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Anti-inflammatory analgesics and drugs used in rheumatism and gout
L. F. Prescott
9
anti-inflammatory analgesics and drugs used in rheumatism and gout
These drugs are often used in m a x i m u m dosage and for prolonged periods in patients with chronic and disabling conditions. The anti-inflammatory analgesics are organic acids and many of their actions are thought to be related to inhibition of prostaglandin synthesis. They all cause gastrointestinal toxicity and most, if not all, are potentially nephrotoxic. A large number of new anti-inflammatory analgesics have been introduced and although their relative efficacy and safety remains to be established there is evidence that some may produce less toxicity than equi-effective doses of aspirin.
PYRAZOLONES AM1DOPYRINE AND RELATED DRUGS
In toxication A 4-week-old infant was given half a suppository containing amidopyrine, allobarbital, hexahydroadiphenine and codeine in the mistaken belief that it was a laxative. Symptoms were initially controlled with naloxone, but complications included convulsions, apnoea, bradycardia, paralytic ileus and oliguria. Forty hours after poisoning an exchange transfusion was carried out with eventual recovery (lC). It is difficult to know which drug caused which effect in this case, but convulsions are common in pyrazolone poisoning (SED VIII, pp. 2 0 9 - 2 1 0 ) .
aspirin and other analgesics (3 R, 4r; see also SEDA-1, p. 86).
Blood Amidopyrine and dipyrone are well known to cause agranulocytosis, yet are still freely available in some countries. The exact pattern of the complication varies (SED VIII, p. 210; SEDA-1, p. 87). Of 31 cases of drug-induced agranulocytosis, studied at one centre in France, 27 were caused by these drugs, and there were 6 fatalities. In most cases there was a fulminating clinical course with septicaemia and lesions of the mucous membranes. Bone marrow examination usually revealed selective involvement of the granulocyte series with maturation arrest at the metamyelocyte or myelocyte stage (5 C R). A woman who had reacted to amidopyrine with agranulocytosis 10 years previously used suppositories containing the same drug. Eight days later she developed fever and pharyngitis with tenesmus and the white cell count was 1000/mm 3 (17% granulocytes). Necrosis of the rectum occurred, leaving a rectovaginal fistula (6c).
In another case attributed to amidopyrine there was total absence of neutrophils and granulocytes in the peripheral blood and bone marrow. On admission, and when retested 6 and 12 months later, the patient's serum contained amidopyrine-dependent leuko-agglutinins (7 c).
Allergy
Risk o f carcinogenesis
Amidopyrine may cause a variety of skin reactions, sometimes with involvement of buccal and genital mucous membranes (2c). Amidopyrine and related pyrazolones may cross-react in asthmatics sensitive to
Amidopyrine, like many other drugs, can react with nitrites in food to form potentially carcinogenic nitrosamines in the stomach (SEDA-1, p. 386).. The matter is further discussed in Chapter 47.
L. F. Prescott
92 PHENYLBUTAZONE AND OXYPHENBUTAZONE
Allergy Allergic reactions to these drugs (SED VIII, p. 212) can sometimes take an acute form. A patient developed a generalized rash and collapsed unconscious 15 minutes after an intramuscular injection of 600 mg of phenylbutazone (8e). Three patients developed a haemorrhagic eruption on the hands after taking phenylbutazone. Capillary fragility was increased with a positive Hess test (9c).
Lungs Phenylbutazone and related compounds may precipitate or aggravate asthma in patients who are sensitive to aspirin (SEDA-1, p. 87), but may also cause pulmonary oedema and occasionally changes resembling allergic alveolitis. A 69-year-old man with advanced myxoedema was given phenylbutazone for joint pain. Two weeks later he was admitted to hospital semiconscious, and improved with thyroxine 0.05 mg daily. He was given phenylbutazone again and 18 days after admission was semiconscious with extensive bilateral crepitations throughout the chest and acute respiratory failure (arterial blood pH 7.18, pO 2 45 mm Hg and pCO 2 98 mm Hg.) A chest X-ray showed multiple poorly defined shadows in both lungs, and these extended over the next two weeks despite intermittent positive pressure ventilation. There was a leukocytosis with eosinophilia (14%). Frusemide and ethacrynic acid did not produce a diuresis or improvement. Finally, after treatment with phenylbutazone in hospital for more than 6 weeks the possibility of drug-induced lung damage was considered. The phenylbutazone was stopped and prednisone started. The eosinophilia rapidly disappeared and he improved steadily. The lung fields were completely clear 6~ months later (10C). Although phenylbutazone-induced pulmonary oedema is not u n c o m m o n , this type of reaction must be very rare. The Swedish Adverse Drug Committee has stressed that oxyphenbutazone can produce pulmonary reactions as severe as those due to phenylbutazone. The Committee has filed reports on six such cases, one of them fatal (1 lr).
Blood Phenylbutazone, oxyphenbutazone and related pyrazolones are well known to cause
blood dyscrasias which are often fatal, and the frequency of this complication has been estimated in a British survey. The histories of 269 patients whose death certificates did not mention a drug as the cause o f aplastic anaemia or agranulocytosis were investigated in a survey carried out between October, 1974, and September, 1975. Eighty-three deaths were probably caused by drugs, and o f these, phenylbutazone and o x y ph en b u t azo n e were the commonest cause of aplastic anaemia, together accounting for 39 deaths (47%). The mortality from this cause was estimated as 3.8 per 100,000 for o x y p h en b u t azo n e and 2.2 per 100,000 for phenylbutazone. The mortality from both drugs increased strikingly with age, and was higher in women (12 c).
Perforation o f peptic ulcer In view o f the gastrointestinal toxicity of these drugs in animals and man (SED VIII, p. 214; SEDA-1, p. 87), perforation of peptic ulcers in patients taking these drugs is not surprising. A history of anti-rheumatic drug therapy was obtained in 195 patients with perforated juxta-pyloric ulcers and in another series of 22 patients studied prospectively, 2 had taken phenylbutazone (13 c).
Rectal pain Oxyphenbutazone suppositories may cause rectal pain (14c); phenylbutazone suppositories are known to be capable of eliciting a severe proctitis (SEDA-1, p. 88).
Loss o f taste Loss of the sense o f taste was attributed to phenylbutazone in 3 cases (15 c).
Liver There have been numerous reports of liver involvement in generalized hypersensitivity reactions to phenylbutazone (SED VIII, p. 215) and a recent fatal case merits attention. In one case presented at a clinicopathological conference, liver damage was probably due to a generalized reaction to phenylbutazone, despite polypharmacy with other potentially hepatotoxic drugs. The patient had an intracranial aneurysm which was successfully occluded by neurosurgery. Methyldopa had been given over the previous 4 years and trichloroethylene was given 34 and 18 days and halothane 31 days before there was clinical evidence of liver damage. Other drugs given about one month before included diphenylhydan-
Anti-inflammatory analgesics and drugs used in rheumatism and gout toin, chlorpromazine, prochlorperazine, hydralazine and codeine, although it is not clear how long these were continued. Fourteen days after being given phenylbutazone (dose unstated) for apparently transient fever and calf pain, the patient developed fever, confusion and a generalized maculopapular rash. The liver was enlarged with increased aminotransferases, bilirubin and alkaline phosphatase and there was oliguria with azotaemia. Three days later he was transferred to another hospital, and an impressive variety of investigations was carried out, including a liver biopsy which was complicated by a pneumothora• Phenylbutazone was stopped, but the p'atient died (16C). There are obvious difficulties in attributing liver damage to any particular drug in this complex case, but the combination of fever, rash, liver damage and renal failure has often been reported in generalized hypersensitivity reactions occurring within two weeks of starting phenytbutazone (SED VIII, p. 212, p. 215).
Renal In the case mentioned above there was renal failure with post-mortem evidence of acute tubular damage (16 c). Phenylbutazone can cause renal papillary necrosis in animals, and this has also been observed in man (SEDA-1, p. 87). Thyroid Phenylbutazone and oxyphenbutazone can cause hypothyroidism and goitre (SED VIII, p. 216) which may be reversible. 9 A 63-year-old woman with hypothyroidism and thyroid enlargement had taken phenylbutazone for 1 year followed by oxyphenbutazone tbr 4 years. a ~I uptake was very high (32% at 30 min.) but following the administration of potassium perchlorate at 40 min. there was rapid discharge of isotope from the gland. The oxyphenbutazone was stopped and the patient was clinically euthyroid 4 weeks later and at follow-up 21 months later. The thyroid -was no longer visible or palpable (17C).
Drug interactions Phenylbutazone and related drugs may cause a number of potentially serious drug interactions (SED VIII, p. 216). They may displace other drugs from plasma protein binding sites, inhibit drug metabolism, and interfere with active renal tubular secretion of other acidic drugs and metabolites. Methotrexate toxicity was attributed to interaction with phenylbutazone in two patients with psoriasis (18 c ).
93
KETOPHENYLBUTAZONE (KEBUZONE) Muscle necrosis and gangrene have occurred following intramuscular injection of ketophenylbutazone (19 C). INDOMETHACIN AND RELATED DRUGS
Allergy lndomethacin may aggravate or precipitate severe bronchospasm in patients with aspirin intolerance (SEDA-1, p. 88; 3 c, 4r), and a similar cross-reaction may occur in patients with urticaria who are sensitive to aspirin (20r A 50-year-old man with asthma and allergic rhinitis associated with aspirin intolerance developed severe dyspnoea progressing rapidly to respiratory arrest with a grand mal convulsion 45 minutes after being given 50 nag of indomethacin orally. He was successfully resuscitated (21C). These effects of indomethacin are probably related to its inhibitory effect on prostaglandin synthesis (22 R).
