Pharmacy Blog – Dr Vibore

The effects of digitalis glycosides might be increased by rises inblood calcium levels, and use of intravenous calcium may result in development of potentially life-threatening digitalis-induced cardiac arrhythmias. Teriparatide appears not to affect thecalcium-mediated pharmacodynamics of digoxin.

There is some evidence that increases or decreases in blood calcium levels can increase or decrease, respectively, effects of digitalis. A patient with congestive heart failure and atrial fibrillation was resistant to actions of digoxin serum levels of 1.5 to 3 nanograms/mL until his serum calcium levels were raised from 1.68 to about 2.13 mmol/L by oral calci

Disodium edetate. Disodium edetate,(See reference number 3-5)which lowers blood calcium levels, has been used successfully in treatment of digitalis toxicity, although less toxic drugs are generally preferred.

Teriparatide. A placebo-controlled study in 15 healthy subjects given digoxin 500 micrograms daily, adjusted to maintain steady-state serum levels in range 1 to 2 nanograms/mL, found that a single 20-microgram subcutaneous dose of teriparatide on day 15 or 16 did not alter calcium-mediated effects of digoxin (systolic time interval), or heart rate. Serum calcium increased slightly,with a maximum increase of

The actions of cardiac glycosides (even now not fully understood) are closely tied up with movement of calcium ions into heart muscle cells. Increased concentrations of calcium outside these cells increase inflow of calcium and this enhances activity of glycosides. This can lead to effective over-digitalisation and even potentially life-threatening arrhythmias. Conversely, a drop in calcium levels can attenuate activity of glycosides. However, clinical relevance of these changes in calcium is not fully established.

The report of deaths associated with digitalis and calcium compounds (published in 1936) seems to be only direct clinical evidence of a serious adverse interaction, although there is plenty of less direct evidence that an interaction is possible. Intravenous calcium should be avoided in patients receiving cardiac glycosides. If that is not possible,it has been suggested(See reference number 7)that it should be given slowly or only in small amounts in order to avoid transient serum calcium levels higher than 7.5 mmol/L,but it seems likely that very large doses of calcium would be required to reach this level, even transiently.

The very slight increases in calcium observed with teriparatide were considered insufficient to increase cardiac sensitivity to digoxin at therapeutic dosage (See reference number 6). Nevertheless, manufacturer of teriparatide still advises caution in patients taking digitalis, because of possibility for transiently raised calcium levels (See reference number 8,9).

Bower JO,Mengle HAK. The additive effects of calcium and digitalis. A warning with a reportof two deaths. JAMA (1936) 106, 1151.

Chopra D,Janson P, Sawin CT. Insensitivity to digoxin associated with hypocalcaemia. N EnglJ Med (1977) 296, 917–8.

Jick S,Karsh R. The effect of calcium chelation on cardiac arrhythmias and conduction disturbances. Am J Cardiol (1959) 4, 287–93.

Szekely P,Wynne NA. Effects of calcium chelation on digitalis-induced cardiac arrhythmias.Br Heart J (1963) 25, 589–94.

Rosenbaum JL,Mason D, Seven MJ. The effect of disodium EDTA on digitalis intoxication.Am J Med Sci (1960) 240, 111–18.

Benson CT,Voelker JR. Teriparatide has no effect on the calcium-mediated pharmacodynamics of digoxin. Clin Pharmacol Ther (2003) 73, 87–94.

Nola GT,Pope S, Harrison DC. Assessment of the synergistic relationship between serum calcium and digitalis. Am Heart J (1970) 79, 499–507.

Forsteo (Teriparatide). Eli Lilly and Company Ltd. UK Summary of product characteristics,June 2007.

Forteo (Teriparatide). Eli Lilly and Company. US Prescribing information,September 2004.

Bisacodyl reduces serum digoxin levels to a small extent. Largeamounts of dietary fibre, guar gum and bulk-forming laxativescontaining ispaghula or psyllium appear to have no significant effect on absorption of digoxin. Single-dose studies show thatmacrogol 4000, a laxative polymer, reduces serum levels of digoxin.

Bisacodyl reduced mean serum digoxin levels of 11 healthy subjects by about 12%. When bisacodyl was taken 2 hrs before digoxin, serum digoxin levels were slightly raised, but not to a statistically significant extent (See reference number 1).

