Dr. Ramachandra. K. et al. / Journal of Pharmacy Research 2012,5(1),593-603 Review Article Available online through ISSN: 0974-6943 http://jprsolutions.info Drug abuse in sports

Dr. Ramachandra. K. (MD)1*, Dr. Narendranath.S MD2, Dr. Somashekar HS MD3, Dr. Navin.A.Patil (MD)1 ,Dr. Reshma SR (MD)1 ,Dr. Veena. A (MD) 1PG Student, Dept of Pharmacology,J.J.M. Medical College, Davangere – 577004,Karnataka, India 2Associate Professor, Dept of Pharmacology,J.J.M. Medical College, Davangere,Karnataka, India 3Professor and HOD, Dept of Pharmacology,J.J.M. Medical College, Davangere,Karnataka, India Received on:20-09-2011; Revised on: 15-10-2011; Accepted on:10-12-2011 ABSTRACT Compulsory drug testing was introduced in 1968 by the International Olympic Committee(IOC). Since then, several doping cases have been reported in sports competition world wide. Positive results are based on the detection of prohibited substances, their metabolites and markers in biological (mainly urine) samples supplied by athletes. In some cases, the evidences were not contested and athletesadmitted the use of banned substances. However, in other cases, athletes denied the use of doping to enhance performance and claimed to have inadvertently or passively absorbed the drug. Unfortunately, no current accepted analytical method is capable of distinguishing between a sample from a cheater and one from an athlete who was passively exposed to a doping agent. Athletes’ allegations have included the passive inhalation of drug smoke (e.g.marijuana) or the ingestion of food or products sold as nutritional supplements that contained prohibited substances. In the scientific literature, several studies have been performed to investigate the possibility of an accidental exposure being the reason for the appearance of detectable quantities of banned substances in urine samples. Based on these studies, this article discusses those cases where the athlete’s claims could be possible in generating a positive result in doping control and in which circumstances it would be improbable to happen.

Key words: Abuse, Sports, IOC, Athlete, Doping.

INTRODUCTION: The use of pharmacologic agents to improve athletic performance, or “dop- at the high school level, many athletes are using a variety of drugs to enhance ing,” has been reported as early as the 3rd century BC. “Doping” is described performance.3 These epidemiologic studies under assess the prevalence of by the International Olympic Committee (IOC) as “the administration of or drug use, as their data collected from self-reported questionnaires.2 use by a competing athlete of any substance foreign to the body or any physiological substance taken in abnormal quantity or taken by an abnormal Drug Abuse is defined as persistent or sporadic excessive drug use with or route of entry into the body with the sole intention of increasing in an without acceptable medical practice. Thus the intentional use of excessive artificial and unfair manner his/her performance in competition. When neces- doses, or the intentional use of therapeutic doses for purposes other than the sity demands medical treatment with any substance which because of its indication for which the drug was prescribed.1 nature, dosage, or application is able to boost the athlete’s performance in competition in an artificial and unfair manner, this too is regarded by the IOC Abused drugs are divided into two groups: Hard and soft drugs. Hard drugs as doping.”1 are those which causes severe psychological and physical dependence.This group includes heroin and cocaine. Although there have been anecdotal reports of doping throughout history, at the middle of the twentieth century that documentation of usage became Soft drugs are those which causes psychological dependence but there is little more widespread. One of the reasons for this increased awareness of usage is or no physical dependence except for heavy doses of alcohol. This group that pharmacology has improved significantly. As more potent and effective includes sedatives, tranquilizers, amphetamines, cannabis, hallucinogens, al- drugs were developed, some athletes began to see the potential for artificially cohol, tobacco and caffeine.1 enhancing their own performance.2 Abuse liability is defined as capacity to produce immediate effect. Eg am- Legislation was prompted as rumors for ergogenic enhancement in sports.The phetamine and heroin give rapid effect where as TCA do not.2 IOC’s Medical Commission was founded in 1967. One of their principal Abuse liability depends on route of administration in descending order: duties involved the investigation of possible drug misuse by athletes. Official Inhalation/intravenous/intramuscular/subcutaneous/oral. Drug abuse has drug testing of athletes began with the 1968 Olympic Games in Mexico two prinicipal forms: City. 2 1. Continuous use: when there is true dependence. Eg opiods,alcohol, Bzd’s. 2. Intermittent or occasional use: Eg. Cocaine, cannabis. Despite legislation and increased random testing, the use of pharmacologic agents has continued and actually increased. Reports now indicate that, even General Pattern of the drug use:7 Any age: Alcohol, Tobacco, hypnotics, tranquilizers, LSD and cannabis *Corresponding author. Age:16-35 years: Hard use drugs, chiefly heroin, cocaine and amphetamines Dr. Ramachandra. K. (MD) Aged 14-16 years: cannabis, ectasy, cocaine. PG Student, Dept of Pharmacology, Under 14 yrs: Volatile inhalants. e.g. Solvents of glues, aerosol sprays, J.J.M. Medical College, vaporised paints. Davangere – 577004,Karnataka, India

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 593-603 Dr. Ramachandra. K. et al. / Journal of Pharmacy Research 2012,5(1),593-603 Substances & Athletics Reasons For Use1

