Antipyretic analgesics

J. Van 6ek

9

Antipyretic analgesics

Analgesic nephropathy and urinary tumors (SED 9, 123; SEDA-4, 60; SEDA-5, 76) Analgesic nephropathy is a unique druginduced renal disease characterized by renal papillary necrosis and interstitial nephritis resulting from prolonged excessive consumption o f analgesic mixtures, usually containing phenacetin. The disease, first recognized in 1953 by Spiihler and Zollinger in Switzerland, is particularly c o m m o n in such developed countries as Australia, Europe, the United States, Canada and South Africa. Despite many earlier reviews o f this topic, doubts and unanswered questions remain, and recent papers justify a fresh discussion o f the subject here.

Incidence Statistics from the European Dialysis and Transplant Association (1 R) on the causes o f chronic renal failure in patients receiving treatment f o r this condition currently suggest that about 3.1% or failures are drug-induced, the figures cited varying from 0.4% in Spain to 1 7.5% in Switzerland. This disparity has many causes: misclassification, true geographic differences in prevalence and differences in the selection o f patients f o r dialysis and transplantation (2 R, 3 R ). Abusers o f drugs have also often been found to be less suitable f o r treatment f o r social and psychiatric reasons, and their inclusion or exclusion affects the calculations. Data from Scandinavia (1 R ) and Scotland {4r} have suggested a drop in the number o f cases, and nephrologists in England also believe that the number o f new patients with analgesic nephropathy is decreasing in their clinics as the result o f the withdrawal o f phenacetin f r o m most analgesic mixtures (1R ). The question remains, however, whether paracetamol, which has been widely substituted f o r phenacetin, might not also be nephrotoxic, especially when combined with other analgesic substances. Indeed some nephrologists suggest that even aspirin taken alone may cause renal damage, since like all

other prostaglandin inhibitors it can reduce renal blood f l o w and cause medullary ischemia under certain conditions. As recently as August 1981, a leader in The Lancet expressed the view that '... aspirin is probably a more important cause o f analgesic nephropathy than phenacetin was' {St). In Australia, where phenacetin was removed from popular analgesics during the period 1 9 6 2 - 1 9 7 5 (6r), analgesic abuse and analgesic nephropathy continue to be a major problem. Between 4.6 and 45.1% o f different subpopulations in the community consume analgesics daily, often for inappropriate reasons (7R). Kincaid-Smith has recently presented figures showing that o f 538 patients newly admitted to the Australian Kidney Foundation's dialysis and transplant registry in 1980, no less than 116 (22~) had analgesic nephropathy (6cr); ominously, she adds that: ".. Analgesic nephropathy with clinical features and renal lemons identical to those seen with phenacetin-containing medications has continued to develop in patients who have taken only aspirinsalicylamide-caffeine or aspirin-paracetamol-caffeine mixtures'. This conclusion has been presented from Australia before. I t does not necessarily prove that these latter mixtures are a risk factor, since many o f these patients no doubt earlier used phenacetin mixtures and the onset o f analgesic neuropathy is slow. Nevertheless, the possibility that substituting paracetamol for phenacetin in analgesic mixtures may merely prolong a risk situation still deserves careful atten tion.

Symptoms The 'analgesic s y n d r o m e ' a s it is sometimes called and the frequency o f particular s y m p t o m s has been well documented in some recent papers (8 r 9C), and the picture is summarized in Table 1. The analgesic syndrome is m o s t c o m m o n l y seen between the ages o f 30 and 70 years, with the peak in the fourth decade, and there is a familial predisposition (IOR). Nocturia resulting from

81

Antipyretic analgesics Table

1. The analgesic syndrome Reference Nanra (7)

Piper

(8)

Porp~iezy (9)

Nitzsche (9a)

Female to male sex ratio

6.5 : 1

2:1

3.3:1

2:1

Analgesic consumption

1 0 - 3 0 kg

1 kg

6.18 kg

4.49 kg

Exposure time

-

-

19.9 yr

15 y r

42%

27%

31% 39%

30% 22% 87%

Symptoms: Analgesic nephropathy Urinary tract infections Tubular epith, ceUuria + microscopic hematuria Proteinuria Renal failure

