Systemic symptoms associated with a toms. The patient admitted to "high" periods, and Drug Points bipolar affective disorder was diagnosed. Lithium rubefacient carbonate was started at a dose of 1000 mg/day after Probable fatal interaction between Dr D A N FERGUSSON (Brook Lane Medical Mission, the symptoms were controlled with an increase in ciprofloxacin and theophylline Bromley BRI 4PX) writes: Rubefacients are popular background tricyclic antidepressant therapy (doxepin topical preparations, often bought without prescrip- 75 mg to 175 mg). Mefenamic acid, two 250 mg tablets Dr R HOLDEN (Edinburgh) writes: Thomson et al tion, which by counterirritation bring comfort in three times daily, was her only other medication, BMJ: first published as 10.1136/bmj.297.6659.1339-b on 19 November 1988. Downloaded from recently reported theophylline toxicity in an elderly painful lesions of muscles, tendons, and joints and in taken for two weeks premenstrually. Fluid retention patient concurrently taking ciprofloxacin.' The non-articular rheumatism. They are symptomatically and relative oliguria had been noted perimenstrually Committee on Safety ofMedicines has been notified of effective and there are few reported problems. I in the past. Before the introduction of lithium renal several other cases (R D Mann, personal communica- describe a case where normal use may have produced function was normal (plasma creatinine 0-09 mmol/l, tion). We report a further probable interaction with a unpleasant systemic sensations and fainting. blood urea 3 - 8 mmol/l, and 24 hourcreatinine clearance fatal outcome. Twice an 18 year old girl used a popular proprietary of 1 70 ml/s). Urine analysis gave a normal result. Free A 65 year old woman with a history of a left preparation containing methyl nicotinate 1%, capsicin thyroxine was measured in the reference range at 11-5 hemiplegia, atrial fibrillation, congestive cardiac BPC 0-12% w/w, and preservatives in a cream base. pmol/l. While the patient was taking lithium 1000 mg failure, and inoperable carcinoma of the breast was She was otherwise fit, taking only a combined oral the plasma lithium value was 0 4 mmol/l. An increase admitted after collapsing. Five days before admission contraceptive, being a non-smoker, and having been in the dose to 1250 mg daily was associated one week she had been prescribed ciprofloxacin 250 mg twice discharged as fit after investigation for a symptomless later with nausea and the plasma lithium concentration daily and slow release theophylline (Uniphyllin systolic murmur, with electrocardiogram, chest x ray reached the toxic range at 1-7 mmol/l, leading to Continus) 600 mg daily for a chest infection. Her film, echocardiogram, and Doppler ultrasound all cessation of therapy. We assumed that the lithium condition had been stable until the time of collapse. normal. On the first occasion she had rubbed about toxicity had resulted from concomitant hypovolaemia, She had been taking digoxin 0 25 mg, bumetanide 2-3 g of the rubefacient on to her back. Ten minutes although this was not clinically evident. Renal function 1 mg, and tamoxifen 40 mg daily for more than a year. later she felt a curious burning sensation internally was normal. On examination she was conscious but unable to in her abdomen and felt faint but recovered after Lithium was restarted, but a dose of only 250 communicate and had frequent epileptic seizures, 10 minutes. About a month later she rubbed a larger mg/day produced symptoms of toxicity while she was involving the non-hemiplegic side. She had developed quantity, at most 5 g, on to a painful knee and within also taking mefenamic acid. Serum creatinine con- fast atrial fibrillation with a ventricular rate of 160 five minutes felt nauseated, experienced the internal centration was 0 19 mmol/l and creatinine clearance beats/minute and blood pressure of 120/60 mm Hg, pain even more unpleasantly, and fainted. When seen 1-05 ml/s. Lithium and mefenamic acid were dis- but cardiovascular examination gave otherwise un- some 20 minutes later she was conscious, pale but not continued and the patient instructed to increase her remarkable results. Neurological examination showed shocked, and with a normal pulse and blood pressure. fluid and salt intake. Creatinine clearance rose to features of a previous left hemiplegia and an equivocal There was intense erythema over the area of applica- normal at 1 67 ml/s. A further attempt was made to right plantar response. tion on her knee and lower thigh. reintroduce lithium cautiously at a dose of 250 mg Radiography of