Diuretics & Performance Enhancement




Introduction

A diuretic is a substance that increases the rate of urine excretion. In the human, common substances with a diuretic action include caffeine and alcohol. Diuretic drugs have a direct action on the kidney, which prevent NaCl and water being reabsorbed into the bloodstream prior to excretion. This action induces excess extracellular fluid to be re-absorbed into the blood to reinstate osmotic equilibrium. Therefore, diuretics are used to treat oedematous syndromes such as congestive heart failure in humans. There are 3 main types of diuretics. These include: thiazides, potassium sparing and loop (high ceiling) diuretics. Each type of diuretic has slightly different mechanism, depending on the site of action (as shown below).

The nephron

The Nephron

Vital Statistics – Frusemide

Chemical Formula C12H11ClN2O5S
Chemical name 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid
Bioavailability 43-69% (non IV), 100% IV
Half Life Alpha: 5.6 minutes
Beta: 22.3 minutes
Gamma: 158.5 minutes
Routes of Administration Oral, IV and IM
Dosage        1mg/kg BWT

Loop Diuretics

Loop diuretics are most commonly used in the horse due to their potent action. Thiazides and potassium sparing are relatively weak in comparison, and are not often used. Loop diuretics act on the thick ascending limb of the Loop of Henle. This prevents the re-absorption of 25-30% of the NaCl, resulting in the rapid excretion of this substance. Frusemide (Lasix®, Distl®) is the most commonly administered loop diuretic in the horse. It is used to treat excess swelling, azoturia, poisoning/overdosing, and EIPH although non-clinical usage includes masking prohibited drugs and reducing bodyweight before competition.

Chemical formula of Frusemide

Frusemide is rapidly eliminated from the body although the majority of the drug is eliminated unchanged from the urine after 4 hours if administered intravenously. Intravenous and intramuscular administration of 1mg/kg BWT induces significant excretion of Na+, K and Cl after 3 hours.

Practical Application

Frusemide administration on the day of racing as prophylaxis for EIPH is permitted in almost all TB, Standardbred and QH racing jurisdictions in America and Canada.  In these areas during the late 1990’s approximately 85% of all TB racehorses had received frusemide at some stage in their career & an average 75% of horses in any single race received frusemide (Gross et al., 1999). These proportions have not declined, making frusemide the most commonly used drug in race horses in these regions.

 

Effect on EIPH

As the exact pathogenesis of EIPH is still not known, there is no clear rationale for its use. As a diuretic however, the ultimate effect of frusemide is to decrease plasma volume, this affects systemic haemodynamics by increasing venous compliance, which increases their capacitance. This results in decreased pulmonary arterial pressure, thought to prevent/reduce effects of EIPH if caused by stress failure of pulmonary capillaries (Manohar et al., (1994). Although BP is slightly lowered, there is no conclusive proof that it reduces the incidence or severity of bleeding. Conflicting results have been obtained from research – Erickson et al. (1992, 1990) say no effect on haemorrhaging – Pascoe et al. (1985) and Poole et al. (2004) reported a reduction in severity (but not the incidence) of EIPH.

Effect on Performance

Widespread use of frusemide in race horses raises question of the effect on performance. Studies (with adequate statistical power) demonstrate clearly that frusemide administration before racing is associated with superior performance in both TB & Standardbred horses with and without EIPH (reduced race times, Gross et al.,1999), increased Time to Fatigue (mean 28s) (Poole et al, 2004). How then does frusemide affect race times? Increased weight requires a proportionate increase in the amount of energy required – light horses therefore require less energy to cover a given distance at specified speed. A treated horse will be carrying around 20-30 kg less weight due to fluid loss which allows an increase in VO2max, and therefore increased aerobic capacity.

Side effects

The potential side effects of diuretic application include dehydration from excessive fluid and/or electrolyte losses, pre-renal azotemia (risk of renal failure), hypokalaemia (can promote cardiac arrhythmias), and metabolic alkalosis.

Methylxanthine agents

Caffeine, theophylline and theobromine are often found in animal feed. Regulators view the finding of even small amounts of these stimulants in post-race urine samples as serious infractions of drug and medication rules. If competing under rules, ensure that guaranteed feeds are used (clean-mill policy).

What would the economic, genetic & welfare implications be if the countries currently permitting frusemide use (some also allow bute) were brought into line with UK jurisdiction, e.g. Jockey Club and FEI?


References

Erickson, B. K., Erickson, H. H. and Coffman, J. R. (1990) Exercise-induced pulmonary haemorrhage during high intensity exercise: potential causes and the role of frusemide. Proceedings of the Annual Convention of the American Association of Equine Practitioners. 35 (375-379) (Abstract only).

Erickson, B. K., Erickson, H. H. and Coffman, J. R. (1992) Pulmonary artery and aortic pressure changes during high intensity exercise in the horse: effect of frusemide and phentolamine. Equine Veterinary Journal. 24 (3) 215-219 (Abstract only).

Gross, D. K., Morley, P. S., Hinchcliff, K. W. and Wittum, T. E. (1999) Effect of furosemide on performance of Thoroughbreds racing in the United States and Canada. Journal of the American Veterinary Medical Association. 215 (5) 670-676.

Manohar, M., Hutchens, E. and Coney, E. (1994) Frusemide attenuates the exercise-induced rise in pulmonary capillary blood pressure in horses. Equine Veterinary Journal. 26(1). 51-54 (Abstract only).

Pascoe, J. R., McCabe, A. E., Franti, C. E. and Arthur, R. M. (1985) Efficacy of furosemide in the treatment of exercise-induced pulmonary haemorrhage in Thoroughbred racehorses. Am J Vet Res. 46 (9) 2000-3. (Abstrast only).

Poole, D. C., McDonough, P., Kindig, C. A., Hildreth, T. S., Padilla, D. J., Behnke, B. J. and Erickson, H. H. (2004) Effect of furosemide and the equine nasal strip on exercise-induced pulmonary haemorrhage and time-to-fatigue in maximally exercising horses. Equine and Comparative Exercise Physiology 1 (3) 177-184) (Abstract only).