Drugs 20: 494-499 (1980) 0012-6667 /SO/ 1200-0494/$01.50/0 @ ADIS Press Australasia Pty Ltd. All rights reserved.

Digoxin Dose Precision: Prescribing·Aids or Intuition?

G.D. Johnston Depanment of Therapeutics and Pharmacology, The Queen's University of Belfast, Nonhem Ireland

The dose of digoxin required to produce optimum therapeutic effect varies widely between patients. The recommended standard dose produces little effect in some patients, toxicity in others, and satisfactory results in a few. The inability of standard dosage regi­mens to produce an appropriate pharmacological effect in many patients tends to be interpreted as therapeutic ineffectiveness. On the other hand, digo­xin toxicity is often caused by failure to reduce the standard dose appropriately in other patients. These variations are largely due to pharmacokinetic factors, but pharmacodynamic factors are also important (table I).

1. Pharmacokinetic Considerations

1.1 Bioavailability

Bioavailability covers 2 aspects of drug absorption into the systemic circulation - the rate of absorption and the total amount which is absorbed. These two aspects of absorption are often but not always related. The advantage of the term is in emphasising that the way a drug reaches the tissues is dependent on both the route of administration and on the drug formula­tion.

1.1.1 Formulation One of the most important contributions of

plasma digoxin levels has been to demonstrate that the absorption of digoxin can be greatly influenced by its pharmaceutical formulation. 8 years ago it was reported that tablet preparations containing the same amount of drug produced different concentrations in the plasma of the same individuals, and when patients were changed from a slowly absorbed to a rapidly ab­sorbed preparation there was a 2896 increase in the mean steady-state digoxin level. Of the 91 patients studied, 6 developed signs of digoxin toxicity and the control of the ventricular rate in atrial fibrillation im­proved in 14 (Redfors et aI., 1973). Standard dissolu­tion rate tests are now in use in Britain and elsewhere and have become important facets of digoxin manufacturing quality control. For individual sub­jects the amount absorbed is about 7096 and remains constant during chronic administration if tablets of uniform dissolution are used. Important interin­dividual differences do, however, occur.

1.1.2 Absorption In high bioavailability forms, digoxin taken by

mouth is rapidly absorbed in the fasting patient. Peak plasma concentrations occur 0.5 to I hour after oral administration, and little time is saved by giving the

Digoxin Dose Precision: Prescribing Aids or Intuition?

drug intravenously. Intramuscular injections should be avoided as they result in slower absorption and cause pain due to local muscle necrosis. Absorption is reduced in malabsorption syndromes but no relation­ship appears to exist with the degree of steatorrhoea. If slowly dissolving preparations are used, changes in intestinal motility affect steady-state plasma con­centrations so that anticholinergic drugs increase and metoclopramide decreases steady-state levels. Other drugs which have been shown to impair digoxin ab­sorption include neomycin and some antacid prepara­tions.

I. 2 Distribution

Following intravenous ~ministration, the plasma digoxin level falls rapidly due to tissue distribution. Although plasma protein binding is slight, binding to tissue proteins is extensive and none of the drug ap­pears to be deposited in fat. Thus, only a small amount of a given dose remains in the plasma after distribution is complete, resulting in a large apparent volume of distribution. The clinical importance of the volume of distribution is that it determines the load­ing dose. Unfortunately, there is wide variation in the value of this term ranging from 420 to I 026L in nor­mal individuals to as low as 200L in patients with renal failure. This results in a 5-fold variation in the appropriate loading dose. Other factors which appear to alter the volume of distribution include thyroid disease, serum potassium concentration, and con­comitant administration of quinidine.

1.3 Clearance

Digoxin is principally cleared by the kidney. Glomerular filtration is the main excretory mechan­ism, but a small amount is subject to tubular secre­tion and reabsorption. For patients with normal renal function the plasma half-life is about 1.6 days, but may be as high as 4.4 days in patients with renal failure. Between these 2 extremes, Jelliffe (1971)

