M

Principles of Pharmacology - Week 8 Seminar Notes

Topic = Psychomotor stimulants and drugs that are commonly misused

Overview of Topics for Today

  • Abuse of psychomotor stimulants and drugs used in sport

  • Addiction

  • Specific psychomotor agents – effects and treatment

  • Drug use in sport

Drug Abuse

  • Definition: Use of drugs outside of their clinical indications.

  • Purpose: Often for euphoric or mind-altering effects.

  • Consequences:

    • Leads to physical, mental, and social problems.

What is Addiction?

  • Definition: Complex disorder that leads to compulsive drug-seeking behavior.

  • Features of Addiction:

    • Craving for drugs

    • Loss of control over drug use

    • Continued use despite negative consequences

    • Includes tolerance (need for more of the drug to achieve same effect) and withdrawal effects.

  • Types of Addiction:

    • Physical (bodily changes)

    • Psychological (mental craving and behaviors)

What is Dependence?

  • Definition: The physical state where the body adapts to the presence of the drug.

  • Characteristic: Withdrawal symptoms occur when the drug is not present.

  • Note: Dependence can occur without addiction.

Addiction vs Dependence

  • Comparison of Terms:

    • Addiction involves compulsive use, craving, and impaired control.

    • Physical dependence is more common than addiction.

    • References: Horowitz & Taylor (2023)

  • Definitions:

    • Dependence = physiological dependence on drug

    • Addiction = both behavioral and physiological dependence

    • Most prescription users are not addicted.

How Addiction Develops

  • Mechanism:

    • Dopamine release in the mesolimbic pathway reinforces drug-seeking behavior.

    • Drugs interfere with dopamine systems, causing larger dopamine surges.

    • The brain adapts by producing less dopamine or fewer dopamine receptors (analogy of turning down the volume).

  • Effects:

    • Natural rewards become less effective.

    • Increased need for the drug to achieve a normal state.

    • Leads to desensitization and increased tolerance.

  • Source: Zaratasha et al. (2022)

  • Note: Mesolimbic pathway is involved in cases of psychosis (as discussed in Week 6).

Psychomotor Drugs

Hallucinogenic Drugs

  • Mechanism of Action:

    • Primarily act at serotonin receptors in the Central Nervous System (CNS) to disrupt normal brain activity.

    • Suppress connectivity between brain areas, affecting sensory information filtration.

    • LSD also has an affinity for dopaminergic and adrenergic receptors, influencing both the sympathetic and parasympathetic nervous systems (SNS and PSNS).

  • Physiological Effects:

    • Alterations in sensory perception and cognitive processes.

    • Physical signs:

    • Dilated pupils

    • Increased heart rate and blood pressure (SNS effects)

    • Elevated body temperature, flushing, salivation (PSNS effects)

    • Lack of dependence potential but can lead to tolerance.

    • Therapeutic effects observed for treatment-resistant depression and generalized anxiety disorder.

  • Risks and Management:

    • High therapeutic index.

    • Risks include engaging in risk-taking behaviors, experiencing 'bad trips', and dependence on supportive treatments (calm environments, sometimes antipsychotics for severe cases).

    • Examples include LSD and psilocybin.

Treatment of Depression with Psychedelic Drugs

  • Reclassification:

    • MDMA and Psilocybin were reclassified from Schedule 9 (Poisons) to Schedule 8 (Controlled substances) on a restricted basis as of July 2023.

  • Current Developments:

    • January 2024 witnessed the first treatments of psychedelic-assisted therapies being administered in Australia under the TGA's Authorised Prescriber (AP) program.

  • Supervision:

    • All treatments are conducted by experienced clinicians trained through Mind Medicine Australia’s Certificate in Psychedelic-Assisted Therapies and other accredited programs.

  • Challenges:

    • Slow uptake and limited evidence for effectiveness.

    • Concerns include patient vulnerability, inconsistent state regulations, and inequitable access to treatments.

    • Further research is necessary to understand the mechanisms through which these psychedelic drugs could assist in treatment effectively.

Stimulants

  • Mechanism of Action:

    • Stimulants increase the release of and inhibit the reuptake of monoamine neurotransmitters.

    • They provide direct stimulation to the CNS and sympathetic nervous system.

  • Physiological Effects:

    • Increased heart rate, blood pressure, and dilated pupils.

    • Decreased appetite and weight loss.

