DIGOXIN THERAPY: TEXTBOOKS, THEORY AND PRACTICE

Transcription

1 Br. J. lin. Pharma. (1976), 3, DIGOXIN THERAPY: TEXTBOOKS, THEORY AND PRACTICE J.K. ARONSON & D.G. GRAHAME-SMITH MRC Unit and University Department of Clinial Pharmaology, Radliffe Infirmary, Woodstok Road, Oxford OX2 6HE 1 Reommendations for orret therapy with digoxin from twenty-five soures are reviewed. 2 Some reommendations may be unsuitable for use with high bioavailability tablets; some are aompanied by insuffiient data relating to fators affeting both the response to digoxin and its handling by the body. 3 Guidelines based on pharmaokineti and pharmaodynami priniples are suggested to help deide optimal digoxin treatment shedules in the presene and absene of non-ardia disease. Introdution Now that digoxin tablets of uniform and high bioavailability are to be standard in the United Kingdom (Department of Health and Soial Seurity, 1975) it seemed of interest to review the dosage reommendations in a number of ommonly available textbooks of general mediine, ardiology, linial pharmaology and therapeutis. We think that some of the reommendations made in these texts may not be suitable for use with high bioavailability tablets, and that there are some inonsistenies whih need examining. Table 1 lists the reommendations from twenty-five different soures with partiular regard to the reommended loading doses and maintenane doses, to the fators whih may enhane toxiity in any patient and to some other important omments made in relation to therapy. We have omitted referenes to ontraindiations to therapy with ardia glyosides and to dosage shedules in infants and hildren, being onerned here only with the orret dosages required in adults. Only digoxin has been dealt with sine it is the most ommonly used ardia glyoside in the United Kingdom. Chiou (1975) has reently disussed the therapeuti impliations of inorret reommendations in nine soures, some of whih we have not listed in Table 1. Critique of the textbook reommendations In this setion we shall analyse the various suggestions for therapy with digoxin and shall make some statements of opinion for whih we shall give reasons in the following setions along with appropriate referenes. Loading dose The oral loading dose shedules in many of the texts ited would appear to be more suitable for use with tablets of low bioavailability; the parenteral dosage reommendations are similar and usually between.5 and 1. mg (although some exeed these values) while the oral doses reommended range from 1. to 4. mg in the first 24 h; the ratio of reommended oral to parenteral loading dose varies from about 9: 8 to 4: 1. Assuming a bioavailability of about 67% (Doherty & Kane, 1975) the intravenous dose should be about 33% less than the intended oral dose (i.e a ratio of 3 : 2). Maintenane dose Most reommendations are for.25 to.75 mg daily. Only two texts mention the possibility of a daily maintenane dose of.125 mg and none of.625 mg although some mention the fat that tablets of one or both strengths are available and some reommend lower maintenane doses in renal failure and in the elderly. Only two texts suggest that the orret maintenane dose be alulated as a perentage of the loading dose depending on renal funtion.

