Opioid Pharmacology

Opioid Basics - Receptors & Roadways

• Opioids: Substances binding opioid receptors; mimic endogenous peptides (e.g., endorphins, enkephalins, dynorphins).
• Receptors (All are GPCRs - Gi/Go coupled):
  • μ (Mu - MOR): Primary target for analgesia (supraspinal & spinal). Also causes euphoria, respiratory depression, miosis, ↓GI motility, dependence.
  • κ (Kappa - KOR): Spinal analgesia, sedation, dysphoria, miosis.
  • δ (Delta - DOR): Analgesia (spinal & supraspinal), antidepressant effects, may be proconvulsant.
  • NOP (Nociceptin/Orphanin FQ - ORL-1): Complex role; may modulate pain, anxiety, or opioid effects.
• Mechanism of Action:
  • Presynaptic: ↓Ca²⁺ influx → ↓release of excitatory neurotransmitters (e.g., Substance P, glutamate).
  • Postsynaptic: ↑K⁺ efflux → hyperpolarization → ↓neuronal excitability.
• Pain Pathway Modulation:
  • Inhibit ascending pain transmission pathways (e.g., spinothalamic tract).
  • Activate descending inhibitory pathways (e.g., PAG → RVM → dorsal horn).

⭐ Activation of μ-opioid receptors in the brainstem (medulla) is primarily responsible for the life-threatening side effect of respiratory depression associated with opioids like morphine and fentanyl.

Opioid Journey - 'Kinetics Express'

• Absorption:
  • Oral: Variable bioavailability (F); Morphine F ~30% (high first-pass).
  • IV/IM/SC: Reliable. Transdermal (Fentanyl): Slow onset, prolonged effect. Transmucosal (Fentanyl, Buprenorphine): Rapid.
• Distribution:
  • Lipid solubility dictates speed & duration:
    • High (e.g., Fentanyl): Rapid CNS entry & redistribution; quick on/off.
    • Low (e.g., Morphine): Slower CNS entry, longer action.
• Metabolism:
  • Hepatic: Predominant. Key enzymes:
    • CYP2D6: Codeine → Morphine; Tramadol activation.
    • CYP3A4: Fentanyl, Methadone, Oxycodone.
  • Glucuronidation: Morphine → M6G (active analgesic), M3G (neuroexcitatory).
  • Plasma Esterases: Remifentanil (ultra-short acting).
• Excretion:
  • Renal: Primary route. Dose adjust for active metabolites (e.g., M6G, Normeperidine) in renal failure.

⭐ Codeine is a prodrug requiring CYP2D6 metabolism to morphine; its analgesic efficacy is highly variable due to genetic polymorphisms (poor, intermediate, extensive, or ultra-rapid metabolizers).

The Opioid Arsenal - Uses & Agents

Opioid Pitfalls - Dangers & Detox

• Acute Dangers:
  • ⚠️ Respiratory depression (lethal); CNS depression.
  • GI: Nausea, vomiting, severe constipation (no tolerance).
  • Pupils: Miosis (pethidine: mydriasis).
• Chronic Issues:
  • Tolerance (not miosis, constipation, convulsions).
  • Dependence (physical/psychological).
  • Opioid-Induced Hyperalgesia (OIH).
  • Serotonin Syndrome (tramadol, pethidine, methadone + MAOI/SSRI).
  • Seizures (pethidine metabolite, tramadol).
• Opioid Overdose: Triad: Coma, Resp. Depression, Miosis.

• Withdrawal (📌 FINISH Mnemonic):
  • Fever, Insomnia, Nausea, Increased lacrimation, Sweating, Hyperreflexia/Hypertension. Also: yawning, mydriasis, piloerection, GI upset.
• Detox:
  • Symptomatic: Clonidine.
  • Substitution: Methadone, buprenorphine.

⭐ Naloxone's short half-life (30-90 min) vs. opioids necessitates repeat doses or infusion for sustained reversal, especially with long-acting opioids.

High‑Yield Points - ⚡ Biggest Takeaways

• Opioids act primarily on μ (mu) receptors; others include κ (kappa) and δ (delta).
• Morphine is the prototype; Fentanyl is highly potent (80-100x morphine).
• Naloxone is the specific antagonist for opioid overdose, reversing respiratory depression.
• Key adverse effects: Respiratory depression (most critical), constipation, miosis (pinpoint pupils).
• Pethidine is unique: causes mydriasis, tachycardia; its metabolite norpethidine can cause seizures.
• Buprenorphine, a partial μ-agonist, exhibits a ceiling effect for respiratory depression.