Two Further Serum Pseudocholinesterase Phenotypes as Causes of Suxamethonium Apnoea

Abstract

Suxamethonium, a muscle relaxant whose properties were first described by Bo vet and his colleagues in 1949, has proved useful in anaesthesia because the duration of its action is short. Thus after the administration of 50-100 mg. the muscle paralysis and associated apnoea last only about two minutes. This brief action is due to the rapid destruction of the drug by serum pseudo cholinesterase (Bovet-Nitti, 1949). Rare individuals exist who possess a low level of serum pseudocholin esterase, and who, after the usual dose of suxa methonium, develop a prolonged apnoea which may last several hours (Bourne, Collier, and Somers, 1952 ; Evans, Gray, Lehmann, and Silk, 1952). This low serum pseudocholinesterase activity and the associated suxa methonium sensitivity have been shown to be inherited (Lehmann and Ryan, 1956). Kalow and his colleagues have shown that these individuals are homozygotes for a rare gene, and possess not a low level of the normal enzyme but an abnormal serum pseudocholinesterase. This abnormal or atypical enzyme differs from the usual type in two ways: it is less active in hydrolysing a large number of substrates, including suxamethonium (Davies, Marton, and Kalow, 1960), and more resistant to a majority of cholinesterase inhibitors (Kalow and Davies, 1958). Kalow and Genest (1957) have proposed the use of one such inhibitor, the local anaesthetic dibucaine (cinchocaine, nupercaine ), as a screening test to identify these homozygotes. In this test a 10~* M concentration of dibucaine inhibits the normal enzyme by about 80% and that found in suxamethonium sensitive individuals by only 20%. The percentage inhibition is called the dibucaine number, or DN. H?t?rozygotes, possessing a mixture of both enzymes, have dibucaine numbers of between 50 and 69. Various population surveys have shown that the suxamethonium sensitive homozygote occurs with a frequency of about 1 in 2,800, while 3.8% of the population are h?t?rozygotes (Kalow and Gunn, 1958 ; Kattamis, Zannos-Mariolea, Franco, Liddell, Lehmann, and Davies, 1962). Another genetic variant has been described in which the homozygote, detected because of a prolonged apnoea following suxamethonium administration, showed a complete absence of serum pseudocholin esterase activity (Liddell, Lehmann, and Silk, 1962). The gene responsible has been called the silent pseudocholinesterase gene. Harris and Whittaker (1961, 1962) have described a third variant of the enzyme. They discovered that sodium fluoride, like dibucaine, inhibits the atypical enzyme less strongly than normal pseudocholinesterase. Thus a 5 x 10~5 M concentration of sodium fluoride inhibits the normal enzyme by about 60%, the atypical enzyme by about 25%, and sera from h?t?rozygotes by abou 45%. Harris and Whittaker called this inhibition the fluoride number, or FN. When sera from large numbers of persons were examined a few individuals were found the dibucaine numbers of whose sera were sl ghtly lower and the fluoride numbers markedly lower than expected. Harris and Whittaker suggested that this was due to the presence of another variant of pseudocholinesterase with a slightly lower dibucaine number and markedly lower fluoride number than normal. Using both the dibucaine and fluoride te hniques, five types of individual can be recognized : 1. DN 80, FN 63 ; normal enzyme. 2. DN about 74, FN about 52 ; h?t?rozygotes possessing both he normal enzyme and the fluoride-resistant enzyme described by Harris and Whittaker. 3. DN about 64, FN about 48 ; h?t?rozygotes possessing oth the normal and atypical enzymes. 4. DN about 54, FN about 34 ; h?t?rozygotes possessing both the atypical and the fluoride-resistant enzymes. 5. DN about 20, FN about 23 ; homozygotes for the atypical enzyme.