Prolonged digitoxin half-life in very elderly patients

Age and Ageing, March, 1998 by Thomas Bohmer, Arne Roseth

Introduction

The role of digitalis glycosides in heart failure has recently been re-evaluated [1-3]. In addition to their inotropic effect, they exert neuro-endocrine suppression, sympathetic inhibition and arterial vasodilation. Four large, controlled trials have shown digoxin to be of benefit in patients with heart failure and sinus rhythm [1]. Digoxin is therefore an adjunct to diuretics and angiotensin-converting enzymes [4].

Digoxin and digitoxin are the two glycosides mainly used, the former due to its more rapid elimination in case of intoxication [5]. Prospective toxicity studies with digoxin showed adverse effects similar to placebo [1], compared with 5.8% of digitoxin users [61. Digitoxin has a more stable absorption [7] and its elimination is not changed by reduced liver or kidney function [8-10].

The serum concentrations of digitoxin (but not digoxin) can be predicted from daily intake of the drug related to body weight [11]. An intake of digitoxin of 0.05 mg/day is considered unlikely to give serum concentrations high enough to cause toxicity. This study shows that low doses of digitoxin in elderly subjects can result in increased serum concentrations and cause digitalis intoxication.

Materials and methods

Patients

The patients were admitted consecutively with an acute illness from homes or institutions to the geriatric unit at Aker Hospital over 2 months with a primary diagnosis of stroke (patients 3, 5 and 6), cardiac failure (patients 1, 2 and 4). The inclusion criterion was symptomatic digitalis intoxication [5] when on 0.05 mg/day digitoxin. Serum digitoxin concentrations were measured on admission. The patients with increased digitoxin concentrations were not given specific treatment to increase digitoxin elimination. Their serum digitoxin concentrations were usually measured weekly until they returned to normal. No drug known to interact with digitoxin was taken by any patient.

Methods

Serum sodium, potassium, creatinine, albumin and magnesium concentrations were analysed by a Hitachi 717 multianalyser (Boehringer-Mannheim, Mannheim, Germany). Serum digitoxin was analysed in the Clinical Chemistry Department of Ullevaal University Hospital, Oslo by TDx/TDxFlx Digitoxin assay (Abbott Laboratories, Abbott Park, IL, USA) which gives a suggested therapeutic range of 10-30 ng/ml (15-40 nmol/l) [12]. The slope of the digitoxin elimination curve was calculated by linear regression by the data program Enzfit (Robin Leatherborrow, Cambridge, UK) and the half-life calculated from this curve.

Results

Patients had a mean age of 86.5 [ or -] 5.9 years and moderately increased serum creatinine concentrations (Table 1). Serum digitoxin concentrations were high or well above the usual therapeutic range (10-30 ng/ml) and all the subjects had reduced serum albumin concentration. The digitoxin/albumin ratio ranged from 0.80 to 1.93. Three patients had weights in the normal range, two had reduced weights. One patient had reduced serum magnesium and two had slightly reduced serum potassium concentrations. During the period of discontinuation of digitoxin, the patients recovered from general weakness or gastrointestinal symptoms. None of the patients had cardiac arrhythmia. The digitoxin concentrations decreased slowly, with a mean half-life of 25.2 [ or -] 9 days (Figure 1 and Table 1).

Table 1. Clinical characteristics and laboratory
findings in elderly subjects with delayed elimination
of digitoxin

                               Serum concentration

Case   Age         Weight      Albumin   Creatinine
no.    (years)     (kg)        (g/l)     ([micro] mol/l)

1      93          52          32        83
2      90          39          35        87
3      89          45          28        109
4      88          42          29        117
5      82          66          30        116
6      77          60          30        144
Mean   86.5        50.7        30.7      109
SD     5.9         10.7         2.5       22

                   Digitoxin
Case   Digitoxin   half-life   D:A       Condition
no.    (ng/ml)     (days)(a)   ratio     improved

1      26          12          0.81      Nausea
2      28          18          0.80      Diarrhoea
3      45          29          1.60      Anorexia
4      30          25          1.04      Anorexia
5      33          37          1.11      Weakness
6      58          30          1.93      Anorexia
Mean   36.7        25.2        1.2
SD     12.4        9           0.5

Case
no.    Comments

1
2
3      [K.sup. ], 3.2; [Mg.sup.2 ], 0.62
4      [K.sup. ], 3.4; [Mg.sup.2 ], 0.68
5
6
Mean
SD

(a) Reference value: 6.7 [ or -] 1.2 [5].

D:A, digitoxin:albumin.

Discussion

The mean half-life of digitoxin in our patients was much longer than that previously reported (6.7 [ or -] 1.7 days) [5]. Such a prolonged half-life may lead to accumulation and increased serum concentrations even on a low dose of the agent. A high intake of digitoxin before hospitalization could possibly explain the increase in digitoxin concentrations, but this explanation is unlikely, due to the very slow elimination of digitoxin observed in our patients while in hospital.