The fibre was given in this way to simulate conditions that might be encountered clinically (for example to reduce symptoms of diverticular disease) (See reference number 2)

Wheat bran 7.5 g twice daily caused a small 10 % reduction in plasma digoxin levels of 14 geriatric patients after 2 weeks, but there was no significant change after 4 weeks (See reference number 3). Bran fibre 11 g caused a 6 to 7 % reduction in absorption and steady-state serum levels of digoxin in 16 healthy subjects (See reference number 4). The cumulative urinary recovery of a single oral dose of digoxin in healthy subjects was reduced almost 20 % by 5 g of fibre,whereas 0.75 g of fibre had no effect (See reference number 5).

In 10 healthy subjects Guarem (95% guar gum) 5 g reduced peak serum levels of a single 500-microgram oral dose of digoxin by 21 % and AUC0-6 was reduced by 16%, but amount excreted in urine over 24 hrs was only minimally reduced (See reference number 6). Guar gum 18 g with a test meal did not affect steady-state plasma digoxin levels in 11 healthy subjects given digoxin 1mg on day 1,then 750 micrograms on day 2, then 500 micrograms daily for 3 days (See reference number 7).

A randomised, crossover study in 18 healthy subjects found that 20 g of macrogol 4000 daily over an 8-day period reduced maximum serum levels of a single 500-microgram dose of digoxin by 40%, and reduced AUC by 30%. Heart rate and PR interval were unchanged (See reference number 9). More study is needed to assess effects of this interaction on steady-state digoxin levels.

Not established. Digoxin can bind to some extent to fibre within gut (See reference number 10). However, in vitro studies (with bran, carrageenan, pectin, sodium pectinate, xylan and carboxymethylcellulose) have shown that most of binding is reversible (See reference number 11).

Information seems to be limited to these reports. The reduction in serum digoxin levels caused by bisacodyl is small, and not expected to be of clinical importance, and apparently preventable by giving bisacodyl 2 hrs before digoxin. Neither dietary fibre (bran), guar gum nor two bulk-forming laxatives (Vi-Siblin and Metamucil) have a clinically important effect on serum digoxin levels. No special precautions would appear to be necessary. The importance of interaction between digoxin and macrogol 4000 awaits further assessment, but on available evidence it would be prudent to be alert for need to increase digoxin dosage.

Wang D-J,Chu K-M, Chen J-D. Drug interaction between digoxin and bisacodyl. J Formos Med Assoc (1990) 89, 913, 915–9.

Woods MN,Ingelfinger JA. Lack of effect of bran on digoxin absorption. Clin Pharmacol Ther (1979) 26, 21–3.

Nordström M,Melander A, Robertsson E, Steen B. Influence of wheat bran and of a bulk-forming ispaghula cathartic on the bioavailability of digoxin in geriatric in-patients. Drug Nutr Interact (1987) 5, 67–9.

Johnson BF,Rodin SM, Hoch K, Shekar V. The effect of dietary fiber on the bioavailabilityof digoxin in capsules. J Clin Pharmacol (1987) 27, 487–90.

Brown DD,Juhl RP, Warner SL. Decreased bioavailability of digoxin due to hypocholesterolemic interventions. Circulation (1978) 58, 164–72.

Huupponen R,Seppälä P, Iisalo E. Effect of guar gum, a fibre preparation, on digoxin andpenicillin absorption in man. Eur J Clin Pharmacol (1984) 26, 279–81.

Lembcke B,Häsler K, Kramer P, Caspary WF, Creuzfeldt W. Plasma digoxin concentrationsduring administration of dietary fibre (guar gum) in man. Z Gastroenterol (1982) 20, 164–7.

Walan A,Bergdahl B, Skoog M-L. Study of digoxin bioavailability during treatment with abulk forming laxative (Metamucil). Scand J Gastroenterol (1977) 12 (Suppl 45), 111.

Ragueneau I,Poirier J-M, Radembino N, Sao AB, Funck-Brentano C, Jaillon P. Pharmacokinetic and pharmacodynamic drug interactions between digoxin and macrogol 4000, a laxative polymer, in healthy volunteers. Br J Clin Pharmacol (1999) 48, 453–6.

Floyd RA. Digoxin interaction with bran and high fiber foods. Am J Hosp Pharm (1978) 35,

660.

