The Journal of Emergency Medicine, Vol. 50, No. 1, pp. 108–115, 2016 Copyright 2016 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2015.07.017
Pharmacology in Emergency Medicine
SUBLINGUAL SUBLINGUAL VS. ORAL CAPTOPRIL IN HYPERTENSI HYPERTENSIVE VE CRISIS Adnan Kaya, MD,* Mustafa Adem Tatlisu, MD,* Tugba Kaplan Kaya, PHARM,† Ozlem Yildirimturk, MD,* Baris Gungor, MD,* Baran Karatas, MD,* Selcuk Yazici, MD,* Muhammed Keskin, MD,* Sahin Avsar, MD,* and Ahmet Murat, MD* *Department of Cardiology, Dr. Siyami Ersek Cardiovascular and Thoracic Surgery Center, Istanbul, Turkey and †Department of Clinical Pharmacology, Yeditepe University Faculty of Pharmacy, Istanbul, Turkey Reprint Address: Adnan Kaya, MD , Dr.Siyami Ersek Cardiovascular and Thoracic Surgery Center, 34087, Istanbul, Turkey
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Abstract— Abstract—Back Backgrou ground: nd: There There are confusing confusing data in literatu literature re regardi regarding ng oral oral and sublingua sublinguall captopri captoprill effe effects cts over blood pressure (BP) decrease. Objectives: In our study we compared compared oral oral and sublingua sublinguall captopri captoprill effe effectiv ctivenes enesss over BP decrease in patients admitted to our Emergency Departme Department nt with hyperten hypertensive sive urgency urgency.. Methods: Methods: Our study was conducted from January 2012 to January 2013 in patien patients ts with with hyper hyperten tensiv sivee urgenc urgency y. In this this crosscrosssectional study after two initial BP measurements, patients were identified as eligible for the study. An initial electrocardiogram was obtained and blood samples were drawn. A total of 212 212 patie patients nts were were accept accepted ed as eligib eligible le for for thestudy, thestudy, and 25 mg of captopril was randomly given orally or sublingually; BP was measured at 10, 30, and 60 min. We selected the patients to the groups consecutively. consecutively. A 25% reduction of initial BP 1 h after initiation of the treatment was accepted as an accompli accomplishmen shment. t. A second second 25 mg of captopri captoprill was given if the target of 25% reduction of BP was not reached after the first tablet. Intravenous drugs were administered to the patients resistant to the captopril and these patients were excluded from the study. Results: The 10-min systolic BP (SBP), diastolic BP, and mean BP (MBP) decrease was more more prom promin inen entt in the the subl sublin ingu gual al capt captop opri rill grou group p ( p < 0.001). This decrease was statistically significant in the SBP and MBP at 30 min ( p < 0.001), and no statistical difference was recorded at 60 min ( p > 0.05). Conclusions: In our study, sublingual captopril was found to decrease BP more efficiently in the first 30 min, but this difference equalized at 60 min. 2016 Elsevier Inc.
