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Annals of African Medicine
Annals of African Medicine Society
ISSN: 1596-3519
Vol. 4, Num. 3, 2005, pp. 118-121

Annals of African Medicine, Vol. 4, No. 3, 2005, pp. 118-121

ANGIOTENSIN CONVERTING ENZYME- INHIBITORS ASSOCIATED COUGH: A PROSPECTIVE EVALUATION IN HYPERTENSIVES

A. K. Salami and I. A. Katibi

College of Medicine, Faculty of Clinical sciences, Department of Medicine, University of Ilorin, Ilorin, Nigeria
Reprint requests to: Dr. A. K. Salami, College of Medicine, Faculty of Clinical sciences, Department of Medicine, University of Ilorin, P. M. B. 1515, Ilorin, Nigeria. E-mail: Salkaz2000@yahoo.com

Code Number: am05030

Abstract

Background/Objective: To determine the prevalence of ACE-Is induced cough among Nigerian hypertensives and evaluate any association with patients’ age or sex.
Methods: A prospective case-control study.One hundred and sixty-eight hypertensive patients on angiotensin converting enzyme-inhibitors (ACE-Is; captopril and lisinopril) were matched in age and sex with controls that were on anti-hypertensives that excluded ACE-Is (nifedipine, aldomet and moduretic). Both groups of patients were followed up on either drug as a monotherapy over an average of 9 months.
Results: The prevalence of ACE-Is induced cough was 20.2%, while that of the alternative group was 0.6%. There was a significant statistical difference between ACE-Is and the alternatives medications-induced cough: OR=42.37(95%CI; 6.11-843.32), P< 0.0001.There was however, no significant statistical difference between captopril and lisinopril-induced cough, OR=1.30 (95%CI;0. 6-2.81), P value=0.587 and no significant age or sex differences were observed in the occurrence of cough; OR=0.97 (95%CI; 0.52-1.81), P value= 0.95 and OR=0.79(95%CI; 0.27-2.28), P value=0.808 respectively.
Conclusion: Cough complicating ACE-Is therapy is not uncommon; however, it has no link with the patients’ age or sex.

Keywords:Prevalence, cough, ACE-inhibitor, hypertension

Résumé

Fond/Objectif :Pour déterminer la prédominance de la toux induite de ACE-Is parmi des hypertensifs nigérians et évaluer n'importe quelle association avec l'âge ou le sexe des malades.
La méthode : une étude éventuelle de cas commande.cent et soixante-huit de malades hypertensifssur inhibiteurs de l'enzyme de conversion de l'angiotensine(ACE-Is : captopril et lisinopril) ont été égalé en l'âge et en sexe avec les contrôles qui étaient sur anti-hypertensifs excluant l’ACE-Is (nifédipine, aldomet et modulatoire). Les deux groupes de malades ont été observés sur la drogue comme une monothérapie par-dessus une moyenne de 9 mois.
Résultats :la prédominance  de la toux induite d’ACE-Is était 20,2 %, pendant que celle du groupe alternatif était 0,6 %. Il y avait une différence statistique significative entre l'ACE-Is et  la toux induite médications alternatives : OR=42.37 (95%CI; 6.11-843.32), P <0.0001. Il y avait pourtant, aucune différence statistique significative entre captopril et latoux  induite lisinopril, OR=1.30 (95%CI; 0. 6-2.81), P valeur=0,587 et aucun âge significatif ou différences sexuelles n'a été observé dans l'occurrence de toux; OR=0.97 (95%CI; 0.52-1.81), P valeur = 0.95 et OR=0.79 (95%CI; 0.27-2.28), P valeur=0.808 respectivement.
La conclusion : la Toux compliquant  de la thérapie d'ACE-Is n'est pas rare ; cependant, il n'a pas de lien avec l'âge ou le sexe  des malades.

