Effect of cimetidine and ranitidine on cardiovascular drugs

Robalino

29.

30.

31.

32. 33.

et al.

American

ventricular infarction, and related conditions. J Am Co11 Cardiol 1985;6:1083-95. Kopelman HA, Forman MB, Wilson H, Kolodgie FD, Smith RF, Friesinger GC, Virmani R. Right ventricular myocardial infarction in patients with chronic lung disease: possible role of right ventricular hypertrophy. J Am Co11 Cardiol 1985: 5:1302-7. Forman M, Goodin J, Phelan B, Kopelman H, Virmani R. Electrocardiographic changes associated with isolated right ventricular infarction. J Am Co11 Cardiol 1984;4:640-3. Antonelli D, Schiller D, Kaufman N, Barzilay J. Isolated right ventricular infarction: a diagnostic challenge. Cardiology 1984;71;273-6. Vesterby A, Steen M. Isolated right ventricular myocardial infarction. A case report. Acta Med Stand 1984;216:233-5. Weiss AT, Flugelman MY, Lewis BS, Raz I, Halon DA, Gots-

34.

35.

36. 37.

man MS. Isolated right ventricular infarction with ventricular tachycardia. AM HEART J 1984;108:425-6. Bellamy GR, Hollman J. Isolated right ventricular infarction following percutaneous transluminal coronary angioplasty. AM HEART J 1986;111:168-9. Kriwisky M, Ackerman Z, Mosseri M, Gotsman MS, Hasin Y Right ventricular infarction: unusual electrocardiographic and electrophysiologic manifestations. Clin Cardiol 1987; 10:57-61. Erhardt LR, Sjogren A. Electrocardiographic changes in right ventricular infarction. Acta Med Stand 1978;204:331-3. Lew AS, Maddahi J, Shah PK, Weiss AT, Peter T, Berman DS, Ganz W. Factors that determine the direction and magnitude of precordial ST-segment deviations during inferior wall acute myocardial infarction. Am J Cardiol 1985;55:883-8.

Effect of cimetidine and ranitidine cardiovascular drugs Anne M. Baciewicz, PharmD,

July 1989 Heart Journal

on

and Frank A. Baciewicz, Jr., MD. CYeue2and and

Toledo, Ohio

The Hz receptor antagonists effectively decrease gastric acid secretion and have been shown to be efficacious in peptic ulcer disease and in the ZollingerEllison syndrome. Additionally, the drugs are used in the treatment of acute gastrointestinal bleeding, gastroesophageal reflux, gastritis, pancreatic insufficiency, for prophylaxis of stress ulceration, and for prevention of pulmonary acid aspiration syndrome associated with anesthesia.1 These agents are widely prescribed by the clinician and most likely will be taken with other medications. Therefore the potential for Hz receptor antagonist-related interactions with cardiovascular drugs exists. Several mechanisms have been postulated for the interactions that may occur between cimetidine or ranitidine and other drugs. Some proposed theories are: (1) impaired P-450 hepatic drug metabolism due to inhibition of hepatic microsomal enzymes; (2) re-

duced hepatic blood flow resulting in decreased clearance of drugs that are highly extracted by the liver; (3) competition in the renal tubules for secretion and excretion between two drugs. Select drugs may interact with one Ha antagonist but have no effect on the other Hz blocker. This is possibly due to differences in (1) binding affinity to the P-450 enzyme system between cimetidine and ranitidine; (2) potency of the agents; (3) dose-dependent effect between high and low doses of the H2 antagonist, especially cimetidine; and (4) lipophilicity of the H:! blockers. Interactions may be classified as pharmacokinetic if drug absorption, distribution, metabolism, or excretion are affected, while a pharmacodynamic interaction constitutes a clinically significant change in the biochemical or physiologic effects of a drug.2 This article will review studies and case reports of interactions between Hz antagonists and cardiovascular drugs. BETA

From the Department of Pharmacy Services, University Hospitals of Cleveland; and the Department of Surgery, Medical College of Ohio, ‘roledo. Received for publication Jan. 9, 1989; accepted March 1, 1989. Reprint requests: Anne M. Baciewicz, PharmD, Dept. of Pharmacy Services, University Hospitals of Cleveland, 2074 Abington Rd., Cleveland, OH 44106. 144

BLOCKERS

Propranolol, metoprolol, and atenolol are commonly used beta blockers. Propranolol has a high hepatic extraction ratio and is almost completely eliminated by hepatic metabolism. According to pharmacokinetic principles, drugs with high hepatic

Volume Number

118 1

extraction ratios have systemic clearance determined mainly by liver blood flow, while oral clearance is determined primarily by decreases or increases in the drug metabolizing enzyme activity in the liver. Metoprolol has an intermediate hepatic extraction ratio, therefore mainly hepatic metabolizing enzyme activity is noted, with possibly some liver blood flow activity. Conversely, atenolol and nadolol, which are primarily excreted unchanged by the kidneys, should not interact with the Hz blockers. Propranolol. Donovan et a1.3 observed a patient who had profound sinus bradycardia and hypotension when a beta blocker was added to their cimetidine regimen. They studied one patient with a duodenal ulcer who received 6 weeks of cimetidine, 200 mg orally three times daily and 400 mg at night, both before and after a single oral 80 mg propranolol dose. There was a 340 % increase in oral propranolol’s area under the concentration time curve (AUC) in the presence of cimetidine. Warburton et a1.4 studied the effects of either cimetidine, 200 mg orally three times daily plus 400 mg at night for 2 days, propranolol, 400 mg orally every 6 hours for 4 days, or a combination of cimetidine and propranolol as described above in 10 volunteers. Cimetidine did not alter heart rate or blood pressure nor exaggerate the effect of beta blockade by propranolol. Heagerty et al5 assessed the influence of 2 weeks of cimetidine, 200 mg orally three times daily and 400 mg at night, and no treatment on a single oral 80 mg propranolol dose in six patients with peptic ulcer. The mean blood propranolol concentrations were higher during the sample period when cimetidine was given concurrently, with the difference being statistically significant between 1 and 4 hours. Propranolol’s AUC was significantly higher (60%) during cimetidine administration. The data were interpreted as a reduction of the first-pass extraction of propranolol by cimetidine. Heagerty et al6 studied the effects of ranitidine, 150 mg orally twice daily for 2 weeks, and no treatment on a single oral 80 mg propranolol dose. There was no significant difference between propranolol’s AUC or plasma levels for ranitidine or the control group. Feely et a1.7 studied the influence of cimetidine on liver blood flow and propranolol metabolism. They observed that a single oral 600 mg dose of cimetidine reduced liver blood flow over the short term by 25 % as measured by indocyanine green clearance in eight normal subjects. Long-term cimetidine therapy, 300 mg orally four times daily for 7 days, reduced hepatic blood flow by 33 % as measured by simultaneous administration of 80 mg oral and 40 &i intravenous

