LITHUANIAN UNIVERSITY OF HEALTH SCIENCES ACADEMY OF MEDICINE INSTITUTE OF PHYSIOLOGY AND PHARMACOLOGY

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES

ACADEMY OF MEDICINE

INSTITUTE OF PHYSIOLOGY AND PHARMACOLOGY

BLANCA ZOROZA ARROYO

Influence of ACE inhibitors and other anti-hypertensive drugs on

indigestion and irritable bowel syndrome symptoms.

Final Master’s Thesis

Supervisor: Mantas Malinauskas, PhD

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1. SUMMARY

Author name: Blanca Zoroza Arroyo

Research title: Influence of ACE inhibitors and other anti-hypertensive drugs on indigestion and irritable bowel syndrome symptoms.

Aim: Evaluate the prevalence of the indigestion and irritable bowel syndrome symptoms among hypertensive patients treated by ACEI inhibitors and other drugs involved in hypertension treatment.

Objectives:

1. Investigate the frequency and severity of indigestion and irritable bowel syndrome symptoms among hypertensive patients of the present study.

2. Determine the age-associated difference in the frequency of indigestion and irritable bowel syndrome symptoms among hypertensive patients of the present study.

3. Determine the gender-associated difference in the frequency of indigestion and irritable bowel syndrome symptoms among hypertensive patients of the present study.

4. Determine the treatment-related relationship with the frequency of indigestion and irritable bowel syndrome symptoms between patients treated by plain ACEI (C09A) and combined ACEI (C09B).

Methodology: This observational descriptive study was performed between January 2018 and June 2018, a total of 90 patients from Kaunas Clinic’s Cardiology Department completed the questionnaire Gastrointestinal Symptom Rating Scale (GSRS) in order to study the possible relationship between anti-hypertensive treatments and indigestion and irritable bowel syndrome symptoms.

Results: The patients understudy were mainly elderly (62,97±1,47 years) and females (55,2%). The most used anti-hypertensive drugs were ACEIs (51,3%) both plain and combined. ‘Upper abdominal discomfort’, ‘loose stools’ and ‘bloating’ were minimally severe and the most frequent symptoms, while mild severity was described for ‘loose stools’ and diarrhea’ symptoms among the studied patients. ‘Acidic reflux’ (p<0,036) was statistically significant for patients over 65 years and ‘heartburn’ (p<0,02) for female gender. ‘Burping’ (p<0,029) and ‘flatus’ (p<0,025) showed to be statistically significant during ACEIs intake.

Conclusions: ‘Upper abdominal discomfort’, ‘loose stools’ and ‘bloating’ showed minimal severity and were the most frequent symptoms among the studied sample, while ‘loose stools’ and diarrhea’ symptoms showed mild severity. Regarding age and gender association with the presence of symptoms, there was statistical significant difference for ‘acidic reflux’ (p<0.036) among patients over 65 years old and ‘heartburn’ (p<0.02) among female gender. Even if patients under ACEIs (pain and combined) treatment were statistically significant for ‘flatus’ and ‘burping’, we can’t affirm that these symptoms were related to the treatment due to the small amount of respondents understudy.

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2. ACKOWELDGEMENTS

3. CONFLICTS OF INTEREST

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5. ABBREVIATIONS

ADR - Adverse drug reactions

ACEI - Angiotensin converting enzyme inhibitors ARB - Angiotensin II receptor blocker

ATC – Anatomical Therapeutic Chemical BP – Blood pressure

CVD - Cardiovascular disease DDD – Daily Defined Dose

GERD – Gastro-oesophageal reflux disease GIT - Gastrointestinal tract

IBS – Irritable bowel syndrome

GSRS - Gastrointestinal Symptom Rating Scale GVP – Pharmacovigilance practices

RAAS – Renin-angiotensin-aldosterone system SD - Standard deviation

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6. INTRODUCTION

Hypertension represents the most common long-term medical condition in the world. It remains the major modifiable cause of cardiovascular disease (CVD) and all-cause death globally and Europe. The total prevalence of hypertension in adults is around 30-45%, with a global age-standardized prevalence of 24 and 20% in men and women, respectively in 2015. It is increasingly more common as age advances, with a prevalence of > 60% in people who are over 60 years[1].

There are two well-established strategies to lower blood pressure: life-style modifications and pharmacological treatment. According to the data collected by the State Medicines Control Agency of Lithuania (SMCA), the most consumed class of drugs in Lithuania in 2013-2015 were the drugs acting on the cardiovascular system. The most popular anti-hypertensive drugs were drugs acting on renin-angiotensin system, especially ACEI [2].

