4. Neuromuscular Blocking Drugs (and Sugammadex)

Question 1

Classification

Answer 1

: Depolarizing muscle relaxants.

These drugs, of which suxamethonium is the only example in clinical use,
act as agonists at the acetylcholine (ACh) receptor.

Binding to the two α-subunits depolarizes the membrane, during which
process the voltage-sensitive sodium channels first open and then close. In this closed
conformation they are inactivated.

After a normal physiological depolarization, the
membrane potential is restored within 1 ms by the action of acetylcholinesterase.

As depolarizing relaxants are not metabolized in this way,
the acetylcholine receptors remain activated and the sodium channels remain closed.

The action of the drug is terminated as it diffuses away from the receptors down a concentration gradient to be hydrolyzed in plasma by plasma (butyryl) cholinesterase (pseudocholinesterase).

Question 2

Non-depolarizing muscle relaxants

Answer 2

These drugs in contrast are primarily competitive inhibitors of
ACh at the post-junctional nicotinic receptors

They also antagonize prejunctional receptors and block the normal positive feedback
cycle whereby acetylcholine stimulates its own release.

The drugs are quaternary ammonium compounds with one or more quaternary nitrogen groups

effect. The lipophilic bridge between the radicals varies with different nondepolarizing
relaxants and is a prime determinant of their potency

The receptor binding is not static because the competitive antagonism is a continuous process of repeated association and dissociation.

At the onset of block, there is a decremental reduction in the end-plate potential to the point at which it does not reach the threshold to generate an action potential for the initiation of muscle contraction

Question 3

Groups

Answer 3

All of the non-depolarizing relaxants are quaternary amines, whose potency is
increased if the molecule contains two quaternary ammonium radicals.

There are two main groups:

1. the benzylisoquinoliniums (drugs ending in ‘–urium’),
2. and the aminosteroids (drugs ending in ‘–uronium’).

The aminosteroids in general show greater cardiovascular stability
and cause less histamine release.

Question 4

Established agents:

Answer 4

(the duration of action that is quoted here is the time following
an intubating dose at which there is 25% recovery and pharmacological reversal can
be used.)

Question 5

Atracurium

Answer 5

Atracurium: this is a bisquaternary amine, a benzylisoquinolinium mixture of
16 potential isomers. It has a medium duration of action which is reversible
pharmacologically at 25 minutes. It may cause histamine release.

Question 6

Cisatracurium

Answer 6

: this is one of the isomers of atracurium,

which has a slightly longer duration of action (45 minutes), and has greater cardiovascular stability
because it is less likely to provoke histamine release. It is more potent than
atracurium; a typical intubating dose is 0.1 mg kg–1.

Question 7

Mivacurium

Answer 7

This is a benzylisoquinolinium diester,

with a short duration of action (15 minutes).

Mivacurium undergoes ester hydrolysis and so, in theory,
should not require reversing with anticholinesterases.

In practice, residual curarization is still possible,
and so conventional reversal agents can be used.

Its capacity to cause histamine release is similar to that of atracurium.

An intubating
dose is 0.15 mg kg–1.

Question 8

Pancuronium

Answer 8

: this is a bisquaternary aminosteroid whose vagolytic and sympathomimetic
actions made its use traditionally popular in haemodynamically

compromised patients. It is long acting (75 minutes) after an intubating dose of
0.1–0.15 mg kg–1.

Question 9

Vecuronium:

Answer 9

this is the monoquaternary homologue of pancuronium, which was
developed in an attempt to create a ‘clean’ version of the older drug. Its structure
includes a tertiary amine which becomes increasingly protonated in an acidotic
circulation, thereby increasing both its potency and its duration of action. It has
minimal cardiovascular effects and a short duration of action (30–35 minutes). Its
effects are antagonized by sugammadex.

Question 10

Rocuronium:

Answer 10

Rocuronium: this is another monoquaternary aminosteroid which is very similar
to vecuronium when used in equipotent doses.

Its tertiary amine similarly becomes protonated in a patient who is acidotic.

It provokes minimal histamine release and is cardiostable apart from modest vagolytic effects after large doses.

When given in high doses (0.9 mg kg−1) it provides good conditions for tracheal intubation within 60–75 seconds (hence its name: ‘rapid onset vecuronium’)

lasts for around 45 minutes.

Lower doses of 0.6 mg kg–1 (2xED95, as is typical for muscle
relaxants) last for around 35 minutes.
It has a specific antagonist: sugammadex

Question 11

Sugammadex

Answer 11

This is a γ-cyclodextrin (the ‘su’ prefix refers to ‘sugar’ and the ‘-gammadex’ to the
gammacyclodextrin moiety) modified by the addition of eight side chains to the
cyclodextrin ring.

The ring consists of cyclic dextrose units linked by 1–4 glycosyl
bonds. This specific modification allows better accommodation of the aminosteroid
molecule within what is described as a toroidal structure.