Stimulants:1 Cocaine: Stimulants are used by athletes in the belief that they may reduce fatigue as Cocaine is one of the most commonly used narcotics by athletes. It is found well as increase alertness, response time, and strength. This category in- in the leaf of the coca plant and has been used in the past by South American cludes a variety of central nervous system stimulants as well as sympatho- Indians to ease the strain of their work at high altitudes. The mechanism of mimetics. action is by inhibition of the re-uptake of norepinephrine and dopamine at their respective postsynaptic sites.2 Modern use is reflected in a 2006 Amphetamines: survey of the National Football League (NFL), which described it as the Amphetamines were first developed in 1920.Their vasoconstrictive prop- most commonly abused drug. This same survey suggested that use was erties were initially utilized for treatment of nasal congestion. The ergo- more for recreation than as an ergogenic agent.4 genic qualities became more apparent during World War II, when amphet- amines were commonly used by soldiers as a means of increasing alertness It is believed that low doses may act along a similar path to that of amphet- 2 on patrol duty. Although amphetamines are still commonly used today. amines. Users of cocaine report experiencing a “high” with increased alert- ness and feeling more mentally and physically powerful. Structurally, amphetamines are similar to endogenous catecholamines, such as epinephrine. Their mechanism of action is believed to be augmentation of Cocaine affects the cardiovascular system by increasing cardiac activity neurotransmitter release, especially norepinephrine, thereby stimulating and sensitivity, which may lead to hypertension, tachycardia, and even the sympathetic nervous system. Their peak effect is usually noted in 1 to arrhythmias. Chronic rhinitis or septal necrosis results from the nasal route 4 2 hours. Although there are conflicting reports as to whether athletic per- of ingestion. The most dramatic side effect of cocaine use is sudden cardiac formance is enhanced by amphetamines, there may be a mild improvement death. This has been reported in some athletes by coronary occlusion. in swimming or throwing sports, such as shot put. Some studies suggest Cerebrovascular accidents have also been associated with cocaine use, from that they prolong the time to exhaustion, but there is no effect on actual sudden elevations in blood pressure.4 speed.5 Herbal Coca Tea: The athlete may be able to prolong exercise time by blunting pain percep- The consumption of herbal coca tea is common in some countries of South tion and the symptoms of fatigue and exhaustion. This decrease in ability to America, such as Peru and Bolivia. The tea consists of pure coca leaves or sense the body’s limitations may lead to an increased incidence of heat coca leaves mixed with different herbs and is often package in individual injury. Amphetamines also increase aggression, increasing the potential for servings as tea bags that contain approximately 1g of plant material. injury in contact sports.6 Contains benzoylecgonine, Cocaine metabolite, its concentrations ranged Side effects include thermoregulatory difficulties, such as heatstroke. Neu- from 1400 to 2800 |mg/L and occurred 4-11 hours post-ingestion. Positive rologic symptoms include restlessness, tremor, irritability, insomnia, and immunoassay results were obtained for 21-26 hours after tea ingestion.4 increased aggressive behavior, as well as the potential for addiction. Cardio- vascular effects include angina, dysrhythmias, headache, palpitations, Therefore, if an athlete consumed coca tea within hours before the compe- changes in blood pressure, and changes in heart rate. Adverse gastrointesti- tition, his or her urine test for doping control would probably indicate a 6 nal side effects include abdominal pain, vomiting, and decreased appetite. positive result for cocaine.

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 593-603 Dr. Ramachandra. K. et al. / Journal of Pharmacy Research 2012,5(1),593-603

Narcotic Analgesics: Caffeine: Narcotic analgesics act on the central nervous system to depress fear, Caffeine is a methylxanthine that occurs naturally in many species of plants, anxiety, concentration, and pain sensation. They include morphine, heroin, including coca, coffee beans, and tea leaves. It is also found in numerous and other compounds of a similar chemical structure. All act by reproducing cola drinks and chocolate. The most important central nervous system the effects of endogenous opiates, such as endorphins and encephalins.2 action is from its role as an adrenergic receptor antagonist. Other systemic The main ergogenic benefit is derived from the analgesic properties. De- effects may include increased muscle contractility from an increased per- creased pain perception allows athletes to exert themselves beyond their meability of the sarcoplasmic reticulum to calcium. Caffeine also inhibits normal pain threshold. This may pose a hazard by encouraging competing phosphodiesterases and potentiate the role of hormones.4 Generally, caf- despite an existing injury, and it may predispose the athlete to incurring feine will have an effect on the central nervous system at a concentration of even greater harm. There is strict legal control over most narcotics because 85 to 200 mg. At this point, it will decrease fatigue and improve the level of of the high potential for addiction. consciousness. The ergogenic dose is is between 250 and 350 mg. The IOC considers a urine concentration of greater than 12 mg/mL as consistent with The exception to this control is codeine, which is widely available in a doping. The National Collegiate Athletic Association’s (NCAA) defined variety of medicines, such as cough syrups and cold remedies. Generally, limit is 15 mg/mL. As an example of the quantity of caffeine that this the levels of codeine in these medicines are too low to produce the adverse represents, an athlete would need to drink six to eight cups of coffee in one effects associated with narcotic analgesics; however, codeine may be de- sitting and be tested within 2 to 3 hours to reach the required urine concen- tected during drug testing because it is metabolized along a similar path as tration. Potentially, the amount of caffeine needed for the ergogenic benefits for morphine. is less than defined limits.4

Narcotics are famous for their ability to cause tolerance and dependence. Side effects include anxiety, irritability, restlessness, tremor, headaches, Common side effects include dry mouth, pupillary constriction, pruritus, insomnia, diuresis, gastrointestinal disturbances, and tachycardia. These and respiratory depression. Most cases of fatal overdose are secondary to effects may occur after just a few cups. If used to excess, caffeine can be respiratory distress. Withdrawal symptoms after habituated use include lethal at a dose of 3 to 10 g, causing seizures, tachycardia, or ventricular restlessness, nausea, vomiting, diarrhea, and muscular cramps. dysrrhythmias.8