Hz antagonist-cardiovascular

drug interactions

145

propranolol. The systemic and oral clearance of propranolol fell by 27 % and 19%) respectively, after treatment with cimetidine. No significant effect on propranolol’s half-life, volume of distribution (Vd), protein binding, or bioavailability was noted. There was also a significantly lower resting heart rate after propranolol and cimetidine administration as opposed to propranolol alone. This study suggested that cimetidine reduced the oxidative metabolism of propranolol, possibly related to cimetidine’s imidazole ring structure. Rielly et al.* observed the effects of cimetidine, 600 mg orally twice daily for 6 days alone, and when given with a single oral 80 mg and 50 &i intravenous propranolol dose to nine volunteers. Cimetidine reduced propranolol’s oral clearance by 50% and increased propranolol’s bioavailability by 11% . This was consistent with inhibition of drug metabolism. Indocyanine green clearance and hepatic plasma flow measured by the propranolol dual route technique did not change after cimetidine administration, in contrast to the findings of Feely et al7 Kirch et a1.g and Mutschler et allo studied the effects of propranolol, 80 mg orally twice daily for 7 days, followed by a week of combined therapy with cimetidine, 200 mg orally three times daily and 400 mg at night, in six volunteers. The mean peak plasma propranolol level increased by 95 % and propranolol’s AUC increased by 95% with cimetidine. No inhibition of exercise-induced tachycardia was evident when comparing monotherapy and combined therapy. Propranolol did not significantly alter cimetidine kinetics. Other authorsllv l2 have noted similar findings of the effects of cimetidine on propranolol. Pate1 and Weerasuriya13 did a placebo-controlled, single-blind, randomized study in 12 volunteers to investigate the disposition of a single 0.15 mg/kg intravenous dose of propranolol after placebo, cimetidine, 300 mg orally twice daily and 400 mg at night, and ranitidine, 150 mg orally twice daily, were administered on separate occasions for 4 days. Cimetidine caused a significant decrease (20 % ) in propranolol’s clearance and a significant increase (24 % ) in propranolol’s AUC. Ranitidine caused no significant change in any propranolol parameter. Reimann et all4 studied the effects of cimetidine, 1000 mg daily in a 1 day pretreatment, and ranitidine, 300 mg daily in 1 and 6 days pretreatment after 7 days of treatment with propranolol, 160 mg sustained release once daily, in five normal subjects. Physical exercise or isoproterenol sensitivity testing increased plasma propranolol levels from 25 % to 67 % with cimetidine but remained unchanged with ranitidine. Heart rate and blood pressure were not influenced by

146

Baciewicz

and Baciewicz

either HZ antagonist. However, the authors thought that if higher propranolol doses are needed, possible reinforcement of beta blocking effects may manifest if propranolol and cimetidine are taken concurrently. Donn et a1.15 investigated the influence of Hz antagonists on the steady-state concentration of propranolol and 4-hydroxypropranolol. Twelve volunteers were treated with cimetidine, 300 mg orally four times daily, ranitidine, 300 mg daily, or a control preparation for seven days, by a Latin-square design. Propranolol, 80 mg orally every 12 hours for nine doses, was initiated on the third day of each treatment period. Cimetidine treatment was associated with a 47 % increase in propranolol’s AUC and a 17 % increase in propranolol’s elimination half-life. There was a significant decrease in the average li-hydroxypropranolol-to-propranolol steady-state concentration ratio during cimetidine therapy. Ranitidine had no significant effect on the concentration time profile of propranolol. No significant difference in heart rate was noted during any of the treatments. The increase in propranolol concentrations during cimetidine treatment appears to be due to a decrease in metabolic metabolism without alterations in hepatic blood flow. Similar findings were noted in another study by this same group of investigators16 comparing the effect of cimetidine dose timing on oral propranolol kinetics in adults. Metoprolol. Kirch et al99 r7and Mutschler et al.1° studied the effects of metoprolol, 100 mg orally twice daily for 1 week, followed by a week of concomitant administration with cimetidine, 200 mg orally three times daily and 400 mg at night, in six volunteers. Cimetidine increased metoprolol’s mean peak plasma level and AUC by 65 % and 62 % , respectively. No inhibition of tachycardia was noted during monotherapy or combined therapy. Metoprolol did not significantly alter cimetidine kinetics. Houtzagers et a1.18 investigated the effect of a single oral 100 mg dose of metoprolol alone and during concomitant cimetidine therapy, 200 mg orally three times daily and 400 mg at night, in seven patients. Cimetidine caused no change in metoprolol’s AUC or elimination rate. The beta-adrenoreceptor blocking effect was the same for metoprolol alone or when it was combined with cimetidine. Ellis et alI9 observed similar findings. These results differ from those of Kirch et al.g, l7 and Mutschler et al.,1° possibly due to differences in the treatment period of beta blockers. The former studies determined the plasma levels after 7 days of metoprolol therapy while the latter studies used a single metoprolol dose. Mutschler et al.1° also studied the interaction between metoprolol, 100 mg orally twice daily, and ranitidine, 150 mg orally twice daily, for 1 week in six

American

July 1989 Heart Journal

volunteers. Ranitidine enhanced peak plasma metopro101 levels by about 30 % . Kirch et a1.l’ and Spahn et a1.20 studied the influence of ranitidine, 150 mg orally twice daily on metoprolol, 100 mg orally twice daily, after concurrent therapy for 7 days in six volunteers. They also investigated the kinetics of metopro101 alone for ‘7 days. Ranitidine increased both metoprolol’s AUC and mean peak plasma level by about 50 % and 33 % , respectively. Ranitidine had no effect on the pharmacodynamics of metoprolol. A flaw of the study by Spahn et a1.20 was that monotherapy and combined therapy were separated by 10 months. Kelly et a1.21 examined the effects of ranitidine on the pharmacokinetics of metoprolol in two studies. In the first study, the pharmacokinetics of single oral 100 mg and 50 mg intravenous doses of metoprolol were assessed in six subjects before, during, and after ranitidine, 150 mg orally twice daily for 1 week. Ranitidine did significantly increase oral metoprolol’s mean peak plasma concentration (60%) and AUC (34%). In the second randomized, double-blind study, 12 subjects received metoprolol, 100 mg orally twice daily for 1 week, once with ranitidine, 150 mg orally twice daily, or placebo. Ranitidine had no effect on the chronic dose pharmacokinetics or pharmacodynamics of metoprolol. Possibly, the effect of ranitidine on single doses of metoprolol is due to absorption or to some unknown mechanism. Kendall et a1.22investigated the effects of a single, oral 100 mg metoprolol dose on ranitidine, 300 mg orally once daily, cimetidine, 800 mg orally once daily, or placebo for 8 days using a Latin crossover design in eight volunteers. Cimetidine significantly increased metoprolol’s peak plasma concentration (50%) and AUC (18%). Ranitidine had no effect on metoprolol. Toon et a1.23assessed the effects of concomitant Hz antagonists on metoprolol in 12 volunteers. Each subject received three 8-day treatments of metoprolol, 100 mg orally every 12 hours, with concurrent once-daily oral administration of either cimetidine, 800 mg, ranitidine, 300 mg, or placebo. Metoprolol pharmacokinetics were assessed for racemic metopro101 and the individual (R) and (S) enantiomers. Cimetidine did not effect the pharmacodynamics of metoprolol, but did produce a 60% increase in metoprolol’s AUC through inhibition of enzymes responsible for first-pass elimination of the beta blocker. The effect was stereoselective (40%) for the less pharmacologically active (R) enantiomer. Ranitidine had no effect on metoprolol. Atenolol. Kirch et a1.g and Mutschler et a1.l” studied the effects of atenolol, 100 mg orally daily for 7 days, followed by a week of combined therapy with