Table I. Factors modifying digoxin effect

1. Pharmacokinetic factors a) Bioavailability

formulation route of administration malabsorption intestinal motility drugs - neomycin/antacids

b) Distribution renal failure thyroid disease serum potassium quinidine

c) Clearance renal failure increased metabolism thyroid disease

2. Pharmacodynamic factors a) Electrolyte status b) Age c) Thyroid disease d) Hypoxaemia e) Myocardial ischaemia

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postulated a direct relationship between digoxin elimination and creatinine clearance, and it was on this assumption that much of the nomogram prescribing is based. Less than 1/3 of a digoxin dose is metabolised to both active and inactive metabolites. Variations in metabolism tend to have little effect on digoxin prescribing except in a small group of patients who are able to tolerate very high doses of digoxin because of extensive metabolism to an inactive meta­bolite, dihydrodigoxin. Digoxin clearance is increased in hyperthyroidism and reduced in hypothyroidism.

2. Pharmacodynamic Considerations

2.1 Definition of Therapeutic Effect

The establishment of an adequate therapeutic effect with digoxin is often difficult. In atrial fibrilla­tion the slowing of the ventricular rate is a useful, if

Digoxin Dose Precision: Prescribing Aids or Intuition?

fallible, guide to the adequacy of digoxin therapy. In sinus rhythm, when the drug is being given for its in­otropic effect, the situation is more difficult to assess. The slight slowing of the heart rate due to increased vagal tone is often obscured by other effects on the sinus node, and in this situation (unlike the slowing seen in atrial fibrillation) the effect on heart rate is not a useful guide to therapy. The beneficial effects of digoxin in heart failure are often difficult to assess because of other variables in therapy such as bed rest and diuretics and the fact that no useful bedside method is available to measure inotropic effect. In ad­dition, the inotropic effect of digoxin is often slight and difficult to demonstrate on continued therapy Oohnston and McDevitt, 1979).

2.2 Factors Modifying Digoxin Effect

One of the most important and easily identifiable factors accounting for variation in response in patients with the same plasma digoxin concentration is the electrolyte status. Hypokalaemia and hypomag­nesaemia increase the toxic effects of digoxin and there is experimental evidence to suggest that hy­ponatraemia and hypercalcaemia both increase tox­icity. Other factors which have been cited as being responsible for increased susceptibility to digoxin in­clude old age, hypothyroidism, hypoxaemia, and changes in acid-base balance. A recent myocardial in­farction and severe myocardial ischaemia are also said to increase digoxin toxicity, while patients with a nor­mal myocardium who take digoxin in overdose often tolerate high concentrations without adverse effect.

3. Prescribing Aids

It is clear from the previous discussion that prescribing the correct digoxin dose for an individual patient is difficult. In recognition of this, various prescribing aids have been developed in the form of nomograms, computer programs, equations and scor­ing systems. The application of predictive phar-

496

macokinetics, based on data obtained from patient populations is associated with problems caused by in­dividual differences in pharmacokinetics and cardiac responsiveness. For most of the prescribing aids, pharmacodynamic factors are ignored and 2 main assumptions made - that lean body weight is useful in determining loading dose, and that the correct maintenance dose can be calculated using measures of renal function. The main limitation of digoxin prescribing aids would appear to be the wide variation in the apparent volume of distribution which is reduced in patients with renal failure, in the elderly and in patients with hypothroidism, and increased in infants and in patients with hyperthyroidism. Body weight (including lean body weight), and other measures of body size, correlate poorly with the ap­parent volume of distribution, a fact which par­ticularly limits those aids in which maintenance doses are calculated from the loading dose.

With all the prescribing aids, the main indicator of dosage for maintenance digoxin therapy is renal func­tion, using either serum creatinine or creatinine clearance. To use the relationship between creatinine and digoxin clearance one must assume that the drug is not subject to secretion or reabsorption. As·will be clear from the section on digoxin pharmacQkinetics, this is untrue. In addition, Dobbs et al. (1977) found that calculation of individual doses from creatinine clearance had little effect on their ability to achieve a chosen serum digoxin concentration. It would appear that variations in renal function contribute only partly to the wide variation in steady-state plasma concentrations. Calculation of creatinine clearance from the serum creatinine also produces an additional source of error, especially the relationship used by JeUiffe (1971) which takes no account of age and is limited to creatinine clearance values less than SOml/ minute. Other factors which limit the accuracy of nomogram prescribing include variations in ab­sorption and metabolism, cardiac (e.g. myocardial ischaemia) and extracardiac abnormalities (e.g. hy­pokalaemia and thyroid disease) influencing end organ responsiveness and other drugs (e.g. quinidine and spironolactone). Most studies which have looked