Mots-clés : Prédominance, toux, ACE  -inhibiteur,  hypertension

Introduction

Angiontensin converting enzyme inhibitors (ACE-Is) are anti-hypertensive agents that reduce peripheral resistance by acting as vasodilators.1 They have beneficial effects on left ventricular dysfunction, and they reduce proteinuria associated with kidney disease.2 Therefore they are prescribed in the management of systemic hypertension, heart failure, myocardial infarction and diabetic nephropathy.3 However, ACE-Is have cough as one of its drawbacks. This has been described as dry and irritating4 cough that could be paroxysmal or persistent in nature.5 It has been reported in patients receiving captopril,6 enalapril,7 lisinopril,8 ramipril9 and cilazapril.10 The incidence of this cough varied widely, depending, probably on the method of each study. It ranged from as low as 0.2 –18.6 %6,7,11 in some reports to as high as 20- 41.8% in others.5,8,10  Some of these studies also reported female preponderance7,8  while some found it to be commoner in the older ones12,13and some reported racial predilection.13,14 Others did not find any association with the patients’ age or sex.14-16 We are therefore set to determine the prevalence of ACE-Is induced cough in some of our hypertensive patients, and to know if there is any link with the patients’ age or sex. 

Materials and Method

Consecutive patients with systemic hypertension were recruited from the clinics over a two and half year period. Each of them was randomized into ACE-I or alternative group by a blind slot after seeking and obtaining their informed consent. The two groups were matched in age (within ±5years age range) 17 and sex. Each patient was informed of the possibility of a dry cough developing during the course of drug therapy. The medication was to be discontinued if the cough disturbs the patient’s routine chores or prevented sleep. The types of ACE-Is and the alternatives used in each group after randomization was determined by cost and local availability. The alternative was medication other than ACE-Is, either of which (ACE-I or the alternative) was used as monotherapy. At each clinic visit each patient was questioned about dry cough and time of it onset. Patients’ biodata, type and dosage of ACE-I or alternative prescribed were recorded in questionnaires. Hypertensive patients with condition that can cause cough such as heart failure, respiratory tract infection, COPD or asthma were excluded. Systemic hypertension was defined as a systolic blood pressure of greater than 140mmHg and/ or a diastolic blood pressure of greater than 90mmHg measured twice at two separate clinic visits.18

The frequencies and percentages of all the variables were generated. The mean and standard deviation (SD) were determined by analysis of variance (ANOVA). Test of significance was conducted by chi- square technique among; (1) intergroup (captopril and lisinopril). (2) ACE-I and the alternative. 

Results

One hundred and sixty-eight patients (89 males and 79 females) aged 31- 73years (mean of 45±22.9 years) were on ACE-Is. Table 1. Ninety-two (54.8%) were on captopril 12.5mg-50mg/day, while 76 (45.2%) were on lisinopril 5mg-20mg/day. Table II. The age range of patients in the alternative group was 35-78 years with a mean of 47.36±7.4years. Fifty-eight (35%) of them were on nifedipine 20-60mg/day, 43(25%) on aldomet 500mg-1500mg/day and 67(40%) were on moduretic 1 tablet/ day. Table 2. Duration of patients’ follow-up in the clinics ranged from 5.7months to 17.3months with an average of about 9 months.  Thirty-four (20.2%) patients on ACE-Is; 19(11.3%) on captopril and 15(9%) on lisinopril, developed a dry cough, while a female patient (0.6%) on aldomet reported a spontaneous cough. Table 1. The time of onset of this cough ranged from 5-180days of initiating therapy, with an average of 37.7± 8.5days. The dosage of the drugs was not reduced in any of the patients but medication was discontinued in 3 (8%) of them and the cough disappeared within 10 days. There was no significant statistical difference between captopril and lisinopril; X2=0.26, OR=1.30 (95%CI; 0. 6-2.81), P value=0.587. There was also no significant sex difference observed; X2=0.06, OR=0.79(95%CI; 0.27-2.28), P=0.808. The mean age of 34 patients on ACE-Is that developed cough was not significantly higher than that of their controls that did not develop cough; (53.72+5.8 vs. 47.36±7.4 years). X2=0.01, OR=0.97 (95%CI; 0.52-1.81) P value= 0.95, There was, however, a significant statistical difference in cough induction between the ACE-Is and the other medications; X2=32.66, OR=42.37(95%CI 6.11-843.32), P< 0.0001.