Volume Number

118 1

cimetidine, 200 mg orally three times daily and 400 mg at night, in six volunteers. Cimetidine did not alter atenolol pharmacokinetics or tachycardia. Atenolol did not significantly alter cimetidine pharmacokinetics. Ellis et al.lg observed similar findings. Houtzagers et al.18 investigated the effect of a single oral 100 mg atenolol dose alone and during combined cimetidine administration, 200 mg orally three times daily and 400 mg at night, in seven patients. Cimetidine caused no change in atenolol’s AUC but a significant increase (21% ) in atenolol’s half-life was noted after pretreatment with cimetidine. The beta blocking effect was not changed by the addition of cimetidine. Possibly cimetidine affects atenolol’s clearance by decreasing renal function or by increasing atenolol’s Vd. These results differ from those of Kirch et aLg and those of Mutschler et al.,1° possibly due to differences in treatment regimens of beta blockers. Mutschler et al.1° and Spahn et a1.20 studied the pharmacokinetics of atenolol, 100 mg orally daily for 7 days, in six volunteers. Additionally, they assessed the effect of ranitidine, 150 mg orally twice daily, on atenolol for 7 days. Ranitidine had no pharmacokinetic or pharmacodynamic effect on atenolol. The study by Spahn et ab20 was influenced by the separation of monotherapy and combined therapy by 10 months. Several authors have investigated the effect of Ha antagonists on pindolol,1° nadolol,l’ and labetalol.24 Cimetidine used orally in combination with propranolol may increase propranolol plasma concentrations and potentiate beta blocking effects. A patient’s cardiac and hemodynamic status should be closely monitored and necessary dosage adjustments should be made when both drugs are given concurrently. Cimetidine appears to reduce the oral clearance of propranolol by inhibition of hepatic microsomal enzymes. Possibly increased bioavailability of propranolol may occur by a decrease in first-pass hepatic extraction. Cimetidine may possibly reduce the systemic clearance of propranolol by reducing hepatic blood flow, although the mechanism is questioned.8l 25y26 Ranitidine has no effect on propranolol. Cimetidine given simultaneously with metoprolol may cause an increase in plasma metoprolol concentrations or bioavailability through inhibition of P450 hepatic metabolizing enzymes. No effect of cimetidine on metoprolol pharmacodynamics was noted. Ranitidine had no effect on metoprolol’s pharmacokinetics or pharmacodynamics. Metoprolol may be safely administered concurrently with the Hz antagonists. Neither cimetidine nor ranitidine significantly alters the pharmacokinetics or pbarmaco-

Hz antagonist-cardiovascular

drug interactions

147

dynamics of atenolol. Atenolol may be the drug of choice in patients receiving cimetidine or ranitidine, as no interaction has been noted. CALCIUM

CHANNEL

BLOCKERS

Several reports have appeared in the literature of Hz antagonist-calcium channel blocker interactions, particularly for nifedipine. Adams et a1.27studied the effect of single dose nifedipine in a basal state and 2 hours after oral ranitidine, 300 mg, in six volunteers. Ranitidine caused a significant increase (32 % ) in nifedipine’s bioavailability through suppression of gastric acid secretion. Kirch et a1.28 assessed the influence of ranitidine, 300 mg orally once daily, on nifedipine pharmacokinetics in seven volunteers. Ranitidine increased nifedipine’s mean peak plasma levels about 70 % and the AUC above 18%. A pharmacodynamic interaction was not evident between ranitidine and nifedipine. The authors thought ranitidine may cause dose-dependent interactions with nifedipine, which is biotransformed by oxidative liver metabolism. Kirch et a 1.17,2g studied the effect of nifedipine, 10 mg orally four times daily for 1 week, alone and after concurrent l-week administration with cimetidine, 200 mg orally three times daily and 400 mg at night, or ranitidine, 150 mg orally twice daily, in six volunteers. Simultaneous administration of cimetidine and nifedipine caused a significant increase of 80% in both nifedipine’s AUC and its maximum plasma levels. Additionally, mean arterial blood pressure fell by 13 % when nifedipine and cimetidine were administered concurrently to seven volunteers. Concomitant administration of ranitidine and nifedipine caused a nonsignificant rise of 25% in nifedipine’s AUC and maximum plasma levels. No effect was observed pharmacodynamically between ranitidine and nifedipine. Smith et a130 investigated the effects of cimetidine, 800 mg orally once daily, or ranitidine, 300 mg orally once daily, for 5 days on the disposition of single (20 mg orally) or multiple (10 mg orally three times daily for 5 days) doses of nifedipine in placebo-controlled crossover studies with 12 volunteers. Cimetidine produced a significant increase in nifedipine’s AUC for both single (77 % ) and multiple (92 % ) doses. The peak steady-state nifedipine concentration was significantly greater (67 % ) during cimetidine administration. Ranitidine did not produce any changes in nifedipine kinetics. Cimetidine influenced nifedipine pharmacokinetics through inhibition of the oxidative hepatic pathway. Schwartz et al.“l assessed the effect of cimetidine or ranitidine on single (10 mg orally) and multiple (20 mg orally three times daily for 1 week) doses of nife-

148

Baciewicz and Baciewicz

dipine. Cimetidine, 300 mg orally four times daily, was received by 11 healthy subjects and ranitidine, 150 mg orally twice daily, was given to 12 subjects in combination with nifedipine. Cimetidine administration significantly increased nifedipine’s AUC by approximately 80% and 52 % for single and multiple doses, respectively. Nifedipine’s clearance was decreased by 50% and 43%) respectively, for single and multiple doses by concurrent cimetidine therapy. Nifedipine kinetics did not differ between single and multiple dosing. Cimetidine given concomitantly with nifedipine, either single or multiple dose, caused an approximate doubling of the heart rate both in the supine and standing positions that was of a longer duration than after nifedipine administration alone. Ranitidine coadministration did not alter nifedipine pharmacokinetic or pharmacodynamic responses. These results are likely due to decreased hepatic clearance of nifedipine by cimetidine through P-450 cytochrome inhibition. Three studies32-34 have assessed the interaction between Hz antagonists and diltiazem or verapamil. Patients receiving cimetidine and nifedipine concurrently should be monitored for pharmacodynamic alterations in heart rate and blood pressure. Cimetidine appears to increase both nifedipine’s peak concentration and AUC, probably due to inhibition of oxidative liver metabolism. Ranitidine has no effect on nifedipine’s pharmacokinetics or pharmacodynamics. Studies are needed for the other calcium channel blockers, diltiazem and verapamil, during concomitant administration with an HZ antagonist. ANTIARRHYTHMIC

AGENTS

Lidocaine is a drug with a high liver blood flow and a narrow therapeutic index. Consequently, any agent that could decrease hepatic blood flow could potentially cause lidocaine toxicity. Alterations in the oxidative metabolism of lidocaine could also potentially alter lidocaine kinetics. Studies35> x have shown that the systemic clearance of lidocaine decreases approximately 35% over 24 hours. Feely et a1.,37 in a randomized placebo-controlled study in six volunteers, examined the influence of cimetidine, 300 mg orally four times daily for 1 day, on the disposition of lidocaine, 1 mg/kg, by a lo-minute intravenous infusion. Cimetidine reduced lidocaine’s systemic clearance, Vd, and plasma protein binding by 25 % , 7 % , and 7 % , respectively. The mean peak lidocaine concentration was 50% higher during cimetidine administration, with 83% of patients noting symptoms of lidocaine toxicity. Bauer et a1.38 studied the effects of a single 2 mg/kg intravenous bolus of lidocaine alone and following 3 days of cimeLidocaine.

