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  IN THIS Article
 ::  Abstract
 ::  Introduction
 ::  Material and Methods
 ::  Results
 ::  Discussion
 ::  References
 ::  Article Figures

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ARTICLE
Year : 1978  |  Volume : 24  |  Issue : 1  |  Page : 20-23

Furosemide pharmacokinetics and its relevance to ototoxicity


1 Department of Pharmacology, Seth G.S. Medical College, Parel, Bombay-400 012, India
2 Department of Medicine, Seth G.S. Medical College, Parel, Bombay-400 012, India

Correspondence Address:
Nilima A Kshirsagar
Department of Pharmacology, Seth G.S. Medical College, Parel, Bombay-400 012
India
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Source of Support: None, Conflict of Interest: None


PMID: 731608

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 :: Abstract 

Our earlier studies have demonstrated a possible pharmaco­kinetic explanation for the rate dependent ototoxicity of furose­mide. The present study was carried out to find out possible role of plasma protein levels and drug protein binding in furosemide pharmnacokinetics and toxicity. Twenty patients with different pro­tein patterns were given furosemide intravenously at different rates and doses. Plasma furosemide levels were fluorimetrically estimated in serial blood samples. The results indicate that dose and rate of administration and extent of binding to plasma proteins alter furosemide pharmacokinetics and the chances of toxicity are greater in hypoproteinemic patients.



How to cite this article:
Kshirsagar NA, Dahanukar SA, Shah B P, Vora K K, Karandikar S M, Acharya VN, Sheth U K. Furosemide pharmacokinetics and its relevance to ototoxicity. J Postgrad Med 1978;24:20-3

How to cite this URL:
Kshirsagar NA, Dahanukar SA, Shah B P, Vora K K, Karandikar S M, Acharya VN, Sheth U K. Furosemide pharmacokinetics and its relevance to ototoxicity. J Postgrad Med [serial online] 1978 [cited 2019 Nov 17];24:20-3. Available from: http://www.jpgmonline.com/text.asp?1978/24/1/20/42682



 :: Introduction Top


In the past few years large doses of intravenous furosemide have increasingly been used for the treatment of renal failure. [6] There have been several reports of transient hearing loss and tinnitus after intravenous infusion of high doses of furosemide. [7] With ethacrynic acid ototoxic effect seems to occur at more con­ventionally used doses. [4] With furosemide however, the ototoxic effect is not noted at low doses and it has been observed that it can be prevented by giving furosemide as a slow infusion. [2]

It is possible that the distribution of furosemide may vary depending on the rate and dose of administration and this may be responsible for the ototoxic effect. We therefore thought worthwhile to study furosemide pharmacokinetics given in different doses at different rates. Since the elimination pattern of a drug can give some idea about the distribution pattern of the drug, furosemide elimination pat­tern was studied.

Our earlier studies [5] conducted in cats have shown that a secondary rise, signi­fying initial entry in some other com­partment and then re-entry into plasma compartment, occurs when the drug is given in high doses as a fast infusion but not when given in low doses or as a slow infusion. It is possible that this occurs because of a larger fraction of the drug remaining free-not bound to protein­when it is given in high doses and as fast infusion.

In the present work, we have studied furosemide pharmacokinetics in high and low doses in patients with normal and low plasma protein levels and with nor mal and abnormal kidney functions.


 :: Material and Methods Top


The study was carried out in 2 parts: Part-I: This involved giving furosemide in high doses to patients with chronic renal failure in their post-dialysis period. Four patients were given 25 mg/ kg furosemide over 1 hr. (high dose fast infusion), and four patients were given same dose over 4 hrs. (high dose slow in­fusion). The urine output in these patients, during furosemide infusion period, varied from 0-300 ml. in 24 hrs, Part-II: This involved giving furose­mide low doses-80 mg (over 10 sets.) to normal and hypoproteinemic patients.

Part-II: (a) included four normal volunteers with normal plasma protein and normal kidney and liver function.

Part-II (b) included chronic renal failure patients with total serum proteins less than 6.5 gm% and albumin levels less than 2.5 gm%. These patients had abnor­mal renal functions as judged by their blood urea nitrogen and serum creatinine levels.

Part-II: (c) comprised of four pa­tients, who had hypoproteinemia (total serum proteins <6.5% and serum albu­min <2.5 gm%) but no renal dysfunc­tion.

