|Year : 2017 | Volume
| Issue : 3 | Page : 114-119
A profile of adverse effects of antihypertensive medicines in a tertiary care clinic in Nigeria
Abimbola O Olowofela, Ambrose O Isah
Department of Medicine, Clinical Pharmacology and Therapeutics Unit, University of Benin, University of Benin Teaching Hospital, Benin City, Edo State, Nigeria
|Date of Web Publication||28-Jun-2017|
Abimbola O Olowofela
Department of Medicine, Clinical Pharmacology and Therapeutics Unit, University of Benin Teaching Hospital, Benin City, Edo State
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: There has been a dearth of comprehensive data on the profile of adverse reactions to antihypertensive medicines in the Nigerian setting despite increased use.
Objective: This study was aimed to characterize the adverse reactions experienced in the homogenously black African population.
Methods: The study was carried out at the University of Benin Teaching Hospital, Benin City, Nigeria, in consenting eligible hypertensive patients ≥18 years. Adverse reactions were sought using patient's self-report and a medicine-induced symptom checklist.
Results: A total of 514 patients (340 females) aged 22–97 years were studied. Thirteen percent, 27.6%, 26.7%, 22.0%, and 10.7% were on 1, 2, 3, 4, and ≥5 medicines, respectively, for control of their blood pressure with the frequency of adverse effects increasing proportionately up to four medicines. Adverse reactions to antihypertensive medicines were reported by a total of 93 (18.1%) patients. Diuretics – 27.9%, calcium channel blockers (CCBs) – 26.8%, and angiotensin-converting enzyme inhibitors (ACEIs) – 26.8% accounted for most of the adverse reactions seen, notably frequent micturition and headaches (CCB); excessive micturition and dizziness (diuretics); dry irritating cough (ACEI). Notable complaints for all patients using the checklist were increased frequency of micturition, reduction in libido, and headaches. The reactions resulted in the discontinuation and substitution of therapy in 49.5% of the patients.
Conclusions: The characterization of these reactions in Nigerians requires further studies as frequent micturition reported is still a neglected complaint in antihypertensive therapy.
| Abstract in French|| |
Contexte: Il y a eu une pénurie de données complètes sur le profil des réactions indésirables aux médicaments antihypertenseurs dans le cadre nigérian malgré une utilisation accrue. Objectif: Cette étude visait à caractériser les effets indésirables de la population africaine homogène noir. Méthodes: L'étude a été réalisée à l'hôpital universitaire de l'Université du Bénin, dans la ville de Benin, au Nigeria, dans des patients hypertendus admissibles ≥18 ans qui ont consenti à l'étude. Des réactions indésirables ont été recherchées en utilisant l'auto-évaluation du patient et une liste de contrôle des symptômes induite par un médicament. Résultats: Un total de 514 patients (340 femmes) âgés de 22 à 97 ans ont été étudiés. Treize pour cent, 27,6%, 26,7%, 22,0% et 10,7% étaient en 1, 2, 3, 4 et ≥5 médicaments, respectivement, pour le contrôle de leur pression artérielle avec la fréquence des effets indésirables augmentant proportionnellement jusqu'à quatre médicaments. Les réactions indésirables aux antihypertenseurs ont été rapportées par un total de 93 patients (18,1%). Les diurétiques - 27,9%, les inhibiteurs des canaux calciques (CCB) - 26,8% et les inhibiteurs de l'enzyme de conversion de l'angiotensine (ACEI) - 26,8% ont représenté la plupart des effets indésirables observés, notamment la miction et les maux de tête fréquents (CCB); Miction excessive et vertiges (diurétiques); Toux irritante sèche (ACEI). Des plaintes notables pour tous les patients utilisant la liste de contrôle étaient une fréquence accrue de miction, une réduction de la libido et des maux de tête. Les réactions ont entraîné l'arrêt et la substitution du traitement chez 49,5% des patients. Conclusions: La caractérisation de ces réactions chez les Nigérians nécessite d'autres études car les miction fréquentes rapportées sont encore une plainte négligée dans le traitement antihypertenseur.
