VIRAL HEPATITIS

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Annotations INFLUENCE OF ACID-BASE BALANCE ON THE ACTION OF DRUGS

CHANGES in acid-base balance have long been known influence both the therapeutic and toxic effects of salicylates. Administration of sodium bicarbonate reduces the toxicity and plasma level of salicylate 1; and Smith et al. showed that this was due to increased rate of excretion of salicylate in alkaline urine. The clearance of unconjugated salicylate is much lower than that of inulin in acid urine, but is higher in alkaline urine.3 Hyperventilation and acetazolamide, both of which produce an alkaline urine, are as effective as sodium bicarbonate in increasing salicylate excretion.4 Since acetazolamide produces systemic acidosis,5 the increased salicylate excretion in alkaline urine must be directly related to the urinary pH and not to change in systemic acid-base balance. More recently the excretion of two other important drugs, phenobarbitone and mecamylamine (’Inversine), has been shown to resemble that of salicylate. Phenobarbitone, which is a weak acid, is excreted more rapidly when the urine is alkaline.6 Barbitone itself, although also largely eliminated in the urine, is little affected by variation in acid-base balance. Mecamylamine, a weak base, is excreted more rapidly when the urine is acid. 7-9 Other ganglion-blocking drugs, such as hexamethonium and pentolinium, are much stronger bases and are unaffected by acidosis or alkalosis. Many other weak bases, including mepacrine and chloroquine,IO 111 procaine,12 and quinine," 13 are excreted in the same way as mecamylamine. Variation in excretion-rate in the case of the weak-base drugs is, however, of little importance since only a small proportion of any dose appears in the urine. Alkalinisation of the urine increases the hypotensive effect of mecamylamine,89 and reduces the toxicity of phenobarbitone and salicylate. Acidification of the urine by ingestion of ammonium chloride has the opposite effect. Treatment with sodium bicarbonate has been recommended both in salicylate4 and in phenobarbitone6 poisoning. Other workers have recommended dialysis with the artificial kidney in salicylate 14 and barbiturate 15 intoxication. Probably the ideal method of removing the drugs from the body in severe poisoning is a combination of the two methods. Variation in the rate of excretion of these drugs influences the amount retained in the body, and therefore there is a gradual modification of their pharmacological effects. In contrast, sudden changes in systemic acidbase balance may rapidly alter the distribution of drugs within the body, while the total amount remains unchanged. This may be associated with corresponding to

1. 2. 3. 4. 5. 6. 7.

8. 9. 10. 11.

12. 13. 14. 15.

Smull, K., Wegria, R., Leland, J. J. Amer. med. Ass. 1944, 125, 1173. Smith, P. K., Gleason, H. L., Stoll, C. G., Ogorzalek, S. J. Pharmacol. 1946, 87, 237. Gutman, A. B., Yu, T. F., Sirota, J. H. J. clin. Invest. 1955, 34, 711. Macpherson, C. R., Milne, M. D., Evans, B. M. Brit. J. Pharmacol. 1955, 10, 484. Counihan, T. B., Evans, B. M., Milne, M. D. Clin. Sci. 1954, 13, 583. Waddell, W. J., Butler, T. C. J. clin. Invest. 1957, 36, 1217. Baer, J. E., Paulson, S. F., Russo, H. F., Beyer, K. H. Amer. J. Physiol. 1956, 186, 180. Milne, M. D., Rowe, G. G., Somers, K., Muehrcke, R. C., Crawford, M. A. Clin. Sci. 1957, 16, 599. Allanby, K. D., Trounce, J. R. Brit. med. J. 1957, ii, 1219. Jailer, J. W., Rosenfeld, M., Shannon, J. A. J. clin. Invest. 1947, 26, 1168. Orloff, J., Berliner, R. W. ibid. 1956, 35, 223. Terp, P. Acta pharm. tox., Kbh. 1951, 7, 259. Haag, H. B., Larson, P. S., Schwartz, J. J. J. Pharmacol. 1943, 79, 136. Doolan, P. D., Walsh, W. P., Kyle, L. H., Wishinsky, H. J. Amer. med. Ass. 1951, 146, 105. Kyle, L. H., Jeghers, H., Walsh, W. P., Doolan, P. D., Wishinsky, H., Pallotta, A. J. clin. Invest. 1953, 32, 364; Anthonisen, P., Brun, C., Crone, C., Lassen, N. A., Munck, O., Thomsen, Aa. C. Lancet, 1956, ii, 1277.

