The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: Pharmacology, toxicology and analysis

British Journal of Pharmacology

Volumn 161, Issue 1, 2010, Pages 1-16

  Cadwallader, Amy B ^a   De La Torre, Xavier ^a   Tieri, Alessandra ^a   Botrè, Francesco ^a,b  

^a Laboratorio Antidoping   (Italy)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

diuretics; masking agents; doping analysis; GC MS; LC MS MS

Indexed keywords

ACETAZOLAMIDE; AMILORIDE; AZOSEMIDE; BENDROFLUMETHIAZIDE; BUMETANIDE; CANRENONE; CARBONATE DEHYDRATASE INHIBITOR; CHLOROTHIAZIDE; CHLORTALIDONE; DICLOFENAMIDE; DIURETIC AGENT; ETACRYNIC ACID; FUROSEMIDE; HYDROCHLOROTHIAZIDE; HYDROFLUMETHIAZIDE; INDAPAMIDE; LOOP DIURETIC AGENT; MANNITOL; METHAZOLAMIDE; METHYCLOTHIAZIDE; METOLAZONE; OSMOTIC DIURETIC AGENT; POLYTHIAZIDE; QUINETHAZONE; SPIRONOLACTONE; THIAZIDE DIURETIC AGENT; TORASEMIDE; TRIAMTERENE; TRICHLORMETHIAZIDE; UNINDEXED DRUG;

ALKALOSIS; ALTITUDE DISEASE; ATHLETIC PERFORMANCE; CHOLESTEROL BLOOD LEVEL; CONGESTIVE HEART FAILURE; DEHYDRATION; DERIVATIZATION; DIARRHEA; DIURESIS; DIURETIC THERAPY; DIZZINESS; DOPING; DRUG BIOAVAILABILITY; DRUG EFFECT; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG MECHANISM; DRUG POTENTIATION; DRUG STRUCTURE; EDEMA; ERECTILE DYSFUNCTION; EXERCISE; GYNECOMASTIA; HEART ARRHYTHMIA; HUMAN; HYPERCALCEMIA; HYPERGLYCEMIA; HYPERKALEMIA; HYPERNATREMIA; HYPERTENSION; HYPERURICEMIA; HYPOCHLOREMIA; HYPOKALEMIA; HYPOMAGNESEMIA; HYPONATREMIA; HYPOTENSION; IMPOTENCE; LABORATORY; LEG CRAMP; LUNG EDEMA; MASS FRAGMENTOGRAPHY; MENSTRUAL IRREGULARITY; METABOLIC ACIDOSIS; METABOLIC ALKALOSIS; NAUSEA; PHOSPHATE EXCRETION; PRIMARY HYPERALDOSTERONISM; PRIORITY JOURNAL; PROTEIN EXPRESSION; RESPIRATORY ACIDOSIS; REVIEW; SHOCK; SIDE EFFECT; SINGLE DRUG DOSE; SKIN BLOOD FLOW; THERMOREGULATION; THROMBOEMBOLISM; URIC ACID URINE LEVEL; VOMITING; WEIGHT REDUCTION;

DIURETICS; DOPING IN SPORTS; HUMANS;

EID: 77955838660     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/j.1476-5381.2010.00789.x     Document Type: Review

References (86)