    • Heightened alertness, energy, and focus.

    • Associated psychological effects: anxiety, agitation, and irritability (common with amphetamines/cocaine) or positive mood and creative thinking (e.g., MDMA).

  • Risks and Management:

    • Increased sympathetic activity may lead to hyperthermia, sweating, tremors, and cardiovascular effects.

    • Severe risks include paranoia, anxiety, addiction (both physical and psychological).

    • Examples include Amphetamine, Cocaine, MDMA; Dexamphetamine is used for ADHD and narcolepsy.

Ketamine

  • Classification: Dissociative anaesthetic.

  • Mechanism of Action:

    • Antagonist of glutamate receptors in the brain and spinal cord.

    • Inhibits amine uptake by binding to opioid receptors, thus exhibiting some sympathomimetic effects.

    • May also act at muscarinic receptors.

  • Physiological Effects:

    • Alters perception leading to a sense of detachment.

    • Produces analgesic and anaesthetic actions.

    • Utilized in treating resistant depression.

  • Risks and Management:

    • Intoxication risks include cardiovascular effects, respiratory depression, confusion, and agitation.

    • High potential for abuse with onset of psychological and physical dependence.

    • Bladder issues are reported alongside psychotherapeutic treatment adjuncts.

    • Slow-release tablets and FDA-approved nasal spray (esketamine) show promise.

Phencyclidine (PCP)

  • Characteristics:

    • The drug's mechanism remains not entirely understood; it bears similarities to ketamine.

  • Mechanism of Action:

    • Acts as an antagonist at glutamate (NMDA) receptors.

    • May also promote monoamine production.

  • Physiological Effects and Risks:

    • Users may experience euphoria, hallucinations, and disconnection from their environment.

    • Physical effects include numbness (reduced pain sensation), unpredictable behavior, and can result in severe effects such as violent behavior, high blood pressure, tachycardia, and potential rhabdomyolysis (kidney failure).

    • Management may include benzodiazepines and anti-hypertensives as treatment.

Opioids

  • Mechanism of Action:

    • Bind to opioid receptors in the CNS.

  • Effects:

    • Provide euphoria and pain relief; reduces gastrointestinal motility.

  • Risks:

    • Associated with overdose risks, needle use, high likelihood of physical dependence, and addiction.

    • Withdrawal symptoms can occur, leading to significant social consequences.

  • Management:

    • Treatment includes opioid antagonists (Naloxone) and agonists (Methadone), focusing on slow onset and lower intensity of euphoria, longer half-life, and safer options.

    • Prescription opioids now broadly recognized as major contributors to opioid-related harm.

Drugs in Sport

Who Uses Performance-Enhancing Drugs (PEDs)?

1. High-Performance Athletes

  • Context: Especially prevalent in elite or competitive sports where the pressure to win is substantial.

  • Motivations:

    • Win at all costs, maintain performance despite fatigue/injury, and extend careers.

    • Example: Lance Armstrong, multiple Tour de France winner, admitted EPO and other drug use, referencing doping as “part of the culture” in cycling during his time.

2. Specific Sports

  • Trends: Different sports have favored specific drugs:

    • Power-Based Sports (e.g., sprinting, weightlifting): Anabolic steroids, stimulants

    • Endurance Sports (e.g., cycling, long-distance running): EPO and blood doping

    • Precision Sports (e.g., shooting, archery): Beta-blockers

    • Aesthetic/Weight-Class Sports (e.g., boxing, horse-racing): Diuretics, steroids

3. Young Athletes

  • Dynamics: Young athletes in elite development programs may feel intense pressure to improve swiftly.

  • Influences: May be persuaded by coaches, peers, or doctors to experiment with performance-enhancing substances.

  • Ethical Concern: This scenario raises complex ethical questions.

4. Athletes Returning from Injury

  • Increased Pressure: A rise in temptation to utilize steroids or growth hormones during rehabilitation for upcoming major competitions.

  • Complexity in Medical Necessity: Distinctions between what constitutes medically necessary versus performance-enhancing use.

  • Regulatory Situations: Bans on therapeutic usage based on in-competition vs. out-of-competition guidelines and exemptions.

5. Systemic or Organised Doping

  • Historical Context: Instances such as the East German government dosing athletes with PEDs during the 1970s and 1980s.

  • Results: The notorious East German swim team's dominance at the 1976 Olympics where they won 11 out of 13 gold medals, funded by state resources aimed at concealing doping practices.

