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Three cases of severe anaphylaxis to gallamine triethiodide are described. All reported cases of anaphylaxis to gallamine have occurred in women, and all the confirmed cases in Australasia. There is evidnece that women may be exposed to some substance which leaves them sensitive to gallamine triethiodide.
The fate of gallamine triethiodide has been investigated in patients undergoing cholecystectomy with choledochostomy (group I), pelvic operations (group II) and orthopaedic operations (group III). Following a single i.v. injection of gallamine 2.5 mg kg(-1) the disappearance of the drug from the serum occurred in three phases with half-lives of less than 5, 30, 138 min, less than 5, 39, 141 and less than 5, 48, 144 min in the respective groups. Twenty-four hours after injection the renal excretion of the unchanged drug was 53% (15-100%) of the administered dose in group I, 67% (40-90%) in group II and 95% (89-100%) in group III. The biliary excretion of gallamine appeared to be negligible in man. The relationship between renal excretion and duration of action of gallamine, and the influence of some intraoperative factors on drug disposition, are discussed.
The cardiovascular effects of gallamine triethiodide and succinylcholine chloride were studied in Beagle dogs during controlled halothane anesthesia. Small but significant increases in heart rate and mean arterial presssure were observed 1 minute after intravenous injection of succinylcholine chloride. Intravenous injection of gallamine triethiodide did not produce significant cardiovascular changes.
.1 mol/L CaCl2 0.5 microliters, 0.06 mol/L ACh 0.5 microliters, 5.4 x 10(-3) mol/L gallamine triethiodide (cholinergic nicotinic receptor blocker) 0.5 microliter and 14.4 x 10(-3) mol/L atropine (cholinergic muscarinic receptor blocker) 0.5 microliter were injected through bilateral intracranial cannulae in rat habenula. Pain threshold was measured by the latency of tail-flick reflex elicited by radiant heat exposure before and after intracerebral injection. CaCl2 significantly reduced the basic pain threshold and weakened the effect of the acupuncture analgesia. ACh apparently antagonized the effect of acupuncture analgesia. Gallamine triethiodide could recover the pain threshold almost to the raised level by acupuncture, but atropine only strengthened the effect on pain threshold weakly and briefly. The results suggest that the antagonistic effect of Ca2+ may be mediated via ACh in habenula.
Gallamine triethiodide ("Flaxedil") is in common clinical and experimental use specifically to block neuromuscular transmission. Voltage-clamp studies show that gallamine also has direct effects on amphibian and mammalian nerve fibers, whether applied externally or internally. With external application, gallamine (0.1-10.0 mM) is about 5 times more potent than tetraethylammonium chloride in blocking the delayed potassium conductance (gk), where this is present. The sodium conductance is completely unaffected by external gallamine in both species. Internal application of gallamine to myelinated nerve fibers slows sodium inactivation. In addition, at positive potentials, gallamine can enter Na+ channels and occlude them, thereby almost eliminating outward sodium currents. In rat fibers, a significant fraction of the sodium channels fail to inactivate and thus large inward sodium tail currents occur upon repolarization. The general consequences of these findings with regard to possible "side-effects: in gallamine-paralyzed preparations is discussed.
A central action of gallamine triethiodide has been demonstrated in cats with permanently implanted electrodes that permit direct repetitive stimulation and recording of afterdischarges from cerebral cortex. Systemically administered gallamine produced a consistent and reproducible augmentation of duration of afterdischarge at doses just sufficient to produce skeletal muscle paralysis. Simultaneous examination of expiratory carbon dioxide, blood pressure, body temperature, blood glucose, and direct cortical response to brief single stimuli failed to reveal any consistent peripheral change to which the centrally observed effecte Could be attributed.
The onset, depth and recovery from paralysis produced by gallamine triethiodide were studied using the tibialis anterior muscle/sciatic nerve preparation in mongrel dogs, during changes in blood flow to this muscle. A roller pump was used to effect the blood flow changes via an aorto-femoral shunt. The onset and depth of paralysis were related directly to muscle blood flow. There was no correlation between the rate of recovery from paralysis and the blood flow to the muscle.
Gallamine triethiodide (Flaxedil) is commonly used as a neuromuscular blocking agent. Voltage-clamp studies show that gallamine also directly affects amphibian and mammalian myelinated nerve fibers. Externally, gallamine is about five times more potent than tetraethylammonium in blocking potassium conductance, where this is present, but has no effect on the sodium channel. Internal application slows sodium inactivation, which in addition is often incomplete. At positive potentials, gallamine can occlude sodium channels, thereby almost eliminating outward sodium currents.
Gallamine triethiodide, a drug commonly used in neurophysiological experiments, causes statistically significant and inconsistent changes in the information-carrying capacity of trains of action potentials generated by members of a population of gamma motor neurons recorded from the same cat under the same conditions during the same time period.