11. Hamamura J,Burros BC, Clemens RA, Smith CH. Dietary fiber and digoxin. Fedn Proc (1985) 44, 759.

Digoxin toxicity developed in 4 patients when they were given ciclosporin before cardiac transplantation. In two cases described in detail, ciclosporin 10 mg/kg daily was added to digoxin 375 micrograms daily. Fourfold rises in digoxin levels,from 1.2 to 4.5 nanograms/mL and from 2 to 8.3 nanograms/mL,were seen within 2 to 3 days. This was accompanied by rises in serum creatinine levels from 110 to 120 micromol/L and from 84 to 181 micromol/L respectively, which were considered insufficient to explain rise in digoxin levels. As a consequence of these findings, same authors conducted a study in 4 patients given ciclosporin and digoxin. Two patients developed acute renal failure. In other 2 patients, volume of distribution of digoxin was decreased by 69 % and 72%, while clearance was reduced by 47 % and 58 % (See reference number 1). In a further 7 patients,digoxin pharmacokinetics were assessed before cardiac transplantation, then after transplantation during maintenance ciclosporin therapy (See reference number 2). The total body clearance of digoxin remained unchanged, which appeared to be at odds with earlier results (See reference number 1). It was suggested that haemodynamic improvements brought about by successful cardiac transplantation may have counterbalanced any inhibitory effect ciclosporin had on renal clearance (See reference number 2).

Not fully understood. The authors of studies concluded that ciclosporin has no specific inhibitory effect on renal elimination of digoxin, but that it causes a non-specific reduction in renal function after acute administration, which reduces digoxin elimination (See reference number 2). Conversely, another study in animals suggested that ciclosporin can reduce secretion of digoxin by kidney tubular cells by inhibiting P-glycoprotein (See reference number 3).

Information seems limited to studies cited. Nevertheless, effects of concurrent use should be monitored very closely, and digoxin dosage should be adjusted as necessary.

1. Dorian P,Cardella C, Strauss M, David T, East S, Ogilvie R. Cyclosporine nephrotoxicity andcyclosporine-digoxin interaction prior to heart transplantation. Transplant Proc (1987) 19, 1825–7.

Robieux I,Dorian P, Klein J, Chung D, Zborowska-Sluis D, Ogilvie R, Koren G. The effectsof cardiac transplantation and cyclosporine therapy on digoxin pharmacokinetics. J Clin Pharmacol (1992) 32, 338–43.

Okamura N,Hirai M, Tanigawara Y, Tanaka K, Yasuhura M, Ueda K, Komano T, Hori R. Digoxin-cyclosporin A interaction: modulation of the multidrug transporter P-glycoprotein in thekidney. J Pharmacol Exp Ther (1993) 266, 1614–9.

Serum digoxin levels are increased by about 40 % by verapamil160 mg daily,and by about 70 % by verapamil 240mg daily. Digoxin toxicity may develop if dosage is not reduced. Deathshave occurred. Verapamil causes a rise of about 35 % in digitoxinlevels. There is a risk of additive bradycardia and conduction disturbances when cardiac glycosides are given with verapamil.

Eight out of 10 patients had a mean 35 % rise (range 14 to 97%) in plasma digitoxin levels over a 4 to 6 week period while taking verapamil 240mg daily,in three divided doses. In 2 patients (and 3 other healthy subjects given a single dose of digitoxin) pharmacokinetics of digitoxin were not affected by verapamil (See reference number 1,2).

After 2 weeks of treatment with verapamil 240mg daily, in three divided doses, mean serum digoxin levels of 49 patients with chronic atrial fibrillation had risen by 72%. The rise was seen in most patients, and it occurred largely within first 7 days. A rise of about 40 % has been seen with verapamil 160mg daily (See reference number 3,4).

A single-dose study indicated that cirrhosis magnifies extent of this interaction (See reference number 18)

The rise in serum digoxin levels is due to reductions in renal and especially extra-renal (biliary) clearance; a diminution in volume of distribution also takes place (See reference number 4,9,10,19). It has been suggested that P-glycoprotein may be involved (See reference number 20). An in vitro study found that verapamil can inhibit P-glycoprotein-mediated transcellular transport of digoxin,(See reference number 21) which suggests that any interaction may occur, at least in part, by inhibiting renal tubular excretion of digoxin. Impaired extra-renal excretion is suggested as reason for rise in serum digitoxin levels (See reference number 1).

The increased plasma levels of digoxin caused by verapamil are reported to increase both inotropism(See reference number 22) and toxic effects (See reference number 23). Verapamil may enhance digoxin-induced elevation of intracellular sodium, which may increase risk of arrhythmias (See reference number 23,24). A synergistic effect on heart rate and atrioventricular conduction is also possible.

