Effect of two different doses of nitrendipine on steady-state plasma digoxin level and systolic time intervals

Abstract

The effect of two different doses of nitrendipine on plasma digoxin levels, urinary recovery and systolic time intervals was investigated in 8 healthy volunteers. Following a loading dose, digoxin 0.25 mg b.d.p.o. was given alone for 2 weeks. Then 0.25 mg digoxin b.d. was administered for two 1-week periods combined with nitrendipine 10 mg or 20 mg once daily. The study was completed with another digoxin monotherapy phase lasting 7 days. Nitrendipine 20 mg daily led to a significant increase in plasma digoxin levels and in its area under the plasma concentration-time curve AUC (0-12) was 9.7 ng ml-1h when digoxin alone was given and 11.2 ng ml-1h on co-administration of the calcium antagonist. Urinary recovery and renal clearance of digoxin were slightly but not significantly increased by nitrendipine. Nitrendipine 10 mg once daily caused a small, insignificant tendency to elevate the plasma digoxin level. Nitrendipine co-administration (10 and 20 mg once daily) did not significantly alter systolic time intervals, as non-invasively measured haemodynamic parameters, compared to digoxin treatment alone. Thus, nitrendipine 20 mg daily caused a significant increase in plasma digoxin concentrations and in its AUC, which would rarely be of clinical relevance.

Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels

“…Finally, nitridipine fails to block either digitoxin channels or digitoxin-mediated calcium entry into cells. This failure also is paralleled by clinical experience (4). Although other entry mechanisms cannot be excluded, these data together constitute strong evidence that intrinsic calcium channel activity constitutes a biologically important, calcium-dependent toxicity mechanism for digitoxin and other clinically important cardiac glycosides.…”

“…A consequence of this slight depolarization process is that voltagedependent calcium channels may open, thereby permitting calcium entry into the cell. However, this reasoning has been challenged by the fact that nitrendipine, a classical voltage-dependent calcium channel blocker, fails to reverse cardiac glycoside-induced side effects in healthy human volunteers (4). An alternative mechanism has been a slight increase in intracellular Na, followed by exchange for extracellular Ca 2ϩ by the NCX sodium/calcium exchanger (5).…”

Calcium Antagonists

“…According to Kirch et al, [82] nitrendipine 20mg daily, but not 10mg daily, caused a significant increase in the plasma concentrations and AUC of digoxin, which would rarely be of clinical relevance. However, in this study 1 patient out of 8 withdrew from the study because of adverse reactions, including nausea and dizziness, showing that the interaction between nitrendipine and digoxin may be of clinical relevance in certain patients.…”