Poppy Seed-Containing Food: Ephedra: Poppy seeds (derived from Papaver somniferum) are frequently used in Ephedra or ma huang is the herbal form of ephedrine. Until 2004, it was the baking of bread and cakes all over the world. Studies have shown the promoted as being “natural” and was often sold in combination with caf- presence of two major opium alkaloids, codeine and morphine, in these feine in US. seeds. Consumption of opiates after their separation from poppy seeds result in significant concentrations in urine specimens. Therefore, positive For those sports-governing organizations that ban ephedrine, they do not opiate results obtained during analyses for doping control could be related differentiate between sources (e.g., herbal versus synthetic).Athletes using to the ingestion of food containing poppy seeds, rather than doping use of herbal ephedra products are at risk of experiencing ephedrine-like adverse narcotics. reactions (e.g., CNS and cardiovascular stimulation) and deaths have been attributed or associated with the use of ephedra. Herbal ephedra products Following the ingestion of poppy seed cake containing an average of 4.69g used for weight loss or as an ergogenic aid are marketed in combination with of seed per slice, a maximum concentration of morphine in urine was only herbs containing caffeine, which potentiate the effects on the CNS and 302 g/L.2 The threshold value (urinary concentration) for morphine in the cardiovascular system.9 IOC list is 1000 g/L. FDA received approximately 17,000 adverse event reports concerning ephe- Marijuana: drine alkaloids. The potential risks of ephedra received national attention Although being an illicit drug in most countries, marijuana (Cannabis sa- after the tragic death of Baltimore Orioles pitcher Steve Bechler was linked tiva) is smoked in social situations where some present smoke the drug. to a supplement that contained ephedrine.9 Theoretically, it is possible that non-smokers could passively inhale enough marijuana smoke to excrete detectable amounts of cannabinoids in their Athletes under the NCAA, WADA, NFL, or other sports-governing bodies urine. In cases like this it is very hard to state whether the individual was that ban ephedrine must be careful not to consume dietary products that engaged in the use of the drug or just passively exposed.7 contain ephedra alkaloids, whether listed among the ingredients or not.

Studies have shown that the amount of cannabinoids detected in the urine Anabolic-Androgenic Steroids of a passive smoker is dependent on the size and ventilation of the room in Anabolic-androgenic steroids are testosterone derivatives that exert ana- which he or she was present, the concentration of tetrahydrocannabinol bolic (THC) in marijuana cigarettes that are being smoked and the amount of the (tissue building) and androgenic (masculinizing) influences on the body. smoke he or she passively inhaled. Physiologic action of AAS is similar to native of testosterone.The molecule Individual can produce detectable levels of cannabinoids in urine samples diffuses across the cell membrane after binding to receptor.This complex only after extremely severe conditions of passive exposure to marijuana then binds to the nucleus of a cell,stimulating messenger RNA synthesis,which smoke. However, according to the IOC list, sports federations consider leads to an increase in structural and contractile protein. AAS combat (sup- urine samples positive for cannabis use if the concentration of 11-nor- press) the catabolic effects of cortisol through competitive inhibition of delta-9-tetrahydrocannabinol-9-carboxylic acid (the main metabolite of glucocorticoid receptor.10 THC) is >15 mg/L.

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 593-603 Dr. Ramachandra. K. et al. / Journal of Pharmacy Research 2012,5(1),593-603 Commonly Used Anabolic Androgenic Steroids

Anabolic steroids increase protein synthesis. They also decrease the cata- castrated males, females, and old animals, often show substantial increases in bolic effect of naturally occurring glucocorticoids by competing for their muscle mass with steroid use. In endurance sport, anabolic steroids have receptor sites. The central nervous system effects occur through increases in been shown to increase erythropoiesis, therefore potentially improving aerobic acetylcholine and monoamine and peripherally by increasing acetylcholine at capacity. They also have an anticatabolic effect, allowing increased exercise the neuromuscular junction. tolerance, intensity, duration, and frequency of training.

During the past 50 years, anabolic steroids have been used in various repro- Another important effect is the decrease in recovery time, which is advanta- ductive dysfunctions, anemia, hereditary angioedema, metastatic breast can- geous to the athlete. In strength and power sports, anabolic steroids have cer, depression, psychoses, and protein deficiency states, as well as in pa- been shown to increase lean mass and decrease fat percentage in the well- tients convalescing from severe infections, surgery, burns, and trauma. In trained athlete. 1990, the American Medical Association (AMA) listed specific clinical uses for anabolic-androgenic steroids including the following: hypotestoster- 17-alkyl androgens (oral forms) have a profound effect in altering lipids. The onemia, anemia, metastatic breast cancer, hereditary angioedema, endo- lowering of the high-density lipoprotein (HDL) is greatest, with a less sig- metriosis, and fibrocystic breast disease.11 nificant increase in low-density lipoprotein (LDL) and triglycerides; pro- longed use suggests an increased risk of cardiac disease.13 More than 40 anabolic-androgenic steroids are on the market today. Oral, parenteral, and transdermal forms are available in the United States, and Animal studies have shown that collagen abnormalities occur. Male pattern intranasal forms are available in other countries.11 Although most of these baldness and acne are also increased. Gynecomastia is a common effect, drugs are obtained through the “black market,” it is estimated that 10% to resulting from peripheral conversion of the androgen to estradiol. There is 15% of them are obtained by prescription.10 minimal effect on blood pressure, and the effect on glucose metabolism is equivocal. The risk of HIV and hepatitis A and B is great with needle sharing. Athletes use many regimens to maximize their steroid effect like: There is a definite association of the 17-alkyl androgens (oral forms) with Continuous dosing means the athlete never stops the use of steroid, whereas peliosis hepatis, cholestatic jaundice, and hepatocellular adenoma. Deaths in cycling the athlete has some time off of the drugs to prevent plateauing or occurred due to necrosis and rupture of the tumor or the cysts in peliosis tolerance. The average cycle lasts from 6 to 12 weeks. Stacking means that hepatis. Portal hypertension can occur in peliosis hepatis. Temporary infer- more than one anabolic steroid is used at a time, usually with staggered cycles tility is also associated with steroid use.13 of the individual drugs. Pyramiding is a gradual increase in dosage, with a gradual taper after maximum dosage is attained, whereas an array is the use With steroid use there may also be the following: myocardial infarction, of multiple drugs to counteract side effects or to enhance the effect of the cerebrovascular accident, prostate cancer, testicular atrophy, cardiomyopa- steroids. These drugs include tamoxifen, levothyroxine, diuretics, high-dose thy, Wilms’s tumor, lymphoma, colonic adenocarcinoma, and bleeding esoph- potassium supplements, growth hormone, and human chorionic gonadotro- ageal varices. pin. AAS cause significant changes in personality profile. Psychological changes Endurance athletes use anabolic steroids primarily for their catabolism blocking include increased aggressiveness, depression, mania, psychosis, and increased effects, allowing increased training and more rapid recovery. They generally libido. Psychological dependence also occurs, and it is suggested that physi- use doses at or below physiologic levels (7 mg/ day in men). Sprinters use cal dependence may occur in some instances via opiate receptors. them to increase strength and power and to improve recovery, and they generally use doses one to two times greater than physiologic doses. In Cause of death among power lifters includes suicide, acute MI, hepatic coma strength sports, it is common to use 10 to greater than 100 times physiologic and non hodgkins lymphoma.Side effects in women: Reversible changes doses. Women, regardless of sport, are generally thought to use lower doses include the following: menstrual abnormalities, increased libido, breast atro- than do men.12 phy, acne, and increased aggressiveness.