The pharmacokinetic interaction between digoxin and verapamil is well documented,well established and it occurs in most patients (See reference number 10,25). Serum digoxin levels should be well monitored and downward dosage adjustments made to avoid digoxin toxicity (deaths have occurred(See reference number 15)). An initial 33 to 50 % dosage reduction has been recommended (See reference number 26,27). The interaction develops within 2 to 7 days,approaching or reaching a maximum within 14 days or so (See reference number 3,8). The magnitude of rise in serum digoxin is dosedependent(See reference number 28) with a significant increase if verapamil dosage is increased from 160 to 240mg daily,(See reference number 3) but with no further significant increase if dose is raised any higher (See reference number 6). The mean rise with verapamil 160mg daily is about 40%, and with 240mg or more is about 60 to 80%, but response is variable. Some patients may show rises of up to 150 % while others show only a modest increase. One study found that although rise in serum digoxin levels was 60 % within a week, this had lessened to about 30 % five weeks later (See reference number 10). Regular monitoring and dosage adjustments would seem to be necessary. Note that potential for additive bradycardia and heart block should also be borne in mind.

The documentation of digitoxin and verapamil interaction is limited, but interaction appears to be established. Downward dosage adjustment may be necessary,particularly in some patients (See reference number 1).

Kuhlmann J,Marcin S. Effects of verapamil on pharmacokinetics and pharmacodynamics ofdigitoxin in patients. Am Heart J (1985) 110, 1245–50.

Kuhlmann J. Effects of verapamil,diltiazem, and nifedipine on plasma levels and renal excretion of digitoxin. Clin Pharmacol Ther (1985) 38, 667–73.

Klein HO,Lang R, Weiss E, Di Segni E, Libhaber C, Guerrero J, Kaplinsky E. The influenceof verapamil on serum digoxin concentration. Circulation (1982) 65, 998–1003.

Lang R,Klein HO, Weiss E, Libhaber C, Kaplinsky E. Effect of verapamil on digoxin bloodlevel and clearance. Chest (1980) 78, 525.

Doering W. Effect of coadministration of verapamil and quinidine on serum digoxin concentration. Eur J Clin Pharmacol (1983) 25,517–21.

Belz GG,Doering W, Munkes R, Matthews J. Interaction between digoxin and calcium antagonists and antiarrhythmic drugs. Clin Pharmacol Ther (1983) 33, 410–17.

Klein HO,Lang R, Di Segni E, Kaplinsky E. Verapamil-digoxin interaction. N Engl J Med (1980) 303, 160.

Merola P,Badin A, Paleari DC, De Petris A, Maragno I. Influenza del verapamile sui livelliplasmatici di digossina nell’uomo. Cardiologia (1982) 27, 683–7.

Hedman A,Angelin B, Arvidsson A, Beck O, Dahlqvist R, Nilsson B, Olsson M, Schenck-Gustafsson K. Digoxin-verapamil interaction: reduction of biliary but not renal digoxin clearance. Clin Pharmacol Ther (1991) 49, 256–62.

Pedersen KE,Dorph-Pedersen A, Hvidt S, Klitgaard NA, Pedersen KK. The long-term effectof verapamil on plasma digoxin concentration and renal digoxin clearance in healthy subjects.Eur J Clin Pharmacol (1982) 22, 123–7.

Klein HO,Lang R, Di Segni E, Sareli P, David D, Kaplinsky E. Oral verapamil versus digoxin in the management of chronic atrial fibrillation. Chest (1980) 78, 524.

Schwartz JB,Keefe D, Kates RE, Harrison DC. Verapamil and digoxin. Another drug-druginteraction. Clin Res (1981) 29, 501A.

Rendtorff C,Johannessen AC, Halck S, Klitgaard NA. Verapamil-digoxin interaction inchronic hemodialysis patients. Scand J Urol Nephrol (1990) 24, 137–9.

Gordon M,Goldenberg LMC. Clinical digoxin toxicity in the aged in association with co-administered verapamil. A report of two cases and a review of the literature. J Am Geriatr Soc (1986) 34, 659–62.

Zatuchni J. Verapamil-digoxin interaction. Am Heart J (1984) 108,412–3.

Kounis NG. Asystole after verapamil and digoxin. Br J Clin Pract (1980) 34,57–8.