Mots-clés: Effets indésirables des médicaments, agents antihypertenseurs, Nigéria
Keywords: Adverse drug reactions, antihypertensive agents, Nigeria
|How to cite this article:|
Olowofela AO, Isah AO. A profile of adverse effects of antihypertensive medicines in a tertiary care clinic in Nigeria. Ann Afr Med 2017;16:114-9
| Introduction|| |
Hypertension is a global disease considered as the leading risk factor for cardiovascular diseases with significant health burden and accounts for 9.4 million deaths as well as 7.0% disability-adjusted life years (DALYs) of global DALYs in 2010. The prevalence in Nigeria is estimated at over 28.9%. It is associated with a high morbidity and mortality, from increased risks of stroke, ischemic heart disease, renal failure, congestive heart failure as well hypertensive heart diseases and the observation that it is worse in people of black ancestry.,,, The use of medicines and other forms of nonpharmacological therapy in treating hypertension has been shown to reduce this morbidity and mortality., There has been a considerable increase in the arsenal of antihypertensive medicines in the past few decades, and their use may be associated with the development of adverse reactions which is likely to result in nonadherence to therapy, increased morbidity and mortality as well as economic consequences., It has also led to the withdrawal of some of these medicines from use.
Adverse reactions in outpatient care have been estimated to occur in about 25% of patients  and factors that have been associated with increased frequency of adverse reactions include, number of medicines taken by the patient's genetic disposition, age, pregnancy, and exogenous factors such as food and interactions with other medicines. Identification of adverse reactions using different methods has also been advocated to limit the poor prognosis that is associated with adverse reactions. The profile of adverse reactions to antihypertensive medicines in our environment has not been properly characterized given the antihypertensive armamentarium in use in this setting. There is a need to properly characterize the tolerability profile of these medicines in this environment.
| Methods|| |
This cross-sectional study was carried out at the consultant medical outpatient department (COPD) of a tertiary hospital in Southern Nigeria. The teaching hospital is a 730-bed tertiary center, which also serves as a referral center to the neighboring states of Ondo, Anambra, Bayelsa, and Delta states. The COPD houses the hypertension clinic as well as other medical subspecialties. The study was carried out over 9 months and patients with a diagnosis of hypertension on therapy who attended the medical outpatient clinic. Hypertensive patients on antihypertensive medicines who were aged 18 years and above and consented to the study were included in the study.
For this cross-sectional study, the sample size calculation was based on a previous study by Isah et al. on the assessment of patient's knowledge and experience of hypertension and it revealed that about 24.8% reported that an adverse event affected their compliance. Using this figure as an estimate of the desired proportion of an adverse drug reaction (ADR), at a confidence interval of 95%, the formula for simple proportions was used. A sample of 289 hypertensive patients was the minimum sample size calculated for this study. Furthermore, anticipating a 70% response to the questionnaire a sample size of 376 was estimated. However, 514 patients consented and were recruited into the study.
The patients were classified as being hypertensive (defined according to the Nigerian Hypertension Society guidelines that were based on the 1999 WHO/International Society of Hypertension recommendations), as blood pressure ≥140/90 mmHg. All patients who fulfilled the inclusion criteria and consented to the study were included. During the visit, their demographic characteristics, duration of hypertension as well as comorbidities were recorded in an interviewer-administered questionnaire. Antihypertensive medicines, other prescribed medications and indication for their use were noted, use of other nonprescribed medicines and herbal medicines were also recorded. ADRs to antihypertensive medicines prescribed at the last clinic visit were sought.
Following the self-reported sessions, a modified checklist of antihypertensive medicines – induced symptoms as described by Bulpitt and Dollery  and modified based on previous studies , was administered to the patients to determine what symptoms they experienced that was related to medicine use. Reported adverse reactions were also documented and classified using the Medical Dictionary for Regulatory Activities (MedDRA) system organ classification, and the probability of the event being an ADR was assessed with the WHO and Naranjo causality algorithms., The outcome of the reaction was noted as well as the action patient took following the ADR.
Ethical approval was obtained from the Ethics and Research Committee of the University of Benin Teaching Hospital, and informed consent was obtained from each patient verbally. The quality of the data and its confidentiality were ensured by keeping the patients' identity coded with their initials only. The data were fully anonymized and aggregated. Any information about any patient was kept strictly confidential and not shared with unauthorized individuals. The patient's right to confidentiality, information and privacy were respected.
Antihypertensive medications were classified into different classes: (angiotensin converting enzyme inhibitors [ACEI], beta-blockers, calcium channel blockers [CCBs], diuretics, centrally acting agents, and angiotensin receptor blockers [ARBs]). Data were analyzed using SPSS (Statistical package for the Social Sciences, SPSS Inc., Chicago, IL, USA) software version 16 for windows. Descriptive and inferential analyses were conducted as appropriate, and level of significance was set at P< 0.005.
| Results|| |
A total of 514 patients were recruited into the cross-sectional descriptive study. The male:female ratio was 1:2, and the age ranged from 22 to 97 years with a mean ± (standard deviation [SD]) age of 57.91 ± 12.0 years, there was no statistically significant difference between the mean ages of the men 58.8 (12.4) and women 57.5 (11.8) studied (t-test = 0.213; P = 0.552). A total of 146 patients (28.4%) were aged 65 years and above. Regarding the educational status of the population, 172 (33.5%) had tertiary education representing the largest group.