Studies in healthy young male animals have shown equivocal effects, but Irreversible changes are the following: facial hair growth, extension of pubic animals with lower natural hormone levels than in young men, such has hair, hypertrophy of the clitoris, deepening of voice, and loss of scalp hair.

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 593-603 Dr. Ramachandra. K. et al. / Journal of Pharmacy Research 2012,5(1),593-603 Androstenedione: Adverse effects are the same as for other ß2 agonists, including tremor, It is a precursor of both testosterone and estrone and has weak intrinsic tachycardia, anxiety, palpitations, headache, nausea, anorexia, and insomnia. androgenic properties. The mechanism of action as a performance-enhancing More serious side effects include cardiac muscle hypertrophy, dysrrhythmia, substance is an increase in the body’s production of testosterone by having and hyperthermia.18 an abundance of the precursor for conversion.10 Sympathomimetics: Androstenedione increases muscle mass or strength. In 1998, the popularity Sympathomimetics are also used to decrease fatigue and enhance strength. of androstenedione soared when Mark McGwire mentioned took the supple- They are generally synthetic drugs that mimic the sympathetic nervous ment after he set a new MLB home run record. The administration of system through activation of adrenoreceptors. The a2 receptors trigger an androstenedione increases the synthesis of estrogenic compounds and hence 1 increase in heart rate and ventricular force of contraction. ß2 receptors act to estrogen-related effects can be anticipated (e.g., gynecomastia in men). dilate bronchioles and coronary vessels. Ephedrine, phenylpropanolamine, and pseudoephedrine are found in over-the-counter asthma and cold medica- Androstenedione is banned by the NCAA, WADA, and the NFL. In March 2 tions. ß2 agonists are frequently used in treatment of asthma. 2004, the FDA announced that it considers androstenedione to be a new dietary ingredient; and since no pre-market safety notification has been sub- Although the IOC has banned medications, such as albuterol and terbutaline mitted by any manufacturer or distributor, products containing androstene- in the oral form, they are allowed in aerosol or inhalant form.19 dione are considered adulterated and their marketing is prohibited under the Federal Food, Drug, and Cosmetic Act.11 Erythropoietin Erythropoietin (EPO) is a naturally occurring compound, produced by the Dehydroepiandrosterone: kidney to stimulate red blood cell production by the bone marrow. This, in Dehydroepiandrosterone (DHEA) is the endogenous precursor to a variety turn, leads to an increase in the red blood cell mass and the hemoglobin and of hormones and has weak androgenic properties. Although the FDA re- hematocrit. Purified EPO was first isolated from human urine in 1977. By moved DHEA from the market as a drug in 1985, it is now marketed in 1985, the gene that codes for EPO was cloned, and soon after recombinant the United States as a dietary supplement. DHEA has been stated to be a human erythropoietin (rHuEpo) became available.20 Its half-life varies de- “superhormone,” effective for strengthening the immune system, enhancing pending on the route of administration, with 20 hours being the longest when libido, preventing cancer and cardiovascular disease, and providing an “anti- administered subcutaneously. Red cell production will continue for as long as dote for aging.”10 2 weeks; however, rHuEpo is used mainly to treat anemia caused by renal disease.6 As an ergogenic aid, DHEA is promoted to increase testosterone concen- trations since it is the precursor to androstenedione and androstenediol. The rHuEpo provide all the benefits of blood doping, without the risks involved NCAA, WADA, and other sports-governing agencies prohibit the use of in blood transfusion. Increased hemoglobin and hematocrit could result in DHEA. Sequelae from long-term use are not known still. In women, hyperviscosity of the blood, with many of the same risks as seen in blood adverse effects similar to those seen with anabolic-androgenic steroids doping.21 (e.g., masculinization) have been reported.11 Currently it is impossible to identify rHuEpo by drug testing. rHuEpo is Clenbuterol: virtually identical to the endogenous protein and is excreted in the urine in an

Clenbuterol is a ß 2 agonist used as a bronchodilator, and it is available in both amount that is too small to be tested. Also, it is rapidly metabolized, and its oral and aerosolized forms. The FDA has not approved its use in the United effects extend far beyond any test’s capability to detect.12 States. Clenbuterol came to public awareness at the 1992 Summer Olympics in Barcelona when an American hammer thrower, Jud Logan, and shot-putter, Growth Hormone: Bonnie Dasse, were disqualified after testing positive for this substance.14 Human growth hormone (hGH) is a polypeptide hormone produced and The mechanism of action has not been completely elucidated. Clenbuterol stored in the anterior pituitary gland. Animal breeders in the 1930s discov- has been shown to cause skeletal and cardiac muscle hypertrophy, 16 but not ered that animals given extract from species-specific pituitary glands devel- hyperplasia, even in denervated muscle. This occurs by suppression of both oped increased muscle mass, decreased body fat, and an accelerated growth muscle synthesis and to a lesser degree muscle degradation, with the net rate. Researchers in the 1950s realized that hGH stimulated the production result being muscle hypertrophy. 15 Clenbuterol directly stimulates lipolysis of somatomedins, which increased growth. Soon thereafter, hGH was used in as well. As a result of its lipolytic activity, it is currently being studied for use humans for growth hormone deficiency in children and in Turner’s syndrome in obesity. Clenbuterol also causes sympathetic stimulation of ß2 receptors, to promote normal growth. In 1985 two forms of synthetic growth hormone causing peripheral and central effects similar to those of other ß2 agonists. were produced. One form was identical to the human hormone and the other Athletes generally use the oral form of this drug at a starting dose of twice differed by one additional amino acid. Antibody production was quite high in that is used in the treatment of bronchospasm (0.0172 mg/kg).15Animal these early preparations. Prior to this advancement, hGH was derived from studies used doses of 0.33 to 2.0 mg/kg. Owing to rapid downregulation of cadaveric specimens. This resulted in cases of Creutzfeldt-Jakob disease in receptors, athletes often cycle clenbuterol, taking it on and off in 2-day recipient.22 cycles for 8 to 10 weeks, followed by 10 to 12 weeks without the drug. Clenbuterol has been used following the discontinuation of steroids to retard With improved drug testing techniques in the 1980s, anabolic steroid usage muscle mass loss and to aid in stripping subcutaneous fat for improved was more easily detected. As a result, athletes turned to other substances muscle definition.16 that mimicked the benefits of anabolic steroids but were not detectable by current drug testing methods. Use of hGH is particularly in bodybuilding and