Kounis NG,Mallioris C. Interactions with cardioactive drugs. Br J Clin Pract (1986) 40, 537–8.

Maragno I,Gianotti C, Tropeano PF, Rodighiero V, Gaion RM, Paleari C, Prandoni R,Menozzi L. Verapamil-induced changes in digoxin kinetics in cirrhosis. Eur J Clin Pharmacol (1987) 32, 309–11.

Pedersen KE,Dorph-Pedersen A, Hvidt S, Klitgaard NA, Nielsen-Kudsk F. Digoxin-verapamil interaction. Clin Pharmacol Ther (1981) 30, 311–16.

Verschraagen M,Koks CHW, Schellens JHM, Beijnen JH. P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil. Pharmacol Res (1999) 40, 301–6.

Takara K,Kakumoto M, Tanigawara Y, Funakoshi J, Sakaeda T, Okumura K. Interaction ofdigoxin with antihypertensive drugs via MDR1. Life Sci (2002) 70, 1491–1500.

Pedersen KE,Thayssen P, Klitgaard NA, Christiansen BD, Nielsen-Kudsk F. Influence of verapamil on the inotropism and pharmacokinetics of digoxin. Eur J Clin Pharmacol (1983) 25, 199–206.

Pedersen KE. The influence of calcium antagonists on plasma digoxin concentration. Acta Med Scand (1984) (Suppl 681),31–6.

Pedersen KE,Christiansen BD, Kjaer K, Klitgaard NA, Nielsen-Kudsk F. Verapamil-induced changes in digoxin kinetics and intraerythrocytic sodium concentration. Clin Pharmacol Ther (1983) 34, 8–13.

Belz GG,Aust PE, Munkes R. Digoxin plasma concentrations and nifedipine. Lancet (1981)i, 844–5.

Marcus FI. Pharmacokinetic interactions between digoxin and other drugs. J Am Coll Cardiol (1985) 5,82A–90A.

Klein HO,Kaplinsky E. Verapamil and digoxin: their respective effects on atrial fibrillationand their interaction. Am J Cardiol (1982) 50, 894–902.

Schwartz JB,Keefe D, Kates RE, Kirsten E, Harrison DC. Acute and chronic pharmacodynamic interaction of verapamil and digoxin in atrial fibrillation. Circulation (1982) 65, 1163–

70.

Clinical evidence,mechanism, importance and management

A placebo-controlled, crossover study in 12 healthy subjects found that pharmacokinetics of steady-state digoxin 375 micrograms daily were not affected by an infusion of argatroban 2 micrograms/kg per minute for 120 hours. Steady-state argatroban levels were obtained within 3 hrs and maintained throughout infusion. Dosage adjustments should not be necessary during concurrent use (See reference number 1).

1. Inglis AML,Sheth SB, Hursting MJ, Tenero DM, Graham AM, DiCicco RA. Investigation ofthe interaction between argatroban and acetaminophen, lidocaine, or digoxin. Am J Health-Syst Pharm (2002) 59, 1258–66.

Cimetidine and ranitidine can reduce or abolish effects of tolazoline used as a pulmonary vasodilator in children

A newborn infant with persistent foetal circulation was given a continuous infusion of tolazoline to reduce pulmonary hypertension. The oxygenation improved but gastrointestinal bleeding occurred. When cimetidine was given, condition of child deteriorated with a decrease in oxygen saturation and arterial pO2 values (See reference number 1). A second case report describes a similar outcome in a 2-day-old neonate,who had an initial improvement with tolazoline alone, but then developed worsening hypoxaemia when cimetidine was given (See reference number 2).

These reports are similar to another, in which tolazoline-induced reduction in pulmonary arterial pressure in a child was reversed when cimetidine was given, for acute gastrointestinal haemorrhage (See reference number 3). Another study in 12 children found that intravenous ranitidine 3 mg/kg abolished tolazoline-induced reduction in pulmonary and systemic vascular (See reference number 4).

Tolazoline dilates pulmonary vascular system by stimulating both H1and H2-receptors. Cimetidine and ranitidine block H2-receptors so that at least part of effects of tolazoline are abolished

Cimetidine and ranitidine are not suitable drugs for prophylaxis of gastrointestinal adverse effects of tolazoline in children

Roll C,Hanssler L. Interaktion von Tolazolin und Cimetidin bei persistierender fetaler Zirkulation des Neugeborenen. Monatsschr Kinderheilkd (1993) 141, 297–9.

