- Email: [email protected]
Antipyretic analgesics
L.F. Prescott
9 Acetylsalicylic and salicylic acids
Antipyretic analgesics
tion of aspirin and heparin for prophylaxis of deep vein thrombosis was abandoned beIntoxication (SEDA-2, 79; SEDA-3, cause of serious bleeding complications in 8 78) There have been several further reports of 12 patients without reduction o f venous of salicylate-induced pulmonary oedema, in thrombosis compared to a control group resome cases inappropriately referred to as ceiving warfarin (14c). In another study, pa'adult respiratory distress syndrome' (1 C, tients undergoing coronary artery bypass 2 C, 3c). All these cases were associated with graft surgery who had taken aspirin in the chronic or acute-on-chronic salicylate intoxi- previous week had more than double the cation and cardiac catheterization studies ex- mean post-operative mediastinal blood loss cluded left ventricular failure as a primary (919 ml) than a matched control group who cause of the pulmonary oedema. Positive had not taken aspirin (437 ml) (15c). Alpressure ventilation was required to maintain most identical results were presented by the oxygenation in two patients. One patient same authors in a similar report, and prowas hypoglycaemic on admission, and this longed chest tube drainage was required in complication (previously thought to occur the aspirin takers (16c). Serious post-operaonly in children) was also reported in a tive bleeding has also been attributed to aspi78-year-old woman with 'therapeutic' aspirin rin in neurosurgical and dental practice (17 C, 18c). poisoning (4c). Therapeutic salicylate poisoning remains The adverse effects of aspirin on haemoa pro'olem in adults as well as in children. stasis are of particular concern to the surSerious poisoning in children has again been geon. The most important action of aspirin reported after the use of aspirin for trivial in this context is interference with platelet reasons (5 c ) and in the USA chronic poison- function which may persist for a week or ing with aspirin given with therapeutic intent more after the last dose. The defect can be accounts for nearly all deaths and most hos- treated by platelet infusion. Aspirin ingespital admissions due to salicylate poisoning tion is often overlooked by doctors and is in children (6R). During chronic use, the risk not thought important by patients, many of of salicylate intoxication is increased by the whom do not even consider it to be a drug. dose-dependent kinetics of elimination, the Even worse, some patients may deliberately susceptibility of young children to the tox- withhold the information that they are icity of salicylate and great individual varia- taking aspirin. Indeed, one patient with retion in the dose required to provide opti- current posterior fossa haematoma managed mum plasma concentrations (7 R, 8). In this to consume 2 0 - 3 0 aspirin tablets daily context, it is important to remember that while in hospital (17). Spontaneous subdural salicylic acid is readily absorbed through the haematoma has been attributed to aspirin skin and poisoning may occur through the but it was impossible to establish a cause and use of creams and ointments containing the effect relationship (19c). d r u g ( 9 C, 10 C, llC). Aspirin may have a biphasic effect on bleeding time since significant pralongation Blood and haemostasis (SEDA-3, 78) The was observed with doses of 0 . 3 - 1 . 0 g, but rare occurrence of aspirin-induced aplastic not with 3.9 g (20, 21). On the other hand, anaemia has been noted again (12 C) and in a the bleeding time was prolonged in all papatient with t h r o m b o c y t o p e n i a thought to tients referred with clotting defects who had be caused by aspirin there was cross-sensitivi- taken large amounts of aspirin (more than ty to paracetamol (13c). 1.5 g daily (22). Jorgensen et al. (76 Cr) The anti-haemostatic effects of aspirin have, however, pointed out that some of the continue to attract attention. The combina- findings as regards the dose-dependency of
57
Antipyretic analgesics these effects on bleeding time may have been distorted by differences in the age and sex of the subjects involved. Jorgensen's group themselves found that bleeding time in men apparently decreased with age. In the study by Girolami et al. (22) aspirin was a more common cause of impaired haemostasis than yon Willebrand's disease. In contrast to the well-documented acute effects of aspirin on platelet function, conflicting results have been obtained with the use of aspirin as an inhibitor of platelet aggregation in the prevention of coronary heart disease (23).
Gastrointestinal system Further studies have confirmed the association between daily consumption of analgesics containing aspirin and chronic gastric ulcer in women (24). Hepatotoxicity (SEDA-3, 79) There have been more reports of salicylate hepatitis in patients with connective tissue disease (ineluding rheumatic fever) ( 2 5 c - 2 8 c, 29c). Four patients aged 221-13 years were said to have developed encephalopathy. Manifestations included lethargy, disorientation and tremor. One patient was said to have 'concrete responses to proverbs', another became comatose and a third developed generalized convulsions. Plasma salicylate concentrations ranged from 1 3 0 - 540/zg/ml (mean 317/lg/ml) (26 C, 29c). It seems unlikely that 'encephalopathy' could be attributed to salicylate intoxication per se with salicylate levels in this range and liver biopsies and the liver function tests mentioned were not consistent with hepatic failure. The possible role of hyperventilation and hypoglycaemia seems to have been overlooked. There was no mention of blood glucose values and the results of arterial blood gas analysis were reported for only one patient who had a respiratory alkalosis. Bulagahapitava et al. (71Cr) have reported a case of salicylate hepatitis in a 7-month-old boy; in this particular case the hyperventilation, metabolic acidosis, respiratory alkalosis, hyperammonaemia and raised transaminase activities suggested a diagnosis of Reye's syndrome, but there was no disturbance of the sensorium or hypoglycaemia. The authors point out that the hazards of giving salicylate to infants - as in this case for teething troubles - are insufficiently known to the general public.
Interaction with levamisole Since in rheumatic patients there is a possibility that levamisole and aspirin may be used concurrently, it seems important to note that a report by Laidlaw to the effect that levamisole caused a rise in plasma salicylate levels had not been confirmed in more recent work in a small series of volunteers studied by Rumble et al. (72Cr). Renal (see also Analgesic nephropathy, below) Like other anti-inflammatory drugs which inhibit prostaglandin synthesis, aspirin may cause marked impairment of renal function in patients with systemic lupus erythematosus (30 c, 31c). Aspirin also increases the urinary excretion of N-acetyl-/3-glucosaminidase (NAG) and this effect was thought to indicate renal tubular damage (32,33). Pregnancy (SEDA-2,
83) The indiscriminate use of aspirin during pregnancy is contraindicated. Experimental and human epidemiological evidence for the teratogenicity of aspirin, its effects on foetal mortality, its effects on the duration and complications of pregnancy and labour and its adverse effects on haemostasis in the mother and newborn have been reviewed (34R). Whether the recently postulated favourable effect of aspirin on pregnancy-associated hypertension and pre-eclampsia (68 cr) - which might be explained by the platelet activity of the drug justifies accepting the risks associated with its use in pregnancy would seem dubious.
Deafness and long-acting aspirin The suggestion by Miller that aspirin-associated deafness is more common in patients using longacting aspirin preparations has been challenged (69R); there appears to be no doubt that the finding was valid for Miller's own series, but it has been suggested that it was due not so much to the fact that the longacting product produced higher plasma levels as to better compliance in patients using this product, or simply to the fact that the individuals involved were on average older than the control group taking plain aspirin. Salicylsalicylic acid (Salsalate) It was pointed out in an earlier volume (SEDA-3, 85) that this old drug, which is once more being actively promoted, causes adverse reactions of a type similar to those
58 induced by aspirin. In a series of studies from 1969 onwards evidence had, however, been produced that salsalate was no more likely than was placebo to produce gastric blood loss, whilst lower doses of salsalate were adequate to produce clinically effective blood levels. In a recent study Cohen (70 c R) claims to have confirmed these findings in a placebo-controlled study of both salsalate (300 mg/day) or aspirin (3900 mg/day); headache and nausea were the most prominent side effects of each drug. Faecal blood loss was measured using sl Cr labelled erythrocytes. Whilst there is no reason to doubt the validity of these specific findings, one should recall that salsalate does produce dyspepsia and faecal occult blood loss when used therapeutically (35c), and that the absence of minor blood loss in a small series of healthy volunteers in a 23-day study such as that conducted by Cohen by no means excludes the risk o f major gastrointestinal bleeding in a larger series of patients. It may well be that both this drug and diflunisal have less severe acute erosive effects on the gastric mucosa than acetylsalicylic acid, but as anti-inflammatory agents they are almost by definition likely to produce a certain incidence of gastric irritation and haemorrhage.
