K4ii / 14A24: MoA of opiates

14A24: Exam Report

Describe the mechanism of action of the analgesic effect of opiates. (70% of marks) Explain the mechanism by which morphine causes respiratory depression and constipation. (30% of marks)

11% of candidates passed this question.

This question was poorly answered with a low pass rate; which was unexpected for this core topic.  In  general,  completed  answers  demonstrated  good  understanding  of  the  analgesic mechanisms  of  opiates,  but  only  superficial  understanding  of  respiratory  depression  and constipation.  Better  answers  explained  the  decreased  responsiveness  of  the  respiratory centre to CO2, and the effects of opiates on the enteric nervous system and peristalsis.

K4ii / 14A24: Describe the mechanism of action of opiates (70 marks) + Explain the mechanism by which morphine causes respiratory depression & constipation (30 marks)

  • Opium = dry powdered mixture of alkaloids from the poppy plant → the 1° alkaloid being Morphine (50%)
  • Opiate = drug derived from opium
  • Opioid = all exogenous substances which bind opioid receptors to produce an agonist effect
  • Morphine = the 1° alkaloid of opium & the prototype agonist at µ OPIOID RECEPTORS
  • Opioids act at OPIOID RECEPTORS

µ Receptor

2 subtypes

µ1 = SUPRASPINAL ANALGESIA

  • Analgesia
  • Miosis
  • Euphoria

µ2 = SPINAL ANALGESIA

  • Resp D
  • Inhibition
  • GI motility
  • Euphoria
  • Dependence
  • Urinary retention
  • Pruritus

δ Receptor

2 subtypes

Activation = analgesia + resp depression

Spinal analgesia

K Receptor

3 subtypes

Activation

  • Miosis
  • Dysphoria
  • Inhibition of ADH release (diuresis)

 Less analgesia

Dependence

  • Opiates produce analgesia by binding to µ OPIOID RECEPTORS
  • µ receptors
    • Located throughout CNS
    • Concentrated in periaqueductal grey matter near 4th ventricle & Substantia Gelatinosa of Dorsal Horns of SC
  • Gi GPCR
    • Closure of voltage sensitive Ca2+ channel on presynaptic membrane → ↓ Ca2+
    • Post synaptic stimulation of K efflux → hyperpolarisation
    • Inhibition of AC → ↓cAMP
    • OVERALL: ↓ cell membrane excitability + ↓transmission of nociceptic signals
  • Analgesia by inhibition of nociceptic NT release
  • But also: sedation + euphoria

Respiratory Depression

  • Dose dependent: incidence of 1%
  • ↓ response to hypercapnia
    • Due to ↓ACh release from medulla neurons

↓

Shifts PaCO2 response curve to RIGHT

  • ↓RR & ↓MV
    • Agonist at µ2 receptors of medulla ventilation centre of brainstem

Timing of Respiratory Depression

Early (<2hrs)

    • Due to systemic absorption of parenterally administered or intrathecally administered high lipid solubility e. fentanyl

Late (>2hrs)

    • Due to Bulk Flow of CSF containing intrathecal M caudally
    • M is less lipid soluble cf. other opioids
    • Stays in CSF for prolonged period
    • CSF bulk flow eventually reaches Medulla Resp Centre
    • F is more lipid soluble & more likely to be absorbed systemically before movement to Resp Centre can occur

Constipation

  • Bowel contains µ & δ opioid receptors
  • Activation = ↑smooth m tone
  • ↓forward peristalsis & spasm of anal sphincter
  • ↑transit time in bowel = ↑H2O absorption