Blood Menkes et al. (23 c r ) have described a case of fatal aplastic anaemia in a woman treated with both indomethacin and acetylsalicylic acid. They point to three earlier fatal cases where the same combination of drugs had been taken. However, indomethacin can produce this effect on its own (SED VIII, p. 218). Gastrointestinal system The gastrointestinal toxicity of indomethacin (SEDA-1, p. 88) has been attributed to inhibiton of prostaglandin synthesis and methyl analogues of prostaglandin E z inhibit indomethacin-induced gastric erosions (24). Consumption of indomethacin has been linked with perforation of peptic ulcers (13r Renal (See SED VIII, p. 219) Indomethacin decreased glomerular filtration rate and renal plasma flow in nephrotic patients but not in healthy subjects (25c). Impaired renal function has been observed in patients with systemic lupus erythematosus and Bartter's syndrome given indomethacin, and it may increase the serum creatinine and cause renal insufficiency in infants (26 c, 27c). In another report rapidly progressive
94 r e n a l failure a n d t u b u l a r n e c r o s i s was associated w i t h i n d o m e t h a c i n t h e r a p y in a 26year-old p a t i e n t w i t h g l o m e r u l o n e p h d t i s (28c). I n d o m e t h a c i n , b e c a u s e it i n h i b i t s prostag l a n d i n s y n t h e s i s , m a y alleviate t h e m e t a b o l i c a b n o r m a l i t i e s o f B a r t t e r ' s s y n d r o m e , a cond i t i o n associated w i t h excessive prostaglandin p r o d u c t i o n ( 2 9 c, 30e). H o w e v e r , in o n e such. case, a d m i n i s t r a t i o n o f i n d o m e t h a c i n (3 m g / k g / d a y ) r e s u l t e d in a gain in w e i g h t o f 4 kg in 5 days w i t h h y p e r n a t r a e m i a and severe t e t a n y . T h e p a t i e n t was c o m p l e t e l y i m m o b i l i z e d f o r 3 6 h o u r s w i t h generalized m u s c l e c r a m p s a n d c a r p o p e d a l spasms (29c). Central n e r v o u s s y s t e m H e a d a c h e is p r o b a b l y t h e c o m m o n e s t side e f f e c t o f i n d o m e t h a c i n t h e r a p y , a n d m a y be associated w i t h dizziness a n d m o o d c h a n g e s s u c h as d e p r e s s i o n (SED VIII, p. 2 1 9 ) . C o n f u s i o n a n d h a l l u c i n a t i o n s m a y o c c u r , especially in t h e elderly. Six of 45 elderly patients and one young woman developed hallucinations after being given indomethacin. All the patients were lucid and the hallucinations were generally pleasant rather than unpleasant, but were accompanied by anxiety and anguish. All the patients experienced visual hallucinations, one also had auditory hallucinations and 2 had nightmares. These manifestations seemed to be dose-related, and may be caused by cerebral vasoconstriction. Three patients experienced micropsia ('Alice in Wonderland' phenomena) in their hallucinations, and this has also been described in migraine (31C). Pregnancy and labour I n d o m e t h a c i n delays t h e o n s e t o f l a b o u r ( S E D VIII, p. 2 2 0 ) a n d h a s b e e n used t o prev e n t p r e m a t u r e l a b o u r . It m a y also stimulate closure o f t h e f o e t a l d u c t u s arteriosus. B o t h these a c t i o n s are t h o u g h t t o be mediat e d b y i n h i b i t i o n o f p r o s t a g l a n d i n synthesis. Serious d o u b t s have arisen r e c e n t l y conc e r n i n g t h e safety of i n d o m e t h a c i n given just before or during labour. lndomethacin (l mg/kg) was given daily for 7 days before anticipated delivery to pregnant mongrel bitches. The foetuses were removed by Caesarean section but were 'non-viable'. There was no obvious cause apart from some placental separation, and premature closure of the ductus arteriosus had not occurred (32). In a n o t h e r s t u d y , p r e g n a n t rats were treated with indomethacin. Compared with
L. b: Prescott c o n t r o l animals, t h o s e receiving i n d o m e t h a cin h a d m o r e s t i l l b i r t h s a n d t h e survivors h a d severe n e u r o n a l n e c r o s i s a t t r i b u t e d t o vasoc o n s t r i c t i o n a n d h a e m o d y n a m i c changes o r d i r e c t t o x i c i t y (33). T h e use o f i n d o m e t h a c i n to delay t h e o n s e t o f l a b o u r m a y cause p r i m a r y p u l m o n a r y h y p e r t e n s i o n in t h e n e w b o r n . An 18-year-old girl was given 25 mg of indomethacin 6-hourly for 4 days because of vaginal bleeding at 33 weeks of gestation. She received the last dose 4 hours before delivery. Fever and a foul vaginal discharge developed, anda Caesarean section was performed. A 2-kg infant girl was delivered through foul-smelling anmiotic fluid and required resuscitation with endotracheal intubation, positive-pressure ventilation and intravenous albumin. Physical examination of the infant was normal, there were no cardiac munuurs and she was given 40% oxygen. Three hours later reduction of the oxygen concentration to 35% resulted in cyanosis and lethargy. At 8 hours of age 80% oxygen was required to maintain a pO~ of 5 0 r a m Hg and a chest X-ray showed possible cardiomegaly. The patient improved and was breathing room air the next day. In a 38-year-old woman the membranes ruptured after a fall 7 weeks before delivery at 34 weeks. Uterine contractions were controlled after the fall with bed rest and indomethacin 50 mg 6 hourly for 7 days. Thereafter she took 50mg once or twice weekly over the next 6 weeks. Four days before delivery she had vaginal bleeding and took 50 mg every 6 hours. A breech-extraction was required and she received oxytocin, a mepivacaine pudendal block, morphine, and secobarbitone. The infant was cyanosed but the lungs were clear and there were no cardiac murmurs. At 2 hours of age he was receiving 90% oxygen and was tachypnoeic with a systolic murmur and a gallop rhythm. Simultaneous right radial and umbilical arterial blood pO 2 measurements differed by 34ram Hg. At 7 hours the pO 2 was 105 mm Hg breathing 50% oxygen and at 48 hours the infant was breathing room air (34C). In b o t h o f t h e s e p r e m a t u r e i n f a n t s a diagnosis o f p r i m a r y p u l m o n a r y h y p e r t e n s i o n was m a d e o n t h e basis o f h y p o x i a in the a b s e n c e o f p a r e n c h y m a l p u l m o n a r y disease or cardiac m a l f o r m a t i o n . A l t h o u g h o t h e r p r e d i s p o s i n g causes are k n o w n , i n d o m e t h a cin was i m p l i c a t e d b y t h e a u t h o r s because it is k n o w n t o increase p u l m o n a r y vascular rea c t i v i t y in r e s p o n s e to h y p o x i a in animals. In a n o t h e r r e p o r t , i n d o m e t h a c i n was given to p r e - t e r m i n f a n t s in a t t e m p t s to close t h e d u c t u s arteriosus. S e r i o u s clinical p r o b l e m s developed within 48hours and included renal i n s u f f i c i e n c y , v o m i t i n g , gross a b d o m i -
Anti-inflammatory analgesics and drugs used in rheumatism and gout
nal distension, melaena, necrotizing enterocolitis and a flare-up of lower respiratory tract infection (27c). Until further information becomes available, indomethacin and other inhibitors of prostaglandin synthesis (e.g. aspirin) should not be used indiscriminately during late pregnancy. CLOMETHAC1N
This drug has been associated with acute upper gastrointestinal haemorrhage (35 c). SULINDAC
This drug seems to have similar properties to indomethacin, but needs to be given only twice daily. It may cause gastrointestinal toxicity as shown by the occurrence of anorexia, nausea, vomiting and abdominal pain, and central nervous system effects such as headache, drowsiness, blurred vision, dizziness, vertigo and tinnitus ( 3 6 c - 4 0 c ) . Excessive sweating (36 c) and oedema (37 c) have also been observed. Sulindac inhibits collagen-induced platelet aggregation but does not cause significant prolongation of the bleeding time (41). In one study it did not appear to increase occult gastrointestinal blood loss (42). Other side effects listed in product data sheets officially approved for this drug include constipation or diarrhoea, peptic ulcer, gastric haemorrhage, derangement of sleep, hypersensitivity reactions and deranged liver function tests, rash, pruritus and stomatitis. In animal studies, aspirin appeared to reduce its anti-inflammatory activity. ARYLCARBOXYLIC ACID DERIVATIVES Adverse reactions to phenylpropionic acids (ibuprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, flurbiprofen, and pirprofen) have been reviewed (43 R). IBUPROFEN
Allergy Skin rashes may occur and ibuprofen may precipitate bronchospasm in sensitive individuals (SEDA-1, p. 91; 17r). About 25% of patients with aspirin intolerance also reacted to a single oral dose of ibuprofen. Two such patients who also had systemic lupus erythematosus developed acute reactions to ibuprofen with cutaneous, nasal and ocular symptoms (44c).
95
Fever Fever, reproduced on several occasions, has been observed with ibuprofen, again in patients with systemic lupus erythematosus.
A 36-year-old woman with systemic lupus crythematosus developed spiking fever and chills followed by cpigastric pain, nausea and vomiting a week aftcr starting ibuprofen. On admission to hospital, the tcmperature was 40.4~ and there was mouth ulceration and lymphadenopathy. After 4 days without ibuprofen the temperature returned to normal. Ibuprofen was started again because of joint pain and within 6 hours fever and abdominal pain recurred. The patient was subsequently re-admitted to hospital and given another dose of ibuprofen. Twelve hours later she developed fever, chills, nausea, vomiting, and severe abdominal pain with ulceration of the lip. A similar febrile reaction has been described in another young woman (45C). Febrile reactions to this drug are not confined to lupus patients. In another report, fever, anorexia, malaise, weakness, vomiting, increased joint pain and disturbed liver function tests occurred in a 12-year-old girl with juvenile rheumatoid arthritis shortly after she was started on ibuprofen. When the drug was stopped she rapidly became afebrile and the arthritis improved (46 c). Gastrointestinal system As repeatedly observed in the past, all forms of gastrointestinal irritation occur with this drug (SED VIII, p. 221; SEDA-1, p. 91), including overt haemorrhage (e.g. as reported again recently by E n g b a e k ) ( 4 9 c). It has often been concluded that occult blood loss is less than with aspirin, but a loss of almost 100 ml over 4 days has been recorded (47c). The combination of fluid retention and blood loss may be responsible for a slight but significant fall in haemoglobin concentration (48). Ibuprofen causes an acute erosive gastritis with mucosal necrosis in rats, and these lesions could be prevented with antacids and cimetidine (50). Liver Liver function tests may be abnormal in patients with acute febrile reactions to ibuprofen (45 c, 46c). Renal Ibuprofen (2.4 g daily) may cause a fall in creatinine clearance (51c), and this fact must be viewed in the light of the various
96 renal complications attributed earlier to the drug (SEDA-I, p. 91). Oedema, weight gain and congestive cardiac failure Like other anti-inflammatory drugs, ibuprofen may cause fluid retention and weight gain (SEDA-1, p. 91; 48c). In some cases, the fluid retention may result in frank oedema and congestive cardiac failure. A 71-year-old man was prescribed ibuprofen (1.6 g daily) for back pain. He was admitted to hospital 17 days later with ankle oedema and weight gain of nearly 15 kg over the preceding 10 days. He was found to be in congestive cardiac failure with peripheral and sacral oedema, bilateral pleural effusions and radiological evidence of pulmonary vascular congestion. The ibuprofen was stopped and there was a good diuretic response to frusemide. Ten days after admission his weight had returned to normal and the frusemide was discontinued. Six months later he remained free of oedema (52C). KETOPROFEN Gastrointestinal tract As pointed out in SEDA-1 (p. 92), and repeatedly confirmed in clinical reports, gastrointestinal toxicity is common, and anorexia, nausea, vomiting, heartburn, epigastric pain, dyspepsia, and gastrointestinal erosions, ulceration and haemorrhage may occur (35 c, 43 c, 5 3 c - 5 7 c ) . Ketoprofen increases occult gastrointestinal blood loss (58, 59) and may cause massive upper gastrointestinal haemorrhage (43 c , 57r In addition, the use of ketoprofen (with and without other anti-inflamm a t o r y drugs) has been associated with anaemia and gastric, duodenal and jejunal ulceration. Perforation has occurred with peritonitis and death. In one case an elderly man developed profuse melaena and bled to death after taking ketoprofen for 4 days (43c). The use of ketoprofen suppositories does not prevent upper gastrointestinal toxicity and in addition m a y cause colic and severe rectal pain (60 c, 61c). Furthermore, severe gastric haemorrhage has followed the use of ketoprofen suppositories (61 c). Ketoprofen causes acute erosive gastritis with mucosal necrosis in rats. These effects are reduced by antacids and H2 antagonists (50).