Diflunisal This salicylate derivative has properties which are generally similar to those of aspirin (SEDA-3, 85) but claims have been made for a lower incidence of adverse reactions. The results of further comparative studies have been published and while these are consistent with better tolerance, it is important to remember that toxicity can only be compared with equi-effective doses of both drugs. In a multicentre 5-day trial in general practice involving 1902patients, efficacy was similar and the incidence of side effects was slightly lower with diflunisal than with aspirin. Nausea, indigestion and abdominal pain were the commonest side effects, occurring in 12% of the patients given diflunisal and 16.3% of the aspirin group. Diarrhoea was more common with diflunisal. The starting doses of diflunisal and aspirin were 0 . 5 - 1 . 0 g and 2.4 g daily respectively. However, by the 5th day 76.5% of the patients were still taking 2.4 g of aspirin while only 42.9% were taking 1.0 g of diflunisal (36c). In another comparative study of diflu-
L. F. Prescott nisal ( 5 0 0 - 7 5 0 mg daily) and aspirin ( 2 - 3 g daily) in 30 patients with osteoarthritis, side effects were reported in 44% taking diflunisal and in 64% taking aspirin. Again, gastric complaints were commonest but dizziness, faintness, anxiety, headache and oedema were also n o t ed (37c). Diflunisal was better tolerated than aspirin in another study in patients with osteoarthritis (3 8 c). Although the overall incidence of gastric side effects with diflunisal may be less than with equivalent doses of aspirin, gastrointestinal toxicity remains a major problem. There have been several further reports of massive gastrointestinal haemorrhage following the use of diflunisal. A 79-year-old woman with osteoarthritis had a haematemesis while taking aspirin in 1968. A barium meal showed a hiatus hernia but no ulceration. She subsequently took a variety of anti-inflammatory drugs without gastric irritation. She was started on diflunisal (500 mg daily) in April, 1978, and the dose was doubled five weeks later. Almost immediately she developed nausea, anorexia and epigastric pain followed two weeks later by a haematemesis. On admission to hospital the haemoglobin was 7.9 g/100 ml and a blood transfusion was given. The indigestion cleared when the diflunisal was stopped and a barium meal failed to reveal a peptic ulcer (39C). A very active 78-year-old woman with no previous history of peptic ulcer was prescribed diflunisal for herpes zoster. After 10 days, melaena occurred, and three days later haematemesis. On admission the haemoglobin was 6.6 g/100 rnl and endoscopy revealed a very extensive superficial ulcer extending from the cardia to the angulus on the lesser curve and containing patches of clot. Her gastrointestinal symptoms disappeared when diflunisal was stopped and the ulcer had healed when endoscopy was repeated six weeks later (40C). A 66-year-old woman with no previous history of indigestion or peptic ulcer was given 500 mg of diflunisal daily for backache. Ten days later she collapsed with melaena. A barium meal was negative but endoscopy showed blood clots in the stomach and acute fundal and antral erosions with mild duodenitis (41c). Most published reports of gastrointestinal haemorrhage associated with diflunisal have involved elderly women and bleeding has usually occurred within a few days of starting the drug. Up to February, 1979, the Committee on Safety of Medicines (U.K.) had received reports of 46 patients with gastrointestinal bleeding while taking diflunisal. Like aspirin, diflunisal causes renal tubular damage as shown by increased urinary excretion of N-acetyl-/3-glucosaminidase
Antipyretic analgesics (NAG) (32, 38). The elimination of diflunisal is impaired in patients with renal disease, and the plasma half-time increases progressively as renal function declines. The mean half-life in patients with terminal renal failure was 115 hours compared with 10.8 hours in normal subjects. The half-life of diflunisal was not significantly reduced by haemodialysis (43). In another study in healthy volunteers, alkaline diuresis did not shorten the plasma diflunisal half-life (44). Stevens-Johnson syndrome It was pointed out in SEDA-3 (p. 85) that two cases of Stevens-Johnson syndrome had been published relating to patients taking diflunisal, and the Committee on Safety of Medicines in the U.K. has in the meantime received in all seven reports of erythema multiforme occurring during the use of this drug; three of these were mild, but four were severe cases of the Stevens-Johnson syndrome requiring corticosteroid treatment (42r). Interactions Verbeeck and co-workers (66 C) have reported from Belgium that in four healthy volunteers concurrent administration of aluminium hydroxide reduced the bioavailability of diflunisal by about 40%; no conclusions could be drawn as to the mechanism of the interaction. Paracetamol Blood (SEDA-2, 84) Toxic effects on the blood are uncommon. In one patient thrombocytopenia developed after the occasional use of paracetamol for several years. There was a history of a previous episode of thrombocytopenia following the use of aspirin (13c). In another patient thrombocytopenia and haemolytic anaemia occurred on two separate occasions after the use of paracetamol (45c). Intoxication The continuing problem of acute hepatic necrosis following paracetamol overdosage has been reviewed (SEDA-2, 85; SEDA-3, 81 ;46 R, 47R). Of a series of 201 patients with paracetamol poisoning admitted to hospital in Newcastle upon Tyne from November 1974 to November 1975, only 16% had 'toxic' plasma paracetamol concentrations. Severe liver damage, as judged by histological appearances on biopsy, was associated with serum aspartate aminotransferase of 600 IU/litre or
59 more, and occurred in 20% of 123 patients in whom liver biopsy was performed. Nine patients developed hepatic encephalopathy and the overall mortality rate was 3.5% (48c). Children have hitherto been considered to be relatively resistant to the hepatotoxic effects of paracetamol and severe liver damage was thought to be very u n c o m m o n (49, 50). One possible explanation is that its metabolism in children is different, with a greater proportion being converted to the sulphate conjugate (51). However, there have been a number of recent reports of severe fiver damage in young children takhlg large doses of paracetamol and in some cases the outcome was fatal (SEDA-3, 81;49, 50, 5 2 c - 5 5 c ) . In many cases, poisoning was due to the overenthusiastic use of paracetatool by parents and doctors for therapeutic purposes. In one case a 20-month-old girl was given paracetamol in excessive doses first by parents and then by a physician. She was admitted to hospital obtunded, toxic, febrile, hypotensive, with blood in her mouth and hepatomegaly, only to be given even more paracetamol (53c). Intravenous N-acetylcysteine is now considered the treatment of choice for paracetamol poisoning. It is more effective than intravenous cysteamine or methionine in preventing fiver damage and it also prevents renal failure and death when given within 10 hours of ingestion. The critical ingestiontreatment interval for complete protection against severe liver damage with intravenous N-acetylcysteine, cysteamine and L-methionine is eight hours. There is little, if any, protection after 12 hours and none after 15 hours (46 C, 56c). Oral N-acetylcysteine and methionine have also been used for the treatment of paracetamol poisoning(50), but the feasibility of oral therapy has been questioned because of the very high incidence of nausea and vomiting in severely poisoned patients (56c). Regrettably, there is still mismanagement of paracetamol poisoning. A 53-year-old woman was admitted stuporous after taking paracetamol and codeine. She was given intravenous mannitol to promote diuresis, intubated and ventilation was assisted. The plasma paracetamol was estimated using a totally unsuitable method which can give as much as a 700% overestimate because of interference by metabolites. Charcoal haemoperfusion was then carried out while cyste-
60 amine was given intravenously. Fever and t h r o m b o c y t o p e n i a developed during the haemoperfusion, persisting for 60 hours and 5 days respectively. About 8% of the ingested dose of paracetamol was said to have been removed by haemoperfusion but the true figure would have been much less if an appropriate analytical method had been u s e d . The patient recovered after mild disturbance of liver function (57c). In the first place, the severity of paracetamol poisoning was undoubtedly overestimated, and treatment might not even have been necessary. Forced diuresis is ineffective and potentially dangerous in paracetamol poisoning, and assisted ventilation would not have been necessary if naloxone had been given to reverse the effects of the codeine. A misleading impression of efficacy of removal of paracetamol by haemoperfusion was obtained and, finally, the possibility that haemoperfusion would remove the cysteamine being infused at the same time seems to have been overlooked. Since haemoperfusion does not prevent severe liver damage and death after paracetamol overdosage, the combined treatment was likely to have been considerably less effective than cysteamine alone.
