INTRODUCTION:

Angiotensin-converting enzyme (ACE) inhibitors are the most commonly used cardiovascular medications due to their documented efficacy in the treatment of hypertension, heart failure, post-myocardial infarction complications, and diabetic nephropathy¹. Perindopril is an ACE inhibitor with long lasting effects and established cardioprotective and renoprotective effects^2,3. However, ACE inhibitors efficacy are limited by their characteristic dry cough that markedly impacts medication adherence, quality of life, and cardiovascular consequences⁴.

The available data based on passive report of cough by patients or elicited by researcher or physician rather than being systematically collected on certain population resulting in missing cases underestimating the exact prevalence of cough⁵. Moreover, clinical trials draw backed by their screening criteria which do exclude patients with pre-existing cough, respiratory deficits, or prior ACE inhibitor intolerance, creating selective criteria demonstrating false-negative results with inherently better tolerability profiles⁶. The present study sought to identify the prevalence of perindopril-induced cough among patients in Duhok city (Kurdistan Region of Iraq).

MATERIALS AND METHODS:

Study design:

This cross sectional study was accomplished among adult hypertensive patients visiting private clinics in Duhok city (Iraq) during June 2024 to June 2025, who had been treated by perindopril for at least two weeks. The study sought to identify the rate of cough prevalence in these patients. All patients signed participation consent before participation.

Study population:

Inclusion criteria patients enrolled in the present study were those aged >18 and were using perindopril for cardiovascular diseases. Exclusion criteria include those patients with recent respiratory infection.

Data Collection:

A questionnaire was handed to individuals to collect demographic data, duration and indication of perindopril use, presence of cough, time of onset of cough, smoking history, and comorbidities.

Statistical Analysis:

Descriptive statistics were used to analyze the results which have been presented as frequencies and percentages for non-continuous parameters, while continuous variables presented as mean±standard deviation. The association between cough and potential risk factors (e.g., gender, age, dose, duration, comorbidities) was determined using the chi-square test as appropriate. The significance level was set at p<0.05.

RESULTS:

The results revealed that 61% (n=51) of participants accepted the perindopril without cough, while 39% (n=33) demonstrated non-tolerable cough (Table 1). Chi-square shown marked association between sex and cough tolerability (χ² = 0.002, p = 0.961). The prevalence of tolerability in male (76.7%) and female (83.3) patients were higher compared to non-tolerable participants. Marked differences found between age and cough tolerability (χ² = 6.682, p = 0.010). Patients aged ≤50 years demonstrated higher cough tolerability (72%). However, >50 years old participants demonstrated lower tolerability rates (55.9%), with 44.1% demonstrated non-tolerable cough. Non-significant differences (χ² = 2.524, p = 0.112) existed between residency and cough tolerability. Rural residents showed a higher non-significant tolerability rate (72%) compared to urban residents (55.9%).

Drug combinations tolerability: 66.3% of patients tolerated their medication without significant (χ² = 5.92, p = 0.116) cough, while 35% demonstrated non-tolerable cough side effects (Table 2). Perindopril + Indapamide (n=55, 64.0% of sample): This was the most commonly prescribed combination with a tolerability rate of 60.9% (38/55) versus 30.9% (17/55) experienced non-tolerable cough. Perindopril monotherapy The three patients tolerated perindopril alone. Perindopril + indapamide + amlodipine: This triple therapy showed a tolerability rate of 61.5%, with 38.5% experiencing non-tolerable cough. Perindopril/amlodipine: although only 2 participants used this combination, they were non-tolerable.

Based on age and sex, the cough tolerability rate in 84 perindopril-users, was high (Table 3). The interaction between age and sex groups showed no significant association with cough tolerability (χ² = 2.844, p = 0.416). This indicates that the pattern of cough tolerability across age groups does not differ significantly between males and females, and there is no significant interaction effect between age and sex.

Table 2. Drug-specific cough tolerability profiles

Drug Name	Tolerable	Non-tolerable	Chi square	P value
Perindopril+ Indapamide	38 (69.1%)	17 (30.9)	5.92	0.116
Perindopril	3 (100)	0 (0)
Perindopril arginine + Indapamide + Amlodipine	16 (61.5)	10 (38.5)
Perindopril/Amlodipine	0(0)	2 (100)

Table 3. Cough tolerability by age and sex

Age, years	Male Tolerable	Male Non-Tolerable	Female Tolerable	Female Non-Tolerable	Chi square	P value
≤50	9	3	6	4	2.844	0.416
>50	14	4	27	17	2.844	0.416
Chi square	0.051		0.214
P value	0.822		0.644

Male patients showed non-significant tolerability rates than females in both age group, males maintained stable tolerability across age groups, while females showed a slight numerical increase with age (Table 4).