These drugs, provide benefits to the patients by reducing and controlling blood pressure (BP), but at the same time, they can produce unwanted effects on different human body systems, were many studies have focused [3,4]. As it was stated in the Guideline on good pharmacovigilance practices (GVP), adverse drug reactions (ADRs) were described as a response to a medicinal product which is noxious and unintended, that is, a causal relationship between a medicinal product and an adverse event[5].

The incidence of ADRs on the gastrointestinal tract (GIT) is not entirely clear, it is thought to be rare. Although, the most studied and reported relation between anti-hypertensive drugs and GIT symptoms have been the angiotensin II receptor blockers (ARBs) caused sprue-like enteropathy on the lower tract, specially by olmesartan [6–12]. However, there are less known researches presenting gastrointestinal ADRs, such as indigestion and IBS symptoms, caused by ACEI, whose references keep growing progressively [13–17]. Insomuch as it’s one of the most used group of drugs, leads us to the urge of adding ACEIs intake as a possible differential diagnosis among patient who suffer indigestion and IBS-like symptoms of GIT (vomits, diarrhea…) even if it’s an uncommon ADRs.

Correspondingly, the aim of this study is to evaluate the prevalence of indigestion and IBS symptoms among hypertensive patients treated by the ACEIs and other drugs involved in hypertension treatment.

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7. AIM AND OBJECTIVES

AIM: Evaluate the prevalence of the of indigestion and IBS symptoms among hypertensive patients

treated by ACEIs and other drugs involved in hypertension treatment.

OBJECTIVES:

1. Investigate the frequency and severity of indigestion and irritable bowel syndrome symptoms among hypertensive patients of the present study.

2. Determine the age-associated difference in the frequency of indigestion and irritable bowel syndrome symptoms among hypertensive patients of the present study.

3. Determine the gender-associated difference in the frequency of indigestion and irritable bowel syndrome symptoms among hypertensive patients of the present study.

4. Determine the treatment-related relationship with the frequency of indigestion and irritable bowel syndrome symptoms between patients treated by plain ACEI (C09A) and combined ACEI (C09B).

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8. LITERATURE REVIEW

According to the Hypertension Treatment Guidelines [1] ACEIs are the most used group of drugs for the treatment of hypertension, since they act by decreasing either peripheral and systemic resistance and arterial systolic and diastolic pressures in different states of hypertension. They have probed to the efficient in the treatment of left ventricle systolic dysfunction with or without heart insufficiency. Likewise, in addition to high blood pressure, ACEIs are prescribed for the treatment of patients at high risk of cardiovascular diseases (CVD), after myocardial infarction, whit dilated cardiomyopathy, or with chronic kidney disease [18].

The first synthesized drug belonging to this category was captopril, whose clinical trials began on 1975. Later, enalapril was developed (1984) followed by other sixteen different new ACEIs [4]. Captopril, enalapril, lisinopril, perindopril, ramipril, quinapril, fosinopril, trandopril, spirapril and zofenopril are the ones prescribed in Lithuania. [2].

The control of arterial blood pressure is made by a proteolytic cascade which is connected to a signal transduction system, renin-angiotensin-aldosterone system (RAAS). The formation of angiotensin II hormone, the most powerful known vasoconstrictor, is the main objective of the complex. ACEIs produce vasodilation by blocking the formation of angiotensin II and aldosterone, and a parallel increment of vasodilators bradykinin and prostaglandins. Trying to decrease the adverse drug reactions (ADRs) secondary to these drugs, a new group of drugs was born, angiotensin receptor blockers (ARBs), whose first drug, losartan, was the first one reaching the market on 1995. Both drugs with cardioprotective and renoprotective effects[19].

Along with these beneficial effects, almost since the first year of their entrance in the market, there have been recorded different ADRs which frequently suggest or resemble allergic pathologies. The first ACEIs induced angioedema case was reported 34 years ago, on 1980, secondary to captopril intake, which was the first publication reporting this gastrointestinal adverse reaction[20]. The development of asthma-like cough was the main concern at first, which was probed to disappear after withdrawal of its intake. Later, preoccupations increased after the first cases of angioedema were reported[21], without response to conventional treatment and sometimes lethal and 10 years later, ACEIs started to be replaced by ARBs, in an attempt of decreasing the striking ADRs caused by ACEIs. Initially, their main indication was the substitution of non-tolerated ACEIs intake due to cough [22].

