Diallyl Nor-Toxiferine-A New Relaxant

Vol. 4, No. 2. SINGAPORE MEDICAL JOURNAL June, 1963. 90 DIALLYL NOR-TOXIFERINE-A NEW RELAXANT By George Tay, M.B.,B.S., F.F.A.R.C.S., F.F.A.R.C.S. (I) (The Yeoh Clinic, Singapore) Ever since 1914, when George Crile Senior, tres after clinical trials were carried out. One put forward his theory of anoci-association, was diohexadecanium bromide (Prestonal) anaesthesia began to develope along certain which was found to act for 6 to 8 minutes; lines. Instead of just producing an unconscious claimed at first to be a non -depolarizing agent, patient who felt no pain, the anaesthetist began it was found (Jolly, 1957) that anti-cholinestera- to divide the anaesthetic state into its compo- ses actually potentiated the block instead of re- nents parts of sleep, analgesia and muscular re- versing it. In addition, it produces a marked laxation. The neuromuscular blocking agents tachycardia and peripheral vasodilatation, and were used with increasing frequency, and, from despite the fact that it produces apnoea, the jaw 1948 onwards, when Gray and Halton publish- muscles remain stiff, rendering intubation diffi- ed their paper on curare, these agents became cult. an essential part of the armamentarium of the present day anaesthetist. The other compound, hexamethylene bis-car- bominoylcholine bromide (Imbretil) is still However, the neuromuscular blocking agents being used in certain centres; like suxametho- in common use, in particular the shorter acting nium it produces fasciculations and cramp -like ones, have certain disadvantages which preclude pains; believed at first to have both depolariz- their use in operative procedures lasting half ing and non -depolarizing properties, it has sub- to one hour. sequently been shown that it is a depolarizing agent, which in large doses will give rise to Suxamethonium. This depolarizing a agent, given dual block. In addition, it crosses the placental in intermittent doses, should be the ideal re- barrier. laxant for operative procedures like appendicectomies and herniorraphies, but for the fact that it produces a rather high incidence of post- DIALLYL NOR-TOXIFERINE operative muscle pains, which may be particul- Diallyl nor-toxiferine is a synthetic derivative larly distressing to the highly sensitive type of of the Calabash alkaloid, C-toxiferine I, and patient. The reason for these pains has not been like the latter, contains 2 quaternary ammonium fully established, but amongst the contributory atoms separated by about 15 Angstrom units; factors may be: (a) liberation of potassium it. may be recalled that these 2 properties are ions, (b) the initial muscle fasciculations caus- essential to make up the key, so that the door ing mechanical lesions, and (c) the liberation of muscle -excitation can be locked or opened of lactic acid. In addition, suxamethonium may at will. exhibit a marked parasympathomimetic effect, Diallyl nor-toxiferine is colourless, more so in the unatropinised patient, in whom odourless and crystalline. It is unstable in the presence it may precipitate cardiac arrest. of air and light; the ready -packed solutions ap- Decamethonium. Also a depolarizing agent, de- peared to deteriorate in strength, even when camethonium has a duration of action lasting kept in a cool, dark place. This was evident about 30 minutes; it is a useful agent, but it also during the clinical trials when more than the produces post -operative muscle pains which calculated dose had to be used if the ready - may last a few hours. Again, there is the danger packed solutions were used. The preparation of of a dual block developing if used in doses of powder and solvent, mixed just before using, more than 10 mgms. appeared to keep better in Singapore, and de- terioration in potency was not so pronounced. Gallamine Triethiodide. This non -depolarizing Diallyl nor-toxiferine is incompatible with bar- agent also has disadvantages-it produces a biturates. marked vagal blocking effect, leading to tachycardia, and it crosses the placenta, limiting its Like C-toxiferine I, diallyl nor-toxiferine is use in obstetric procedures like Caesarian sec- a non -depolarizing relaxant; it does not produce tions. the preliminary muscle fasciculations seen with the depolarizing agents, and does not give rise Newer relaxants. Recently, 2 other neuromus- to post -operative muscle pains. Being a non -de- cular blocking agents were developed, but their polarizing agent one would expect it to be re- use has been discarded in the majority of cen- versed by neostigmine. In actual fact, smaller 91 SINGAPORE MEDICAI. JOURNAL doses of neostigmine were needed for reversal cedures like appendicectomies and herniorra- when using diallyl nor-toxiferine. phies, provided intubation was not attempted. Increasing the dose to 1.5 mgms. per stone body C-toxiferine I was to be Originally, claimed weight made intubation easier, but at 2.0 mgms. the natural successor to d-tubocurarine chlo- per stone body weight, intubation was as easy ride, but it has fallen into disuse for the follow- as with suxamethonium, though