Huang C-B,Huang S-C. Caution with use of cimetidine in tolazoline induced upper gastrointestinal bleeding. Changgeng Yi Xue Za Zhi. (1996) 19, 268–71.

Jones ODH,Shore DF, Rigby ML. The use of tolazoline hydrochloride as a pulmonary vasodilator in potentially fatal episodes of pulmonary vasoconstriction after cardiac surgery in children. Circulation (1981) 64 (Suppl II), 134–9.

Bush A,Busst CM, Knight WB, Shinebourne EA. Cardiovascular effects of tolazoline and ranitidine. Arch Dis Child (1987) 62, 241–6.

Plant extracts containing cardiac glycosides have been in use for thousands of years. The ancient Egyptians were familiar with squill (a source of proscillaridin), as were Romans who used it as a heart tonic and diuretic. The foxglove was mentioned in writings of Welsh physicians in thirteenth century and features in An Account of Foxglove and some of its Medical Uses, published by William Withering in 1785, in which he described its application in treatment of dropsy or oedema that results from heart failure.

The most commonly used cardiac glycosides are those obtained from members of foxglove family, Digitalis purpurea and Digitalis lanata. The leaves of D. lanata are source of a number of purified glycosides including digoxin, digitoxin, acetyldigoxin, acetyldigitoxin, lanatoside C, deslanoside, of gitalin (an amorphous mixture largely composed of digitoxin and digoxin), and of powdered whole leaf digitalis lanata leaf.

D. purpurea is source of digitoxin, digitalis leaf, and standardised preparation digitalin. Metildigoxin is a semi-synthetic digitalis glycoside. Occasionally ouabain or strophanthin-K (also of plant origin) are used for particular situations, while for a number of years Russians have exploited cardiac glycosides from lily of valley (convallaria). Bufalin is a related cardioactive compound obtained from toads,and is found in a number of Chinese medicines.

The cardiac glycosides have two main actions and two main applications. They reduce conductivity within atrioventricular (AV) node, hence are used for treating supraventricular tachycardias (especially atrial fibrillation), and they have a positive inotropic effect (i.e. increase force of contraction), hence are used for congestive heart failure, although this use has declined.

Because most commonly used glycosides are derived from digitalis, achievement of desired therapeutic serum concentration of any cardiac glycoside is usually referred to as digitalisation. Treatment may be started with a large loading dose so that therapeutic concentrations are achieved reasonably quickly, but once these have been reached amount is reduced to a maintenance dose. This has to be done carefully because there is a relatively narrow gap between therapeutic and toxic serum concentrations. Normal therapeutic levels are about one-third of those that are fatal, and serious toxic arrhythmias begin at about two-thirds of fatal levels. The normal range for digoxin levels is 0.8 to 2 nanograms/mL (or

1.02 to 2.56 nanomol/L). To convert nanograms/mL to nanomol/L multiply by 1.28,or to convert nanomol/L to nanograms/mL multiply by 0.781. Note that micrograms/L is same as nanograms/mL.

If a patient is over-digitalised,signs of toxicity will occur, which may include loss of appetite, nausea and vomiting, and bradycardia. These symptoms are often used as clinical indicators of toxicity,and a pulse rate of less than 60 bpm is usually considered to be an indication of over-treatment. Note that paroxysmal atrial tachycardia with AV block and junctional tachycardia can also occur as a result of digitalis toxicity. Other symptoms include visual disturbances,headache, drowsiness and occasionally diarrhoea. Death may result from cardiac arrhythmias. Patients treated for cardiac arrhythmias can therefore demonstrate arrhythmias when they are both under- as well as over-digitalised.

Interactions of cardiac glycosides

The pharmacological actions of these glycosides are very similar,but their rates and degree of absorption, metabolism and clearance are different. For example, digoxin is mainly renally cleared whereas digitoxin undergoes a degree of metabolism by liver. It is therefore most important not to extrapolate an interaction seen with one glycoside and apply it uncritically to any other. Because therapeutic ratio of cardiac glycosides is low, a quite small change in serum levels may lead to inadequate digitalisation or to toxicity. For this reason interactions that have a relatively modest effect on serum levels may sometimes have serious consequences.

