Hemodynamic effects of muscle relaxants
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Hemodynamic effects of
muscle relaxants
T h e hemodynamic effects of neuromuscular
blocking drugs (muscle relaxants) may be attrib-
uted to two basic mechanisms: (1) histamine
release; and (2) acetylcholinelike effects that may
Anis Baraka, M.D. be central, neuromuscular, or autonomic.
Beirut, Lebanon H i s t a m i n e release
In 1939, Alam et al 1 demonstrated for the first
time that intraarterial injection of ¿/-tubocurarin^
in dogs resulted in release of histamine. Consider-
able range of organic bases can directly mobilize
histamine from its bound state in the mast cells.
All muscle relaxants may stimulate histamine
release. T h e most important relaxant in this con-
nection is ¿-tubocurarine. 3 This direct histamine-
releasing effect can be clinically important in atopic
patients. In contrast with this direct effect, the
histamine release that follows antigen-antibody re-
action is not limited to ¿/-tubocurarine, and has
been reported with other relaxants.
Acetylcholinelike effects
Neuromuscular blocking agents are structurally
similar to acetylcholine. They are positively
charged quaternary ammonium compounds, which
mimic or compete with acetylcholine at the central,
neuromuscular, and autonomic cholinoceptive sites.
Central sites. Muscle relaxants are ionized hy-
16
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require permission.Spring 1981 Hemodynamic effects of muscle relaxants 17
drophylic molecules that do not cross mitter at the neuromuscular junction,
readily the blood-brain barrier. How- at the ganglia of both sympathetic and
ever, Piess and Manning 4 found that parasympathetic systems (nicotinic),
moderate doses of curare have a central and at the muscarinic postsynaptic re-
action on the mechanism controlling ceptors. In analogy with the different
cardiovascular function. Also, Forbes et adrenergic receptors, it appears that nic-
al 5 showed that pancuronium reduces otinic and muscarinic receptors vary ac-
halothane requirements in man. These cording to the target organs. Nicotinic
effects can be explained by considering receptors at the neuromuscular junction
the blood-brain barrier as a relative and may be different from those present at
not an absolute barrier, which can allow the ganglia, and muscarinic receptors of
the passage of relaxants. Following in- the heart may be different from musca-
travenous injection, the intrathecal con- rinic receptors present elsewhere.
centration of rf-tubocurarine is about Muscle relaxants either mimic (ago-
1/1000 the plasma concentration. 6 Both nists) or block the effect (antagonists) of
nicotinic and muscarinic cholinergic acetylcholine not only at the neuromus-
pathways exist in the central nervous cular junction, but also on these auto-
system, and may be inhibited by relax- nomic cholinoceptive sites.
ants. 7 " 10
Neuromuscular effects. T h e hemo- Agonists
dynamic effects of muscle relaxants may Succinylcholine, consisting of two
also be secondary to the neuromuscular acetylcholine molecules linked together,
effects. T h e loss of muscle tone and pe- appears to display all stimulating effects
ripheral pooling of blood, together with of the chemical transmitter on both the
the initiation of intermittent positive nicotinic and muscarinic cholinergic re-
respiration, can greatly impede venous ceptors. 3 T h e net effect is a balance of
return and lower cardiac output. T h a t the two actions. After the first dose of
is why relaxants that lack histamine succinylcholine, the nicotinic effect usu-
release or autonomic side effects, such as ally predominates and results in hyper-
metocurine and alcuronium, may lower tension, tachycardia, a n d arrhythmia.
the blood pressure. 11 However, after repeated doses and
In contrast, the initial muscle fascic- sometimes after the first dose, the mus-
ulation associated with depolarizing re- carinic effect predominates and mani-
laxants such as succinylcholine can aug- fests itself as bradycardia. 19 " 24 Bradycar-
ment venous return. Also, the supersen- dia can even be observed in isolated
sitivity response of denervated muscles, hearts denoting a direct muscarinic ef-
extensive burns, massive trauma, and fect of succinylcholine on the pace-
severe sepsis to succinylcholine can in- maker. 25 It can be prevented by prior
duce massive hyperkalemia and trigger administration of an anticholinergic
serious cardiac arrhythmias. 12 " 18 drug or a pretreatment dose of nonde-
Autonomic side effects. Neuromus- polarizing relaxant.
cular blocking drugs can be classified
according to their effect on autonomic Antagonists
transmission. A clear understanding of Nondepolarizing relaxants can have
autonomic transmission is the basis of different autonomic effects 26 : (1) No or
such classification. minimal autonomic effects, e.g., dime-
Acetylcholine is the chemical trans- methyl tubocurarine (metocurine) and
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require permission.18 Cleveland Clinic Quarterly Vol. 48, No. 1
diallylnortoxiferine (alcuronium). (2) manent quaternary nitrogen, whereas
Nicotinic blockers, e.g., rf-tubocurarine. the other nitrogen is a tertiary amine
(3) Muscarinic blockers, e.g., gallamine, with a p K a 8.1. ¿/-Tubocurarine can
pancuronium. O r g NC45, a homologue release histamine and block ganglionic
of pancuronium was found to have nicotinic transmission of both the vagus
fewer autonomic effects than that of and sympathetic pathways within the
pancuronium. 2 7 neuromuscular-blocking dose range.