the chest showed slight cardio- Neither the Committee on Safety of Medicines nor three times a day, and blood concentrations at weekly megaly, and electrocardiography showed atrial fibril- the manufacturer has any reports of such effects. The intervals were stable at 0-5 mmol/l over the next lation with a heart rate of 160 beats/minute and cream used was later tested by the manufacturers and month. Mefenamic acid 250 mg tablets, two three widespread ST segment depression. Plasma concen- found to be satisfactory. With the full cooperation of times a day, were again added for dysmenorrhoea, and trations of sodium were 133 mmol/l, potassium 2-8 the manufacturer and the informed consent of the six days later the lithium concentration was 2-0 mmol/ mmolIl, and urea 4-1 mmol/l. Liver function was patient standard skin patch testing was performed to 1, with symptoms of acute toxicity. Four days after substantially altered: serum aspartate transaminase identify which ingredient might be responsible, and cessation of lithium the blood value was 0 5 mmol/l, activity was 319 IU/l (normal range 12-42 IU/1) and she reacted with erythema to the methyl nicotinate plasma creatinine 0-06 mmol/l, and creatinine clear- alanine transferase activity was 660 IU/I (normal range and to the whole preparation, but without any systemic ance 2-0 mlbs. 10-50 IU/A); alkaline phosphatase activity was 493 IU/l effects as much smaller quantities were used. This case was unique in two respects. Renal function (normal range 90-300 IU/1); and serum total bilirubin The maximum amount of methyl nicotinate applied was documented as normal before lithium treatment, concentration was 59 p.molIl (normal range < 17 in the second episode would have been 50 mg. Had deteriorated sharply when both therapeutic agents imol/l) and albumin concentration 32 g/l (normal this all been absorbed systemically the effect might were used, and reverted to normal after their withd- range 36-52 g/l). Haemoglobin concentration was 118 have been similar to intravenous dosing. In 1975 rawal. This sequence occurred after rechallenge with g/l and white cell count 17 6x 109/l with moderate Davidson et al gave 50 mg of nicotinic acid by slow both agents. In the only previous report of their neutrophilia. Serum concentration of digoxin was intravenous injection over 30 seconds to 16 patients association renal function was impaired before treat- 1-3 nmol/l (reference range 1-3-2-5 nmol/l) and theo- with Gilbert's syndrome and six controls, and the only ment.2 Blood lithium values were considerably raised phylline 188 [smol/l (55-110 tmol/l). side effects reported were mild flushing and a transient in our patient, in association with clinical toxicity, The patient was treated with intravenous digoxin metallic taste.' Methyl nicotinate would be expected but only equivocally so in the previous case.2 On 0-5 mg and subcutaneous diazepam 10 mg, but one to have a similar effect to nicotinic acid, although there rtchallenge with both agents renal function again hour later her heart rate was still the same, she are no known data on intravenous dosing. deteriorated, although lithium alone did not produce a continued to have frequent seizures, and she had As many thousands of people use such preparations measurable change in renal function. become unconscious. Phenytoin 250 mg was given without untoward effects there is no obvious ready Mefenamic acid has been reported to produce a http://www.bmj.com/ intravenously, abolishing the seizures. Over the next explanation in this case for the patient's symptoms, variety of renal syndromes," and non-steroidal anti- six hours the patient remained deeply unconscious, although the history of the two episodes suggests a inflammatory agents as a group may be responsible for her heart rate remaining between 140 and 150 beats/ clear cause and effect. Perhaps she had a local acute and chronic renal syndromes, both predictable minute, and she died seven hours after admission. sensitivity to topical nicotinate which through vaso- and idiosyncratic.`- Impairment of concentrating Permission to perform a necropsy was not obtained. dilatation would then enhance systemic absorption, ability occurs in over half of patients taking lithium.' In this case abnormal liver function due to metastatic and she may also have been abnormally sensitive Acute reversible renal functional impairment with disease could have contributed to theophylline toxi- systemically to pharmacological effects of nicotinate. associated lithium toxicity probably occurred in our city. Alternatively, the hepatic abnormalities may As these popular treatments are usually obtained over patient because of the interaction of a reduction in have been due to uncontrolled atrial fibrillation with the counter systemic effects may be underreported. renal blood flow and glomerular filtration rate induced