1. Repeated flashes of diffuse light were presented to the cat's eye over long periods of time (hours) while the mixed ganglion cell response was recorded from single axons in the optic tract. This was done for cats receiving gallamine triethiodide intravenously and for cats who did not receive the drug.2. All responses were transformed into instantaneous pulse density tracings. Such tracings from control and gallamine cells were compared to observe possible effects of gallamine: (a) the shape (time course) did not change during gallamine administration; (b) maximum firing frequency, total number of spikes and latency was measured for both the on- and the off-component on the pulse density tracings and plotted versus time. Statistical methods failed to reveal any difference between the manner in which these response features of control cells and of gallamine cells varied with time.
Plasma concentrations of gallamine were determined in 6 patients undergoing anaesthesia for elective surgery receiving a single intravenous bolus dose of 2 mg/kg and in a further 11 patients requiring additional doses (0.5 to 2 mg/kg) of the relaxant. The two-compartment open model was found to characterize adequately both the single and multiple dose data. No significant differences were noted when the model-independent pharmacokinetic parameters between the two groups of patients were compared with the exception of the distribution phase half-life (t1/2 alpha) (6.70 min single vs 9.19 min multiple p less than 0.05). Mean values for the pooled data for the half-life (t1/2 beta), plasma clearance (Clp) and volume of distribution (Vd beta) were 134.58 min, 1.20 ml/min/kg and 225.28 ml/kg respectively. Evoked twitch response was monitored in each patient to assess the degree of neuromuscular blockade. In only one patient was the bolus dose sufficient to produce complete (100%) blockade, thus the degree of maximal response varied between 78 to 100% and took some 3 to 10 minutes after dose administration. The concurrently measured gallamine plasma concentrations ranged from 9.30 to 19.20 micrograms/ml. Linear regression of the offset data (20 to 80% paralysis) in 10 patients revealed a recovery rate of 0.35 to 1.33%/min. For 5 patients where offset data was available over the entire range of response (0 to 100%) the calculated mean effective plasma concentrations for gallamine at 50 and 95% paralysis (ECp50, ECp95) were found to vary between 3.43 to 10.28 micrograms/ml, and 5.66 to 23.37 micrograms/ml respectively.
Pharmacokinetics and pharmacodynamics of gallamine were assessed in seven patients undergoing surgery for correction of total biliary obstruction. Results were compared to those obtained in a previous study of 17 patients without obstruction. A significant increase in the steady-state volume of distribution of gallamine was noted in patients with biliary obstruction as compared to the group without obstruction, but no significant differences between the groups were apparent for the biologic half-life and total clearance of the drug. Duration of action of gallamine and rate of recovery together with onset characteristics were similar in both patient groups. Slight accumulation of gallamine was noted in two of the four patients with biliary disease receiving multiple doses of gallamine, but this was also characteristic of data obtained in the patients without obstruction. At completion of surgery to relieve the biliary obstruction all patients showed a measurable degree of recovery from paralysis, and no difficulties were experienced in the reversal of relaxant effect. Contrary to the observed "resistance" of patients with liver disease to the action of d-tubocurarine no such finding was apparent in this study with gallamine. Gallamine may be the relaxant of choice for surgery to relieve total biliary obstruction provided no complicating renal pathology is also present.
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Two cases are described in which patients developed acute anaphylactic reactions to precurarising doses of gallamine. Life threatening complications can arise from the use of small doses of drugs as adjuncts to anaesthesia and raises the question whether the benefits of precurarisation outweigh the risks of anaphylaxis.
A patient suffered profound anaphylactoid reaction during anaesthesia. Intradermal skin testing confirmed the clinical impression that gallamine caused the reaction. The method of testing is discussed. Previous reports of hypersensitivity to the drug are reviewed, and the use of adrenaline, antihistamines and corticosteroids in patient management are considered.
Fourteen patients undergoing elective surgery were studied at two levels of gallamine dosage. Seven patients received a single bolus dose of 4 mg/kg, and the remainder received 6 mg/kg. The venous plasma concentration-time data from both groups were characterized in terms of a two-compartment open model. No significant differences in the various pharmacokinetic parameters were noted. However the distribution and clearance terms from these two patient groups were significantly higher than those obtained with a previous group of patients receiving lower (2 mg/kg) single and multiple doses. Assessment of neuromuscular twitch response showed that maximum blockade was attained in all patients within 5 min with the time to peak effect being dose dependent. Recovery from paralysis as assessed at 99, 95 and 90% paralysis indicated that the duration of action was similarly dose dependent. The concurrently measured plasma concentrations showed wide variation but were higher at more profound levels of paralysis. Arterial blood samples for 5 patients receiving the 4 mg/kg gallamine dose were taken simultaneously with the venous samples over the first sixty minutes. No significant arterio-venous differences in gallamine plasma concentration were noted at any time interval in all subjects.
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