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4 642 J.K. ARONSON & D.G. GRAHAME-SMITH Fators whih may enhane toxiity There are serious omissions in many of the ited soures regarding fators whih may preipitate the onset of toxiity in patients who would otherwise be free of toxiity on a similar dosage shedule in the absene of those fators. Hypokalaemia, renal failure and old age are ommonly ited (although by no means always) but other eletrolyte abnormalities, hypothyroidism, and D.C. ardioversion are negleted in several texts while the diverse ardia onditions said to ause inreased sensitivity to digoxin emerge as an ill-defined group ranging from aute myoardial insuffiieny to diphtheriti myoarditis. Other omments (a) Route of administration: Only three texts orretly aution against the use of the intramusular route, and of those reommending the intravenous route for parenteral administration about half (orretly) reommend slow injetion. (b) Assessment of therapy: Some texts still seem to suggest that digoxin be administered in loading doses until toxi signs or symptoms result; ertainly if toxi manifestations our treatment should be stopped but one should not aim to produe toxiity beause toxi arrhythmias, for example, may be sudden in onset without prior symptoms and it is far better to undertreat at first than to fae the problem of established toxiity; this is espeially the ase in the presene of renal failure. Review of the linial pharmaology of digoxin To understand better the priniples of digoxin dosage it is neessary first to have an outline of its linial pharmaology. Absorption Digoxin is rapidly and, in high bioavailability forms, well absorbed from the gastrointestinal trat; peak plasma levels of the drug are attained within 4-1 hour (White, Chamberlain, Howard & Smith, 1971) and about 67% of the total drug in the tablet is absorbed (Doherty & Kane, 1975); patients with malabsorption may absorb smaller amounts of digoxin (Heizer, Smith & Goldfinger, 1971) but it has been suggested that this is due to lowered bioavailability in these patients (Hall & Doherty, 1974). Conurrent administration of some drugs (Lindenbaum, 1973; Binnion, 1973) may redue absorption. Distribution In renal failure there is a lowered apparent volume of distribution of digoxin (Koup, Jusko, Elwood & Kohli, 1975) and the available data suggest that this may also be the ase in hypothyroidism (Doherty & Perkins, 1966); this lowered apparent volume of distribution is another fator apart from dereased renal elimination of digoxin whih may result in higher plasma levels than would our following the same dose in the absene of renal failure but the signifiane of the elevation due to abnormal distribution is not fully understood. Digoxin is widely distributed throughout the tissues of the body being hiefly onentrated in the heart, kidneys, liver and skeletal musle (inluding diaphragm) (Doherty, Perkins & Flanigan, 1967); it is not, however, distributed into fat (Ewy, Groves, Ball, Nimmo, Jakson & Marus, 1971). Binding to plasma proteins does not play a very important part in the distribution of digoxin. Metabolism Usually only a small amount of digoxin is onverted to metabolites, both ative and inative (Doherty & Kane, 1975), although individuals may differ widely in the degree to whih they metabolize the drug (Clark & Kalman, 1974). There is no impairment of metabolism in ongestive ardia failure (Marus, Kapadia & Kapadia, 1964) or hypothyroidism (Doherty & Perkins, 1966) although there may be some inrease in metabolism in renal failure (Marus, Peterson, Salel, Sully & Kapadia, 1966). Exretion Eighty per ent of an administered dose of digoxin is exreted in the urine unhanged in 7 days (Doherty & Perkins, 1962); glomerular filtration is the hief mehanism of this exretion although a small amount is subjet to both tubular seretion (Steiness, 1974) and re-absorption (Halkin, Sheiner, Pek & Melmon, 1975). The half-time of elimination (T_) of digoxin from the plasma is about 1.6 days and in renal failure this value may inrease up to 4.4 days (Jelliffe, 1968)-the latter value applies to omplete anuria when about 14% is eliminated daily by extra-renal (prinipally hepati) mehanisms, about 6.5% being normally subjeted to enterohepati reyling (Doherty, Flanigan, Murphy, Bulloh, Dalrymple, Beard & Perkins, 197). The fall in renal learane orrelates linearly with the deline in reatinine learane. In patients with hypothyroidism and normal blood urea nitrogen the exretion rate and

