Show the model answerAttempt it first — that is what makes it stick
What earns the marks10 marks
| (a) Onset, not duration | 4 marks. The single commonest failure on this paper. Read the word twice before writing |
|---|---|
| (a) Potency is the answer | Low potency means a larger molar dose, a steeper gradient, faster onset. Everything else is secondary |
| (a) Not local anaesthetic factors | pKa and lipid solubility belong to a different class of drug and earned nothing here |
| (b i) Physicochemical | 2 marks. Modified γ-cyclodextrin, the cone shape, hydrophobic core and hydrophilic exterior, the modified side chains |
| (b ii) Pharmacokinetic | 2 marks. Dose-linear, not metabolised, renally excreted, with volume and half-life |
| (b iii) Pharmacodynamic | 2 marks, and where the marks were lost. 1:1 encapsulation, the concentration gradient, no ceiling, no anticholinergic needed |
| Elaborate, do not list | The examination said explicitly that bare statements in the pharmacodynamics section scored nothing |
4 marks
Factors that increase the speed of onset
Four marks, and the highest failure rate in the bank. Before writing anything, note that almost every factor which speeds onset also shortens or leaves duration unchanged — they are not the same list.
Why potency is the first thing to write
The governing relationship
Onset time is inversely related to potency. Rocuronium’s ED₉₅ is 0.3 mg/kg; cisatracurium’s is 0.05 mg/kg.
An equipotent dose of the weaker drug contains many more molecules. Potency and molar dose are the same number read from opposite ends.
More molecules in plasma builds a steeper concentration gradient from blood to junctional cleft, so the receptor reserve is saturated sooner.
At the same multiple of ED₉₅, rocuronium reaches maximum block in 1.7 minutes, atracurium in 3.2, and cisatracurium in 5.2. The price of speed is that the weaker drug must be given in bulk.
| Factor | Effect on onset | Mechanism, and the cost |
|---|---|---|
| Choice of drug — the largest single effect | ||
| Low potency | Faster | A higher ED₉₅ means a larger molar dose and a steeper plasma-to-junction gradient. Rocuronium is the fastest non-depolariser because it is the weakest one |
| Suxamethonium | Fastest of all | Maximum block in about 1.1 minutes. An agonist needs only to depolarise, not to out-compete acetylcholine at a receptor reserve |
| Dose and technique | ||
| A larger multiple of ED₉₅ | Faster | Rocuronium 1.2 mg/kg is faster than 0.6 mg/kg. The cost is duration: an intense block that then has to be waited out or reversed with 16 mg/kg of sugammadex |
| Priming | Faster by 30–60 seconds | A subparalysing dose — about 20% of the ED₉₅, or 10% of the intubating dose — 2 to 4 minutes ahead partly occupies the receptor reserve in advance. It costs a degree of block in an awake patient: discomfort, difficulty swallowing and breathing, visual disturbance and aspiration risk, and the conditions still do not match suxamethonium |
| Combining two relaxants of different chemical classes | Faster | Structurally dissimilar agents are synergistic. Mivacurium with rocuronium achieves rapid onset without undue prolongation; other cross-class pairings can prolong markedly |
| Magnesium pretreatment | Faster | The one co-administered drug with a measured effect on onset rather than only on depth: after magnesium sulphate 40 mg/kg the ED₅₀ of vecuronium fell by 25% and the onset time was nearly halved. The cost is on the other side of the case — recovery time nearly doubled, and neostigmine-induced recovery is attenuated |
| The patient | ||
| High cardiac output | Faster | Delivery to the junction is the rate-limiting step. A low-output state delays onset for the same dose |
| Muscle blood flow | Well-perfused muscles block first | Not a drug property at all. See the table below |
| Short circulation time | Faster | The corollary of the above, and why onset is slower in the elderly |
| Drug and dose | Laryngeal adductors | Adductor pollicis |
|---|---|---|
| Suxamethonium 1.0 mg/kg | 34 ± 12 s | 56 ± 15 s |
| Rocuronium 0.5 mg/kg | 84 ± 6 s | 144 ± 12 s |
| Vecuronium 0.07 mg/kg | 198 ± 12 s | 342 ± 18 s |
| Mivacurium 0.2 mg/kg | 89 ± 26 s | 202 ± 45 s |
The centrally located muscles equilibrate with plasma faster, and that difference “probably represents little more than differences in regional blood flow”. It is the reason the airway can be secured while the monitored hand is still twitching, and the reason a train-of-four at the thumb understates how profoundly the diaphragm is blocked early on.
Commonly lost: Almost everything above speeds onset without prolonging the block, and several factors that prolong a block — hypothermia, acidosis, aminoglycosides, hepatic and renal impairment — do nothing useful to onset. Writing the duration list here is the error that produced a 6.03% pass rate.