15-60%

13%

35% 40% 85%

55% 100%

Gastric ulcer

35%

-

Hematologic manifestations Anemia Splenomegaly

60-90% 10%

-

-

Neurologic manifestations Headaches

-

90%

9% 70%

Cardiovascular manifestations Hypertension 15 - 7 0 % Malignant hypertension Ischemic heart disease 33%

56% -

58% 7%

failure to concentrate urine is the earliest functional defect. Capillarosclerosis is pathognomonic f o r phenacetin abuse and is present in roughly 8 0 ~ o f patients (llr}. The renal-cortical and medullary tubules are similarly affected, as overuse o f analgesic-containing preparations may affect the metabolism o f the basem e n t membranes o f capillaries and tubules and result in the thickening o f the walls. In a recent study o f skin biopsy specimens from patients with a history o f excessive intake o f analgesics, thickening o f dermal capillaries suggested that the microangiopathy was not confined to the renal tract but also occurred in other organs (12 r} Patients with analgesic nephropathy are known to have a higher risk o f atherosclerosis. In a retrospective study their serum cholesterol and serum triglyceride concentrations were significantly higher as compared to a control group with other renal diseases o f similar age and degree o f renal insufficiency (13C}. S o m e possible mechanisms for hyperlipemia in analgesic nephropathy have been discussed, as this phenomenon is not sufficiently explained by endstage renal failure or by protein loss as in the nephrotic syndrome.

-

9%

44%

60%

84%

84%

Risk factors The association between analgesic abuse and renal papillary necrosis is well established, but the existence o f other, unrecognized factors is highly probable (3R ). The female to male ratio o f analgesic abusers as a whole in the Australian community is 2:1, y e t that in analgesic nephropathy is approximately 6.5:1 (7R). Climatic factors and fluid intake have also been incriminated. Reports o f an association between HLA genotype and analgesic nephropathy (14 R ) might explain why only a f e w o f the many individuals who take large quantities o f analgesics develop renal failure. Such important questions remain after 2 decades o f research and speculation. Carcinoma The causative association between analgesic nephropathy and transitional cell carcinoma o f the urinary tract has been recognized since 1965 (15 c) and repeatedly confirmed, e.g. in Sweden (SED 9, 125), Belgium (SED 8, 185} (16 c, 17c}, Switzerland (18RJ, Denmark ISED 8, 185) and Australia fSED 8, 185}. In a recent investigation 40 cases o f renal papillary carcinoma were studied (19R ). The overall crude incidence rate was 1.6 per 100,000 population per year; 49% o f the tu-

82 mors were associated with analgesic abuse and analgesic nephropathy. The estimated risk o f renal papillary carcinoma among patients who regularly take analgesics was estimated at 8 per 100,000 patients per year. Renal papillary carcinoma had a female to male ratio among analgesic abusers o f 2.6:1, compared with 1:2 among those without analgesic-associated nephropathy. A similar epidemiologic study from the USA (20 R ) supports this association. Six o f 115 cases (5.2%) o f transitional carcinoma o f the urinary tract diagnosed over 3 years had analgesic-associated nephropathy. The patients were predominantly female, younger, and had renal pelvis tumors instead o f bladder tumors and a higher mortality rate. In a historical prospective study o f 146 patients with interstitial nephritis 84 cases were analgesic-associated, and in 4 patients transitional cell carcinoma developed. None o f 98 nephritic patients without analgesic-associated nephropathy developed transitional cell carcinoma (P <(0.001). These data strongly incriminate analgesic abuse as a risk factor. In Belgium analgesic-associated nephropathy was present in more than 20% o f patients starting treatment with regular hemodialysis during 1977, and was the most common nephropathy in this country (21C). During the period 1 9 7 5 - 1 9 8 0 16 o f 212 patients (5%) with analgesic-associated nephropathy presented transitional cell carcinoma in the upper urinary tract. In 10 cases there was a renal pelvic tumor and in 4 cases a ureteral tumor; 2 patients were found with both tumors. A morphologic study o f 21 transitional cell carcinomas in an Australian histopathology department disclosed 16 cases with papillary changes o f the analgesic type. O f these patients, only 2 were known as analgesic abusers [22c).