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10 Fig. 8.1: Chronogram of anti-hypertensives: marketing and description of adverse effects [4]

O’Hollaren et al. [23] published on 1990 an article summarizing and reviewing the ADRs due to ACEIs intake, highlighting the most frequent: cough, rhinitis, dysgeusia, pharyngeal dryness, angioedema and possibly asthma. Among this entity there are benign or mild forms and others much more aggressive which might be mortal. As it happens with the sequence of appearance of symptoms, some forms start incredibly fast in days or after the first week of treatment and for others it takes months or even years since the beginning of its intake. The organs and tissues involved vary from the skin, mucosa, respiratory tract, blood vessels, central nervous system, digestive tract and hematological cells. Clinical symptoms are described with different severity from mild (rhinitis, conjunctivitis, cough, exanthema, hives, purpura) up to refractory anaphylaxis and death due to respiratory tract involvement. Suggesting a physio-pathological mechanism whose origin is focused on the RAAS inhibition and lack of degradation of bradykinin, P substance and prostaglandins. As a consequence of this mechanism, there is a clear fact that all these reactions can be produced by all the drugs belonging to this group of drugs [24,25]. Other authors [16,26,27], have studied the effects on angiotensin II inhibition on an intestinal contractility level as an elicitor of this process.

On 2006, another Italian study presented 85 cases of patients with ACEIs induced-angioedema, describing the most common ways of presentation, locations and frequencies of appearance. The face was the most affected body part, followed by the tongue and the oral cavity; upper respiratory tract, other peripheral locations were skin and last, gastrointestinal angioedema[28]. Other authors, have described posteriorly this finding[29–34]. Makani et al. [35] on 2012, performed a clinical trial review between 1998-2011 and found more ADRs cases induced by ACEIs than by ARBs.

Most recently, Bruetman [36] reported a case of an isolated intestinal angioedema associated with the use of enalapril. ACEIs induced angioedema is a rare entity characterized by skin and mucosal edema, due to increased vascular permeability caused by inhibition of the converting enzyme and successive increase in bradykinin. It often presents with facial and mucosal involvement, being uncommon intestinal or airway compromise. Intestinal angioedema may be related with facial or isolated angioedema, being the last one exceptional. It is associated with recurrent episodes of pain, abdominal

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11 distension and watery diarrhea with complete recovery after two or three days. The author suggests, that even if it is a rare entity, the fact that it is associated with one of the most popular group of drugs brings us to the need of including it in the differential diagnosis of recurrent abdominal pain: irritable bowel syndrome, Mediterranean familiar fever, inflammatory bowel disease and porphyria in severe cases.

Several authors tried to detect the possible risk factors that could influence and facilitate the appearance of the ACEI-induced angioedema: women, Afro-American race, smoking, age over 65 years old, seasonal allergy history, C1-esterase defect and possible NSAIDs effect due to interactions with other drugs[15,29,31,37–41].

The same year of the losartan marketing, 1995, the first case report was published about ARBs induced-angioedema. From that date until now [36], the rest of drugs acting by inhibiting the RAAS (ACEI, ARBs and renin inhibitors) have been involved in this kind of ADR[35,42,43].

This ADR is described by multiple bibliographical sources with higher or lower frequencies and with a wide variability as it happened with cough, but with an increased tendency from its marketing until now. Since the beginning of 90s, several researches stated that this ADR is much more common than what was previously published and warn about increasing tendency [35,44]. In general, the frequencies are lower than other ADRs, but since angioedema is a severe condition which could even lead to death of the patient, makes it an important situation to watch out. Angioedema occurs in 0,1%-0,7% of patients treated with ACEI and they account for 20% to 30% of all angioedema cases attending to emergency departments. Patients with this disease present with one or more episodes of abdominal pain associated with nausea, vomiting and/or diarrhea[13,17]. Visceral angioedema should receive the same level of attention by providers as the classic facial angioedema [34]. The mortality of this ADR was stated to be 0,1%-5% of cases. Considering that now a days more than 40 millions of people are under ACEI treatment, this drug could kill up to 160 patients per year according to previous studies[4,45]. In fact, Nosbaum proposed in France special recommendations about angioedemas as a consecuence of what was seen to be related with the intake of these drugs [46].

On 1981, the WHO recommended ATC/DDD System [47] for international studies based on drug usage. The purpose of this ATC/DDD System is to provide an investigation tool for a better and universal usage of medical drugs. In this Anatomical Therapeutical Chemical (ATC) System, active substances are divided in different groups depending on the organ or body system they are targeting and their therapeutical, pharmacological and chemical properties. They are classified in groups at different levels. There are fourteen main groups (first level), with pharmacological and therapeutical subgroups (second level). The third and fourth subgroups include chemical, pharmacological and

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12 therapeutical aspects and the fifth level belongs to the chemical substance. Being the second, third and fourth levels the most used ones. Daily Defined Dose (DDD) is the mean diary dose for the maintenance of a drug which is used for its main indication in an adult. See ATC/DDD in Annex 1.

