Dr Welder Research

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Cocaine and Anabolic-Androgenic Steroid Toxicity: 

Cocaine and Anabolic-Androgenic Steroid Toxicity Allison Anne Welder, Ph.D. Associate Professor of Pharmacology and Toxicology University of Oklahoma College of Pharmacy

Drugs of Abuse: 

Drugs of Abuse Alcohol Cocaine Anabolic Steroids

Physiological Profiles: 

Physiological Profiles Exercise trained Sedentary Drug interactions

History of Cocaine Use: 

History of Cocaine Use Archaeological evidence - 3000 BC Introduced into Europe - 18th century

Clinical History of Cocaine: 

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

Harrison Act of 1914: 

Harrison Act of 1914 Classified cocaine as a narcotic Potential for drug abuse was recognized Banned from Coca Cola

Toxicity of Cocaine Recognized: 

Toxicity of Cocaine Recognized Summer of 1986 Len Bias Don Rogers Life threatening consequences

Cardiac Toxicity: 

Cardiac Toxicity Tachycardia Systemic hypertension Ventricular arrhythmias Acute myocardial infarction Sudden death

Adverse Cardiac Events: 

Adverse Cardiac Events Independent of: route of administration amount of cocaine used underlying heart disease

Time of Onset of Cardiac Event: 

Time of Onset of Cardiac Event Acute - less than one hour Chronic - after years of abuse

Mechanisms of Cardiotoxicity: 

Mechanisms of Cardiotoxicity Local anesthetic effect Nerve transmitter interactions Active metabolites Coronary artery injury

Direct Local Anesthetic Effect: 

Direct Local Anesthetic Effect Sino-atrial node Arterioventricular node Bundle of His Perkinjie fibers

Cocaine Neurotransmitter Effects: 

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

Cocaine Metabolite Effects: 

Cocaine Metabolite Effects Blood esterases ecgonine methyl ester benzoylecgonine ecgonine Liver norcocaine norcocaine nitroxide cocaethylene

Cocaine Affects Coronary Arteries: 

Cocaine Affects Coronary Arteries Cocaine causes swelling of endothelial cells Reduces the supply of oxygen and nutrients Myocardial infarct

Cell Culture: 

Cell Culture In vitro vs in vivio No drug administration to animals

“Alternatives” to Animal Testing: 

“Alternatives” to Animal Testing Spares the numbers of animals used in testing No pain or discomfort to animals

Cocaine and Alcohol Abuse: 

Cocaine and Alcohol Abuse Widespread in the United States 1990s it has been documented that 12 million individuals use cocaine and alcohol together

Cocaethylene: 

Cocaethylene Unique metabolite Formed by the liver Cocaine and alcohol

Autopsy Results: 

Autopsy Results 1991 Dade County Florida 237 cocaine related deaths 124 detected cocaine and alcohol 62% were positive screens for cocaethylene

Toxicity: Cocaethylene > Cocaine: 

Toxicity: Cocaethylene > Cocaine Blood Liver Brain

Toxicity - LD50: 

Toxicity - LD50 Cocaethylene 62 mg/kg Cocaine 93 mg/kg

Peak Plasma Concentrations: 

Peak Plasma Concentrations Cocaine - 47 to72 min Cocaethylene - 111 min

Toxic Cardiac Effects: 

Toxic Cardiac Effects Acute Chronic

Anabolic Steroids: 

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

Approved Medical Uses of Anabolic Steroids: 

Approved Medical Uses of Anabolic Steroids Anemias Hypogonadism Retarded growth Hypopituitarism Impotence

Current Knowledge of Anabolic Steroid Abuse: 

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

Department of Health and Human Services Recommendations for Anabolic Steroid Research: 

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

Status of Anabolic Steroids in the State of Oklahoma: 

Status of Anabolic Steroids in the State of Oklahoma July 1990 became controlled substances Several major drug busts since 1990 Pharmacist suspended

American College of Sports Medicine: 

American College of Sports Medicine Athletes are abusing anabolic steroids “Win-At-All-Costs” mentality

Steroid Trafficking Act 1990: 

Steroid Trafficking Act 1990 40% of high school students polled are abusing anabolic steroids Predominant as “crack” cocaine

History of Anabolic Steroid Use: 

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

Physiological Anabolic Steroid Adverse Effects: 

Physiological Anabolic Steroid Adverse Effects Heart Liver Sexual development (androgenic) Muscle growth (anabolic)

Adverse Endocrine Effects: 

Adverse Endocrine Effects Children virilization gynecomastia Women virilization Men feminization gynecomastia testicular atrophy decreased sperm count

Adverse Liver Effects: 

Adverse Liver Effects Jaundice Hepatic dysfunction Peliosis hepatis Hyperplasia Neoplasias

Adverse Cardiovascular Effects: 

Adverse Cardiovascular Effects Altered plasma lipids decreased HDL increased LDL increased LDL/HDL ratio Left ventricular hypertrophy Myocardial infarction Cardiomyopathy

Psychological Anabolic Steroid Adverse Effects: 

Psychological Anabolic Steroid Adverse Effects Addiction, tolerance, withdrawal Aggression Violence “Roid Rages” Altered libido

Toxicity Studies: Anabolic Steroid Effects on Liver and Heart: 

Toxicity Studies: Anabolic Steroid Effects on Liver and Heart Identify toxic anabolic steroids Emphasize high dose administration “Stacking”

Anabolic Steroids: 

Anabolic Steroids Do anabolic steroids improve athletic performance?

Athletic Performance: 

Athletic Performance Positive nitrogen balance Diminishes fatigue Reverses catabolic processes Aerobic performance? Muscle strength?

Who Should be Concerned?: 

Who Should be Concerned? Parents Teachers Coaches

“Stacking”: 

“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

17-alpha-Alkylated Anabolic Steroids: 

17-alpha-Alkylated Anabolic Steroids Stanozolol (Winstrol) Oxandralone (Anavar) Methyltestosterone (Metandren) Fluoxymesterone (Halotestin) Danazol (Danocrine)

17-beta-Esterified Steroids : 

17-beta-Esterified Steroids Testosterone (Cypionate, Ethanate, Propionate) Nandrolone (decanoate, phenpropionate)

Anabolic Steroid Mechanism of Action: 

Anabolic Steroid Mechanism of Action

Preliminary Studies: 

Preliminary Studies Stanozolol (Winstrol) Fluoxymesterone (Halotestin) Testosterone Cypionate (Depo-testosterone)

Cell Culture Studies: 

Cell Culture Studies Liver 17-alpha-Alkylated steroids Heart 17-beta-Esterified Steroids Target Organ Toxicity

Summary: 

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.