1. Amendola L, Colamonici C, Mazzarino M, Botrè F (2003). Rapid determination of diuretics in human urine by gas chromatography - mass spectrometry following microwave assisted derivatization. Anal Chim Acta 475 : 125 136. (Pubitemid 35447620)
2. Appleby M, Fisher M, Martin M (1994). Myocardial infarction, hyperkalaemia and ventricular tachycardia in a young male body-builder. Int J Cardiol 44 : 171 174.
3. Armstrong LE, Costill DL, Fink WJ (1985). Influence of diuretic-induced dehydration on competitive running performance. Med Sci Sports Exerc 17 : 456 461.
4. Barroso O, Mazzoni I, Rabin O (2008). Hormone abuse in sports: the antidoping perspective. Asian J Androl 10 : 391 402.
5. Baum K, Essfeld D, Stegemann J (1986). The influence of furosemide on heart rate and oxygen uptake in exercising man. Eur J Appl Physiol Occup Physiol 55 : 619 623.
6. Beermann B (1984). Aspects on pharmacokinetics of some diuretics. Acta Pharmacol Toxicol (Copenh) 54 (Suppl. 1 17 29.
7. Beyer J, Bierl A, Peters FT, Maurer HH (2005). Screening procedure for detection of diuretics and uricosurics and/or their metabolites in human urine using gas chromatography-mass spectrometry after extractive methylation. Ther Drug Monit 27 : 509 520. (Pubitemid 41098828)
8. Bonen A, Dohm GL, van Loon LJ (2006). Lipid metabolism, exercise and insulin action. Essays Biochem 42 : 47 59.
9. Bordenave S, Brandou F, Manetta J, Fedou C, Mercier J, Brun JF (2008). Effects of acute exercise on insulin sensitivity, glucose effectiveness and disposition index in type 2 diabetic patients. Diabetes Metab 34 : 250 257.
10. Botrè F (2008). New and old challenges of sports drug testing. J Mass Spectrom 43 : 903 907.
11. Botrè F, Botrè C (1993). The carbonic anhydrases: are these enzymes still a good deal for a pharmacologist? Curr Top Med Chem 1 : 313 347.
12. Bradwell AR, Dykes PW, Coote JH, Forster PJ, Milles JJ, Chesner I et al. (1986). Effect of acetazolamide on exercise performance and muscle mass at high altitude. Lancet 1 : 1001 1005.
13. Brechue WF, Stager JM (1990). Acetazolamide alters temperature regulation during submaximal exercise. J Appl Physiol 69 : 1402 1407.
14. Caldwell JE (1987). Diuretic therapy and exercise performance. Sports Med 4 : 290 304.
15. Caldwell JE, Ahonen E, Nousiainen U (1984). Differential effects of sauna-, diuretic-, and exercise-induced hypohydration. J Appl Physiol 57 : 1018 1023.
16. Carreras D, Imaz C, Navajas R, Garcia MA, Rodriguez C, Rodriguez AF et al. (1994). Comparison of derivatization procedures for the determination of diuretics in urine by gas chromatography-mass spectrometry. J Chromatogr A 683 : 195 202.
17. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL et al. (2003). Seventh report of the Joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 42 : 1206 1252.
18. Claremont AD, Costill DL, Fink W, Van Handel P (1976). Heat tolerance following diuretic induced dehydration. Med Sci Sports 8 : 239 243.
19. Clarkson PM, Thompson HS (1997). Drugs and sport. Research findings and limitations. Sports Med 24 : 366 384.
20. Coote JH (1991). Pharmacological control of altitude sickness. Trends Pharmacol Sci 12 : 450 455.
21. Cowan DA, Kicman AT (1997). Doping in sport: misuse, analytical tests, and legal aspects. Clin Chem 43 : 1110 1113.
22. Deventer K, Delbeke FT, Roels K, Van Eenoo P (2002). Screening for 18 diuretics and probenecid in doping analysis by liquid chromatography-tandem mass spectrometry. Biomed Chromatogr 16 : 529 535.
23. Deventer K, Van Eenoo P, Delbeke FT (2005). Simultaneous determination of beta-blocking agents and diuretics in doping analysis by liquid chromatography/mass spectrometry with scan-to-scan polarity switching. Rapid Commun Mass Spectrom 19 : 90 98.
24. Deventer K, Pozo OJ, Van Eenoo P, Delbeke FT (2009). Detection of urinary markers for thiazide diuretics after oral administration of hydrochlorothiazide and altizide-relevance to doping control analysis. J Chromatogr A 1216 : 2466 2473.