Table 1: Prevalence of cough in patients treated with ACE-Is and alternative medications

Variable

ACE-I

Control

TNP

168

168

Male

89(53)

93(55)

Female

79(47)

75(45)

Age ±SD

45±22.9

47.36±7.4

NDC

34(20.2)

1(0.6)

Male

16(9.5)

-

Female

18(10.8)

1(0.6)

Age ±SD

53.72+5.8

41.

Table 2: Distribution of ACE-I and Alternative medication by sex

Variable

Medication

 

ACE-I

Alternative

 

Captopril

Lisinopril

Nifedipine

Aldomet

Moduretic

 

Total

92(54.8)

76(45.2)

58(35)

43(25)

67(40)

Male

58(34.5)

31(18.4)

36(21)

18(11)

39(23)

Female

34(20.2)

45(26.8)

22(13)

25(15)

28(17)

NDC

19(11.3)

15(9)

-

1(0.6)

-

Male

10(5.9)

6(3.6)

-

-

-

Female

9(5.4)

9(5.4)

-

1(0.6)

-

ACE-I = Angiotensin converting enzyme-inhibitor; NDC= Number that developed cough

Discussion

ACE-Is are useful as single drug therapy for many patients with hypertension, hypertensive and diabetic nephropathy.3,19 There has been conflicting results20 on the effectiveness of ACE-I monotherapy in controlling blood pressure among hypertensive Nigerians; it was ineffective as a sole drug in some studies21,22 others found it effective in mild to moderate hypertension23 and even in severe and resistant hypertension.24 The blood pressure of each patient in this study was controlled and maintained with ACE-I or alternative drug monotherapy. This effectiveness is derived from the inhibition of angiotensin converting enzyme5 (ACE), the enzyme involved in the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor). However, the link of ACE-Is with a dry, non-productive cough could be puzzling12 since the rennin- angiotensin system does not appear to have any important function in the lung.6 The frequency of this cough in our study was 20.2% and there was no significant difference in the prevalence of cough induced by captopril (11.3%) and lisinopril (9%). Sex involvement was about equal; occurring in 9.5% of males and 10.8% of females respectively. The age difference between those with ACE-I induced cough and the controls was also not statistically significant (53.7± 5.8 years vs. 47.4±7.4 years, P-value=0.95). ACE-I was discontinued in 3(8%) patients; 2 on captopril and 1 on lisinopril because of persistent cough that disturb their sleep, however, it was tolerated in others.

ACE-Is are pro-drugs that are converted to active form after oral administration1 with little significant differences between them. One of these is the presence or absence of sulphydryl group1 that is known to affect the time of onset and the duration of action of individual drug. However, the specific mechanism of cough in some patients receiving this class of drugs is not fully understood. A number of studies4, 5, 19, 25 have related it to the effects of the drugs on the kininogen-kinin (bradykinin) system. Immunochemistry has shown nerves containing substance P26 and neurokinin A27 in human lung. Most of such neurons arise from the vagus nerve and present beneath the respiratory epithelium of the tracheal and the major bronchi12.   ACE is known to be identical with bradykininase or kininase II12 that degrades kinins (bradykinin and tachykinin). ACE-I may therefore reduce the degradation of bradykinin leading to local accumulation in the lungs. This may activate pro-inflammatory peptides (e.g. substance P, neuropeptide Y) 5, 28 in the airways with consequent stimulation of vagal afferents4 that subserve cough reflex, particularly the unmyelinated or the C fibres4 and the rapidly adapting receptors in the airway. 29 Prostaglandin and histamine that are released in the respiratory tract due to the same effect of bradykinin can also cause cough reflex hypersensitivity.4,5 These putative mechanisms of ACE-I induced cough may explain the increase in frequency of cough seen in those group of patients on it (20.2%) far above that of their control subjects (0.6%). The cough may improve spontaneously14,15,16,19 in some patients as observed in our patients or with agents that inhibit prostaglandin synthesis.9,29 Improvements have also been reported with calcium channel blockers30 and theophyllines.31   

In conclusion, dry cough, complicating therapy with ACE-I as a class of drugs is not uncommon. It is however, unrelated to patients’ age or sex.

References 

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