For both studies furosemide was given intravenously and blood samples with drawn from the antecubital vein before and 0, 1, 5, 10, 15, 30, 60, 120, 180 and 240 mins. after stopping the infusion.

Furosemide was estimated fluorimetri­cally by the method described by Haus­sler and Hajdu. [3]


 :: Results Top


Furosemide levels in plasma at different times are plotted on a semilog graph paper as log plasma concentrations vs time.

1. It is observed that a secondary rise in plasma levels occurs after high doses (25 mg,/kg) of furosemide (in chronic renal failure patient) whether it is given slowly or rapidly [Figure 1].

2. When furosemide is given in low doses (80 mg.) the secondary rise occurs only in patients with low plasma pro­teins presumably low plasma protein drug binding, but does not occur in volunteers with normal plasma proteins [Figure 2].


 :: Discussion Top


Our earlier [5] furosemide pharmacokine­tic studies conducted in cats have demon­strated that a secondary rise occurs in the plasma level only after the drug is given in high doses as a fast infusion. This rise signifies an entry into some com­partment producing high concentrations there initially and then a re-entry in plasma compartment as plasma concen­trations start falling, producing a secondary rise in plasma. Such a sudden high concentration in some compartment may lead to toxicity such as ototoxicity (inner ear may be a part of the compart­ment). We postulated that when the drug is given in high doses as a fast infusion a substantial fraction of the drug may re­main free, not bound to plasma proteins and therefore can enter compartments other than plasma, producing high con­centrations there.

When the plasma protein and therefore protein drug binding is low, greater amount of free drug remains in plasma as in hypoproteinemic and chronic renal failure patients. Thus toxicity is likely to occur even when the drug is given slowly and at times even when given in low doses.

The results of the present study show that the secondary rise in plasma signi­fying entry into another compartment and then re-entry in plasma occur when the drug is given in high doses rapidly or slowly and in hypoproteinemic patients it occurs even when low: doses of furosemide are given.

We encountered a case of ototoxicity even when furosemide 25 mg/kg was given slowly (over 4 hours) as advised by other workers. [2]

Thus, changes in the free fraction of the drug in serum have important clinical implications particularly from the toxicity point of view. Such changes in the free fraction are particularly liable to occur in hypoproteinemic individuals with highly protein bound drugs like furose­mide. [1]

Patient population in this country may be having low plasma protein-drug bind­ing and therefore may be more susceptible to effects that may occur on account of low protein binding.

 
 :: References Top

1.Andreasen, F. and Jakobsen, P.: Deter­mination of furosemide in blood plasma and its binding to proteins in normal plasma and in plasma from patients with acute renal failure. Acta. Pharmacol. et Toxicol., 35: 49-57, 1974.  Back to cited text no. 1    
2.Cantarovich, F., Locatelli, A., Fernandez, J. C., Loredo, J. P. and Cristhot, J. Furosemide in high doses in the treatment of acute renal failure. Postgrad. Med. J. Apr. Suppi. 47: 13-17, 1971.  Back to cited text no. 2    
3.Haussler, A., and Hajdu, P.: Investiga­tions with the diuretic 4-chloro-N-fury U-5-Sulphamoylanthranilic acid. Arzneim, Forsch., 14: 710-713, 1964.  Back to cited text no. 3    
4.Homer, M. J.: Deafness after ethacrynic acid. New Eng. J. Med. 285: 1152-1153, 1971.  Back to cited text no. 4    
5.Kshirsagar Nilima, A., Shah, B. P., Vora, K. K., Karandikar, S. M., Acharya, V. N. and Sheth, U. K.: Pos­sible Pharmacokinetic explanation for the rate dependent toxicity of furosemide. Ind. J. Pharmac., 8: 161-166, 1976.  Back to cited text no. 5    
6.Lloyd Mostyn, R. H.: Ototoxicity of in­travenous furosemide. Lancet, 2: 1156, 1971.  Back to cited text no. 6    
7.Schwartz, G. H., David, D. S., Riggio, R. R. Stenzel, K. H., and Rubin, A. L.: Ototoxicity induced by furosemide New Eng. J. Med. 282: 1413, 1970.  Back to cited text no. 7    


    Figures

  [Figure 1], [Figure 2]



 

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