L. F. Prescott Renal Mild elevation of blood urea, frequency of micturition and dysuria have occasionally been reported (55 c, 57 c, 60 c, 62 c, 63c). Oedema, blood pressure Dependent oedema may occur (53 c, 57 c) and in one report ketoprofen had to be withdrawn because of water retention and hypertension (56c). Central nervous system Headache, lethargy, depression, giddiness, vertigo and tinnitus have been reported (53 c, 57 c, 64 c, 65c). Local pain and abscess after intramuscular in]ection Intramuscular ketoprofen is not well tolerated and may cause severe local pain with induration and abscess formation (66c). It is difficult to understand the rationale for administration of ketoprofen by this route. FENOPROFEN The properties o f fenoprofen have been reviewed (67R). Dyspepsia, abdominal pain, heartburn, and brisk gastrointestinal bleeding have been observed (68c). Fenoprofen may cause occult gastrointestinal bleeding, and antral ulceration (69r Decreased hearing, tinnitus and pyuria have been noted (68c). When one recalls the side effects reported earlier, including renal papillary necrosis, hepatic function changes, asthmatic reactions in aspirin-sensitive patients and mental effects (SED VIII, p. 222; SEDA-I, p. 92), it is evident that the drug's pattern of side effects is more or less typical for the class to which it belongs. INDOPROFEN Gastrointestinal intolerance (70 c) and increased occult blood loss (71 c) have been noted. FLURBIPROFEN Nausea, vomiting, abdominal pain, anorexia, skin rash and dizziness have been reported (48c). FENBUFEN Further reports have confirmed the conclusion in SEDA-I (p. 93) that this drug may cause gastrointestinal upsets, somnolence and occult gastrointestinal bleeding (43 r, 72c).
Anti-inflammatory analgesics and drugs used in rheumatism and gout
NAPROXEN Skin rashes may occur (73e), but most adverse reactions involve the gastrointestinal tract. Especially serious complications include bleeding gastric ulcer, perforated duodenal ulcer (74 c) and granulomatous colitis (75c). Naproxen increases occult gastrointestinal blood loss (58 c, 76 c) and causes acute erosive gastritis in animals (50). A further case of liver damage with jaundice has been reported (77 c ) and naproxen therapy may be associated with a deterioration in renal function in patients with disseminated lupus erythematosus (26e). Oedema has also been reported (78c). Other adverse reactions include headache, lightheadedness, dizziness, vertigo, tinnitus, confusion and drowsiness (74 c, 79 c) and in the latter report naproxen had to be discontinued in 13 of 39 patients (33%) because of side effects. Naproxen may also provoke or exacerbate asthma in patients with sensitivity to aspirin (22r). As little as 30 mg of naproxen may cause rhinorrhoea, tightness in the chest, wheezing and dyspnoea (80 C). Naproxen lowers plasma salicylate concentrations under experimental conditions (81) and interaction with aspirin might therefore occur.
DICLOFENAC Skin rashes, gastrointestinal upsets, headache, vertigo, insomnia and agitation have been reported ( 8 2 c - 8 7 c ) . Suppositories were not well tolerated and do not prevent upper gastrointestinal symptoms (88c). Diclofenac did not appear to cause severe gastric injury as shown by an endoscopic study (89), but this conclusion must be set against earlier reports of significant occult gastrointestinal blood loss. Diclofenac may provoke or precipitate asthma in patients with aspirin intolerance (22 r, 80c). TOLMETIN Skin rashes, central nervous system effects, gastrointestinal disturbances, falls in haematocrit and elevation of blood pressure have been observed ( 9 0 c - 9 2 e, 93r). Tolmetin causes an acute erosive gastritis in experimental animals (50).
97
ANTHRANILIC ACID DERIVATIVES MEFENAMIC ACID This drug has in some countries been withdrawn from sale; the question put six years ago in the Medical Letter whether mefenamic acid offers therapeutic benefits which outweigh its hazards does at all events not appear to have received a positive answer, and some severe reactions continue to be reported. A llergy Mefenamic acid may precipitate or aggravate asthma or urticaria in patients who are sensitive to aspirin (4 e, 20 r, 22e). An acute anaphylactic reaction has been reported.
A 66-year-old Chinaman with a history of previous reactions to a variety of drugs presented with epigastric, shoulder and leg pain. He was given antacids, oxethazaine and mefenamic acid on the spot and developed itchy hands 1-~ hours later at the bus station. He returned to the doctor who then gave him oral antihistamines and prednisolone. The pruritus increased and he began to cough. The patient's wife insisted that he be given injections, and while these were being prepared he became unresponsive with no detectable respiration or cardiac action. He recovered with clearing of the airway and external cardiac massage for 1 minute. Half an hour later he was able to walk. He subsequently had no complaints except that he nearly lost his life (8C). There is no proof that this reaction was caused by the mefenamic acid, but it is a reasonable assumption since he had previously suffered an almost identical reaction to phenylbutazone. Gastroin testinal system Mefenamic acid is a potent gastric irritant and has been implicated in acute upper gastrointestinal haemorrhage (35e). It may cause gastritis and duodenitis with ulceration and haemorrhage (94c). Mefenamic acid may also cause profuse steatorrhoea, abdominal distension and weight loss (95 c , 96c).
MECLOFENAMIC ACID Diarrhoea, nausea, vomiting and confusion have been observed (97e). Cumulated evidence (SED VIII, p. 222 ff; SEDA-1, p. 89) does not suggest that the pattern of side effects as a whole is different from that of other anthranilic acid derivatives.
98 GLAI"ENINE Serious toxicity continues to be recorded with this drug (SEDA-1, pp. 8 9 - 9 1 ) . A lie rgy
Skin rashes and acute reactions, including new cases of anaphylaxis, have been reported (98R). Fever and eosinophilia may complicate haematotoxicity and nephrotoxicity induced by glafenine (99 c , 100 c). Blood
A patient developed acute renal failure and haemolytic anaemia with a positive Coombs test following therapeutic doses of glafenine (100c). The case is very similar to that described in detail in SEDA-1 (p. 90). Gastrointestinal system
Upper gastrointestinal haemorrhage has been reported (35c). Renal
There have been many reports of acute renal failure following overdosage of glafenine, but this may also occur with therapeutic doses (98 r, 99 C, 100c). The plasma half-life of glafenine is prolonged in patients with chronic renal failure ( 101 c). FLOCTAFEN 1NE This drug closely resembles glafenine structurally, and must be assumed to have similar toxicity until proved otherwise. Floctafenine increases occult gastrointestinal blood loss, but to a lesser extent than aspirin (102c).
OTHER DRUGS USED IN RHEUMATOID ARTHRITIS DIFTALONE Skin rashes, nausea, vomiting, diarrhoea, heartburn, abdominal pain, persistent increases in transaminases, headache, dizziness, sedation and leukopenia have all been reported ( 1 0 3 c - 1 0 8 c ) . Side effects occurred in 38% of a series of 140 patients given diftalone. Treatment had to be discontinued in 5% of patients because of adverse effects and in one patient there was a marked rise in the blood urea (108c). As pointed out in SEDA1, the drug has also raised other problems, including agranulocytosis, and would appear to have little future. Late in 1977 investigation of diftalone
L. F. Prescott
was abandoned because of the discovery o f carcinogenic potential (hepato.mas) in high dosage studies in rodents. It was not known whether these findings might be relevant to man or not (124). !
AZAPROPAZONE Bizarre bullous skin e r u p t i o n s may occur (109 c). Azapropazone is a gastrointestinal irritant and is ulcerogenic (110). It may also interact with warfarin, causing marked potentiation of anticoagulant action (11 lC). One patient on long-term warfarin therapy suffered a severe haematemesis 4 days after being given azapropazone. The prothrombin time was prolonged to 220 seconds (control 14 seconds). Bleeding stopped after administration o f vitamin K and gastroscopy revealed a benign gastric ulcer (112 c). It is remarkable that in recent literature this interaction of azapropazone is still described as 'unexpected', whereas in fact it is a wellestablished problem (SEDA-1, p, 265). PROTIZINIC ACID (SEDA-1, p. 93) A syndrome resembling malignant hyperthermia with a fatal outcome has been reported in a 17-year-old girl who took an overdose of aspirin (6 g) and protizinic acid (8 g) (113c). BUCLOXIC ACID An acute febrile illness with fever, rash, splenomegaly and salivary gland enlargement has been attributed to bucloxic acid (114c). CHLOROQUINE See Chapter 26. LEVAMISOLE See Chapter 28. PENICILLAMINE See Chapter 21. DRUGS USED IN THE TREATMENT O F GOUT ALLOPURINOL Allergy
Allopurinol is said to cause allergic reactions in 15% of patients with renal disease (115); this estimate seems to confirm those given earlier (SEDA-1, p. 94). However, a recent report does suggest that desensitization is feasible.