ACETYLSALICYLIC ACID AND RELATED COMPOUNDS Aspirin Aspirin, the most widely used drug in the world today, is often listed among the 10 drugs most frequently involved in adverse reactions (23R), and its potential toxicity has been summarized in one word as 'formidable' (5R), the same writer arguing that 'aspirin has a much greater potential for toxicity than paracetamol and there is much to be

Z Van~&k

said for restricting its use in favor of paracetamol, particularly in children' (5 R). Hypersensitivity In a 17-year prospective study at the Speer Allergy Clinic in Kansas, 205 cases of aspirin allergy were identified. 64.9% of these showed urticaria/angioedema, whilst other common manifestations were asthma (35.6%), allergic rhinitis (6.8%) and eczema (2.4%). Women of child-bearing age seemed especially prone to develop aspirin sensitivity. 76% of the patients were also sensitive to inhalants (e.g. moulds, house dust) and 74% to foods, but no cross-reaction to tartrazine was found. Nasal polyps developed in only 12.3% of cases (24C). Some hypersensitivity reactions to aspirin are of the idiosyncratic type, resembling IgEmediated hypersensitivity; however, an immunologic basis for this reaction could be excluded. Most individuals intolerant to aspirin are suffering from chronic asthma or chronic urticaria (25 r 26r Ketotifen administered prior to aspirin was able to protect 13 of 14 patients with aspirin-sensitive asthma against bronchoconstriction and resuited in total prevention of 4 other subjects suffering from urticaria and/or angioedema (25c). A number of mechanisms have been postulated to explain the acute systemic reaction to aspirin. These theories include alteration in the sensitivity of receptors in the respiratory tree and nasal mucosa, activation of complement with increased release o f histamine, or sensitization by impurities such as acetylic acid anhydride. These concepts have recently been critically reviewed (27R). The current explanation is based on the knowledge that aspirin, like other non-steroidal anti-inflammatory drugs, inhibits prostaglandin biosynthesis (28R; SEDA-5, 77). These drugs interfere with the metabolism of arachidonic acid by inhibiting the enzyme cyclo-oxygenase, which in turn prevents the generation of endoperoxides, thromboxanes, and the prostaglandins PGE2 and PGF2a. The E prostaglandins are bronchodilators, while prostaglandin F2a is a bronchoconstrictor. In susceptible individuals inhibition is thought to be predominantly directed toward the E prostaglandins, resulting in bronchospasm. Augmented release of slow reacthag substance of anaphylaxis (SRS-A) is also a part of this reaction. Similar asthmatic reactions can also be produced by other nonsteroidal anti-inflammatory drugs such as in-

