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.