July American

Heart

1989 Journal

tidine, 300 mg orally every 6 hours, in seven volunteers. Cimetidine decreased lidocaine’s mean clearance by 30% and increased lidocaine’s half-life by 40%. Due to decreased clearance, higher lidocaine levels were seen during cimetidine therapy. Wing et a1.3g assessed the effects of pretreatment with cimetidine, 200 mg orally three times daily and 400 mg at night for 3 days, on the disposition of lidocaine in 18 healthy subjects. Lidocaine was given both orally, 200 mg, and intravenously, 75 or 100 mg, on separate occasions before and after cimetidine. After cimetidine, lidocaine’s systemic clearance and Vd decreased 21% and 20%. Cimetidine also decreased lidocaine’s oral clearance by 42% and increased the oral bioavailability by 33 % . The effects of cimetidine on lidocaine parameters were similar in both sexes. The results suggest that cimetidine reduces metabolic clearance of lidocaine through hepatic extraction. Knapp et a1.4* investigated the effect of cimetidine on lidocaine. They studied 21 patients receiving lidocaine, 2 to 3 mg/min infusions for 26 hours, after an initial bolus of 1 mg/kg. Six patients received lidocaine only, while 15 patients received cimetidine, 300 mg orally every 6 hours for 1 day, in combination with lidocaine. An average rise of serum lidocaine levels of 64% was noted in 93% of patients receiving both cimetidine and lidocaine. Six of 15 patients (40%) had lidocaine levels in the toxic range, with two patients (13 % ) being symptomatic. No change was observed in the control group. Patterson et a.41 studied the influence of a continuous cimetidine infusion, 0.75 mg/kg/hr for 12 hours, on lidocaine plasma concentrations after a minimum 8-hour lidocaine infusion in six patients with suspected myocardial infarction (MI). Total and unbound lidocaine plasma concentrations before, during, and after administration of cimetidine were not consistent with a large decrease in lidocaine clearance. Cimetidine did not cause a significant increase in the rate of lidocaine infusion. Cimetidine’s effect on lidocaine clearance is probably due to inhibition of lidocaine metabolism. The lack of effect of cimetidine on lidocaine parameters might possibly be due to lower cimetidine hepatic tissue levels with continuous infusion, with higher levels produced by intermittent oral or intravenous therapy. This could explain the discrepancy between studies. Berk et al.“” administered cimetidine, 300 mg orally every 4 hours for two doses, in six patients receiving a continuous infusion of lidocaine, 2 mg/min for 11 to 20 hours. Total lidocaine concentrations increased by 8%) 16%) and 28%) at 6,12, and 24 hours after oral cimetidine, respectively. Unbound

Volume

118

Number

1

lidocaine increased by 14% and 18% at 6 and 24 hours following cimetidine administration. In three patients with MI, total lidocaine levels increased by 24 % whereas unbound lidocaine levels increased by 9% at 24 hours after cimetidine. Increases in serum lidocaine levels were considerably less than those reported by Knapp et al.*O and empiric reduction of lidocaine infusion rates during concomitant therapy may not be appropriate. Powell et al.43 studied the effect of lidocaine infusion and the route of cimetidine administration on lidocaine pharmacokinetics in a randomized, threephase crossover study of six healthy men. Lidocaine hydrochloride, 100 mg intravenously, was given over 2 minutes; then 3 hours later a second 100 mg dose of lidocaine was administered, followed by a constant infusion of 2 mg/min for 21 hours. The following treatments were given in a crossover design: a placebo tablet every 6 hours; cimetidine, 300 mg orally every 6 hours beginning 2 days prior to lidocaine; and cimetidine, 300 mg intravenously every 6 hours commencing 1 hour prior to lidocaine administration. Oral cimetidine increased lidocaine’s AUC by 15% and its half-life by 14%. Oral cimetidine significantly increased plasma lidocaine concentrations at 15, 30, and 32 hours. Intravenous cimetidine did not have a significant effect on lidocaine disposition. Lidocaine clearance was 34% lower under steady-state than under single dose conditions, but the effects of cimetidine on lidocaine kinetics were similar under both conditions. Excretion of the metabolite glycinexylidide was decreased by oral and intravenous cimetidine. The data suggest that possibly oral cimetidine has a greater effect on lidocaine disposition than does intravenous cimetidine and that the interaction is caused by an inhibition of drug metabolism. There are discrepancies among the studies, possibly due to small sample size, oral versus intravenous cimetidine administration, differences in pharmacokinetics between healthy volunteers versus patients, and alterations in lidocaine kinetics at steady-state versus single-dose kinetics. Feely and Guy4* noted that a placebo-controlled study pretreatment with ranitidine, 150 mg orally twice daily for 1 day, did not alter the systemic clearance, half-life, or Vd of lidocaine, 1 mg/kg intravenous infusion over 10 minutes, in six volunteers. Robson et a1.45 assessed the effect of pretreatment with ranitidine, 150 mg orally twice daily for 5 days, on the disposition of lidocaine in 10 volunteers. Lidocaine hydrochloride, 250 mg orally or 1.5 mg/kg intravenously, was given to each subject before and after ranitidine. Ranitidine reduced lidocaine’s systemic clearance by 9 % and steady-state Vd by 15 % .

Hz antagonist-cardiovascular

drug interactions

149

Ranitidine did not change any of lidocaine’s parameters after oral administration or manifest any differ,ences in response between the sexes. These effects appear to be due to a small decrease in hepatic blood flow and reduction of tissue binding of lidocaine. Possibly cimetidine does not alter hepatic blood flow but the small change is overshadowed by a much greater reduction by the inhibition of hepatic metabolism. Results differ from those of Feely and Gu~,~* possibly due to pretreatment length, number of subjects, or measurement of plasma versus whole blood. Jackson et a1.46gave lidocaine infusions of 2 mg/kg for 10 minutes to six healthy men. Lidocaine kinetics were studied in an untreated state and in a doubleblind, double-dummy design after 2 days of placebo, cimetidine, 300 mg orally every 6 hours, or ranitidine, 150 mg orally twice daily, Cimetidine significantly decreased lidocaine’s steady-state Vd by 21% with a trend noted toward a decrease (15%) in lidocaine’s clearance. Lidocaine’s Vd appeared limited only by higher levels of al acid glycoprotein. Ranitidine had no significant effect on lidocaine kinetics. Patients should be closely observed when lidocaine is administered intravenously by repeated small doses or by slow infusion simultaneously with cimetidine. Careful monitoring of serum lidocaine concentrations is needed before and during cimetidihe therapy. Patients should be observed for clinical symptoms and/or, signs of lidocaine toxicity. Reduction of lidocaine infusions should not be empiric but should be based on clinical symptomatology and serum lidocaine levels. The mechanism involved in this interaction is possibly a reduction in lidocaine’s systemic clearance, probably caused by a decrease in hepatic blood flow and Vd. Oral rather than intravenous cimetidine may have a greater effect on lidocaine kinetics, suggesting inhibition of oxidative drug metabolism. Ranitidine has no significant effect on lidocaine pharmacokinetics. Quinidine. Several reports of interactions between Ha antagonists and quinidine appear in the literature. Hardy et al. 47 studied the influence of oral cimetidine, 300 mg orally four times daily for 7 days, on the disposition and pharmacodynamics of a single oral 400 mg dose of quinidine in six volunteers. Cimetidine significantly decreased quinidine’s oral clearance by 38% while increasing quinidine’s halflife and peak plasma concentrations by 55% and 21% , respectively. Treatment with cimetidine potentiated electrocardiographic parameters but did not achieve significant differences compared with the administration of quinidine alone. Cimetidine appears to impair the elimination of oral quinidine,