change in their specific action. Respiratory acidosis induced by breathing 10% C02 increases the plasma levels of the bases mepacrine and chloroquine 16 and of mecamylamine, 177 but reduces those of the acids phenobarbitone 6 and thiopentone.18 Except in the case of thiopentone, this is associated with a reverse change in the intracellular concentration of the drugs. Thiopentone is largely stored in adipose tissue, and in this case acidosis causes mobilisation of the drug from body fat.188 An increased plasma level caused by acid-base change increases the pharmacological effect of mecamylamine, 17 but reduces that of phenobarbitone.*. This observation may be of considerable practical importance during anaesthesia. VIRAL

HEPATITIS

VIRAL hepatitis remains common, and, though mortality rarely exceeds 0-2-0-5%, the illness may be long and unpleasant and permanent hepatic damage the final result. Large epidemics are fortunately rare, but under conditions civilian catastrophe big outbreaks have been during the past two centuries. The disease has been intensely studied in recent years, and it was the subject of a symposium at the last annual meeting of the American Medical Association. Advances in treatment have unfortunately been trivial, but some progress in the understanding of xtiology and epidemiology has been achieved and was well reviewed at the symposium of

war

or

common

by Havens.19 The two varieties of the disease are distinguished mainly by the route of infection and the incubation period. The causal agent of the naturally acquired disease (infective hepatitis) can be demonstrated during the period of infectivity in the blood-stream as well as in nasopharyngeal washings and in the fseces. The second variety of the disease has been given the name " homologousserum jaundice " and the causal agent has been found only in the blood of patients and never in the pharynx or fxces. This second variety is transmitted only as a result of artificial procedures-e.g., blood-transfusions or injections given with an imperfectly sterilised syringe. Transmission of infective hepatitis, on the other hand, is usually by close personal contact or by faecal contamination of food or water; but, since the virus is also present in the blood-stream at least for some days or weeks, it can also be transmitted in the same way as homologous-serum jaundice. The viruses responsible for these two diseases belong to the class of filter-passers, and they are both remarkably resistant to chemical and physical methods of sterilisation. The relationship between them remains an intriguing problem. The coincidence between outbreaks of hepatitis among patients attending venereal-disease clinics for arsenical therapy and the presence of an epidemic of infective hepatitis in the same locality suggested a close connection between the viruses .20 But the fairly consistent and striking difference between the incubation periods of the two forms of the disease and the difference in the distribution of viruses in the infected person rules out the possibility that the viruses are identical. This conclusion is firmly supported, moreover, by two further pieces of Jailer, J. W., Zubrod, C. G., Rosenfeld, M., Shannon, J. A. J. Pharmacol. 1948, 92, 345. 17. Payne, J. P., Rowe, G. G. Brit. J. Pharmacol. 1957, 12, 457. 18. Brodie, B. B., Mark, L. C., Papper, E. M., Lief, P. A., Bernstein, E., Rovenstine, E. A. J. Pharmacol. 1950, 98, 85. 19. Havens, W. P. J. Amer. med. Ass. 1957, 165, 1091. 20. Ellis, F. P. J. Hyg., Camb. 1953, 51, 145. 16.

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evidence. Firstly, the agent of infective hepatitis confers a strong and lasting immunity against reinfection by infective hepatitis, without apparently enhancing the resistance to the serum jaundice. Secondly, an injection of normal adult human gamma-globulin gives considerable protection against infective hepatitis but is without demonstrable effect against the other form of the disease. Nor can these differences be entirely attributable to the different routes of infection, since parenteral transmission of infective hepatitis results in a disease with the characteristic short incubation period and the appearance of the virus in the throat and faeces. The conclusion, therefore, that virus hepatitis may result from infection by either of two immunologically distinct agents seems well founded. Their usual mode of transmission is equally distinct and well established, and the prophylactic measures are plain. All that is required, therefore, to reduce the incidence of this disease is their widespread and meticulous application. As Dr. Morton remarks in a letter on p. 164, efficient syringe sterilisation and a scrupulous injection technique are more than ever important at present, when large programmes of prophylactic inoculation are about to be carried out. FAILURE TO GAIN WEIGHT IN INFANCY