Combinations of paraeetamol with d-propoxyphene The serious problems of very rapid onset of fatal respiratory depression with overdosage of these combinations has been discussed previously (SEDA-3, 84). The reader is referred to Chapter 8 for a full review of this topic.
Phenacetin Although at the time of writing the United Kingdom authorities were about to issue an order prohibiting the sale, supply or importation of phenacetin in medicinal products (75R), doubt as to the validity of some of the accusations levelled at this compound, discussed at length in previous volumes in this series, persists. Though it is perhaps late in the day to continue the debate, a review by Macklin et al. (74 R) of Wellcome Research Laboratories challenging the view that phenacetin is a carcinogen may be noted; these authors point out, among other things, that many reports relating to the carcinoganicity of analgesics in general have
L. F. Prescott
emanated from countries where for many years antipyrine and aminopyrine were in use; aminopyrine is a known mutagen, and nitrosocompounds of both substances are also mutagenic. As has been said so often before, the risks of one widely-used analgesic can all too easily be attributed to another.
Analgesic nephropathy (SEDA-3, 79) There have been few further developments in this area. However, an excellent and comprehensive series of reviews covering many important aspects of this subject has recently been published (58 R). There is considerable concern over the occurrence of tumours of the urinary tract in patients with analgesic nephropathy, and several more cases have been reported (59 c, 60 R, 61 c , 62c). Routine urine cytology has been recommended in all patients with analgesic nephropathy (62c). As previously, attention has been focussed on phenacetin as the probable aetiological agent, despite the lack of sound supporting evidence. The combination of aspirin, phenacetih and caffeine does not cause tumours of the urinary tract in experimental animals (63) although urothelial hyperplasia has been observed with phenacetin (60) and its N-hydroxy metabolite is converted to reactive, potentially carcinogenic alkylating glucuronide and sulphate conjugates (64, 65). Further investigations are required to investigate the potential carcinogenicity of the analgesics and other drugs invariably taken with phenacetin.
Ureteric stricture Ureteric stricture is an unusual but recognized complication of analgesic nephropathy (SEDA-I, 71) and has been thought to be associated with a form of retroperitoneal fibrosis. A recent female case reported from Australia showed a very localized area of stricture through which the ureteric catheter would not pass and no evidence of peri-ureteric fibrosis (67Cr). Diagnosis at autopsy Abrahams has recently pointed out that a characteristic postmortem finding in some cases of analgesic nephropathy is a deep brown discolouration of the urinary tract which may extend from the renal pelvis to the bladder (73c).
Antipyretic analgesics
61
REFERENCES 1. Heffner, J., Starkey, T. and Anthony, P. (1979): Salicylate-induced noncardiogenic pulmonary edema. West. J. Med., 130,263. 2. Andersen, R. and Refstad, S. (1978): Adult respiratory distress syndrome precipitated by massive salicylate poisoning, lntens. Care Med., 4, 211. 3. Sgrensen, S.C. (1979): Adult respiratory-distress syndrome in salicylate intoxication. Lancet, L 1025. 4. Arena, F.P., Dugowson, C. and Saudek, C. D. (1978): Salicylate-induced hypoglycemia and ketoacidosis in a nondiabetic adult. Arch. intern. Med., 138, 1153. 5. Mitchell, I. (1979): 'Therapeutic' salicylate poisoning in children. Brit. med. J., 1, 1081. 6. Done, A. K. (1978): Aspirin overdosage: Incidence, diagnosis and management. Pediatrics, 62/ SuppL, 890. 7. Levy, G. (1978): Clinical pharmacokinetics of aspirin. Pediatrics, 62/Suppl., 867. 8. Cassell, S., Furst, D., Dromgoole, S. and Taulus, H. (1979): Dosage schedule of choline magnesium trisalicylate. Arthr. Rheum., 22, 384. 9. Le Roux, P., Le Bihan, G., Bourlier, D. and Litoux, P. (1979): Intoxication salicyl~e par voie cutan~e. Rev. mEd. Alpes fr., 8, 57. I0. Davies, M.G., VeUa Briffa, D. and Greayes, M. W. (1979): Systemic toxicity from topicaUy applied salicylic acid. Brit. med. J., 1, 661. 11. Aspinall, J. B. and Goel, K. M. (1978): Salicylate poisoning in dermatological therapy. Brit. med. J., 2, 1373. 12. Eldar, M., Aderka, D., Shoenfeld, Y., Livni, E. and Pinkhas, J. (1979): Aspirin-induced aplastic anaemia. S. Aft. med. J., 55, 318. 13. Scheinberg, I. H. (1979): Thrombocytopenic reaction to aspirin and acetaminophen. New Engl. J. Med., 300, 678. 14. Yett, H. S., Skillman, J. J. and Salzman, E. W. (1978): The hazards of aspirin plus heparin. New Engl. J. Med., 298, 1092. 15. Michelson, E. L., Morganroth, J., Torosian, M. and MacVaugh, H. (1978): Relation of preoperative use of aspirin to increased mediastinal blood loss after coronary artery bypass graft surgery. J. thorac, cardiovasc. Surg., 76, 694. 16. Torosian, M., Michelson, E. L., Morganroth, J. and MacVaugh, H. (1978): Aspirin and coumadin related bleeding after coronary-artery bypass graft surgery. Anrt intern. Med., 89, 325. 17. Merriman, E., Bell, W. and Long, D. M. (1979): Surgical postoperative bleeding associated with aspirin ingestion. J. Neurosurg., 50, 682. 18. McGaul, T. (1978): Postoperative bleeding caused by aspirin. J. Dent., 6, 207. 19. Borne, G., B~dou, G. and Ar~su, P.-J. (1979): H6matome sous-dural subalgu - r61e possible de l'acide ac~tylsalicylique. Coneours mEd., 101, 1293.
20. O'Grady, J. and Moncada, S. (1978): Aspirin: A paradoxical effect on bleeding-time. Lancet, If, 78O. 21. Rajah, S.M., Penny, A. and Kester, R. (1978): Aspirin and bleeding-time. Lancet, H, 1104. 22. Girolami, A., Cella, G., Zanon, R. D. B., Cappellato, M. G. and Randi, M. L. (1979): Aspirin and bleeding-time. Lancet, H, 205. 23. Hennekens, C.H., Karlson, L.K. and Rosner, B. (1978): A case-control study of regular aspirin use and coronary deaths. Circulation, 58, 35. 24. Piper, D.W., Greig, M., Landecker, K. D., Shinners, J., Wailer, S. and Canalese, J. (1977): Analgesic intake and chronic gastric ulcer. Acute upper gastrointestinal haemorrhage, personality traits and social class. Proc. roy. Soc. Med., 70/
Suppl. 7, 11. 25. Travers, R. L. and Hughes, G. R.V. (1978): Salicylate hepatotoxicity in systemic lupus erythematosus: a common occurrence? Brit. med. J., 2, 1532. 26. Ulshen, M.H., Grand, R. J., Crain, J. D. and Gelfand, E. W. (1978): Hepatotoxicity with encephalopathy associated with aspirin therapy in rheumatoid arthritis. J. Pediat., 93, 1034. 27. Knudsen, F.U. (1978): Acetylsalicylic acid and liver damage. Ugeskr. Laeg., 140, 2233. 28. Jespersen, J. (1978): Salicylate hepatitis in rheumatic fever. Ugeskr. Laeg., 140, 2247. 29. Petty, B.G., Zahka, K.G. and Bernstein, M.T. (1978): Aspirin hepatitis associated with encephalopathy. J. Pediat., 93, 881. 30. Kimberley, R.P., Gill, J.R., Bowden, R. E., Keiser, H. R. and Plotz, P. H. (1978): Elevated urinary prostaglandins and the effects of aspirin on renal function in lupus erythematosus. Ann. intern. Med., 89, 336. 31. Kimberley, R.P., Sherman, R.L., Mauradian, J. and Lockshin, M. D. (1979): Apparent renal failure associated with therapeutic aspirin and ibuprofen. Arthr. Rheum., 22, 281. 32. Dieppe, P.A., Burry, H.C., Doyle, D. V., Tucker, S.M., Corke, C. and Huskisson, E. C. (1978): Nephrotoxicity of analgesic anti-inflammatory and anti-rheumatic drugs. Aust. N.Z.J. Med., 8, 114. 33. Proctor, R. A. and Kunin, C. M. (1978): Salicylate-induced enzymuria: Comparison with other anti-inflammatory agents. Amer. J. Med., 65, 987. 34. Corby, D.G. (1978): Aspirin in pregnancy: Maternal and fetal effects. Pediatrics, 62/Suppl., 930. 35. Regalado, R. G. (1978): The use of salsalate for control of long-term musculo-skeletal pain: an open, non-comparative assessment. Curr. Med.
