salbutamol.pdf

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Br J Clin Pharmacol 1997; 44 : 573575

Benazepril, an angiotensin converting enzyme inhibitor: drug interaction with salbutamol and bronchial response to histamine in normal subjects

K. G. Bauer, 1 P. Brunel, 2 G. Nell, 2 & G. Quinn 2 & G. A. Kaik 11Department of Clinical Pharmacology, University of Vienna Medical School, Vienna, Austria and

2Medicine and Clinical Development Department, Ciba

Geigy Ltd, Basle, Switzerland

Aims To investigate the e ff ect of the angiotensin converting enzyme inhibitor,benazepril, on pulmonary function.Methods We investigated the inuence of benazepril, on lung function and theinteraction with inhaled salbutamol (0.1 to 6.6 mg) and histamine (0.03 to30.69 g l

1) in normal subjects. Benazepril 20 mg, salbutamol 8 mg, propranolol

160 mg, and placebo were given orally once daily over 10 days.Results On day 8, there was no di ff erence in the area under the salbutamol dose-response curves between benazepril, placebo and oral salbutamol ( P > 0.05),propranolol shifted the curves to the right ( P < 0.05). On day 10, histamine

challenge resulted in following P D 35 sGaw values ( geometric mean and 95% CI):with placebo 1.02 (0.951.09) g l 1, benazepril 1.04 (0.991.08), salbutamol 1.19

(1.131.25), propranolol 0.57 (0.500.65).Conclusions Benazepril had no inuence on baseline lung function, caused nointeraction with inhaled salbutamol and the bronchial response to histamine wassimilar to placebo. However, our ndings in normal subjects cannot be extrapolatedautomatically to asthmatics.

Keywords: inhibitor, angiotensin converting enzyme, benazepril, challenge, histamine,salbutamol, interaction, subjects, normal

written informed consent was obtained. Specic airwayIntroductionconductance (sGaw) was measured by body plethysmography( Jaeger, Germany) and nger tremor by accelerometer (Zak,Adverse airway reactions following angiotensin converting

enzyme (ACE) inhibitors have been reported such as Germany) [5]. Heart rate was assessed by Holter ECG(Hewlett Packard, USA), plasma potassium and bloodincreased bronchial obstruction in asthmatics [1] and cough

in patients with and without previous bronchial hyperreactiv- glucose by ame photometry. Histamine was inhaled froma jet nebulizer (Pari, Germany).ity [13]. Benazepril is the prodrug of benazeprilat, a new

nonsulphhydryl inhibitor of ACE. The antihypertensive Subjects received single daily doses of 20 mg benazepril,8 mg salbutamol, 160 mg propranolol, or placebo over 10effi cacy of benazepril is comparable with that of other drugs,

benazepril improves clinical symptoms and exercise capacity days each in a randomized, double-blind, crossover designwith at least a 7 day washout phase. Assessments werein congestive heart failure [4]. The inuence of benazepril

on respiratory function has not yet been investigated. performed 2 h after administration ( t max ) [4] on days 8 and10, respectively.We investigated the inuence of benazepril on baseline

pulmonary function and on bronchial response to histamine On day 8 of each medication period, increasing doses of salbutamol (0.1, 0.2, 0.3, 0.4, 0.8, 1.6, 3.2 mg) were inhaledin healthy volunteers. Secondly, we assessed the interaction

of benazepril with cumulative doses of inhaled salbutamol. at 20 min intervals. sGaw, tremor, heart rate, and bloodpressure were measured at each dose increment, plasmaPlacebo, propranolol and oral salbutamol were used for

comparison. potassium and blood glucose before and after salbutamolinhalation. On day 10, bronchial response to inhaledhistamine was measured [2, 6]. The initial concentration of Methodshistamine was 0.03 g l

1after inhalation of saline (control).

Histamine concentration was doubled to a maximum of Twenty-four healthy subjects (nonsmokers, mean age 25 years) completed the study. During screening procedure, 15.36 g l

1(maximum cumulative dose of 30.69 g l

1) or

until sGaw decreased by more than 35% of postsalinelung function was tested to guarantee measurable bronchodil-atation (salbutamol) and to exclude bronchial hyperreactivity baseline [2, 7]. sGaw was recorded 30 and 90 s after each

dose. Data were analyzed with an analysis of variance model.(acetylcholine). Approval by the ethics committee and

Response to inhaled salbutamol was expressed as the areaCorrespondence: Professor G. Kaik, Reisnerstrasstrasse 35/16, A-1030 Vienna, under the dose-response curves (AUC) by trapezoidal ruleAustria.

method. The provocative dose of histamine required toReprint requests: Professor G. Kaik, University of Vienna Medical School, ClinicalPharmacology, AHKEbene 6, Waehringer Guertel 18-20, A-1090 Vienna, Austria. cause a 35% fall in sGaw (PD 35 sGaw) was determined by

1997 Blackwell Science Ltd 573


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K. G. Bauer et al.

linear interpolation [2, 7]. The log transformed PD 35 sGaw Discussiondata are presented as geometric mean and 95% condenceintervals (CI). A P value of < 0.05 was considered as being For evaluation of inhalative challenge tests, the provocative

cumulative dose of the respective inhaled irritant requiredof signicance.to cause a 20% fall in FEV 1 [3, 8, 9] or a 35% decrease insGaw [2, 7] is generally accepted. However, baseline sGawResultsvalues were aff ected by the medications. To correct for the

drug eff

ect, calculation of P D corr values has been suggestedBenazepril resulted in postmedication baseline values similar to those after placebo ( P > 0.05) for all parameters (Table 1). [10]. P D corr was dened as that provocative dose of histamine required to cause a FEV 1 value 20% below thePropranolol showed signicantly lower postmedication base-

line values ( P < 0.05) for sGaw, heart rate and tremor minimum placebo postsaline FEV 1 [10]. In our study,evaluation of P D 35corr sGaw showed results similar to thoseamplitude; oral salbutamol resulted in higher baseline values

