Pharmacodynamics and Potential Adverse Effects

To the Editor:—We appreciate the three articles in the April 2004 issue of ANESTHESIOLOGY regarding GW280430A. Although remarkable advances in developing intermediate and short-acting muscle relaxants were realized, anesthetists have not yet been provided with a substance comparable to succinylcholine in terms of its rapid onset and ultrashort-acting pharmacodynamic profile. However, this aim should not be lost. A survey in Germany revealed that, despite its undesirable side effects, succinylcholine is still the most used drug for both rapid sequence inductions and for elective case induction. An overwhelming majority (76.6%) of respondents answered that they would appreciate a nondepolarizing substitute for succinylcholine if a similar pharmacodynamic profile was preserved. Assuming that this is not an isolated German viewpoint, a substance replacing succinylcholine would be highly desirable. The developers and the researchers have a great responsibility when introducing a new drug into clinical practice, particularly in neuromuscular blocking drugs. Dr. Caldwell addresses this issue in his editorial when he compares the side effects of rapacuronium and GW280430A. Because we were involved in the clinical evaluation of rapacuronium, we would like to comment on some relevant aspects of the side effect profiles of both drugs and on the drug approval processes. First, in clinically relevant concentrations, rapacuronium potentates bronchoconstriction most probably by destabilization of the balance between M2 and M3 muscarinic receptors. In contrast, GW280430A seems to release histamine and therefore may possibly induce bronchoconstriction. Second, although many antihistaminic drugs and prophylactic strategies are available, an effective treatment to rebalance the muscarinic effects of rapacuronium was and is still missing. Third, because rapacuronium did not release histamine, because different M2 versus M3 muscarinic effects of muscle relaxants were unknown at that time, and because clinical symptoms of the pulmonary side effects differed from those seen during typical bronchoconstriction, the clearly described dose-dependent pulmonary side effects (from 10.7% with 1.5 mg/kg rapacuronium to 18.5% with 2.5 mg/kg rapacuronium) may have been questioned—unfortunately until patients were badly harmed. Therefore, we agree with Dr. Caldwell that the recent experience with rapacuronium must be considered during the trials with GW280430A, e.g., by in addition investigating its effects on M2 and M3 receptors. The fiasco with rapacuronium, however, must not induce pessimism if new drugs and especially GW280430A may have the potency to improve anesthesia practice. GW280430A was, of course, not compared with rapacuronium, but it was also not compared to succinylcholine. Regardless, the hope that GW280430A will be a substitute for succinylcholine has been advanced with this first presentation. Expectations that this new drug will approximate the rapid onset of succinylcholine may in high doses, high injection speeds, and, therefore, the risk for high incidences of side effects. The presentations primarily suggest that GW280430A may be an ultrashort-acting rather than a rapid-onset muscle relaxant. Unfortunately, preclinical and clinical trials to approve new drugs are expensive, and, in this context, the substance to be replaced is already very cheap. Nevertheless, we (and many other anesthetists) would like to encourage the recent attempts to develop better muscle relaxants (or reversal drugs, e.g., Org 25969) to improve safety and efficiency of neuromuscular treatment during anesthesia.