25. Dormans TP, van Meyel JJ, Gerlag PG, Tan Y, Russel FG, Smits P (1996). Diuretic efficacy of high dose furosemide in severe heart failure: bolus injection versus continuous infusion. J Am Coll Cardiol 28 : 376 382.
26. Edwards A, Daniels BS, Deen WM (1999). Ultrastructural model for size selectivity in glomerular filtration. Am J Physiol 276 (6 Pt 2 F892 F902.
27. Fagard R, Staessen J, Thijs L, Amery A (1993). Influence of antihypertensive drugs on exercise capacity. Drugs 46 (Suppl. 2 32 36.
28. Faris R, Flather M, Purcell H, Henein M, Poole-Wilson P, Coats A (2002). Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials. Int J Cardiol 82 : 149 158.
29. Friedman PA, Bushinsky DA (1999). Diuretic effects on calcium metabolism. Semin Nephrol 19 : 551 556.
30. Furlanello F, Serdoz LV, Cappato R, De Ambroggi L (2007). Illicit drugs and cardiac arrhythmias in athletes. Eur J Cardiovasc Prev Rehabil 14 : 487 494.
31. Georgakopoulos CG, Vonaparti A, Stamou M, Kiousi P, Lyris E, Angelis YS et al. (2007). Preventive doping control analysis: liquid and gas chromatography time-of-flight mass spectrometry for detection of designer steroids. Rapid Commun Mass Spectrom 21 : 2439 2446.
32. Goebel C, Trout GJ, Kazlauskas R (2004). Rapid screening method for diuretics in doping control using automated solid phase extraction and liquid chromatography electrospray tandem mass spectrometry. Anal Chim Acta 502 : 65 74.
33. Heigenhauser GJF, Sutton JR, Jones NL (1980). Ventilation and carbon dioxide output during exercise: effects of glycogen depletion and carbonic anhydrase inhibition. Med Sci Sports Exerc 12 : 123.
34. van der Heijden M, Donders SH, Cleophas TJ, Niemeyer MG, van der Meulen J, Bernink PJ et al. (1998). A randomized, placebo-controlled study of loop diuretics in patients with essential hypertension: the bumetanide and furosemide on lipid profile (BUFUL) clinical study report. J Clin Pharmacol 38 : 630 635.
35. Hemmersbach P, de la Torre R (1996). Stimulants, narcotics and beta-blockers: 25 years of development in analytical techniques for doping control. J Chromatogr B Biomed Appl 687 : 221 238.
36. Jackson EK (2006). Diuretics. In : Brunton L, Lazo J, Parker K (eds). Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th edn. McGraw-Hill : New York, pp. 737 770.
37. Koutlianos N, Kouidi E (2006). Renal disorders and electrolyte metabolism. In : Sarikaya H, Peters C, Schulz T, Schonfelder M, Michna H (eds). Congress Manual: Biomedical Side Effects of Doping. A Project of the European Union : Munich, pp. 112 118. Available for order from the Institute of Public Health Research, Technische Universität München.
38. Kowalchuk JM, Heigenhauser GJ, Sutton JR, Jones NL (1992). Effect of acetazolamide on gas exchange and acid-base control after maximal exercise. J Appl Physiol 72 : 278 287.
39. Levinsky NG, Bernard DB (1988). Mannitol and loop diuretics in acute renal failure. In : Brenner BM, Lazarus JM (eds). Acute Renal Failure, 2nd edn. Churchill-Livingstone : New York, pp. 841 856.
40. Lisi AM, Trout GJ, Kazlauskas R (1991). Screening for diuretics in human urine by gas chromatography-mass spectrometry with derivatisation by direct extractive alkylation. J Chromatogr 563 : 257 270.
41. Lisi AM, Kazlauskas R, Trout GJ (1992). Diuretic screening in human urine by gas chromatography-mass spectrometry: use of a macroreticular acrylic copolymer for the efficient removal of the coextracted phase-transfer reagent after derivatization by direct extractive alkylation. J Chromatogr 581 : 57 63.
42. McGrath JC, Cowan DA (2008) Drugs in sport. Br J Pharmacol 154 : 493 495.
43. Maurer HH (1992). Systematic toxicological analysis of drugs and their metabolites by gas chromatography-mass spectrometry. J Chromatogr 580 : 3 41.