  • Post-Cold War Trials: Following Germany’s reunification, individuals responsible were prosecuted and held accountable.

Drugs Abused in Sport

1. Anabolic Steroids

  • Function: Promote muscle growth and enhance strength.

  • Common Use: Predominant in power sports such as bodybuilding, sprinting, and rugby.

  • Examples: Testosterone, Nandrolone, etc.

  • Risks: Hormonal imbalances leading to infertility and gynecomastia, aggressive behavior termed 'roid rage', and risks of cardiovascular diseases.

  • Detection: Conducted via urine testing and blood profiles.

2. Stimulants

  • Function: Heighten alertness, diminish fatigue, and improve reaction times.

  • Common Use: Especially in sprinting, team sports, and combat sports.

  • Examples: Amphetamines, ephedrine, pseudoephedrine, cocaine.

  • Risks: Can cause elevated heart rate, high blood pressure, anxiety, potential heart attacks, or sudden death in susceptible individuals.

3. Erythropoietin (EPO) and Blood Doping

  • Function: Heightens red blood cell count, thereby enhancing oxygen delivery, improving endurance.

  • Common Use: Predominantly in cycling, distance running, cross-country skiing.

  • Examples: EPO, blood transfusions.

  • Risks: Increased blood viscosity leading to blood clots, strokes, or heart failure.

4. Human Growth Hormone (hGH)

  • Function: Stimulates growth in muscle and bone, accelerates recovery.

  • Common Use: Utilization prominent in injury recoveries and body composition improvements.

  • Risks: Joint pain, fluid retention, diabetes, carpal tunnel syndrome, enlarged organs (acromegaly).

5. Peptides

  • Function: Mimic naturally occurring hormones/signaling molecules to promote recovery, fat loss, or growth for anabolic effects.

  • Common Use: Frequently utilized by bodybuilders and combat athletes.

  • Examples: Growth hormone-releasing peptides (GHRPs), Insulin-like growth factor (IGF-1).

  • Risks: Long-term effects largely unexplored, potential tumor growth, insulin resistance, risk of contamination or counterfeit products.

6. Diuretics

  • Function: Accelerate fluid loss; employed to ‘make weight’ or conceal other drug usage.

  • Common Use: Commonly seen in boxing, wrestling, MMA, and jockeys.

  • Examples: Furosemide, hydrochlorothiazide.

  • Risks: Can lead to severe dehydration and electrolyte imbalances, causing cramps and arrhythmias, and possible kidney damage.

7. Beta-Blockers

  • Function: Lower heart rate and reduce situational anxiety, improving precision and calmness.

  • Common Use: Frequently found in sports requiring precision like archery and shooting.

  • Examples: Propranolol, atenolol.

  • Risks: Can lead to fatigue, dizziness, and breathing difficulties in asthmatic individuals; reduces exercise tolerance.

The Fall of Lance Armstrong

  • Historically, Armstrong denied all doping allegations, frequently citing his clean drug test record despite later confirmations of PED usage.

  • Doping Techniques: Employed sophisticated methods such as IV erythropoietin administration or micro-doses and masking agents like saline infusions.

  • Institutional Support: Understood by cycling authorities that public exposure would damage cycling’s reputation and financial viability.

  • Cult of Personality: His identity as a cancer survivor made allegations of doping hard to believe.

  • Intimidation and Retaliation: Aggressive denial tactics employed against accusers; legal actions were pursued against them.

Detection Problems in Doping

  • Challenges in Urine Testing:

    • Natural occurrence of some banned substances complicates detection.

    • Individual variability in substance levels complicates regulation.

    • Illness can affect substance levels, making detection ambiguous.

  • Case Study:

    • British 800m runner Diane Modahl served a four-year ban for testosterone use, later exonerated as increased testosterone levels were found to be due to improper handling of urine samples.

    • Following her exoneration, she won a Commonwealth Games bronze medal in the same year.

General Advice for Athletes

  • Verify medication on Global Drug Reference Online (Global DRO) before consumption.

  • Consult healthcare providers about medications, disclosing athlete status for potential tests.

  • Pursue Therapeutic Use Exemptions for banned medications as necessary.

  • Exercise caution with supplements; no supplement is entirely safe in sports, understanding the risks is essential based on advice from Sports Integrity Australia (SIA).