Anti-inflammatory analgesics and drugs used in rheumatism and gout A patient with severe gout corhplicated by renal impairment and hypertension repeatedly developed a severe rash when treatment with allopurinol or thiopurinol was attempted. Over a period of 30 days he was given increasing doses of allopurinol, starting with a daily dose of 8 ~g until he was taking 300 mg daily on the 30th day. This was tolerated without incident and his gout was adequately controlled on this dose subsequently (115C). Boyer et al. (116) have recently described three patients with severe reactions to allopurinol including h e p a to c e U u la r necrosis, hepatic granulomata, renal failure and exfoliative dermatitis, all resulting from hypersensitivity. The reactions appeared 3 - 4 weeks after starting treatment and responded in two cases to corticosteroids. Such reactions are fortunately rare but extremely dangerous. COLCHICINE Colchicine causes severe toxicity when taken in overdosage (SEDA-I, p. 95). Initially there is anorexia, vomiting and profuse diarrhoea, followed by hepatic and renal damage. Bone marrow aplasia occurs between the 3rd and 6th days and death may result from haemorrhage or infection. In patients who survive there may be polyneuritis and alopecia (117 R, 118c). Pulmonary oedema and consumptive coagulopathy have also been observed in the acute phase of intoxication ( 119 c). In a recent case reported by Naidus et al. (120 c ) a 50 mg dose of colchicine was instilled into the penile urethra for the treat-
99
ment of condyloma acuminata, and a multisystemic reaction of the above type, including severe but reversible m y o p a t h y and respiratory failure, developed. SULPHINPYRAZONE Mild renal failure with elevation of serum creatinine and blood urea and celluria was observed in a 33-year-old man given 800 mg of sulphinpyrazone daily (12 lC). Allergic reactions, blood dyscrasias and a reduction in platelet adhesion have been reported earlier (SED VIII, p. 227; SEDA-1, p. 94). BENZBROMARONE
Persistent diarrhoea and skin rashes have been noted (122c). The former is apparently one of the drug's most characteristic side effects (SED VIII, p. 227; SEDA-1, p. 94).
MISCELLANEOUS PHENAZOPYRIDINE This drug may cause methaemoglobinuria, crystalluria and renal damage (SED VIII, p. 224; SEDA-1, p. 94). Hepatic damage has also been reported, and one patient developed symptoms of hepatitis on four occasions after being given phenazopyridine for urinary tract infections (123c). It is important to recognize that cumulation of orangered metabolites of this drug may cause skin pigmentation that could readily be mistaken for jaundice. Phenazopyridine is, however, so nephrotoxic that it is best avoided.
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Presse mdd., 5, 2633. 7. Barrett, A. J., Weller, E., Rozengurt, N., Longhurst, P. and Humble, J. G. (1976): Amidopyrine agranulocytosis: Drug inhibition of granulocyte colonies in the presence of patient's serum. Brit. reed. J., 2,9 8. Leong, L. L. Y. (1976): A case of cardiac arrest following oral 250 mg mefenamic acid. Med. J. Malaysia, 30, 229. 9. Millard, L. G. (1977): A haemorrhagic bullous eruption of the hands caused by phenylbutazone. A Report of 3cases. Acta derm.-venereol. (Stockh.), 5 7, 83. 10. Thurston, J. G. B., 9 P. and Trapnell, D. (1976): Lung changes associated with phenylbutazone treatment. Brit. med. J., 2, 1422. 11. Swedish Adverse Drug Reaction Committee (1977): Pulmonary reactions to oxyphenbutazone. Notice Nr. 26, May 1977. 12. lnman, W. H. (1977): Study of fatal bone mar-
1O0 row depression with special reference to phenylbutazone and oxyphenbutazone. Brit. reed. J., 1, 1500. 13. J~brgensen, T.G. (1977): Drug consumption before perforation of peptic ulcer. Brit. J. Surg., 64, 247. 14. Louvent, F. (1976): Prevention des accidents thrombo-emboliques post-op6ratoires en chirurgie visct~rale par le tanderil. M~d. Chir. dig., 5, 319. 15. Rollin, H. (1976): Gustatory disturbances as side effect of medical treatment, Arch. OtoRhino-Laryngol., 213, 433. 16. Clinicopathological Conference (1977): Diagnostic difficulties in a case of polypharmacy.
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L.F. Prescott drome. Acta paediat, belg., 30, 31. 30. Norby, L., Lentz, R., Flamenbaum, W. and Ramwell, P. (1976): Prostaglandins and aspirin therapy in Bartter's syndrome. Lancet, 2, 604. 31. Borgkvist, K. and Samuelsson, S.-M. (1976): Psykiska biverkningar av lndometacin hos ~ildre patienter. Opusc. reed. (Stockh.), 21, 121. 32. Parks, B. R., Rawson, J. E. and Douglas, B. H. (1977): ln-utero death as a possible consequence of prenatal administration of indomethacin. Pe-
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Antbinflammatory analgesics and drugs used in rheumatism and gout fen. J. Pediat., 90, 657. 47. Schmid, F. R. and Culic, D. D. (1976): Antiinflammatory drugs and gastrointestinal bleeding: A comparison of aspirin and ibuprofen. J. clin. Pharmacol., 16, 418. 48. Mena, H.R., Ward, J.R., Zuckner, J., Wolski, K.P., Briney, W.G. and Giansiracusa, J. (1977): Treatment of rheumatoid arthritis with flurbiprofen or ibuprofen. J. clin. PharmacoL, 17, 56. 49. Engbaek, J. (1977): Gastro-intestinal haemorrhage during treatment with ibuprofen (Brufen). Ugeskr. Laeg., 139, 401. 50. Mann, N. S. (1977): Drug-induced acute erosive gastritis. Amer. J. Proctol., 28, 23. 51. Kimberly, R. P. and Plotz, P. H. (1977): Aspirin and renal function. New Engl. J. Med., 296, 1169. 52. Schooley, R.T., Wagley, P.F. and Lietman, P. S. (1977): Edema associated with ibuprofen therapy. J. Amer. med. Ass., 237, 1716. 53. Lussier, A., Camerlain, M., Menard, H., Myhal, D. and Wehner, S. (1976): A double-blind cross-over evaluation of ketoprofen and aspirin in rheumatoid arthritis. Scand. J. Rheumatol., 5/ SuppL 14, 99. 54. Zutshi, D. and Mason, M. (1976): Ketoprofen in rheumatoid arthritis: Its tolerance and therapeutic effect. Scand. J. Rheumatol., 5/Suppl. 14, 77. 55. EI-Ghobarey, A.F., Rennie, J. A.N., Hadidi, T., Abdel Hamid, H. and Mavrikakis, M. (1976): A comparative trial of large doses of ketoprofen and indomethacin in the treatment of rheumatoid arthritis. Curt. reed. Res. Opin., 4, 432. 56. Famaey, J. P. and Colinet, E. (1976): A double-blind trial of ketoprofen in the treatment of osteoarthritis of the hip. Scand. J. RheumatoL, 5/ SuppL 14, 129. 57. Cardoe, N. (1976): Double-blind cross-over study of ketoprofen and phenylbutazone in patients with chronic osteoarthrosis of the hip. Rheumatol. Rehabil., 15, 27. 58. Magnusson, B., S61vell, L. and Arvidsson, B. (1977): A comparative study of gastrointestinal bleeding during administration of ketoprofen and naproxen. Scand. J. Rheumatol., 6, 62. 59. Arsenault, A. and Lussier, A. (1976): Gastrointestinal microbleeding under acetylsalicylic acid, ketoprofen and placebo. Rheumatol. Rehabil., 15, 87. 60. Sany, J. and Serre, H. (1976): A study of ketoprofen in rheumatoid arthritis. Rheumatol. Rehabil., 15, 67. 61. Queneau, P., Amourdedieu, J. and Daumont, A. (1976): Clinical study of ketoprofen administered rectally in rheumatology. Rheumatol. Rehabil., 15, 61. 62. Jessop, J.D. (1976): Double-blind study of ketoprofen and phenylbutazone in ankylosing spondylitis. Rheumatol. Rehabil., 15, 37. 63. Gomez, G. (1976): Long-term safety study of
101
ketoprofen. Rheumatol. Rehabil., 15, 85. 64. Barragan, A., Bonne, A., Brees, A., Geyter, P. De., Daenens, L., Debeuckelaere, M., Ooghe, R., De Moor, M., Michielsen, P., Vansteenland, H. and Verbeke, R. (1977): Het inspuitbaar Ketoprofen: Multicenter studie in de reumatologie. Ars. Med. (Brux.), 6, 377. 65. Grahame, R. and Burry, H.C. (1976): Ketoprofen - A new anti-rheumatic agent. Scand. J.
RheumatoL, 5/Suppl. 14,133. 66. Gougeon, J., Mireau-Hottin, J. and Gaillard, F. (1976): Clinical trial of the injectable form of ketoprofen. Rheumatol. Rehabil., 15, 75. 67. Brogden, R. N., Pinder, R.M., Speight, T. M. and Avery, G. S. (1977): Fenoprofen: A review of its pharmacological properties and therapeutic efficacy in rheumatic diseases. Drugs, 13, 241. 68. Davis, J.D., Turner, R.A., Collins, R. L., Ruchte, I. R. and Kaufmann, J. S. (1977): Fenoprofen, aspirin, and gold induction in rheumatoid arthritis. Clin. Pharmacol. Ther., 21, 52. 69. Loebl, D. H., Craig, R. M., Culic, D. D., Ridolfo, A. S., Falk, J. and Schmid, F. R. (1977): Effect of aspirin, fenoprofen, and acetaminophen in rheumatoid arthritis as determined by sequential gastroscopy and radioactive fecal markers. J. Amer. reed. Ass., 237, 976. 70. Marcolongo, R., Mandelli, V., Magni, D. and Sacchetti, G. (1977): Indoprofen in knee joint osteoarthritis: A double-blind crossover clinical trial. J. clin. Pharmacol., 1 7, 48. 71. Bianchi Porro, G. B., Corvi, G., Fucella, L. M., G01daniga, G. C. and Valzelli, G. (1977): Gastrointestinal blood loss during administration of indoprofen, aspirin and ibuprofen. J. Int. reed. Res., 5, 155. 72. Klein, B. (1976): Double-blind comparative cross-over study between fenbufen and indomethacin in the treatment of hip and knee osteoarthritis. Folha todd., 73, 549. 73. Renier, J.-C. (1977): Etude clinique du Naproxen en rhumatologie. Gaz. m~d. Ft., 84, 363. 74. Smith, R.D. (1977): Experience with naproxen in a rheumatology practice. Curr. ther.
Res., 21,415. 75. Baas, E.U., Ewe, K. and Hbhn, P. (1976): Granulomat6se Kolitis nach Naproxen. Dtsch. reed. Wschr., 101, 1434. 76. Uthgenannt, H. (1977): Gastrointestinale Blutausscheidung unter der Einnahme yon Feprazon, Naproxen, Diclofenac. Med. Welt., 28, 989. 77. Law, I. P. and Knight, H. (1976): Jaundice associated with naproxen. New Engl. J. Med., 295, 1201. 78. Sturge, R. A., Scott, J. T., Hamilton, E. B. D., Liyanage, S.P., Dixon, A. St. J., Davies, J. and Engler, C. (1977): Multicentre trial of naproxen and phenylbutazone in acute gout. Ann. rheum. Dis., 36, 80. 79. Jaffe, G. (1976): A double-blind, multi-centre comparison of naproxen and indomethacin in acute musculo-skeletal disorders. Curr. med. Res. Opin., 4, 373.
