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Drugs of Abuse and Addiction

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General Concepts & Neurobiology - Addiction's Core

  • Addiction: Compulsive drug use despite harm; chronic relapsing disorder.
  • Reward Pathway (Mesolimbic):
    • VTA → NAc; Dopamine (DA) is key for reward.
    • Involves Prefrontal Cortex (PFC), amygdala, hippocampus. Mesolimbic reward pathway diagram
  • Neuroadaptation:
    • Tolerance: ↓ drug effect, ↑ dose needed.
    • Dependence: Physiological state; withdrawal on stopping.
    • Withdrawal: Symptoms opposite to drug.
    • Sensitization: ↑ drug effect (e.g., stimulants).
  • Key Terms:
    • Reinforcement: Drug promotes self-use.
    • Craving: Intense urge.

⭐ All addictive drugs increase dopamine in the Nucleus Accumbens (NAc) via the mesolimbic pathway.

Opioids - Perilous Pleasure

  • Examples: Morphine, heroin, fentanyl, codeine.
  • Mechanism: µ, κ, δ receptor agonists in CNS. Presynaptic: ↓$Ca^{2+}$ influx. Postsynaptic: ↑$K^{+}$ efflux. Overall: ↓neurotransmitter release.
  • Intoxication: Triad:
    • Miosis (pinpoint pupils)
    • Respiratory depression (life-threatening)
    • Coma
    • 📌 CPR: Coma, Pinpoint pupils, Respiratory depression.
  • Withdrawal: Severe flu-like: N/V/D, myalgia, lacrimation, rhinorrhea, piloerection, mydriasis, yawning.
  • Management:
    • Overdose: Naloxone (opioid antagonist), 0.4-2mg. Titrate to respiratory effort.
    • Maintenance: Methadone (long-acting oral agonist), Buprenorphine (partial µ-agonist), Naltrexone (oral antagonist, prevents relapse).

⭐ Fentanyl is 50-100x more potent than morphine; high overdose risk.

Signs of Opioid Overdose

Depressants (Alcohol & Sedatives) - The Slowdown Spiral

  • Alcohol:
    • MOA: GABA-A receptor activation (indirectly), NMDA receptor inhibition. Follows zero-order kinetics of elimination.
    • Acute: Disinhibition, euphoria, ataxia, slurred speech, respiratory depression, coma.
    • Chronic: Liver disease (fatty liver, hepatitis, cirrhosis), pancreatitis, cardiomyopathy, Wernicke-Korsakoff syndrome (thiamine/B1 deficiency).
    • Withdrawal: Tremor, anxiety, insomnia, autonomic hyperactivity (tachycardia, HTN), seizures. Delirium Tremens (DTs) after 48-96 hrs (hallucinations, disorientation, agitation).
      • Management: Benzodiazepines (e.g., Chlordiazepoxide, Diazepam, Lorazepam), thiamine.
    • Dependence Rx: Disulfiram (aversive), Naltrexone (reduces craving), Acamprosate (modulates glutamate).
    • Methanol/Ethylene Glycol Poisoning: Antidotes - Fomepizole (preferred) or Ethanol.
  • Sedative-Hypnotics:
    • Benzodiazepines (BZDs): (e.g., Diazepam, Lorazepam, Alprazolam)
      • MOA: ↑ Frequency of GABA-A $Cl^{-}$ channel opening. 📌 Ben Frequently opens.
      • Uses: Anxiety, insomnia, seizures, muscle relaxation, alcohol withdrawal.
      • Antidote: Flumazenil. ⚠️ Can precipitate seizures in BZD-dependent patients or in TCA overdose.
    • Barbiturates: (e.g., Phenobarbital, Thiopental)
      • MOA: ↑ Duration of GABA-A $Cl^{-}$ channel opening; direct GABA-mimetic at high doses. 📌 Barb increases Duration.
      • Uses: Seizures (Phenobarbital), induction of anesthesia (Thiopental).
      • High abuse potential, severe respiratory depression, cardiovascular collapse. Potent CYP450 inducer. No specific antidote.

⭐ Flumazenil, a BZD antagonist, can precipitate seizures in patients with BZD dependence or those on TCAs, limiting its use.

Alcohol effects on brain pathways and neurotransmitters

Stimulants & Hallucinogens - Highs & Illusions

  • Stimulants: ↑CNS activity, euphoria, sympathetic overdrive.

    • Cocaine:
      • Mech: Blocks DA, NE, 5-HT reuptake.
      • Intox: Mydriasis, tachycardia, HTN, formication (📌 "cocaine bugs"), seizures.
      • Withdrawal: "Crash" (depression, fatigue).
    • Amphetamines (Meth, MDMA):
      • Mech: ↑Release & ↓reuptake DA, NE, 5-HT.
      • Intox: Similar to cocaine. MDMA: +hyperthermia, hyponatremia. Meth: neurotoxic, "meth mouth".
      • Withdrawal: Similar.
    • Nicotine:
      • Mech: nAChR agonist.
      • Withdrawal: Irritability, craving.
  • Hallucinogens: Altered perception, mood, thought.

    • Cannabis (THC):
      • Mech: CB1/CB2 agonist.
      • Intox: Conjunctival injection, ↑appetite, dry mouth, amotivational syndrome (chronic).
      • Withdrawal: Irritability, anxiety.
    • LSD:
      • Mech: 5-HT2A agonist.
      • Intox: Visual hallucinations, synesthesia, flashbacks. No significant physical withdrawal.
    • PCP & Ketamine:
      • Mech: NMDA antagonists. Dissociative.
      • Intox (PCP): Nystagmus (rotatory/vertical), aggression, psychosis, analgesia.

      ⭐ PCP intoxication: unpredictable violence, analgesia, nystagmus.

      • Intox (Ketamine): Shorter acting PCP-like effects.

Neurotransmitter effects of drugs of abuse

High‑Yield Points - ⚡ Biggest Takeaways

  • Acute opioid overdose triad: Pinpoint pupils, respiratory depression, coma. Antidote: Naloxone.
  • Benzodiazepine overdose: Antidote is Flumazenil.
  • Cocaine toxicity: Sympathomimetic crisis. Manage with benzodiazepines; beta-blockers contraindicated.
  • Alcohol withdrawal: Treat with benzodiazepines. Delirium tremens is a medical emergency.
  • Disulfiram: Inhibits aldehyde dehydrogenase, causing acetaldehyde syndrome with alcohol.
  • Smoking cessation: Key drugs include Varenicline and Bupropion.
  • Cannabis: Chronic use linked to amotivational syndrome; hyperemesis syndrome also seen.

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Practice Questions: Drugs of Abuse and Addiction

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A 55-year-old drug addict from California presents with euphoria, altered time perception, and conjunctival injection, along with impairment of judgment. The most likely cause of this is addiction to which substance?

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Flashcards: Drugs of Abuse and Addiction

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Neuro/Psych_____, barbiturates, and alcohol all bind different allosteric sites of the GABAA receptor

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Neuro/Psych_____, barbiturates, and alcohol all bind different allosteric sites of the GABAA receptor

Benzodiazepines

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