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9. RESEARCH METHODOLOGY AND METHODS

Retrospective descriptive study based on the data collected between January 2018 and June 2018. A total of 90 patients from Kaunas Clinic’s Cardiology Department completed a questionnaire about Gastrointestinal Symptom Rating Scale (GSRS) in order to study the possible relat ion between antihypertensive and indigestion and IBS symptoms. The patients were instructed to complete the GSRS, where they were asked about their gender, age, presence of hypertension and current antihypertensive medication in case of prescription. Questionnaires were collected anonymously. Patients over 18 year-old age were included in the study. Unconscious patients (patients depending on other people for medicine administration) were excluded. No physical examinations were performed. The GSRS is a disease-specific validated instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal pain, Indigestion, Diarrhea and Constipation. The GSRS has a seven-point graded Likert-type scale, where 1 represents absence of troublesome symptoms (no discomfort at all) and 7 represents very troublesome symptoms (severe discomfort). The questionnaire was done in the official language of Lithuania, through a validated version in Lithuanian which corresponds with the English one.

Antihypertensive medication is presented according to the Anatomical Therapeutical Chemical (ATC) System, where drugs are grouped as: antihypertensives (C02), beta-blocking agents (C07), calcium channel blockers (C08), ACEI plain (C09A), ACEI combined (C09B), ARB plain (C09C) and ARB combined (C09D).

The data were collected and grouped from the questionnaires through the SPSS (Statistical Package for Social Sciences) program. The data analysis was processed using MS Excel 2010 and analysed using SPSS Statistics, version 2.

The descriptive analysis included the calculation of the prevalence of patients age: minimum, maximum and median. Categorical data were presented as percentages (n, %). Continuous variables were presented as mean ± standard deviation (SD). Comparisons were done using the Chi-Square Independence Test, Mann-Whitney U Test (indicated for comparing small samples) and Pearson Correlation Test. The statistical significance level was set at 95% (p<0,05).

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10. RESULTS

In this chapter of master thesis are presented the results of the survey. A total of 90 patients filled the GSRS questionnaire, out of which 78 suffered hypertension and 12 did not.

Fig. 10.1. Distribution of hypertensive patients by age and gender (in N).

In Figure 10.1. we can see the distribution by age and gender of these 78 patients. The mean age was 62,96±1,47 years. The range of age was set from 24 years (the youngest patient) to 91 years (the oldest patient). Out of these hypertensive patients, 43 were females (55,2%) and 35 were males (44,8%). Therefore, according to the graph, we can see that people aged over 45 years and female gender where the most common profiles.

Fig. 10.2. Antihypertensive drug usage distribution of patients under study (according to ATC System). 4 18 13 1 22 20 0 5 10 15 20 25

<45 years 45-65 year >65 years

Distribution by age and gender

Males Females 1,30% 12,80% 10,30% 26,90% 24,40% 7,70% 16,70%

Drug usage distribution

Antihypertensives (C02) Beta blocking agents (C07) Calcium channel blockers (C08) Ace inhibitors, plain (C09A) Ace inhibitors, combinations (C09B) Angiotensin II antagonists, plain (CO9C)

Angiotensin II antagonists, combinations (C09D)

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15 Figure 10.2. describes the anti-hypertensive drug usage distribution by hypertensive patients classified according to the ATC System. The collected therapies were grouped as: anti-hypertensives (C02), beta-blocking agents (C07), calcium channel blockers (C08), ACEI plain (C09A), ACEI combined (C09B), ARB plain (C09C) and ARB combined (C09D). Where ACEI, either plain drugs with 26,9% and combined prescriptions with 24,4%, showed to be the most used drugs for the treatment of this condition, followed by combined ARBs with 16,7% and beta blocking agents with 12,8%.

Fig. 10.3. Frequency and severity of symptoms among hypertensive patients.

Figure 10.3 shows the prevalence of indigestion and IBS symptoms as presented in GSRS which were collected among the studied population suffering from hypertension. The collected answers ranged from ‘0 - no discomfort at all’ until ‘3- mild discomfort’. The symptoms showing the highest clinical prevalence were: ‘upper abdominal discomfort’ (34,6%), ‘loose stools’ (33,3%) and ‘bloating’ (26,9%) respectively. While ‘incomplete emptying’ (2,5%), ‘emptiness’ (7,6%) and ‘constipation’ (7,6%) appeared to be the less common symptoms. On the other hand, ‘loose stools’ (7,6%) and ‘diarrhea’ (5,1%) showed the highest severity among the results. ‘Loose stools’ and ‘diarrhea’ showed mild severity.