Res. Opin., 5,454. 36. Huskisson, E.C. (1979): Diflunisal - a new analgesic. Practitioner, 223,415.
62 37. Grayson, M.F. (1978): A clinical trial of diflunisal against aspirin in osteoarthritis. Rheumatol. Rehab.i 17, 265. 38. Dieppe, P.A. and Huskisson, E.C. (1979): Diflunisal and aspirin: A comparison of efficacy and nephrotoxicity in osteoarthritis. Rheumatol. Rehab., 18, 53. 39. Mason, A. M. (1979): Bleeding massive gastric ulcer on diflunisal (Dolobid). Brit. reed. J., 1, 888. 40. Scott, B. (1979): Bleeding massive gastric ulcer on diflunisal (Dolobid). Brit. med. J., 1,489. 41. Admani, A.K. and Khaleque, D. M. N. F. (1979): Gastrointestinal haemorrhage associated with diflunisal. Lancet, I, 1247. 42. Committee on Safety of Medicines. Current Problems, April, 1979, No. 4. 43. Verbeeck, R., Tjandramaga, T. B., MuUie, A., Verbesselt, R., Verberckmoes, R. and De Schepper, P. J. (1979): Biotransformation of diflunisal and renal excretion of its glucuronides in renal insufficiency. Brit. J. clin. PharmacoL, 7, 273. 44. Balali, M. and Prescott, L. F.: unpublished observations. 45. Kornberg, A. and Polliack, A. (1978): Paracetamol-induced thrombocytopenia and haemolyric anaemia. Lancet, H, 1159. 46. Prescott, L.F. (1979): The nephrotoxicity and hepatotoxicity of antipyretic analgesics. Brit. J. din. Pharmacol., 7, 453. 47. Lechat, P., Lagier, G. and Boiteau, J. (1978): Le parac~tamol. Thdrapie, 33, 552. 48. Hamlyn, A. N., Douglas, A. P. and James, O. (1978): The spectrum of paracetamol (acetaminophen) overdose: clinical and epidemiological studies. Postgrad. reed. J., 54,400. 49. Meredith, T. J., Newman, B. and Goulding, R. (1978): Paracetamol poisoning in children. Brit. reed. J., 2, 478. 50. Rumack, B.H. and Peterson, R.G. (1978): Acetaminophen overdose: Incidence, diagnosis and management in 416 patients. Pediatrics, 62/ Suppl., 898. 51. Peterson, R.G. and Rumack, B.H. (1978): Pharmacokinetics of acetaminophen in children. Pediatrics, 62/Suppl., 877. 52. Arena, J. M., Rourk, M. H. and Sibrack, C. D. (1978): Acetaminophen: Report of an unusual poisoning. Pediatrics, 61, 68. 53. Calvert, L. J. and Linder, C. W. (1978): Acetaminophen poisoning. J. Fant Pract., 7, 953. 54. Nogen, A. G. and Bremner, J. E. (1978): Fatal acetaminophen overdosage in a young child. J. Pediat., 92, 832. 55. Bickers, R.G. and Roberts, R.J. (1979): Combined aspirin/acetaminophen intoxication. J. Pediat., 94, 1001. 56. Prescott, L.F., Illingworth, R.N., Critchley, J. A. J. H., Stewart, M. J., Adam, R. D. and Proudfoot, A. T. (1979): Intravenous N-acetylcysteine; the treatment of choice for paracetamol poisoning. Brit. med. Z, 2, 1097. 57. Rigby, R.J., Thomson, N.M., Parkin, G. W. and Cheung, T. P.F. (1978): The treatment of
L. F. Prescott paracetamol overdose with charcoal haemoperfusion and cysteamine. Med. J. Aust., 1,386. 58. Symposium on Analgesic Nephropathy (1978): Kidney int., 13, 1-113. 59. Lornoy, W., Morelle, V., Begaus, L. and Fonteyne, E. (1979): Analgesic nephropathy. New Engl. J. Med., 300, 319. 60. Bengtsson, U., Johansson, S. and Angervall, L. (1978): Malignancies of the urinary tract and their relation to analgesic abuse. Kidney int., 13, 107. 61. Schelstraete, J., Boelaert, J., Daneels, R. and Vergison, R. (1979): Uroepitheliale tumoren van het nierbekken geassocieerd met misbruik van fenacetinehoudende analgetica. T. Geneesk., 35, 395. 62. Jackson, B., Kirkland, J. A., Lawrence, J. R., Narayan, A.S., Brown, H.E. and Mills, L. R. (1978): Urine cytology findings in analgesic nephropathy. J. Urol., 120, 145. 63. Bioassay of a mixture of aspirin, phenacetin and caffeine for possible carcinogenicity. Nat. Cancer Inst. Carcinogen. Techn. Rep. Set., 1978, No. 67. 64. Mulder, G. J., Hinson, J. A. and Gillette, J. R. (1977): Generation of reactive metabolites of N-hydroxyphenacetin by glucuronidation and sulfation. Biochem. Pharmacol., 26, 189. 65. Mulder, G. J., Hinson, J. A. and Gillette, J. R. (1978): Conversion of the N-O-glucuronide and N-O-sulfate conjugates of N-hydroxy-phenacetin to reactive intermediates. Biochem. Pharmacol., 27, 1641. 66. Verbeeck, R., Tjandramaga, T. B., MuUie, A., Verbesselt, R. and De Schepper, P. J. (1979): Effect of aluminium hydroxide on diflunisal absorption. Brit. J. clin. Pharmacol., 7, 519. 67. McGregor, B., Saker, B. M. and England, E. J. (1979): Ureteric stricture associated with analgesic nephropathy. Med. J. Aust., 1,287. 68. Crandon, A. J. and Isherwood, D. M. (1979): Effect of aspirin on incidence of pre-eclampsia. Lancet, I, 1356. 69. Day, R. Q. (1979): Deafness due to aspirin. J. clin. Pharmacol., 19, 328. 70. Cohen, A. (1979): Fecal blood loss and plasma salicylate study of salicylsalicylic acid and aspirin. J. clin. Pharmacol., 19,242. 71. Bulugahapitiya, D. T.D., Hebron, B. and Beck, P. R. (1979): Salicylate hepatitis with acidosis in an infant. Lancet, b,, 1295. 72. Rumble, R.H., Brooks, P.M. and Roberts, M. S. (1979): Interaction between levamisole and aspirin in man. Brit. J. clin. Pharmacol., 7, 631. 73. Abrahams, C. (1979): More on the pathology of analgesic abuse. New Engl. J. Med., 301,437. 74. Macklin, A.W., Welch, R.M. and Cuatrecasas, P. (1979): Drug safety: Phenacetin. Science, 205, 144. 75. Anonymous (1979): Phenacetin prohibition order about to be signed. Pharma. J., Sept. 8, 20. 76. Jorgensen, K.A., Olesen, A. S., Dyerberg, J. and Stoffersen, E. (1979): Aspirin and bleeding time: Dependency of age. Lancet, II, 302.