Many interactions between digoxin and other drugs are mediated by Pglycoprotein. Drugs that inhibit activity of P-glycoprotein in renal tubules may reduce elimination of digoxin in urine and this may result in toxic serum levels. Further, induction or inhibition of P-glycoprotein in gut may affect oral absorption of digoxin. See also Drug transporter proteins,.

Evidence from one study suggests that ciprofloxacin increases theserum levels of pentoxifylline, and may increase incidence ofadverse effects. In some clinical studies ciprofloxacin has beenused to boost levels of pentoxifylline.

Because patients taking pentoxifylline and ciprofloxacin often complained of headache, possibility of a pharmacokinetic interaction was studied in 6 healthy subjects. The study showed that ciprofloxacin 500mg daily for 3 days increased peak serum levels of a single 400mg dose of pentoxifylline by almost 60 % (from 114.5 to 179.5 nanograms/mL), and increased AUC by 15%. All 6 subjects complained of a frontal headache (See reference number 1).

The evidence suggests that ciprofloxacin inhibits metabolism of pentoxifylline (a xanthine derivative) by liver

Information on this interaction and its clinical relevance is limited. The author of pharmacokinetic study suggests that, if drugs need to be used together, dosage of pentoxifylline should be halved (See reference number 1). In absence of other information, if a short-course of ciprofloxacin is required in a patient taking pentoxifylline, this may be a sensible precaution. Alternatively, because increase in AUC was minor, it may be sufficient to recommend a reduction in pentoxifylline dose only in those who experience adverse effects (e.g. nausea,headache). Note that ciprofloxacin has been used to boost pentoxifylline levels in studies investigating possible therapeutic value of pentoxifylline’s ability to inhibit various cytokines. For example,ciprofloxacin 500mg twice daily was used with pentoxifylline 800mg three times daily for up to one year in patients with myelodysplastic syndrome (See reference number 2).

Cleary JD. Ciprofloxacin (CIPRO) and pentoxifylline (PTF): a clinically significant drug interaction. Pharmacotherapy (1992) 12,259–60.

Raza A,Qawi H, Lisak L, Andric T, Dar S, Andrews C, Venugopal P, Gezer S, Gregory S,Loew J, Robin E, Rifkin S, Hsu W-T, Huang R-W. Patients with myelodysplastic syndromesbenefit from palliative therapy with amifostine, pentoxifylline, and ciprofloxacin with or without dexamethasone. Blood (2000) 95, 1580–87.

Phenobarbital and phenytoin reduce serum levels of tirilazadmesilate whereas ketoconazole increases them. Finasteride inhibits metabolism of tirilazad to its active metabolite

Clinical evidence,mechanism, importance and management

A study in 16 healthy men found that cimetidine 300mg every 6 hrs for 4 days had no effect on pharmacokinetics of a single 2-mg/kg dose of tirilazad mesilate, given by infusion over 10 minutes on day 2, nor on U-89678, its active metabolite (See reference number 1). No special precautions would seem necessary if cimetidine is given with tirilazad mesilate.

In a study,8 healthy men were given finasteride 5mg daily for 10 days, with tirilazad mesilate 10 mg/kg orally or 2 mg/kg intravenously on day 7. Finasteride increased AUCs of intravenous and oral tirilazad by 21 % and 29%, respectively. Oral finasteride reduced AUCs of active metabolite (U-89678) by 92 % when tirilazad was given intravenously and by 75 % when tirilazad was given orally. Although metabolism of tirilazad to U-89678 was inhibited there was only a moderate effect on overall clearance of tirilazad and interaction was considered unlikely to be of clinical significance (See reference number 2).

Tirilazad mesilate,10 mg/kg orally or 2 mg/kg intravenously, was given to 12 healthy men and women, either alone or on day 4 of a 7-day regimen of ketoconazole 200mg daily. The ketoconazole more than doubled absolute bioavailability of oral tirilazad mesilate (from 8.7 % to 20.9%), apparently because its metabolism by cytochrome P450 isoenzyme CYP3A in gut wall and during first pass through liver was inhibited (See reference number 3). The clinical importance of this interaction awaits assessment.