150

Baciewicz and Baciewicz

probably through hepatic enzyme inhibition, reduced liver blood flow, or both. Possibly quinidine absorption may be increased by cimetidine. Kolb et a1.48investigated the effects of a single oral 400 mg quinidine dose alone and after cimetidine, 300 mg orally four times daily for 3 days, was administered to nine volunteers. Cimetidine significantly decreased quinidine’s total body clearance by 25% and increased the half-life and AUC by 23% and 15%, respectively. Farringer et a1.4g observed a patient who developed on two occasions a 50 % increase in plasma quinidine concentrations when cimetidine, 300 mg orally every 6 hours, was added to his quinidine regimen of 300 mg orally every 6 hours. The interaction was evident 48 hours following cimetidine therapy and abated in the same time span when cimetidine was withdrawn. Polish et a1.50 reported a patient who had cimetidine, 300 mg orally or 600 mg intravenously every 6 hours, added to her medication regimen of digitoxin, 0.1 mg daily, and quinidine, 200 mg orally every 6 hours. The patient had a 50% increase in the quinidine dose in the same time period. Signs and symptoms of drug toxicity occurred as well as marked increases in the digitoxin (56 % ) and quinidine (114 % ) concentrations. This case suggests that cimetidine inhibited the metabolism of quinidine and possibly digitoxin or may have reduced the metabolic clearance of quinidine, which subsequently decreased the renal clearance of digitoxin. Iliopoulou et a1.51 reported a patient who developed ventricular premature contractions in the form of bigeminy when ranitidine, 300 mg orally once daily, was added to the quinidine sulfate, 100 mg orally three times daily. Ranitidine did not the serum quinidine levels. This interaction occurs by an unknown mechanism. Patients receiving quinidine and cimetidine concurrently should be observed for enhanced arrhythmic effects and quinidine toxicity. Close monitoring of quinidine levels is warranted, as the drug has a narrow therapeutic index. This interaction would be most significant in patients with liver disease, patients with preexisting near toxic plasma quinidine concentrations, and in the elderly. The mechanism appears to be inhibition of hepatic drug metabolism of quinidine by cimetidine. Ranitidine may also enhance the arrhythmic effect of quinidine. Procainamide. Procainamide is a basic drug predominantly eliminated by the kidneys through active tubular secretion in the proximal tubules. Possibly other basic drugs with similar properties may compete for renal tubular secretion. Somogyi et al.“’ studied the effects of a single 1 gm oral procainamide dose before and during a 1 gm oral cimetidine dose.

American

July 1999 Heart Journal

Cimetidine significantly increased procainamide’s AUC and half-life by 35% and 30%) respectively while procainamide’s renal clearance was reduced by 42 % . Cimetidine significantly increased N-acetylprocainamide’s (NAPA) AUC by 25% due to a significant reduction in NAPA’s renal clearance (24 % ). The data suggest that the tubular secretion of both procainamide and NAPA is inhibited by cimetidine. Christian et a1.5” investigated the effects of a single 1 gm oral dose of procainamide alone and in pretreatment with cimetidine, 300 mg orally four times daily for 3 days, in volunteers. Cimetidine significantly increased procainamide’s AUC and half-life by 40% and 24%) respectively, and decreased procainamide’s renal clearance by 36 % . Cimetidine significantly increased NAPA’s AUC by 26 % without a decrease in renal excretion. The results suggested that cimetidine alters procainamide and NAPA kinetics through both inhibition of active secretion of procainamide by the proximal renal tubule and inhibition of nonrenal clearance. Higbee et a1.54 reported a patient who developed symptoms of procainamide toxicity and increased procainamide and NAPA serum concentrations when cimetidine, 300 to 400 mg orally every 6 hours, was added to the medication regimen. A procainamide dosage reduction of 47%---from 937.5 to 500 mg orally every 6 hours-was necessary to maintain therapeutic procainamide and NAPA serum levels. The interaction occurs at the renal tubular excretory level and may be exaggerated in the elderly due to decreased renal function. Somogyi and Bochner55 studied the pharmacokinetics of a single oral 1 gm procainamide dose alone and during dosing with ranitidine, 150 mg orally twice daily in six volunteers. Additionally, three subjects received ranitidine, 750 mg, with procainamide. Ranitidine significantly increased procainamide’s AUC by 14% while procainamide’s renal clearance decreased by 19 % . Ranitidine significantly increased NAPA’s AUC by 14% due to a reduction in NAPA’s renal clearance of 11% . The larger ranitidine dose produced similar but greater alterations in procainamide and NAPA kinetics, suggesting both dose- and concentration-dependent effects. Ranitidine reduced the absorption of procainamide by 10 % and by 24 % at the higher dose. This study suggests alteration of procainamide and NAPA by ranitidine through competition for active tubular secretion in the kidney and possibly by reduction of gastrointestinal absorption. The interpretation of the data was challenged by Martin.5” Rodvold et a1.57compared the effects of cimetidine

Volume Number

118 1

and ranitidine on steady-state procainamide pharmacokinetics. Six healthy men were given sustainedrelease procainamide, 500 mg orally every 6 hours, for 13 doses on three occasions. Subjects were randomly assigned to receive cimetidine, 300 mg orally four times daily, ranitidine, 150 mg orally twice daily, or control placebo for 4 days. Cimetidine significantly increased both procainamide’s and NAPA’s AUC by 43 % and 43 % , respectively, and decreased procainamide’s and NAPA’s renal clearance by 36% and 27 % , respectively. Ranitidine did not significantly alter procainamide or NAPA steady-state parameters. Cimetidine’s increase in the AUC of procainamide and NAPA was similar to that reported by et a1.53 after Somogyi et a1.52 and by Christian administration of a single dose of rapid release procainamide. In contrast to the study of Somogyi and Bochner,55 which found ranitidine to reduce the clearance of procainamide in a dose- and concentration-dependent manner, no effect was seen in this study. Patients should be carefully monitored when they receive both procainamide and Hz antagonists concurrently. Cimetidine could significantly increase both procainamide and NAPA serum concentrations, especially in the elderly and in patients with renal dysfunction. Increased serum concentrations could predispose patients to adverse and toxic side effects, necessitating a reduction in procainamide dosage. This interaction appears to be mediated by a reduction of the tubular secretion of procainamide and NAPA by cimetidine. Conflicting results have been found for ranitidine’s influence on procainamide. Possibly, ranitidine may alter procainamide and NAPA kinetics through competition for active tubular secretion or by inhibition of absorption. DIGOXIN