5 DIGOXIN THERAPY 643 plasma T7 do not seem to be altered (although some publiations have erroneously stated that they are); however, plasma onentrations of digoxin in hypothyroidism are higher than in euthyroid patients, the rate of elimination from plasma (ng ml-l min- ) probably being kept onstant by a derease in true renal plasma learane (ml/min) (Doherty & Perkins, 1966). Pharmaodynami onsiderations The patient's eletrolyte status may determine the degree of response to digoxin-thus, hypokalaemia potentiates the toxi effets of the drug in man (Jelliffe, 1971 a) as may hypomagnesaemia (Beller, Hood, Smith, Abelmann & Waker, 1974); there is experimental evidene to suggest that hyponatraemia (Harrison & Wakim, 1969) and hyperalaemia ola, Pope & Harrison, 197) may also inrease the suseptibility to toxiity. The elderly may beome toxi following doses of digoxin whih would be well tolerated by younger patients, partly beause of diminished renal funtion (Ewy, Kapadia, Yao, Lullin & Marus, 1969). Patients with hypothyroidism are more sensitive to digoxin but whether this is due to high plasma levels or to truly inreased pharmaologial sensitivity to the drug is not known. Plasma level measurement It has been well doumented in numerous studies (for referenes see Smith, 1975) that plasma or serum digoxin level measurements are useful in distinguishing between toxi and non-toxi patients in the absene of sensitizing fators suh as hypokalaemia. There is a wide range of non-toxi plasma levels usually varying from to 3 ng/ml and sometimes being as high as 5 ng/ml, but inidene of toxiity begins to inrease at levels greater than 1.5 ng/ml (Smith & Haber, 197). Therapeuti guidelines It is unwise to be dogmati and advise universal dosage regimens of any drug and partiularly one with a low toxi: therapeuti ratio suh as digoxin. However, it is important to lay down some guidelines along whih a deision may be taken. Route of administration Beause of its rapid absorption the oral route is the route of hoie. If, for some reason (vomiting, oma, et), the patient is unable to take an oral dose or if extremely rapid digitalization is desired, then slow intravenous infusion (over about 5 min) of the undiluted solution (e.g. digoxin injetion, BP,.25 mg/ml) is the best hoie; the intramusular route should be avoided if possible-it is sometimes painful (Greenblatt, Duhme & Koh- Weser, 1973), has been shown to ause areas of nerosis at the site of injetion in animals (Steiness, Svendsen & Rasmussen, 1974) and may do so in man, and there is variable absorption of the drug from the site of injetion (Steiness et al., 1974) making assessment of the patient's state by plasma level measurement diffiult. Loading dose It has been shown (Kolendorf, Christiansen, Siersbaek-Nielsen & Mqlholm Hansen, 1972) that a total oral loading dose of between 1 and 2 Mg/kg body weight followed by a suitable maintenane dose results in plasma levels in the therapeuti range, and this has been our own experiene using high bioavailability tablets (unpublished observations). Loading doses in patients with normal renal and thyroid funtion, normal eletrolyte balane, and who are not elderly may be alulated on this basis. Body weight may be estimated if not known and in the obese should be orreted for lean body weight from the known or estimated weight less an amount estimated from the apparent degree of obesity. Jelliffe (1969) has suggested that suh a loading dose should be administered in three divided doses about 5 h apart; 12 pg/kg for a patient in sinus rhythm and 2 Mg/kg for a patient in atrial fibrillation resulting in total body digoxin levels of 8 and 13 Mg/kg respetively are appropriate (Jelliffe, Buell & Kalaba, 1972) and arry 5% and 9% risks of toxiity (Jelliffe, 1969). Let us say one administers suh a loading dose in three