Antipyre~c analgesics

83

domethacin, ibuprofen, mefenamic acid, tive blood loss for those receiving aspirin was not phenylbutazone, dextropropoxyphene, para- increased in 6 of 8 subsets by operation and anesthesia when compared with historical control subcetamol, and pentazocine (29 R). Workers who question the prostaglandin jects. Neither a bleeding time greater than 10 mintheory point out that while non-steroidal an- utes nor a prolongation of the bleeding time by aspirin of more than 4 minutes over baseline bleedti-inflammatory drugs inhibit prostaglandin ing times was associated with increased peri-operasynthetase, the azo-dye tartrazine, which in- tive blood loss. duces similar adverse effects in aspirin-sensitive patients, does not inhibit the cyclo-oxyIt is well known that aspirin can, under genase enzymes in the prostaglandin system appropriate conditions, prolong the bleeding (30R; SEDA-5, 24). Tartrazine is one of the time by inhibiting prostaglandin endoperoxcompounds which most frequently provoke ides and thromboxane A2 in the platelets. It the intolerance syndrome in individuals in- appears that the aspirin concentration necestolerant to aspirin (31 c ; SEDA-5, 20). sary for inactivation of platelet thromboxane Generally it is estimated that about A2 is at least 10 times lower (37 r) than that 15-20% of reported reactions are azo-dye- needed for inactivation of subendothelial induced (32 R, 33r). This is a n u m b e r which prostacyclin formation. A single small dose can hardly be dismissed as 'observed sporadi- of aspirin given every few days will thus stop cally in aspirin-sensitive asthmatics', as some platelet thromboxane A2 formation without authors have it (28R). influencing the prostacyclin generating capaWhen testing for aspirin sensitivity in city of the vessel wall (38r). asthmatics, administration of the lysine salt A single dose of 40 mg aspirin has no of the drug by inhalation is recommended effect on prostacyclin synthesis, whereas (34c). The main advantages over oral chal- 300 mg aspirin inhibits synthesis for more lenge (35 e) are that responses are faster than 48 hours. Both doses have an inhibitory (within 1 5 - 3 0 minutes), confined only to effect on thromboxane synthesis which lasts the respiratory tree (no rhinitis, no conjunc- for at least 96 hours (39r). The dose of 40 tivitis, no flushing), and always easily con- mg aspirin has been found sufficient to retrollable. The majority of sensitive patients duce platelet thromboxane synthesis, but react to 1.3 mg of aspirin. It is possible to the length of time during which the amount 'desensitize' these patients by inhalation of thromboxane synthesized was insufficient over 1 5 - 2 0 days so that they can tolerate to induce platelet aggregation and the platetherapeutic doses of aspirin. let release reactions differ in different individuals (40 r, 41r). One of the factors influEffects on bleeding and thrombogene- encing the effects of aspirin in this respect is sis The current debate on the possible use the age of the patient (42 r, 43r). It has been of aspirin to prevent thrombo-embolic com- shown that 40 mg aspirin taken daily can plications associated with surgery necessarily have a cumulative inhibitory effect on involves consideration of the risk that it thromboxane synthesis (41r). Long-term admight increase peri-operative blood loss. In ministration of 40 mg aspirin daily may perthat respect, a recent study by Amrein et al. haps have a cumulative effect on PGI2 from Boston is of considerable interest synthesis as well. (36CR): Five randomized controlled trials published recently were designed to assess the efOne hundred twenty-nine patients undergoing fects of aspirin alone or in combination with total hip replacement were treated with aspirin at a other drugs ( 4 4 c - 4 8 c ) on mortality and level of either 300 mg 4 times a day (1.2 g/day) or morbidity in persons with previous myocar900 mg 4 times a day (3.6 g/day). Baseline bleed- dial infarction. The doses of about 1 g/day ing times before aspirin treatment averaged 4.18 • employed in most such trials caused dyspep1.44 minutes. Two hours after 300 mg and 900 mg sia, nausea, or even vomiting in 1 0 - 2 0 % of of aspirin, the bleeding times were 5.83 • 1.88 and 5.72 • 1.57 minutes, respectively. After 3-5 days patients, induced constipation, gout, and of aspirin therapy at 1.2 g/day and 3.6 g/day, the melena each in about 1% per year, and bleeding times were 6.27 • 2.27 and 6.43 • 2.11 caused hematemesis in about 0.1% per year minutes, respectively. The bleeding times for all (SEDA-5, 81). It has been suggested that a the aspirin-treated groups were longer than baseline lower dosage than 1.0 g/day might better times. No paradoxical shortening of the bleeding achieve the goal, and would also minimize time was noted at the 3.6-g/day dose. Peri-opera- the undesirable gastrointestinal symptoms

84 (49r These adverse reactions can usually be dealt with by stopping treatment, but they are not trivial (SEDA-5, 81).