Digoxin is eliminated mainly by renal excretion. Potentially, other drugs that have renal excretion as a major route of elimination may affect digoxin kinetics. Jordaens et a1.58 assessed the effect of oral digoxin, 0.75 mg alone, and with concomitant oral cimetidine, 600 mg, in eight volunteers in a crossover study. Cimetidine had no influence on single-dose digoxin kinetics. Ochs et a1.5g studied the effect of a single intravenous 1.25 mg digoxin dose alone and concurrently with cimetidine, 200 mg orally three times daily and 400 mg at night for 3 days, in 11 volunteers. Pharmacokinetics variables for digoxin were similar between control and cimetidine trials. Cimetidine significantly reduced glomerular filtration rate but did not impair digoxin clearance, suggesting that different

Hz antagonist-cardiouascular

drug interactions

15 1

mechanisms affect the renal clearance of digoxin and cimetidine. Fraley et aL60 studied the effect of oral digoxin, 0.125 or 0.25 mg alone, and then during concurrent administration with cimetidine, 300 mg orally or intravenously fou r times daily for 1 week, in 11 patients with congestive heart failure (CHF). Cimetidine caused a 25% lower mean serum digoxin concentration. This possibly was due to an alteration in the bioavailability of the oral digoxin tablets. Garty et al.sl conducted a randomized crossover acute study in six patients with duodenal ulcers. Each patient received a single 0.75 mg intravenous digoxin dose with and without cimetidine, 200 mg orally three times a day and 400 mg at night. Cimetidine did not significantly alter the pharmacokinetics of digoxin. However, cimetidine reduced the creatinine clearance by 15 % . These findings are similar to those of Jordaens et al.58 and Ochs et a1.,5g who also did short-term studies, while the study of Fraley et a1.60showed opposite results with a steady-state drug administration. Crome et a1.62 studied the interaction between digoxin and cimetidine in a series of studies. In a single dose crossover study in six volunteers, cimetidine, 400 mg orally, increased digoxin’s AUC by 23% and peak plasma concentration by 51% after a single oral 0.5 mg digoxin dose. In repeated dose studies in volunteers taking either digoxin, 0.25 or 0.50 mg daily, coadministration with cimetidine, 400 mg orally four times daily, resulted in a significant increase in plasma digoxin concentrations of 0.15 rig/ml and 0.19 rig/ml, respectively. In another repeated dose study, 11 patients who received long-term digoxin, 0.0625 to 0.25 mg daily for atria1 fibrillation, plus concurrent administration with cimetidine, 400 mg orally four times daily, had no significant effect in plasma digoxin concentrations. Differences in dosage amount and form, measurement of plasma concentration, and disease states could account for discrepancies among studies. Cimetidine did not significantly alter digoxin pharmacokinetics. Cimetidine could possibly decrease serum digoxin concentration because of the decreased oral absorption of digoxin tablets. OTHER DRUGS

Potential interactions may exist between Hz antagonists and other drugs. Further investigation is warranted for pindolol,1° nadolol,ll labetalol 24 verapamil,327 33 diltiazem,34 mexiletine,63p’64 encainide,@ flecainide,66 and captopril.67 Studies need to be done of the interactions between famotidine and cardiovascular drugs.68

152

Baciewicz

and Baciewicz

Table

I. Cardiovascular

American

drug interactions

with

Hz Antagonists

Drug Beta blockers Propranolo13-16 Metoprololgr lo, 17-23 Atenolol% 10,18-20 Calcium channel blockers Nifedipinez7-s1 Lidocaine35-46 Quinidine47-51 Procainamide52-s7 DigoxinSs6* NAPA,

July 1999 Heart Journal

Cimetidine

Ranitidine

Can monitor propranolol level, monitor blood pressure, heart rate Can monitor metoprolol level, no pharmacodynamic effect None

None None None

Can monitor nifedipine level, monitor blood pressure, heart rate Monitor lidocaine level, monitor symptoms of lidocaine toxicity Monitor quinidine level, monitor symptoms of quinidine toxicity, monitor arrhythmias Monitor procainamide and NAPA level, monitor symptoms of procainamide toxicity Monitor digoxin level

None None Same Variable

N-acetylprocainamide.

SUMMARY

A compilation of drug interactions between Hs antagonists and cardiovascular drugs is found in Table I. Cimetidine’s potency, lipophilicity, and affinity for binding to the P-450 cytochrome system can probably be attributed to the drug interactions that have been identified with the Hz antagonists. The mechanism for most cimetidine drug interactions is inhibition of hepatic metabolism. There is conflicting evidence regarding significance of altered liver blood flow for both cimetidine and ranitidine and their influence on other agents. Cimetidine may increase propranolol’s blood concentrations and potentiate beta blocking effects through inhibition of hepatic microsomal enzymes and possibly through reduction of hepatic blood flow. Ranitidine has no effect on propranolol. Cimetidine, when administered concurrently with metoprolol, could possibly cause an increase in plasma metopro101 concentrations or bioavailability through inhibition of hepatic P-450 metabolizing enzymes. No effect of cimetidine on metoprolol pharmacodynamits was evident. Ranitidine has no effect on metopro101 pharmacokinetics or pharmacodynamics. Neither HZ antagonist altered the kinetics or physiologic effects of atenolol. Atenolol is the drug of choice in patients receiving H2 antagonists, since no interaction has been observed. Metoprolol could probably be used safely in most patients, as no change in pharmacodynamics has been evident. Concurrent administration of cimetidine and nifedipine may result in alterations in heart rate and blood pressure. The mechanism is inhibition of oxidative liver metabolism. Ranitidine has no effect on nifedipine. Studies are needed to investigate the interaction between the H:! antagonists and diltiazem or verapamil.

Cimetidine, given concomitantly with lidocaine, may increase lidocaine concentrations and clinical symptoms of lidocaine toxicity. The mechanism involved is probably a reduction in oxidative drug metabolism or liver blood flow. Ranitidine has no significant effects on lidocaine pharmacokinetics. Cimetidine may increase quinidine levels and symptoms of quinidine toxicity. Additionally, enhanced arrhythmic effects may be observed. The interaction probably caused by an inhibition of hepatic drug metabolism of quinidine by cimetidine would be most significant in patients with liver disease and in the elderly. Ranitidine may enhance quinidine’s arrhythmic effect. Cimetidine can possibly increase procainamide and NAPA serum concentrations, especially in the elderly and in patients with r,enal dysfunction, predisposing them to adverse side effects. The interaction is mediated by a reduction of tubular secretion of procainamide and NAPA. Conflicting results have been found for ranitidine’s influence on procainamide and NAPA. Ranitidine, particularly at higher doses, may alter procainamide and NAPA kinetics. Cimetidine did not alter digoxin pharmacokinetics. Concurrent cimetidine and digoxin administration may possibly increase digoxin serum levels due to altered bioavailability of digoxin tablets. Dosage increases or decreases of cardiovascular drugs usually will not be necessary when HZ antagonists are administered simultaneously. Patients should be assessed for signs and/or symptoms of adverse or toxic side effects of their cardiac drugs. Monitoring of lidocaine, quinidine, procainamide, NAPA, and digoxin concentratians is recommended to complement clinical judgment and avoid toxicity. Based on the literature, no significant pharmacokinetic clinical effects on cardiac drugs have been noted

Volume

118

Number

1

with ranitidine, while cimetidine may have significant kinetic effects on propranolol, nifedipine, lidocaine, quinidine, procainamide, and NAPA. Since pharmacokinetics, dosing regimens, and cost of cimetidine and ranitidine are comparable, ranitidine is probably the Hz receptor antagonist of choice to use when concurrent cardiovascular agents are administered. Future investigations will identify other Hz antagonist-cardiovascular interactions. REFERENCES

1.

