Chapter 13  ·  Module 2

Opioid Agonists: Classification, Pharmacokinetics, and Drug Profiles

Chemical families, metabolism, active metabolites, and high-yield drug distinctions

Chemical Classification

Family 1

Phenanthrenes

  • Natural: morphine, codeine
  • Semisynthetic: oxycodone, hydrocodone, hydromorphone, buprenorphine
  • Also: naloxone, naltrexone
  • Largest opioid chemical family
  • Most reactions are histamine release, not true allergy

Family 2

Phenylpiperidines

  • Meperidine — neuroexcitatory metabolite normeperidine
  • Fentanyl family — highly lipophilic, rapid onset
  • Fentanyl ~100x more potent than morphine
  • Metabolized by cytochrome P450 3A4

Family 3

Phenylheptylamines

  • Methadone — mu agonist + N-methyl-D-aspartate antagonist
  • Long, unpredictable half-life (24–36 hours)
  • QTc prolongation risk
  • Metabolized by cytochrome P450 3A4

Pharmacokinetic Concepts

Concept Mechanism Clinical Implication
First-pass effect Oral opioids metabolized in liver before reaching circulation Oral dose must be higher than intravenous dose for same effect
Lipophilicity High lipophilicity = rapid blood-brain barrier penetration Fentanyl onset 1–2 min; morphine onset 15–20 min
Active metabolites Morphine-6-glucuronide (more potent than morphine); normeperidine (neuroexcitatory) Accumulate in renal failure; morphine-6-glucuronide causes respiratory depression; normeperidine causes seizures
Cytochrome P450 2D6 polymorphism Codeine and tramadol require conversion to active metabolite Poor metabolizers: no analgesia; ultrarapid metabolizers: toxicity risk
Transdermal depot Fentanyl patch builds subcutaneous reservoir over 12–24 hours Effect persists 12–24 hours after patch removal; heat accelerates absorption

High-Yield Drug Profiles

Prototype

Morphine

  • Full mu agonist prototype
  • Active metabolite: morphine-6-glucuronide (more potent)
  • Accumulates in renal failure → prolonged respiratory depression
  • Histamine release with rapid intravenous injection

Prodrug

Codeine

  • Requires cytochrome P450 2D6 conversion to morphine for analgesia
  • Poor metabolizers: no analgesia
  • Ultrarapid metabolizers: morphine toxicity
  • Contraindicated in children under 12 and breastfeeding mothers
  • Also used as antitussive at subanalgesic doses

High Potency

Fentanyl

  • ~100x more potent than morphine
  • Rapid onset (1–2 min intravenous) due to high lipophilicity
  • Transdermal patch: 72-hour delivery; do not cut; avoid heat
  • Cytochrome P450 3A4 metabolism — drug interactions important
  • Illicit fentanyl driving overdose epidemic

Long-Acting

Methadone

  • Mu agonist + N-methyl-D-aspartate receptor antagonist
  • Half-life 24–36 hours (variable); analgesic duration only 4–8 hours
  • QTc prolongation → monitor electrocardiogram
  • Cytochrome P450 3A4 interactions (inducers/inhibitors alter levels)
  • Used for opioid use disorder and chronic pain

High-Yield Danger Pairs

Meperidine + monoamine oxidase inhibitors: serotonin syndrome or excitatory hyperthermic reaction — potentially fatal.

Tramadol + monoamine oxidase inhibitors or selective serotonin reuptake inhibitors: serotonin syndrome risk.

Morphine + renal failure: morphine-6-glucuronide accumulates → respiratory depression.

Meperidine + renal failure: normeperidine accumulates → seizures.

Methadone + cytochrome P450 3A4 inhibitors: elevated methadone levels → QTc prolongation and respiratory depression.