Hydrophilicity Among Opioids

Key Properties of Morphine (Hydrophilic Prototype)

Why Hydrophilicity Matters Clinically

1. Slow BBB penetration - Morphine's poor lipid solubility slows its crossing of the blood-brain barrier, leading to a slower onset compared to fentanyl.
2. Neuraxial use - When given intrathecally or epidurally, morphine stays in the CSF much longer and spreads rostrally (upward toward the brain). This explains its risk of delayed respiratory depression hours after administration - a rare but serious complication.
3. Longer duration - Because it is not rapidly taken up by neural tissue or fatty tissue, morphine persists in the CSF and provides analgesia for up to 24 hours with a single intrathecal dose.
4. High intrathecal:IV potency ratio - The relative intrathecal-to-intravenous potency of morphine is 200-300:1, whereas for fentanyl it is only 10-20:1, reflecting how effectively morphine works at the spinal level.
5. Drug interactions - Because morphine is metabolized by hepatic glucuronidation rather than the CYP450 system, it has fewer pharmacokinetic drug-drug interactions than many other opioids.

Summary

• Miller's Anesthesia, 10e - Table 77.3 (Neuraxial Opioids) and Hydrophilic Opioids section
• Lippincott Illustrated Reviews: Pharmacology - Morphine hydrophilicity and metabolism

Intrathecal Fentanyl in Labour - When Can It Be Given?

Short Answer

Stage-by-Stage Breakdown

First Stage of Labour (Most Common Indication)

• Early first stage - when the patient has severe pain early in labour and desires fast-onset relief
• Active first stage - as part of a CSE technique, providing almost immediate analgesia while the epidural catheter is placed for subsequent top-ups

Approaching / Just Prior to Delivery (Second Stage / Operative Vaginal Delivery)

Key Clinical Points

Important Caveat: Fetal Bradycardia

• Morgan and Mikhail's Clinical Anesthesiology, 7e - Combined Spinal & Epidural Analgesia section
• Miller's Anesthesia, 10e - Spinal Additives and Neuraxial Opioids

What Happens When Adenylyl Cyclase is Inhibited

The Normal Pathway (for context)

Step-by-Step: What Inhibition of Adenylyl Cyclase Does

Receptor (e.g. α2, opioid, muscarinic M2) binds agonist
        ↓
Gi protein activated → αi subunit dissociates with GTP
        ↓
αi inhibits adenylyl cyclase
        ↓
↓ ATP → cAMP conversion  (less cAMP produced)
        ↓
↓ cAMP binds PKA regulatory subunits
        ↓
↓ Free catalytic subunits of PKA released
        ↓
↓ Phosphorylation of target proteins
        ↓
Tissue-specific effects (see below)

Tissue-Specific Consequences of Reduced cAMP

Which Receptors Work by Inhibiting Adenylyl Cyclase?

Clinical Examples

1. Opioids (morphine, fentanyl): All opioid receptors couple to Gi/Go and inhibit adenylyl cyclase → reduced cAMP → decreased Ca²⁺ channel conductance, increased K⁺ channel opening → neuronal hyperpolarization → analgesia, sedation, and reduced pain transmission at all levels of the neuraxis.
2. Clonidine / Dexmedetomidine (α2 agonists): Activate Gi via α2 receptors → inhibit adenylyl cyclase → lower cAMP → presynaptically reduce noradrenaline release → sedation, analgesia, reduced sympathetic tone.
3. Pertussis toxin (Bordetella pertussis): Permanently ADP-ribosylates and inactivates Gi, so adenylyl cyclase can no longer be inhibited. This is a key pharmacological tool (and virulence mechanism).
4. Pseudohypoparathyroidism: Defective Gs (αs subunit mutation) prevents PTH from activating adenylyl cyclase, resulting in hypocalcaemia and hyperphosphataemia despite elevated PTH levels.

Summary

• Katzung's Basic and Clinical Pharmacology, 16e - Adrenoceptors, Figure 9-2
• Neuroscience: Exploring the Brain, 5e - Second Messenger Cascades, Figure 6.26
• Medical Physiology (Boron & Boulpaep) - G Proteins Coupled to Adenylyl Cyclase
• Miller's Anesthesia, 10e - Opioid receptor Gi/Go coupling

Inward Rectifier Potassium Channels (Kir / IK1)

What is "Inward Rectification"?

Mechanism of Rectification

• At resting/hyperpolarized potentials: Mg²⁺/polyamines are electrostatically pulled away from the pore → channel open → K⁺ can flow inward (and small outward current is allowed)
• At depolarized potentials: Mg²⁺/polyamines are driven into the pore → channel blocked → outward K⁺ flow is prevented

Structure

• Kir channels are tetramers - four subunits, each with only 2 transmembrane domains (M1 and M2), unlike voltage-gated K⁺ channels which have 6
• They lack the classic S4 voltage-sensing domain
• A P-loop (H5) between M1 and M2 forms the ion selectivity filter
• Gene family: KCNJ genes (e.g., KCNJ2 encodes Kir2.1)

Major Subtypes and Their Roles

Role in the Cardiac Action Potential

• Phase 4 (resting): IK1 (Kir2.1) is active - provides the dominant K⁺ conductance that holds the cell near -85 mV
• Phase 0-2 (depolarization/plateau): IK1 is blocked by intracellular Mg²⁺/polyamines at depolarized voltages - this is critical for maintaining the long plateau (phase 2) of the cardiac action potential; if IK1 were not blocked, the plateau would collapse immediately
• Phase 3 (repolarization): As the membrane repolarizes, the Mg²⁺/polyamine block is progressively relieved → IK1 activates again → accelerates terminal repolarization back to resting potential
• Pacemaker cells (SA node): IK1 density is very low in pacemaker cells - this is why they spontaneously depolarize (phase 4 slope); without strong IK1 to anchor the resting potential, spontaneous depolarization driven by If (funny current) is possible

GIRK Channels - G Protein-Gated Inward Rectifiers

ACh → M2 muscarinic receptor → Gi activation
       ↓
Gβγ subunit released
       ↓
Gβγ binds and opens GIRK (IKACh) channel
       ↓
K⁺ flows out → hyperpolarization of SA node
       ↓
Slower phase 4 depolarization → reduced heart rate

KATP Channels - Metabolic Sensors

• High ATP (fed state): Channel closed → cell depolarizes → β-cell secretes insulin
• Low ATP (ischaemia, fasting): Channel opens → K⁺ efflux → hyperpolarization → cell protected from Ca²⁺ overload (cardioprotective in ischaemia)

• Sulfonylureas (glibenclamide, glipizide): Block SUR1 on β-cells → close KATP → stimulate insulin secretion (type 2 diabetes treatment)
• Diazoxide: Opens KATP → inhibits insulin secretion (used in insulinoma/persistent hyperinsulinism)
• Nicorandil: Opens KATP in smooth muscle → vasodilation (anti-anginal)

Disease Associations

Summary

1. Set and stabilize the resting membrane potential (Kir2/IK1)
2. Mediate neurotransmitter/hormone-gated hyperpolarization (Kir3/GIRK - vagal heart slowing)
3. Act as metabolic sensors linking ATP levels to membrane excitability (Kir6/KATP - insulin secretion, ischaemic protection)
4. Allow a long cardiac action potential plateau by being blocked at depolarized voltages

• Braunwald's Heart Disease, 2e - Table 62.1, Transsarcolemmal Ionic Currents
• Miller's Anesthesia, 10e - Action Potential phases, IK1 and inwardly rectifying K⁺ current
• Yamada's Textbook of Gastroenterology, 7e - KIR channels in smooth muscle cells