Verapamil

Brand Names: Calan, Isoptin, Verelan

Clinical Names: Verapamil

Summary

generic name: Verapamil

trade names: Calan®, Isoptin®, Verelan®

type of drug: Calcium channel blocking agents

used to treat: Angina (chest pain), arrhythmias (irregular heartbeat), or hypertension (high blood pressure).

overview of interactions:
• nutrient affecting drug performance: Calcium

• nutrient affecting drug performance: Vitamin D

• diet affecting drug toxicity: Fiber and Fluids

• herbal constituent affected by drug: Caffeine, as in Theobroma cacao (Cacao, Chocolate tree), Cola nitida, Cola acuminata seed (Cola nut), Coffea arabica (Coffee), Paullinia cupana seeds (Guarana), Ilex paraguayensis leaves (Mate), and Camellia sinensis (Tea).

• diet affecting drug performance and toxicity: Grapefruit Juice

• herbal constituent affecting drug toxicity: Tetrandrine, an alkaloid derived from Stephania tetrandra

• herb affecting drug performance and toxicity: Stevia rebaudiana (Stevia)



Interactions

nutrient affecting drug performance: Calcium

• mechanism: It is possible that calcium supplements may interfere with the blood pressure-lowering activity of and reduce the therapeutic response to this drug. Depending on the condition for which the drug has been prescribed calcium may be problematic or beneficial. In fact, some physicians routinely prescribe very low dosages of supplemental calcium, often in the range of 25-30 mg per day, for patients who have been diagnosed with angina pectoris or cardiac arrhythmias, but have no history of high blood pressure, as a means of reducing excessive and unnecessary blood pressure-lowering activity on the part of the verapamil.
(Drug Evaluations Subscription. Spring, 1992; Bar-Or D, Gasiel Y. Br Med J (Clin Res Ed) 1981 May 16;282(6276):1585-1586; Kuhn M, Schriger DL. Am Heart J 1992;124:231-232; Fox J, Della-Santina CP. Am J Physiol 1989 Nov;257(5 Pt 1):E632-638.)

• nutritional concerns: Individuals taking verapamil for the treatment of hypertension should avoid calcium supplementation, even in small doses.
Individuals taking verapamil for the treatment of angina and arrhythmias without hypertension can usually take small levels of supplemental calcium to reduce unnecessary hypotensive effect without diminishing the drug's therapeutic efficacy. Anyone taking verapamil should consult their prescribing physician and/or a nutritionally trained healthcare professional before beginning or significantly changing their level of calcium supplementation.

nutrient affecting drug performance: Vitamin D

• mechanism: Supplementation with vitamin D may interfere with the therapeutic effectiveness of verapamil.
(Threlkeld DS, ed. Nov 1992; Fox J, Della-Santina CP. Am J Physiol 1989 Nov;257(5 Pt 1):E632-638.)

• nutritional concerns: Individuals taking verapamil should consult their prescribing physician and/or a nutritionally trained healthcare professional before using supplements containing vitamin D.

diet affecting drug toxicity: Fiber and Fluid

• mechanism: Individuals taking calcium channel blockers such as verapamil often complain of constipation as an undesirable side effect of taking such drugs. Verapamil is especially known to inhibit colonic motor activity, reduce colonic transit, and increase water absorption.
(Bassotti G, et al. Dis Colon Rectum 1998 Mar;41(3):377-380; Krevsky B, et al. Dig Dis Sci 1992 Jun;37(6):919-924; Threlkeld DS, ed. Nov 1992.)

• nutritional support: Individuals taking verapamil may be able to reduce drug-induced constipation by increasing daily intake of fiber and fluid, especially water.

herbal constituent affected by drug: Caffeine, as in Theobroma cacao (Cacao, Chocolate tree), Cola nitida, Cola acuminata seed (Cola nut), Coffea arabica (Coffee), Paullinia cupana seeds (Guarana), Ilex paraguayensis leaves (Mate), and Camellia sinensis (Tea)

• mechanism: Verapamil inhibits the metabolism and/or clearance of caffeine, thereby increasing its stimulant effects.
(Stockey IH. 1996.)

