19. Neuromuscular Blocking Drugs Flashcards
Describe the nicotinic acetylcholine receptor (nAChR).
The nAChR is an integral membrane
protein found on the postsynaptic membrane
of the neuromuscular junction.
It is a ligand-gated ion channel
composed of five subunits:
two α,
one β,
one δ and
one γ,
which are all arranged around
a central pore.
Its molecular weight is about 250 000 Daltons.
When a molecule of ACh binds
to each of the α subunits,
the receptor undergoes conformational change,
which = in opening of the central pore.
This pore is a non-specific ion channel,
through with Na+, K+ and Ca2+ ions can flow,
causing miniature end-plate potentials.
When the threshold level of depolarisation is reached, voltage-gated Na+ channels open and the action potential is propagated across the muscle.
How does suxamethonium exert its effects?
> Suxamethonium is a depolarising neuromuscular-blocking drug.
Its structure is that of two
conjugated acetylcholine molecules
and as such it is much more stable
than the natural ligand.
Suxamethonium binds to
the α subunit of the nAChR and
causes the ion channel to open, with
resulting muscle depolarisation.
This results in muscular fasciculations as
the depolarisation caused by suxamethonium is not orderly.
> S uxamethonium is not broken down by acetylcholine esterase and therefore its effects at the receptor are more sustained than the natural ligand.
This persistent depolarisation causes the Na+ channels to become inactive, preventing repolarisation and rendering the neuromuscular end plate refractory to further stimulation.
This produces a flaccid paralysis in the patient.
With time, the drug diffuses away
from the neuromuscular junction
and is broken down by pseudocholinesterase
(also known as plasma cholinesterase or
butyrylcholinesterase) in the plasma.
Now, repolarisation can occur and
muscle action potentials are again possible.
What are the characteristics of the ideal neuromuscular blocker?
Physical properties:
> Cheap and easy to manufacture > Long shelf life at room temperature > Water soluble and therefore easy to store > Painless on injection > Safe if injected intra-arterially > Ultra rapid onset time > Predictable duration of action > Able to reverse its effects quickly following an intubating dose > No accumulation following infusion > No interaction with other drugs
Biological properties:
> Analgesic
> No systemic effects other than neuromuscular blockade
> No toxic effects
How are non-depolarising neuromuscular blocking drugs classified?
They are classified into two groups
according to their chemical composition:
> Aminosteroids,
e.g. vecuronium, rocuronium, pancuronium
> Benzylisoquinolinium esters,
e.g. atracurium, mivacurium
How do these drugs work?
> Both classes exert their effects by
binding to the α subunits of the nAChR
and competitively inhibiting ACh.
> The drug needs to occupy only one of the α subunits but must occupy at least 70% of all receptors, before any effect is clinically evident.
> This feature highlights the
margin of safety that exists
within an individual
with regards to neuromuscular function.
It is well demonstrated in
patients with myasthenia gravis
where a significant proportion of nAChR
must be affected before symptoms become evident.
What factors affect the speed of onset of the drug?
Non-depolarising muscle relaxants have
bulky structures and are relatively polar.
Their volumes of distribution are therefore
small and they are not significantly redistributed.
They do not undergo first-pass metabolism,
and are all administered intravenously.
Hence, their speed of onset is governed
by the concentration gradient between
plasma and effect site.
Rocuronium is a much less potent
drug than vecuronium,
and therefore a higher dose of
rocuronium must be given in
order to achieve the same
degree of muscle relaxation.
At first, this sounds undesirable
but this increase in intubating dose
(from vecuronium 0.1 mg/kg
to rocuronium 0.6 mg/kg)
means that a greater number of
rocuronium molecules are being given,
which increases the relative
concentration gradient between the
plasma and the nAChR.
This results in more rapid movement
of rocuronium molecules onto the receptors,
and therefore a faster onset of action
when compared with vecuronium.
At a rapid sequence intubating dose of
1 mg/kg,
its speed of onset is
comparable with suxamethonium.
What are ED50 and ED95?
This is the dose of neuromuscular blocking agent required to produce either a 50% or 95% depression in twitch height when measuring train of four using a nerve stimulator
The standard intubating dose is 2 × ED95. When high-dose rocuronium is used in order to produce intubating conditions within 60 s, a dose equivalent to 4 × ED95 is used.
What factors affect the speed of recovery from non-depolarising muscle relaxation?
Initial dose:
The greater the dose,
the longer recovery takes.
Drug metabolism: > Aminosteroids are minimally metabolised in the liver and excreted in the bile and urine (both as unchanged and changed products).
Liver and renal impairment
can lead to accumulation of the drugs
and therefore prolong their effects.
> Atracurium (benzylisoquinolinium ester)
is broken down by Hoffman degradation,
a process of spontaneous drug breakdown
at body pH and temperature.
Acidosis and hypothermia will
slow this breakdown and prolong its effects.
Drug interactions:
> Drugs that induce liver enzymes
will reduce the effects of the
aminosteroids,
e.g. co-administration of phenytoin results
in an 80% increase in the necessary dose of aminosteroid.
