Clinical Pharmacokinetics 2: 281-291 (1977) ©ADIS Press 1977
Prediction of Digoxin Dose Requirements S.M. Dobbs and G.E. Mawer Department of Pharmacology and Therapeutics, The Middlesex Hospital Medical School, London, and the Department of Pharmacology, Materia Medica and Therapeutics, University of Manchester, Manchester.
Summary
Succes~ful withdrawal of digoxin in small highly selected groups of patients and in larger groups, in which many patients had no cardiac lesion, have led to speculation as to the value of maintenance digoxin following an episode of heart failure. Recent experience in general medical outpatients receiving'maintenance digoxin, and also in many cases potent diuretics, suggests that such doubts are largely misplaced. D(fferences in bioavailability between formulations have hindered the prediction of dose requirements. Standardisation of dissolution rate has reduced this contribution to the measured variation in individual absorption, but substantial variation remains which is probably due to individual differences in gastrointestinal function. The best criterion by which to judge the appropriateness of a prescription would be the clinical response of the patient. Nevertheless, guidelines are required for initial treatment and even for long term treatment of those patients in whom there is no convenient indicator of therapeutic response. In both situations, renal function, measured by creatinine clearance, has been the best gUide to the dose schedule required to achieve the desired mean steady state serum digoxin concentration. In adult patients with normal or only slightly impaired renal function, and normal atrio-ventricular conduction, the most practical procedure may be to start all patients on the same dose schedule. Symptoms of toxicity can occur at mean serum concentrations within the published therapeutic range. In these circumstances, reduction of the dose by small steps may abolish toxicity without loss of therapeutic response. Failure to reduce the dose encourages non-compliance. Further reduction during fott'ow-up may be necessary because of deterioration of renal function or progression of cardiac disease.
Prescription of digoxin is a controversial matter. Disagreement exists as to the indications for the drug and the best formulation. Although there is concern that many patients are prescribed inappropriate doses, prescribing aids are not generally used. The value of digoxin treatment after an episode of heart failure has been disputed, and reduction of the number of patients needlessly exposed to the drug
urged by recent editorials (British Medical Journal, 1975; Lancet, 1976). Attempts to increase the consistency of absorption of digoxin between subjects by using tablets of very high dissolution rate, fluid-fJ11ed capsules and more fat soluble, semisynthetic derivatives of digoxin are based on the assumption that the problem lies in the bioavailability of the drug, rather than the absorptive capacity of individual patients.
282
Prediction of Digoxin Dose Requirements
The published mortality and morbidity figures associated with digoxin therapy are alarming, whilst other studies report inadequate therapy due to lack of compliance in outpatients. Measurement of the serum digoxin concentration has proved of use in choosing the dose for individual patients (Sheiner, 1974), but its value in practice is limited by the restricted availability of the assay and by delays in receiving results. The need to use a reduced dose in patients with severe renal impairment is well established. However, such patients comprise only a small proportion of the population receiving digoxin and it is questionable whether prescribing aids based on renal function are of wider application.
1. Is Digoxin Indicated?
. Table I. Reasons for starting digoxin treatment in 53 patients (Dall, 1970)' Indication
'Diagnosis' (comment)
'Tachycardia'
Iron deficiency. anaemia Thyrotoxicosis Chronic renal failure Chronic arthritis Gastrointestinal bleeding Myeloma
Number of pts
8 4 4 4 2
23
'Cardiac failure'
Coronary disease Respiratory infection Pernicious anaemia Atherosclerotic heart disease
7 (4)2
3
12
Digoxin is widely prescribed. It has been estimated that about 300,000 people take it in the UK (Editorial 1 (1) Lancet, 1976), whilst studies in the USA (Shapiro et 'Oedema' Coronary disease 2 Gross varicose veins ai, 1969; Beller et aI., 1971) report that about 20 % of 2 Hypoproteinaemia alll'~tie~ts hospitalised ~~~!!le~i
Prediction of Digoxin Dose Requirements S.M. Dobbs and G.E. Mawer Department of Pharmacology and Therapeutics, The Middlesex Hospital Medical School, London, and the Department of Pharmacology, Materia Medica and Therapeutics, University of Manchester, Manchester.