• nutritional concerns: Individuals taking verapamil might benefit from avoiding caffeine-containing beverages while taking verapamil. Individuals being treated for arrythmias, angina and hypertension might generally benefit from avoiding consumption of caffeine since it may aggravate these conditions.

diet affecting drug performance and toxicity: Grapefruit Juice

• mechanism: While not as pronounced as with many other medications, the consumption of grapefruit juice at the same time as verapamil may measurably increase levels of drug in the blood.
(Bailey DG, et al. Br J Clin Pharmacol 1998 Aug;46(2):101-110.)

• research: In a two-day study involving ten hypertensive patients on chronic verapamil treatment Zaidenstein found no significant effect on the pharmacokinetics of verapamil as a result of a single administration of grapefruit juice in conjunction with short-acting verapamil.
(Zaidenstein R, et al. Eur J Clin Pharmacol 1998 Jun;54(4):337-340.)

• nutritional concerns and possible synergy: The clinical significance of the interaction between verapamil and grapefruit juice has yet to demonstrated in clinical studies. Some physicians and researchers have discussed a possible role for grapefruit juice as a drug-sparing agent which might facilitate a reduction in the prescribed dose of the drug. The clinical application of this possible synergistic interaction seems premature at this time given the lack of data on the effectiveness and side effects of such a combined treatment approach. Individuals taking verapamil should heed the warning against drinking grapefruit juice unless they have consulted their prescribing physician and are under direct supervision and monitoring.
(Fuhr U. Drug Saf 1998 Apr;18(4):251-272; Holt GA. 1998, 274-275.)

herbal constituent affecting drug toxicity: Tetrandrine, an alkaloid derived from Stephania tetrandra

• mechanism: Tetrandrine, a bis-benzylisoquinoline alkaloid derived from the Chinese medicinal herb Stephania tetrandra, is a structurally unique Ca2+ entry blocker.
(King VF, et al. J Biol Chem 1988 Feb 15;263(5):2238-2244; Low AM, et al. Life Sci 1996;58(25):2327-2335.)

• herbal concerns: Stephania is a component of several Chinese herbal formulae used traditionally in the treatment of edema. Even though research with isolated chemical constituents is far removed from use of a whole herb especially as part of a formula, individuals taking verapamil and Stephania at the same time could experience a potentiating effect on the drug's action. Individuals taking verapamil or other calcium channel blockers should avoid the use of Stephania, alone or in combination with other herbs, unless they are under the direct supervision of their prescribing physician and a healthcare professional trained and highly experienced in the prescription of Chinese medicinal herbs. The proper prescription and dispensing of Stephania is critical since numerous reports have appeared in the literature involving the substitution of Aristolochia for Stephania and resultant adverse reactions, including kidney failure.

herb affecting drug performance and toxicity: Stevia rebaudiana (Stevia)

• research: Research with rodents indicates that stevioside, a constituent of Stevia rebaudiana leaves, can produce a drop in systemic blood pressure, as well as diuresis and natriuresis. Given the possibility that stevioside may act as a calcium antagonist there is a theoretical risk that it may potentiate verapamil if the two substances are taken at the same time.
(Melis MS. Braz J Med Biol Res. 1992;25(9):943-949; Melis MS, Sainati AR. J Ethnopharmacol. 1991 Jul;33(3):257-262.)

• herbal concerns: Even though this is a speculative interaction, individuals taking verapamil should consult with their prescribing physician and/or pharmacist before using Stevia in any significant volume or for an extended period of time.

Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

References

[No Author Listed] Drug Evaluations Subscription. Chicago, IL: American Medical Association, Volume I, Section 7, Chapter 2, Spring, 1992

Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice-drug interactions. Br J Clin Pharmacol 1998 Aug;46(2):101-110. (Review)
Abstract: The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.

Bar-Or D, Gasiel Y. Calcium and calciferol antagonise effect of verapamil in atrial fibrillation. Br Med J (Clin Res Ed) 1981 May 16;282(6276):1585-1586.