abdominal re- ing (a) it has the longest duration of reasons:- laxation persisted for as long as 40 minutes, action of all the known non -depolarizing agents, compared with the 10 to 15 minutes after doses including laudexium methylsulphate, making it of 1 mgm. per stone body weight. In the useful only in long operations and in the treat- ma- jority of cases, 1.5 to 2.00 mgms. per stone body ment of tetanus. (b) there is also the danger of weight were used, smaller doses recurarization, even after apparently adequate being used for the very ill patient and the geriatric reversal by neostigmine. case. At this dosage level, diallyl nor-toxiferine is about The duration of action of diallyl nor-toxife- one and a half times to twice the strength of rine corresponds approximately to that of galla - d-tubocurarine chloride which is used in doses mine triethiodide, that is, 20 to 25 minutes, but of 3 mgms. per stone body weight. this, of course, depends on the dosage used, Diallyl nor-toxiferine was administered intra- higher initial doses tending to cause a longer period of block. Diallyl nor-toxiferine produces venously, via a Mitchell's needle, before or after a more profound relaxation of the abdorìtinal a sleep dose of either methohexitone or thio- musculature compared with equipotent doses of pentone, and in most cases, a test dose of 2 gallamine triethiodide. It is said to have no mgms. was given. The test dose was given rou- ganglion blocking effect and does not cause his- tinely to all patients undergoing subtotal thyroi- tamine -release, as does curare and gallamine. dectomy for thyrotoxicosis, in view of the pos- sible relationship between thyrotoxicosis and Clinical Applications: - Diallyl nor-toxiferine myasthenia gravis. The patient has to be ven- has been used in 302 cases, distributed as fol- tilated with nitrous oxide and oxygen for at lows :- least 2 minutes before direct vision intubation General surgery 207 can be performed. In certain instances, where Orthopaedic cases 42 difficulty is anticipated with intubation because Gynaecological cases - - 35 of anatomical peculiarities, suxamethonium in Obstetric cases 13 25 to 50 mgm. doses was given; diallyl nor- Radiological investigations 2 toxiferine was given after the resumption of Oral surgery 2 breathing. On some occasions, d-tubocurarine in 3 Otorhinolaryngology - - 1 chloride mgm. doses, was used to supple- ment diallyl nor-toxiferine. This was very satis- The 207 cases listed under general surgery were factory, and there were no cases of prolonged comprised of 26 operations in the head and block as a result of combining the 2 non -depo- neck region, 23 operations in the thorax, and larizing agents together. The other cases were 158 abdominal operations. Most of the 42 supplemented with intermittent doses of diallyl orthopaedic cases were major procedures, such nor-toxiferine. In all cases, anaesthesia was as laminectomies and pin and plating of frac- maintained with nitrous oxide, oxygen and hy- tured femurs. perventilation (Geddes and Gray, 1959). The 35 gynaecological cases were all major Ether and halothane, which are said to po- operations and the 13 obstetric procedures were tentiate the action of non -depolarizing agents, all lower segment Caesarian sections. have not been used in conjunction with diallyl nor-toxiferine, because it was felt that the in- DOSAGE AND METHOD OF ADMINIS- travenous barbiturate, relaxant, nitrous oxide, TRATION oxygen sequence was adequate for most types of major and minor surgery, without having re- Initially, the dose used was based on the re- course to other potent agents which only tend commendation of Hugin and Kissling (1961), to complicate the picture should any eventuality and modified to mgms. per stone body weight. occur. The dose first used for intubation and relaxation was 1 mgm. per stone body weight, but it There was no noticeable effect on the blood was found that at such dosage, endotracheal pressure or pulse rate, and no evidence of his- intubation was difficult even after waiting for tamine release as occasionally seen in the form 5 minutes; relaxation with this dosage, how- of wheals after the administration of d-tubocu- ever, was sufficient for lower abdominal pro- rarine chloride. Reversal was adequately achie- JUNE, 1963 92 ved in most cases with only half the amount of were in no way affected, and it was deduced neostigmine usually used for d-tubocurarine that the drug either did not cross the placenta, chloride, i.e. 2.5 mgms. instead of 5.0 mgms.; in or if it did, the quantities going across were in- all cases the neostigmine was preceded by atro- sufficient to affect the foetus. pine in 1.3 mgm. doses. Diallyl nor-toxiferine is eminently suited for SUMMARY plastic operations on the head and neck, block Diallyl nor-toxiferine is a non -depolarizing dissections of the neck and thyroidectomies, agent about one and a half times to twice the where the surgeon desires to infiltrate the skin potency of d-tubocurarine chloride, but of shor- and tissues with adrenaline.

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