Ther 2001; 43: 43–8.
4. Sudhop T, von Bergmann K. Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia. Drugs 2002; 62: 2333–47.
5. www.drugs.com.
6. Clark’s analysis for drugs and poisons, Published by The pharmaceutical press,London ,2004;1105
7. Comprehensive Pharmacy Review ; Pubilshed by B.I Pulications, India: 5th edition, 2004 ; 718
8. Matrindale,The complete drug reference, Published by The pharmaceutical press,London, 2006 : 44th edition ; 914.
9. Adverse Drug Reactions Advisory Committee (ADRAC). Ezetimibe and muscle disorders. Aust Adverse Drug React Bull 2005; 24: 15
10. Fux R, et al. Ezetimibe and statin-associated myopathy. Ann Intern Med 2004; 140: 671
11. Current Index of Medical Sciences, by At medica (India) private ltd, Bangalore ,October 05-January 06;182
12. Indian Drug Review, published by MHPL Publications, New Delhi September-October-05;608

About Authors

Dr.Chitra.K, M.Pharm,Ph.D.
Professor, Depatment of Pharmaceutical chemistry, Sri Ramachandra College of Pharmacy, SRMC&RI(DU), Porur, Chennai-116.

Miss.Vinodhini.C,M.Pharm,
Lecturer, Depatment of Pharmaceutical chemistry, Sri Ramachandra College of Pharmacy, SRMC&RI(DU),
Porur, Chennai-116.

*Mohamed iliyas .M, PGDCP, M.Pharm,
Quality assurance, Sri Ramachandra College of Pharmacy, SRMC&RI(DU), Porur, Chennai-16. E-mail: miliyas@gmail.com

*For correspondence