or four divided doses at 5-hourly intervals over a period of 1-15 hours. The patient would be observed for early signs of toxiity before the administration of eah dose and if no toxiity ourred the full loading dose would be given. The maintenane dose would then be based on this, presumed orret, loading dose (see below). When extremely rapid digitalization is thought neessary (as, for example, in a patient with fast atrial fibrillation and severe ardia failure) the loading dose may be given as a single dose, the need for speedy treatment outweighing the inreased risk of toxiity. There is at present some ontroversy over orret loading dose in renal failure between pharmaokinetiists, one group of whom believes in lowering the loading dose (Reuning, Sams & Notari, 1973) and one (Wagner, 1974) who believes that the loading dose should be the same as for patients with normal renal funtion

6 644 J.K. ARONSON & D.G. GRAHAME-SMITH (although the latter agrees that the reommended loading doses in the literature for patients without renal failure are too high); we have observed three patients in renal failure to whom normal or low loading doses were administered, two of whom developed frank toxiity and one equivoal toxiity. We would reommend reduing the loading dose by up to 1/2 in renal failure, augmenting the dose only if the desired therapeuti response is not ahieved. In all ases if the intravenous route of administration is hosen doses should be 33% lower than oral doses. Maintenane dose The maintenane dose should be based on the perentage of the loading dose eliminated daily, a value whih depends on renal funtion. With a reatinine learane (Clr) of 1 ml/min about 34% of total body digoxin is eliminated daily; when Clr falls to ml/min only about 14% is leared; between these two values the relationship is roughly linear and the perentage an easily be alulated from the formula: % eliminated daily Then: = 14 (Clr/5)(Jelliffe, 1969) Daily maintenane dose = Loading dose x % eliminated. Dialysis, whether peritoneal (Doherty, Perkins & Wilson, 1964) or haemodialysis (Bloom, Nelp & Tuell, 1966), removes only about 2-3% of total body digoxin and need not therefore be onsidered in deiding the orret maintenane dose. Treatment without a loading dose In some instanes it may be diffiult or the physiian may not desire to administer a loading dose. In suh ases the orret oral loading dose should be deided upon and the orresponding oral maintenane dose alulated as desribed above. This maintenane dose an then be given as a single daily dose; after about five half-times of elimination (7.5 days in a patient with normal renal funtion and 22 days in an anuri patient) a steady state will be reahed (Jelliffe, 1968). Suh an approah, however, results in a loss of ontrol over therapy if the orret alulations, as is so often the ase, are diffiult to make and, as has been illustrated by Jelliffe (1971b), may result in serious toxiity. Monitoring the patient's progress during rapid loading is the ideal, although not always attainable, means of therapy. Dobbs, Mawer, Rodgers & Woodok (1976) have devised a regression equation whih may be of use in deiding the orret dose for daily treatment: Daily dose (pg/day) = 3.56 Clr 93. It should be pointed out that one should not rely totally on Clr measurements in individual patients. Aside from the pitfalls in measuring Clr, not all patients respond in a fashion whih orresponds with the above outline and eah should be arefully observed and treated on his own merits. Nevertheless, the above approah provides a useful initial guide to therapy. Speial ases (a) Eletrolyte imbalane: There are sant data on the degree to whih eletrolyte abnormalities affet the response to digoxin but it has been estimated that a fall of plasma potassium to 3. mmol/l results in redution in digoxin requirements of about 1/3 (Jelliffe, 1971a). Should hypokalaemia our in a patient already taking digoxin it is best to stop therapy until the abnormality an be orreted or, if it is deemed neessary to ontinue, to redue the dose by 1/3. No figures are available for other eletrolytes. (b) Old age and thyroid disease: Unfortunately no data