2. 3. 4. *

5. 6. I. 8. 9.

10.

11.

12.

13. 14.

15.

16. 17.

18.

Berardi RR, Tankanow RM, Nostrant TT. Comparison of famotidine with cimetidine and ranitidine. Clin Pharm 1988; 7~271-84. Powell JR, Donn KH. The pharmacokinetic basis for Hz-antagonist drug interactions: concepts and implications. J Clin Gastroenterol 1983;5(Suppl 095-113. Donovan MA, Heagerty AM, Pate1 L, Castleden M, Pohn JEF. Cimetidine and bioavailability of propranolol (Letter). Lancet 1981;1:164. Warburton S, Opie LH, Kennelly BM, Miiller FO. Does cimetidine alter the cardiac response to exercise and propranolol. S Afr Med J 1979;55:1125-7. Heagerty AM, Donovan MA, Castleden CM, Pohl JF, Pate1 L, Hodges A. Influence of cimetidine on pharmacokinetics of propianolol. Br Med J 1981;282:1917-19. Heagertv AM. Castleden CM. Pate1 L. Failure of ranitidine to interact with propranolol. B; Med J 1982;284:1304. Feely J, Wilkinson GR, Wood AJJ. Reduction of liver blood flow and propranolol metabolism by cimetidine. N Engl J Med 1981;304:692-5. Rielly CS, Biollaz J, Koshakji RP, Wood AJJ. Enprostil, in contrast to cimetidine, does not inhibit propranolol metabolism. Clin Pharmacol Ther 1986;40:37-41. Kirch W. Snahn H. Kahler H. Ohnhaus EE. Mutschler E. Interaction of metoprolol, propranolol and aienolol with concurrent administration of cimetidine. Klin Wochenschr 1982;60:1401-7. Mutschler E, Spahn H, Kirch W. The interaction between Hz-receptor antagonists and @-adrenoreceptor blockers. Br J Clin Pharmacol 1984;17:518-578. Duchin KL, Stern MA, Willard DA, McKinstry DN. Comparison of kinetic interactions of nadolol and propranolol with cimetidine. AM HEART J 1984;108:1084-6. Reimann IW, Klotz U, Siems B, Frijlich JC. Cimetidine increases steady-state plasma levels of propranolol. Br J Clin Pharmacol 1981;12:78&90. Pate1 L. Weerasuriva K. Effect of cimetidine and ranitidine on propranolol clearance [Abstract]. Br Med J 1982;284:152P. Reimann IW, Klotz U, Friilich JC. Effects of cimetidine and ranitidine on steady-state propranolol kinetics and dynamics. Clin Pharmacol Ther 1982;32:749-57. Donn KH, Powell JR, Rogers JF, Eshelman FN. The influence of Hz-receptor antagonists on steady-state concentrations of propranolol and 4-hydroxypropranolol. J Clin Pharmacol 1984;24:500-8. Asharnejad M, Powell JR, Donn KH, Danis M. The effect of cimetidine dose timing on oral _ propranolol kinetics in adults. J Clin Pharmacol 1988;28:339-43. Kirch W, Rlimsch K, Janisch HD, Ohnhaus EE. The influence of two histamine Hz-receptor antagonists, cimetidine and ranitidine, on the plasma levels and clinical effect of nifedipine and metoprolol. Arch Toxic01 1984;7(Suppl):256-9. Houtzagers JJR, Streurman 0, Regardh CG. The effect of pretreatment with cimetidine on the bioavailability and disposition of atenolol and metoprolol. Br J Clin Pharmacol 1982;14:67-72.

Hz antagonist-cardiovascular

drug interactions

153

19. Ellis ME, Hussan M, Webb AK, Barker NP, Fitzsimons TJ. The effect of cimetidine on the relative cardioselectivity of atenolol and metoprolol in asthmatic patients. Br J Clin Pharmacol1984;17:598-648. 20. Spahn H, Mutschler E, Kirch W, Ohnhaus EE, Janish HD. Influence of ranitidine on plasma metoprolol and atenolol concentrations. Br Med J 1983;286:1546-7. 21. Kelly JG, Salem SAM, Kinney CD, Shanks RG, McDevitt DG. Effects of ranitidine on the disposition of metoprolol. Br J Clin Pharmacol 1985;19:219-24. 22. Kendall MJ, Laugher SJ, Wilkins MR. Ranitidine, cimetidine and metoprolol-a pharmacokinetic interaction study [Abstract]. Gastroenterology 1986;90:1490. 23. Toon S, Davidson EM, Garstanh FM, Batra H, Bowes RJ, Rowland M. The racemic metoprolol Hz-antagonist interaction. Clin Pharmacol Ther 1988;43:283-9. 24. Daneshmend TK, Roberts CJC. Cimetidine and bioavailability of labetaolol (Letter). Lancet 1981;1:565. 25. Jackson JE. Reduction of liver blood flow by cimetidine (Letter). N Engl J Med 1981;305:99-100. 26. Lebrec D, Goldfarb G, Behanou P. Reduction of liver blood flow by cimetidine (Letter). N Engl J Med 1981;305:100-1. 27. Adams LJ, Antonow DR, McClain CJ, McAllister R. Effect of ranitidine on bioavailability of nifedipine [Abstract]. Gastroenterology 1986;90:1320. 28. Kirch W, Ohnhaus EE, Hoensch H, Janisch HD. Ranitidine increases bioavailability of nifedipine [Abstrct]. Clin Pharmacol Ther 1985;37:204. 29. Kirch W, Janisch HD, Heidmann H, Rlimsch K, Ohnhaus EE. Influence of cimetidine and ranitidine on the pharmacokinetits and antihypertensive effects of nifedipine. Dtsch Med Wochenschr 1983;108:1757-61. 30. Smith SR, Kendall MJ, Lobo J, Beerahee A, Jack DB, Wilkins MR. Ranitidine and cimetidine; drug interactions with single dose and steady-state nifedipine administration. Br J Clin Pharmacol 1987;23:311-5. 31. Schwartz JB, Upton RA, Lin ET, Williams RL, Benet LZ. Effect of cimetidine or ranitidine administration on nifedipine pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 1988;43:673-80. 32. Smith MS, Benyunes MC, Bjornsson TD, Shand DG, Pritchett ELC. Influence of cimetidine on verapamil kinetics and dynamics. Clin Pharmacol Ther 1984;36:551-4. 33. Loi CM, Dukes GE, Rollins DE, Peat MA. The effect of multiple-dose cimetidine on the pharmacokinetics of verapamil [Abstract]. Drug Intel1 Clin Pharm 1984;18:494. 34. Winship LC, McKenney JM, Wright JT Jr, Wood JH, Goodman RP. The effect of ranitidine and cimetidine on single-dose diltiazem pharmacokinetics. Pharmacotherapy 1985;5:16-19. 35. Bauer LA, Brown ‘I’, Gibaldi M, et al. Influence of long-term infusions on lidocaine kinetics. Clin Pharmacol Ther 1982; 31:433-7. 36. Presott LF, Adjepon-Yamoah KK, Talbot RG. Impaired lidocaine metabolism in patients with myocardial infarction and cardiac failure. Br Med J 1976;1:939-41. 37. Feely J, Wilkinson GR, McAllister CB, Wood AJJ. Increased toxicity and reduced clearance of lidocaine by cimetidine. Ann Intern Med 1982;96:592-4. 38. Bauer LA, Edwards WAD, Randolph FP, Blouin RA. Cimetidine-induced decrease in lidocaine metabolism. AM HEART J 1984;108:413-5.

