C. J. A. O'neill

Serum concentration monitoring of cardiac glycosides : how helpful is it for adjusting dosage regimens ?

The first question to be asked when considering the helpfulness of therapeutic drug monitoring of cardiac glycosides is whether the target concentration is known. What concentrations are optimal for achieving efficacy, both in relation to controlling ventricular rate in patients with atrial fibrillation and in treating congestive cardiac failure (CCF), and for avoiding both cardiac and extracardiac manifestations of toxicity? Given such knowledge, the point for consideration is whether monitoring is of general usefulness, useful only in subgroups of patients or of no practical use. Factors which may contribute to variability in the measured serum digoxin concentration need to be considered. These include the formulation, the assay itself, the timing of the sample in relation to the dosage interval, patient compliance, the effects of exercise and diet on the serum concentration and, again, whether there are groups of patients particularly prone to variability or unpredictability in concentration. These questions are addressed below_

Therapeutic drug monitoring of digoxin: help or hindrance?

SummaryA major role of therapeutic drug monitoring services is to advise on the dose of a drug which would be required to bring the concentration in the blood to within specific ‘therapeutic’ limits. Monitoring digoxin usage constitutes a substantial part of the work load.We have examined the potential variability in recommendations for digoxin dosages based on a series of serum digoxin measurements in each of 80 out-patients.In over a third of cases a dose, which seemed to be optimal on the basis of the first assay result, would have produced concentrations outside the conventional therapeutic range when the measurement was repeated. This was despite careful supervision of medication and the timing of the blood sample in relation to its administration. In routine practice the apparent variability in dose requirements would be far greater.Objectives of therapeutic drug monitoring services remain the same, the way forward would seem to lie in their taking on a heavy commitment to counsel and supervise patients before repeated blood sampling. However, effort and resources might be better channelled into producing simple prescribing aids relating the risk of cardiotoxicity directly to the size of the maintenance dose and the individuals renal function.

Evaluation of the safety of enalapril in the treatment of heart failure in the very old

SummaryWe have introduced enalapril, in doses equal to or less than the 2.5 mg currently recommended, as an adjuvant to digoxin and diuretics in 17 patients of mean (SD) age 83 (5) years with severe heart failure. Only eleven patients tolerated its introduction. Unlike those reported in younger patients, all but one of the adverse drug reactions occurred 8 h or more after the first dose. Aged patients started on ACE inhibitors should be observed in hospital until stabilized on a maintenance dose. Three patients had an adverse reaction which differed in nature from those previously reported: acute confusional state, ataxia and mesenteric ischaemia.Ten patients were discharged on 5 mg or 10 mg maintenance doses of enalapril. In nine of them improvement on triple therapy was sustained for a minimum of three months. ACE inhibition was lost in the other patient when her compliance with enalapril therapy fell to around 75%: monitoring compliance is essential when ACE inhibitors are used in low dosages.Enalapril was withdrawn during follow up in three patients because of symptoms of mesenteric ischaemia and in four because of dramatic deterioration of renal function. One of the latter was found subsequently to have severe bilateral atheromatous renal artery stenosis. When isosorbide dinitrate was substituted for enalapril, symptoms of mesenteric ischaemia resolved and renal function returned to baseline. Continuing surveillance for adverse effects is essential in patients of this age group with severe heart failure, and the risk of occult renal artery stenosis requires regular biochemical screening during follow up.The benefit to cost ratio of ACE inhibitors might be improved in aged patients by their use at an earlier stage in the natural history of heart failure, when perfusion of essential organs is not grossly impaired, but carefully monitored trials would be necessary to establish this.

Prescribing digoxin in geriatric units: The unexplained variability in dosage requirements

SummarySome physicians regard patients of Geriatric Units as a homogeneous population with respect to digoxin dosage requirements. Others advocate the use of pharmacokinetic models in prescribing digoxin for the elderly.Sixty in-patients of Geriatric Units were studied and the results compared with those previously obtained from 129 patients of other adult Units; all were receiving maintenance digoxin.For each patient the dose required to achieve a mean steady-state serum digoxin concentration of 1.6 nmol·l−1, the standardized dose, was calculated, assuming proportionality between the dose given and the concentration achieved. A mean of four estimates of standardized dose for each individual was used in the analysis.Threefold ranges of standardized dose covered the requirement of approximately 85% of patients both of Geriatric Units (62.5 to 187.5 μg per day) and of other adult Units (125 to 375 μg per day).The variables, serum creatinine concentration, sex, age, and body weight were of relatively little value in predicting the standardized dose for the patients in Geriatric Units. There was a sub-group of these in-patients for whom the standardized dose was extremely large.

Objective evidence for tolerance, against a background of improvement, during maintenance therapy with controlled release levodopa/carbidopa.