9 Acetylsalicylic and salicylic acids
Antipyretic analgesics
tion of aspirin and heparin for prophylaxis of deep vein thrombosis was abandoned beIntoxication (SEDA-2, 79; SEDA-3, cause of serious bleeding complications in 8 78) There have been several further reports of 12 patients without reduction o f venous of salicylate-induced pulmonary oedema, in thrombosis compared to a control group resome cases inappropriately referred to as ceiving warfarin (14c). In another study, pa'adult respiratory distress syndrome' (1 C, tients undergoing coronary artery bypass 2 C, 3c). All these cases were associated with graft surgery who had taken aspirin in the chronic or acute-on-chronic salicylate intoxi- previous week had more than double the cation and cardiac catheterization studies ex- mean post-operative mediastinal blood loss cluded left ventricular failure as a primary (919 ml) than a matched control group who cause of the pulmonary oedema. Positive had not taken aspirin (437 ml) (15c). Alpressure ventilation was required to maintain most identical results were presented by the oxygenation in two patients. One patient same authors in a similar report, and prowas hypoglycaemic on admission, and this longed chest tube drainage was required in complication (previously thought to occur the aspirin takers (16c). Serious post-operaonly in children) was also reported in a tive bleeding has also been attributed to aspi78-year-old woman with 'therapeutic' aspirin rin in neurosurgical and dental practice (17 C, 18c). poisoning (4c). Therapeutic salicylate poisoning remains The adverse effects of aspirin on haemoa pro'olem in adults as well as in children. stasis are of particular concern to the surSerious poisoning in children has again been geon. The most important action of aspirin reported after the use of aspirin for trivial in this context is interference with platelet reasons (5 c ) and in the USA chronic poison- function which may persist for a week or ing with aspirin given with therapeutic intent more after the last dose. The defect can be accounts for nearly all deaths and most hos- treated by platelet infusion. Aspirin ingespital admissions due to salicylate poisoning tion is often overlooked by doctors and is in children (6R). During chronic use, the risk not thought important by patients, many of of salicylate intoxication is increased by the whom do not even consider it to be a drug. dose-dependent kinetics of elimination, the Even worse, some patients may deliberately susceptibility of young children to the tox- withhold the information that they are icity of salicylate and great individual varia- taking aspirin. Indeed, one patient with retion in the dose required to provide opti- current posterior fossa haematoma managed mum plasma concentrations (7 R, 8). In this to consume 2 0 - 3 0 aspirin tablets daily context, it is important to remember that while in hospital (17). Spontaneous subdural salicylic acid is readily absorbed through the haematoma has been attributed to aspirin skin and poisoning may occur through the but it was impossible to establish a cause and use of creams and ointments containing the effect relationship (19c). d r u g ( 9 C, 10 C, llC). Aspirin may have a biphasic effect on bleeding time since significant pralongation Blood and haemostasis (SEDA-3, 78) The was observed with doses of 0 . 3 - 1 . 0 g, but rare occurrence of aspirin-induced aplastic not with 3.9 g (20, 21). On the other hand, anaemia has been noted again (12 C) and in a the bleeding time was prolonged in all papatient with t h r o m b o c y t o p e n i a thought to tients referred with clotting defects who had be caused by aspirin there was cross-sensitivi- taken large amounts of aspirin (more than ty to paracetamol (13c). 1.5 g daily (22). Jorgensen et al. (76 Cr) The anti-haemostatic effects of aspirin have, however, pointed out that some of the continue to attract attention. The combina- findings as regards the dose-dependency of
57
Antipyretic analgesics these effects on bleeding time may have been distorted by differences in the age and sex of the subjects involved. Jorgensen's group themselves found that bleeding time in men apparently decreased with age. In the study by Girolami et al. (22) aspirin was a more common cause of impaired haemostasis than yon Willebrand's disease. In contrast to the well-documented acute effects of aspirin on platelet function, conflicting results have been obtained with the use of aspirin as an inhibitor of platelet aggregation in the prevention of coronary heart disease (23).
Gastrointestinal system Further studies have confirmed the association between daily consumption of analgesics containing aspirin and chronic gastric ulcer in women (24). Hepatotoxicity (SEDA-3, 79) There have been more reports of salicylate hepatitis in patients with connective tissue disease (ineluding rheumatic fever) ( 2 5 c - 2 8 c, 29c). Four patients aged 221-13 years were said to have developed encephalopathy. Manifestations included lethargy, disorientation and tremor. One patient was said to have 'concrete responses to proverbs', another became comatose and a third developed generalized convulsions. Plasma salicylate concentrations ranged from 1 3 0 - 540/zg/ml (mean 317/lg/ml) (26 C, 29c). It seems unlikely that 'encephalopathy' could be attributed to salicylate intoxication per se with salicylate levels in this range and liver biopsies and the liver function tests mentioned were not consistent with hepatic failure. The possible role of hyperventilation and hypoglycaemia seems to have been overlooked. There was no mention of blood glucose values and the results of arterial blood gas analysis were reported for only one patient who had a respiratory alkalosis. Bulagahapitava et al. (71Cr) have reported a case of salicylate hepatitis in a 7-month-old boy; in this particular case the hyperventilation, metabolic acidosis, respiratory alkalosis, hyperammonaemia and raised transaminase activities suggested a diagnosis of Reye's syndrome, but there was no disturbance of the sensorium or hypoglycaemia. The authors point out that the hazards of giving salicylate to infants - as in this case for teething troubles - are insufficiently known to the general public.
Interaction with levamisole Since in rheumatic patients there is a possibility that levamisole and aspirin may be used concurrently, it seems important to note that a report by Laidlaw to the effect that levamisole caused a rise in plasma salicylate levels had not been confirmed in more recent work in a small series of volunteers studied by Rumble et al. (72Cr). Renal (see also Analgesic nephropathy, below) Like other anti-inflammatory drugs which inhibit prostaglandin synthesis, aspirin may cause marked impairment of renal function in patients with systemic lupus erythematosus (30 c, 31c). Aspirin also increases the urinary excretion of N-acetyl-/3-glucosaminidase (NAG) and this effect was thought to indicate renal tubular damage (32,33). Pregnancy (SEDA-2,
83) The indiscriminate use of aspirin during pregnancy is contraindicated. Experimental and human epidemiological evidence for the teratogenicity of aspirin, its effects on foetal mortality, its effects on the duration and complications of pregnancy and labour and its adverse effects on haemostasis in the mother and newborn have been reviewed (34R). Whether the recently postulated favourable effect of aspirin on pregnancy-associated hypertension and pre-eclampsia (68 cr) - which might be explained by the platelet activity of the drug justifies accepting the risks associated with its use in pregnancy would seem dubious.
Deafness and long-acting aspirin The suggestion by Miller that aspirin-associated deafness is more common in patients using longacting aspirin preparations has been challenged (69R); there appears to be no doubt that the finding was valid for Miller's own series, but it has been suggested that it was due not so much to the fact that the longacting product produced higher plasma levels as to better compliance in patients using this product, or simply to the fact that the individuals involved were on average older than the control group taking plain aspirin. Salicylsalicylic acid (Salsalate) It was pointed out in an earlier volume (SEDA-3, 85) that this old drug, which is once more being actively promoted, causes adverse reactions of a type similar to those
58 induced by aspirin. In a series of studies from 1969 onwards evidence had, however, been produced that salsalate was no more likely than was placebo to produce gastric blood loss, whilst lower doses of salsalate were adequate to produce clinically effective blood levels. In a recent study Cohen (70 c R) claims to have confirmed these findings in a placebo-controlled study of both salsalate (300 mg/day) or aspirin (3900 mg/day); headache and nausea were the most prominent side effects of each drug. Faecal blood loss was measured using sl Cr labelled erythrocytes. Whilst there is no reason to doubt the validity of these specific findings, one should recall that salsalate does produce dyspepsia and faecal occult blood loss when used therapeutically (35c), and that the absence of minor blood loss in a small series of healthy volunteers in a 23-day study such as that conducted by Cohen by no means excludes the risk o f major gastrointestinal bleeding in a larger series of patients. It may well be that both this drug and diflunisal have less severe acute erosive effects on the gastric mucosa than acetylsalicylic acid, but as anti-inflammatory agents they are almost by definition likely to produce a certain incidence of gastric irritation and haemorrhage.