Digoxin Dose Precision: Prescribing Aids or Intuition?

at the ability of prescribing aids to improve digoxin prescribing have resulted in negative conclusions. For example, when Peck et al. (1973) used a computer to assess the digoxin dosage necessary to achieve a con­centration of I ng/ ml, the computer could only assure that the resulting value would lie between 0.0 and 2.1 ng/ ml, or from 'subtherapeutic' to potentially tox­ic. In another study by Wagner et al. (1973), the com­puter was only marginally better at predicting serum digoxin concentrations than physicians knowledge­able in digoxin pharmacokinetics, and was similar to predictions based on dosage alone disregarding body size and renal function. In a more recent study it was shown that despite the development of further prescribing aids the situation has remained unaltered (Johnston et al., 1979). In fact, many of the aids were less accurate than intuitive prescribing by physicians. Because of this, and the fact that many of the methods are complicated and time-consuming, requiring infor­mation difficult to obtain in general practice, none of the aids can be recommended for routine prescrib­ing.

4. Therapeutic Guidelines

The simple answer to the question posed at the beginning of the article is that neither prescribing aids nor intuitive prescribing result in accurate digoxin prescribing. However, improved prescribing is pos­sible by combining knowledge of digoxin pharmaco­kinetics and factors which alter pharmacodynamic responses, and by using plasma concentrations com­bined with clinical assessment (table 11).

4.1 Route of Administration

Since the drug is rapidly absorbed froni the gastro­intestinal tract, the oral route should be used when possible. If the patient is unable to take the drug orally or if extremely rapid digitalisation is required, then slow intravenous infusion of the undiluted solu­tion (213 of the calculated oral dose) should be used.

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Tllble II. Summary of therapeutic guidelines for digoxin administration

1. Use oral route if possible. If rapid digitalisation is required use 2/3 of oral dose intravenously

2. Choose a preparation of known bioavailability and do not change the brand

3. For normal individuals a loading dose of 0.75 to 1.5mg is usually correct. For those with reducad apparant volume of distrubution. decrease to 0.25-O.75mg. Give in divided doses 6 to 8 hours apart and check for toxicity before each dose

4. Give 0.25mg digoxin for normal indivkluals and decrease to 0.125mg in patients with reduced clearance

5. Monitor therapy through clinical observation and critical use of steedy-state plasma digoxin concentrations

For the reasons stated previously, (section 1.1.2) the intramuscular route should be avoided.

4.2 Choice of Preparation

An oral preparation of known and consistent bioavailability should be chosen and changes from one brand of digoxin to another avoided. For the ma­jority of patients tablet sizes of 0.125mg and 0.25mg are suitable for maintenance therapy, even for elderly patients with impaired renal function, the 0.0625mg dose usually being inadequate.

4.3 Loading Dose

A loading dose between 0.75mg and l.Smg is sufficient for the majority of patients who are not elderly, have normal renal and thyroid function, whose electrolyte status is normal and using tablets of 70% bioavailability. Such a loading dose involves a low risk of toxicity provided the drug is given in divided doses about 6 hours apart and the patient ob­served for early signs of toxicity before each ad­ministration. For patients with renal failure, hy-

Digoxin Dose Precision: Prescribing Aids or Intuition?

pothyroidism, hypokalaemia and in the elderly in whom digitalisation is considered necessary, a range of 0.25 to 0.7 5mg would seem to be more appropri­ate. Reduction of the loading dose by 50 % is proba­bly also required in patients already taking quinidine therapy. If digoxin therapy is not urgent, then the loading dose can be omitted and the patient started on maintenance therapy. Monitoring treatment is then more difficult, however, because toxicity tends to oc­cur later.