Part (b) · 2 marks
Sugammadex — physicochemical properties
A sugar built into a cage. Two marks for the structure and what each structural modification was for.
| Property | Detail |
|---|---|
| Chemical class | A modified γ-cyclodextrin, and the first selective relaxant binding agent. The name is literal: su for sugar, gammadex for γ-cyclodextrin |
| The parent structure | Cyclodextrins are rings of six (α), seven (β) or eight (γ) dextrose units joined by 1→4 glycosyl bonds. Sugammadex is built on the eight-unit γ ring |
| Shape | A hollow truncated cone, or doughnut, with a hydrophobic cavity and a hydrophilic exterior, the latter from its polar hydroxyl groups. That arrangement is what makes it water-soluble while still able to hold a lipophilic guest |
| First modification | The natural γ cavity is too shallow for the rigid steroid nucleus of rocuronium, so eight side chains extend it to 11 Å, deep enough to admit the four hydrophobic steroidal rings |
| Second modification | Negatively charged carboxyl groups at the ends of those side chains, which bind electrostatically to the positively charged quaternary nitrogen of rocuronium. This is what makes the encapsulation selective rather than merely possible |
| Forces holding the complex | Van der Waals forces, hydrogen bonding and hydrophobic interaction — no covalent bond, and no chemical reaction |
| Molecular mass | Sugammadex 2002 g/mol; the sugammadex–rocuronium complex 2532 g/mol; the sugammadex–vecuronium complex 2640 g/mol |
| Presentation | A solution of 100 mg/mL in 2 or 5 mL vials, with a shelf-life of 3 years. A 16 mg/kg dose in an adult therefore needs several vials |
Structure image for sugammadex not available.
Part (b) · 2 marks
Sugammadex — pharmacokinetic properties
Short and factual. The interesting half is what it does to rocuronium's kinetics, which is worth writing if the basic list is already down.
| Property | Detail |
|---|---|
| Kinetics | Dose-linear at therapeutic doses |
| Volume of distribution | Approximately 11–18 L across sources — essentially the extracellular fluid volume, as expected for a large, highly polar molecule that does not enter cells |
| Metabolism | None. The drug is not metabolised at all, and no metabolite exists to accumulate |
| Excretion | Unchanged by the kidney; up to 80% of the dose appears in urine within 24 hours |
| Half-life | Approximately 1.5–2.5 hours across sources |
| Clearance | About 120 mL/min, close to the glomerular filtration rate |
| Renal impairment | Both sugammadex and the complex are renally cleared, so both accumulate. High-flux haemodialysis removes them effectively — measured blood clearances on dialysis of 78 mL/min for sugammadex and 89 mL/min for rocuronium |
Part (b) · 2 marks — where the marks were lost
Sugammadex — pharmacodynamic properties
Many candidates gained nothing here through lack of elaboration. A pharmacodynamics answer is not a list of indications; it is what the drug does, to what, and with what consequence.
How encapsulation reverses a block
The bond
Sugammadex forms a rigid 1:1 complex with an aminosteroid. The association-to-dissociation ratio for rocuronium is 25,000,000:1 — it captures the molecule 25 million times faster than the complex falls apart, which is why the binding is effectively irreversible in clinical time.
Free rocuronium disappears from plasma almost immediately, even though total plasma rocuronium rises.
That creates a concentration gradient running the wrong way for the block: high free drug at the junction, almost none in plasma.
Rocuronium diffuses off the receptor and back into plasma down that gradient, where each molecule is encapsulated in turn.
The consequence
The junction is cleared of antagonist. Acetylcholine was never involved, which is why there is no ceiling and no muscarinic effect to cover.
| Property | Detail |
|---|---|
| Selectivity | Aminosteroids only: rocuronium, and vecuronium with an affinity about 2.5 times lower but still ample. There is measurable affinity for pancuronium, too low to be clinically useful, and none for the benzylisoquinoliniums or for suxamethonium |
| Site of action | Plasma, not the neuromuscular junction. It has no direct or indirect action on any component of cholinergic transmission — not cholinesterase, not nicotinic receptors, not muscarinic receptors |
| No effect given alone | Sugammadex has no neuromuscular effect of its own, which is why it can be given when there is no response to train-of-four stimulation at all |
| No ceiling effect | Effective at every depth from shallow to profound. Neostigmine cannot reverse a post-tetanic count of 1 to 2 at any dose, because the enzyme is already fully inhibited |
| Speed | After 4 mg/kg, mean recovery of the train-of-four ratio to 0.90 is 1.1 minutes for rocuronium and 1.5 minutes for vecuronium. After rocuronium 1.2 mg/kg reversed immediately with 16 mg/kg, 2.2 minutes — faster than spontaneous recovery from suxamethonium, which takes about 10.9 minutes |
| Dose must match depth | Underdosing is the failure mode. At 0.5 to 1.0 mg/kg given during a deep block, residual blockade and frank recurrence of block were both seen; at the recommended 4.0 mg/kg neither occurred |
| System | Effect | Why, and the evidence |
|---|---|---|
| Cardiovascular | Essentially none | No effect on the electrocardiogram and no QTc prolongation, studied in healthy subjects at doses up to 32 mg/kg alone and with rocuronium or vecuronium; a patient with long QT syndrome was reversed with 2 mg/kg without the QT interval being affected. Not associated with cardiovascular side effects in healthy patients or in those with cardiovascular comorbidity. Severe bradycardia is reported, but very rarely |