Diflunisal This salicylate derivative has properties which are generally similar to those of aspirin (SEDA-3, 85) but claims have been made for a lower incidence of adverse reactions. The results of further comparative studies have been published and while these are consistent with better tolerance, it is important to remember that toxicity can only be compared with equi-effective doses of both drugs. In a multicentre 5-day trial in general practice involving 1902patients, efficacy was similar and the incidence of side effects was slightly lower with diflunisal than with aspirin. Nausea, indigestion and abdominal pain were the commonest side effects, occurring in 12% of the patients given diflunisal and 16.3% of the aspirin group. Diarrhoea was more common with diflunisal. The starting doses of diflunisal and aspirin were 0 . 5 - 1 . 0 g and 2.4 g daily respectively. However, by the 5th day 76.5% of the patients were still taking 2.4 g of aspirin while only 42.9% were taking 1.0 g of diflunisal (36c). In another comparative study of diflu-
L. F. Prescott nisal ( 5 0 0 - 7 5 0 mg daily) and aspirin ( 2 - 3 g daily) in 30 patients with osteoarthritis, side effects were reported in 44% taking diflunisal and in 64% taking aspirin. Again, gastric complaints were commonest but dizziness, faintness, anxiety, headache and oedema were also n o t ed (37c). Diflunisal was better tolerated than aspirin in another study in patients with osteoarthritis (3 8 c). Although the overall incidence of gastric side effects with diflunisal may be less than with equivalent doses of aspirin, gastrointestinal toxicity remains a major problem. There have been several further reports of massive gastrointestinal haemorrhage following the use of diflunisal. A 79-year-old woman with osteoarthritis had a haematemesis while taking aspirin in 1968. A barium meal showed a hiatus hernia but no ulceration. She subsequently took a variety of anti-inflammatory drugs without gastric irritation. She was started on diflunisal (500 mg daily) in April, 1978, and the dose was doubled five weeks later. Almost immediately she developed nausea, anorexia and epigastric pain followed two weeks later by a haematemesis. On admission to hospital the haemoglobin was 7.9 g/100 ml and a blood transfusion was given. The indigestion cleared when the diflunisal was stopped and a barium meal failed to reveal a peptic ulcer (39C). A very active 78-year-old woman with no previous history of peptic ulcer was prescribed diflunisal for herpes zoster. After 10 days, melaena occurred, and three days later haematemesis. On admission the haemoglobin was 6.6 g/100 rnl and endoscopy revealed a very extensive superficial ulcer extending from the cardia to the angulus on the lesser curve and containing patches of clot. Her gastrointestinal symptoms disappeared when diflunisal was stopped and the ulcer had healed when endoscopy was repeated six weeks later (40C). A 66-year-old woman with no previous history of indigestion or peptic ulcer was given 500 mg of diflunisal daily for backache. Ten days later she collapsed with melaena. A barium meal was negative but endoscopy showed blood clots in the stomach and acute fundal and antral erosions with mild duodenitis (41c). Most published reports of gastrointestinal haemorrhage associated with diflunisal have involved elderly women and bleeding has usually occurred within a few days of starting the drug. Up to February, 1979, the Committee on Safety of Medicines (U.K.) had received reports of 46 patients with gastrointestinal bleeding while taking diflunisal. Like aspirin, diflunisal causes renal tubular damage as shown by increased urinary excretion of N-acetyl-/3-glucosaminidase
Antipyretic analgesics (NAG) (32, 38). The elimination of diflunisal is impaired in patients with renal disease, and the plasma half-time increases progressively as renal function declines. The mean half-life in patients with terminal renal failure was 115 hours compared with 10.8 hours in normal subjects. The half-life of diflunisal was not significantly reduced by haemodialysis (43). In another study in healthy volunteers, alkaline diuresis did not shorten the plasma diflunisal half-life (44). Stevens-Johnson syndrome It was pointed out in SEDA-3 (p. 85) that two cases of Stevens-Johnson syndrome had been published relating to patients taking diflunisal, and the Committee on Safety of Medicines in the U.K. has in the meantime received in all seven reports of erythema multiforme occurring during the use of this drug; three of these were mild, but four were severe cases of the Stevens-Johnson syndrome requiring corticosteroid treatment (42r). Interactions Verbeeck and co-workers (66 C) have reported from Belgium that in four healthy volunteers concurrent administration of aluminium hydroxide reduced the bioavailability of diflunisal by about 40%; no conclusions could be drawn as to the mechanism of the interaction. Paracetamol Blood (SEDA-2, 84) Toxic effects on the blood are uncommon. In one patient thrombocytopenia developed after the occasional use of paracetamol for several years. There was a history of a previous episode of thrombocytopenia following the use of aspirin (13c). In another patient thrombocytopenia and haemolytic anaemia occurred on two separate occasions after the use of paracetamol (45c). Intoxication The continuing problem of acute hepatic necrosis following paracetamol overdosage has been reviewed (SEDA-2, 85; SEDA-3, 81 ;46 R, 47R). Of a series of 201 patients with paracetamol poisoning admitted to hospital in Newcastle upon Tyne from November 1974 to November 1975, only 16% had 'toxic' plasma paracetamol concentrations. Severe liver damage, as judged by histological appearances on biopsy, was associated with serum aspartate aminotransferase of 600 IU/litre or
59 more, and occurred in 20% of 123 patients in whom liver biopsy was performed. Nine patients developed hepatic encephalopathy and the overall mortality rate was 3.5% (48c). Children have hitherto been considered to be relatively resistant to the hepatotoxic effects of paracetamol and severe liver damage was thought to be very u n c o m m o n (49, 50). One possible explanation is that its metabolism in children is different, with a greater proportion being converted to the sulphate conjugate (51). However, there have been a number of recent reports of severe fiver damage in young children takhlg large doses of paracetamol and in some cases the outcome was fatal (SEDA-3, 81;49, 50, 5 2 c - 5 5 c ) . In many cases, poisoning was due to the overenthusiastic use of paracetatool by parents and doctors for therapeutic purposes. In one case a 20-month-old girl was given paracetamol in excessive doses first by parents and then by a physician. She was admitted to hospital obtunded, toxic, febrile, hypotensive, with blood in her mouth and hepatomegaly, only to be given even more paracetamol (53c). Intravenous N-acetylcysteine is now considered the treatment of choice for paracetamol poisoning. It is more effective than intravenous cysteamine or methionine in preventing fiver damage and it also prevents renal failure and death when given within 10 hours of ingestion. The critical ingestiontreatment interval for complete protection against severe liver damage with intravenous N-acetylcysteine, cysteamine and L-methionine is eight hours. There is little, if any, protection after 12 hours and none after 15 hours (46 C, 56c). Oral N-acetylcysteine and methionine have also been used for the treatment of paracetamol poisoning(50), but the feasibility of oral therapy has been questioned because of the very high incidence of nausea and vomiting in severely poisoned patients (56c). Regrettably, there is still mismanagement of paracetamol poisoning. A 53-year-old woman was admitted stuporous after taking paracetamol and codeine. She was given intravenous mannitol to promote diuresis, intubated and ventilation was assisted. The plasma paracetamol was estimated using a totally unsuitable method which can give as much as a 700% overestimate because of interference by metabolites. Charcoal haemoperfusion was then carried out while cyste-
60 amine was given intravenously. Fever and t h r o m b o c y t o p e n i a developed during the haemoperfusion, persisting for 60 hours and 5 days respectively. About 8% of the ingested dose of paracetamol was said to have been removed by haemoperfusion but the true figure would have been much less if an appropriate analytical method had been u s e d . The patient recovered after mild disturbance of liver function (57c). In the first place, the severity of paracetamol poisoning was undoubtedly overestimated, and treatment might not even have been necessary. Forced diuresis is ineffective and potentially dangerous in paracetamol poisoning, and assisted ventilation would not have been necessary if naloxone had been given to reverse the effects of the codeine. A misleading impression of efficacy of removal of paracetamol by haemoperfusion was obtained and, finally, the possibility that haemoperfusion would remove the cysteamine being infused at the same time seems to have been overlooked. Since haemoperfusion does not prevent severe liver damage and death after paracetamol overdosage, the combined treatment was likely to have been considerably less effective than cysteamine alone.