L. F. Prescott
102 80. Szczeklik, A., Gryglewski, R. J., CzerniawskaMysik, G. and Pieton, R. (1977): Asthmatic attacks induced in aspirin-sensitive patients by diclofenac and naproxen. Brit. reed. J., 2, 231. 81. Stitt, F.W. and Vaughan, J.H. (1977): Naproxen-aspirin drug interactions studied with response surface analysis. Clin. exp. Pharmacol.
PhysioL, 4, 216. 82. Vignon, E. (1977): Etude clinique du Voltar~ne en rhumatologie. Gaz. todd. Fr., 84, 1737. 83. Commandr6, F., Mercier, A., Viani, J.-L., |:ourrc, J.-M. and Plas, J.-N. (1976): Effets antiinflammatoires en pathologie ost6o-articulaire et rhumatismale du G.P. 45840 (comprim6s). Gaz. todd. Fr., 83, 3020. 84. Gualtieri, 1. (1976): Valutazione clinica del diclofenac sodico in ortopedia. Minerva ortop., 27, 66t. 85. Rogier, M. (1977): Exp6rimentation clinique en rhumatologie du 'Diclof6nac de Sodium'. J. ScL m~d. Lille, 95, 19. 86. Seda, H. and Cardozo, P. C. (1976): Efficacy and tolerability of Diclofenac Sodium vs. Ibuprofen in osteoarthritis, bblha m~d., 72, 633. 87. Olah, J. and Meyer, W. (1977): Klinische Erfahrungen mit Diclofenac bei rheumatischen Erkrankungen. Med. Welt., 28, 987. 88. Appelboom, T., Batthazar-Letawe, D., Boes, Ph., Claessens, J. and Famaey, J.-P. (1976): Etudc du Voltaren suppositoires ~ 100 mg dans l'ostfo-arthrose. Brux.-m(d., 56,273. 89. Spongano, P., D'lmperio, N., Milandri, M., Sarti, F., Soffritti, M., Blotta, A. and Dal Monte, P. R. (1977): Studio sulla tollerabilita gastrica di una nuova molecola antiinflammatoria: I1 Diclofenac sodico. Clin. ter., 80, 123. 90. Bachmann, F,, Stroescu, O. and Hartl, W. (1977): Doppelblind- und Dosisbereichsstudie mit Tolcctin bei rheumatoider Arthritis. Therapiewoche, 27, 2262. 91. Cordrey, L.J. (1976): Tolmetin sodium, a new anti-arthritis drug: Double-blind and longterm studies..L Amer. Geriat. Soc., 24, 440. 92. Bahous, I. (1976): Clinical experiences with tolectin in rheumatic diseases. Praxis, 65, 1025. 93. Lewis, J . R . (1977): New antirheumatic agents: fenoprofen calcium (Nalfon), naproxen (Naprosyn), and tolmetin sodium (Tolectin). J. Amer. rned. Ass., 237, 1260. 94. Wolfe, J.A., Plotzker, R., Safina, F. J., Ross, M., Popky, G. and Rubin, W. (1976): Gastritis, duodenitis, and bleeding duodenal ulcer following mefenamic acid therapy. Arch. intern.
Med., 136,923. 95. Chadwick, R. G., Hossenbocus, A. and ColinJones, D.G. (1976): Steatorrhoea complicating therapy with mefenamic acid. Brit. reed. J., 1, 397. 96. Marks, J. S. and Gleeson, M. H. (1975): Steatorrhoea complicating therapy with mefenamic acid. Brit. med. J., 4, 442. 97. Rennie, J. A.N., MacLeod, M.M., Reynolds, P. N.G. and EI-Ghobarey, A.F. (1977):
Comparison of sodium meclofenamate and indomethacin in rheumatoid arthritis. Curr. med. Res. Opin., 4, 580. 98. Kerst, A. J. 1:. and Vosmaer, G. D. C. (1976): Glafenine: bijwerking en intoxicatie. Ned. T. Ge. neesk., 120, 1224. 99. Stork, J. (1976): Glafenine en nefrotoxiciteit. Ned. T. Geneesk., 120, 338. 100. Andrieu, J., Audebrand, C., Chassaigne, M. and Renier, E. (1976): An~mie h~molytique et insuffisance r6nale imputables ~ la glaf~nine. Nouv. Presse m~d., 5, 2394. 101. Mallein, R., Boucherat, M., Rondelet, J., Fillastre, J.-P. and Mantel, O. (1976): Pharmacocin~tique de la glaf~nine chez des sujets ayant une fonction r~nale normale et chez des malades atteints d'insuffisance r~nale chronique. ThEra-
pie, 31,739. 102. Baird, 1. M. (1976): A comparative blood loss study of floctafenine and aspirin in normal subjects. Brit. J. clbl. Pharmacol., 3, 936. 103. Chalem, F., Farias, P., Lizarazo, H. and Pena, P. (1977): Diftalone: A new non-steroidal anti-inflammatory agent: Comparative study with phenylbutazone in the treatment of rheumatoid arthritis. J. Int. reed. Res., 5, 18. 104. Mattara, L., Leardini, G., Luvar~, A. and Mazzucco, A. (1977): Treatment of osteoarthritis of the hip. Clin. TrialsJ., 14, 30. 105. Brown, L., Costazos, J. and Roisimblit, A. (1977): Treatment of rheumatoid arthritis. A double-blind comparison of diftalone (Aladione) and phenylbutazone in a three-months' treatment course. Clin. Trials J., 14, 50. 106. Pieroni, P.F., Gramajo, R.J., Cutroneo, E.J., C~iceres Maldonado, J.C. and Gibson, J. L. (1976): Therapeutic activity and safety of diftalone in rheumatoid arthritis: A doubleblind evaluation in comparison with indomethatin. Pharmatherapeutica, 1, 262. 107. Tausch, G., Br611, H., Dunky, A. and Eberl, R. (1976): Comparative clinical trial with a new substance, diftalone, versus indomethacin in 30 patients affected with rheumatoid arthritis. Scand. J. Rheumatol., 5, 145. 108. Pinheiro, G. C., Rachid, A., Brito, A. S., Buoniconti, A., Atra, E., Gomes de Freitas, G., Chahade, W. H. and Sobrinho, P. S. (1976): Open multicentre clinical trial of diftalone in osteoarthrosis. Curr. reed. Res. Opin., 4, 402. 109. Barker, D. J. and Cotterill, J. A. (1977): Skin eruptions due to azapropazone. Lancet, 1, 90. 110. Ancill, R.J. (1977): Ulcer0genic action of azapropazone. Brit. reed. J., 1, 1469. 111. Green, A. E., Hort, J. F., Korn, H. E. T. and Leach, H. (1977): Potentiation of warfarin by azapropazone. Brit. rned. J., 1, 1532. 112. Powell-Jackson, P. R. (1977): Interaction between azapropazone and warfarin. Brit. med. J., I, 1193. 113. Ginies, G., Choutet, P., Gorge, R , Lamisse, F., Gautier, J., Bourin, M. and Breteau,M. (1976): Hyperthermie mortelle au cours d'une in-
Anti-inflammatory analgesics and drugs used in rheumatism and gout toxication volontaire par l'acide protizinique et l'acide ac~tyl salicylique. Th~rapie, 31, 755. 114. Verliac, F., Calamy, G., Palangi6, A. and Bastin, R. (1976): Atteinte des glandes salivaires au cours de certains traitements anti-inflammatoires. Ann. M~d. interne., 127, 561. 115. Meyrier, A. (1976): Desensitisation in a patient with chronic renal disease and severe allergy to allopurinol. Brit. reed. J., 2, 458. 116. Boyer, T.D., Sun, N. and Reynolds, T.B. (1977): Allopurinol-hypersensitivity vasculitis and liver damage. West. J. Med., 126, 143. 1 l 7. Favarel-Garrigues, J.-CI. (1976): Intoxication aigu~ per la colchicine. J. Mdd. Chir. prat., 197, 688. 118. Bismuth, C., Gaultier, M. and Conso, F. (1977): Aplasie m~dullaire apr~s intoxication aigu~ ~t la colchicine. Nouv. Presse m(d., 6, 1625.
119. Besson-Leaud, M.,
103
Dulmet, Y., Lavaud, J., Bondeux, D. and Cloup, M. (1977): Intoxication aigu~ par la colchicine chez l'enfant. Apropos de 4 observations. Sem. H6p. Paris, 53, 363. 120. Naidius, R. M. et al. (1977): Colchicine toxicity. Arch. intern. Med., 137, 394. 121. Braun, J. (1976): Abnormalities of urinary sediment and renal failure following sulfinpyrazone therapy. Arch. intern. Med., 136, 1060. 122. Masbernard, A. and Giudicelli, C.-P. (1976): Une th~rapeutique nouvelle de la goutte et des hyperuric~mies. R~sultats a long terme. Sem. HOp. Paris, 52, 369. 123. Badley, B. W. D. (1976): Phenazopyridine-induced hepatitis. Brit. med. J., 2, 850. 124. Anonymous (1977): Dow Lepetit drops diftalone. Scrip, October 15th, 22.
9
anti-inflammatory analgesics and drugs used in rheumatism and gout
These drugs are often used in m a x i m u m dosage and for prolonged periods in patients with chronic and disabling conditions. The anti-inflammatory analgesics are organic acids and many of their actions are thought to be related to inhibition of prostaglandin synthesis. They all cause gastrointestinal toxicity and most, if not all, are potentially nephrotoxic. A large number of new anti-inflammatory analgesics have been introduced and although their relative efficacy and safety remains to be established there is evidence that some may produce less toxicity than equi-effective doses of aspirin.
PYRAZOLONES AM1DOPYRINE AND RELATED DRUGS
In toxication A 4-week-old infant was given half a suppository containing amidopyrine, allobarbital, hexahydroadiphenine and codeine in the mistaken belief that it was a laxative. Symptoms were initially controlled with naloxone, but complications included convulsions, apnoea, bradycardia, paralytic ileus and oliguria. Forty hours after poisoning an exchange transfusion was carried out with eventual recovery (lC). It is difficult to know which drug caused which effect in this case, but convulsions are common in pyrazolone poisoning (SED VIII, pp. 2 0 9 - 2 1 0 ) .
aspirin and other analgesics (3 R, 4r; see also SEDA-1, p. 86).