Table 10.1. Distribution of The GSRS symptoms according to age.

GSRS symptom Age <65 years ≥65 years p-value (<0,05)

Upper abdominal Yes 14 13 0,45

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Frequency and severity of symptoms

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discomfort No 31 20

Heartburn Yes 6 7 0,359

No 39 26

Acidic reflux Yes 7 12 0,036*

No 38 21 Emptiness Yes 4 2 0,645 No 41 31 Nausea Yes 9 5 0,584 No 36 28 Rumbling Yes 9 8 0,656 No 36 25 Bloating Yes 11 10 0,567 No 34 23 Burping Yes 9 5 0,584 No 36 28 Flatus Yes 6 2 0,299 No 39 31 Constipation Yes 2 4 0,212 No 43 29 Diarrhea Yes 7 9 0,208 No 38 24

Loose stools Yes 13 13 0,334

No 32 20

Hard stools Yes 3 5 0,225

No 42 28 Fecal incontinence Yes 0 9 0 No 45 24 Incomplete emtying Yes 0 2 0,096 No 45 31

*p-value ‒ statistical significance comparing subjects by the age (Mann-Whitney’s U test).

Table 10.1. shows the distribution of GSRS symptoms and within the patients in our study, according to patients’ age group. Since most of the patients were either younger or older than 65 years old, for the statistical calculation two ages were taken into account: those who were younger than 65 years old (<65) and those who were over (65 ≤). Calculations showed that there was a statistically significant

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17 difference for ‘acidic reflux’ 0.036 (p<0,05) for those hypertensive patients which were older than 65 years old compared to those who were under 65 years old. We found no significant differences in other GSRS symptoms between these two age groups.

Table 10.2. Distribution of The GSRS symptoms by gender.

GSRS symptom Gender

Male Female p-value

(<0,05) Upper abdominal discomfort Yes 11 16 0,596 No 24 27 Heartburn Yes 2 11 0,02* No 33 32

Acidic reflux Yes 6 13 0,183

No 29 30 Emptiness Yes 2 4 0,557 No 33 39 Nausea Yes 7 7 0,672 No 28 36 Rumbling Yes 6 11 0,372 Mo 29 32 Bloating Yes 8 13 0,468 No 27 30 Burping Yes 7 7 0,672 No 28 36 Flatus Yes 1 7 0,054 No 34 36 Constipation Yes 2 4 0,557 No 33 39 Diarrhea Yes 6 10 0,509 No 29 33

Loose stools Yes 11 15 0,749

No 24 28

Hard stools Yes 5 3 0,293

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18 Fecal incontinence Yes 4 5 0,978 No 31 38 Incomplete emtying Yes 0 2 0,199 No 35 41

*p-value ‒ statistical significance comparing subjects by the age (Mann-Whitney’s U test).

The results in Table 10.2. describe the distribution of the GSRS symptoms and the gender of the hypertensive interviewed patients. Calculations showed that there was a statistically significant difference related to ‘heartburn’ 0,02 (p<0,05) for those hypertensive women understudy compared to men.

Out of the 78 interviewed patients suffering from hypertension which were under anti-hypertensive pharmacological therapy, 40 (51,28%) of them were treated by ACEI. 21 (52,5%) of them were taking plain ACEI (C09A) and 19 (47,5%) of them combined ACEI (C09B). In the Table 10.3., we gather up the statistical results between the intake of ACE inhibitors, our study group of interest, and GSRS symptoms representing indigestion and IBS symptoms.

Table 10.3. Treatment-related distribution of The GSRS symptoms.

GSRS symptom Angiotensin converting enzyme inhibitors

(ACEI) Statistical level

Value <0,05 Plain – C09A Combined – C09B p-value r-value

Pearson correlation Count Column N % Count Column N % Upper abdominal discomfort Yes 8 38,1 7 36,8 0,936 0,13 No 13 61,9 12 63,2 Heartburn Yes 2 9,5 5 26,3 0,168 -0,221 No 19 90,5 14 73,7 Acidic reflux Yes 4 19,0 6 31,6 0,367 -0,145 No 17 81,0 13 68,4 Emptiness Yes 2 9,5 1 5,3 0,614 0,081 No 19 90,5 18 94,7 Nausea Yes 7 33,3 4 21,1 0,391 0,137 No 14 66,7 15 78,9