Combinations of paraeetamol with d-propoxyphene The serious problems of very rapid onset of fatal respiratory depression with overdosage of these combinations has been discussed previously (SEDA-3, 84). The reader is referred to Chapter 8 for a full review of this topic.
Phenacetin Although at the time of writing the United Kingdom authorities were about to issue an order prohibiting the sale, supply or importation of phenacetin in medicinal products (75R), doubt as to the validity of some of the accusations levelled at this compound, discussed at length in previous volumes in this series, persists. Though it is perhaps late in the day to continue the debate, a review by Macklin et al. (74 R) of Wellcome Research Laboratories challenging the view that phenacetin is a carcinogen may be noted; these authors point out, among other things, that many reports relating to the carcinoganicity of analgesics in general have
L. F. Prescott
emanated from countries where for many years antipyrine and aminopyrine were in use; aminopyrine is a known mutagen, and nitrosocompounds of both substances are also mutagenic. As has been said so often before, the risks of one widely-used analgesic can all too easily be attributed to another.
Analgesic nephropathy (SEDA-3, 79) There have been few further developments in this area. However, an excellent and comprehensive series of reviews covering many important aspects of this subject has recently been published (58 R). There is considerable concern over the occurrence of tumours of the urinary tract in patients with analgesic nephropathy, and several more cases have been reported (59 c, 60 R, 61 c , 62c). Routine urine cytology has been recommended in all patients with analgesic nephropathy (62c). As previously, attention has been focussed on phenacetin as the probable aetiological agent, despite the lack of sound supporting evidence. The combination of aspirin, phenacetih and caffeine does not cause tumours of the urinary tract in experimental animals (63) although urothelial hyperplasia has been observed with phenacetin (60) and its N-hydroxy metabolite is converted to reactive, potentially carcinogenic alkylating glucuronide and sulphate conjugates (64, 65). Further investigations are required to investigate the potential carcinogenicity of the analgesics and other drugs invariably taken with phenacetin.
Ureteric stricture Ureteric stricture is an unusual but recognized complication of analgesic nephropathy (SEDA-I, 71) and has been thought to be associated with a form of retroperitoneal fibrosis. A recent female case reported from Australia showed a very localized area of stricture through which the ureteric catheter would not pass and no evidence of peri-ureteric fibrosis (67Cr). Diagnosis at autopsy Abrahams has recently pointed out that a characteristic postmortem finding in some cases of analgesic nephropathy is a deep brown discolouration of the urinary tract which may extend from the renal pelvis to the bladder (73c).
Antipyretic analgesics
61
REFERENCES 1. Heffner, J., Starkey, T. and Anthony, P. (1979): Salicylate-induced noncardiogenic pulmonary edema. West. J. Med., 130,263. 2. Andersen, R. and Refstad, S. (1978): Adult respiratory distress syndrome precipitated by massive salicylate poisoning, lntens. Care Med., 4, 211. 3. Sgrensen, S.C. (1979): Adult respiratory-distress syndrome in salicylate intoxication. Lancet, L 1025. 4. Arena, F.P., Dugowson, C. and Saudek, C. D. (1978): Salicylate-induced hypoglycemia and ketoacidosis in a nondiabetic adult. Arch. intern. Med., 138, 1153. 5. Mitchell, I. (1979): 'Therapeutic' salicylate poisoning in children. Brit. med. J., 1, 1081. 6. Done, A. K. (1978): Aspirin overdosage: Incidence, diagnosis and management. Pediatrics, 62/ SuppL, 890. 7. Levy, G. (1978): Clinical pharmacokinetics of aspirin. Pediatrics, 62/Suppl., 867. 8. Cassell, S., Furst, D., Dromgoole, S. and Taulus, H. (1979): Dosage schedule of choline magnesium trisalicylate. Arthr. Rheum., 22, 384. 9. Le Roux, P., Le Bihan, G., Bourlier, D. and Litoux, P. (1979): Intoxication salicyl~e par voie cutan~e. Rev. mEd. Alpes fr., 8, 57. I0. Davies, M.G., VeUa Briffa, D. and Greayes, M. W. (1979): Systemic toxicity from topicaUy applied salicylic acid. Brit. med. J., 1, 661. 11. Aspinall, J. B. and Goel, K. M. (1978): Salicylate poisoning in dermatological therapy. Brit. med. J., 2, 1373. 12. Eldar, M., Aderka, D., Shoenfeld, Y., Livni, E. and Pinkhas, J. (1979): Aspirin-induced aplastic anaemia. S. Aft. med. J., 55, 318. 13. Scheinberg, I. H. (1979): Thrombocytopenic reaction to aspirin and acetaminophen. New Engl. J. Med., 300, 678. 14. Yett, H. S., Skillman, J. J. and Salzman, E. W. (1978): The hazards of aspirin plus heparin. New Engl. J. Med., 298, 1092. 15. Michelson, E. L., Morganroth, J., Torosian, M. and MacVaugh, H. (1978): Relation of preoperative use of aspirin to increased mediastinal blood loss after coronary artery bypass graft surgery. J. thorac, cardiovasc. Surg., 76, 694. 16. Torosian, M., Michelson, E. L., Morganroth, J. and MacVaugh, H. (1978): Aspirin and coumadin related bleeding after coronary-artery bypass graft surgery. Anrt intern. Med., 89, 325. 17. Merriman, E., Bell, W. and Long, D. M. (1979): Surgical postoperative bleeding associated with aspirin ingestion. J. Neurosurg., 50, 682. 18. McGaul, T. (1978): Postoperative bleeding caused by aspirin. J. Dent., 6, 207. 19. Borne, G., B~dou, G. and Ar~su, P.-J. (1979): H6matome sous-dural subalgu - r61e possible de l'acide ac~tylsalicylique. Coneours mEd., 101, 1293.
20. O'Grady, J. and Moncada, S. (1978): Aspirin: A paradoxical effect on bleeding-time. Lancet, If, 78O. 21. Rajah, S.M., Penny, A. and Kester, R. (1978): Aspirin and bleeding-time. Lancet, H, 1104. 22. Girolami, A., Cella, G., Zanon, R. D. B., Cappellato, M. G. and Randi, M. L. (1979): Aspirin and bleeding-time. Lancet, H, 205. 23. Hennekens, C.H., Karlson, L.K. and Rosner, B. (1978): A case-control study of regular aspirin use and coronary deaths. Circulation, 58, 35. 24. Piper, D.W., Greig, M., Landecker, K. D., Shinners, J., Wailer, S. and Canalese, J. (1977): Analgesic intake and chronic gastric ulcer. Acute upper gastrointestinal haemorrhage, personality traits and social class. Proc. roy. Soc. Med., 70/
Suppl. 7, 11. 25. Travers, R. L. and Hughes, G. R.V. (1978): Salicylate hepatotoxicity in systemic lupus erythematosus: a common occurrence? Brit. med. J., 2, 1532. 26. Ulshen, M.H., Grand, R. J., Crain, J. D. and Gelfand, E. W. (1978): Hepatotoxicity with encephalopathy associated with aspirin therapy in rheumatoid arthritis. J. Pediat., 93, 1034. 27. Knudsen, F.U. (1978): Acetylsalicylic acid and liver damage. Ugeskr. Laeg., 140, 2233. 28. Jespersen, J. (1978): Salicylate hepatitis in rheumatic fever. Ugeskr. Laeg., 140, 2247. 29. Petty, B.G., Zahka, K.G. and Bernstein, M.T. (1978): Aspirin hepatitis associated with encephalopathy. J. Pediat., 93, 881. 30. Kimberley, R.P., Gill, J.R., Bowden, R. E., Keiser, H. R. and Plotz, P. H. (1978): Elevated urinary prostaglandins and the effects of aspirin on renal function in lupus erythematosus. Ann. intern. Med., 89, 336. 31. Kimberley, R.P., Sherman, R.L., Mauradian, J. and Lockshin, M. D. (1979): Apparent renal failure associated with therapeutic aspirin and ibuprofen. Arthr. Rheum., 22, 281. 32. Dieppe, P.A., Burry, H.C., Doyle, D. V., Tucker, S.M., Corke, C. and Huskisson, E. C. (1978): Nephrotoxicity of analgesic anti-inflammatory and anti-rheumatic drugs. Aust. N.Z.J. Med., 8, 114. 33. Proctor, R. A. and Kunin, C. M. (1978): Salicylate-induced enzymuria: Comparison with other anti-inflammatory agents. Amer. J. Med., 65, 987. 34. Corby, D.G. (1978): Aspirin in pregnancy: Maternal and fetal effects. Pediatrics, 62/Suppl., 930. 35. Regalado, R. G. (1978): The use of salsalate for control of long-term musculo-skeletal pain: an open, non-comparative assessment. Curr. Med.