Altogether, inhaled ß2 agonists have therapeutically minimal influence on football athletes. power, maximal oxygen consumption, work, and results of most respiratory function tests. This is a result of the short half-life of inhaled albuterol. Growth hormone exerts its effect on all cells of the body. Skeletal and soft- Clenbuterol is not permitted in any form.17 Journal of Pharmacy Research Vol.5 Issue 1.January 2012 593-603 Dr. Ramachandra. K. et al. / Journal of Pharmacy Research 2012,5(1),593-603 tissue growth is stimulated. Glucose intolerance and lipolysis occur, and skeletal muscle where it is partially converted to creatine phosphate. There protein synthesis is increased. Increased protein deposition occurs with are several mechanisms whereby muscle cells produce adenosine triphos- concurrent reduction in protein catabolism. phate (ATP), which provides the energy for muscle contraction.27

The GH-mediated growth is different from the growth that occurs as a result Creatine is used as a performance-enhancing supplement by increasing the of work. New RNA must be synthesized for exercise-induced muscle growth, muscle stores of creatine and creatine phosphate for producing and replen- whereas GH-mediated growth occurs as a result of increase in the rate and ishing ATP. translation of already existing RNA.23 Creatine, taken to improve athletic performance, has become one of the most Little information exists in athletes, where they use 20 times the therapeutic popular dietary supplements (excluding vitamin and mineral supplements) dosage. The therapeutic dose is 0.06 mg/kg (1.5 mg/day) three times per among both amateur and professional athletes. It is also popular with middle week by the intramuscular route. The cost of an 8-week supply was esti- school and high school athletes for a variety of sports, including cheerlead- mated at $1000 to $1500.24 ing. Promoters of creatine supplementation claim that it increases the pro- duction of energy, promotes the growth and strength of skeletal muscle, Athletes use this drug to enhance definition and to increase the size and reduces recovery time, increases stamina, and buffers lactic acid build up.28 strength of muscle.There is an increase in lean body mass with a decrease in fat percentage. More studies must be performed to determine if there is truly Creatine supplementation aid in brief (< 30-60 seconds), intermittent, high- an ergogenic benefit with the use of hGH. burst, anaerobic exercise, which would benefit sprinters in running, cycling, swimming, and rowing, and perhaps power events such as weight lifting and Adverse effects of hGH include acromegaly, antibody formation, hypothy- throwing. Subjects with low creatine stores (e.g., vegetarians or low-protein roidism, hypercholesterolemia, coronary artery disease, congestive heart fail- diets) may gain the most benefit from creatine supplementation. ure, cardiomyopathy, myopathies, arthritis, diabetes mellitus, impotence, osteoporosis, menstrual irregularities, and Cru-etzfeldt-Jakob disease. The ergogenic effect of creatine on endurance or aerobic exercises (e.g., long distance running, swimming, cycling, rowing) is less clear and inconsistent. “Black market” sources of hGH often include the former Soviet Union. Creatine phosphate is a minor source of ATP production after 10-20 These products are still derived from cadaveric specimens. Crueztfeldt-Jakob seconds of maximal anaerobic work. With respect to promoting the growth disease is a real and significant risk when using black-market hGH because it and strength of skeletal muscle, creatine indirectly effects by increasing the is produced from cadaveric specimens and sold as recombinant hGH. Ac- productivity of weight or resistance training. romegaly occurs in patients at concentrations of 5 to 30 ng/mL, which is equivalent to 1.5 to 9 mg/ day. 25 This dosage is generally exceeded by ath- The most common adverse effects reported to be associated with creat- letes, and the potential for developing acromegaly and other adverse effects ine include fluid retention and weight gain. These effects may are detrimental of growth hormone is significant. It is the prohibitive cost of hGH that in some sporting events. Additionally, creatine supplementation causes in- prevents the frequent occurrence of these effects. crease in pressure in anterior compartment in the lower leg, or lower extrem- ity pain or tightness in the lower leg during exercise. Other adverse effects Other Peptide Hormones : include dehydration, emesis, diarrhea, fatigue, muscle cramps, myopathy, Human chorionic gonadotropin (hCG), leuteinizing hormone (LH), adreno- polymyositis, fatigue, migraine, renal impairment, rash, and dyspnea.Due to corticotropic hormone (ACTH), gonadotropin-releasing hormone (GnRH), its supplementation, the body will downregulate the endogenous production corticotropin-releasing factor (CRF), and growth hormone re-leasing-hor- of creatine. mone (GHRH) are available owing to advances in recombinant DNA.26 Currently, creatine is not banned by the NCAA, WADA, or other sports- HCG has identical biologic effects as LH, and it is used by athletes to governing bodies; however, many of these organizations urge caution be- stimulate endogenous sources of testosterone production without disrupting cause of the unknown long-term effects of creatine use. Despite the cautions, the natural testosterone-to-epitestosterone ratio. LH is apparently not used a substantial number of sports teams in the NFL, MLB, the National by athletes owing to the greater availability of hCG. When assays are devel- Basketball Association (NBA), and the National Hockey League (NHL) oped, LH levels can be used to indirectly identify anabolic steroid users. have supplied their players with creatine.29