Bassotti G, Calcara C, Annese V, Fiorella S, Roselli P, Morelli A. Nifedipine and verapamil inhibit the sigmoid colon myoelectric response to eating in healthy volunteers. Dis Colon Rectum 1998 Mar;41(3):377-380.
Abstract: BACKGROUND: Constipation is not an infrequent side effect complained of by patients taking calcium channel blockers. This effect may reduce patients' compliance and yield potentially serious consequences. However, the underlying mechanisms for constipation caused by such compounds are not known. AIMS: The purpose of the present study was to assess the effects of nifedipine and verapamil on the sigmoid myoelectric response to eating, a physiologic test of colonic motor function. SUBJECTS AND METHODS: Nine healthy male volunteers with no previous abdominal surgery were recruited for the study and underwent three paired studies at two-week intervals. Myoelectric sigmoid activity was recorded by means of two clip electrodes introduced within the viscus without preparation for 30 minutes basally and 90 minutes postprandially. Each study was preceded by placebo, nifedipine (20 mg), or verapamil (120 mg). RESULTS: Analysis of the tracings revealed that nifedipine strongly inhibited the sigmoid myoelectric response to the meal. This response was also significantly reduced in those taking verapamil compared with the placebo group, although to a much lesser extent than in those taking nifedipine. CONCLUSIONS: We conclude that constipation as a result of some calcium channel blockers may be caused by inhibition of colonic motor activity by nifedipine and, to a lesser extent, by verapamil. The latter compound probably displays other mechanisms (reduced colonic transit, increased water absorption) also responsible for this side effect.

Fox J, Della-Santina CP. Oral verapamil and calcium and vitamin D metabolism in rats: effect of dietary calcium. Am J Physiol 1989 Nov;257(5 Pt 1):E632-638.

Fuhr U. Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance. Drug Saf. 1998 Apr;18(4):251-72. (Review)
Abstract: Concomitant intake with grapefruit juice increases the concentrations of many drugs in humans. The effect seems to be mediated mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine wall. This results in a diminished first pass metabolism with higher bioavailability and increased maximal plasma concentrations of substrates of this enzyme. The effect was most pronounced in drugs with a high first pass degradation and in many cases has the clear potential to reach clinical relevance, as shown by an occasional change in drug effects or tolerability. For felodipine, nitrendipine, nisoldipine and saquinavir, the interaction was most marked with median increases of area under the curve (AUC) and/or the maximum (peak) plasma drug concentration after single-dose administration (Cmax) values exceeding 70% of respective control periods. Less pronounced, but possibly relevant, concentration increases were found for nifedipine, nimodipine, verapamil, cyclosporin, midazolam, triazolam and terfenadine. This list is not complete because many drugs have not been studied yet. The components of grapefruit juice which are the most probable causes of the interactions are psoralen derivatives, but the flavonoid naringenin may also contribute. Concomitant grapefruit juice intake does not generally decrease the variability of drug pharmacokinetic parameters. Therefore, it is recommended that patients refrain from drinking grapefruit juice when they are taking a drug that is extensively metabolised, unless a lack of interaction has already been demonstrated for the drug. It is also recommended that drugs possibly interacting with grapefruit juice should be appropriately labelled. A place for grapefruit juice as a drug-sparing agent in treatment involving expensive medicine cannot be derived from the information currently available on grapefruit juice interactions.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998, 274-275.

Jameson SJ, Hargarten SW. Calcium pretreatment to prevent verapamil-induced hypotension in patients with SVT. Ann Emerg Med 1992 Jan;21(1):68. (Editorial)

