Alfentanil and Sufentanil Pharmacology

Quick Answer

Alfentanil and sufentanil are synthetic 4-anilidopiperidine opioid agonists derived from fentanyl, sharing its characteristic phenylpiperidine structure but with distinct pharmacokinetic profiles that determine their clinical applications. Alfentanil (Rapifen) is distinguished by its low pKa (6.5), resulting in 89% unionised fraction at physiological pH and rapid blood-brain equilibration (t1/2keo 0.9-1.4 minutes), making it ideal for short procedures and TCI applications despite having only one-quarter the potency of fentanyl. Its short context-sensitive half-time (CSHT 50-60 minutes after 4-hour infusion) results from a small volume of distribution (0.4-1.0 L/kg) rather than rapid clearance. Sufentanil (Sufenta) is the most potent clinically used opioid (5-10x fentanyl, 500-1000x morphine), with highest lipophilicity (octanol:water partition coefficient 1778) and exceptional mu-receptor affinity (Ki 0.15 nM). Its cardiac surgery applications exploit cardiovascular stability at high doses, while neuraxial use benefits from high lipophilicity producing segmental analgesia with minimal rostral spread. Both undergo hepatic CYP3A4 metabolism without clinically significant active metabolites, making them safer than morphine in renal impairment. [1-8]

Chemical Structure and Classification

4-Anilidopiperidine Family

Alfentanil and sufentanil belong to the 4-anilidopiperidine class of synthetic opioids, sharing a common structural backbone with fentanyl—the prototype of this drug class. The 4-anilidopiperidine structure consists of a piperidine ring (six-membered nitrogen-containing ring) with an anilide (phenyl amide) substituent at the 4-position. This core structure provides the essential three-dimensional configuration for mu-opioid receptor binding, mimicking the pharmacophoric elements of morphine (tyramine moiety and piperidine nitrogen). [9-12]

Fentanyl (N-(1-phenethyl-4-piperidinyl)-N-phenylpropanamide) serves as the reference compound:

• Molecular formula: C22H28N2O
• Molecular weight: 336.5 Da
• pKa: 8.4

Alfentanil (N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide) incorporates:

• Tetrazole ring at the N1-piperidine position (replaces phenethyl group)
• Methoxymethyl group at the 4-position (instead of hydrogen)
• Molecular formula: C21H32N6O3
• Molecular weight: 416.5 Da
• pKa: 6.5 (critically lower than fentanyl)

Sufentanil (N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide) features:

• Thiophene ring (2-thienyl) replacing the phenyl ring of fentanyl's phenethyl group
• Methoxymethyl group at the 4-position (shared with alfentanil)
• Molecular formula: C22H30N2O2S
• Molecular weight: 386.5 Da
• pKa: 8.0

The structural modifications profoundly affect physicochemical properties and consequently pharmacokinetics. The tetrazole ring of alfentanil is electron-withdrawing, lowering the pKa of the piperidine nitrogen and increasing the unionised fraction at physiological pH. The thiophene ring of sufentanil enhances lipophilicity and receptor binding affinity. [13-18]

Structure-Activity Relationships

The 4-anilidopiperidine structure-activity relationships (SAR) relevant to ANZCA examination include:

The carbonyl oxygen of the propionamide group forms a critical hydrogen bond with the mu-receptor, and the nitrogen atoms provide additional receptor interactions. The lipophilicity ladder (sufentanil > fentanyl > alfentanil > morphine) directly correlates with speed of CNS penetration but inversely correlates with duration of action after single bolus doses. [19-22]

Alfentanil Pharmacology

Physicochemical Properties

Alfentanil hydrochloride is the clinically used salt form, presented as a clear, colourless solution at pH 4.0-6.0. Key physicochemical parameters:

The low pKa of 6.5 is alfentanil's defining characteristic. At physiological pH 7.4, 89% of alfentanil molecules are in the unionised, lipid-soluble form compared to only 9% for fentanyl. This dramatically accelerates blood-brain barrier penetration despite alfentanil's lower lipophilicity than fentanyl. [23-26]

Pharmacokinetics

Absorption and Distribution:

Alfentanil is administered exclusively by intravenous injection. Following IV bolus, alfentanil demonstrates the most rapid onset of effect among the fentanyl congeners:

• t1/2keo (effect-site equilibration half-time): 0.9-1.4 minutes
• Peak effect occurs within 1.5-2 minutes of IV bolus
• Time to maximal respiratory depression: 1-2 minutes

Distribution parameters:

• Central compartment volume (Vc): 0.1-0.2 L/kg
• Volume of distribution at steady state (Vdss): 0.4-1.0 L/kg (smaller than fentanyl 4.0 L/kg)
• Protein binding: 92% to alpha-1-acid glycoprotein (AAG)

The small Vdss reflects alfentanil's lower lipophilicity compared to fentanyl, limiting distribution to peripheral compartments. In critically ill patients, AAG concentrations increase (acute phase response), potentially reducing free alfentanil fraction and requiring dose adjustment. Conversely, in hepatic failure, reduced AAG levels increase free fraction. [27-32]

Metabolism:

Alfentanil undergoes extensive hepatic metabolism via cytochrome P450 3A4 (CYP3A4):

1. N-dealkylation (primary pathway): Produces noralfentanil (inactive)
2. O-demethylation: Produces N-phenyl-N-(4-piperidinyl)propionamide (inactive)
3. Amide hydrolysis: Minor pathway

Less than 1% is excreted unchanged in urine. The metabolites are pharmacologically inactive, meaning alfentanil is safe in renal impairment (unlike morphine).

CYP3A4 Drug Interactions:

The intermediate hepatic extraction ratio means alfentanil clearance depends on both hepatic blood flow AND enzyme activity—a combination of "restrictive" and "flow-limited" clearance. This makes alfentanil pharmacokinetics more variable between patients compared to fentanyl (high extraction, flow-limited) or morphine (low extraction, capacity-limited). [33-40]

Context-Sensitive Half-Time

The context-sensitive half-time (CSHT) describes the time required for effect-site concentration to decrease by 50% after stopping an infusion of specified duration. Alfentanil's CSHT is clinically favourable:

The key observation: alfentanil's CSHT increases only modestly with infusion duration, while fentanyl's CSHT increases dramatically. This is because alfentanil's small Vdss limits peripheral compartment accumulation, so there is less drug to redistribute back into plasma after stopping the infusion. After infusions exceeding 2-3 hours, alfentanil provides more predictable offset than fentanyl. [41-46]

Clinical Pharmacology of Alfentanil

Indications:

1. Short procedures (<30 minutes): Alfentanil's rapid onset and short CSHT make it ideal for brief, stimulating procedures (e.g., laryngoscopy, bronchoscopy, cardioversion)

2. Total intravenous anaesthesia (TIVA): Combined with propofol for procedures requiring rapid emergence

3. Supplementation of regional anaesthesia: Small boluses during neuraxial block placement

4. Blunting intubation response: 10-20 mcg/kg attenuates haemodynamic response to laryngoscopy

5. Sedation procedures: GI endoscopy, interventional radiology

Dosing:

Potency comparison:

• Alfentanil: Fentanyl = 1:4 (alfentanil is one-quarter as potent)
• Alfentanil 40 mcg = Fentanyl 10 mcg = Morphine 1 mg

[47-52]

Sufentanil Pharmacology

Physicochemical Properties

Sufentanil citrate is the clinical formulation, presenting as a clear solution. It is the most potent opioid in routine clinical use:

Sufentanil's exceptional lipophilicity (partition coefficient 1778, double fentanyl's 816) results from the thiophene ring, which is more lipophilic than fentanyl's phenyl ring. This lipophilicity drives rapid CNS penetration and high receptor affinity. [53-56]

Pharmacokinetics

Distribution:

Sufentanil follows a three-compartment pharmacokinetic model:

• t1/2keo: 5.7-6.2 minutes (longer than alfentanil due to higher lipophilicity)
• Vc: 0.15-0.20 L/kg
• Vdss: 1.7-2.9 L/kg (intermediate between alfentanil and fentanyl)
• Protein binding: 93% to AAG

The Vdss of sufentanil is smaller than fentanyl (4.0 L/kg) despite higher lipophilicity. This apparent paradox reflects sufentanil's extremely high protein binding and the fact that lipophilicity above a certain threshold does not further increase tissue distribution—receptor binding sites become saturated. [57-60]

Metabolism:

Sufentanil undergoes hepatic biotransformation via CYP3A4:

1. O-demethylation (primary): Produces desmethyl sufentanil (10% potency of parent)
2. N-dealkylation: Produces norsufentanil (inactive)
3. Oxidative N-dealkylation: Minor pathway

Sufentanil's high hepatic extraction ratio means clearance is primarily flow-dependent, similar to fentanyl. Hepatic enzyme inhibition has less effect on sufentanil clearance than on alfentanil, but reduced hepatic blood flow (cardiac failure, shock) significantly prolongs effect. [61-66]

Context-Sensitive Half-Time

Sufentanil has the most favourable CSHT profile among the traditional fentanyl congeners:

Sufentanil's short CSHT despite high lipophilicity results from:

1. High hepatic clearance (10-15 mL/kg/min)
2. Rapid redistribution from effect site to peripheral compartments
3. Efficient metabolism preventing accumulation

This makes sufentanil ideal for prolonged procedures, including cardiac surgery, where high-dose opioid techniques are used with expectation of early extubation. [67-70]

Clinical Pharmacology of Sufentanil

Indications:

1. Cardiac anaesthesia: High-dose sufentanil (10-30 mcg/kg) provides haemodynamic stability
2. Neurosurgery: Stable cerebral perfusion pressure
3. Major surgery with planned extubation: Predictable emergence after prolonged infusion
4. Epidural analgesia: Labour, postoperative pain (5-10 mcg bolus, 2-5 mcg/hour)
5. Intrathecal analgesia: Caesarean section (2.5-10 mcg), postoperative pain (2-5 mcg)

Dosing:

Potency comparison:

• Sufentanil: Fentanyl = 5-10:1 (sufentanil is 5-10 times more potent)
• Sufentanil 1 mcg = Fentanyl 5-10 mcg = Morphine 0.5-1 mg

[71-78]

Mechanism of Action

Mu-Opioid Receptor Binding

Both alfentanil and sufentanil are full agonists at the mu (mu)-opioid receptor (MOP receptor, encoded by OPRM1 gene). The mu-receptor belongs to the G protein-coupled receptor (GPCR) superfamily, specifically the rhodopsin-like (Class A) family.

Receptor binding affinities (Ki values, lower = higher affinity):

Sufentanil has the highest mu-receptor affinity of all clinically used opioids (Ki 0.15 nM), approximately 7-fold higher than fentanyl. This exceptional affinity underlies its high potency and cardiovascular stability at anaesthetic doses. The high mu-selectivity means sufentanil produces predictable mu-mediated effects with minimal kappa (dysphoria) or delta activation. [79-84]

G-Protein Signalling Cascade

Upon alfentanil or sufentanil binding, the mu-receptor activates inhibitory G proteins (Gi/Go), initiating:

1. Adenylyl cyclase inhibition: Reduced intracellular cAMP production
2. GIRK channel activation: G protein-coupled inwardly rectifying potassium channels open, causing K+ efflux and membrane hyperpolarisation
3. Voltage-gated calcium channel inhibition: Reduced Ca2+ influx at nerve terminals, decreasing neurotransmitter release
4. Protein kinase modulation: Altered phosphorylation of intracellular targets

The net effects at relevant anatomical sites:

[85-90]

Pharmacokinetic Comparison

Summary Table

Onset Time Comparison

The clinical onset (time to peak effect) depends on t1/2keo:

Key point for exams: Alfentanil has the fastest onset of the fentanyl congeners despite NOT being the most lipophilic—its low pKa (high unionised fraction) is the determining factor. [91-96]

Cardiovascular Effects

Haemodynamic Profile

Both alfentanil and sufentanil maintain haemodynamic stability, which is the primary advantage of synthetic opioids over morphine:

Bradycardia:

Both drugs cause vagally-mediated bradycardia, which is:

• Dose-dependent
• More pronounced with sufentanil (higher mu-receptor affinity)
• Enhanced by concurrent beta-blockers or calcium channel blockers
• Attenuated by pre-treatment with glycopyrrolate (muscarinic antagonist)
• Rapidly responsive to atropine

Sufentanil may cause more pronounced bradycardia than fentanyl, particularly at high doses used for cardiac anaesthesia. This is thought to relate to its higher mu-receptor affinity affecting central vagal nuclei. [97-100]

Cardiac Surgery Applications

Sufentanil is widely used for cardiac anaesthesia due to:

1. Haemodynamic stability: Blood pressure and cardiac output maintained at doses sufficient for surgical anaesthesia
2. Coronary vasodilation: Some evidence of favourable coronary blood flow effects
3. Myocardial protection: Opioid preconditioning may reduce ischaemia-reperfusion injury
4. Predictable emergence: CSHT allows early extubation despite prolonged surgery
5. Blunted stress response: High-dose technique attenuates catecholamine release

The "high-dose opioid technique" typically uses sufentanil 10-30 mcg/kg total, combined with a benzodiazepine and muscle relaxant. Modern "fast-track" cardiac anaesthesia uses lower doses (5-10 mcg/kg) combined with propofol and volatile agents, permitting extubation within 4-6 hours. [101-104]

Respiratory Effects

Respiratory Depression

Both alfentanil and sufentanil cause dose-dependent respiratory depression through:

1. Pre-Botzinger complex depression: Reduced inspiratory neuron firing rate
2. Chemoreceptor sensitivity reduction: Right-shift and reduced slope of CO2 response curve
3. Hypoxic drive blunting: Reduced peripheral chemoreceptor responsiveness

Comparative respiratory effects:

The rapid onset of alfentanil respiratory depression (1-2 minutes) requires immediate airway management capability. Sufentanil produces more prolonged respiratory depression per bolus dose.

Chest wall rigidity ("wooden chest"):

Both drugs can cause truncal and chest wall rigidity through:

• Mu-receptor activation in striatal and spinal motor neurons
• More common with rapid bolus injection
• More common at high doses
• Prevents adequate ventilation

Prevention: Slow injection (over 30-60 seconds), neuromuscular blockade Treatment: Neuromuscular blocking agents (succinylcholine or rocuronium), naloxone [105-110]

Clinical Uses

Alfentanil Clinical Applications

1. Short procedures requiring rapid emergence:

• Laryngoscopy and bronchoscopy
• Cardioversion
• Electroconvulsive therapy (ECT)
• Day surgery with rapid discharge

2. TIVA with propofol:

• Effect-site targeting 50-150 ng/mL
• Synergistic interaction reduces both drug requirements
• Predictable emergence

3. Bolus for attenuating intubation response:

• 10-20 mcg/kg given 60-90 seconds before laryngoscopy
• Rapid onset allows precise timing

4. Supplementation of regional anaesthesia:

• Small boluses during neuraxial block placement
• Sedation during procedure

Sufentanil Clinical Applications

1. Cardiac anaesthesia:

• High-dose technique (10-30 mcg/kg) or moderate-dose with volatile
• Haemodynamic stability during sternotomy and bypass

2. Major surgery with planned early extubation:

• Neurosurgery, major abdominal, thoracic surgery
• CSHT allows predictable emergence

3. Epidural analgesia:

• Labour: 10-25 mcg bolus + infusion 0.5-1 mcg/mL with bupivacaine
• Post-operative: Combined with local anaesthetic
• High lipophilicity produces segmental analgesia

4. Intrathecal analgesia:

• Caesarean section: 2.5-10 mcg with bupivacaine
• Rapid onset, segmental analgesia, minimal rostral spread
• Lower pruritus incidence than fentanyl (controversial)

5. Sublingual sufentanil:

• Newer formulation (Dsuvia) for acute moderate-to-severe pain
• 30 mcg sublingual tablet
• Onset 15-30 minutes, duration 2-3 hours [111-118]

Target-Controlled Infusion (TCI)

Alfentanil TCI

Alfentanil was one of the first opioids for which pharmacokinetic models enabled TCI. The Maitre model (1987) and Scott model are commonly used:

Maitre Model Parameters:

• Three-compartment model
• Covariates: Age, weight
• Validated for effect-site targeting

Typical TCI targets (effect-site concentration):

Advantages of alfentanil TCI:

• Rapid onset allows quick achievement of target
• Rapid offset when target reduced
• Predictable CSHT

Sufentanil TCI

Sufentanil TCI uses the Gepts model or Bovill model:

Typical TCI targets:

Clinical pearls:

• Sufentanil targets are ~100-fold lower than alfentanil (reflecting potency difference)
• Longer equilibration time (t1/2keo ~6 min) means target changes take longer to manifest
• Ideal for prolonged cases where CSHT advantage over alfentanil becomes apparent [119-124]

Drug Interactions

Pharmacokinetic Interactions (CYP3A4)