ACTH has no ergogenic benefit and is, in fact, detrimental to athletic perfor- Beta-Blockers: mance. GnRH and CRF, if administered exogenously, cause rapid Beta-blockers are commonly used in conditions affecting the cardiovascular downregulation of hypothalamic receptors, and are, therefore, ineffective in system. They act primarily to decrease heart rate, cardiac output, stroke enhancing performance. volume, and mean arterial pressure. Increased use in treating hypertension, as well as after myocardial infarction. GHRH administered exogenously increases hGH levels and has potential for abuse. At the present time, no assays can effectively detect the use of these In sporting events, beta-blockers are used when a calming effect is required, substances in the athlete, but because of their anecdotal increase in use by the such as during shooting events for archery. Beta-blockers would tend to athletic community, the Medical Commision of the IOC is supporting the hinder maximal performance in events that require an increase in cardiac development of these assays.26 response. As such, they are not used for endurance or aerobic activities.2

Creatine: The main benefit is by reducing anxiety and alleviating tremors. Negative side Creatine is an amino acid compound produced naturally in the body,and is a effects include bronchospasm, heart failure, and heart block, aggravation of byproduct of muscle metabolism. Creatine is obtained in the diet, largely peripheral vascular disease, impaired glucose control in diabetes mellitus, from meat and fish. The vast majority of creatine in the body is stored in fatigue, and a decreased ability to perform endurance activities.30

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 593-603 Dr. Ramachandra. K. et al. / Journal of Pharmacy Research 2012,5(1),593-603 urine sample to have a pH of 7.5 or less. Furthermore, alkalinizing agents, Alcohol: such as acetazolamide, are banned by the NCAA and WADA, and they Beverage alcohol is a simple organic compound which easily crosses blood can be detected by the drug tests.34 brain barrier quickly, affecting brain centers for balance and co-ordination,fluid retention,judgement,and reasoning,emotional control, level of alertness,sexual Adulterants have been used by athletes to mask the use of banned sub- interest and socialization.31 stances, either by adding something that degrades or denatures the drug and its metabolites or by interfering with the analysis in some manner to deceive Rates of alcohol use among college atheletes are higher than general public.Use it. Such adulterants are surreptitiously added to a urine specimen by an rates differ by sport-swimming/diving,soccer,and baseball/softball rates are athlete after the specimen has been produced. Examples of such adulter- higher than basketball,volleyball and track and field rates.32 ants—which may or may not be effective masking agents—are bleach, vin- egar, lemon juice, salt, hand soap, Drano, and various acids.Tampering, adul- The National Collegiate AthleteAssociation(NCAA)2001 studyhad showed terating, or manipulating a urine specimen is banned, and evidence of such act that college athletes drink mostly for social reasons(83.9%)compared with constitute a positive drug test, depending on the sports-governing body. 34 feeling good (12.9%),performance (0.2%).Swimmers,divers and basketball players have higher levels of social motivation than track/cross-country BLOOD DOPING: athletes.Lowest rates are seen for cycling ,horse racing and tennis.31 It has long been noted that an athlete’s performance in endurance events improved after long-term training in a high altitude. As the body produces In low doses or amounts, alcohol reduces essential tremor. However, in higher more red blood cells, there is an increase in arterial oxygen concentration and amounts, alcohol can have a negative effect on athletic performance, par- delivery capabilities. This improved oxygen delivery to skeletal muscle would ticularly for events that require endurance, speed, quick reaction times, enhance endurance capabilities during exercise. Undergoing the physical in- balance, and coordination. convenience and time required to acclimate to altitude, artificial hemoconcen- tration by red blood cell infusion have a similar ergogenic effect. The first Alcohol’s negative effects on aerobic performance and psychomotor skills such documented use occurred in the 1976 Olympic Games in Montreal.4 are due to its slow /fixed rate of metabolism(zero order kinetics)and its toxic interference with energy and carbohydrate metabolism. The blood used, is drawn from the same individual (autologous) or from a different donor (homologous), which has been type matched with the Adverse effects of alcohol include drowsiness, sedation, impaired balance, recipient’s blood. Generally, two units of blood are removed and preserved psychologic and physical dependence, impaired judgment, and impaired psy- by freezing at — 80°C. The athlete’s body then compensates for this relative chomotor skills.Long-term use of alcohol can result in other alcohol-related anemia with production of new red blood cells, restoring a normal hemoglo- problems such as liver damage. The NCAA and WADA ban the use of bin and hematocrit. The previously frozen blood is then thawed and re- alcohol for certain events, such as rifle and archery, respectively. 33 infused at 1 week before competition.35 Diuretics Post-transfusion hemoglobin should be less than 17 g/dL, and the hematocrit Diuretics are used for the elimination of excess fluid from the body. Athletes should be less than 50%. Otherwise, a hyperviscosity syndrome develops. obtain benefit by causing the forced loss of body fluid can bring about a rapid This involves an elevation in blood viscosity, leading to decreased blood- decrease in weight. This is of advantage in sports in which competitors are flow velocity. This could progress to a decreased cardiac output with intra- matched by weight divisions, such as in boxing, weightlifting, or wrestling.25 vascular clotting, potential heart failure, and death. Thrombosis could mani- Diuretics have also been used by competitors to increase urine production at fest as cerebrovascular accidents, myocardial infarction, pulmonary embo- times when they are likely to undergo drug testing. The belief is that an lism, or deep vein thrombosis. Also, with any transfusion, there is risk of increase in urine volume will dilute the doping agent; however, given the infection. With homologous transfusion, mismatch in blood typing can also specificity of drug testing, using techniques, such as immunoassay, chroma- lead to potentially fatal hemolytic reaction and renal failure, allergic reac- tography, and mass spectrometry, this type of masking is not likely to be tions, and contracting of infectious diseases such as viral hepatitis, malaria, effective.34 cytomegalovirus, or HIV. 6 Masking Agents COLLECTING A URINE SAMPLE Masking agents are substances that athletes use to prevent detection of The testing procedure must be strictly adhered to so that all athletes receive drugs in the urine. These include substances ingested by the athlete as well as the same treatment. Collection of the urine sample has to be observed be- adulterants that are surreptitiously added to a urine specimen in an attempt cause drug abusers may attempt to falsify the results by tampering with the to fool the drug assay. In 1987, the IOC requested that urine samples be samples. Volume, pH, and in some cases specific gravity and temperature of screened for the presence of probenecid at the Pan American Games, the sample are tested immediately. These simple tests check for some of the because probenecid was suspected of being used to prevent the excretion of known methods of cheating the drug tests at this early stage.36 certain anabolic-androgenic steroids in an attempt to cheat on a drug test. After probenecid was indeed detected in a number of urine samples of strength The urine pH is tested to detect attempts at changing the nature of the athletes, it was subsequently added to the banned substance list by the IOC. sample, which can affect the analysis of certain drugs, as well as their me- The mechanism of action is believed to be an inhibition of renal tubular tabolism and clearance. Sodium bicarbonate, for example, can be taken orally secretion of these drugs. Both the NCAA and WADA now ban probenecid.25 in order to change urine pH. The specific gravity is checked for attempts to By taking a substance to alkalinize the urine, the urinary excretion rate of dilute the concentration of drugs, as is the case by deliberate diuretic use.37 basic compounds (e.g., amphetamine analogues) can be reduced. By decreas- ing the excretion of the drug, the urine concentration may be too low for the To ensure that the sample actually comes from the athlete, the testing officer analysis to detect. For this reason, strict drug-testing protocols require a must be able to see the urine flow from the athlete into the bottle. At least

