Page 1: Pharmacology of Drugs of Abuse Preparation

Preparation Objectives

This material aims to prepare you for the readiness assessment test (RAT). The RAT will assess your ability to:

1. Compare and contrast the mechanisms underlying the development of drug tolerance, dependence, withdrawal symptoms, and addiction.

2. Relate the mechanisms of action of abused substances to their withdrawal symptoms and signs of intoxication.

3. Summarize the molecular mechanisms of common substance-use disorders, including alcohol, opioid, sedative, cannabis, and stimulant-use disorders.

4. Evaluate reasons why some substances have more chronic abuse potential than others.

5. Categorize pharmacological treatments used for drug addiction into:

   • Drugs used for intoxication

   • Alleviation of withdrawal symptoms

   • Mimicking abused drugs to a lesser extent

   • Reversing the addiction process

Associated Weekly Learning Outcomes

By the end of class, you will be able to:

• Evaluate the probable cause of substance abuse symptoms by determining if they are due to overdose, intoxication, or withdrawal based on drug mechanism of action and signs and symptoms, patient history, and drug paraphernalia.

• Compare and contrast treatment strategies for drug intoxication and overcoming addiction for commonly used substances of abuse.

Supplemental (Optional) Reading

• Golan DE, Armstrong EJ, and Armstrong AW. Principles of Pharmacology: The Pathophysiological Basis of Drug Therapy, 4th edition. Chapter 19: Pharmacology of Drugs of Abuse.

• Katzung BG. Basic & Clinical Pharmacology, 14th edition. Chapter 32

Page 2: Concepts of Addiction, Tolerance, and Dependence

Addiction

• Addiction is defined as a pattern of substance use leading to significant impairment or distress.

• It is often confused with tolerance and dependence but is characterized by drug-seeking behavior.

Tolerance

• Tolerance occurs when the effectiveness of a substance decreases with continuous use.

• Patients require larger doses to achieve the same effect, shifting the dose-response curve to the right.

• Key Points:

  • Toxicity curve remains unchanged.

  • Increased doses can lead to increased side effects.

  • Cross-tolerance may occur between drugs acting on the same receptor (e.g., fentanyl and morphine).

• Mechanisms of Tolerance:

  • Innate Tolerance: Environmental or genetic factors.

  • Acquired Tolerance: Results from repeated drug administration, involving:

    • Pharmacokinetics: Increased metabolism or excretion.

    • Pharmacodynamics: Changes in neurotransmitter release, receptor sensitivity, or receptor number.

• Long-term exposure alters gene expression affecting receptors and enzymes, leading to neuroadaptive changes and cravings post-discontinuation.

Dependence and Withdrawal

• Dependence involves withdrawal symptoms upon cessation of the drug, marked by drug cravings.

• Addiction is psychological; dependence is physical.

• Withdrawal symptoms vary by substance and mechanism, often opposing the drug's effect (e.g., sedative withdrawal leads to increased CNS activity).

Pathophysiological Mechanisms of Substance Use Disorders

• Chronic drug self-administration induces permanent changes in the nervous system.

• Emotional baselines are altered, leading to diminished emotional ranges in addicts.

• Drug-seeking behavior stems from:

  • Positive reinforcement (euphoria) or negative reinforcement (relief of anxiety).

• As disorders progress, motivation changes from obtaining euphoria to avoiding withdrawal symptoms.

Drug Nature in Substance Use

• Pharmacokinetic Factors: Drugs with rapid concentration increases activate reward pathways more effectively.

• Drugs that are quickly absorbed or have shorter durations of action tend to be more addictive due to swift onset of withdrawal symptoms.

Page 3: Risk Factors and Common Substance Abuse

Individual Variability

Several risk factors predispose individuals to substance use disorders, including:

• Resistance or sensitivity to specific drugs.

• Genetic differences in metabolism and neuroadaptive potential.

• Personality traits and coexisting psychiatric disorders.

• Acquired disabilities or painful illnesses.

Common Substances of Abuse

Opioids

• Euphoric effects arise from μ receptor activity, inhibiting GABAergic neurons, causing dopaminergic activation.

• Intravenous routes increase potential for abuse.

• Fast-rising opioids have higher abuse potential (e.g., heroin vs. morphine).

Treatment for Opioid Use Disorder

• Naloxone: Fast-acting opioid antagonist for overdose.

• Naltrexone: Longer-acting opioid antagonist, prevents pleasurable effects but not withdrawal symptoms.

• Buprenorphine: A partial agonist that reduces cravings and drug appeal.

• Methadone: Long-acting, reduces cravings but has high abuse potential; used under control.

Sedatives and Hypnotics

• Benzodiazepines and barbiturates may create euphoria and anxiolytic effects early in use.

• Chronic use results in GABA pathways down-regulating, leading to severe withdrawal symptoms.

• Flumazenil: Used for benzodiazepine overdose but is short-acting.

Alcohol

• Alcohol-use disorder is widespread; has two types:

  • Type I: Occurs later in life, less spontaneous and antisocial behavior.

  • Type II: Occurs earlier, often includes antisocial behavior and loss of control.

• Ethanol affects GABA-A receptors, NMDA receptors, and cannabinoid receptors, leading to withdrawal effects similar to other GABA potentiators.

Page 4: Mechanisms and Treatments

Alcohol (continued)

• Disulfiram: Inhibits aldehyde dehydrogenase; creates unpleasant symptoms that deter drinking but suffers from low compliance.

Nicotine

• Strongly affects dopaminergic reward pathways; withdrawal includes anxiety and strong cravings.

• Treatments feature replacement therapy and varenicline, a partial agonist for nicotine receptors.

Cocaine and Amphetamines

• Cocaine induces stronger euphoric effects but shorter duration than amphetamine.

• Both increase synaptic neurotransmitters by blocking transporters, enhancing alertness.

• Withdrawal leads to bradycardia, sleepiness, fatigue, and psychological symptoms that do not improve with additional drug intake.

MDMA (Ecstasy)

• Similar structure to methamphetamine; has both stimulant and hallucinogenic properties, posing risks to serotonergic neurons.

• Dantrolene can counteract MDMA-induced hyperthermia.

Cannabis

• THC acts as a partial agonist of CB1 receptors, facilitating dopaminergic activity.

• Effects include euphoria followed by cognitive impairment and relaxation, but high doses can induce anxiety and psychosis.

• Tolerance develops through down-regulation of receptors and mild withdrawal symptoms.

Page 5: Other Substances and General Treatment

Hallucinogens

• Lower potential for abuse with no significant withdrawal symptoms; psychological addiction may still occur.

Methylxanthines

• Commonly found in beverages and medications; block adenosine receptors, boosting dopamine and norepinephrine.

• Withdrawal symptoms include lethargy and headaches, but addiction is rare.

Inhalants

• Include volatile organic compounds that create psychoactive effects; high doses can result in serious health risks.

General Treatment of Substance Use Disorders

• Detoxification: The initial step, helping the body adjust to drug absence, often accompanied by tapering dosage.

• Long-acting drugs can mitigate withdrawal symptoms.

• Other treatments may address dysfunctional reward mechanisms, such as bupropion, which aids withdrawal from various disorders, including gambling.