THEOPHYLLINE BENEFITS AND DIFFICULTIES
METHYLXANTHINE-containing beverages were advised for the treatment of asthma 125 years ago.’ 80 years elapsed before the specific introduction of theophylline in the management of acute, severe asthma.2During the past decade the advent of convenient, reliable theophylline assays3,4 and of sustained-release theophylline preparations,5,6 together with information on the pharmacokinetics,7,8 has led to a great increase in use of this drug. The disadvantage of theophyllines, to be set against their usefulness in management of reversible airflow obstruction,9,IO is a narrow therapeutic index. On p 610 this week, Dr Woodcock and coworkers present some disturbing data from the Brompton Hospital and conclude that theophyllines are difficult to use. How can these difficulties be lessened? Improvement in pulmonary function is related to plasma theophylline levels over the range 3-25 mg/1.11 However, the degree of improvement at less than 10 mg/1 is small, and serious toxic effects may arise at more than 25 mg/l;1z,13 thus the "therapeutic range" is taken as 10-20 mgIU,14,15 (On p 618 correspondents discuss management ofself-poisoning.) Within these limits minor adverse effects (headache, nausea, abdominal discomfort) may occur, and 1% of children and 4% of adults 17 are unable to tolerate even low serum levels. The doses oftheophyllines required to achieve "therapeutic" plasma levels vary considerably between individuals,7,17 largely because of differences in clearance. The drug is extensively metabolised in the liver by dealkylation and hydroxylation, and clearance may be affected by factors influencing the liver microsomal cytochrome PI-450/P-448 system. 18 In practice theophylline clearance has been observed to vary with age," smoking,2° disturbed hepatic 1 Salter H. On 2 3
some points in the treatment and clinical history of asthma. Edinb Med J 1858-59; iv: 1109-15. Herrman G, Aynesworth MB, Martin J. Successful treatment of persistent dyspnoea "status asthmaticus". J Lab Clin Med 1937; 23: 135-48. Soldin SJ, Hill JG. A rapid micromethod for measuring theophylline in serum by reverse-phase high performance liquid chromatography. Clin Biochem 1977; 10:
74-77. 4. Ishizaki T, Watanabe
M, Morishita M. The effect of assay methods on plasma levels and pharmacokinetics of theophylline: HPLC and E1A. Br J clin Pharmacol 1979; 7: 333-41. 5. Weinberger M, Hendeles L, Bighley L. The relation of product formulation to absorption of oral theophylline. N Engl J Med 1978; 299: 852-57. 6. Spangler DL, KaloffDD, Bloom FL, Witty HJ. Theophylline bioavailability following oral administration of six sustained release preparations. Ann Allergy 1978; 40: 6-11 7 Jenne JW, Wyze E, Rood FS, MacDonald FM. Pharmacokinetics of theophylline. Application to adjustment of the clinical dose of aminophylline. Clin Pharmacol Therap 1972; 13: 349-60. 8. Hendeles L, Weinberger M, Bighley L. Disposition of theophylline after a single intravenous infusion of aminophylline. Am Rev Respir Dis 1978; 118: 97-103. 9. Weinberger M, Hendeles L Experience with theophylline for the management of chronic asthma. Eur J Respir Dis 1980; 109 (suppl): 120-33. 10. Barnes PJ, Greening AP, Neville L, Timmers J, Poole GW. Single-dose slow-release aminophylline at night prevents nocturnal asthma. Lancet 1982; i: 299-301. 11 Mitenko PA, Ogilvie RI. Rational intravenous doses of theophylline. N Engl J Med 1973; 289: 600-03. 12 Zwillich CW, Sutton FD, Neff TA, Cohn WM, Matthay RA, Weinberger M. Theophylline-induced seizures in adults; Correlation with serum concentrations. Ann Intern Med 1975; 82: 784-87. 13 Jacobs MH, Senior RM, Kessler G Clinical experience with theophylline. Relationships between dosage, serum concentration and toxicity. JAMA 1976; 235: 1983-86 14 Turner-Warwick M. Study of theophylline plasma levels after oral administration of new theophylline compounds. Br Med J 1957; iii: 67-69. 15 Weinberger M, Matthay RA, Grinchansky EJ, Chidsey CA, Petty TL. Intravenous aminophylline dosage: Use of serum theophylline measurement for guidance. JAMA 1976, 235: 2110-13. 16 Weinberger M, Grinchansky EJ. Theophyllinization of the child with chronic asthma. In Gouveia WA, Tognoni G, Van der Kleijn E, eds. Proceedings of the International Symposium on Clinical Pharmacy and Clinical Pharmacology. Amsterdam North-Holland Biomedical Press, 1976: 319-28. 17 Greening AP, Baillie E, Gribbin HR, Pride NB. Sustained release oral aminophylline in patients with airflow obstruction. Thorax 1981; 36: 303-07. 18 Lohmann SM, Miech RP. Theophylline metabolism by the rat liver microsomal system. J Pharmacol Exp Ther 1976; 196: 213-25.
