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Opioids

Lipid solubility, pKa and potency — and the apparent paradox at the centre of it: why alfentanil is faster than fentanyl despite being far less lipid soluble.

The alfentanil paradox

This single comparison is the most examined idea in opioid pharmacology, and it turns on pKa, not lipid solubility.

Two properties, pulling in different directions

Alfentanil is about 7× LESS lipid soluble than fentanyl — which alone would make it slower.
But alfentanil has a pKa of 6.5, well below physiological pH, so about 90% is un-ionised at pH 7.4.
Fentanyl has a pKa of 8.4, so only a small fraction is un-ionised.
Only un-ionised drug crosses membranes. Alfentanil therefore presents a far larger diffusible fraction to the blood–brain barrier, and reaches its effect site faster.
Net result: alfentanil has the fastest onset, despite the lower lipid solubility. Fentanyl is more potent and longer acting because of its lipid solubility and higher protein binding.

The rule to carry into the exam

Low pKa → more un-ionised → crosses the BBB easily → fast onset.
Low pKa + high lipid solubility = fastest of all.
Remifentanil has both a low pKa AND high lipid solubility — hence its very rapid onset, on top of its esterase metabolism giving rapid offset.

Rankings worth memorising

Lipid solubility — least to most

morphine < pethidine < alfentanil < fentanyl < sufentanil

Morphine is the least lipid soluble — which is why it has slow CNS penetration, a delayed peak effect, and why intrathecal morphine spreads widely and lasts so long.
Sufentanil is the most lipid soluble.

Potency

Sufentanil ≈ 9× fentanyl.
Buprenorphine ≈ 100× more potent than morphine — a partial μ agonist with very high receptor affinity, which is why naloxone reverses it poorly.
Approximate ladder relative to morphine: pethidine 0.1× · morphine 1× · alfentanil 10–20× · fentanyl 100× · remifentanil 100–200× · sufentanil ~1000×.

	pKa	Lipid solubility	Onset	Defining feature
Morphine	8.0	Lowest	Slow (peak 15–30 min)	M6G active metabolite, renally cleared — accumulates in renal failure
Pethidine	8.7	Low	Moderate	Norpethidine is proconvulsant; avoid with MAOIs
Alfentanil	6.5	7× less than fentanyl	Fastest of the fentanyls	~90% un-ionised at pH 7.4; small Vd (~25 L)
Fentanyl	8.4	High	Fast	High protein binding; context-sensitive half-time rises steeply with infusion
Sufentanil	8.0	Highest	Fast	Most potent — about 9× fentanyl
Remifentanil	7.1	High	Very fast	Non-specific plasma and tissue esterases; context-sensitive half-time constant at 3–4 min

Receptors and effects

Receptor	Effects
Mu (μ)	Analgesia (supraspinal and spinal), respiratory depression, euphoria, miosis, reduced gut motility, bradycardia, physical dependence
Kappa (κ)	Spinal analgesia, sedation, dysphagia and dysphoria, miosis, less respiratory depression
Delta (δ)	Analgesia, modulation of μ activity, some respiratory depression

Points that recur

All opioid receptors are G-protein coupled (Gi) — they reduce cAMP, open potassium channels and close calcium channels, hyperpolarising the neurone.
Respiratory depression is a reduction in the sensitivity of the medullary centres to CO₂ — the CO₂ response curve shifts right and flattens. Rate falls before tidal volume.
Miosis is the one effect to which tolerance does NOT develop — hence pinpoint pupils in overdose.
Naloxone has a duration of only 30–60 minutes, shorter than morphine — so re-narcotisation is a real risk and an infusion may be needed.
Codeine is a prodrug requiring CYP2D6 conversion to morphine: poor metabolisers get little effect, ultra-rapid metabolisers risk toxicity.
Tramadol is a weak μ agonist that also inhibits serotonin and noradrenaline reuptake — hence seizure risk and serotonin syndrome.

Built from handwritten page IMG_1283. Potency ratios and pKa values shown are the standard reference figures.