Blood Amidopyrine and dipyrone are well known to cause agranulocytosis, yet are still freely available in some countries. The exact pattern of the complication varies (SED VIII, p. 210; SEDA-1, p. 87). Of 31 cases of drug-induced agranulocytosis, studied at one centre in France, 27 were caused by these drugs, and there were 6 fatalities. In most cases there was a fulminating clinical course with septicaemia and lesions of the mucous membranes. Bone marrow examination usually revealed selective involvement of the granulocyte series with maturation arrest at the metamyelocyte or myelocyte stage (5 C R). A woman who had reacted to amidopyrine with agranulocytosis 10 years previously used suppositories containing the same drug. Eight days later she developed fever and pharyngitis with tenesmus and the white cell count was 1000/mm 3 (17% granulocytes). Necrosis of the rectum occurred, leaving a rectovaginal fistula (6c).
In another case attributed to amidopyrine there was total absence of neutrophils and granulocytes in the peripheral blood and bone marrow. On admission, and when retested 6 and 12 months later, the patient's serum contained amidopyrine-dependent leuko-agglutinins (7 c).
Allergy
Risk o f carcinogenesis
Amidopyrine may cause a variety of skin reactions, sometimes with involvement of buccal and genital mucous membranes (2c). Amidopyrine and related pyrazolones may cross-react in asthmatics sensitive to
Amidopyrine, like many other drugs, can react with nitrites in food to form potentially carcinogenic nitrosamines in the stomach (SEDA-1, p. 386).. The matter is further discussed in Chapter 47.
L. F. Prescott
92 PHENYLBUTAZONE AND OXYPHENBUTAZONE
Allergy Allergic reactions to these drugs (SED VIII, p. 212) can sometimes take an acute form. A patient developed a generalized rash and collapsed unconscious 15 minutes after an intramuscular injection of 600 mg of phenylbutazone (8e). Three patients developed a haemorrhagic eruption on the hands after taking phenylbutazone. Capillary fragility was increased with a positive Hess test (9c).
Lungs Phenylbutazone and related compounds may precipitate or aggravate asthma in patients who are sensitive to aspirin (SEDA-1, p. 87), but may also cause pulmonary oedema and occasionally changes resembling allergic alveolitis. A 69-year-old man with advanced myxoedema was given phenylbutazone for joint pain. Two weeks later he was admitted to hospital semiconscious, and improved with thyroxine 0.05 mg daily. He was given phenylbutazone again and 18 days after admission was semiconscious with extensive bilateral crepitations throughout the chest and acute respiratory failure (arterial blood pH 7.18, pO 2 45 mm Hg and pCO 2 98 mm Hg.) A chest X-ray showed multiple poorly defined shadows in both lungs, and these extended over the next two weeks despite intermittent positive pressure ventilation. There was a leukocytosis with eosinophilia (14%). Frusemide and ethacrynic acid did not produce a diuresis or improvement. Finally, after treatment with phenylbutazone in hospital for more than 6 weeks the possibility of drug-induced lung damage was considered. The phenylbutazone was stopped and prednisone started. The eosinophilia rapidly disappeared and he improved steadily. The lung fields were completely clear 6~ months later (10C). Although phenylbutazone-induced pulmonary oedema is not u n c o m m o n , this type of reaction must be very rare. The Swedish Adverse Drug Committee has stressed that oxyphenbutazone can produce pulmonary reactions as severe as those due to phenylbutazone. The Committee has filed reports on six such cases, one of them fatal (1 lr).
Blood Phenylbutazone, oxyphenbutazone and related pyrazolones are well known to cause
blood dyscrasias which are often fatal, and the frequency of this complication has been estimated in a British survey. The histories of 269 patients whose death certificates did not mention a drug as the cause o f aplastic anaemia or agranulocytosis were investigated in a survey carried out between October, 1974, and September, 1975. Eighty-three deaths were probably caused by drugs, and o f these, phenylbutazone and o x y ph en b u t azo n e were the commonest cause of aplastic anaemia, together accounting for 39 deaths (47%). The mortality from this cause was estimated as 3.8 per 100,000 for o x y p h en b u t azo n e and 2.2 per 100,000 for phenylbutazone. The mortality from both drugs increased strikingly with age, and was higher in women (12 c).
Perforation o f peptic ulcer In view o f the gastrointestinal toxicity of these drugs in animals and man (SED VIII, p. 214; SEDA-1, p. 87), perforation of peptic ulcers in patients taking these drugs is not surprising. A history of anti-rheumatic drug therapy was obtained in 195 patients with perforated juxta-pyloric ulcers and in another series of 22 patients studied prospectively, 2 had taken phenylbutazone (13 c).
Rectal pain Oxyphenbutazone suppositories may cause rectal pain (14c); phenylbutazone suppositories are known to be capable of eliciting a severe proctitis (SEDA-1, p. 88).
Loss o f taste Loss of the sense o f taste was attributed to phenylbutazone in 3 cases (15 c).
Liver There have been numerous reports of liver involvement in generalized hypersensitivity reactions to phenylbutazone (SED VIII, p. 215) and a recent fatal case merits attention. In one case presented at a clinicopathological conference, liver damage was probably due to a generalized reaction to phenylbutazone, despite polypharmacy with other potentially hepatotoxic drugs. The patient had an intracranial aneurysm which was successfully occluded by neurosurgery. Methyldopa had been given over the previous 4 years and trichloroethylene was given 34 and 18 days and halothane 31 days before there was clinical evidence of liver damage. Other drugs given about one month before included diphenylhydan-
Anti-inflammatory analgesics and drugs used in rheumatism and gout toin, chlorpromazine, prochlorperazine, hydralazine and codeine, although it is not clear how long these were continued. Fourteen days after being given phenylbutazone (dose unstated) for apparently transient fever and calf pain, the patient developed fever, confusion and a generalized maculopapular rash. The liver was enlarged with increased aminotransferases, bilirubin and alkaline phosphatase and there was oliguria with azotaemia. Three days later he was transferred to another hospital, and an impressive variety of investigations was carried out, including a liver biopsy which was complicated by a pneumothora• Phenylbutazone was stopped, but the p'atient died (16C). There are obvious difficulties in attributing liver damage to any particular drug in this complex case, but the combination of fever, rash, liver damage and renal failure has often been reported in generalized hypersensitivity reactions occurring within two weeks of starting phenytbutazone (SED VIII, p. 212, p. 215).
Renal In the case mentioned above there was renal failure with post-mortem evidence of acute tubular damage (16 c). Phenylbutazone can cause renal papillary necrosis in animals, and this has also been observed in man (SEDA-1, p. 87). Thyroid Phenylbutazone and oxyphenbutazone can cause hypothyroidism and goitre (SED VIII, p. 216) which may be reversible. 9 A 63-year-old woman with hypothyroidism and thyroid enlargement had taken phenylbutazone for 1 year followed by oxyphenbutazone tbr 4 years. a ~I uptake was very high (32% at 30 min.) but following the administration of potassium perchlorate at 40 min. there was rapid discharge of isotope from the gland. The oxyphenbutazone was stopped and the patient was clinically euthyroid 4 weeks later and at follow-up 21 months later. The thyroid -was no longer visible or palpable (17C).
Drug interactions Phenylbutazone and related drugs may cause a number of potentially serious drug interactions (SED VIII, p. 216). They may displace other drugs from plasma protein binding sites, inhibit drug metabolism, and interfere with active renal tubular secretion of other acidic drugs and metabolites. Methotrexate toxicity was attributed to interaction with phenylbutazone in two patients with psoriasis (18 c ).
93
KETOPHENYLBUTAZONE (KEBUZONE) Muscle necrosis and gangrene have occurred following intramuscular injection of ketophenylbutazone (19 C). INDOMETHACIN AND RELATED DRUGS
Allergy lndomethacin may aggravate or precipitate severe bronchospasm in patients with aspirin intolerance (SEDA-1, p. 88; 3 c, 4r), and a similar cross-reaction may occur in patients with urticaria who are sensitive to aspirin (20r A 50-year-old man with asthma and allergic rhinitis associated with aspirin intolerance developed severe dyspnoea progressing rapidly to respiratory arrest with a grand mal convulsion 45 minutes after being given 50 nag of indomethacin orally. He was successfully resuscitated (21C). These effects of indomethacin are probably related to its inhibitory effect on prostaglandin synthesis (22 R).