cardiac failure,22 virus infections,23 and with other drugS.24,25 In the management of acute, severe asthma intravenous aminophylline remains an important therapy, particularly in general practice where nebulisers are unlikely to be available. In hospital the initial therapy would preferably be with nebulised 02-agonists plus intravenous hydrocortisone with the addition of nebulised ipratropium bromide if required. For profoundly ill patients, or those in whom the peak expiratory flow rate has not increased after an hour’s treatment, intravenous aminophylline can be beneficial. Initial recommendations ofdoselproved too high for general use and current advice for adults is to give 5’ 6 mg/kg over 20-30 min followed by 0’ 5 mg/kg per hour8with a check on plasma levels at 24 h. There should be no difficulties with such a regimen provided that there is no liver disease, heart failure, or current medication with oral theophyllines. If any of these factors apply, the recommended doses should be halved and plasma levels closely monitored. Several groups of patients with non-life-threatening asthma have been shown to benefit from slow-release theophyllines-children, 9,26 adults with mild to moderate asthma and predominantly nocturnal symptoms, 10 and adults with severe, chronic asthma on multiple drugs. 17 In prescription of twice-daily medication the principal difficulty lies in the wide interpatient variation.9,17 General practitioners tend to underdose so as to avoid toxic plasma concentrations, but this reduces the clinical benefit. For mild asthma the daytime treatment of choice would anyway be inhaled &bgr;2-agonists,27 with slow-release theophyllines in one dose at night to control nocturnal symptoms. Barnes et al’o achieved therapeutic plasma levels with slow-release aminophylline 10-4 mg/kg (range 9’ 1 -11’ 4 mg/kg) at night; this is equivalent to 8’7 mg/kg theophylline (range 7-6-9-55 , mg/kg). If, in a patient with severe asthma, twice-daily theophylline treatment is decided upon, the dose should be adjusted according to plasma levels. A peak (4-6 h post-dose) and a trough (10-12 h post-dose) plasma theophylline measured about a week after the start of therapy will allow suitable modification of the regimen. Thereafter, testing every six or twelve months should be sufficient. In chronic bronchitis with airflow obstruction the value of theophyllines is more controversial, though there is some evidence that in this group of patients they can improve exercise tolerance 28 and have a bronchodilating effect additional to that of salbutamol (provided that there is some reversibility with salbutamol alone29). Such patients may
19. Jusko WJ,
Kroup JR, Vance JW, Schentag JJ, Kuritzky P. Intravenous theophylline therapy nomogram guidelines. Ann Intern Med 1977; 86: 400-04. 20. Powell JR, Thiercelin J-F, Vozeh S, Sansom L, Riegelman S. The influence of cigarette smoking and sex on theophylline disposition. Am Rev Respir Dis 1977; 116: 17-23. 21. Piafsky KM, Sitar DS, Rangno RE, Ogilvie RI. Theophylline disposition in patients with hepatic cirrhosis. N Engl J Med 1977; 296: 1495-97. 22. Piafsky KM, Sitar DS, Rangno RE, Ogilvie RI. Theophylline kinetics in acute pulmonary oedema. Clin Pharmacol Ther 1977; 21: 310-16. 23. Chang KC, Bell TD, Lauer BA, Chai H. Altered theophylline pharmacokinetics during acute respiratory virus illness. Lancet 1978; i: 1132-33. 24. Kozak PP, Cummins LH, Gillman SA. Administration of erythromycin to patients on theophylline. J Allergy Clin Immunol 1977; 60: 149-51. 25. Reitberg DP, Bernhard H, Schentag JJ. Alteration of theophylline clearance and halflife by cimetidine in normal volunteers. Ann Intern Med 1981; 95: 582-85. 26. Hambleton G, Weinberger M, Taylor J, Cavanaugh M, Grinchansky E, Godfrey S, Tooley M, Bell T, Greenberg S. Comparison of cromoglycate (cromolyn) and theophylline in controlling symptoms of chronic asthma. Lancet 1977; i: 381-85. 27. Flenley DC. New drugs in respiratory disorders: I. Br Med J 1983; 286: 871-75. 28. Leitch AG, Morgan A, Ellis DA, Bell G, Haslett C, McHardy GJR. Effect of oral salbutamol and slow-release aminophylline on exercise tolerance in chronic bronchitis. Thorax 1981; 36: 787-89. 29.
Barclay J, Whiting B, Meredith PA, Addis JG. Theophylline-salbutamol interaction: bronchodilator response to salbutamol at maximally effective plasma theophylline concentrations. Br J Clin Pharmacol 1981; 11: 203-08.
require closer monitoring of plasma theophylline levels since they are more likely than others to smoke2O and to receive erythromycin.24 A final difficulty that applies to all groups of patients is the number of theophylline preparations on the market. As Dr Woodcock and his colleagues show, there is serious potential for duplicate prescribing. Matters would be improved by generic prescribing and by complete avoidance of compound preparations and aminophylline suppositories.