King VF, Garcia ML, Himmel D, Reuben JP, Lam YK, Pan JX, Han GQ, Kaczorowski GJ. Interaction of tetrandrine with slowly inactivating calcium channels. Characterization of calcium channel modulation by an alkaloid of Chinese medicinal herb origin. J Biol Chem 1988 Feb 15;263(5):2238-2244.
Abstract: Tetrandrine, a bis-benzylisoquinoline alkaloid derived from the Chinese medicinal herb Stephania tetrandra, is a putative Ca2+ entry blocker whose mechanism of action is unknown. To investigate this mechanism, the effects of tetrandrine were characterized on binding of three chemical classes of Ca2+ entry blockers in cardiac sarcolemmal membrane vesicles. In the range 25-37 degrees C, tetrandrine completely blocks diltiazem binding, partially inhibits D-600 binding, and markedly stimulates nitrendipine binding, with greatest enhancement occurring at 37 degrees C. The potency of tetrandrine is increased 10-fold as temperature is raised from 25 to 37 degrees C. Scatchard analyses indicate that inhibition of diltiazem binding and stimulation of nitrendipine binding result from changes in ligand affinities while inhibition of D-600 binding is due to both an increase in KD and decrease in Bmax of aralkylamine receptors. Ligand dissociation studies reveal that tetrandrine increases D-600 off-rates, decreases nitrendipine off-rates, but has no effect on diltiazem dissociation kinetics. In addition, tetrandrine reversibly blocks inward Ca2+ currents through L-type Ca2+ channels in GH3 anterior pituitary cells. These results indicate that tetrandrine interacts directly at the benzothiazepine-binding site of the Ca2+ entry blocker receptor complex and allosterically modulates ligand binding at other receptors in this complex. These findings suggest that tetrandrine is a structurally unique natural product Ca2+ entry blocker and provide a rationale explanation for the therapeutic effectiveness of this agent.

Krevsky B, Maurer AH, Niewiarowski T, Cohen S. Effect of verapamil on human intestinal transit. Dig Dis Sci 1992 Jun;37(6):919-924.
Abstract: Although constipation is a well-known side effect of calcium channel blockers such as verapamil, this side effect has not been evaluated in a quantitative manner. In a double-blind, randomized, crossover trial, the effect of verapamil (240 mg/day) was compared to placebo in 15 normal male volunteers. Subjects recorded their bowel movements and any side effects. Scintigraphy was used to quantitate gastric emptying, small intestinal transit, and colonic transit. In the study period of four days, verapamil did not change the frequency, consistency, or passage of bowel movements. A significantly increased number of side effects was noted during verapamil treatment--notably abdominal pain and dry mouth. The slope of gastric emptying was not significantly different for verapamil (0.012 +/- 0.02) than for placebo (0.013 +/- 0.001). Distal ileum filling was also not different for verapamil (0.41 +/- 0.13%/min) than placebo (0.33 +/- 0.05%/min). Progression of the colonic geometric center was significantly delayed at 48 hr by verapamil (5.2 +/- 0.4 vs 6.2 +/- 0.23; P less than 0.01). This study suggests that the constipating effect of verapamil is due to a delay of colonic transit and not due to an effect on upper gastrointestinal transit.

Kuhn M, Schriger DL. Low-dose calcium pretreatment to prevent verapamil-induced hypotension. Am Heart J 1992 Jul;124(1):231-232.

Low AM, Berdik M, Sormaz L, Gataiance S, Buchanan MR, Kwan CY, Daniel EE. Plant alkaloids, tetrandrine and hernandezine, inhibit calcium-depletion stimulated calcium entry in human and bovine endothelial cells. Life Sci 1996;58(25):2327-2335.
Abstract: Depletion of internal Ca2+ stores causes capacitative Ca2+ entry which occurs through non-selective cation channels sensitive to blockade by SK&F 96365. Recently, alkaloids of Chinese herbal medicinal origin, tetrandrine and hernandezine, have been shown to possess actions including inhibition of Ca2+ channels in non-excitable cell types. In this study, we compared the actions of these novel inhibitors to those of SK&F 96365 in fura-2-loaded endothelial cells from human umbilical vein and bovine pulmonary artery. Depletion of Ca2+ from the internal stores was accomplished in Ca(2+)-free medium using an endoplasmic reticulum Ca2+ pump inhibitor, cyclopiazonic acid (CPA) or receptor agonists, histamine and bradykinin. Stimulation with histamine or bradykinin caused a marked and rapid transient increase in Ca2+ signal whereas CPA caused a smaller amplitude increase of longer duration. Restoring Ca2+ to the medium caused marked and sustained increases in the fluorescence indicating movement of Ca2+ into the cytosol presumably stimulated by the emptied Ca2+ stores. SK&F 96365 as well as tetrandrine and hernandezine antagonized depletion-induced Ca2+ entry. The results suggest that these putative inhibitors interact with Ca2+ entry triggered by depletion of the internal Ca2+ stores and their action is presumed to be on the non-selective cation channels. Their effectiveness may be enhanced by the mechanisms which lead to the opening of the Ca2+ influx channel.

