2018A Question 12
Compare and contrast the pharmacology of neostigmine and sugammadex.
Examiner Report
73% of candidates achieved a pass in this question.
This question was generally answered well. Many candidates included pharmaceutics. However there was inconsistency regarding light stability of sugammadex (manufacturer recommends use within 5 days if not protected from light). Some candidates demonstrated a lack of understanding of basic chemistry, with confusion between amides and amines, tertiary and quaternary groups and the consequences of covalent bonds.
Good answers included the hydrophilic outer substitution and hydrophobic inner substitution of sugammadex, an excellent answer would have included that gamma cyclodextrin has eight sugar moieties, carboxyl outer substitution or hydroxyl inner substitution.
Indications for the use of neostigmine were often limited to reversal of neuromuscular blockade. Better answers also included pseudo-obstruction, atonic bladder and myasthenia gravis.
Glaucoma was seldom mentioned. Two candidates mentioned the intrathecal use for analgesia. Although bioavailability is poor, oral preparations are available, with dosing in the order of 30mg. Neostigmine dosing was highly variable (0.5 microgram per kg – 50 mg per kg). Better answers mentioned a ceiling effect at 70 microgram per kg. Metabolism was frequently believed to be hepatic, rather than hydrolysis by plasma esterases. Better answers included a description of how neostigmine interacts with acetylcholinesterase to inhibit it.
Frequently, side effects of neostigmine were categorised as cholinergic, with no differentiation between muscarinic or nicotinic effects.
Model Answer
Structure:
- PC
- PK
- PD
Physicochemical
| Neostigmine | Sugammadex | |
|---|---|---|
| Structure | Quaternary amine i.e. doesn’t cross blood-brain barrier |
γ-cyclodextrin Ring structure 6 sugar moieties Hydrophilic outer (COOH substitution) Hydrophobic inner (OH substitution) |
| Need for reconstitution | No (i.e. quick) | No (i.e. quick) |
| Stability | ✓ | Requires protection from light (or use within 5 days) |
Pharmacokinetics
| Neostigmine | Sugammadex | |
|---|---|---|
| Admin: | ||
- Route: |
IM, IV | IV only |
- Profound blockade |
Can’t | 16mg.kg-1 |
- Deep blockade (TOF count 1-2) |
Can’t | 4mg.kg-1 |
- Moderate blockade (TOF count 3+) |
0.05mg.kg-1 Ceiling effect 0.07mg.kg-1 |
2mg.kg-1 |
| Time course: | ||
- Onset |
3 min | ≤1min |
- Peak |
10 min | |
- Duration |
30-60min | |
| Absorption: | ||
- OBA |
2% | |
| Distribution | ||
- Extent |
Leaves plasma → NMJ Doesn't cross BBB |
Confined to plasma Encapsulates drug in plasma Create concentration gradient++ |
| Metabolism/excretion | ||
- Route |
50% metabolized (plasma esterases) 50% excreted |
100% renal unchanged |
- t1/2β |
1 hour | 2 hours |
Pharmacodynamics
| Neostigmine | Sugammadex | |
|---|---|---|
| Effects: | ||
| MoA: | Forms reversible carbamylate complex with esteratic site of AChE Displacement of drug |
Encapsulate relaxant Hydrophobic inner for steroid Hydrophilic outer for solubility Electrostatic attraction |
| Effect on plasma cholinesterase | Inhibit | Nil |
| Effect on non-depolarisers | Augment mivacurium (inhibit PChE) Reverse all others |
Reverse roc > vec >> panc |
| Effect on depolarisers | Augment | Nil |
| Other | - Reverse any non-depolarising blockade - Pseudo-obstruction - Atonic bladder - Myasthaenia gravis (Other factors only if crossing BBB): - Alzheimer’s disease - Glaucoma - Benzo overdose - Anti-histamine overdose - TCA overdose |
Reverse aminosteroids only (roc > vec >> panc) |
| Side effects: | ||
- Pair with antimuscarinic |
Y (glycopyrrolate – similar time course) | N |
- Muscarinic side effects |
Y Bradycardia, bronchospasm SLUDGE No CNS cholinergic toxicity |
N |
- Chelates progesterone → Failed contraception |
N | Y |