Cocaine and AnabolicAndrogenic Steroid Toxicity
Allison Anne Welder, Ph.D. Associate Professor of Pharmacology and Toxicology University of Oklahoma College of Pharmacy
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Drugs of Abuse
• Alcohol • Cocaine • Anabolic Steroids
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Physiological Profiles
• Exercise trained • Sedentary • Drug interactions
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History of Cocaine Use
• Archaeological evidence - 3000 BC • Introduced into Europe - 18th century
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Clinical History of Cocaine
• 1860 - Albert Nieman isolated the cocaine alkaloid • 1880 - Von Anrep discovered cocaine’s anesthetic properties • Sigmund Freud - used cocaine to treat addiction • 1903 - active ingredient in Coca Cola
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Harrison Act of 1914
• Classified cocaine as a narcotic • Potential for drug abuse was recognized • Banned from Coca Cola
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Toxicity of Cocaine Recognized
• Summer of 1986
» Len Bias » Don Rogers
• Life threatening consequences
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Cardiac Toxicity
• • • • Tachycardia Systemic hypertension Ventricular arrhythmias Acute myocardial infarction • Sudden death
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Adverse Cardiac Events
• Independent of:
» route of administration » amount of cocaine used » underlying heart disease
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Time of Onset of Cardiac Event
• Acute - less than one hour • Chronic - after years of abuse
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Mechanisms of Cardiotoxicity
• Local anesthetic effect • Nerve transmitter interactions • Active metabolites • Coronary artery injury
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Direct Local Anesthetic Effect
• Sino-atrial node • Arterioventricular node • Bundle of His • Perkinjie fibers
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Cocaine Neurotransmitter Effects
• Cocaine acts at the nerve endings • Excess norepinephrine • Binds to the cardiac receptors • Increases heart rate • Increase stress and workload on the heart • Heart attack
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Cocaine Metabolite Effects
• Blood esterases
» ecgonine methyl ester » benzoylecgonine » ecgonine
• Liver
» norcocaine » norcocaine nitroxide » cocaethylene
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Cocaine Affects Coronary Arteries
• Cocaine causes swelling of endothelial cells • Reduces the supply of oxygen and nutrients • Myocardial infarct
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Cell Culture
• In vitro vs in vivio • No drug administration to animals
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“Alternatives” to Animal Testing
• Spares the numbers of animals used in testing • No pain or discomfort to animals
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Cocaine and Alcohol Abuse
• Widespread in the United States • 1990s it has been documented that 12 million individuals use cocaine and alcohol together
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Cocaethylene
• Unique metabolite • Formed by the liver • Cocaine and alcohol
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Autopsy Results
• 1991 Dade County Florida • 237 cocaine related deaths • 124 detected cocaine and alcohol • 62% were positive screens for cocaethylene
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Toxicity: Cocaethylene > Cocaine
• Blood • Liver • Brain
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Toxicity - LD50
• Cocaethylene 62 mg/kg • Cocaine 93 mg/kg
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Peak Plasma Concentrations
• Cocaine - 47 to72 min • Cocaethylene - 111 min
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Toxic Cardiac Effects
• Acute • Chronic
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Anabolic Steroids
• 1991 Department of Health and Human Services Task Force
» Anabolic steroids are a major drug problem in the United States » Abused by over 1 million Americans » Male and female » Children, high school, college and professional athletes
• Schedule III Controlled substance • Black Market Sales - > $1 million/year
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Approved Medical Uses of Anabolic Steroids
• • • • • Anemias Hypogonadism Retarded growth Hypopituitarism Impotence
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Current Knowledge of Anabolic Steroid Abuse
• Anecdotal • Few, if any, federal funded studies to evaluate toxicity • Abusers use 10 to 100 times the therapeutic doses
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Department of Health and Human Services Recommendations for Anabolic Steroid Research
• • • • Animal and human investigations Psychological and physiological studies High dose administration and “stacking” Mature and immature organs
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Status of Anabolic Steroids in the State of Oklahoma
• July 1990 became controlled substances • Several major drug busts since 1990
» Pharmacist suspended
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American College of Sports Medicine
• Athletes are abusing anabolic steroids • “Win-At-All-Costs” mentality
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Steroid Trafficking Act 1990
• 40% of high school students polled are abusing anabolic steroids • Predominant as “crack” cocaine
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History of Anabolic Steroid Use
• • • • • 1935: Charles Kochakian 1940s: Hitler 1960s: USSR 1976: Olympic Games 1983: Pan American Games
» 19 athletes disqualified » dozens more withdrew
• 1988: Ben Johnson • 1991: Lyle Alzado
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Physiological Anabolic Steroid Adverse Effects
• Heart • Liver • Sexual development (androgenic) • Muscle growth (anabolic)
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Adverse Endocrine Effects
• Children
» virilization » gynecomastia
• Women
» virilization
• Men
» » » »
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feminization gynecomastia testicular atrophy decreased sperm count
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Adverse Liver Effects
• • • • • Jaundice Hepatic dysfunction Peliosis hepatis Hyperplasia Neoplasias
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Adverse Cardiovascular Effects
• Altered plasma lipids
» decreased HDL » increased LDL » increased LDL/HDL ratio
• Left ventricular hypertrophy • Myocardial infarction • Cardiomyopathy
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Psychological Anabolic Steroid Adverse Effects
• Addiction, tolerance, withdrawal • Aggression • Violence • “Roid Rages” • Altered libido
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Toxicity Studies: Anabolic Steroid Effects on Liver and Heart
• Identify toxic anabolic steroids • Emphasize high dose administration • “Stacking”
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Anabolic Steroids
• Do anabolic steroids improve athletic performance?
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Athletic Performance
• • • • • Positive nitrogen balance Diminishes fatigue Reverses catabolic processes Aerobic performance? Muscle strength?
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Who Should be Concerned?
• Parents • Teachers • Coaches
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“Stacking”
• Administration of 2 or more anabolic steroids • Injectable and oral • In excess of therapeutic concentrations • Administration 12 to 16 weeks prior to athletic event
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17-alpha-Alkylated Anabolic Steroids
• • • • • Stanozolol (Winstrol) Oxandralone (Anavar) Methyltestosterone (Metandren) Fluoxymesterone (Halotestin) Danazol (Danocrine)
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17-beta-Esterified Steroids
• Testosterone (Cypionate, Ethanate, Propionate) • Nandrolone (decanoate, phenpropionate)
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Anabolic Steroid Mechanism of Action
Target Cell
mRNA Ribosomes Protein Synthesis
Cell Response
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Preliminary Studies
• Stanozolol (Winstrol) • Fluoxymesterone (Halotestin) • Testosterone Cypionate (Depotestosterone)
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Cell Culture Studies
• Liver
» 17-alpha-Alkylated steroids
• Heart
» 17-beta-Esterified Steroids
• Target Organ Toxicity
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Summary
• Cocaine and anabolic steroids are major drugs of abuse in the United States today. • Abusers include children, adolescents, and adults. • Sedentary individuals as well as athletes abuse these drugs. • Cardiac and liver toxicity are serious consequences as are result of abusing these drugs.
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