are available to enable the alulation of orret dosage regimens in these onditions. Experiene, however, seems to suggest that in the elderly and those with myxoedema the loading dose should be ut by up to o; in the elderly, unless there is ontrary evidene, renal funtion should be assumed to be diminished by 5% (Ewy et al., 1969). In thyrotoxiosis doses require to be inreased but no good guidane is available and the linial ondition must be arefully monitored. Equally important is the need to alter dosage shedules as thyroid disease is treated and requirements hange or as a patient beomes elderly while taking long-term therapy. () Cardioversion and ardia operations: It has been shown that plasma levels probably need to be lowered at least below.8 ng/ml (1. nmol/l) before ardia operations if postoperative arrhythmias due to digoxin are to be avoided (Rose, Glassman & Spener, 1975); no doubt a similar need exists where ardioversion is to be arried out but no information is available. It is therefore best if digoxin therapy is stopped at least 3 days before operation or ardioversion if neither is urgent-plasma level measurement an help deide the timing more aurately in individual ases. When ardioversion is urgent the areful tehnique outlined by Hagemeijer

7 DIGOXIN THERAPY 645 & Van Houwe (1975) may be useful in the absene of digoxin toxiity. Cardiopulmonary bypass does not affet total body digoxin levels although there is a slight fall in plasma level during operation due to haemodilution (Carruthers, Cleland, Kelly, Lyons & MDevitt, 1975). (d) Hepati disease: No hange in dosage is neessary (Marus & Kapadia, 1964; Zilly, Rihter & Rietbrok, 1975). Some theoretial examples Table 2 lists a few examples of dosage regimens whih might be adopted in different hypothetial patients. It is important to point out that it is impossible, indeed unwise, to be dogmati about suh shedules-eah patient should be judged on his own merits and there should be no hesitation i,n inreasing loading doses if the required linial response is judged not to have been attained. If reatinine learane values are not available then they an be alulated from the plasma reatinine ( mg%) using the nomogram of Siersbaek-Nielsen, Molholm Hansen, Kampmann & Kristensen (1971) or from Jelliffe's (less aurate but handier) formulae (for values below 5 ml/min): Clr (men) = 1/ -12 Clr (women) = 8/ - 7 (Jelliffe, 197 lb) Aids to deiding dosage shedules It is not our intention to disuss the use of plasma level measurements in monitoring digoxin therapy-this has been done elsewhere (Smith, 1975; Aronson, 1975); suffie it to say that digoxin assay servies have been shown to help in reduing toxiity in hospital populations (Jelliffe, 1969; Duhme, Greenblatt & Koh-Weser, 1974). Nomograms have been developed as a bedside aid in adult euthyroid patients in normal eletrolyte balane (Jelliffe & Brooker, 1974; Dettli, Spring & Ryter, 1971) although in pratie their use may be limited (Dobbs et al., 1976), and where omputer assistane is available it has been shown to be able to aurately predit serum digoxin levels in individual patients (Sheiner, Halkin, Pek, Rosenberg & Melmon, 1975). Where these aids are available the physiian's task may be made muh easier. Most important of all, however, is the physiian's own understanding of the problems involved-a reent eduational programme has shown that the inidene of toxiity in a suseptible hospital population an be redued without the aid of plasma level measurements (Ogilvie & Ruedy, 1973). Conlusion We are not unaware of the real nature of medial pratie. The areful onsideration of digoxin dosage regimens and their appliation by areful monitoring of the individual patient's linial state may not always be possible. Exessive use of plasma digoxin measurement would be ostly and in many instanes not pratial or even indiated. Moreover, the largely pharmaokineti approah outlined above takes into aount preditable plasma and tissue onentrations only, there being little information on pharmaologial methods of monitoring the tissue response to digoxin. In every ase the response of the individual patient must be Table 2 Approximate suggested doses of digoxin in different linial onditions* * See text for disussion Age Weight Renal funtion (years) (kg) Reason for Loading Daily treatment dose (mg) * maintenane dose (mg) * 5 7 Normal Cardia failure Clr = 5 Cardia failure Normal AF Assumed 5% Cardia failure Clr= Clr= Cardia failure AF /.625 alternate days 42