IN

symposium on the relationship between disorders and nutrition, Holt1 discusses paediatric excessive loss of nitrogen from the body as a cause of failure to thrive in infancy. Cystic fibrosis of the pancreas is one condition in which there is abnormal fxcal loss of nitrogen; and in malignant malnutrition, or kwashiorkor, this faecal loss is augmented by losses through the kidney. It seems likely that in kwashiorkor both digestive and tissue enzymes are deficient, so that much of what little nitrogen is absorbed cannot be used and escapes in the urine. Holt also draws attention to the need for caution in the treatment of patients with protein starvation. High levels of non-protein nitrogen have been found in the blood of patients with kwashiorkor who were taking protein by mouth,2and toxic effects have followed intravenous feeding with hydrolysed protein or amino-acids. Careful investigation of most cases of " marasmus will often reveal some obvious cause such as a congenital abnormality of the alimentary tract, heart, or nervous system, or perhaps an unsuspected infection. On the other hand, much elaborate effort may be needed to uncover certain metabolic anomalies. The symposium gives up-todate information about such disorders as infantile renal acidosis, idiopathic hypercalcsemia, and galactosaemia, and refers to the various types of aminoaciduria. In these and allied disorders, the metabolic anomaly may exert its effect largely through impairment of appetite, and calorie losses in the excreta are unlikely to be large unless there is an accompanying glycosuria. Holt also refers to a further group of children in whom there is a discrepancy between the amount of food the child is thought to be taking and the amount he actually receives. The difference may be the result of inaccurate or careless preparation of feeds, rumination or unreported vomiting, or, on occasion, downright deceit. Such children are often said to be suffering from " mismanagement " or "psychological upset"; and a spell under close observation in nursery or hospital may disclose a steady weight gain even though the food intake is apparently no different from that given at home. a recent

1. 2.

Holt, L. E., Jr. Amer. J. clin. Nutr. 1957, 5, 500. Dean, R. F. A., Schwartz, R. Courrier, 1954, 4, 293.

PRESSURE GROUPS

TODAY the words " pressure group " often drop off the journalist’s pen or the orator’s tongue; and to most readers and listeners they suggest yet another disagreeable development of the modern world. But this reaction is often unreasonable; for it is the name rather than the device that is novel. Runnymede, for instance, was the scene of one effective pressure group; and such reforms as the abolition of slavery, the Factory Acts, and (in more modern times) equal pay for women were all initiated by small groups of people, who, by exerting pressure, gradually brought the Government and the public round to their way of thinking. Nevertheless, though they can thus claim respectable ancestry and good service in the past, pressure groups, like other useful institutions, are changing with the changing times, and their new name is perhaps a sign of the community’s uneasy recognition of their growing importance and power. The part they are now playing in the political life of the nation is examined with discernment and tolerance in the current issue of the Political Quarterly,! where the social scientist as well as the politician will find much of interest. As the machinery of government has changed, so have the methods of the pressure group. The Runnymede group was small, and its methods direct and swift; but in a parliamentary democracy they would be less effective. New means of communication and ease of transport have given the modern pressure group new opportunities, but literacy and universal suffrage mean that it must convince more people if the climate of opinion is to be altered. The multiplication of pressure groups has in part been fostered by the Government’s pervasion of the life of the citizen. To the courts of justice, the Army, and the Navy, for which the State has long been responsible, have been added such diverse enterprises as schools, roads, hospitals, pensions, mines, postal services, and museums, and each addition has provided a focus (or indeed foci) for several pressure groups. The Association of the ex-Bowmen of Agincourt, for instance, may have met annually on St. Crispin’s day; but, unlike the exService associations of our own time, it probably did not press the pension claims of its members. Among these new groups the most conspicuous are the innumerable vocational ones formed by workers, whether members of a profession, traders, or artisans; and Sir Winston Churchill, with his historian’s outlook, has perceptively described the trade unions as " an estate of the realm ". While some of these are profoundly concerned with the public interest, others are concerned mainly or entirely with the interest of their members. Besides these, however, there are still the groups whose sole purpose is to work for a cause-the legalisation of abortion or the abolition of capital punishment, True to their traditional to take two topical examples. these most of groups are small, with meagre pattern, influence cannot be measured by their but their funds; size or their finances, and it is largely through the kind of enlightened and disinterested pressure they exercise that so many wrongs have been righted by persuasion and that British history records so few revolutions. Unfortunately today the small ill-financed pressure group may be somewhat at a disadvantage, for publicity has become a more expensive commodity: to reach the public’s ear and eye usually costs money, while competition for the public’s mind and interest is keen. It is indeed perhaps 1. Political

Quarterly, January-March, 1958.