The mean (SD) duration of diagnosis of hypertension in the 514 patients was 7.8 (7.9) years, (range: 1 month–40 years) while they had been receiving treatment for a mean (SD) duration of 7.4 (7.8) years (range: 2 weeks–36 years).
Only 16 (3.1%) patients were currently smoking and 67 (13%) admitted to social use of alcohol. Fifty percent (254) of the patients had comorbidities, with 85% having one comorbidity only and 14.2%, 0.8% having two and three, respectively. The different comorbidities as documented in the case records were mainly diabetes mellitus 131 (25.5%), osteoarthritis 78 (15.2%), obesity 16 (3.1%), and peptic ulcer disease 15 (2.9%) among others.
Antihypertensive medicines prescribed
A total of 67 (13%) patients were on one antihypertensive medicine (monotherapy), of which 11/67 (16.4%) of them had only antihypertensive medicine prescribed, whereas the other 56/67 (83.6%) had other medicines besides antihypertensive medicines. Four hundred and forty-seven (87%) were on combination therapy of two or more antihypertensive medicines, (combination therapy). In the patients on combination therapy, 142 (27.63%), 137 (26.63%), 113 (21.98%), and 55 (10.70%) of them had 2, 3, 4, and 5 or more antihypertensive medicines prescribed.
CCBs were the most prescribed class of antihypertensive medicines 362 (70.4%) and alpha-blockers the least prescribed group 9 (1.8%). Beta-blockers 118 (23.0%) and alpha-blockers - 9 (1.8%) were prescribed only in combination therapy. The most common combinations of antihypertensive medicines were diuretics and CCBs. In patients using only one antihypertensive medicine, more patients were on ACEI 31 (46.3%), and this was closely followed by CCB at 26 (38.8%), other medicines used include ARB 5 (7.5%), centrally acting medicine 3 (4.5%), and diuretics 2 (3.0%).
Adverse drug reactions experienced
Ninety-three (18.1%) patients experienced an ADR to their antihypertensive medicines. Using the causality assessment scales to classify the probability of the adverse reactions, with WHO assessment  29 (31.2%), had their adverse reactions classified as probable and 56 (60.2%) as possible. However, 7 (7.5%) and 1 (1.1%) patient(s) had experienced adverse reactions judged as being unlikely and conditional, respectively.
Using the Naranjo assessment algorithm  to assess the adverse reactions, 55 (59.1%) were classified as having had a possible adverse reaction, 37 (39.8%) were probable, and 1 (1.1%) was doubtful.
ADRs increased with increase in the number of antihypertensive medicines, and it was statistically significant [Table 1].
|Table 1: Distribution of the number of antihypertensive medicines used by the 514 patients and frequency of adverse reactions experienced|
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Proportionately, more men 35/174 (20.1%) than women 58/340 (17.1%) reported an adverse reactions to their antihypertensive medications, but it was not statistically significant (χ2 = 0.725, df = 1, P = 0.39). Elderly patients 20/146 (13.7%) reported fewer ADR compared to younger patients 73/368 (19.8%), although it was not significant. (χ2 = 2.658. df = 1. P = 0.103).
Profile of adverse reactions reported
Dry cough was present in 15/24 (62.5%) of those who had an adverse reaction to ACEI, and a patient had passage of loose stools, excessive micturition was seen in 19/26 (73.1%) of the patients on diuretics, while 11/25 (44%) of the patients on CCB (either as monotherapy or in combination) complained of increased frequency of micturition to their medicines distinct from an increase in volume (polyuria) seen with diuretics. The reactions are also documented in [Table 2]. The system organ classification is shown in [Table 3], renal and urinary disorders being the most commonly reported system. Following the development of adverse reactions in these 93 patients, 46 of them (49.5%) discontinued their medicines with five of them substituting with another brand while 30 (32.2%) reduced their doses; however, 17 (18.3%) took no action [Table 2].
