AND OFFSET OF
EFFECT?
ONSET
OF ACTION
Neuromuscular blocking drugs are water-soluble,
ionised substances of low molecular weight. A good example of such a drug is
succinylcholine, which consists of two bisquaternary ammonium groups connected
by a carbon chain. Succinylcholine is a drug of low potency – a much larger dose
is administered intravenously than is required to produce neuromuscular block.
In part, this is necessary because the breakdown of the drug in the plasma by
plasma cholinesterase (clearance), reduces the amount reaching the effect site
– the post-synaptic nicotinic receptor. But nevertheless, the plasma – effect
site gradient is steep. This is a prerequisite for rapid onset of block. But
depolarising drugs only need to block 20% of the nicotinic receptors to have a
clinically useful effect. With non-depolarising agents, a much larger
percentage of the nicotinic receptors, greater than 75%, have to be occupied to
produce a clinical effect. Thus a rapid onset of effect from a non-depolarising
agent has been difficult to achieve.
It is not therefore difficult to imagine that a
large dose of a non-depolarising drug, in terms of number of molecules, would
need to be administered to produce rapid onset of block comparable with
succinylcholine. The drug also needs to equilibrate rapidly with the extracellular
fluid adjacent to the receptor; this is often referred to as the biophase. A large gradient between the
higher plasma concentration and the concentration at the effect site will
potentiate this effect. Bowman1 theorised that within a chemical
group of drugs, the less potent the molecule, the greater would be the dose
required, and the more rapid would be its onset of action. This has been
demonstrated for 2 x ED95 of the aminosteroid agents: time to 95%
depression of the train-of- four twitch response after pancuronium 0.08 mg kg-1
is about 4.0 min; after vecuronium 0.1 mg kg-1 it is 3.0 min; and after
rocuronium 0.6 mg kg-1 it is 75 sec. So on this principle alone, if
one was searching for an aminosteroid with a rapid onset of effect, one would
study molecules of low potency. Two times the ED95 for rapacuronium
is 1.0-1.5 mg kg-1, - an even lower potency than rocuronium -
suggesting that the newer agent would have the more rapid onset. Clinical
investigations have demonstrated times to 95% depression of the twitch response
after rapacuronium to be 66 - 90 sec.2,3
There is another factor governing the rate of onset
of neuromuscular blocking drugs; the equilibration rate constant (keo) between
plasma and the effect site, i.e. the nicotinic receptor, which determines how
rapidly the two concentrations become equal. This value is greater for
rapacuronium at the adductor pollicis muscle (0.405 per min),4 than
for other neuromuscular blocking drugs such as rocuronium (0.168 per min),5
and vecuronium (0.12 per min),6 and at the laryngeal muscles (0.63,
0.26 and 0.18 per min respectively).
Time Course of Action
A more rapid decrease in plasma concentration of a
neuromuscular blocking drug (a shorter distribution half-life) results from a
more rapid plasma clearance or distributional clearance. It would hasten the
time at which the peak concentration of drug occurred at the effect site. A
larger dose may also be required. The plasma clearance of rapacuronium (6.4 ml
kg-1 min-1),7 is larger than that of
vecuronium (up to 5.1 ml kg-1 min-1), or rocuronium (2.9
ml kg-1 min-1). The active isomers of the
benzylisoquinolinium compound, mivacurium, have much higher clearances e.g. trans-trans mivacurium 57 ml kg-1 min-1,8
but mivacurium has a much longer onset of action, probably because of a lower
keo – both factors need to be present for rapid onset of block.
The drug concentration in the laryngeal muscles
equates more rapidly with plasma concentration than does the drug concentration
in the muscles of the hand, (which are frequently used to monitor neuromuscular
block), because of a larger blood flow per gram of tissue. But this effect
applies to varying degrees to all neuromuscular blocking drugs; the ratio of
the keo for the laryngeal muscles and adductor pollicis is similar for
rapacuronium, rocuronium and vecuronium.4,5,9
Values of keo for rapacuronium in women are higher
than in men and onset of action may be faster.4
OFFSET
OF ACTION
Keo has a direct effect on potency. If keo is
smaller, a larger dose of neuromuscular blocking drug is required to achieve an
equivalent peak effect site concentration. A larger dose can, however, also
cause a longer recovery time. Therefore the larger keo of rapacuronium speeds
recovery from block compared with other non-depolarising agents.
As soon as effect site concentration has peaked, the
larger keo of rapacuronium allows the effect site concentration to track the
plasma concentration. If the plasma concentration declines rapidly, recovery
from block will be quicker than for a drug with a lower keo.
Plasma Clearance
The larger plasma clearance of rapacuronium also
contributes to rapid recovery, although this in itself is not sufficient to
explain the more rapid recovery from neuromuscular block produced by
rapacuronium than other non-depolarising drugs. Nevertheless, if plasma
clearance of rapacuronium is reduced by, for instance, chronic renal failure,10
then recovery from block may be prolonged.
Rapacuronium is deacetylated in the liver to
3-desacetyl rapacuronium (Org 9488) which has neuromuscular blocking
properties. This may not influence the
time course of recovery following a bolus dose of rapacuronium, because the
plasma concentration of Org 9488 will be low. However, the metabolite may delay
recovery after infusion of rapacuronium for over 1 hr, as in these
circumstances, Org 9488 accumulates.11 Org 9488 has a lower
clearance (1.06 – 1.28 ml kg-1 min-1), and a higher rate
of renal excretion (greater than 50%) than rapacuronium, both of which cause
plasma concentrations of the metabolite gradually to rise. The concentration in
the biophase at 50% neuromuscular effect is higher for rapacuronium (4.7 ug ml-1)
than for Org 9488 (1.83 ug ml-1), but the latter value can still
have clinical significance.
The smaller steady state volume of distribution of
rapacuronium in women than men,7 could produce slightly longer
recovery times.
REFERENCES
1.
Bowman
WC, Rodger IW, Houston J, Marshall RJ, McIndewar I. Structure: action
relationships among some desacetoxy analogues of pancuronium and vecuronium in
the anesthetized cat. Anesthesiology 1988;
69: 57-62
2.
Kahwaji
R, Bevan DR, Bikhazi G, Shanks CA, Fragen RJ, Dyck JB, Angst MS, Matteo R.
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rapid-onset, short-duration muscle relaxant. Anesth Analg 1997; 84:
1011-8
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Plaud
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modeling of muscle relaxants? Anesthesiology
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dose of rapacuronium bromide. Anesthesiology 1999; 90: 24-35
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AG, Devlin JC, Parker CJR, Hunter JM.
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Fisher
DM, Szenohradszky J, Wright PMC, Lau M, Brown R, Sharma M. Pharmacodynamic
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equilibration explains faster onset at resistant laryngeal muscles than at
adductor pollicis. Anesthesiology 1997;
86: 558-66
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Fisher
DM, Dempsey GA, Atherton DPL, Brown R, Abengochea A, Hunter JM. Effect of renal failure and cirrhosis on the
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bolus followed by infusion. Anesthesiology
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S, Proost JH, Schuringa M, Wierda JMKH.
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