Summary
Succes~ful withdrawal of digoxin in small highly selected groups of patients and in larger groups, in which many patients had no cardiac lesion, have led to speculation as to the value of maintenance digoxin following an episode of heart failure. Recent experience in general medical outpatients receiving'maintenance digoxin, and also in many cases potent diuretics, suggests that such doubts are largely misplaced. D(fferences in bioavailability between formulations have hindered the prediction of dose requirements. Standardisation of dissolution rate has reduced this contribution to the measured variation in individual absorption, but substantial variation remains which is probably due to individual differences in gastrointestinal function. The best criterion by which to judge the appropriateness of a prescription would be the clinical response of the patient. Nevertheless, guidelines are required for initial treatment and even for long term treatment of those patients in whom there is no convenient indicator of therapeutic response. In both situations, renal function, measured by creatinine clearance, has been the best gUide to the dose schedule required to achieve the desired mean steady state serum digoxin concentration. In adult patients with normal or only slightly impaired renal function, and normal atrio-ventricular conduction, the most practical procedure may be to start all patients on the same dose schedule. Symptoms of toxicity can occur at mean serum concentrations within the published therapeutic range. In these circumstances, reduction of the dose by small steps may abolish toxicity without loss of therapeutic response. Failure to reduce the dose encourages non-compliance. Further reduction during fott'ow-up may be necessary because of deterioration of renal function or progression of cardiac disease.
Prescription of digoxin is a controversial matter. Disagreement exists as to the indications for the drug and the best formulation. Although there is concern that many patients are prescribed inappropriate doses, prescribing aids are not generally used. The value of digoxin treatment after an episode of heart failure has been disputed, and reduction of the number of patients needlessly exposed to the drug
urged by recent editorials (British Medical Journal, 1975; Lancet, 1976). Attempts to increase the consistency of absorption of digoxin between subjects by using tablets of very high dissolution rate, fluid-fJ11ed capsules and more fat soluble, semisynthetic derivatives of digoxin are based on the assumption that the problem lies in the bioavailability of the drug, rather than the absorptive capacity of individual patients.
282
Prediction of Digoxin Dose Requirements
The published mortality and morbidity figures associated with digoxin therapy are alarming, whilst other studies report inadequate therapy due to lack of compliance in outpatients. Measurement of the serum digoxin concentration has proved of use in choosing the dose for individual patients (Sheiner, 1974), but its value in practice is limited by the restricted availability of the assay and by delays in receiving results. The need to use a reduced dose in patients with severe renal impairment is well established. However, such patients comprise only a small proportion of the population receiving digoxin and it is questionable whether prescribing aids based on renal function are of wider application.
1. Is Digoxin Indicated?
. Table I. Reasons for starting digoxin treatment in 53 patients (Dall, 1970)' Indication
'Diagnosis' (comment)
'Tachycardia'
Iron deficiency. anaemia Thyrotoxicosis Chronic renal failure Chronic arthritis Gastrointestinal bleeding Myeloma
Number of pts
8 4 4 4 2
23
'Cardiac failure'
Coronary disease Respiratory infection Pernicious anaemia Atherosclerotic heart disease
7 (4)2
3
12
Digoxin is widely prescribed. It has been estimated that about 300,000 people take it in the UK (Editorial 1 (1) Lancet, 1976), whilst studies in the USA (Shapiro et 'Oedema' Coronary disease 2 Gross varicose veins ai, 1969; Beller et aI., 1971) report that about 20 % of 2 Hypoproteinaemia alll'~tie~ts hospitalised ~~~!!le~i
