Psychostimulants: Cocaine and Amphetamines

Psychostimulants: Cocaine, Amphetamines

• Lecture Outcomes: Familiarize with examples, understand mechanism of action and side effects of abuse.
• CNS Stimulants:
  • Cocaine: Crack (freebase or hydrochloride);
  • D-Amphetamine, Methamphetamine, methylphenidate;
  • Phenmetrazine (Preludin) used for obesity;
  • Hallucinogens: MDA, MDMA, DOM, methylenedioxymethamphetamine ("ecstasy");
  • Khat: Cathinone, methcathinone;
  • Methylxanthines: caffeine (coffee), theophylline, theobromide (chocolate).
• Cocaine Overview:
  • Alkaloid from Erythroxylon coca plant, indigenous to western South America.
  • Coca leaves have religious, mystical, social, stimulant, and medicinal uses.
  • Main stimulant uses: endurance, feeling of well-being (euphoria), appetite suppression.
  • Medical uses: local anesthetic, vasoconstrictor (nasal congestion).
• Cocaine Production:
  • Coca paste (60-80% cocaine) extracted from soaked and mashed leaves.
  • Cocaine powder made by mixing paste with hydrochloric acid (HCI).
  • Freebase/crack extracted from powder with baking soda (smokable).
• Amphetamine Overview:
  • Synthetic analog of ephedrine, active ingredient in mahuang (used in China for asthma).
  • Methamphetamine and Methylphenidate (Ritalin) are similar.
  • Medical uses: obesity, ADHD, narcolepsy.
• Chemical Structures: (Illustrations).
• Neurophysiology: Cocaine blocks the reuptake of norepinephrine, thus norepinephrine stays at the synaptic membrane.
• Cocaine Pharmacology (by Route of Administration):
  • Inhalation ("Crack"): onset: 8 seconds, peak: 2-5 minutes, duration: 10-20 minutes.
  • Intranasal: onset: 2-5 minutes, peak 5-10 minutes, duration: 30 minutes.
  • Intravenous: onset: seconds, peak: 10-20 minutes, duration: 60-90 minutes;
  • Oral: onset: 30-60 minutes, unknown peak and duration.
  • "Skin popping": onset and duration unknown
  • Subcutaneous: stays longer.

Effects on Mind, Brain, and Behavior

• Increase: alertness/vigilance, concentration, mental acuity, sensory awareness, euphoria/elevated mood, brain electrical activity, self-confidence, grandiosity, need for sleep (insomnia).
• Decrease: appetite, brain blood flow, glucose metabolism, judgment, complex multi-tasking.

- Anxiety, suspiciousness, paranoia.
- Convulsions, tremor, seizures. 
- Psychosis, delirium;
- Locomotion issues (staying in one place) at low/moderate doses. 
- Reinforcement/addiction.

Peripheral Effects (Sympathomimetic)

• Fight/Flight/Fright Syndrome (sympathetic nervous system arousal).

  • Increase in blood pressure, blood sugar, heart rate, irregular heart beat, vasoconstriction, body temperature, bronchodilation, impaired breathing.
  • Cause of death is heart affected AV node causing ventricular tachycardia.

• Mechanism: Na channel blocker (mainly cocaine) increases blood pressure, blood sugar, HR, vasoconstriction, hyperthermic.

Sympathomimetic Toxidrome

• Avoid Beta-blockers: Unopposed alpha-receptor stimulation will occur (worsening hypertension) if beta-blockers are used
• Dry skin: anticholinergic
• Sweaty: sympathomimetic;

Clinical Effects (Box 152-1)

• Hyperthermia, Hypertension, Tachycardia, Mydriasis, Diaphoresis, CNS excitation.

Cocaine Cardiac Features

• Cocaine dysrhythmias: Sodium and Potassium blockade.
• Supraventricular tachycardia (SVT).
• Wide or prolonged QRS is dangerous.
• Prevention: Sodium bicarbonate subacute.
• Atrial fibrillation/flutter, Wide complex tachycardia.

Body Packing/Stuffing

• Body Packer: "Packing a suitcase" (smuggling drugs).
• Body Stuffer: Stuffing drugs down in the mouth to elude police.

Cocaine Pharmacokinetics: Absorption

• Routes of administration: Insufflated (snorted); intravenous (mainlined); inhaled (freebased); Oral.

Pharmacokinetics: Distribution and Metabolism

• Cocaine and amphetamines penetrate the blood-brain barrier easily.
• Cocaine half-life: ~50-90 minutes.
• Amphetamine half-life: ~5-10 hours; Meth: ~12 hours.
• Metabolites: active and inactive compounds.
• Cocaine is unique: autometabolizes in the blood in addition to normal liver metabolism.
• Cocaine breakdown products: norcocaine, ecgonine methyl ester, benzoylecgonine.

Cocaethylene

• Alcohol inhibits cocaine metabolism - alcohol makes cocaine accumulate, lasting longer.
• Alcohol + cocaine chemically react to form cocaethylene.
• Only known example where the body forms a new psychoactive compound from two others.
  • Similar effects to cocaine, but with greater cardiac toxicity.
  • 3-5x the half-life of cocaine.
  • Associated with seizures, liver damage, and immune system compromise.

Cocaine Pharmacodynamics

• Indirect agonist for dopamine (high affinity), norepinephrine (high affinity), serotonin (modest affinity).
• Mechanism: blocks monoamine reuptake.

Amphetamine Pharmacodynamics

• Indirect agonist for dopamine (high affinity), norepinephrine (high affinity), serotonin (low affinity)
• Mechanisms:
  • Blocks monoamine reuptake.
  • Inhibits vesicular storage.
  • Inhibits MAO metabolism.
  • Reverses reuptake.

Tolerance, Withdrawal, Addiction

• Withdrawal: Physically mild-moderate (hunger, fatigue, anxiety, irritability, depression, panic attacks, dysphoric syndrome (1–5 days after crash, characterized by decreased activity, amotivation, intense boredom, anhedonia, intense “craving” for cocaine). Syndrome may last 1-10 weeks
• Intense cravings:
• Route of administration: importance to addiction risk

Khat (Catha edulis)

• Large amounts cause sympathomimetic effects, seizures, and cardiac arrhythmias.
• Addiction is usually physiological.

Causes of Stimulant-Induced Chest Pain (Box 152-5)

• Noncardiac: pneumothorax, pneumomediastinum, pneumopericardium, aortic dissection, pulmonary infarction, infection, foreign body aspiration, cardiac chest pain, endocarditis, pericarditis, ischemia/infarction, acute intoxication, coronary stent thrombosis.

Sympathomimetic Treatment

• Benzodiazepines: First-line for any toxic case.
• Seizures: Benzodiazepines, Propofol
• β-blockers: Contraindicated (unopposed α-receptor stimulation). α-blockers like phentolamine needed with β-blockers to block both.
• Cocaine-induced wide complex tachycardia: sodium bicarbonate + alprazolam (Xanax).
• Hypertension: unresponsive to benzodiazepines, phentolamine.
• Decontamination: whole bowel irrigation or opening the bowel, taking out the drug.
• Prevention of amphetamine toxicity: activated charcoal.

This quiz focuses on psychostimulants, particularly cocaine and amphetamines. You will familiarize yourself with their mechanisms of action, side effects of abuse, and usage in both medical and social contexts. Gain a deeper understanding of various CNS stimulants and their impact on health.