4.4 Maintenance Dose

It would appear from the previous discussion that knowledge of the serum creatinine or creatinine clearance dose not result in more accurate mainte­nance dose selection. Indeed, it was apparent from our data (Johnston et al., 1979) that a maintenance dose of 0.25mg was just as likely to result in plasma concentrations within the range 0.8 to 2.0ng/ml in individual patients as those chosen by prescribing aids. I would therefore suggest starting the patient on a maintenance dose of 0.25mg and reducing this dose by 50 % in the elderly or uraemic patient, and those with hypokalaemia and myxoedema. Similar reduc­tions are required in patients with severe myocardial ischaemia and those already taking quinidine therapy. If the therapeutic response is considered adequate and the patient does not exhibit clinical evidence of tox­icity for a period of a week, then no further action is required except in patients with severe renal impair­ment when a follow-up period for toxicity of 2 to 3 weeks may be required. If therapeutic response is considered inadequate or difficult to assess, a steady­state plasma digoxin concentration should be obtained after 4 to 5 half-lives (Usually I to 2 weeks) and the dose adjusted to obtain a plasma concentration in the middle of the therapeutic range using the linear rela­tionship between dose and concentration at steady­state:

Previous dose x 1.5 New dose

Plasma cone. (ng/mI) (Calculated to the nearest multiple of 0.125mg).

(Eq. I)

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In some situations, particularly in patients with fast atrial fibrillation, this dose may need to be ex­ceeded and concentrations greater than 2.0ng/ml re­quired to produce adequate control of ventricular rate. If toxicity is suspected, a plasma concentration should be obtained at least 6 hours after the previous dose, and the drug withdrawn until the signs and symptoms of toxicity have abated and the patient's plasma concentration is in the lower therapeutic range. A 50 % reduction in maintenance dose will usually be adequate, but further dose adjustment may be required.

5. Conclusion

There would seem to be little evidence that prescribing aids result in more accurate dosage deter­mination in digoxin prescribing. However, by careful assessment of the patient's clinical condition and the factors which modify digoxin response, by choosing a preparation of uniform bioavailability, and by being aware of between-patient variation in pharmaco­kinetics and of drugs which alter plasma digoxin con­centrations, more accurate initial intuitive prescribing of digoxin should be possible. Provided patient com­pliance can be ensured, dose adjustment using careful clinical observation and critical use of plasma digoxin concentrations should further increase digoxin dose precision.

References and Further Reading

Aronson, J.K.: Monitoring digoxin therapy: Ill. How useful are the nomograms? British Journal of Clinical Pharmacology 5: 55-64 (J 978).

Dobbs, S.M.; Rodgers, E.M.; Kenyon, W.I.; Uvshin, D.; Slater, E. and Godsmark, B.: Digoxin prescribing in perspective. Bri­tish Journal of Clinical Pharmacology 4: 327-335 (J 977).

Doherty, J.E. and Kane, U.: Clinical pharmacology of digitalis glycosides. Annual Review of Medicine, Grege, W.P. et al. (Eds.), pp.1 59-171 (Annual Reviews Incorporated, Palo Alto 1975).

Jelliffe, R.W.: Factors to consider in planning digoxin therapy. Journal of Chronic Disease 24: 407-409 (J 97 J).

Digoxin Dose Precision: Prescribing Aids or Intuition?

Johnston, G.D. and McDevitt, D.G.: Is maintenance digoxin necessary in patients with sinus rhythm? Lancet I: 567-570 ()979).

Johnston, G.D.; Harron, D.W.G. and McDevitt, D.G.: Can digoxin prescribing be improved? A comparison between in­tuitive and assisted dose selection. European 'Journal of Clini­cal Pharmacology 16: 2,29-235 () 979).

Peck, C.C.; Sheiner, L.B.; Martin, C.M.; Combs, D.T. and Melmon, K.L.: Computer assisted digoxin therapy. New Eng­land Journal of Medicine 289: (9) 441-446 () 973).

Redfors, A.; Bertler, A.; Nilsen, R. and Wettre, S.: Changing a population from one digoxin preparation to another; in Stors-

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tein (Ed) Digitalis, pp.390-395 (Oslo GlyndendaJ Norsk Forlag, Oslo 1973).

Wagner, J.G.; Yates, J.D.; Willis, P.W.; Sakmar, E. and Stoll, R.G.: Correlation of plasma levels of digoxin in cardiac patients with dose and measures of renal function. Clinical Pharmacology and Therapeutics 15: 291-30 I () 973).

Author's address: Dr G.D. Johns/on. Department of Thera­peutics and Pharmacology, Whitla Medical Building, 97 Lisburn Road, Belfas/ BT97BL (Northern Ireland).