Editorial Views  |   April 2006
Succinylcholine: New Insights into Mechanisms of Action of an Old Drug
Author Affiliations & Notes
  • Jeevendra Martyn, M.D., F.R.C.A., F.C.C.M.
  • Marcel E. Durieux, M.D., Ph.D.
  • *Harvard Medical School; Clinical & Biochemical Pharmacology Laboratory, Massachusetts General Hospital; and Shriners Hospitals for Children, Boston, Massachusetts. †Departments of Anesthesiology and Neurological Surgery, University of Virginia, Charlottesville, Virginia.
Article Information
Editorial Views / Pharmacology
Editorial Views   |   April 2006
Succinylcholine: New Insights into Mechanisms of Action of an Old Drug
Anesthesiology 4 2006, Vol.104, 633-634. doi:
Anesthesiology 4 2006, Vol.104, 633-634. doi:
EVEN 50 yr after its introduction, succinylcholine continues to be used, because it still has the fastest onset of effect of the clinically available muscle relaxants.1 After the initial description of the neuromuscular blocking properties of succinylcholine by Daniel Bovet,2 S. Thesleff3 at the Karolinska Institute in Stockholm was one of the pioneers who introduced the drug into clinical practice to induce neuromuscular paralysis in humans. (Bovet was awarded the Nobel Prize for Physiology and Medicine in 1957 for his discovery of synthetic compounds that act on the vascular system and skeletal muscle.) Despite half a century of use, several pharmacologic properties of succinylcholine remained essentially unexplained. These include the lack of fade with single-dose treatment, the development of phase II block with larger doses of the drug, and cardiovascular side effects, particularly the bradycardia and cardiac arrest commonly observed after second or third injections of succinylcholine.4,5 Because of the chemical nature of succinylcholine, it was assumed that the cardiovascular side effects were related to the nonneuromuscular actions of succinylcholine on other acetylcholine receptors (AChRs), including the heart, autonomic ganglia, and adrenal medulla. In this issue of Anesthesiology, a report by Jonsson et al.  , also from the Karolinska Institute, provides biophysical insight into some of the mechanisms of action and side effects of succinylcholine.6 
To date, 17 nicotinic AChR subunits have been cloned and consist of α1–α10, β1–β4, δ, γ, and ϵ.7 The mature AChR in muscle is composed of five subunit proteins, including two α1 and one each of β1, ϵ, and δ. The prejunctional nicotinic AChR is purported to consist of α3β2,8 and the AChRs in the ganglion are mainly composed of α3β4.9 Jonsson et al.  use up-to-date methodology to study the interaction of the AChR subtypes with succinylcholine. In essence, they create a simplified version of the AChRs expressed at the neuromuscular junction, presynaptic nerve terminal, and autonomic ganglia by artificially expressing these AChRs in oocytes of the toad Xenopus laevis  . These oocytes are convenient “protein factories” and are frequently used to study receptor properties. Using this model, they found that (1) succinylcholine caused an initial activation of the muscle AChR followed by desensitization; (2) at clinically relevant concentrations, succinylcholine had no stimulatory or inhibitory interaction with α3β2 (presynaptic) or α3β4 (ganglionic) AChRs; and (3) high doses of succinylcholine caused inhibition of both α3β2 and α3β4 receptor.
When acetylcholine binds to the AChR on muscle, the channel opening is of a very short duration because of the rapid transmitter degradation by acetylcholinesterase in the perijunctional area. In contrast, the depolarizing relaxants decamethonium and succinylcholine have a biphasic action—an initial contraction followed by relaxation. This is because both drugs are not susceptible to hydrolysis by acetylcholinesterase and are therefore not eliminated from the junctional cleft easily. Depolarization of the endplate by the relaxant causes the adjacent voltage-gated sodium channels to open, causing a wave of depolarization to sweep along the muscle. If the depolarizing relaxant is not removed from the cleft, the sodium channels adjacent to the endplate remain in the inactivated state, resulting in muscle paralysis or relaxation.10 Jonsson et al.  now demonstrate that in addition to this sodium channel–dependent mechanism, the receptor itself, after initial depolarization, becomes desensitized to further depolarization. This observation is consistent with in vivo  studies and clinical observations: Even long after complete recovery of twitch and train-of-four from succinylcholine-induced paralysis, the neuromuscular junction can often behave in a more sensitive (desensitized) fashion when depolarizing or nondepolarizing relaxant is subsequently administered.5 
The finding that high doses of succinylcholine inhibited presynaptic α3β2 AChRs (i.e.  , the compound behaved like a nondepolarizing relaxant) may help to explain how high or repeated doses of succinylcholine result in a nondepolarizing type of block (phase II block) characterized by fade and posttetanic potentiation. However, the study did not include direct comparisons of the effects of nondepolarizing compounds on α3β2. Therefore, it is not possible to make conclusive statements as to the similarity between effects of succinylcholine and nondeporalarizing muscle relaxants on these prejunctional receptors.
Finally, the lack of effect of succinylcholine on ganglionic receptors (α3β4) suggests that tachyarrhythmias occasionally seen with succinylcholine are unrelated to this interaction. Therefore, this study puts to rest previous hypotheses that such tachyarrhythmias are related to stimulatory effects on the autonomic ganglia or release of catecholamines from the adrenal medulla by succinylcholine. We are still left without a conclusive mechanism of the (more common) succinylcholine-induced bradycardia, which is usually attributed to agonist actions on the muscarinic AChRs of the heart.5 The authors did note, however, that succinylcholine dose-dependently inhibited ganglionic AChRs. Can the inhibition of the autonomic ganglia and the continued agonist action of succinylcholine on the muscarinic (vagus) receptor explain the bradycardia seen with repetitive doses of succinylcholine? If this is correct, how does the previous administration of d-tubocurarine prevent the bradycardia?
In using models as far removed from clinical reality as the Xenopus  oocyte expression model, a number of assumptions have to be made. Two most important questions are whether the receptors expressed in the oocyte truly duplicate all those present at the site that is modeled, and whether the RNAs injected are actually expressed and in the appropriate stoichiometry. The second question is addressed by the authors in the article, but the first one requires some comment. Responses to acetylcholine can be seen even when the critical α subunit is omitted from the RNA mixture used for oocyte injection, suggesting the presence of an endogenous oocyte α subunit (with possibly different responses to succinylcholine).11 It is therefore possible that other receptor subtypes may be present in the model and that the investigators are studying a mixture of receptor subtypes. Furthermore, the exact nature and composition of prejunctional nicotinic and muscarinic AChRs at the nerve terminal are not fully characterized.8,12 Based on monoclonal antibody studies, nicotinic α3 receptors are known to be expressed at the nerve terminal,13 but what other subunits are involved is not known with certainty, except that prejunctional AChRs do exist.12–14 Therefore, did the investigators choose the correct subunit mixture of α3β2? Complementary studies to document that a nondepolarizing relaxant inhibits these purported prejunctional receptors would have been supportive evidence.
Despite these caveats—unavoidable in a study of this nature—Jonsson et al.  , with their elegant and detailed experiments, provide a splendid example of how modern molecular techniques can be used to address old (but important) questions in anesthetic pharmacology.
*Harvard Medical School; Clinical & Biochemical Pharmacology Laboratory, Massachusetts General Hospital; and Shriners Hospitals for Children, Boston, Massachusetts. †Departments of Anesthesiology and Neurological Surgery, University of Virginia, Charlottesville, Virginia.
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