39. Wing LMH, Miners JO, Birkett DJ, Foenamder T, Lillywhite K, Wanwimolruk S. Lidocaine disposition-sex differences and effects of cimetidine. Clin Pharmacol Ther 1984;35:695701. 40. Knapp AB, Maguire W, Keren G, et al. The cimetidinelidocaine interaction. Ann Intern Med 1983;98:174-7. 41. Patterson JH, Foster J, Powell JR, Cross R, Wargin W, Clark JL. Influence of a continuous cimetidine infusion on lidocaine plasma concentrations in patients. J Clin Pharmacol 1985; 25:607-g.

154

Baciewicz

and Baciewicz

42. Berk SI, Gal P, Bauman JL, Douglas JB, McCue JD, Powell JR. The effect of oral cimetidine on total and unbound serum lidocaine concentrations in patients with suspected myocardial infarction. Int J Cardiol 1987:14:91-4. 43. Powell JR, Foster J, Patterson JH,‘Cross R, Wargin W. Effect of duration of lidocaine infusion and route of cimetidine administration on lidocaine pharmacokinetics. Clin Pharm 1986;5:993-8. 44. Feely J, Guy E. Lack of effect of ranitidine on the disposition of lignocaine. Br J Clin Pharmacol 1985;15:378-9. 45. Robson RA, Wing LMH, Miners JO, Lillywhite KJ, Birkett DJ. The effect of ranitidine on the disposition of lignocaine. Br J Clin Pharmacol 1985;20:170-3. 46. Jackson JE, Bentley JB, Glass SJ, Fukui T, Gandolfi AJ, Plachetka JR. Effects of histamine-2 receptor blockade on lidocaine kinetics. Clin Pharmacol Ther 1985;37:544-8. 47. Hardy BG, Zador IT, Golden L, Lalka D, Schentag JJ. Effect of cimetidine on the pharmacokinetics and pharmacodynamits of quinidine. Am J Cardiol 1983;52:172-5. 48. Kolb KW, Garnett WR, Small RE, Vetrovec GW, Kline BJ, Fox T. Effect of cimetidine on quinidine clearance. Ther Drug Monit 1984;6:306-12. 49. Farringer JA, McWay-Hess K, Clement WA. Cimetidine-quinidine interaction. Clin Pharm 1984;3:81-3. 50. Polish LB, Branch RA, Fitzgerald GA. Digitoxin-quinidine interaction: potentiation during administration of cimetidine. South Med J 1981;74:633-4. 51. Iliopoulou A, Kontogiannis D, Tsoutsos D, Moulopoulos S. Quinidine-ranitidine adverse raction (Letter). Eur Heart J 1986;7:360. 52. Somogyi A, McLean A, Heinzow B. Cimetidine-procainamide pharmacokinetic interaction in man: evidence of competition for tubular secretion of basic drugs. Eur J Clin Pharmacol 1983;25:339-45. 53. Christian CD, Meredith CG, Speeg KV Jr. Cimetidine inhibits renal procainamide clearance. Clin Pharmacol Ther 1984;36:221-7. 54. Higbee MD, Wood JS, Mead RA. Procainamide-cimetidine interaction: a potential toxic interaction in the elderly. J Am Geriatr Sot 1984;32:162-4. 55. Somogyi A, Bouchner F. Dose and concentration dependent

American

56. 57.

58.

59. 60.

61.

62.

63.

64.

July 1989 Heart Journal

effect of ranitidine on procainamide disposition and renal clearance in man. Br J Clin Pharmacol 1984,18:175-81. Martin BK. Effect of ranitidine on procainamide disposition (Letter). Br J Clin Pharmacol 1985;19:858-60. Rodvold KA, Paloucek FP, Jung D, Gallastegui J. Interaction of steady-state procainamide with Hz-receptor antagonists cimetidine and ranitidine. Ther Drug Monit 1987;9:378-83. Jordaens L, Hoegaerts J, Belpaire F. Non-interaction of cimetidine with digoxin absorption. Acta Clin Belg 1981;36:109-10. Ochs HR, Gugler R, Guthoff T, Greenblatt DJ. Effect of cimetidine on digoxin kinetics and creatinine clearance. AM HEART J 1984;107:170-2. Fraley DS, Britton HL, Schwinghammer TL, Kalla R. Effect of cimetidine on steady-state serum digoxin concentrations. Clin Pharm 1983;2:163-5. Garty M, Perry G, Shmueli H, et al. Effect of cimetidine on digoxin disposition in peptic ulcer patients. Eur J Clin Pharmacol 1986;30:489-91. Crome P, Curl B, Holt D, Volans GN, Bennett PN, Cole DS. Digoxin and cimetidine: investigation of the notential for a drug interaction. Hum Toxic01 i985;4:391-9. _ Klein AL, Sami MH. Usefulness and safety of cimetidine in patients receiving mexiletine for ventricular arrhythmia. AM HEART J 1985;109:1281-6. Klein A, Sami M, Selinger K. Mexiletine kinetics in healthy subjects taking cimetidine. Clin Pharmacol Ther 1985;37:66973.

Quart BD, Gallo DG, Sami MH, Wood AJJ. Drug interaction studies and encainide use in renal and hepatic impairment. Am J Cardiol 1986;58:104C-13C. 66. Tjandramaja TB, Verbesselt R, VanHeckon A, VanMelle P, DeSchenner PJ. Oral flecainide kinetics: effects of cimetidine [Abstract]. Circulation 1983;68(Suppl III):III-416. 67. Richer C, Bah M, Cadilhac M, Thuillez C, Giudicelli JF. Cimetidine does not alter free unchanged captopril pharmacokinetics and biological effects in healthy volunteers. J Pharmacol 1986;17:338-42. 68. Klotz U, Arvela P, Rosenkranz B. Famotidine, a new Hzreceptor antagonist, does not affect hepatic elimination of diazepam or tubular secretion of procainamide. Eur J Clin Pharmacol 1985;28:671-5. 65.