6-day treatment began 48 hr later. After a therapy-free interval of 4 wk, the same subjects received the same dose of atenolol with 1 gm ampicillin, 500 mg ...
Atenolol interaction with aspirin, allopurinol, and ampicillin Atenolol kinetics were investigated in six healthy subjects after 100 mg orally, as monotherapy a 6-day treatment began 48 hr later. After a therapy-free interval of 4 wk, the same subjects received the same dose of atenolol with 1 gm ampicillin, 500 mg aspirin, and with 300 mg
allopurinol. Allopurinol and aspirin did not substantially alter the kinetics of atenolol. After a single oral dose of 100 mg atenolol combined with 1 gm ampicillin, the bioavailability of atenolol was reduced to 36 ± 5% compared to 60 ± 8% after monotherapy. During long-term treatment with atenolol and ampicillin the bioavailability of atenolol fell to 24% (P 0.05). Thus, atenolol alone led to a 21%
286
Clin. Pharmaeol. Ther. March 1983
Schafer-Korting et al.
500
4 3 5 2 Atenolol 100 mg a day monotherapy
0-0 fr---AtenoIoI
100 mg +Ampicillin 1g a
7 [days]
a
day
Fig. 2. Mean atenolol plasma levels (-± SEM) during and after long-term treatment with 100 mg atenolol a day and during concurrent administration of 100 mg atenolol with 1000 mg ampicillin a day.
reduction in tachycardia 12 hr after dosing, whereas ampicillin coadministration led to an 11% reduction. Twenty-four hours after ingestion this difference amounted to 9.0% versus 5.5%. Plasma levels 12 and 24 hr after atenolol alone were 190 and 46 ng/ml, whereas they reached values of 118 and 21 ng/ml at the same time intervals when ampicillin taken simultaneously. Blood pressure during daily treatments. Blood pressures over a 4-wk therapy with 100 mg atenolol alone were reduced from mean pretreatment values of 167/111 mm Hg to an average of 142/95 mm Hg after a week of therapy and to 136/92 mm Hg after 4 wk of treatment. There were no significant differences between blood pressures after atenolol alone and after atenolol combined with ampicillin (P > 0.05). After a week of the combination, blood pressure fell to an average of 137/98 mm Hg; after 4 wk it was 139/96 mm Hg. Discussion
Although beta-adrenoceptor blockers are frequently used in angina pectoris and arterial hypertension, only recently has information become available on the effects on the kinetics and dynamics of beta blockers of drugs given concurrently. Donovan et al.3 and Kirch et al.' reported an impressive example of drug interfer-
ence. Cimetidine given simultaneously with propranolol or metoprolol greatly increased the AUC of those lipophilic beta blockers leading, in one patient, to bradycardia and hypotension. Recently in this Journal we reported that kinetics of the more hydrophilic beta blocker atenolol were distinctly altered by calcium.' Mean Cm., AUC, and Au of atenolol were reduced by about 50%, whereas the t1/2 of atenolol nearly doubled, leading to cumulation of the beta blocker during long-term combined treatment. After oral doses of 100 mg atenolol and 500 mg calcium, inhibition of exercise-induced tachycardia induced by the beta blocker was significantly reduced compared to after atenolol alone (P < 0.01).8 F of atenolol proved to be decreased by about 20% to 30% due to use of aluminium hydroxide."' " Kinetics of atenolol were not changed by furosemide. On the other hand, the latter could have been shown to influence the kinetics and dynamics of propranolo1.2 In our present study simultaneous administration of atenolol and allopurinol with aspirin did not result in a kinetic interaction. Antibiotics such as neomycin or paraaminosalicylic acid are known to impair drug absorption due to their toxic effect on the gastrointestinal mucosa.4. 14 Ampicillin has been shown to interact with coumarin anticoagulants and to enhance their effect'. 1°
Volume 33 Number 3
Interactions with atenolol
287
Table HI. Mean heart rate and systolic /diastolic blood pressure values (±SEM) during exercise in six subjects on placebo, 100 mg atenolol, atenolol in combination with
1
gm ampicillin
Time after dosing (hr)
Treatment and
parameters Atenolol, 100 mg Heart rate (bpm) Blood pressure (mm Hg) Atenolol, 100 mg, with ampicillin, 1000 mg Heart rate (bpm) Blood pressure (mm Hg)
Placebo
2
176 ± 5 192 ± 8/
126 ± 5 156 ± 6/ 86 ± 6
125
124 ± 7 172 ± 8/ 88 ± 4
129
105
±
3
179 ± 6 203 ± 5/ 97 ± 5
4
3
154 88
± 3 ± 11/ ± 8
± 7 ± 6/ 88 ± 5
163
126 ± 3 155 ±
8/
84 ± 8
123 ± 3 168 ± 6/
86 ± 6
6
12
24
133 ± 2 165 ± 9/
139 ± 6 180 ± 9/
87 ± 5
89 ± 3
159 ± 3 198 ± 5/ 93 ± 3
136 ± 9 176 ± 10/
88 ± 7
160 ± 6* 197 ± 8/ 93 ± 6
169 ± 4 189 ± 8/
90 ±
8
*P < 0.01 when compared with atenolol alone.