In a single-dose study in 12 healthy men,there was no pharmacokinetic or pharmacodynamic interaction between intravenous tirilazad mesilate 2 mg/kg and oral nimodipine 60mg (See reference number 4). No special precautions would seem necessary if nimodipine is given with tirilazad mesilate

The pharmacokinetics of tirilazad mesilate (1.5 mg/kg as 10 minute intravenous infusions every 6 hrs for 29 doses) were studied in 15 healthy subjects before and after they took phenobarbital 100mg daily for 8 days. The phenobarbital increased clearance of tirilazad by 25 % in male subjects and 29 % in female, and AUC of active metabolite of tirilazad (U-89678) was reduced by 51 % in males and 69 % in females. The reason is thought to be that phenobarbital acts as an enzyme inducer, which increases metabolism of tirilazad (See reference number 5). The clinical importance of these reductions awaits assessment,but be alert for evidence of reduced effects if both drugs are given. It is doubtful if full enzyme-inducing effects of phenobarbital would have been reached in this study after only one week, so anticipate a greater effect if it is given for a longer period.

After taking phenytoin 200mg every 8 hrs for 11 doses then 100mg every 8 hrs for 5 doses, AUC0-6 of tirilazad mesilate was reduced by 35 % in 12 healthy subjects. The AUC of active metabolite, U-89678, was reduced by 87 % (See reference number 6). Another report by same group of workers(See reference number 7)found that phenytoin every 8 hrs for 7 days (9 doses of 200mg followed by 13 doses of 100 mg) reduced clearance of tirilazad by 92 % and of U-89678 by 93%. In another report authors noted that phenytoin increased metabolism of tirilazad and its metabolite in men and women to similar extents (See reference number 8). The clinical importance of these reductions is still to be assessed,but be alert for any evidence of reduced tirilazad effects if both drugs are given.

Fleishaker JC,Hulst LK, Peters GR. Lack of pharmacokinetic interaction between cimetidineand tirilazad mesylate. Pharm Res (1994) 11, 341–4.

Fleishaker JC,Pearson PG, Wienkers LC, Pearson LK, Moore TA, Peters GR. Biotransformation of tirilazad in human: 4. effect of finasteride on tirilazad clearance and reduced metabolite formation. J Pharmacol Exp Ther. (1998) 287, 591–7.

Fleishaker JC,Pearson PG, Wienkers LC, Pearson LK, Peters GR. Biotransformation of tirilazad in humans: 2. Effect of ketoconazole on tirilazad clearance and oral bioavailability. J Pharmacol Exp Ther (1996) 277, 991–8.

Fleishaker JC,Hulst LK, Peters GR. Lack of a pharmacokinetic/pharmacodynamic interactionbetween nimodipine and tirilazad mesylate in healthy volunteers. J Clin Pharmacol (1994) 34, 837–41.

Fleishaker JC,Pearson LK, Peters GR. Gender does not affect the degree of induction of tirilazad clearance by phenobarbital. Eur J Clin Pharmacol (1996) 50, 139–45.

Fleishaker JC,Hulst LK, Peters GR. The effect of phenytoin on the pharmacokinetics of tirilazad mesylate in healthy male volunteers. Clin Pharmacol Ther (1994) 56, 389–97.

Fleishaker JC,Pearson LK, Peters GR. Induction of tirilazad clearance by phenytoin. Biopharm Drug Dispos (1998) 19, 91–6.

Fleishaker JC,Pearson LK, Peters GR. Effect of gender on the degree of induction of tirilazadclearance by phenytoin. Clin Pharmacol Ther (1996) 59, 168.

Clinical evidence,mechanism, importance and management

In 6 elderly patients acipimox 250mg three times daily for a week was found to have no significant effect on plasma digoxin levels,clinical con

dition,ECGs, plasma urea or electrolyte levels (See reference number 1). No special precautions during concurrent use would seem necessary.

1. Chijioke PC,Pearson RM, Benedetti S. Lack of acipimox-digoxin interaction in patient volunteers. Hum Exp Toxicol (1992) 11, 357–9.

Clinical evidence,mechanism, importance and management

A woman who had previously had bilateral lumbar sympathectomy for Raynaud’s disease developed total urinary incontinence when given methyldopa 500mg to 1.5 g with phenoxybenzamine 12.5mg daily,but not when she was taking either drug alone. This would seem to be outcome of additive effects of sympathectomy and two drugs on sympathetic control of bladder sphincters (See reference number 1). Stress incontinence has previously been described with these drugs. The general importance of this interaction is probably small.

1. Fernandez PG,Sahni S, Galway BA, Granter S, McDonald J. Urinary incontinence due to interaction of phenoxybenzamine and :5.5pt; font-weight:normal; color:#000000″>α-methyldopa. Can Med Assoc J (1981) 124, 174.