Z Van,!~ek

year (SED 8, 166) and it is not certain whether the relationship is one of cause and effect or not. Epidemiologic evidence suggests that only persons who take aspirin Reye's syndrome In 1977 and 1978 the regularly or in large doses (more than 15 tabCenter for Disease Control received reports lets a week) are likely to suffer acute gasof 655 cases of Reye's syndrome from Utah, trointestinal bleeding or gastric ulceration Arizona and Colorado, of which 32% were (51R). Some studies (SEDA-I, 69; 53 R) fatal (50c). The resemblance of severe sali- have shown reasonable evidence for an assocylate intoxication to Reye's syndrome has ciation between frequent aspirin ingestion repeatedly been noted (SEDA-5, 78). A re- and gastric ulceration, but the nature of the cent study (50 C) has evaluated the symp- relationship has remained uncertain, and it toms o f the viral-like illness and the medi- has been argued that the adverse effects of cines taken by 7 school-age children with aspirin may have been overemphasized Reye's syndrome and sick control subjects (52R). during an outbreak of influenza. The data One of the best documented recent show that the mean salicylate dose for pa- studies is that by Piper et al. from Australia, tients was 5.164 + 4.238 rag, the dose for who compared the patterns of analgesic incontrol patients was 1.303 _+ 1.742 mg. Sali- gestion in gastric and duodenal ulcer patients cylate was not only consumed in larger with those of matched community controls. quantities, but also more frequently by pa- It was found that there was a strong positive tients than by control subjects and increas- association between heavy analgesic intake ing doses of salicylate and the severity of and chronic gastric ulcer with a relative risk Reye's syndrome were directly related. Two of 29.5. The association was most marked in of the 7 children died, post-mortem findings female patients, where the relative risk was were consistent with Reye's syndrome. As 51.8. The involvement of aspirin- and pararepeatedly seen in this syndrome, the cetamol-eontaining drugs was of similar sigamount of salicylate taken by these children nificance, with relative risks of 17.3 and was not in the range generally considered to 24.4 respectively. No association was found be toxic (SEDA-5, 78). between chronic duodenal ulcer and analgesic intake. As these workers point out, the Gastrointestinal Current knowledge of the strong association found between gastric gastrointestinal side effects of acetylsalicylic ulcer and heavy analgesic usage does not acid has been summarized in various reviews necessarily indicate a causal relationship (SEDA-5, 39; 51R--55R). The analysis of (56Cr). published reports and attempts to underThe effects of continued exposure to asstand the problem (SEDA-5, 75) have been pirin thus remain controversial and we may hampered by widespread reliance on frag- suppose, in the light of animal experiments, mentary data and a plethora of uncontrolled that the mucosa develops resistance to some and retrospective studies. Prospective con- types of damage after an initial exposure. trolled trials are very scarce. Further studies are required (52R). The validity of the sl Cr-tagged red cell There is convincing evidence that dyspepsia, nausea and vomiting occur in 2 - 6 % of technique has been questioned, as it did not patients after aspirin ingestion (SED 9, 129). distinguish between gastric bleeding and These s y m p t o m s are p o o r predictors of the blood loss elsewhere in the gastrointestinal incidence of mucosal damage. At the same system. Furthermore, salicylates can stimutime the loss of blood in stools may be in- late bile secretion; the increased fecal excrecreased 1 0 - 2 0 - f o l d depending on the dose. tion of sl Cr after aspirin may thus be reGastroscopy has shown clear but non-spe- lated to effects on biliary secretion rather cific mucosal damage in up to 100% of pa- than to gastric bleeding. tients, though the observations have often When the published evidence linking aspibeen subjective and uncontrolled (SED 9, rin ingestion to gastric mucosal damage is 130). Rheumatoid patients seem to be more looked at in more detail, and a more exact sensitive and the frequency of aspirin-in- description of the effects of the drug is duced dyspepsia is 1 0 - 3 0 % (SEDA-5, 79). sought, the picture becomes less clear. Some The risk of major gastrointestinal bleeding is have taken the view that the case against asonly 15:100,000 in heavy aspirin takers per pirin in the pathogenesis o f serious gastric

Antipyretic analgesics

85

disturbances may have been overstated and that more controlled studies are still needed (SEDA-5, 78). The pathogenesis of the aspirin-related gastric lesion has been discussed (54 R) with special attention to prostaglandins of the E series (PGE2), which inhibit gastric secretion and increase gastric mucosal blood flow (55r); it could be expected that inhibition of cyclo-oxygenase by aspirin and other acidic non-steroidal anti-inflammatory agents might be followed by increased gastric secretion and diminished blood flow. The view has been advanced that PGE2 synthesis inhibitors may play a role in the production of gastric mucosal lesions by producing vasoconstriction that might lead to local ischemia, tissue death and bleeding (57r). Stable synthetic forms of PGE2 have been shown to significantly increase the rate of healing of gastric ulcers.