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19 Rumbling Yes 2 9,5 4 21,1 0,314 -0,161 No 19 90,5 15 78,9 Bloating Yes 5 23,8 7 36,8 0,375 0,142 No 16 76,2 12 63,2 Burping Yes 7 33,3 1 5,3 0,029* 0,350** No 14 66,7 18 94,7 Flatus Yes 5 23,8 0 0.0 0,025* 0,360** No 16 76,2 19 100 Constipation Yes 1 4,8 3 15,8 0,252 -0,184 No 20 95,2 16 84,2 Diarrhea Yes 7 33,3 3 15,8 0,206 0,202 No 14 66,7 16 84,2

Loose stools Yes 6 28,6 9 47,4 0,226 -0,194

No 15 71,4 10 2,6

Hard stools Yes 0 0,0 3 15,8 0,062 -0,299

No 21 100 16 84,2 Fecal incontinence Yes 1 4,8 2 10,5 0,495 -0,109 No 20 95,2 17 89,5 Incomplete emtying Yes 0 0,0 0 0,0 0 0 No 21 100 19 100

*p-value ‒ statistical significance comparing subjects by the age (Mann-Whitney’s U test). **r-value – Pearson correlation.

Results in Table 10.3. related to ‘burping’ 0,029 (p<0,05) and ‘flatus’ 0,025 (p<0,05) were the only symptoms showing statistically significant difference, while the rest of the symptoms described no statistically significant difference. Pearson’s correlation presents a moderate association between variables plain (C09A) and combined (C09B) ACEIs for ‘burping’ (r=0,35) and ‘flatus’ (r=0,36).

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11. DISCUSSION

According to the Country Health Profile of 2017 made by the State of Health in the EU in Lithuania, heart diseases and stroke are the leading causes of death in the country now a days[48]. What brings us back to the importance of hypertension control in order to avoid further CVD and the study of possible side effects caused by these drugs.

The distribution by age of the hypertensive patients of our study supports the previous stated values by European Guidelines, with a prevalence > 60% among patients over 60 years old[1]. However, our study showed a higher prevalence among women over men, while guidelines described men (24%) gender more prone to suffer from this long-term condition that women (20%).

Regarding the therapeutic distribution of anti-hypertensive drug groups, our results correlate with the stated data in Europe and Lithuania on 2017, and also internationally[4,49]. Where in all of them, the presented drugs acting on RAAS are the most popular drugs acting on the cardiovascular system as we described in our study.

Out of the symptoms described by GSRS, ‘upper abdominal discomfort’, ‘loose stools’ and ‘bloated’ were the most frequent symptoms, were ‘loose stools’ would match IBS symptomatology and ‘bloated’ with indigestion clinical symptomatology. Anyway, none of them is referred with a high severity degree. In this sense, researches talk about the pathophysiological roles of RAAS in the GIT and about unspecified abdominal pain, which suggests further studies about them[16,27,50].

The distribution of GSRS symptoms related to age, showed a higher tendency of suffering from ‘acidic reflux’ on hypertensive patients over 65, which might be due to a higher comorbidity prevalence and usage of other drugs acting on upper GIT[3,35,36,51]. The fact that female gender showed to be more prevalent over 65 years old and more prone to suffer from ‘heartburn’ compared to men supports this finding. Previously mentioned studies [15,25,29,31,37–40], include female gender as a risk factor for suffering ADRs induced by this drugs. Other symptoms in our study with significant differences: burping, flatus and acidic reflux suggest upper GIT involvement. Cohen, supports the presence of upper GIT as proximal to the oral cavity ADRs which have been studied more deeply. Other authors refer that nausea and vomits [4,14,15,17] are the main clinic of the ACEI-induced ADRs. In our study we can see that the absence of clinical manifestations overpowers the presence of the symptoms related to the GSRS scale among patients under ACEIs intake. However, ‘burping’ (p<0,029) and (r:

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21 0,3 to 0,5) and ‘flatus’ (p<0,025) and (r: 0,3-0,5) are moderately associated and must be still considered. It is possible to think that they might be the first symptoms expressing indigestion and the key for the preliminary diagnosis of these ADRs among our population understudy.

Furthermore, the presence of GIT symptoms on patients under anti-hypertensive treatment acting on RAAS has been studied by different authors. Especially, regarding ARBs and their intestinal involvement [6,8,10,27,52,53], all these were studied case-reports based on hospitalized patients and made by specialists. Also, within ACEI based studies, several authors speak about the necessity of a retrospective study due to the limited casuistry and the difficulty of having access to a suitable volume for study[3,15,17,35], which is a limitation for us.

On the other hand. in our study we ignore the dosage, time of exposure to the treatment by the interviewed patients and existence of other concomitant treatment together with the studied anti-hypertensives which could be related with indigestion and IBS symptoms, by modifying our results and its comparisons.

