NON CLINICAL OVERVIEW OF BUMETANIDE.

Krishna MahidaRoll no : 118

M.Pharm ( PMRA)K.B.I.P.E.R

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BUMETANIDE :

Therapeutic class : Potent loop diuretic Therapeutic Use:Treatment of oedema associated

with congestive heart failure, hepatic and renal diseases, acute pulmonary congestion and premenstrual syndrome and in forced diuresis during and after surgery.

Bumetanide is 40 times more potent than furosemide.

INTRODUCTION

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Bumetanide is a potent loop diuretic which acts primarily upon the thick ascending limb of the loop of henle with a possible additional action in the proximal tubule by competing at the chloride –binding site of the Na+K+2Cl- cotransporter in the thick ascending limb.

It inhibits sodium reabsorption in the loop of henle.

It is a weak inhibitor of carbonic anhydrase activity and this gives the drug a weak effect on proximal tubule.

PHARMACOLOGY

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Absorption:• Bumetanide is well absorbed after oral

administration with 65-96% bioavailability.• BA is not influenced by food as opposed to

furosemide.• Onset of action occurs within 30-60 min if taken

orally. Distribution :• Bumetanide is 95% bound to plasma proteins in

healthy subjects, but is less in patients with renal failure.

• Degree of protein binding is inversely related to serum albumin concentration.

PHARMACOKINETICS

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Metabolism and Elimination:

• Bumetanide is cleared from the circulation at a rate of 120-150 ml min_1 with approx half of the drug excreted unchanged via the renal route and the remainder via bile into the faeces.

• 80% of an oral route can be recovered in urine with 50% as the original drug and the remainder primarily as conjugated metabolites.

• Primary urinary metabolite is tertiary alcohol of the N-butyl chain and primary biliary metabolite is secondary alcohol.

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• Toxicity testing in rats, rabbits, dogs, and baboons indicate that bumetanide is well tolerated in various species.

• The toxicity that was observed is, for the most part, the direct consequence of its potent diuretic activity and is similar to that produced by other "loop" diuretics.

TOXICOLOGICAL STUDIES

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SINGLE DOSE TOXICITY :

• LD50 is the dosage producing 50% mortality.• Product contains less than 0.03% Bumetanide.• Acute toxicity studies in mice, rats and rabbits

have been done upto 6000 mg/kg-1, with only one death reported in a rabbit receiving 1000 mg/kg-1 orally.

Ingredient Percent

Test type Value Units Species

Bumetanide

100 LD50 4624>6000350

Mg/kg RatsMiceRabbits

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Ingredient

Percent Test type Value Units Species

Bumetanide

100 LD50(sc) 1660>2000

mg/kg RatsMice

DERMAL TOXICITY STUDY

LD50 (sc) is the value for skin contact

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Bumetanide shows no evidence of mutagenicity in Reverse mutation assay in Salmonella or Eischerichia coli.

Hence NEGATIVE in Ames’ test.

Mutagenicity

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• Bumetanide was foetotoxic at maternal toxic doses in the rabbit, but no evidence of teratogenic effects was observed in rabbits, rats, mice, or hamsters.

• But there is a slight embryocidal effect seen in rats if dose given is 3400 times greater than the standard human dose.

FEMALE REPRODUCTION AND DEVELOPMENTAL TOXICITY STUDIES

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• Rabbits also experience embryocidal effects from the drug at 3.4 times the std human dose.

• Delayed ossification of sternebrae have been seen in both rats and rabbits.

• Growth retardation and decreased foetal weight has been observed in rabbits.

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OTOTOXICITY Ototoxicity has been noted in animals who

were given Bumetanide , secondary to a direct effect on the cochlea.

Comparative studies with furosemide in cats suggest that the absolute ototoxic potential of Bumetanide is 6.5 times that of furosemide;however ,because of its greater diuretic potency by dose,the relative ototoxic potential is 0.11 to 0.16 that of furosemide.

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Carcinogenicity studies should be performed for drugs which are expected to be used clinically for more than 6 months or used in treatment of chronic disease.

It is performed on rodent species preferably rat for the period of 24 months and the drug is to be administered 7 days a week.

Bumetanide was found to be non-carcinogenic in long term rat studies.

CARCINOGENICITY

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http://www.bdipharma.com/MSDS/Hospira/BumetanideInj.pdf

McClain RM, Dammers KD, The studies reported represent the preclinical toxicologic evaluation of bumetanide available from http://www.ncbi.nlm.nih.gov/pubmed

www.rxlist. Colin Dollery , therapeutic drugs , second

edition-1999,volume1, page no.b92

References

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Thank You