The negatively charged hydroxyl groups on the outer surface are hydrophilic
whereas the inner surface is lipophilic. Sugammadex chelates the lipophilic
rocuronium molecule forming a stable structure which encapsulates the drug irreversibly.

It does so in a ratio of 1:1.

This specific action reverses the effect of
rocuronium (and vecuronium) from any depth of neuromuscular block. This means
that rocuronium can replace suxamethonium in a variety of clinical scenarios
because it can be reversed within minutes of administration. A typical reversal dose,
depending on the degree of residual neuromuscular blockade is 2–4 mg kg–
1.
Reversal immediately after an intubating dose, however, requires 16 mg kg–1 which
at current prices in the UK costs around £350 for a patient weighing 70 kg.

Question 12

Sugammadex

Excretion

Interaction

Answer 12

Metabolism and excretion:

The chelated complex is excreted unchanged by the kidneys.
Its elimination half-life is reported as (an unusually precise) 2.2 hours.

— Interactions:
the ability of cyclodextrins to encapsulate molecules is not confined to
aminosteroids, and the compounds find non-medical uses
(for example in air fresheners, specifically Febreze).

Although sugammadex does not appear to effect endogenous hormones
(which are usually strongly protein-bound),
it may encapsulate exogenous progestogens such as those in oral contraceptive preparations.

A small number of drugs have been identified as having the potential of displacing
rocuronium from the sugammadex molecule;

these are the antibiotics fusidic acid and flucloxacillin,
and the anti-oestrogenic agent toremifine,

which is used in the treatment of hormone-sensitive breast cancer.

Question 13

Side effects: Sugammadex

Answer 13

Side effects:

there is little evidence of specific material complications with sugammadex,

although the data sheet lists cardiac arrhythmias as possible sequelae of its
administration.

Prolonged QT interval has also been cited as a potential problem, as
have anaphylactic reactions.

Question 14

Metabolism and elimination:

Answer 14

most are eliminated by more than one mechanism.

Question 15

Suxamethonium

Answer 15

: this predominantly undergoes ester hydrolysis
(by plasma cholinesterase);

a small amount is hydrolyzed by non-specific plasma esterases,
and 10% is excreted unchanged through the kidney

Question 16

Mivacurium

Answer 16

this is also metabolized by plasma cholinesterase
at a slightly slower rate (88%) than suxamethonium.

Abnormal cholinesterases will therefore increase its effective action
more than suxamethonium.

In EuEa heterozygotes (see under ‘Suxamethonium’ in the section that follows)

it will last for 2 hours, and in EaEa homozygotes its action will be prolonged for 8 hours or more. The drug has no active metabolites.

Question 17

Atracurium

Answer 17

: about 10% is excreted renally,

about 40–45% is hydrolyzed by hepatic esters and a

further 45% undergoes Hofmann degradation at body temperature and pH

(this reaction was first identified in industrial processes).

The cleavage occurs at the linkage between the carbon chain and the quaternary
nitrogen.

Ester hydrolysis takes place at the site of the double carbon bond.
Hofmann degradation produces laudanosine, a potentially epileptogenic metabolite
which has not, however, been shown to cause problems in humans.

Blood levels reach around 2 μg ml–1 after a standard bolus dose of 0.5 mg kg–1. Its other product of metabolism is a monoquaternary acrylate compound.

Question 18

Cisatracurium

Answer 18

qualitatively, the metabolism of cisatracurium is similar to atracurium,

except a substantially greater proportion (up to 70%) undergoes
Hofmann elimination, and ester hydrolysis is much less important.

As the drug is five times as potent as atracurium,
it is predictable that laudanosine levels
similarly are lower at around 0.4 μg ml–1 after a bolus dose of 0.1 mg kg

Question 19

Pancuronium

Answer 19

: 60% is excreted renally, unchanged.

The remainder is metabolized in the liver;
3-hydroxy metabolite has 50% of the activity of the parent
compound, and deacetylation also creates 3-desacetyl active metabolites which
are rendered water-soluble by glucuronidation.

Question 20

Vecuronium

Answer 20

: about 30% is excreted renally, while the remainder undergoes
hepatic deacetylation.

Like pancuronium, it produces an active metabolite:
3-desacetylvecuronium.

Question 21

Rocuronium:

Answer 21

its elimination is mainly hepatic. It is metabolized to 17-
desacetylrocuronium, which has around 5% of the activity of the parent compound.

Question 22

Factors That May Potentiate the Action of Non-Depolarizing Muscle Relaxants

Answer 22

magnesium (pre- and post-synaptic inhibition ach rel

direct effect on ion transport at the neuromuscular junction,
such as calcium-channel blockers,
β-adrenoceptor blockers
local anaesthetics

In higher doses, local anaesthetics can also exert a membrane stabilizing effect on the muscle membrane itself.

Lithium potentiates neuromuscular blockade, as do some antibiotics –
particularly the aminoglycosides –
by pre-synaptic inhibition of acetylcholine.

Given the ubiquity of gentamicin use for surgical prophylaxis,
this is not simply a theoretical consideration