|Table 2: Adverse reactions experienced by patients to antihypertensive medicines and actions taken by the patients following the reactions|
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|Table 3: The system organ classifications (Medical Dictionary for Regulatory Activities) of the reported adverse reactions by the hypertensive patients|
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Adverse reactions: Symptoms checklist
With the administration of a modified symptom checklist to determine drug-related symptomatology in all the patients, 405 (78.8%) had adverse reactions related to the use of their medications. The frequency of micturition, poor erection, headaches, and reduced sexual urge were the symptoms most related to drug use with 37.7%, 25.7%, 22.6%, and 21.2%, respectively. The frequencies of the other symptoms are elucidated in [Table 4].
|Table 4: Frequency of symptoms attributed to medicine use in the 514 hypertensive patients using the modified symptoms checklist|
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Serious adverse reactions: Notable in this outpatient-based study was the absence of serious adverse reactions as there were no deaths, hospitalizations, disabilities, or life-threatening events that required intervention to prevent permanent damage.
| Discussion|| |
There is a need to define the present profile of antihypertensive medicines by finding out the present pattern of ADR which may be peculiar to our environment. The study showed that a high proportion of patients have adverse reactions to their antihypertensive medications and the higher the number of medicines used the more the adverse reactions seen, as observed in a study by Lip and Beevers.
Adverse reactions to medicines are an important consideration in the management of patients with hypertension as 50% of the patients who developed an adverse reaction discontinued their medicines. This finding was also seen in other studies on why patients discontinue their therapy., In assessing the causality of the ADR, most of the reactions were adjudged to be ADRs. However, a few patients had ADRs that were adjudged to be unlikely and conditional using the WHO causality assessment algorithm. Although the algorithms improved the ability to characterize the relationship between suspected medicines and the ADR, patients and health-care providers are encouraged to report all cases of adverse reactions even when they are uncertain about the probability as this expands the database of ADRs. The frequency of ADRs appeared to be higher in males, although was not statistically significant. It has been suggested that the female sex may be a risk factor for the development of ADRs due to possible pharmacokinetic differences. The use of the medicine induced symptom checklist was to improve the reporting of patients who may have symptoms associated with the use of their medicines and cannot recall on questioning. Different studies have used this method though modified in this study; it also showed that a high proportion of patients had symptoms that they attributed to their medicines.,,
The frequency of erectile dysfunction reported was more following the use of the symptom checklist. Many patients attribute sexual dysfunction to their antihypertensive medicines,, therefore adherence to these medicines may be poor due to their perceived adverse effect. Assessing the frequency of this complaint using a checklist or questionnaire has been shown to be helpful., It may have also contributed albeit indirectly to more males reporting adverse reactions on direct questioning. The proportion of patients who had ACEI induced cough in this study was higher than shown in other studies., The patients who used diuretics complained of excessive micturition; this had a serious impact on the patient's therapy as diuretics accounted for the highest number of reactions reported. The excessive micturition seen with diuretics may be due to the dose of diuretics, especially hydrochlorothiazide available in this environment. A study carried out in the North Central part of Nigeria also showed diuretics accounting for the highest rate of discontinuations to therapy. Of interest were the reports of increased frequency of micturition following the use of CCBs. As distinct from the excessive micturition with diuretics, the CCB account for increased frequency (number of times) not reflected in the volumes of urine passed. This was observed early following the introduction of the CCBs., This finding need to be further investigated as it was also seen using the MedDRA  system organ classification that the renal and urinary disorders had the highest frequency. We equally note the development of dizziness and dryness of legs to alpha blockers, (though infrequently used in this study) two of the users (22%) had adverse reactions, the reactions observed may be related to the orthostatic hypotensive effect of alpha blockers.
Noticeable in this study, was the absence of reports of ADR to the ARBs. A reduced frequency has also been seen in another review, and ARBs have also been shown to have a good tolerability profile.
| Conclusions|| |
In all, there is a relatively high prevalence of adverse reactions experienced by patients on antihypertensive therapy resulting in a high rate of discontinuations as seen in this study. Notable reactions experienced by the patients include dry cough to ACEIs, excessive micturition to diuretics, and frequent micturition in patients on CCBs. Utilization of a medicine induced symptom checklist revealed symptoms which were not reported on direct questioning such as reduced libido and erectile dysfunction.
Some knowledge of the profile of antihypertensive medicines in use by the physicians will aid the management of hypertension. Further studies are required to characterize this problem.
We would like to thank the University of Benin Teaching Hospital management and members of staff of the Department of Medicine and the consultant outpatient department for their assistance. We would also like to thank the patients who participated in this study. This study was self-funded and there are no potential conflicts of interest.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]
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