in salicylate hepatotoxicity has been studied by Gitlin (60 R). Seventeen patients suffering from an initial attack of acute rheumatic fever were followed during treatment with phenoxymethyl penicillin and salicylates (600 mg orally eveiy 4 or 6 hours). Elevated transaminase (SGOT) levels occurred in 9 patients. The SGOT levels were directly related to serum salicylate levels (r = 0.668) and inversely to serum albumin level (r = - 0 . 4 1 8 ) . The SGOT response was greater in patients with a serum albumin of less than 3.5 g/dl (P 0.001). In hypoalbuminemia, the ratio of free to bound salicylate rises and the free salicylate might be more active and thus more hepatotoxic even at relatively low total serum salicylate levels. In all patients with hypoalbuminemia of less than 3.5 g/dl close monitoring of the SGOT is advisable, especially if the level of total serum salicylate is 15 mg/dl or higher.

Hepatotoxicity (SED 9, 129; SEDA-4, 57; SEDA-5, 78) Aspirin and the salicylates have

Acute renal effects The acute renal effects of aspirin which it has in common with other anti-inflammatory agents have been referred to when discussing analgesic nephropathy (above). Normally, the acute effects of aspirin on the kidney are of minor importance. The drug can cause a transient shedding of tubular renal cells, alterations in urate excretion, inhibition of spironolactone action, and, in certain clinical settings, a reversible decline in renal function manifested as a fall in glomerular filtration. Severe systemic disease involving the liver or kidneys seem to predispose the patient to the effects on renal function (61R).

only recently been recognized as potentially hepatotoxic (58R). Yet during the last 10 years several hundred relevant cases have been described (59R). Almost all the reported cases have occurred in children and young adults with connective tissue disorders such as Stitl's disease, rheumatoid arthritis and systemic lupus erythematosus; females have been affected more often than males. About 50% of patients with juvenile rheumatoid arthritis have shown some degree of liver injury as evidenced by elevation of plasma aminotransferases during conventional highdose aspirin therapy. Plasma salicylate concentrations have usually been in excess of 200 lag/ml and liver function tests return rapidly to normal when the drug is discontinued. In a small minority of cases, however, perhaps 3% of the total, the hepatic injury has proved to be more severe. Salicylate-induced hepatic injury and encephalopathy occurred in 5 persons, injury and coagulopathy in one, and fatality attributed to injury in 2 persons; there are also cases on record of juvenile rheumatoid arthritis and SLE in whom this type of hepatic complication occurred (59R). Finally, there are a very small number of cases of chronic active hepatitis on record which appeared attributable to aspirin (59R). The potential role of hypoalbuminemia

Poisoning with enteric-coated aspirin Enteric-coated aspirin is designed to reduce gastric intolerance; the enteric coating slows down absorption of the active principle, and in cases of severe overdosage this may cause difficulties in diagnosis and treatment, since plasma salicylate measurements are unreliable as a guide to prognosis. In one case reported in a newspaper, salicylate was not detected in a blood sample taken on admission, and the patient was discharged in apparently good condition after gastric lavage; he died at home 15 hours later. In such cases it should be borne in mind that the maximum blood levels may not be attained until 60 or 70 hours after the overdose has been taken (62R).