The relevance of these ADRs with important implications (such as renal failure due to diarrhea [14]), risk of intervention, unnecessary tests and the high consumption of these drugs, either for hypertension and many other cardiovascular indications, forces us to evaluate its possible risks among patients who take it and to perform the follow-up and routine controls of its prescription’s fulfillment and treatment adherence. Taking into account, that clinical symptoms remit once drug intake ceases. We cited before the Guide elaborated in France about this problem [46].

All the beneficial effects of ACEIs makes them one of the most popular group of drugs, especially among patients with cardiovascular pathologies, which at the same creates the need for the medical community of knowing the possible ADRs they can cause. The withdrawal of ACEIs could be the effective solution for the cessation or improval of either indigestion, IBS or any GIT related symptoms. Involving both its early detection to enhance therapeutic adherence and the avoidance of unnecessary, expensive and invasive diagnostic procedures in order to rule out severe, urgent or secondarily caused pathologies.

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12. CONCLUSIONS

1. ‘Upper abdominal discomfort’, ‘loose stools’ and ‘bloating’ were the symptoms showing the highest frequency with minimal severity among the present study participants, while the following symptoms including ‘loose stools’ and ‘diarrhea’ showed mild severity and higher frequency regarding lower GI symptoms.

2. Hypertensive patients of both age groups (<65 years and ≥65 years) showed the highest frequency of the following symptoms including ‘loose stools’, ‘bloating’, ‘acidic reflux’ and ‘upper abdominal discomfort’, however only the patient's group over 65 years old showed a statistically significant difference (p=0.036) for ‘acidic reflux’ symptom.

3. The symptoms including ‘upper abdominal discomfort’, ‘heartburn’, ‘acidic reflux’, ‘bloating’ and ‘loose stools’ were more common among female gender, however, only one symptom ‘heartburn’ showed a statistically significant difference (p=0.02).

4. ‘Flatus’ and ‘burping´’ were statistically significant among hypertensive patients treated with plain ACEI (C09A) and combined ACEI (C09B), however, we can not affirm the treatment-related relationship with the presence of these symptoms, due to a reason of the small number of respondents who answered positively

13. PRACTICAL RECOMMENDATIONS

When facing a patient which presents nonspecific abdominal pain, the first task is to eliminate the potentially severe pathologies requiring urgent treatment and involving a wide source of possible etiological causes, out of which the pharmacological origin could be purposed and easily solved in this case by ceasing its intake.

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15. ANNEXES

ANNEX 1

ATC C Cardiovascular system drug code

DRUG CLASS SUBCLASSIFICATIONS

C01 Cardiac therapy C01A Cardiac glycosides

C01B Antiarrhythmic drugs, class I and II C01C Cardiac stimulants except cardiac glycosides

C01D Vasodilators used in cardiac diseases

C01E Other cardiac preparations C02 Antihypertensives C02A Antiadrenergic agents, centrally

acting

C02B Antiadrenergic agents, ganglion-blocking

C02C Antiadrenergic agents, peripherally acting

C02D Arteriolar smooth muscle, agents acting on

C02K Other antihypertensives

C02L Antihypertensives and diuretics in combination

C02N Combinations of antihypertensives in ATC gr. C02

C03 Diuretics C03A Low-ceiling diuretics, thiazides C03B Low-ceiling diuretics except thiazides

C03C High-ceiling diuretics C03D Potassium-sparing agents C03E Diuretics and potassium-sparing agents in combination

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30 C04 Peripheral vasodilators C04A Peripheral vasodilators

C05 Vasoprotectives C05A Agents for treatment of hemorrhoids and anal fissures for topical use

C05B Antivaricose therapy C05C Capillary stabilizing agents C07 Beta blocking agents C07A Beta blocking agents

C07B Beta blocking agents and thiazides C07C Beta blocking agents and other diuretics

C07D Beta blocking agents, thiazides and other diuretics

C07E Beta blocking agents and vasodilators

C07F Beta blocking agents, other combinations

C08 Calcium channel blockers C08C Selective calcium channel blockers with mainly vascular effects

C08D Selective calcium channel blockers with direct cardiac effects

C08E Non-selective calcium channel blockers

C08G Calcium channel blockers and diuretics

C09 Agents acting on renin-angiotensin system

C09A ACE inhibitors, plain

C09B ACE inhibitors, combinations C09C Angiotensin II antagonists, plain C09D Angiotensin II antagonists, combinations

C09X Other agents acting on renin-angiotensin system

C10 Lipid modifying agents C10A Lipid modifying agents, plain C10B Lipid modifying agents, combinations

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ANNEX 2

Amžius: _________ Lytis: _________ Data _________

 Ar jūs sergate ARTERINE HIPERTENZIJA (aukštas kraujo spaudimas)? TAIP; NE;

 Kokius kraujospūdį mažinančius vaistus Jūs vartojate (žemiau parašykite vaistų pavadinimus)? ...