Both alfentanil and sufentanil are metabolised by CYP3A4, making them susceptible to drug interactions:

Note: Sufentanil has a HIGH hepatic extraction ratio, making it less susceptible to CYP3A4 inhibitor interactions than alfentanil (intermediate extraction ratio). However, both are affected by enzyme inducers. [125-128]

Pharmacodynamic Interactions

Special Populations

Hepatic Impairment

Both drugs depend on hepatic metabolism:

Clinical approach:

• Alfentanil: More affected by hepatic dysfunction; reduce dose 50-75% in severe impairment
• Sufentanil: Less affected (high extraction ratio maintains clearance via hepatic blood flow); reduce dose 30-50%
• Both: Titrate carefully, expect prolonged effect

Renal Impairment

Both drugs are safe in renal impairment:

• No active metabolites that accumulate
• <2% unchanged drug excreted renally
• No dose adjustment required for renal failure or dialysis
• Preferred over morphine in this population

Elderly Patients

Recommendation: Reduce initial dose by 30-50%, titrate to effect, expect prolonged duration.

Obese Patients

Practical approach: Dose on LBM for loading doses; titrate maintenance to effect. Avoid TBW-based dosing which leads to overdose.

Pregnancy

• Both cross placenta (lipophilicity favours rapid transfer)
• Neonatal respiratory depression if administered close to delivery
• Epidural sufentanil widely used for labour analgesia (safer than systemic)
• Intrathecal sufentanil used for caesarean section (2.5-10 mcg) [129-134]

Indigenous Health Considerations

Aboriginal and Torres Strait Islander Populations

Limited pharmacogenomic data exists specifically for Aboriginal and Torres Strait Islander peoples regarding CYP3A4 variants affecting alfentanil and sufentanil metabolism. However, several clinical considerations are relevant for perioperative care in Indigenous Australians.

Higher rates of chronic disease, including diabetes, cardiovascular disease, and chronic kidney disease, affect perioperative planning. While alfentanil and sufentanil are safe in renal impairment (unlike morphine), coexisting cardiac disease requires careful haemodynamic monitoring. The cardiovascular stability of sufentanil makes it a reasonable choice for Indigenous patients with significant cardiac comorbidity.

Remote and rural Indigenous communities often require patient transfer for major surgery, separating patients from family and community support. Day surgery with alfentanil-based TIVA may enable earlier discharge and return to community where appropriate. Cultural considerations include family (mob) involvement in consent discussions and the presence of Aboriginal Health Workers or Liaison Officers during perioperative care.

Pain expression varies across cultures, and assessment should use culturally validated tools where available. Post-operative analgesic plans should account for limited access to strong opioids in remote communities, favouring discharge with simple analgesia regimens.

Maori Health Considerations (Aotearoa New Zealand)

Whanau (family) involvement in healthcare decisions reflects the collective nature of Maori culture and should be supported throughout perioperative care. Tikanga (cultural protocols) should be respected, including karakia (prayer) if requested before induction. Health equity principles require that advanced anaesthetic techniques, including TCI with alfentanil or sufentanil-based cardiac anaesthesia, are equitably available to Maori patients regardless of geographic location. [135-138]

ANZCA Primary Exam Focus

Common MCQ Patterns

1. pKa and ionisation: "Which opioid has the fastest onset?" Answer: Alfentanil (highest unionised fraction 89% due to low pKa 6.5)

2. Lipophilicity order: Sufentanil > Fentanyl > Alfentanil > Morphine (memorise partition coefficients: 1778 > 816 > 128 > 1.4)

3. CSHT comparison: After 4-hour infusion, alfentanil CSHT ~55 min, sufentanil ~35 min, fentanyl ~260 min, remifentanil ~4 min

4. Potency: Sufentanil > Fentanyl > Alfentanil (10:1:0.25)

5. Metabolism: All fentanyl congeners undergo CYP3A4 metabolism (except remifentanil—ester hydrolysis)

6. Drug interactions: Erythromycin/ketoconazole increase alfentanil levels more than sufentanil (intermediate vs high extraction ratio)

7. Cardiac surgery: Sufentanil preferred for haemodynamic stability

8. Neuraxial use: Sufentanil's high lipophilicity produces segmental analgesia; morphine's low lipophilicity causes rostral spread

Primary Viva Question Themes

• Compare and contrast alfentanil and fentanyl pharmacokinetics
• Explain why alfentanil has faster onset than fentanyl despite lower lipophilicity
• Discuss context-sensitive half-time and its clinical implications
• How would you select an opioid for cardiac surgery?
• Describe the TCI principles for alfentanil

Calculation Questions

Example 1: Calculate the effect-site equilibration time for alfentanil (t1/2keo 1.0 min) and fentanyl (t1/2keo 5 min). How long to reach 90% of target Ce after step increase in TCI target?