Blood Menkes et al. (23 c r ) have described a case of fatal aplastic anaemia in a woman treated with both indomethacin and acetylsalicylic acid. They point to three earlier fatal cases where the same combination of drugs had been taken. However, indomethacin can produce this effect on its own (SED VIII, p. 218). Gastrointestinal system The gastrointestinal toxicity of indomethacin (SEDA-1, p. 88) has been attributed to inhibiton of prostaglandin synthesis and methyl analogues of prostaglandin E z inhibit indomethacin-induced gastric erosions (24). Consumption of indomethacin has been linked with perforation of peptic ulcers (13r Renal (See SED VIII, p. 219) Indomethacin decreased glomerular filtration rate and renal plasma flow in nephrotic patients but not in healthy subjects (25c). Impaired renal function has been observed in patients with systemic lupus erythematosus and Bartter's syndrome given indomethacin, and it may increase the serum creatinine and cause renal insufficiency in infants (26 c, 27c). In another report rapidly progressive
94 r e n a l failure a n d t u b u l a r n e c r o s i s was associated w i t h i n d o m e t h a c i n t h e r a p y in a 26year-old p a t i e n t w i t h g l o m e r u l o n e p h d t i s (28c). I n d o m e t h a c i n , b e c a u s e it i n h i b i t s prostag l a n d i n s y n t h e s i s , m a y alleviate t h e m e t a b o l i c a b n o r m a l i t i e s o f B a r t t e r ' s s y n d r o m e , a cond i t i o n associated w i t h excessive prostaglandin p r o d u c t i o n ( 2 9 c, 30e). H o w e v e r , in o n e such. case, a d m i n i s t r a t i o n o f i n d o m e t h a c i n (3 m g / k g / d a y ) r e s u l t e d in a gain in w e i g h t o f 4 kg in 5 days w i t h h y p e r n a t r a e m i a and severe t e t a n y . T h e p a t i e n t was c o m p l e t e l y i m m o b i l i z e d f o r 3 6 h o u r s w i t h generalized m u s c l e c r a m p s a n d c a r p o p e d a l spasms (29c). Central n e r v o u s s y s t e m H e a d a c h e is p r o b a b l y t h e c o m m o n e s t side e f f e c t o f i n d o m e t h a c i n t h e r a p y , a n d m a y be associated w i t h dizziness a n d m o o d c h a n g e s s u c h as d e p r e s s i o n (SED VIII, p. 2 1 9 ) . C o n f u s i o n a n d h a l l u c i n a t i o n s m a y o c c u r , especially in t h e elderly. Six of 45 elderly patients and one young woman developed hallucinations after being given indomethacin. All the patients were lucid and the hallucinations were generally pleasant rather than unpleasant, but were accompanied by anxiety and anguish. All the patients experienced visual hallucinations, one also had auditory hallucinations and 2 had nightmares. These manifestations seemed to be dose-related, and may be caused by cerebral vasoconstriction. Three patients experienced micropsia ('Alice in Wonderland' phenomena) in their hallucinations, and this has also been described in migraine (31C). Pregnancy and labour I n d o m e t h a c i n delays t h e o n s e t o f l a b o u r ( S E D VIII, p. 2 2 0 ) a n d h a s b e e n used t o prev e n t p r e m a t u r e l a b o u r . It m a y also stimulate closure o f t h e f o e t a l d u c t u s arteriosus. B o t h these a c t i o n s are t h o u g h t t o be mediat e d b y i n h i b i t i o n o f p r o s t a g l a n d i n synthesis. Serious d o u b t s have arisen r e c e n t l y conc e r n i n g t h e safety of i n d o m e t h a c i n given just before or during labour. lndomethacin (l mg/kg) was given daily for 7 days before anticipated delivery to pregnant mongrel bitches. The foetuses were removed by Caesarean section but were 'non-viable'. There was no obvious cause apart from some placental separation, and premature closure of the ductus arteriosus had not occurred (32). In a n o t h e r s t u d y , p r e g n a n t rats were treated with indomethacin. Compared with
L. b: Prescott c o n t r o l animals, t h o s e receiving i n d o m e t h a cin h a d m o r e s t i l l b i r t h s a n d t h e survivors h a d severe n e u r o n a l n e c r o s i s a t t r i b u t e d t o vasoc o n s t r i c t i o n a n d h a e m o d y n a m i c changes o r d i r e c t t o x i c i t y (33). T h e use o f i n d o m e t h a c i n to delay t h e o n s e t o f l a b o u r m a y cause p r i m a r y p u l m o n a r y h y p e r t e n s i o n in t h e n e w b o r n . An 18-year-old girl was given 25 mg of indomethacin 6-hourly for 4 days because of vaginal bleeding at 33 weeks of gestation. She received the last dose 4 hours before delivery. Fever and a foul vaginal discharge developed, anda Caesarean section was performed. A 2-kg infant girl was delivered through foul-smelling anmiotic fluid and required resuscitation with endotracheal intubation, positive-pressure ventilation and intravenous albumin. Physical examination of the infant was normal, there were no cardiac munuurs and she was given 40% oxygen. Three hours later reduction of the oxygen concentration to 35% resulted in cyanosis and lethargy. At 8 hours of age 80% oxygen was required to maintain a pO~ of 5 0 r a m Hg and a chest X-ray showed possible cardiomegaly. The patient improved and was breathing room air the next day. In a 38-year-old woman the membranes ruptured after a fall 7 weeks before delivery at 34 weeks. Uterine contractions were controlled after the fall with bed rest and indomethacin 50 mg 6 hourly for 7 days. Thereafter she took 50mg once or twice weekly over the next 6 weeks. Four days before delivery she had vaginal bleeding and took 50 mg every 6 hours. A breech-extraction was required and she received oxytocin, a mepivacaine pudendal block, morphine, and secobarbitone. The infant was cyanosed but the lungs were clear and there were no cardiac murmurs. At 2 hours of age he was receiving 90% oxygen and was tachypnoeic with a systolic murmur and a gallop rhythm. Simultaneous right radial and umbilical arterial blood pO 2 measurements differed by 34ram Hg. At 7 hours the pO 2 was 105 mm Hg breathing 50% oxygen and at 48 hours the infant was breathing room air (34C). In b o t h o f t h e s e p r e m a t u r e i n f a n t s a diagnosis o f p r i m a r y p u l m o n a r y h y p e r t e n s i o n was m a d e o n t h e basis o f h y p o x i a in the a b s e n c e o f p a r e n c h y m a l p u l m o n a r y disease or cardiac m a l f o r m a t i o n . A l t h o u g h o t h e r p r e d i s p o s i n g causes are k n o w n , i n d o m e t h a cin was i m p l i c a t e d b y t h e a u t h o r s because it is k n o w n t o increase p u l m o n a r y vascular rea c t i v i t y in r e s p o n s e to h y p o x i a in animals. In a n o t h e r r e p o r t , i n d o m e t h a c i n was given to p r e - t e r m i n f a n t s in a t t e m p t s to close t h e d u c t u s arteriosus. S e r i o u s clinical p r o b l e m s developed within 48hours and included renal i n s u f f i c i e n c y , v o m i t i n g , gross a b d o m i -
Anti-inflammatory analgesics and drugs used in rheumatism and gout
nal distension, melaena, necrotizing enterocolitis and a flare-up of lower respiratory tract infection (27c). Until further information becomes available, indomethacin and other inhibitors of prostaglandin synthesis (e.g. aspirin) should not be used indiscriminately during late pregnancy. CLOMETHAC1N
This drug has been associated with acute upper gastrointestinal haemorrhage (35 c). SULINDAC
This drug seems to have similar properties to indomethacin, but needs to be given only twice daily. It may cause gastrointestinal toxicity as shown by the occurrence of anorexia, nausea, vomiting and abdominal pain, and central nervous system effects such as headache, drowsiness, blurred vision, dizziness, vertigo and tinnitus ( 3 6 c - 4 0 c ) . Excessive sweating (36 c) and oedema (37 c) have also been observed. Sulindac inhibits collagen-induced platelet aggregation but does not cause significant prolongation of the bleeding time (41). In one study it did not appear to increase occult gastrointestinal blood loss (42). Other side effects listed in product data sheets officially approved for this drug include constipation or diarrhoea, peptic ulcer, gastric haemorrhage, derangement of sleep, hypersensitivity reactions and deranged liver function tests, rash, pruritus and stomatitis. In animal studies, aspirin appeared to reduce its anti-inflammatory activity. ARYLCARBOXYLIC ACID DERIVATIVES Adverse reactions to phenylpropionic acids (ibuprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, flurbiprofen, and pirprofen) have been reviewed (43 R). IBUPROFEN
Allergy Skin rashes may occur and ibuprofen may precipitate bronchospasm in sensitive individuals (SEDA-1, p. 91; 17r). About 25% of patients with aspirin intolerance also reacted to a single oral dose of ibuprofen. Two such patients who also had systemic lupus erythematosus developed acute reactions to ibuprofen with cutaneous, nasal and ocular symptoms (44c).
95
Fever Fever, reproduced on several occasions, has been observed with ibuprofen, again in patients with systemic lupus erythematosus.
A 36-year-old woman with systemic lupus crythematosus developed spiking fever and chills followed by cpigastric pain, nausea and vomiting a week aftcr starting ibuprofen. On admission to hospital, the tcmperature was 40.4~ and there was mouth ulceration and lymphadenopathy. After 4 days without ibuprofen the temperature returned to normal. Ibuprofen was started again because of joint pain and within 6 hours fever and abdominal pain recurred. The patient was subsequently re-admitted to hospital and given another dose of ibuprofen. Twelve hours later she developed fever, chills, nausea, vomiting, and severe abdominal pain with ulceration of the lip. A similar febrile reaction has been described in another young woman (45C). Febrile reactions to this drug are not confined to lupus patients. In another report, fever, anorexia, malaise, weakness, vomiting, increased joint pain and disturbed liver function tests occurred in a 12-year-old girl with juvenile rheumatoid arthritis shortly after she was started on ibuprofen. When the drug was stopped she rapidly became afebrile and the arthritis improved (46 c). Gastrointestinal system As repeatedly observed in the past, all forms of gastrointestinal irritation occur with this drug (SED VIII, p. 221; SEDA-1, p. 91), including overt haemorrhage (e.g. as reported again recently by E n g b a e k ) ( 4 9 c). It has often been concluded that occult blood loss is less than with aspirin, but a loss of almost 100 ml over 4 days has been recorded (47c). The combination of fluid retention and blood loss may be responsible for a slight but significant fall in haemoglobin concentration (48). Ibuprofen causes an acute erosive gastritis with mucosal necrosis in rats, and these lesions could be prevented with antacids and cimetidine (50). Liver Liver function tests may be abnormal in patients with acute febrile reactions to ibuprofen (45 c, 46c). Renal Ibuprofen (2.4 g daily) may cause a fall in creatinine clearance (51c), and this fact must be viewed in the light of the various
96 renal complications attributed earlier to the drug (SEDA-I, p. 91). Oedema, weight gain and congestive cardiac failure Like other anti-inflammatory drugs, ibuprofen may cause fluid retention and weight gain (SEDA-1, p. 91; 48c). In some cases, the fluid retention may result in frank oedema and congestive cardiac failure. A 71-year-old man was prescribed ibuprofen (1.6 g daily) for back pain. He was admitted to hospital 17 days later with ankle oedema and weight gain of nearly 15 kg over the preceding 10 days. He was found to be in congestive cardiac failure with peripheral and sacral oedema, bilateral pleural effusions and radiological evidence of pulmonary vascular congestion. The ibuprofen was stopped and there was a good diuretic response to frusemide. Ten days after admission his weight had returned to normal and the frusemide was discontinued. Six months later he remained free of oedema (52C). KETOPROFEN Gastrointestinal tract As pointed out in SEDA-1 (p. 92), and repeatedly confirmed in clinical reports, gastrointestinal toxicity is common, and anorexia, nausea, vomiting, heartburn, epigastric pain, dyspepsia, and gastrointestinal erosions, ulceration and haemorrhage may occur (35 c, 43 c, 5 3 c - 5 7 c ) . Ketoprofen increases occult gastrointestinal blood loss (58, 59) and may cause massive upper gastrointestinal haemorrhage (43 c , 57r In addition, the use of ketoprofen (with and without other anti-inflamm a t o r y drugs) has been associated with anaemia and gastric, duodenal and jejunal ulceration. Perforation has occurred with peritonitis and death. In one case an elderly man developed profuse melaena and bled to death after taking ketoprofen for 4 days (43c). The use of ketoprofen suppositories does not prevent upper gastrointestinal toxicity and in addition m a y cause colic and severe rectal pain (60 c, 61c). Furthermore, severe gastric haemorrhage has followed the use of ketoprofen suppositories (61 c). Ketoprofen causes acute erosive gastritis with mucosal necrosis in rats. These effects are reduced by antacids and H2 antagonists (50).