44. Mazzarino M, Botrè F, Rossi F, Paone E, Pecori-Giraldi J (2001). Lack of increased diuresis after topical administration of the carbonic anhydrase inhibitor dorzolamide. In : Schänzer W, Geyer H, Gotzman A, Mareck-Engelke U (eds). Recent Advances in Doping Analysis (9). Sport & Buch Strauß : Köln, pp. 269 273.
45. Mazzarino M, de la Torre X, Botre F (2008). A screening method for the simultaneous detection of glucocorticoids, diuretics, stimulants, anti-oestrogens, beta-adrenergic drugs and anabolic steroids in human urine by LC-ESI-MS/MS. Anal Bioanal Chem 392 : 681 698.
46. Monroy A, Plata C, Hebert SC, Gamba G (2000). Characterization of the thiazide-sensitive Na(+)-Cl(-) cotransporter: a new model for ions and diuretics interaction. Am J Physiol Renal Physiol 279 : F161 F169.
47. Morra V, Davit P, Capra P, Vincenti M, Di Stilo A, Botre F (2006). Fast gas chromatographic/mass spectrometric determination of diuretics and masking agents in human urine: development and validation of a productive screening protocol for antidoping analysis. J Chromatogr A 1135 : 219 229.
48. Moser M (1998). Why are physicians not prescribing diuretics more frequently in the management of hypertension? JAMA 279 : 1813 1816.
49. Müller RK, Grosse J, Thieme D, Lang R, Teske J, Trauer H (1999). Introduction to the application of capillary gas chromatography of performance-enhancing drugs in doping control. J Chromatogr A 843 : 275 285.
50. Munyard P, Chung KF, Bush A (1995). Inhaled frusemide and exercise-induced bronchoconstriction in children with asthma. Thorax 50 : 677 679.
51. Nadel ER, Fortney SM, Wenger CB (1980). Effect of hydration state of circulatory and thermal regulations. J Appl Physiol 49 : 715 721.
52. Ouzan J, Perault C, Lincoff AM, Carre E, Mertes M (2002). The role of spironolactone in the treatment of patients with refractory hypertension. Am J Hypertens 15 (4 Pt 1 333 339.
53. Plasqui G, Westerterp KR (2007). Physical activity and insulin resistance. Curr Nutr Food Sci 3 : 157 160.
54. Politi L, Morini L, Polettini A (2007). A direct screening procedure for diuretics in human urine by liquid chromatography-tandem mass spectrometry with information dependent acquisition. Clin Chim Acta 386 : 46 52.
55. Qin Y, Wang XB, Wang C, Zhao M, Wu MT, Xu YX et al. (2003). Application of high-performance liquid chromatography-mass spectrometry to detection of diuretics in human urine. J Chromatogr B Analyt Technol Biomed Life Sci 794 : 193 203.
56. Reents S (2000). Sport and Exercise Pharmacology. Human Kinetics : Champaign, IL.
57. Scheuermann BW, Kowalchuk JM, Paterson DH, Cunningham DA (1999). VCO2 and VE kinetics during moderate- and heavy-intensity exercise after acetazolamide administration. J Appl Physiol 86 : 1534 1543.
58. Schoene RB, Bates PW, Larson EB, Pierson DJ (1983). Effect of acetazolamide on normoxic and hypoxic exercise in humans at sea level. J Appl Physiol 55 : 1772 1776.
59. Schwartz GJ (2002). Physiology and molecular biology of renal carbonic anhydrase. J Nephrol 15 (Suppl. 5 S61 S74.
60. Shankar SS, Brater DC (2003). Loop diuretics: from the Na-K-2Cl transporter to clinical use. Am J Physiol Renal Physiol 284 : F11 F21.
61. Somani SM (1996). Pharmacology in Exercise and Sports. CRC Press : Boca Raton, FL.
62. Stager JM, Tucker A, Cordain L, Engebretsen BJ, Brechue WF, Matulich CC (1990). Normoxic and acute hypoxic exercise tolerance in man following acetazolamide. Med Sci Sports Exerc 22 : 178 184.
63. Tashian RE (2000). Keeping pace with a fast enzyme: steps and missteps. EXS : 569 596.
64. Thevis M, Schanzer W (2007). Mass spectrometry in sports drug testing: Structure characterization and analytical assays. Mass Spectrom Rev 26 : 79 107.
65. Thieme D, Grosse J, Lang R, Mueller RK, Wahl A (2001). Screening, confirmation and quantification of diuretics in urine for doping control analysis by high-performance liquid chromatography-atmospheric pressure ionisation tandem mass spectrometry. J Chromatogr B Biomed Sci Appl 757 : 49 57.