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 593-603 Dr. Ramachandra. K. et al. / Journal of Pharmacy Research 2012,5(1),593-603 75 mL must be given under close scrutiny and the urine is split into 2 that arrives at the laboratory actually comes from the athlete in question, portions as “A” and “B” bottles. The athlete chooses the two coded bottles with no opportunity to tamper with the sample. Once selected for drug and the samples are sealed by the athlete. In most cases, only the athlete testing, the athlete is notified by an official and asked to sign a form acknowl- handles the urine and collection containers until sealed. The containers are edging this notification. The athlete may or may not be accompanied by an sealed with tamper-proof strips, placed inside other sealed containers, official and must attend the testing station within the designated period. The wrapped in tamper-evident seals and coded. The independent official ob- testing station is supposed to be a private, comfortable place. Many times it serving the sample procedure records all of the information on a document. is set up inside a specially designed mobile testing unit. Independent sam- This initiates a chain-of-custody record to be continued by anyone who pling officers, whom are trained and appointed by the respective governing handles the specimen until the urine is used up or discarded in the laboratory. body, carry out the collection of urine samples. Each officer carries a time- The laboratory staff never knows the athlete’s name, only the bottle identi- limited identity card and a letter of authority for the event to which they are fication number. Everyone who handles the sample must understand the allocated.36 importance of the chain of custody and the essential role of maintaining it. The chain of custody guarantees that the sample content is protected and Before giving a urine sample, the athlete is told to select two numbered 36 that the sample tested is from the correct athlete. bottles. After providing the sample (about 100 ml), the athlete must volun- tarily complete a form. The athlete declares any drug treatment taken in the The possibility of sabotage of a urine sample has been raised many times by previous seven days and must check and sign that the sample has been taken athletes. It is for this reason that athletes should ensure that the testing and placed in the bottles correctly. The urine sample is then sent for analysis procedure is observed rigorously for their own protection. Samples should to a laboratory currently accredited by the IOC. In the event of a positive be dispatched in the appropriate containers and all paperwork completed test result, the laboratory will notify the governing body of the sport, who without any errors. After this the athlete is no longer part of the process and will then notify the athlete. The rules of the governing body of the particular must rely on the integrity and accuracy of the system. The sample is then sport determine what happens next. The rules vary across governing bodies, taken and sent by courier, along with a chain-of-custody document, to an sports and countries. An athlete is usually suspended while a positive result 37 accredited laboratory. is investigated, but has the right to have a second analysis of the urine sample. This analysis may be observed directly by the athlete or by the DRUG TESTING PROCEDURE: athlete’s representative. There is then a hearing, at which time the athlete’s The drug testing is highly regulated procedure, to ensure that the urine sample case is presented.37

Abbreviated List of NCAA & WADA Banned Substances41

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 593-603 Dr. Ramachandra. K. et al. / Journal of Pharmacy Research 2012,5(1),593-603