(P < 0.05) for sGaw and tremor, respectively. No baseline obtained without correction.Single doses of b-adrenoceptor antagonists induced adiff erences occurred between treatments ( P > 0.05) for

blood pressure, blood glucose and plasma potassium. No signicant increase in nonspecic reactivity measured byhistamine or methacholine compared with placebo in mildadverse eff ects were reported.

After benazepril and oral salbutamol, salbutamol dose- asthmatics [8, 10, 11]. In our healthy volunteers propranololresulted in a measurable increase in airway response toresponse was similar to placebo for sGaw, heart rate, tremor

and blood pressure ( P > 0.05), propranolol caused a shift to histamine. Combination therapy of the ACE inhibitors captorilor enalapril with a selective b1 -adrenoceptor antagonist wasthe right ( P < 0.05). AUC for sGaw, heart rate, tremor and

systolic blood pressure di ff ered signicantly between pro- found to result in a higher incidence of bronchial hyperreactivitythan a monotherapy regimen with either ACE inhibitors or pranolol and the other drugs ( P < 0.05); there was no

diff erence in AUC between benazepril, placebo and oral b1 -adrenoceptor antagonists in nonasthmatic hypertensivepatients [9]. The results of a follow-up study suggest ansalbutamol ( P > 0.05). ECG revealed no di ff erences between

medications ( P > 0.05). increased risk of the combination therapy to induce side e ff ectsin the respiratory tract [12]. Otherwise, another study showedPlasma potassium decreased in response to inhaled

salbutamol as follows: with placebo by 0.77 mmol l 1

, that almost half the patients whose blood pressure wasinadequately controlled while receiving atenolol monotherapy,benazepril 0.90, oral salbutamol 0.77, propranolol

0.05 (Table 1). Blood glucose increased with placebo by could produce an additional decrease in blood pressure addingbenazepril as a combination therapy [13].2.33 mmol l

1, benazepril 2.20, oral salbutamol 2.15,

propranolol 0.85 (Table 1). Our results in normal subjects cannot be extrapolatedwithout restrictions to asthmatics. Further drug interactionPresaline and postsaline sGaw values did not di ff er

between medications ( P > 0.05). P D 35 sGaw was 1.02 studies may be performed in hypertensives with concomitantasthma. Our ndings on propranolol induced increase in(0.951.09) g l 1

with placebo, 1.04 (0.991.08) withbenazepril, 1.19 (1.131.25) with salbutamol and 0.57 histamine response may require further investigation whether

a combination therapy of benazepril with b-adrenoceptor (0.500.65) with propranolol. No signicant di ff erence wasobserved in airway responsiveness to histamine after benazep- antagonists can be recommended for a longterm anti-

hypertensive treatment regimen.ril and placebo.

Table 1 Salbutamol dose-response. Postmedication baseline values before dose response with inhaled salbutamol and maximum valuesafter the highest cumulative dose of salbutamol (6.6 mg) in 24 normal subjects.

Parameter Placebo Benazepril 20 mg Salbutamol 8 mg Propranolol 160 mg

Specic airway conductance (s 1

kPa 1

)

Baseline 1.96 (1.911.99) 1.95 (1.892.00) 2.35 (2.262.43)* 1.84 (1.791.90)*Maximum 3.83 (3.644.00) 3.82 (3.614.02) 3.80 (3.554.04) 2.74 (2.642.84)*

Heart rate (beats min 1

)Baseline 74.46 (72.1276.79) 74.00 (71.5276.47) 76.33 (73.7678.90) 61.46 (59.8863.02)*Maximum 116.50 (111.53121.46) 116.54 (111.35121.72) 115.42 (110.56120.27) 66.42 (64.3668.47)*

Tremor amplitude (cm s 2

)Baseline 40.62 (36.05 45.19) 38.75 (34.51 42.98) 61.75 (56.16 67.33)* 30.54 (28.0333.04)*Maximum 134.71 (127.67141.74) 132.71 (126.08139.33) 121.75 (113.30130.19) 32.29 (28.6035.97)*

Blood glucose (mmol l 1

)Baseline 5.22 (5.035.40) 5.35 (5.165.52) 5.26 (5.115.40) 5.38 (5.205.55)Maximum 7.54 (7.277.81) 7.55 (7.337.75) 7.40 (7.177.62) 6.23 (5.946.50)*

Plasma potassium (mmol l 1

)Baseline 4.29 (4.184.40) 4.42 (4.304.53) 4.28 (4.184.38) 4.27 (4.154.38)Maximum 3.52 (3.373.67) 3.52 (3.403.63) 3.51 (3.393.63) 4.22 (4.074.37)*

Values are arithmetic mean (95% CI). Within group comparisons showed signicant di ff erences ( P < 0.05) with all medications except for tremor andpotassium with propranolol, respectively.*P < 0.05 for between group comparisons with placebo.

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Benazeprildrug interaction with salbutamol, bronchial response to histamine

8 Ruffin RE, Frith PA, Anderton RC, Kumana CR,References

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