66. Thorngren JO, Ostervall F, Garle M (2008). A high-throughput multicomponent screening method for diuretics, masking agents, central nervous system (CNS) stimulants and opiates in human urine by UPLC-MS/MS. J Mass Spectrom 43 : 980 992.
67. Trout GJ, Kazlauskas R (2004). Sports drug testing - an analyst's perspective. Chem Soc Rev 33 : 1 13.
68. Ventura R, Segura J (1996). Detection of diuretic agents in doping control. J Chromatogr B Biomed Appl 687 : 127 144.
69. Ventura R, Fraisse D, Becchi M, Paisse O, Segura J (1991). Approach to the analysis of diuretics and masking agents by high-performance liquid chromatography-mass spectrometry in doping control. J Chromatogr 562 : 723 736.
70. Ventura R, Roig M, Montfort N, Saez P, Berges R, Segura J (2008). High-throughput and sensitive screening by ultra-performance liquid chromatography tandem mass spectrometry of diuretics and other doping agents. Eur J Mass Spectrom (Chichester, Eng) 14 : 191 200.
71. WADA (2004). The 2003 WADA Laboratory Statistics. Available at http://www.wada-ama.org/rtecontent/document/LABSTATS-2003.pdf (accessed 14 April 2010)
72. WADA (2005). The 2004 WADA Laboratory Statistics. Available at http://www.wada-ama.org/rtecontent/document/LABSTATS-2004.pdf (accessed 14 April 2010)
73. WADA (2006). The 2005 WADA Laboratory Statistics. Available at http://www.wada-ama.org/rtecontent/document/LABSTATS-2005.pdf (accessed 14 April 2010)
74. WADA (2007). The 2006 WADA Laboratory Statistics. Available at http://www.wada-ama.org/rtecontent/document/LABSTATS-2006.pdf (accessed 14 April 2010)
75. WADA (2008a). The 2007 WADA Laboratory Statistics. Available at http://www.wada-ama.org/rtecontent/document/LABSTATS-2007.PDF (accessed 14 April 2010)
76. WADA (2008b). Medical Information to Support the Decisions of TUECs Arterial Hypertension. Available at http://www.wada-ama.org/rtecontent/document/ Arterial-Hypertension-en.pdf (accessed 14 April 2010)
77. WADA (2009a). The 2008 WADA Laboratory Statistics. Available at http://www.wada-ama.org/rtecontent/document/WADA-2008- LaboratoryStatisticsReport-Final.pdf (accessed 14 April 2010)
78. WADA (2009b). The 2009 WADA Prohibited List. Available at http://www.wada-ama.org/rtecontent/document/2009-Prohibited-List-ENG-Final-20- Sept-08.pdf (accessed 14 April 2010)
79. WADA (2009c). International Standard for Laboratories. Available at http://www.wada-ama.org/Documents/World-Anti-Doping-Program/WADPIS-Laboratories/ WADA-Int.Standard-Laboratories-2009-EN.pdf (accessed 14 April 2010)
80. WADA (2009d). International Standard for Therapeutic Use Exemptions. In : International Standard for Therapeutic Use Exemptions. Available at http://www.wada-ama.org/Documents/World-Anti-Doping-Program/WADP-IS-TUE/ WADA-ISTUE-2010-EN.pdf (accessed 14 April 2010)
81. WADA (2009e). Minimum Required Performance Levels for the Detection of Prohibited Substances. Available at http://stage.wada-ama.org/Documents/World- Anti-Doping-Program/WADPIS-Laboratories/WADA-TD2009-MRPL-V2.0-EN.pdf (accessed 14 April 2010)
82. WADA (2009f). World Anti-Doping Code WWW document. URL http://www.wada-ama.org/rtecontent/document/code-v2009-En.pdf (accessed 14 April 2010)
83. Wilcox CS, Welch WJ, Schreiner GF, Belardinelli L (1999). Natriuretic and diuretic actions of a highly selective adenosine A1 receptor antagonist. J Am Soc Nephrol 10 : 714 720.
84. Yoon CN, Lee TH, Park J (1990). Mass spectrometry of methyl and methyl-d3 derivatives of diuretic agents. J Anal Toxicol 14 : 96 101.
85. Young DB, Srivastava TN, Fitzovich DE, Kivlighn SD, Hamaguchi M (1992). Potassium and catecholamine concentrations in the immediate post exercise period. Am J Med Sci 304 : 150 153.
86. Zappe DH, Helyar RG, Green HJ (1996). The interaction between short-term exercise training and a diuretic-induced hypovolemic stimulus. Eur J Appl Physiol Occup Physiol 72 : 335 340.