> Co-administration of magnesium sulphate,
which competes with calcium,
will prolong the action of
neuromuscular blockers by
inhibiting the release of ACh from
its vesicular stores at the neuromuscular junction.
Only 30–50% of the normal dose
of relaxant should be used.
Administration of ‘reversal agents’:
> Anticholinesterases:
Until relatively recently the
only drugs available to
reverse the effects of
non-depolarising neuromuscular blockers
were anticholinesterases,
e.g. neostigmine,
which worked by increasing the concentration
of ACh at the neuromuscular junction.
> Sugammadex:
Licensed for use with rocuronium and vecuronium.
This modified γ-cyclodextrin works
by completely enveloping the aminosteroid
and terminating its effects
as it can no longer interact with the nAChR.
The drug–drug compound is then
excreted in the urine. Given 3 minutes
after an intubating dose of rocuronium, it will terminate its effects in 1.5 minutes.
How does the structure of these drugs govern their effects?
> Aminosteroidal drugs are bulky and polar and therefore they do not easily cross cell membranes and their volume of distribution is low. They contain moieties that resemble ACh which interact with the nAChR.
> Atracurium has an oxygen atom in its
structure that attracts neighbouring electrons,
therefore destabilising the bonds
between constituent atoms.
This leads to breakdown of the molecule
in a process known as Hoffman degradation.
ROCURONIUM BROMIDE
Aminosteroid non-depolarising muscle
relaxant
• Clear, colourless solution:
10 mg/mL
• Stored at 4°C
DOSE
• 0.6 mg/kg allows
intubation in 90–120 s
• 0.9–1.2 mg/kg in 60 s
Duration 45 min
USES Roc
MOA
USES
• To provide muscle relaxation to allow
intubation, ventilation and surgery
MOA
• Competitive inhibition of ACh at nicotinic
receptors at NMJ
• Binds to a-subunit of receptor but does not
stimulate it to open ion channel
Roc
EFFECTS
EFFECTS
• At high doses can exert vagolytic effect,
causing tachycardia
• Otherwise, no
systemic effects
Roc
CHEMICAL PROPERTIES
CHEMICAL PROPERTIES
• Monoquaternary amine analogue of vecuronium
• 7x less potent than vecuronium,
so a higher dose needs
to be given to achieve relaxation.
The higher number of
molecules given causes an increased concentration
gradient between blood and NMJ and so results in a
faster onset of action by rules of kinetics.
Roc
AD
ME
ABSORPTION/
DISTRIBUTION
• Protein binding 10%
• VD 0.2 L/kg
METABOLISM
AND EXCRETION
• Only 5% metabolised by liver
- Excreted in bile (60%) and urine (40%)
- Duration of action may be increased in liver/renal failure
PANCURONIUM BROMIDE
type
dose
Aminosteroid non-depolarising muscle relaxant
• Clear colourless solution:
2 mg/mL in 2 mL vials
• Store at 4°C
DOSE
- 0.1 mg/kg gives intubating conditions in 90–120 s
- Duration 100 min.
Panc
USES
MOA
• To provide muscle relaxation to allow
intubation, ventilation and surgery
• Part of the lethal
injection in USA
• Long acting
MOA
• Competitive inhibition of ACh at nicotinic receptors
at NMJ
• Binds to a-subunit of receptor but does not
stimulate it to open ion channel
CHEMICAL PROPERTIES
• Bromide salt
Panc
A
D
M
E
ABSORPTION/
DISTRIBUTION
• Protein binding 10–40%
• VD 0.27 L/kg
METABOLISM AND EXCRETION
• 35% hepatic metabolism to 3- and 17-hydroxy
and 3,17- dihydroxypancuronium
•
3-hydroxy metabolite is half as potent as parent
- Unmetabolised drug excreted in urine
- Metabolised drug excreted in bile
Panc
EFFECTS
- Stimulates SNS, may block reuptake of noradrenaline
- Blocks cardiac muscarinic receptors
- Tachycardia
- Sweating, flushing
- Salivation
Suxamethonium
Name
type
dose
uses
SUXAMETHONIUM (succinylcholine or scoline)
Depolarising neuromuscular blocker
• Clear colourless solution:
50 mg/mL
- Store at 4°C
- Routes: IV/IM
DOSE
• 1–2 mg/kg
USES
• Rapid sequence induction for fast onset of relaxation (45 s)
SUX
MOA
CHEMICAL PROPERTIES
MOA • Binds to a-subunit of nicotinic receptors at neuromuscular junction, causing chaotic depolarisation of muscle, therefore fasciculation occurs before flaccid paralysis
• Not broken down by acetylcholinesterase, and more stable than endogenous ACh, so occupies receptor for longer maintaining relaxation
• Broken down by
pseuodocholinesterase in
plasma after diffusing away
CHEMICAL PROPERTIES
• Made up of two acetylcholine molecules
joined together by their acetyl groups
• White crystalline substance that is very
soluble in water
• pH of solution = 4
SUX
A
D
M
E
ABSORPTION/
DISTRIBUTION
• Because of rapid hydrolysis, only 20%
of dose reaches NMJ
METABOLISM AND EXCRETION
• Diffuses away from synaptic cleft and
metabolised by plasma cholinesterases
(also called pseudocholinesterase)
• Hydrolysed to choline + succinylmonocholine
• Latter metabolised further to succinic acid
and choline
SUX
Effects
EFFECTS
May precipitate:
• Arrhythmias by binding to muscarinic receptors –
sinus and nodal bradycardia and ventricular ectopics
- Anaphylaxis
- Malignant hyperpyrexia
• Release of potassium from cells causing
hyperkalaemia, especially in burn
patients, effect persists from 24 hours to 2 years
after injury
• Myalgia – especially
in young, fit, ambulant patients
• Inc IOP
• Inc Intragastric pressure
and LOS pressure
• Prolonged neuromuscular blockade with repeated
dosing = Type 2 block, i.e. shows characteristic
of non-depolarising agent, with fade on TOF.