L. F. Prescott Renal Mild elevation of blood urea, frequency of micturition and dysuria have occasionally been reported (55 c, 57 c, 60 c, 62 c, 63c). Oedema, blood pressure Dependent oedema may occur (53 c, 57 c) and in one report ketoprofen had to be withdrawn because of water retention and hypertension (56c). Central nervous system Headache, lethargy, depression, giddiness, vertigo and tinnitus have been reported (53 c, 57 c, 64 c, 65c). Local pain and abscess after intramuscular in]ection Intramuscular ketoprofen is not well tolerated and may cause severe local pain with induration and abscess formation (66c). It is difficult to understand the rationale for administration of ketoprofen by this route. FENOPROFEN The properties o f fenoprofen have been reviewed (67R). Dyspepsia, abdominal pain, heartburn, and brisk gastrointestinal bleeding have been observed (68c). Fenoprofen may cause occult gastrointestinal bleeding, and antral ulceration (69r Decreased hearing, tinnitus and pyuria have been noted (68c). When one recalls the side effects reported earlier, including renal papillary necrosis, hepatic function changes, asthmatic reactions in aspirin-sensitive patients and mental effects (SED VIII, p. 222; SEDA-I, p. 92), it is evident that the drug's pattern of side effects is more or less typical for the class to which it belongs. INDOPROFEN Gastrointestinal intolerance (70 c) and increased occult blood loss (71 c) have been noted. FLURBIPROFEN Nausea, vomiting, abdominal pain, anorexia, skin rash and dizziness have been reported (48c). FENBUFEN Further reports have confirmed the conclusion in SEDA-I (p. 93) that this drug may cause gastrointestinal upsets, somnolence and occult gastrointestinal bleeding (43 r, 72c).
Anti-inflammatory analgesics and drugs used in rheumatism and gout
NAPROXEN Skin rashes may occur (73e), but most adverse reactions involve the gastrointestinal tract. Especially serious complications include bleeding gastric ulcer, perforated duodenal ulcer (74 c) and granulomatous colitis (75c). Naproxen increases occult gastrointestinal blood loss (58 c, 76 c) and causes acute erosive gastritis in animals (50). A further case of liver damage with jaundice has been reported (77 c ) and naproxen therapy may be associated with a deterioration in renal function in patients with disseminated lupus erythematosus (26e). Oedema has also been reported (78c). Other adverse reactions include headache, lightheadedness, dizziness, vertigo, tinnitus, confusion and drowsiness (74 c, 79 c) and in the latter report naproxen had to be discontinued in 13 of 39 patients (33%) because of side effects. Naproxen may also provoke or exacerbate asthma in patients with sensitivity to aspirin (22r). As little as 30 mg of naproxen may cause rhinorrhoea, tightness in the chest, wheezing and dyspnoea (80 C). Naproxen lowers plasma salicylate concentrations under experimental conditions (81) and interaction with aspirin might therefore occur.
DICLOFENAC Skin rashes, gastrointestinal upsets, headache, vertigo, insomnia and agitation have been reported ( 8 2 c - 8 7 c ) . Suppositories were not well tolerated and do not prevent upper gastrointestinal symptoms (88c). Diclofenac did not appear to cause severe gastric injury as shown by an endoscopic study (89), but this conclusion must be set against earlier reports of significant occult gastrointestinal blood loss. Diclofenac may provoke or precipitate asthma in patients with aspirin intolerance (22 r, 80c). TOLMETIN Skin rashes, central nervous system effects, gastrointestinal disturbances, falls in haematocrit and elevation of blood pressure have been observed ( 9 0 c - 9 2 e, 93r). Tolmetin causes an acute erosive gastritis in experimental animals (50).
97
ANTHRANILIC ACID DERIVATIVES MEFENAMIC ACID This drug has in some countries been withdrawn from sale; the question put six years ago in the Medical Letter whether mefenamic acid offers therapeutic benefits which outweigh its hazards does at all events not appear to have received a positive answer, and some severe reactions continue to be reported. A llergy Mefenamic acid may precipitate or aggravate asthma or urticaria in patients who are sensitive to aspirin (4 e, 20 r, 22e). An acute anaphylactic reaction has been reported.
A 66-year-old Chinaman with a history of previous reactions to a variety of drugs presented with epigastric, shoulder and leg pain. He was given antacids, oxethazaine and mefenamic acid on the spot and developed itchy hands 1-~ hours later at the bus station. He returned to the doctor who then gave him oral antihistamines and prednisolone. The pruritus increased and he began to cough. The patient's wife insisted that he be given injections, and while these were being prepared he became unresponsive with no detectable respiration or cardiac action. He recovered with clearing of the airway and external cardiac massage for 1 minute. Half an hour later he was able to walk. He subsequently had no complaints except that he nearly lost his life (8C). There is no proof that this reaction was caused by the mefenamic acid, but it is a reasonable assumption since he had previously suffered an almost identical reaction to phenylbutazone. Gastroin testinal system Mefenamic acid is a potent gastric irritant and has been implicated in acute upper gastrointestinal haemorrhage (35e). It may cause gastritis and duodenitis with ulceration and haemorrhage (94c). Mefenamic acid may also cause profuse steatorrhoea, abdominal distension and weight loss (95 c , 96c).
MECLOFENAMIC ACID Diarrhoea, nausea, vomiting and confusion have been observed (97e). Cumulated evidence (SED VIII, p. 222 ff; SEDA-1, p. 89) does not suggest that the pattern of side effects as a whole is different from that of other anthranilic acid derivatives.
98 GLAI"ENINE Serious toxicity continues to be recorded with this drug (SEDA-1, pp. 8 9 - 9 1 ) . A lie rgy
Skin rashes and acute reactions, including new cases of anaphylaxis, have been reported (98R). Fever and eosinophilia may complicate haematotoxicity and nephrotoxicity induced by glafenine (99 c , 100 c). Blood
A patient developed acute renal failure and haemolytic anaemia with a positive Coombs test following therapeutic doses of glafenine (100c). The case is very similar to that described in detail in SEDA-1 (p. 90). Gastrointestinal system
Upper gastrointestinal haemorrhage has been reported (35c). Renal
There have been many reports of acute renal failure following overdosage of glafenine, but this may also occur with therapeutic doses (98 r, 99 C, 100c). The plasma half-life of glafenine is prolonged in patients with chronic renal failure ( 101 c). FLOCTAFEN 1NE This drug closely resembles glafenine structurally, and must be assumed to have similar toxicity until proved otherwise. Floctafenine increases occult gastrointestinal blood loss, but to a lesser extent than aspirin (102c).
OTHER DRUGS USED IN RHEUMATOID ARTHRITIS DIFTALONE Skin rashes, nausea, vomiting, diarrhoea, heartburn, abdominal pain, persistent increases in transaminases, headache, dizziness, sedation and leukopenia have all been reported ( 1 0 3 c - 1 0 8 c ) . Side effects occurred in 38% of a series of 140 patients given diftalone. Treatment had to be discontinued in 5% of patients because of adverse effects and in one patient there was a marked rise in the blood urea (108c). As pointed out in SEDA1, the drug has also raised other problems, including agranulocytosis, and would appear to have little future. Late in 1977 investigation of diftalone
L. F. Prescott
was abandoned because of the discovery o f carcinogenic potential (hepato.mas) in high dosage studies in rodents. It was not known whether these findings might be relevant to man or not (124). !
AZAPROPAZONE Bizarre bullous skin e r u p t i o n s may occur (109 c). Azapropazone is a gastrointestinal irritant and is ulcerogenic (110). It may also interact with warfarin, causing marked potentiation of anticoagulant action (11 lC). One patient on long-term warfarin therapy suffered a severe haematemesis 4 days after being given azapropazone. The prothrombin time was prolonged to 220 seconds (control 14 seconds). Bleeding stopped after administration o f vitamin K and gastroscopy revealed a benign gastric ulcer (112 c). It is remarkable that in recent literature this interaction of azapropazone is still described as 'unexpected', whereas in fact it is a wellestablished problem (SEDA-1, p, 265). PROTIZINIC ACID (SEDA-1, p. 93) A syndrome resembling malignant hyperthermia with a fatal outcome has been reported in a 17-year-old girl who took an overdose of aspirin (6 g) and protizinic acid (8 g) (113c). BUCLOXIC ACID An acute febrile illness with fever, rash, splenomegaly and salivary gland enlargement has been attributed to bucloxic acid (114c). CHLOROQUINE See Chapter 26. LEVAMISOLE See Chapter 28. PENICILLAMINE See Chapter 21. DRUGS USED IN THE TREATMENT O F GOUT ALLOPURINOL Allergy
Allopurinol is said to cause allergic reactions in 15% of patients with renal disease (115); this estimate seems to confirm those given earlier (SEDA-1, p. 94). However, a recent report does suggest that desensitization is feasible.
Anti-inflammatory analgesics and drugs used in rheumatism and gout A patient with severe gout corhplicated by renal impairment and hypertension repeatedly developed a severe rash when treatment with allopurinol or thiopurinol was attempted. Over a period of 30 days he was given increasing doses of allopurinol, starting with a daily dose of 8 ~g until he was taking 300 mg daily on the 30th day. This was tolerated without incident and his gout was adequately controlled on this dose subsequently (115C). Boyer et al. (116) have recently described three patients with severe reactions to allopurinol including h e p a to c e U u la r necrosis, hepatic granulomata, renal failure and exfoliative dermatitis, all resulting from hypersensitivity. The reactions appeared 3 - 4 weeks after starting treatment and responded in two cases to corticosteroids. Such reactions are fortunately rare but extremely dangerous. COLCHICINE Colchicine causes severe toxicity when taken in overdosage (SEDA-I, p. 95). Initially there is anorexia, vomiting and profuse diarrhoea, followed by hepatic and renal damage. Bone marrow aplasia occurs between the 3rd and 6th days and death may result from haemorrhage or infection. In patients who survive there may be polyneuritis and alopecia (117 R, 118c). Pulmonary oedema and consumptive coagulopathy have also been observed in the acute phase of intoxication ( 119 c). In a recent case reported by Naidus et al. (120 c ) a 50 mg dose of colchicine was instilled into the penile urethra for the treat-
99
ment of condyloma acuminata, and a multisystemic reaction of the above type, including severe but reversible m y o p a t h y and respiratory failure, developed. SULPHINPYRAZONE Mild renal failure with elevation of serum creatinine and blood urea and celluria was observed in a 33-year-old man given 800 mg of sulphinpyrazone daily (12 lC). Allergic reactions, blood dyscrasias and a reduction in platelet adhesion have been reported earlier (SED VIII, p. 227; SEDA-1, p. 94). BENZBROMARONE
Persistent diarrhoea and skin rashes have been noted (122c). The former is apparently one of the drug's most characteristic side effects (SED VIII, p. 227; SEDA-1, p. 94).
MISCELLANEOUS PHENAZOPYRIDINE This drug may cause methaemoglobinuria, crystalluria and renal damage (SED VIII, p. 224; SEDA-1, p. 94). Hepatic damage has also been reported, and one patient developed symptoms of hepatitis on four occasions after being given phenazopyridine for urinary tract infections (123c). It is important to recognize that cumulation of orangered metabolites of this drug may cause skin pigmentation that could readily be mistaken for jaundice. Phenazopyridine is, however, so nephrotoxic that it is best avoided.
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101
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