Melis MS. Influence of calcium on the blood pressure and renal effects of stevioside. Braz J Med Biol Res. 1992;25(9):943-949.
Abstract: 1. The effects of verapamil (V, 0.015 mg/min, i.v.) or CaCl2 (800 mEq/l, 0.025 ml kg-1 min-1, i.v.) on renal function and mean arterial pressure (MAP) were evaluated in male Wistar rats weighing 280-320 g during treatment with stevioside (S, 16 mg kg-1 h-1, i.v.). 2. Verapamil administered to 10 rats significantly increased the hypotensive effect of stevioside on MAP (control, 124 +/- 0.77; S, 96 +/- 1.50; S+V, 67 +/- 0.70 mmHg) and on fractional sodium excretion (control, 0.76 +/- 0.05; S, 1.56 +/- 0.10; S+V, 2.72 +/- 0.25%). Urinary flow, reported as percent glomerular filtration rate (V/GFR), and renal plasma flow (RPF) increased slightly but not significantly during stevioside plus verapamil administration. 3. In contrast, infusion of CaCl2 in 10 rats pretreated with stevioside induced a marked attenuation of MAP (control, 119 +/- 1.83; S, 70 +/- 1.12; S+CaCl2, 109 +/- 1.60 mmHg) and RPF (control, 16.73 +/- 3.76; S, 34.33 +/- 2.55; S+CaCl2, 17.20 +/- 2.87 ml min-1 kg-1). The diuresis and natriuresis induced by stevioside were also inhibited by simultaneous administration of CaCl2. 4. These data are consistent with the view that stevioside acts on arterial pressure and renal function as a calcium antagonist, as is the case for verapamil.

Melis MS, Sainati AR. Effect of calcium and verapamil on renal function of rats during treatment with stevioside. J Ethnopharmacol. 1991 Jul;33(3):257-262.
Abstract: A study conducted on rats using classical clearance techniques and arterial pressure measurements showed that stevioside from Stevia rebaudiana leaves produced a fall in systemic blood pressure, as well as diuresis and natriuresis per milliliter of glomerular filtration rate. Verapamil tended to increase the renal and systemic effects of stevioside. In contrast, an infusion of CaCl2 in rats prepared with stevioside induced a marked attenuation of the vasodilating responses of stevioside. These data are consistent with the possibility that stevioside may act as a calcium antagonist, as is the case for verapamil.

Smits P, Thien T, van't Laar A. Influence of slow calcium-channel blockade on the cardiovascular effects of coffee. Eur J Clin Pharmacol 1986;30(2):171-175.

Stockey IH. Drug Interactions, 4th Edition, London: Pharmaceutical Press, 1996.

Threlkeld DS, ed. Diuretics and Cardiovasculars, Calcium Channel Blocking Agents. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Nov 1992.

Zaidenstein R, Dishi V, Gips M, Soback S, Cohen N, Weissgarten J, Blatt A, Golik A. The effect of grapefruit juice on the pharmacokinetics of orally administered verapamil. Eur J Clin Pharmacol 1998 Jun;54(4):337-340.
Abstract: OBJECTIVE: To investigate the effect of grapefruit juice (GJ) on the pharmacokinetics of orally administered verapamil in hypertensive patients. METHODS: Ten hypertensive patients on chronic verapamil treatment participated in a two-day study. On day 1 200 ml of water was given 1 hour before, and together with the morning verapamil dose; on the day 2, water was replaced by GJ in the same order. Serial blood samples were collected and the concentrations of verapamil and its main dealkylated metabolite (D-617) were determined by high-performance liquid chromatography (HPLC). The area under the concentration versus time curve of verapamil (AUCv) and its metabolite D-617 (AUCM) were calculated before and after GJ ingestion. The peak serum concentration (Cmax) and the time until its appearance (tmax) were also determined. RESULTS: GJ did not affect Cmax, tmax, AUCv or AUVm. The AUCv/AUCm ratio (AUCR) was slightly, but significantly, increased after GJ (1.67 vs 1.92). CONCLUSIONS: A single administration of GJ with short-acting verapamil has no significant effect on the pharmacokinetics, of verapamil.