DISPEPSIJOS (Virškinimo sistemos) SIMPTOMŲ VERTINIMO SKALĖ

Šioje anketoje pateikiami klausimai apie Jūsų savijautą ir nusiskundimus NURODYTI LAIKOTARPĮ METU. Jūsų pasirinktą atsakymą prašome pažymėti langelyje, ženklu "X".

1. Ar praėjusią savaitę Jus vargino SKAUSMAS ARBA DISKOMFORTO JAUSMAS PILVO VIRŠUTINĖJE DALYJE ARBA DUOBUTĖJE PO KRŪTINE?

Simptomų nebuvo Labai nežymūs simptomai Nestiprūs simptomai Vidutiniški simptomai Vidutiniškai stiprūs simptomai Stiprūs simptomai

Labai stiprūs simptomai

2. Ar praėjusią savaitę Jus vargino RĖMUO? (rėmuo - nemalonus deginimo ar graužimo jausmas už krūtinkaulio).

3. Ar praėjusią savaitę Jus vargino ATPYLIMAI RŪGŠČIU TURINIU? ( Atpylimai rūgščiu turiniu - nedidelio kiekio rūgštaus ar kartaus skonio turinio atpylimai iš skrandžio į nosiaryklę).

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4. Ar praėjusią savaitę Jus vargino ALKIO SKAUSMAI PILVO VIRŠUTINĖJE DALYJE? (tuštumos jausmas skrandyje, susijęs su būtinybe dažnai valgyti).

5. Ar praėjusią savaitę Jus vargino PYKINIMAS? (Pykinimas - nemalonus jausmas, galintis pereiti į žagsėjimą ar vėmimą).

6. Ar praėjusią savaitę Jus vargino GURGĖJIMO, URZGIMO jausmas (vibracija ar garsai) skrandyje?

7. Ar praėjusią savaitę Jūs jautėte PILNUMO jausmą skrandyje? (Tai - oro buvimo skrandyje ar skrandžio išsipūtimo jausmas)

8. Ar praėjusią savaitę Jus vargino RAUGĖJIMAS? (Raugėjimas - oro išsiskyrimas iš skrandžio per burną, susijęs su skrandžio išsipūtimo pojūčiu)

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9. Ar praėjusią savaitę Jus vargino VIDURIŲ PŪTIMAS? (suprantamas kaip poreikis “išleisti dujas”, dažnai susijęs su sunkumo jausmo palengvėjimu).

10. Ar praėjusią savaitę Jus vargino VIDURIŲ UŽKIETĖJIMAS? (vidurių užkietėjimu laikomas suretėjęs tuštinimasis).

11. Ar praėjusią savaitę Jus vargino VIDURIAVIMAS? (viduriavimu laikomas padažnėjęs tuštinimasis).

12. Ar praėjusią savaitę Jus vargino TUŠTINIMASIS SKYSTOMIS IŠMATOMIS? (Jei skystos išmatos kaitaliojasi su kietomis, tai atsakykite kokiu laipsniu vargina tuštinimasis skystomis išmatomis).

13. Ar praėjusią savaitę Jus vargino TUŠTINIMASIS KIETOMIS IŠMATOMIS? (Jei kietos išmatos kaitaliojasi su skystomis, tai atsakykite kokiu laipsniu vargina tuštinimasis kietomis išmatomis).

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14. Ar praėjusią savaitę Jus vargino STAIGUS STIPRUS POTRAUKIS TUŠTINTIS? (Šis potraukis susijęs su jausmu, kad jau nebegalite kontroliuoti savęs).

15. Ar praėjusią savaitę Jūs jautėte NEPILNO IŠSITUŠTINIMO POJŪTĮ? (Tai - jausmas, kai, nepaisant visų pastangų, po pasituštinimo Jūs vis dar jaučiate potraukį tuštintis).

PRAŠOME PATIKRINTI, AR VISI KLAUSIMAI ATSAKYTI AČIŪ, KAD ATSAKĖTE Į ŠIUOS KLAUSIMUS!

LITHUANIAN UNIVERSITY OF HEALTH SCIENCES ACADEMY OF MEDICINE INSTITUTE OF PHYSIOLOGY AND PHARMACOLOGY