8 646 J.K. ARONSON & D.G. GRAHAME-SMITH the hief guide to therapy. However, when in pratie one is fored to deviate from the ideal the theoretial onsiderations still apply, ating as guidelines on whih reasonable assumptions an be made and enabling one to treat patients with maximal effiay and minimal risk of toxiity. Referenes ARONSON, J.K. (1975). The appliation of digoxin radioimmunoassay in monitoring drug therapy. In Radioimmunoassay in Clinial Biohemistry, ed. Pasternak, C.A., pp Heyden. BELLER, G.A., HOOD, W.B. Jr., SMITH, T.W., ABELMANN, W.H. & WACKER, W.E.C. (1974). Correlation of serum magnesium levels and ardia digitalis intoxiation. AnL J. Cardiol., 33, BINNION, P.F. (1973). Absorption of different ommerial preparations of digoxin in the normal human subjet, and the influene of antaid, antidiarrhoeal and ion-exhange agents. In Symposium on Digitalis, ed. Storstein,. pp Gyldendal Norsk Forlag. BLOOM, P.M., NELP, W.B. & TUELL, S.H. (1966). Relationship of the exretion of tritiated digoxin to renal funtion. An. J. med. Si., 251, CARRUTHERS, S.G., CLELAND, J., KELLY, J.G., LYONS, S.M. & MDEVITT, D.G. (1975). Plasma and tissue digoxin onentrations in patients undergoing ardiopulmonary bypass. Br. Heart J., 37, CHIOU, W.L. (1975). Potential problem in digoxin therapy due to variation in reommended dosage regimens. J. lin. Pharma., 15, CLARK, D.R. & KALMAN, S.M. (1974). Dihydrodigoxin: A ommon metabolite of digoxin in man. Drug Metab. Disp., 2, DEPARTMENT OF HEALTH AND SOCIAL SECURITY (1975). Cirulars DDL (75) 1 Digoxin tablets BP, DDL (75) 2, CPH (75) 4 Digoxin tablets BP-Reminder. DETTLI, L., SPRING, P. & RYTER, S. (1971). Multiple dose kinetis and drug dosage in patients with kidney disease. Ata Pharma. Tox., SuppL 3, 29, DOBBS, S.M., MAWER, G.E., RODGERS, E.M. & WOODCOCK, B.G. (1976). Can maintenane digoxin dose requirements be predited? Br. J. lin. Pharma., 3, DOHERTY, J.E., FLANIGAN, W.J., MURPHY, M.L., BULLOCH, R.T., DALRYMPLE, G.L., BEARD, O.W. & PERKINS, W.H. (197). Tritiated digoxin. XIV. Enterohepati irulation absorption and exretion studies in human volunteers. Cirulation, 42, DOHERTY, J.E. & KANE, J.J. (1975). Clinial pharmaology of digitalis glyosides. In Annual Review of Mediine, eds Creger, W.P., Coggins, C.H. & Hanok, E.W., 26, pp Annual Reviews In. DOHERTY, J.E. & PERKINS, W.H. (1962). Studies with tritiated digoxin in human subjets after intravenous administration. Am. Heart J., 63, DOHERTY, J.E. & PERKINS, W.H. (1966). Digoxin metabolism in hypo- and hyperthyroidism. Studies with tritiated digoxin in thyroid disease. Ann. int. Med., 64, DOHERTY, J.E., PERKINS, E.H. & FLANIGAN, W.J. (1967). The distribution and onentration of tritiated digoxin in human tissues. Ann int. Med., 66, DOHERTY, J.E., PERKINS, W.H. & WILSON, M.C. (1964). Studies with tritiated digoxin in renal failure. Arm J. Med., 37, DUHME, D.W., GREENBLATT, D.J. & KOCH-WESER, J. (1974). Redution of digoxin toxiity assoiated with measurement of serum levels. Ann. int. Med., 8, EWY, G.A., GROVES, B.M., BALL, M.F., NIMMO, L., JACKSON, B. & MARCUS, F. (1971). Digoxin metabolism in obesity. Cirulation, 44, EWY, G.A., KAPADIA, G.G., YAO, L., LULLIN, M. & MARCUS, F.I. (1969). Digoxin metabolism in the elderly. Cirulation, 39, GREENBLATT, D.J., DUHME, D.W. & KOCH-WESER, J. (1973). Pain and CPK elevation after intramusular digoxin. New Engl. J. Med., 288, 689. HAGEMEIJER, F. & VAN HOUWE, E. (1975). Titrated energy ardioversion of patients on digitalis. Br. Heart J., 37, HALKIN, H., SHEINER, L.B., PECK, C.C. & MELMON, K.L. (1975). Determinants of the renal learane of digoxin. Clin. Pharma. Ther., 17, HALL, W.H. & DOHERTY, J.E. (1974). Tritiated Digoxin XXII. Absorption and exretion in malabsorption syndromes. Am. J. Med., 56, HARRISON, C.E. Jr. & WAKIM, KG. (1969). 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