Assay Techniques Commonly Used in Drug TestingFor Screening 48,49 Pharmacists can provide presentations and information to athletes, coaches, Enzyme immunoassay and athletic trainers on drug and supplement use at all levels of competition. Fluorescence polarization immunoassay Further, pharmacists can develop or participate in educational and rehabilita- Gas chromatography tion programs for athletes that seek assistance or who have been referred due High-performance liquid chromatography to a positive drug test. Radioimmunoassay 36,37 Thin-layer chromatography For Confirmation Doping rules : Gas chromatography · A sample: Once the A sample is positive the athlete is notified. Gas chromatography-mass spectrometry · B Sample: If needed, the athlete can go for a B sample test. He/ High-performance liquid chromatography she can cross check the number and seal on the bottle. But the athletes are not allowed to be with the scientists when the tests are Table 3. Resources for Doping Control and Banned, Restricted, and Permit- done. ted Substances:40 · Hearing: Once the B sample is also positive, the case will go for § International Doping Tests & Management www.idtm.com hearing to any of the three WADA panel will give its verdict after § International Tennis Federation www.itftennis.com/html/rule/ hearing both sides. frameset.html · Punishment: A first-time steroid violation will attract a two-year § Major League Baseball MLB’s Joint Drug Prevention and Treat- ban. ment Program bhttp://mlb.m l b.co m/NASApp/m l b/mlb/ · Medals: There is no provision to reclaim the medals won in CWG official_info/about_m l b/ index.jsp or Asian Games as the athletes were not caught during those com- § Public Relations Department: 212-931-7878 petitions. National Center for Drug Free Sport www.drugfreesport.com/home.htm To make sports free from drug abuse:32,40 § National Collegiate Athletic Association 1) In 1999 Wold anti doping agency (WADA) was setup at Laussane ,Swit- www.ncaa.org zerland. It works with international olympic committee (IOC) to free the § Resource Exchange Center: www.drugfreesport.com/rec sports from drug. § National Football League www.nflpa.org/shared/ bannedSubstances.htm 2)UNESCO intervention convention on Drug abuse in sports 2007 invited § U.S. Anti-Doping Agency www.usantidoping.org doping against sports.It made mandatory participation of other sport federa- § Drug Reference Line: 1800-233-0393 tion on the norms of WADA. It calls for continuous monitoring of sports § www.usantidoping.org/prohibited_sub/list.asp persons and particularly those practices that are manipulating. World Anti-Doping Agency § www.wada-ama.org/en/t1 .asp Indian contribution towards drug abuse:40,46 Ø Article 21 and Article 47 give checks on drug abuse and intoxticating 36,44 Doping Control Programs drinks. The term “DOPING” has been derived from the dutch word “DOOP” (Vis- Ø NDPS(narcotic drugs and pshycotropic substance )Act 1985 cous opium juice) and Doping control is the common international term for Ø In 1988 it was converted into prevention of illicit traffic act1988 to drug testing in sports. Pharmacists are needed to participate in drug testing or check the illegal trade of drugs. doping control programs for the various sports and drug testing organiza- Ø In 2001 NDPS amendment act was passed which has exclusive tions .Roles for pharmacists in this capacity can include being a resource or provisions of quantative base punishment. a consultant on drugs and other substances regarding whether to prohibit, Ø India is signatory to UN convention on narcotic drugs 1961 and restrict or permit them. Such categories are based on the potential for unfair also signatory of UN convention on pshycotropic drug subtance or artificial performance-enhancing ergogenic effects, the potential for abuse, 1971. safety, efficacy, and therapeutic use of the agents. As certain substances Ø UN conviction against illicit traffic on Narcotic drugs and become popularized and serious adverse effects become apparent, those that pshycotropic substances 1988 were once permitted or restricted may then become banned. Also, new drugs Ø Transitional crime convention 2000. and compounds need to be reviewed and categorized as they are introduced to the market. Pharmacists can participate in developing such formularies for NCB:(Narcotic Control Bureau ) Hq;New Delhi.NCB is the regulating agency specific sports organizations and can also provide drug information services. of drugs in India. Pharmacists can get trained and certified to be drug testing collectors for In 2010 DAIRRC (drug abuse information rehabilitation research centre, various sports organizations, including the NCAA, Olympics, USADA, New Delhi) was setup, which initiated HOPE(health oriented prevention International Doping Tests & Management (IDTM), and professional education)it is an effort of checking the relationship of drug and HIV infec- sports organizations. tion.47

Pharmacists with expertise in drug testing and doping control programs and List of Athletes who are named recent Doping Scandal:47 can serve as resources for universities, colleges, high schools, and other · Ashwini Akkunji (Race) institutions that are interested in establishing their own in-house testing · Mandeep Kaur (Race) programs. In this capacity, pharmacists can develop and implement the Juana Murmu (Race) policies and procedures for specimen collection. They can also assist in · formulary management in training rooms. · Sini Jose (Race) · Priyanka Panwar (Race)

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 593-603 Dr. Ramachandra. K. et al. / Journal of Pharmacy Research 2012,5(1),593-603 CONCLUSION: · Tiana Mary Thomas (Race) Given the competitive nature of sports, athletes will always seek advantage · Sonia, (shot putter) over their opponents. Unfortunately, some of these athletes will resort to · Hari Krishna Muralidharan, (long jump) using ergogenic aids. This usage is usually done in secret, with users not wanting peers, coaches, or physicians to be aware of their activities. As Past allegations of doping of Indian Athletes: 47 such, athletes are frequently misinformed and do not have accurate informa- 36 · Rani Yadav during CWG 2010. However she finished sixth in the tion regarding the methods they are using. women’s 20km walk. It is the physician’s responsibility to help maintain the safety and health of · Lakshman Singh, who won a bronze in single sculls at the Na- the athletes with which he or she works. The physician should remain tional Games in Hyderabad in 2003, was slapped with a life ban vigilant for signs of doping. Suspicion should be aroused when there are by the Rowing Federation of India physical changes that involve rapid gains in size and strength, leading to 21 athletes were pronounced guilty by the IOA in April, 2003 for · sudden, erratic improvements in performance. Behavioral changes, such as testing positive at the National Games in Hyderabad in 2002 mood swings, aggressiveness, hostility, and irritability, may also be indica- · In August 2001 Weightlifter Kunjarani Devi has tested positive tors of possible ergogenic use. By maintaining knowledge of current drugs for a banned drug and suspended by the International Weightlifting and their effects, the physician will be able to recognize potential use of Federation from all international events for a period of six months. agents and intervene if necessary. Providing athletes with information about the efficacy, side effects, and policies concerning drug use may help the Sunita Rani case: athlete make an informed decision regarding the use of these substances.40 · Ace distance runner Sunita Rani’s honour was finally restored on If questions arise, various resources are available. The US Olympic Commit- Feb 4, 2004, when she was handed back the two medals she was tee has a drug-testing program that mirrors the IOC’s program. An official stripped off at the Busan Asian Games after ‘testing positive’ for list of banned substances can be requested from them. They also provide a the banned substance nandrolone. toll-free, confidential telephone hotline to answer questions relating to banned substances (1800-233-0393). The National Collegiate Athletic Association also provides a toll free number for their prohibited substances (1800-546- 0441)42

PROMINENENT NAMES OF DOPING IN OLYMPICS43,44,45,46,47

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Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 593-603