J. Van#~ek

86 Diflunisal (SED 9, 133; SEDA-4, 58; SEDA-5, 81) This salicylic acid derivative with analgesic and anti-inflammatory properties lacks aspirin's O-acetyl side chain, and thus does not irreversibly bind to plasma proteins or other macromolecules in vivo. Most of the clinical tests of diflunisal have compared the drug with aspirin and have shown it to be more potent on a weight basis whilst producing fewer adverse reactions. When used in equally effective doses, aspirin causes endoscopically confirmed gastric lesions in a significantly higher incidence than does diflunisal, e.g. 50~ and 10% respectively (63R). Inhibition of platelet aggregation and gastric prostaglandin have been linked to the ulcerogenic property of aspirin (SED 8, 154). A recent study in this connection (64 r) separately examined platelet thromboxane A2 and gastric prostaglandin E2 synthesis in healthy subjects and arthritic patients receiving single oral doses of aspirin or diflunisal. In healthy subjects, aspirin (400 mg) caused a rapid and long-lasting suppression of serum levels of thromboxane B2 (the chemical breakdown product of thromboxane A2) levels: more than 95% inhibition occurred at all time intervals (P < 0 . 0 0 0 5 ; n = 6). Diflunisal (750 mg) caused a slower and less pronounced inhibitory effect with 65% inhibition at 6 hours (P < 0.005 ; n = 6), fully reversible at 48 hours. In arthritic patients, aspirin caused a marked suppression of gastric prostaglandin E2 output which was partially reversible 3 - 4 hours after intake. By contrast, an equally effective dose of diflunisal or placebo caused no statistically significant changes. The results provide evidence for a differential inhibition of platelet and gastric cyclo-oxygenase in vivo. A less pronounced and reversible effect on platelet cyclo-oxygenase and the apparent lack of effect on the gastric enzyme might contribute to the l o w e r incidence of gastric lesions found in patients undergoing diflunisal treatment. In another study (65 r) adenosine diphosphate and collagen-induced platelet aggregation and parameters related to the fibrinolytic system were followed in healthy persons receiving 500 mg of diflunisal in a single dose. This dose resulted in a depression of platelet function in most cases; however, the effect was limited and only of clinical relevance in patients with a defective platelet function.

In approximately one-third of persons, fibrinolytic activity in the saliva rose to levels capable of inducing clot lysis within a few minutes. This could explain the clinical observation that administration of diflunisal prior to dental surgery is followed by dry

socket symptoms. Diflunisal has been found to inhibit platelet aggregation in vitro (66 r) although there was some variation in individual responses. At 200/.tg/ml some samples showed almost complete inhibition. The authors concerned have argued that, in view of such findings, diflunisal may be contraindicated in patients with a bleeding diathesis. The Swedish Adverse Drug Reaction Committee has received 33 reports of adverse reactions to diflunisal since its introduction; 33% of these cases concerned gastrointestinal effects or some form of hemorrhagic complication (67R).

Paracetamol Blood A few publications incriminate paracetamol as a thrombocytopenic agent (SED 8, 186; SED 9, 135; SEDA-4, 59). Some authors (SED 8, 186) have demonstrated in the serum of a thrombocytopenic patient a circulating antibody directed against the sulfated metabolite of acetaminophen, and suggested that the metabolite rather than the drug was responsible for the thrombocytopenia. A new observation of a patient with paracetamol-induced thrombocytopenia (68 e) is of interest in that a positive test for migration-inhibitory factor (MIF) and a rechallenge confirmed the cause and effect relationship: A 70-year-old man presented with generalized purpura that had appeared after the ingestion of paracetamol (1050 mg per day for 2 weeks). During this period he received no other medication. Laboratory tests indicated a low platelet count and a positive test for the presence of an MIF to acetaminophen. Other parameters were within normal limits. The purpuric rash faded spontaneously within several days, and the platelet count rose from 30,000 to 100,000 per mm 3. Three months later the patient ingested in error 750 mg of paracetamol, and again a generalized purpura and thrombocytopenia with a platelet count of 45,000 per mm3 developed and disappeared spontaneously after 5 days. Paracetamol should thus be considered a potential thrombocytopenia-inducing agent.