tutorials in the setting of a clinical clerkship, providing experience of issues raised by health service provision. As Tom Arie emphasised, students should not be protected from concerns such as scarcity and rationing. Each student should complete a personal project, and there should be an examination. In the final year there should be some continuing input, perhaps in the form of joint teaching with other disciplines, sustaining the theme until the end of the undergraduate curriculum. to
NEW TEACHING ABOUT OLD PEOPLE
RENAL TUBULAR ACIDOSIS
MOST oftoday’s medical students will spend much of their working lives caring for the elderly, whether or not this becomes their special interest. How well do we prepare them for dealing with old (and especially very old) people? Peter Millard argued at a symposium held in Manchester on June 241 that what is taught by the teachers of geriatric medicine falls into three parts: what could be taught by others; what should be taught by others; and what only geriatricians can teach. As to which topics might fall into the three categories, and the local factors likely to affect the balance, readers should turn to the papers in this impressive collection and make up their own minds. Only a few these days will deny, at least openly, that the third category exists, and all will certainly be struck by the diversity of approach that is described here, and by the enthusiasm and ingenuity of the teachers of geriatric medicine. Some twenty years after the appointment of Ferguson Anderson to the first British chair in geriatrics, fourteen UK undergraduate medical schools have academic posts, including twelve professors. Should one be heartened by these figures ("nearly half of all medical schools ...") or dismayed ("not even- half...")? Are the schools with no academic geriatric appointments those which are strongest on the first two of "Millard’s triad" or are they the weakest? Read here about a teaching game from Manchester (devised in Saskatoon, and surely likely to catch on in many more places and in many more subjects) and about the joint teaching of medical, nursing, and remedial students at the Middlesex Hospital. Learning together is a good preparation for working together, without the usual suspicions and misconceptions; and sharing the mysteries of initiation into these professions is as likely as anything to dispel fantasies (commonly paranoid) about each other. The description of a Nottingham department where physicians and psychiatrists happily work and teach together in one department is
THE Mayo Clinic’s repository of clinical records has provided a unique source of information on the features and the natural history of disease. Although the accumulation of
similarly heartening. The symposium emphasised that undergraduate teaching in geriatrics is not designed to produce geriatricians but to help future doctors to be more effective and more comfortable in dealing with their aged patients; if a few are inspired to make this their special interest well and good, but undergraduate teaching is no more designed to produce specialists here than it is in other disciplines. John Brocklehurst, who organised the symposium, suggests a composite curriculum derived from what seems best in the many schemes described. During the preclinical course basic gerontology would be taught, with physiology, psychology, and sociology, preferably by gerontologists (rare breed). In the first clinical year there might be a short introductory module provided jointly to medical, nursing, and remedial students, whilst in the second clinical year at least four weeks should be devoted
this information is a selective process and the records tell us nothing about the prevalence of disease in the population as a whole, reports from the Mayo Clinic can help build up a fairly comprehensive picture of less common disorders. One of the latest studies’reviews musculoskeletal symptoms and renal stones as presenting complaints. In the type of patient who was seen at the Mayo Clinic these were common. Out of 48 patients reviewed, musculoskeletal symptoms were the primary complaint in 25. A further 8 patients who presented with renal stones also had musculoskeletal symptoms, giving a frequency of 69% in the group as a whole. The symptoms ranged from the vague to the specific with arthralgia and myalgia as common complaints whilst metabolic bone disease (27%), arthritis (10%), and low back pain (18%) were less common. This immediately raises the question of how far such widely encountered symptoms were genuinely associated with renal tubular acidosis. Without a control population this is difficult to say. In some cases it seems probable that both renal tubular acidosis and the symptoms were secondary to the same disease. Thus of the 33 patients with musculoskeletal complaints, 12 had connective tissue disease: all 5 patients with arthritis belonged to this latter category. However, the Mayo Clinic report does provide some evidence to support the view that musculoskeletal symptoms could be attributed to renal tubular acidosis per se in some patients. Thus, treatment with oral alkalis alleviated symptoms in 76% of the patients with renal tubular acidosis alone whilst only 39% of patients with connective tissue disease as well were helped. Further evidence is afforded by more detailed analysis of the patients. Classical renal tubular acidosis of the distal type (type 1) can take one of two forms. In the complete form systemic acidosis is present in the resting state with an inappropriately high urine pH. In the incomplete form acidosis is only observed after an oral ammonium chloride load.2 In the Mayo Clinic study both arthralgia and arthritis were more common in the complete form of the disease suggesting an association with the underlying metabolic disturbance. The cause of the symptoms was not always clear although in some cases hypokalaemia and loss of bone tissue were probably responsible. These abnormalities by no means provide a complete explanation, however. There is less doubt about the association of renal tubular acidosis and renal stone disease- which was the presenting complaint in 23 patients
(48%). Renal tubular acidosis is often asymptomatic and its prevalence in unselected populations is unknown, although it 1.
Bunch TW, Van Den Berg CJ. Renal tubular acidosis a new look at of musculoskeletal and renal disease. Mayo Clin Proc 1983; 58: 354-60 O, Davies HEF. The excretion of acid in renal disease Quart J Med 1959, 28:
Harrington TM, treatment
JC, 1983 (suppl).