In our study, ampicillin reduced atenolol F from 60% to 36% after a single dose of both drugs (P < 0.01), and to 24% after repeated dosing (P < 0.01). The atenolol plasma levels during long-term dosing are reduced by about one half compared to those after atenolol alone. The kinetic interaction resulted in a significant reduction in inhibition of exercise-induced tachycardia by the beta blocker as compared to that after atenolol alone (P < 0.01). Twelve and 24 hr after combination therapy, exerciseinduced tachycardia was only reduced to 11% and 5.5%, whereas the values after atenolol alone were 24% and 9%. Amery et al .1 showed that atenolol influences exercise heart rate in a dose- and plasma leveldependent manner. During 4 wk treatment with atenolol and ampicillin, the blood pressurelowering effect of atenolol was the same as that after 4 wk on the beta blocker alone. Blood pressure measurements were performed in the morning at about 1 hr after administration, at noon, and in the late afternoon. Our results, obtained from the present study, lead to the following conclusions: With regard to the antihypertensive effect of atenolol, combination therapy with ampicillin requires close clinical control of the treated patients, since 12 hr after the last dose of atenolol and ampicillin blood pressure values during exercise increase over those after atenolol alone. In patients at rest, however, during 4 wk treatment there are no differences in pressure values between the mono-
therapy and the combined treatment phases. Thus, it may be necessary to double the atenolol dose during combination therapy with ampicillin in order to achieve the desired antihypertensive effect. If atenolol is used for treatment of patients with angina pectoris, the dose of atenolol certainly has to be doubled during the period of combination therapy. This therapeutic implication is significant since it may sometimes happen that patients who have to be treated with atenolol might be treated simultaneously with ampicillin for an infectious disease. We are sincerely grateful to Mrs. Silke Podkowik for her excellent technical assistance.
References Amery A, de Plaen JF, Ligner P, McAinsh J, Reybrouck T: Relationship between blood level of atenolol and pharmacologic effect. CLIN PHARMACOL THER 21:691-699, 1977. Chiariello M, Volpe M, Rengo F, Trimarco B, Violini R, Ricciardelli B, Concorelli M: Effect of furosemide on plasma concentration and 0-blockade by propranolol. CLAN PHARMACOL THER 26:433-436, 1979. Donovan MA, Hagerty AM, Patel L, Castleden M, Pohl JEF: Cimetidine and bioavailability of propranolol. Lancet 1:164, 1981. Faloon WW: Drug production of intestinal malabsorption. NY State J Med 70:2189-2192, 1970.
Haller H, Amon I, Amon K: Interaction of nitrofurantoin with other drugs in human organism. International Congress of Chemotherapy, London, 1975, pp. 11-163.
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Kabins SA: Interaction amory antibiotics and other drugs. JAMA 219:206, 1972. Kirch W, Kohler H, Mutschler E, Schafer M: Pharmacokinetics of atenolol in relation to renal function. Eur J Clin Pharmacol 19:65-72, 1981. Kirch W, Schafer-Korting M, Axthelm T, Kohler H, Mutschler E: Interaction of atenolol with furosemide and calcium and aluminium salts. CLIN PHARMACOL THER 30:429-435, 1981. Kirch W, Kohler H, Spahn Hilde, Mutschler E: Interaction of cimetidine with metoprolol, propranolol or atenolol. Lancet 2:531-532, 1981. Koch-Weser J, Sellers EM: Drug interaction with coumarin anticoagulants (second of two parts). N Engl J Med 285:547, 1971. Lundborg P, Regardh C-G: Food, antacids and
Clin. Pharmacol. Ther. March 1983
bioavailability of beta-blockers. International Conference on Drug Absorption, Edinburgh, 1979. Sachs L: Angewandte Statistik. Berlin, 1978, Springer- Verlag, p. 242. Schafer M, Mutschler E: Fluorimetric determination of atenolol in plasma and urine by direct evaluation of thin-layer chromatograms. J Chromatogr 269:477-481, 1979. Toskes PP, Deren JJ: Selective inhibition of vitamin absorption by para-aminosalicylic acid. Gastroenterology 62:1232-1237, 1972. Yesair BW, Blublock FJ, Coffey JJ: The pharmacodynamics of drug interaction. Drug Metab Rev 1:35, 1972.
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