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.