SummaryWe have investigated whether the potential benefits of a controlled release formulation of levodopa (200 mg)/carbidopa (50 mg), Sinemet CR, are realised during maintenance therapy.Eight sufferers from idiopathic Parkinsonism, mean age 69.9 y, were studied: all exhibited “end of dose” effect within 4 h of a dose of their maintenance therapy with levodopa (100 mg)/carbidopa (25 mg) in a conventional release formulation, Sinemet Plus. They received, in random order, initial single dose challenges with one tablet of Sinemet Plus, one and two tablets of Sinemet CR and placebo alone, each on a separate day. After a mean of 21 weeks on maintenance therapy with Sinemet CR, subsequent single dose challenges with Sinemet CR and placebo were made. Objective measures of performance and blood sampling for assay of plasma concentrations of levodopa and the major peripheral metabolite, 3-0-methyldopa (30MD) were carried out immediately before (10.00 h) and serially until 6 h after each challenge.The overall mean stride length was significantly greater in relation to the subsequent (679 mm) than the initial (517 mm) placebo challenge. Moreover, stride length immediately before the challenges was significantly greater on the subsequent occasions. Improved performance, also seen for free walking speed, was not explained by plasma levodopa or 30MD concentrations.In the initial challenges, the mean increment in stride length achieved by active treatment, as compared with placebo, did not differ significantly between the one (210 mm) and two (235 mm) tablet doses of Sinemet CR: a maximal response had been obtained. The increment over placebo values following two active tablets did not differ significantly between initial and subsequent (192 mm) challenges. However, the increment produced by one active tablet in the subsequent (79 mm) challenge was significantly less than that produced by two, and than that which had been produced by one tablet in the initial challenge. Findings for free coalting speed mirrored those for stride length. These differences could, in part, be accounted for by attenuation of the effect of levodopa by 30MD.The improvement in baseline performance, in relation to the subsequent challenges, possibly resulted from striatal dopamine stores being more replete during maintenance therapy with the controlled release formulation. It was seen despite evidence of tolerance to an acute challenge with the lower dose.

Effect of duration of levodopa/decarboxylase inhibitor therapy on the pharmacokinetic handling of levodopa in elderly patients with idiopathic Parkinson's disease

SummaryWe address, from a pharmacokinetic viewpoint, the important question of why some patients with clinical idiopathic Parkinsons disease experience a fall off in benefit from levodopa maintenance therapy.Thirteen such patients, of mean age 78 y, without overt fluctuations in motor control in temporal relation to dosing with a levodopa/decarboxylase inhibitor combination, were studied. Levodopa (currently 400 to 800 mg daily) had been started at between 61 and 81 y of age, the mean duration of therapy being 54 months. Plasma concentrations of levodopa and its peripheral metabolite, 3-0-methyldopa, were measured before a morning dose of levodopa (100 mg)/carbidopa (25 mg) and at hourly intervals for 6 h after.There was a significant negative regression between duration of levodopa therapy (but not age or severity of disease) and the area under the plasma concentration/time curve (AUC) for levodopa attributed to the test dose. A significant negative regression was also seen of duration of therapy on the dose absorbed per unit distribution volume, but not on the elimination rate constant, indicating a decrease in bioavailability and/or an increase in distribution volume with duration. There was a tendency for the plasma 3-0-methyldopa concentration, standardised for daily dose, [30MD], to increase with duration of therapy. Although, the regression of duration on [30MD] did not reach statistical significance, that on the ratio, [30MD]/AUC, did so at the 0.01 level.The amount by, and time for which, the plasma levodopa concentration exceeds any critical threshold for the competitive active uptake process into the brain may thus decrease with duration of therapy. This may explain in part the limited reversal of the neurological deficit, which is more typical of later onset Parkinsonism, and, possibly, the decrement in biological half time with duration of therapy, typical of early onset disease. 3-0-Methyldopa is known to compete for active uptake with levodopa; the ratio, [30MD]/AUC, may be a measure of this competition. Intrinsic activity of neuronal uptake mechanisms, capacity of the basal ganglia for storage of dopamine, and post synaptic neuronal activity may, of course, also be determinants of clinical outcome.

PRESCRIBING DIGOXIN IN GERIATRIC UNITS–EXERCISE AND REDISTRIBUTION OF DRUG

In subjects capable of normal everyday activity, exercise has been shown to lower the serum digoxin concentration by increasing uptake into skeletal muscle. A randomized cross‐over study of the effect on the serum digoxin concentration of treatments consisting of rest for, or exercise during, 30 min was carried out in 20 elderly patients undergoing rehabilitation. In one patient exercise was associated with a marked (40%) reduction in the serum digoxin concentration. In the remainder there was a very small, but statistically significant, fall in concentration in the exercise as compared with the rest period. Unexpectedly low serum digoxin concentrations in in‐patients of geriatric units, may occasionally be an artefact due to temporary redistribution of digoxin.