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
(after induction)

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

↑ [ACh] at NMJ

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
(but slows metabolism of mivacurium)

- 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

Last updated 2021-08-23

results matching ""

    No results matching ""