T h e dose-ratio of autonomic to neu- Both the ganglion-blocking and the his-
romuscular block has been termed the tamine-releasing properties of the drug
"autonomic margin of safety," 28 " 30 and may be attributed to the presence of a
is equal to: tertiary amine.
Muscarinic blockers, e.g., pancuronium
ED 50 for vagal and sympathetic
and gallamine. T h e two drugs do not
inhibition
release histamine or block ganglionic
E D 95 for neuromuscular blockade transmission. However, both block the
Neuromuscular blocking drugs can be vagal muscarinic receptors in the dose
classified according to their "autonomic range required for neuromuscular block.
margin of safety" into two categories: T h e vagolytic properties of gallamine
overlie the neuromuscular blocking ac-
1. High autonomic margin of safety tion, 26 and is dose-related 32 ; that of pan-
T h e drug will show a wide separation curonium is only significant at the up-
of neuromuscular block from its auto- per end of the neuromuscular dose-re-
nomic side effects, e.g., dimethyl tubo- sponse curve. 26 T h e potent vagolytic ef-
curarine and diallylnortoxiferine. fect of pancuronium and gallamine may
Dimethyl tubocurarine (metocurine) be related to their structure. Pancuron-
is a bis-quaternary ammonium molecule ium is the nondepolarizing relaxant
having no ganglionic blocking or hista- most closely related structurally to ace-
mine-releasing properties. Thus, it has tylcholine, whereas the vagolytic prop-
a high autonomic safety margin. T h e erty of gallamine is due to the presence
drug is produced as a result of methyl- of three positively charged nitrogen at-
30
ation of the parent relaxantSpring 1981 Hemodynamic effects of muscle relaxants 19
atory pathway and a multisynaptic in- muscarinic blockers such as gallamine
hibitory pathway. T h e latter contains and pancuronium will increase myocar-
an interneuron possessing a muscarinic dial contractility and arteriovenous con-
receptor, which upon stimulation causes duction, 42 and induce tachycardia and
a release of inhibitory neurohumor, pos- hypertension.
sibly dopamine. 3 4 At the sympathetic T h e hemodynamic effect of muscle
nerve terminals, presynaptic alpha ad- relaxants, and the interaction with the
renergic receptors (alpha 2) mediate a anesthetic used, drug therapy, and the
negative feedback mechanism that condition of the patient, are factors that
leads to inhibition of catecholamine determine the choice of the relaxant.
release probably by restricting the cal- For example, neuromuscular blocking
cium available for the excitation-secre- drugs having a nicotinic blocking effect,
tion coupling. In contrast, presynaptic such as rf-tubocurarine, may be the re-
beta-adrenoreceptors (B3) mediate a laxants of choice in hypertensive pa-
positive feed-back mechanism leading tients or whenever a hypotensive tech-
to an increase in transmitter release; this nique is planned. In contrast, pancuron-
mechanism appears to be mediated ium may be selected in shocked and
through an increase in the levels of hypovolemic patients. Hypotension
cyclic adenosine monophosphate in the should be avoided in patients with cor-
adrenergic nerve endings. In addition to onary artery disease, low fixed cardiac
the alpha- and beta-presynaptic adre- output, and those with intracardiac
nergic receptors, inhibitory muscarinic shunts. Hypertension should be avoided
receptors a n d excitatory nicotinic recep- in patients with coronary artery disease,
tors have been described. 35 aortic insufficiency, a n d mitral insuffi-
Muscle relaxants that have nicotinic ciency. Tachycardia should be avoided
or muscarinic-blocking action can, in patients with coronary artery disease,
therefore, modulate sympathetic trans- aortic and mitral stenosis, and in any
mission and catecholamine release. Pan- patient with small ventricular stroke
curonium a n d gallamine can inhibit the volume. Anesthesiologists should choose
inhibitory muscarinic receptors at the the relaxant that best produces the de-
sympathetic ganglia and the adrenergic sired cardiovascular effects on the indi-
postganglionic nerve terminals and thus vidual patient. 4 3
increase t h e release of catechol-
amines. 34, 3 6 , 3 7 In contrast, ¿-tubocurar-
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