Answer: Time to 90% equilibration = 3.3 × t1/2keo

• Alfentanil: 3.3 × 1.0 = 3.3 minutes
• Fentanyl: 3.3 × 5.0 = 16.5 minutes

Example 2: A patient receives an alfentanil infusion at 1 mcg/kg/min for 4 hours. Estimate the CSHT.

Answer: From CSHT curves, alfentanil CSHT after 4 hours ≈ 55 minutes. This is much shorter than fentanyl (~260 minutes) and slightly longer than sufentanil (~35 minutes).

Example 3: Convert sufentanil 20 mcg IV to equivalent fentanyl and alfentanil doses.

Answer:

• Sufentanil: Fentanyl = 1:5-10 → Fentanyl = 100-200 mcg
• Alfentanil: Fentanyl = 4:1 → Alfentanil = 400-800 mcg [139-142]

Assessment Content

SAQ Practice Question (20 marks)

Question: A 68-year-old, 75 kg man with ischaemic heart disease (previous CABG, EF 40%) is scheduled for elective total hip replacement under general anaesthesia. You plan to use an opioid infusion technique.

(a) Compare the pharmacokinetic properties of alfentanil, sufentanil, and fentanyl that are relevant to opioid selection for this case. Present your answer in table format. (8 marks)

(b) Which opioid would you select, and why? (6 marks)

(c) The patient is also taking diltiazem for rate control. How does this affect your opioid choice? (6 marks)

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Model Answer:

(a) Pharmacokinetic comparison (8 marks)

(b) Opioid selection (6 marks)

I would select sufentanil for this patient for the following reasons:

Cardiovascular considerations [2 marks]:

• Sufentanil provides excellent haemodynamic stability at analgesic doses
• Minimal histamine release preserves preload and afterload
• High mu-receptor affinity allows adequate analgesia at doses that maintain cardiac output
• Particularly important in patient with EF 40% (moderate LV dysfunction)

Pharmacokinetic advantages [2 marks]:

• CSHT of ~30 minutes after 2-3 hour surgery allows predictable emergence
• Shorter CSHT than alfentanil (~55 min) and much shorter than fentanyl (~150 min) for this duration
• Enables extubation in operating theatre or early PACU

Practical considerations [2 marks]:

• High potency reduces injection volumes
• TCI available with established pharmacokinetic models (Gepts)
• Extensive cardiac surgery experience supports safety profile

(c) Diltiazem interaction (6 marks)

Mechanism of interaction [2 marks]:

• Diltiazem is a moderate CYP3A4 inhibitor
• Both alfentanil and sufentanil are CYP3A4 substrates
• Diltiazem can increase opioid plasma concentrations

Differential effect on opioids [2 marks]:

• Alfentanil (intermediate hepatic extraction ratio 0.3-0.5): More susceptible to CYP3A4 inhibition; expect 1.5-2× increase in alfentanil concentrations
• Sufentanil (high hepatic extraction ratio 0.7-0.9): Less affected; CYP3A4 inhibition has minimal effect because clearance is primarily flow-dependent
• This further supports sufentanil selection in this patient

Clinical management [2 marks]:

• If using sufentanil: No dose adjustment required for diltiazem interaction
• Monitor for enhanced bradycardia (additive effect of diltiazem + opioid on AV node)
• Glycopyrrolate available for significant bradycardia
• If using alfentanil: Would need to reduce infusion rate by ~30-50%

Total: 20 marks

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Primary Viva Scenario (15 marks)

Stem: You are the anaesthetist for a 45-year-old woman undergoing laparoscopic cholecystectomy as a day case. You plan to use propofol-alfentanil TIVA. The examiner asks you about alfentanil pharmacology.

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Examiner: Why might you choose alfentanil over fentanyl for a TIVA technique in day surgery?