Table 4. Cough tolerability stratified analysis by age and sex

Age, years	Sex	Tolerable	Non-Tolerable	Chi square	P value
≤50	Male	9	3	0.128	0.721
≤50	Female	14	4	0.128	0.721
>50	Male	6	4	1.524	0.217
>50	Female	27	17	1.524	0.217

DISCUSSION:

The present study explored the demographic parameters of cough tolerability among perindopril users, expressing the differential vulnerability to this adverse effect of ACE inhibitors. The rate of non-tolerable cough was relatively high, a finding that harmonized closely with the published studies reporting ACE inhibitor-induced cough rate ranging from 5% to 35%, with some studies documenting rates as high as 44% in certain populations.

The results demonstrated a marked association between age and cough tolerability, with younger patients (≤50 years) demonstrating markedly higher tolerance compared to their older groups. In systematic study, Mahmoudpour et al. (2013) reported that ageing was connected with increased vulnerability to ACE inhibitor-related adverse effects, including cough⁷, however, the mechanisms remain obscure. These findings could be explained in the context of that older patients may demonstrated reduced degradation of bradykinin, which do accumulate after ACE inhibition and hence concerned in cough reflex⁸. Moreover, ageing associated with modulation in lung tissue, such as, increased airway sensitivity and modulated neural control of the cough reflex, may participate to enhanced susceptibility^9,10.

Results of the present study revealed no significant link between sex and cough tolerability, this finding contrasted to the earlier evidence, which has demonstrated that female sex as a predisposing risk factor for ACE inhibitor-induced cough. Multiple studies, including Mahmoudpour et al. (2013) and Ramsdale et al. (2022), have demonstrated that women presented with cough rates at 1.5 to 3 times higher than men^7,11. The mechanisms for this gender based distinictive cough response include hormonal effects on bradykinine sensitivity, differences in cough reflex threshold, and variations in substance P receptor expression^12-14. Moreover, older patients reported reduced enzymatic degradation of bradykinine and substance P, accumulating and exacerbating in cough reflex^15,16. The lung tissue structural modulation due to ageing process contribute to increased risk of cough^9,10. This finding contrast with meta-analysis by Ramsdale et al. (2022), who have reported that females demonstrated cough at rates 1.5 to 3 times higher than males when using ACE inhibitors¹¹. This sex variation due to sex hormonal effects on bradykinine sensitivity, differences in cough reflex threshold, and potential variations in substance P receptor expression^15,16.

The study confirmed that the residency status and cough tolerability were not affected by each other, perhaps residency impact might be linked to the differences in the quality of life, including environmental exposure, healthcare access, dietary differences, and socioeconomic status^17,18.

When age examined separately in either sex group, no differences existed between groups, this contradicts with literatures confirming more cough prevalence in females¹¹, necessitating drug discontinuation in females regardless of their ages¹⁹, perhaps due to sex hormonal variations affecting ACE inhibitors metabolism and bradykinine desensitization which vary based on age and sex¹⁶, typically estrogen reported to change bradykinine receptor sensitivity^20,21. A study by Packard et al. (2002) reported that males were non-tolerable to cough reflex due to ACE inhibitors, and explained in the context of age and sex based hormonal modulation in sex hormones²². Regitz-Zagrosek (2020) reported the same results regardless of the sex of participants²³. Moreover, A Japanese study conducted on elderly by Elliott et al. (2017) found no sex difference in ACE inhibitor cough rates²⁴.

CONCLUSION:

Perindopril has induced a higher non-tolerable cough in younger age group regardless of gender differences or residency status. The weak impact of perindopril on cough carry impaortant evidence for their application in clinical setting favourably over other ACE inhibitors particularly in younger age groups.

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Received on 08.11.2025 Revised on 07.01.2026

Accepted on 16.02.2026 Published on 16.03.2026

Available online from March 18, 2026

Research J. Pharmacy and Technology. 2026;19(3):1199-1202.

DOI: 10.52711/0974-360X.2026.00171

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Demography		Tolerable, n (%)	Non-tolerable, n (%)	Chi square	P value
Patients, n=84		51 (61)	33 (39)
Sex	Male, n=30	23 (76.7)	7 (23.3)	0.002	0.961
Sex	Female, n=54	45 (83.3)	9 (16.7)	0.002	0.961
Age, year	≤50	18 (72)	7 (28)	6.682	0.010*
Age, year	>50	33 (55.9)	26 (44.1)	6.682	0.010*
Residency	Urban, n=59	33 (55.9)	26 (44.1)	2.524	0.112
Residency	Rural, n=25	18 (72)	7 (28)	2.524	0.112