87

Antipyretic analgesics Agranulocytosis induced by paracetamot is very unusual; until recently, the only known case was one described in 1961 (SED-9, 135). Recently, two French papers have appeared describing this complication in 6 patients aged between 19 and 78 (69 c, 70e). The preparations taken by these patients were mostly pure paracetamol or paracetamol in combination with aspirin, vitamin C or 0l-amylase; only one took paracetamol in combination with a phenothiazine (oxomemazine) which is k n o w n to induce blood dyscrasias. It is very interesting that the authors (69 c) consider the frequency of paracetamol-induced agranulocytosis to be as high as 10%, of all cases of this disorder, which is in agreement with a previous assessment published in the French literature (71c). Overdosage (SED 9, 136) (59 R) The occurrence of acute hepatic necrosis and hepatic failure following the ingestion of large quantities of paracetamol continues to be well documented (72 c) not only in adults, but also in children (73c). Therapy with an appropriate antidote should be instituted without delay, preferably involving infusion of N-acetylcysteine (74c-76c). Of 50 patients in one series (91 c) with fulminant hepatic failure due to a paracetamol overdose only 9 were admitted to hospital early enough to benefit from protective measures, and only 3 of these were treated. Plasma paracetamol assays are important if the patient is admitted at a time when antidotes are unlikely to be effective; if in such a case the plasma level is in the 'high risk' category charcoal hemoperfusion may be beneficial. The same applies in simultaneous barbiturate and paracetamol overdosage (77c). Antidotes should not be used in children, as their adverse effects can be significant and experience of their use in the young population is limited. The application of antidotes is in any case justified only when reasonable confirmation of paracetamol ingestion is obtained (76c). The management of paracetamol overdose can better be based on serum levels than on patient-supplied information, which may be misleading (78c). It seems very probable that certain patients are relatively more susceptible to the hepatotoxic effects of paracetamol, e.g. patients with glutathione synthetase-deficient lymphocytes (79R), chronic ethanol drinkers ( 8 0 c - 8 2 c) or cachectic individuals with gluthatione depletion (92 C).

Chronic ingestion of therapeutic doses of paracetamol has generally been considered safe. A recent critical review of the published reports of 45 patients with chronic active hepatitis (83) failed to uncover any convincing evidence that paracetamol was an initiating factor in the development of chronic active hepatitis. However, there are certain reports (SEDA-3, 84) suggesting that therapeutic doses of paracetamol may result in either toxic hepatitis or chronic active hepatitis, at least in those individuals at risk. The latter point is in fact still undecided, and further studies will be necessary (84 c, 85R; SEDA-3, 84). Nephrotoxicity

In a suicidal attempt a 26-year-old man ingested 11 g of paracetatool (in the form of 25 'Darvocet N-100' tablets). He was also regularly taking promazine and doxepin for anxiety neurosis. Acute renal failure was confirmed by a kidney biopsy which showed tubular necrosis. The patient underwent peritoneal dialysis but ultimately renal function returned to normal. Although renal failure after an acute paracetamol overdose usually occurs in the presence of hypotensive or massive hepatic necrosis, neither of these was present in this patient; there was indeed acute hepatic damage but it was not severe in degree. The renal damage in such cases may result from glutathione combining with toxic intermediates produced by the P-450 mixed function oxidase system in the kidney (86c). In this respect, attention may be drawn to a thoughtful review by Plotz and Kimberly (60R), who again draw attention to the fact that a major dose of paracetamol occasionally causes renal failure unascribable to hepatic failure. They stress the fact, which comes increasingly to the fore in recent literature, that paracetamol has a broader spectrum of effects than was until a few years ago realized; in particular its anti-inflammatory effects have been overlooked for too long; as these authors write, '... not all the effects of aspirin on the kidney have been shown to occur with acetaminophen, but there has been no careful attempt to look for them ...'.

Interference with diagnostic routines Attention has been drawn to the fact that paracetamol can induce false-positive reactions for glucose in serum and blood specimens examined using the YSI glucose analyzer. The effect could be of considerable impor-

88 tance in p a t i e n t s a d m i t t e d w i t h s u s p e c t e d p a r a c e t a m o l overdosage (87c). Use i n l a c t a t i o n Several r e c e n t p a p e r s p r e s e n t s t u d i e s o f the e x c r e t i o n o f paracetam o l in t h e b r e a s t milk. All o f t h e m c o n c l u d e t h a t t h e q u a n t i t i e s e x c r e t e d are very small in-

Z Van~?ek deed; it w o u l d seem t h a t , despite t h e fact that the newborn infant may metabolize s u c h s u b s t a n c e s less e f f i c i e n t l y t h a n an o l d e r child, t h e r e is n o risk in a d m i n i s t e r i n g t h e drug, at least in n o r m a l doses, to a l a c t a t i n g w o m a n ( 8 8 c , 89 c , 9 0 c ) .

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