Res. Opin., 5,454. 36. Huskisson, E.C. (1979): Diflunisal - a new analgesic. Practitioner, 223,415.
62 37. Grayson, M.F. (1978): A clinical trial of diflunisal against aspirin in osteoarthritis. Rheumatol. Rehab.i 17, 265. 38. Dieppe, P.A. and Huskisson, E.C. (1979): Diflunisal and aspirin: A comparison of efficacy and nephrotoxicity in osteoarthritis. Rheumatol. Rehab., 18, 53. 39. Mason, A. M. (1979): Bleeding massive gastric ulcer on diflunisal (Dolobid). Brit. reed. J., 1, 888. 40. Scott, B. (1979): Bleeding massive gastric ulcer on diflunisal (Dolobid). Brit. med. J., 1,489. 41. Admani, A.K. and Khaleque, D. M. N. F. (1979): Gastrointestinal haemorrhage associated with diflunisal. Lancet, I, 1247. 42. Committee on Safety of Medicines. Current Problems, April, 1979, No. 4. 43. Verbeeck, R., Tjandramaga, T. B., MuUie, A., Verbesselt, R., Verberckmoes, R. and De Schepper, P. J. (1979): Biotransformation of diflunisal and renal excretion of its glucuronides in renal insufficiency. Brit. J. clin. PharmacoL, 7, 273. 44. Balali, M. and Prescott, L. F.: unpublished observations. 45. Kornberg, A. and Polliack, A. (1978): Paracetamol-induced thrombocytopenia and haemolyric anaemia. Lancet, H, 1159. 46. Prescott, L.F. (1979): The nephrotoxicity and hepatotoxicity of antipyretic analgesics. Brit. J. din. Pharmacol., 7, 453. 47. Lechat, P., Lagier, G. and Boiteau, J. (1978): Le parac~tamol. Thdrapie, 33, 552. 48. Hamlyn, A. N., Douglas, A. P. and James, O. (1978): The spectrum of paracetamol (acetaminophen) overdose: clinical and epidemiological studies. Postgrad. reed. J., 54,400. 49. Meredith, T. J., Newman, B. and Goulding, R. (1978): Paracetamol poisoning in children. Brit. reed. J., 2, 478. 50. Rumack, B.H. and Peterson, R.G. (1978): Acetaminophen overdose: Incidence, diagnosis and management in 416 patients. Pediatrics, 62/ Suppl., 898. 51. Peterson, R.G. and Rumack, B.H. (1978): Pharmacokinetics of acetaminophen in children. Pediatrics, 62/Suppl., 877. 52. Arena, J. M., Rourk, M. H. and Sibrack, C. D. (1978): Acetaminophen: Report of an unusual poisoning. Pediatrics, 61, 68. 53. Calvert, L. J. and Linder, C. W. (1978): Acetaminophen poisoning. J. Fant Pract., 7, 953. 54. Nogen, A. G. and Bremner, J. E. (1978): Fatal acetaminophen overdosage in a young child. J. Pediat., 92, 832. 55. Bickers, R.G. and Roberts, R.J. (1979): Combined aspirin/acetaminophen intoxication. J. Pediat., 94, 1001. 56. Prescott, L.F., Illingworth, R.N., Critchley, J. A. J. H., Stewart, M. J., Adam, R. D. and Proudfoot, A. T. (1979): Intravenous N-acetylcysteine; the treatment of choice for paracetamol poisoning. Brit. med. Z, 2, 1097. 57. Rigby, R.J., Thomson, N.M., Parkin, G. W. and Cheung, T. P.F. (1978): The treatment of
L. F. Prescott paracetamol overdose with charcoal haemoperfusion and cysteamine. Med. J. Aust., 1,386. 58. Symposium on Analgesic Nephropathy (1978): Kidney int., 13, 1-113. 59. Lornoy, W., Morelle, V., Begaus, L. and Fonteyne, E. (1979): Analgesic nephropathy. New Engl. J. Med., 300, 319. 60. Bengtsson, U., Johansson, S. and Angervall, L. (1978): Malignancies of the urinary tract and their relation to analgesic abuse. Kidney int., 13, 107. 61. Schelstraete, J., Boelaert, J., Daneels, R. and Vergison, R. (1979): Uroepitheliale tumoren van het nierbekken geassocieerd met misbruik van fenacetinehoudende analgetica. T. Geneesk., 35, 395. 62. Jackson, B., Kirkland, J. A., Lawrence, J. R., Narayan, A.S., Brown, H.E. and Mills, L. R. (1978): Urine cytology findings in analgesic nephropathy. J. Urol., 120, 145. 63. Bioassay of a mixture of aspirin, phenacetin and caffeine for possible carcinogenicity. Nat. Cancer Inst. Carcinogen. Techn. Rep. Set., 1978, No. 67. 64. Mulder, G. J., Hinson, J. A. and Gillette, J. R. (1977): Generation of reactive metabolites of N-hydroxyphenacetin by glucuronidation and sulfation. Biochem. Pharmacol., 26, 189. 65. Mulder, G. J., Hinson, J. A. and Gillette, J. R. (1978): Conversion of the N-O-glucuronide and N-O-sulfate conjugates of N-hydroxy-phenacetin to reactive intermediates. Biochem. Pharmacol., 27, 1641. 66. Verbeeck, R., Tjandramaga, T. B., MuUie, A., Verbesselt, R. and De Schepper, P. J. (1979): Effect of aluminium hydroxide on diflunisal absorption. Brit. J. clin. Pharmacol., 7, 519. 67. McGregor, B., Saker, B. M. and England, E. J. (1979): Ureteric stricture associated with analgesic nephropathy. Med. J. Aust., 1,287. 68. Crandon, A. J. and Isherwood, D. M. (1979): Effect of aspirin on incidence of pre-eclampsia. Lancet, I, 1356. 69. Day, R. Q. (1979): Deafness due to aspirin. J. clin. Pharmacol., 19, 328. 70. Cohen, A. (1979): Fecal blood loss and plasma salicylate study of salicylsalicylic acid and aspirin. J. clin. Pharmacol., 19,242. 71. Bulugahapitiya, D. T.D., Hebron, B. and Beck, P. R. (1979): Salicylate hepatitis with acidosis in an infant. Lancet, b,, 1295. 72. Rumble, R.H., Brooks, P.M. and Roberts, M. S. (1979): Interaction between levamisole and aspirin in man. Brit. J. clin. Pharmacol., 7, 631. 73. Abrahams, C. (1979): More on the pathology of analgesic abuse. New Engl. J. Med., 301,437. 74. Macklin, A.W., Welch, R.M. and Cuatrecasas, P. (1979): Drug safety: Phenacetin. Science, 205, 144. 75. Anonymous (1979): Phenacetin prohibition order about to be signed. Pharma. J., Sept. 8, 20. 76. Jorgensen, K.A., Olesen, A. S., Dyerberg, J. and Stoffersen, E. (1979): Aspirin and bleeding time: Dependency of age. Lancet, II, 302.