Candidate: I would choose alfentanil for several pharmacokinetic reasons relevant to day surgery:

Rapid onset [1 mark]:

• Alfentanil has a t1/2keo of 0.9-1.4 minutes compared to fentanyl's 4-6 minutes
• This allows rapid achievement of effect-site target and quick response to TCI adjustments
• Despite being less lipophilic than fentanyl, alfentanil has faster onset due to its low pKa (6.5), meaning 89% is unionised at pH 7.4 compared to only 9% for fentanyl

Predictable offset [1 mark]:

• Alfentanil's context-sensitive half-time is relatively constant (50-60 minutes) regardless of infusion duration
• Fentanyl's CSHT increases progressively—from 20 minutes after 1 hour to over 260 minutes after 4 hours
• For a 1-2 hour procedure, both would be acceptable, but alfentanil provides more predictable emergence

Small volume of distribution [1 mark]:

• Alfentanil Vdss is 0.4-1.0 L/kg versus fentanyl 4.0 L/kg
• This limits peripheral accumulation and contributes to the favourable CSHT profile

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Examiner: What is the mechanism of action of alfentanil?

Candidate: Alfentanil is a synthetic 4-anilidopiperidine opioid that acts as a full agonist at the mu-opioid receptor.

Receptor binding [1 mark]:

• The mu-receptor is a G protein-coupled receptor (GPCR) coupled to inhibitory Gi/Go proteins
• Alfentanil binding causes conformational change, activating the G protein

Intracellular signalling [2 marks]:

• Adenylyl cyclase inhibition reduces intracellular cAMP
• GIRK channels are activated, causing potassium efflux and membrane hyperpolarisation
• Voltage-gated calcium channels (N-type, P/Q-type) are inhibited, reducing calcium influx
• The net effect is reduced neurotransmitter release and neuronal hyperpolarisation

Anatomical sites [1 mark]:

• Supraspinal: Periaqueductal grey, rostral ventromedial medulla, thalamus
• Spinal: Dorsal horn (laminae I, II)—inhibits substance P and glutamate release
• Brainstem: Pre-Botzinger complex (respiratory depression), nucleus tractus solitarius

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Examiner: How is alfentanil metabolised, and what drug interactions should you consider?

Candidate:

Metabolism [2 marks]:

• Alfentanil undergoes extensive hepatic metabolism via cytochrome P450 3A4 (CYP3A4)
• Primary pathway is N-dealkylation producing noralfentanil (inactive)
• Less than 1% is excreted unchanged in urine
• The metabolites are inactive, so alfentanil is safe in renal impairment

Hepatic extraction ratio [1 mark]:

• Alfentanil has an intermediate hepatic extraction ratio (0.3-0.5)
• This means clearance depends on BOTH hepatic blood flow AND enzyme activity
• This makes alfentanil more susceptible to CYP3A4 drug interactions than high-extraction drugs like fentanyl or sufentanil

Drug interactions [2 marks]:

• CYP3A4 inhibitors (erythromycin, fluconazole, ketoconazole, ritonavir) significantly increase alfentanil levels—may double or triple concentrations
• CYP3A4 inducers (rifampicin, phenytoin, carbamazepine) reduce alfentanil effect
• Pharmacodynamic interactions: Synergistic respiratory depression with benzodiazepines, propofol, volatile agents

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Examiner: The surgery takes longer than expected at 3 hours. How does this affect your emergence plan?

Candidate:

CSHT considerations [2 marks]:

• After a 3-hour alfentanil infusion, the CSHT is approximately 55-60 minutes
• This means after stopping the infusion, effect-site concentration will decrease by 50% in about 55 minutes
• For adequate spontaneous ventilation, we typically need 70-80% reduction in Ce, which takes approximately 1.5-2 × CSHT = 80-120 minutes if we simply stop the infusion

Practical management [1 mark]:

• I would reduce the alfentanil target 15-20 minutes before anticipated end of surgery
• This allows effect-site concentration to decline while still providing analgesia during wound closure
• Simultaneously administer multimodal analgesia (paracetamol, NSAID, local infiltration) to cover emergence

Comparison with fentanyl [1 mark]:

• Had I used fentanyl, the CSHT after 3 hours would be approximately 150-200 minutes
• This would significantly delay emergence and potentially day-surgery discharge
• Alfentanil's more predictable emergence is advantageous in this scenario

Total: 15 marks

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References

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