| Respiratory | No bronchoconstriction | It has no interaction with the muscarinic cholinergic system and needs no anticholinergic, which is a stated advantage over neostigmine in a patient with pulmonary disease. In 77 patients with known pulmonary disorders given up to 4 mg/kg, reversal was rapid with no residual block or recurarisation, though 2 developed bronchospasm. It does not affect upper airway tone or normal breathing when given after recovery — unlike an anticholinesterase |
| Autonomic and central | None | No action on cholinesterase, nicotinic or muscarinic receptors means no muscarinic effects to cover and nothing at the ganglia. It is a large, highly polar molecule and does not enter the central nervous system |
| Gastrointestinal | None attributable to the mechanism | The salivation, increased gut motility and cramps that follow neostigmine are muscarinic effects. Sugammadex produces none of them because it never raises acetylcholine |
| Immune | Hypersensitivity — the principal concern | Contraindicated in known hypersensitivity. Concern over hypersensitivity delayed its approval in some countries by several years, and one case of sugammadex-induced anaphylaxis was identified in NAP6 |
| Renal | Accumulation rather than toxicity | Both the drug and the complex are renally cleared, so exposure rises in moderate and severe impairment. Reversal itself was fast and stable in patients with a creatinine clearance below 30 mL/min, but because elimination of the complex in renal impairment remains poorly understood it is not currently recommended in severe renal failure; mild to moderate impairment is acceptable. High-flux haemodialysis removes both |
| Obstetric | Minimal placental transfer in animal work | Preclinical animal data show uteroplacental transfer of under 2% to 6%, with no negative effect on pregnancy or on embryonic, fetal or postnatal development. Quote it as animal data, because that is what it is |
| Interaction | Drugs | What actually happens |
|---|---|---|
| Displacement — a third drug pushes the relaxant back out | ||
| Theoretical recurarisation | Toremifene, fusidic acid, flucloxacillin | These bind the cyclodextrin cavity strongly enough to displace rocuronium or vecuronium, raising the theoretical prospect of a block returning. Worth knowing that the theory has not been borne out: no clinically relevant recurrence of block was identified when sugammadex was used with these drugs, and flucloxacillin specifically was studied and showed no clinically important displacement |
| Capture — sugammadex encapsulates a third drug and reduces its effect | ||
| Hormonal contraception | Oral and implanted progestogens | The one that changes what you tell the patient. Simulations predict that 4 mg/kg captures about 34% of free etonogestrel, an exposure reduction equivalent to one missed daily pill. Patients on hormonal contraception must be told, and advised to use additional contraception |
| Re-paralysing a patient you have just reversed | ||
| Rocuronium or vecuronium after sugammadex | The aminosteroids | The one that changes what you do. Circulating sugammadex will encapsulate a repeat dose, so within 24 hours the conservative recommendation is to use a non-aminosteroid relaxant instead — that interval being the maximum clearance time for sugammadex. In practice a block can be re-established sooner with a high dose: given 5 minutes after reversal, rocuronium produced complete block with an onset of about 3 minutes, and by 30 minutes the onset was back to 1.5 minutes |
| Dose | When | Depth reversed |
|---|---|---|
| 2 mg/kg | T2 visible on a train-of-four | Moderate block |
| 4 mg/kg | No train-of-four response, but post-tetanic twitch present | Profound block |
| 16 mg/kg | Immediately after rocuronium 1.2 mg/kg, before any recovery | Immediate reversal of an intense block — the cannot-intubate rescue |
Commonly lost: The examination recorded that knowledge of the physicochemical and pharmacokinetic properties was generally good, but that many gained no marks in the pharmacodynamics section through a lack of elaboration. “It reverses rocuronium” is not a pharmacodynamic property. “It encapsulates rocuronium in plasma in a 1:1 complex, creating a gradient that draws the drug off the junctional receptor, which is why it has no ceiling effect and needs no antimuscarinic” is three marks’ worth of the same idea.
Writing it in the time you actually have
Ten marks, split four and six
Part (a) is worth four marks and part (b) six, so the sugammadex half deserves more of the page than most candidates give it.
| Minutes | Part | What to write |
|---|---|---|
| 0–1 | Both | Underline onset. Write the three sugammadex headings down the page now, so the six marks in part (b) cannot be squeezed out by overrunning on part (a) |
| 1–8 | (a) · 4 marks | Potency and the gradient first, with an ED₉₅ comparison. Then dose, priming with its costs, cardiac output and muscle blood flow. Add the perfusion-limited sentence. Write nothing about duration |
| 8–11 | (b i) · 2 marks | Modified γ-cyclodextrin, truncated cone, hydrophobic cavity and hydrophilic exterior, extended side chains with terminal carboxyl groups binding the quaternary nitrogen |
| 11–14 | (b ii) · 2 marks | Dose-linear, not metabolised, renally excreted unchanged, volume and half-life, accumulation in renal impairment. If ahead of time, what it does to rocuronium's own clearance |
| 14–18 | (b iii) · 2 marks | The 1:1 complex, the gradient mechanism, aminosteroid selectivity, no ceiling, no anticholinergic required, and one dose figure. Elaborate every statement into its consequence |