Cannot be reversed with neostigmine
ATRACURIUM
type
dose
storage
USES
ATRACURIUM
Benzylisoquinolinium non-depolarising muscle
relaxant
• Clear colourless solution
10 mg/mL in 2.5, 5 and 25 mL vials.
• Store at 4°C to avoid Hofmann degradation.
DOSE
• 0.5 mg/kg provides intubating conditions in 90–120 s.
USES
• To provide muscle relaxation to allow
intubation, ventilation and surgery
• Useful in those with renal and liver disease
as not reliant on these for metabolism
TRAC
MOA
CHEM PROP
MOA
• Competitive inhibition of ACh at nicotinic
receptors at NMJ
• Binds to a-subunits of receptor but does
not stimulate it to open ion channel
CHEMICAL PROPERTIES
• 4 chiral centres
and so 10 stereoisomers make up the solution
• Cis atracurium is available. This single
isomer was developed to avoid unwanted
histamine release and its side effects.
TRAC
adme
ABSORPTION/
DISTRIBUTION
• Protein binding 15%
• VD 0.15 L/kg
METABOLISM AND EXCRETION
• Two modes of metabolism: • Ester hydrolysis (60% of dose) in plasma by non-specific esterases to laudanosine, a quaternary acid and alcohol.
• Hofmann degradation, i.e. spontaneous
breakdown to laudanosine and
monoacrylate.
This occurs at body temp and pH.
Acidosis and cold slow the rate of
degradation.
• Laudanosine can cause seizures, but
not at clinical levels.
Trac EFFECTS
EFFECTS
• Causes histamine release, can precipitate
hypotension and bronchospasm in
susceptible individuals.
Some avoid its use in asthmatics. Slow
IV injection minimises histamine release.
• Associated with critical illness myopathy.
MIVACURIUM
Type
Dose
USES
MIVACURIUM
Benzylisoquinolinium
non-depolarising muscle
relaxant
• Clear colourless solution:
2 mg/mL in 5 and 10 mL vials
DOSE
• 0.2 mg/kg provides intubating conditions in
180–240 s
• Short duration of action, around 15–20 min
USES • To provide muscle relaxation to allow intubation, ventilation and surgery
Mivacurium
MOA
Chem prop
MOA
• Competitive inhibition of ACh at nicotinic
receptors at NMJ
• Binds to a-subunits of receptor but does
not stimulate it to open ion channel
CHEMICAL PROPERTIES
- Acidic aqueous solution (pH 3.5–5)
- A mixture of three stereoisomers
MIVAC
A
D
ME
EFFECTS
ABSORPTION/
DISTRIBUTION
• Protein binding 10%
• VD 0.21–0.32 L/kg
METABOLISM
AND EXCRETION
• Metabolised by plasma cholinesterases
• Hence, if patient has genetically low levels,
effect of mivacurium may be prolonged
• High doses can cause histamine release, and
so precipitate hypotension and bronchospasm
VECURONIUM BROMIDE
Type
Prepartion
DOse
Uses
MOA
Aminosteroid non-depolarising muscle relaxant • White powder: 10 mg/vial, for reconstitution with water
DOSE
• 0.1 mg/kg allows intubation in 90–120 s
• Duration 45 min
USES • To provide muscle relaxation to allow intubation, ventilation and surgery
MOA • Competitive inhibition of ACh at nicotinic receptors at NMJ • Binds to a-subunit of receptor but does not stimulate it to open ion channel
VEC
A
D
M
E
EFFECTS
CHEMICAL PROPERTIES
• Monoquaternary analogue of pancuronium
– differs by one methyl group
ABSORPTION/ DISTRIBUTION • Protein binding 10% • VD 0.23 L/kg
METABOLISM
AND EXCRETION
- Hepatic metabolism by deacetylation to 3 and 17-hydroxy and 3,17-hydroxyvecuronium
- Clinically insignificant metabolites
- Excreted in bile (70%) and urine (30%)
EFFECTS
• Critical illness
myopathy if given for a
prolonged period