by a non-steroidal anti-inflammatory drug concurrent on 1 October 2021 by guest. Protected copyright. hepatic congestion induced by theophylline. Cipro- with intravascular volume contraction produced by a floxacin has been shown experimentally to have a I Davidson AR, Rojas-Bueno A, Thompson RPH, Williams R. minor effect on theophylline metabolism in normal natriuresis and diuresis initiated by lithium. Although Reduced caloric intake and nicotinic acid provocation tests in reversible, this potentially dangerous interaction may subjects.2 The effect may be clinically important in the the diagnosis of Gilbert's syndrome. Br MedJ 1975;ii:480. elderly34 and those with acute and chronic disturbance become more common as use of both agents continues of liver function. Wijnands et al have shown that full to increase. body clearance of theophylline is reduced by 30% and that plasma theophylline concentration is increased by 23% in patients with chronic obstructive airways 1 Boton R, Gaviria M, Batile DC. Prevalence, pathogenesis, and disease taking ciprofloxacin 500 mg twice daily and Toxic interaction of lithium carbonate and treatment of renal dysfunction associated with chronic lithium mefenamic acid therapy. Amj Kidney Dis 1987;10:329-45. suggested that the 4-oxo metabolite common to several 2 Shelley RK. Lithium toxicity and mefenamic acid: a possible quinolones was responsible for the interaction.' This interaction and the rolc of prostaglandin inhibition. Br J potentially common combination should be avoided in Drs JOANNA MAcDONALD and T JAMES NEALE (Hutt Psvchiatrv 1987;151:847-8. the elderly and in acutely ill patients, and the dosage of Regional Community Health Service and Depart- 3 Robertston CF, Ford MJ, Van Someren V, Dlugolecka M, theophylline should be monitored carefully in hospital ment of Medicine, Wellington School of Medicine, Prescott LF. Mefenamic acid nephropathy. Lancet 1980;ii: whenever the combination is used. Wellington, New Zealand) write: Lithium carbonate 232-3. is an indispensable treatment for manic depressive 4 Venning VX, Dixon AJ, Oliver DO. Mefenamic acid nephropathv. illness which has predictable effects on renal tubular Lancet 1980;ii:745-6. I Thomson AH, Thomson GP, Hepburn M, Whiting B. A concentrating ability. It can also produce acute 5 Kincaid-Smith P. Effects of non-narcotic analgesics on the clinically significant interaction between ciprofloxacin and kidney. Drugs 1986;32(suppl 4):109-28. theophylline. EurJ Clin Pharmacol 1987;33:435-6. renal functional impairment, especially in hypo- 6 Carmichael J, Shankel SW. Effects of non-steroidal anti- 2 Niki Y, Soejima R, Kawane H, Sumi M, Umeki S. New synthetic volaemic or dehydrated patients. Drug interactions inflammatory drugs on prostaglandins and renal function. quinolone antibacterial agents and serum concentration of and hypovolaemic states are associated with acute Am J Med 1985;78:992-1000. theophylline. Chest 1987;92:663-9. lithium toxicity, which may include renal functional 7 Scharschmidt L, Simonson M, Dunn MJ. Glomerular prosta- 3 Raoof S, Wollschiager C, Khan F. Ciprofloxacin increases serum impairment. We report here a serious acute drug glandins, angiotensin 1, and non-steroidal anti-inflammatory levels of theophylline. AmJ7 Med 1987;82(suppl 4A): 115-8. interaction between lithium and the non-steroidal drugs. AmJMed 1986;81:30-41. 4 Rybak MJ, Bowles SK, Chandrasekar PH, Edwards DJ. In- anti-inflammatory agent mefenamic acid, which was 8 Garella S, Matarese RA. Renal effects of prostaglandins and creased theophvlline concentrations secondary to ciprofloxacin. clinical adverse effects of non-steroidal anti-inflammatory Drug Intelligence and Clinical Pharnacy 1987;21 :879-81. substantiated by withdrawal and rechallenge. agents. Medicine 1984;63:165-81. 5 Wijnands WJA, Vree TB, van Herwaarden CLA. The influence A 29 year old woman with a 10 year history of 9 Unsworth J, Sturman S, Lunec J, Blake DR. Renal impairment of quinolone derivatives on theophylline clearance. BrJ_ Clin recurrent depression was referred with profound associated with non-steroidal anti-inflammatory drugs. Ann Phar7nacol 1986;22:677-85. depression associated with severe biological symp- Rheum Dis 1987;46:233-6.

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