Interactions with Calcium-Channel Blockers

amlodipine (Norvasc^Ž)
felodipine (Plendil^Ž, Renedil^Ž)
nifedipine (Adalat^Ž, Procardia^Ž)

The grapefruit juice-drug interaction seems to affect mainly the dihydropyridine family of calcium-channel blockers. Tachycardia and decreased diastolic blood pressure were noted when felodipine was given with double-strength grapefruit juice (GJ) in six hypertensive patients. Felodipine area under the curve (AUC) increased by 184%, and an increase in side effects (facial flushing, headache, dizziness) were noted.² Patients in the same study taking nifedipine experienced an increase in AUC by 34%.

In 12 healthy subjects amlodipine AUC was increased by 16% and patients experienced a slight reduction in diastolic blood pressure when amlodipine was given with single-strength GJ.⁹

To confirm that the activity of grapefruit segments and an extract of the peel and rind had similar drug interaction potential to the juice, 12 healthy volunteers (10 male, 2 female) received a single dose of felodipine extended-release 10 mg with either 250 mL single strength GJ, peeled grapefruit segments of one grapefruit equivalent to 250 mL, the ethanol-based extract of a single grapefruit diluted to 250 mL with water, or water in a four-way randomized crossover fashion.

	SS GJ	segments	extract
D AUC	116%	100%	152%
D Cmax	128%	86%	200%

All three forms of grapefruit significantly increased the bioavailability compared with water alone. Time to peak concentration (Tmax) was shortened significantly with GJ and the extract, while none of the 3 grapefruit preparations affected the half-life of felodipine. Clinical effects on blood pressure and heart rate were not reported.

The authors concluded that based on current knowledge of which drugs interact, if there is a concern for a drug interaction with GJ, it seems logical to avoid consumption of grapefruit segments as well during pharmacotherapy with the affected drug(s). Confectioneries, like marmalades, made from grapefruit peel may also cause a drug interaction.¹⁰⁶

A clinical case report described GJ intake resulting in marked hypotension in a patient with renovascular hypertension taking large doses of nifedipine and terazosin (Hytrin^Ž) for blood pressure control.³³

diltiazem (Cardizem^Ž, Tiazac^Ž)

Diltiazem, a benzothiazepine calcium-channel blocker was studied for an interaction with GJ.⁴⁵ Nine healthy male subjects received 120mg diltiazem with either 200 mL of water or single-strength GJ. AUC and Cmax were not affected by GJ, thought elimination half-life did show a small but significant increase (4.1 hours to 5.1 hours when diltiazem given with GJ).

A more recent study looked at 10 healthy male volunteers who received a single dose of 120 mg diltiazem (a regular, non-SR formulation) with either 250 mL unknown strength GJ or water in randomized, crossover fashion. AUC was significantly increased by a mean of 18% (quoted as 20% in the study abstract) (p=0.02). Cmax was increased by a mean of 14% (quoted as 22% in the study abstract). No increased clinical effects were seen on physiological parameters such as blood pressure or heart rate in any of the subjects. The confidence intervals used in this study were 90% CIs, which differ from standard studies which use 95% confidence intervals. The authors concluded that based on the pharmacokinetic interaction observed in this study, an effect of GJ consumption on the pharmacodynamic response of diltiazem cannot be excluded in individuals treated with diltiazem. Although these results differ from the above study, the clinical significance of this interaction appears to be minimal.⁸²

nimodipine (Nimotop^Ž)

Eight healthy male volunteers received a single dose of 30 mg of the dihydropyridine calcium-channel blocker nimodipine with either 250 mL of unknown strength GJ or water in a randomized crossover fashion. AUC was increased a mean of 51%, and Cmax increased a mean of 24% in the GJ group. Time to peak concentration was prolonged from 0.8h to 1.7h. Only minor effects were seen on blood pressure and heart rate, though heart rate was slightly elevated, likely due to baroreflex. The authors concluded that a clinical relevance of the interaction is not probable in the majority of patients using nimodipine. However, since GJ intake may contribute to the variability of nimodipine pharmacokinetics, the interaction should be avoided.¹⁰³

nitredipine
nisoldipine (Sular^Ž)

Two dihydropyridine calcium-channel blockers not available in Canada, nitrendipine and nisoldipine were also demonstrated to interact with GJ. In nine patients, nitrendipine AUC was increased by 106% when given with GJ.¹⁰ In 12 patients, nisoldipine AUC was increased by 98% when given with GJ, and peak concentrations were increased by 406%, with marked inter-individual variability in the magnitude of the interaction. Only minor effects on blood pressure and heart rate were noted in the nisoldipine study.¹¹

pranidipine

Sixteen healthy male volunteers received a single 2mg dose of the new dihydropyridine calcium-channel blocker pranidipine with either 250 mL unknown strength GJ, 250 mL plain orange juice, or water in a randomized crossover fashion with a 10 day washout between study periods. AUC and Cmax were increased with GJ but not with orange juice or water. AUC increased by a mean of 68% and Cmax increased 53% with GJ. No significant differences in systolic or diastolic blood pressure between the two treatments were observed, however, a significant elevation in the heart rate was observed in the GJ group which persisted for the entire 24 hour study period. It was thought that the increase of serum pranidipine appears to enhance its vasodilative effects, and the increase in heart rate after vasodilation might be mediated by baroreflex. [N.B. this reflex tachycardia is similar to the problems experienced with short-acting nifedipine, and believed to be the cause of the increased mortality seen with use of short-acting dihydropyridines ^ref1] The authors concluded that intake of GJ is associated with a significant increase in the bioavailability of pranidipine that may be clinically important.¹⁰²

verapamil (Isoptin^Ž, Calan^Ž)

A recent report showed that co-administration of GJ with verapamil, a non-dihydropyridine calcium channel blocker, led to increased verapamil AUC and serum concentrations. In a crossover study of 24 volunteers, verapamil and norverapamil AUCs were increased 43% and 28%, while the Cmax of verapamil and norverapamil were increased 60% and 32%. Four subjects in the GJ-verapamil phase had a PR interval prolongation to greater than 0.24 seconds. While the interaction was significant, the effect was of a lower magnitude than seen with other calcium channel blockers.³⁰^,99

In a study of 10 hypertensive patients (7 female, 3 male) on variable-dose short-acting (i.e. non-SR formulation) verapamil, patients were given either 2 doses of 200mL single-strength GJ or water 1 hour prior to and at the time of their regular verapamil dose in a linear fashion (water on day 1, GJ on day 2). The authors concluded that GJ had no significant effect on short-acting verapamil pharmacokinetic parameters, increasing AUC by a mean of 18%, and decreasing Cmax by a mean of 15%.¹⁰¹

In most studies, the interactions were tested in healthy subjects. This is an important distinction, as patients with hypertension or other cardiac conditions may experience more pronounced effects on heart rate and blood pressure. GJ can cause substantial increases in bioavailability of certain calcium-channel blockers, primarily the dihydropyridine type. Patients receiving these medications and drinking grapefruit juice regularly should be monitored for increased response. A reasonable guideline for pharmacists and other health care professionals is to tell patients that if they are not currently taking their antihypertensive medications with grapefruit juice regularly, don’t start. If they are already taking their medications with grapefruit juice regularly, and are not experiencing adverse effects, don’t stop.

Last Updated: February 24, 2005