Keywords—hypertensive urgency; oral captopril; sublingual captopril
INTRODUCTION
The World Health Organization defines hypertension as a level of systolic blood pressure (SBP) of 140 mm Hg or higher, or diastolic BP (DBP) of 90 mm Hg or higher in people not under drug therapy (1) (1).. Hypertension is the most common underlying etiology of cardiovascular diseases. eases. Hypert Hypertens ensive ive crisis, crisis, which which is the most most seriou seriouss complication of hypertension, means acute increase of BP that threatens a patient’s life. This is defined as SBP leve levells of 180 180 mm Hg or mo more re,, or DBP DBP leve levells of 120 mm Hg or more (2) (2).. One component of this entity, hyperte hypertensi nsive ve emerge emergency ncy,, is presen presence ce of concom concomitan itantt high BP levels with vital organ damage symptoms like angina, dyspnea, headache, acute neurologic disorders, oliguria, and anuria. The other component of hypertensive urgency is that there is no associated organ damage. Both entities need to be treated with BP-lowering BP-lowering drugs. Hypertensive emergency should be treated with intravenous drugs to achieve aimed BP levels within hours to dimini diminish sh end-or end-organ gan damage damage.. Captop Captopril ril is one of the most mo st used used oral oral or subl sublin ingu gual al drug drugss in emer emerge genc ncy y
RECEIVED: 8 December 2014; F INAL SUBMISSION RECEIVED : 4 July 2015; ACCEPTED: 25 July 2015 108
Sublingual vs. Oral Captopril in Hypertensive Crisis
departments (EDs) to decrease BP to aimed levels. It inhibits angiotensin-converting enzyme (ACE) and decreases angiotensin II (a potent vasoconstrictor), aldosterone, and increases bradykinin levels in tissue (3). There are conflicting views about usage of this medication in literature. Although the sublingual method has been found to reduce BP effectively in hypertensive crises in some studies, some other studies encouraged readers to prefer the oral method to the sublingual (4–10). The objective of our study was to compare oral and sublingual captopril usage in patients with hypertensive urgency admitted to our ED. MATERIALS AND METHODS
This cross-sectional study was conducted from January 2012 to January 2013 in our tertiary cardiovascular surgery hospital ED. We are the referral hospital for all the hospitals around. Our ED is dedicated solely to cardiac emergency cases. Our ED operates with two cardiology residents and three nurses, with other paramedical staff. Our daily admission for the ED varies, but it is about 200. The main admission symptoms are chest pain, dyspnea, palpitation, nausea, and vomiting. Ten to 15% of these patients are hospitalized. Forty to 50% of patients are diagnosed to have nonanginal chest pain and are discharged with no treatment after routine electrocardiography, chest X-ray study, and cardiac enzyme evaluation. There is a group of patients who were treated in the ED, and redirected to cardiology outpatient polyclinics (high blood pressure, supraventricular dysrhythmias, heart failure without decompensation). In our ED, captopril is used as the first drug for patients with high blood pressure without end-organ damage. Oral or sublingual administrations vary according to the physician in charge. Intravenous drugs are used if the treatment fails or if there is end-organ damage. All patients with hypertensive urgency were included in the study except for patients with symptoms suggesting end-organ damage. All patients with chest pain, myocardial infarction, cerebral symptoms suggesting hypertensive encephalopathy or stroke, acute dyspnea, acute renal failure, chronic kidney disease, on chronic dialysis treatment, known to have renal artery stenosis, in the terminal stage of a malignant disease, on cytotoxic therapy and long-term corticosteroid therapy, on oral contraceptive therapy, cocaine and amphetamine overdose, and pregnancy were excluded. We excluded patients with hypertensive emergency because these patients need more rapid BP-lowering strategies. Intravenous drug administration is the preferred method for BP decrease in these cases. Hypertensive urgency was defined as an increase in SBP of 180 mm Hg or more, or DBP of 120 mm Hg or
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more without any end-organ damage symptoms, and findings after two consecutive measurements in the supine position at 3-min interval. An initial electrocardiogram (ECG) was obtained from the all patients eligible for the study. Blood samples were drawn for complete blood count and blood chemistry. All the patients were interrogated for their past medical history and the data were recorded. A total of 212 patients (of these, 114 were female) were accepted to the study. The size of the study was achieved by accepting all the eligible patients admitted to our ED from January 2012 to January 2013. After the initial two BP measurements, patients identified as eligible for the study were given 25 mg of captopril either orally or sublingually. We selected the patients to the groups consecutively. For example, when we administered oral captopril to the first patient, then the second patient was administered sublingual captopril. BPs were measured and recorded after 10, 30, and 60 min. Nurses took the BPs with a mercury sphygmomanometer (Riester Mercury Sphygmomanometer, Jungingen, Germany). To minimize our BP measurements variation, we organized a training workshop for ED nurses at the beginning of the study and sustained it quarterly until the study end. The calibration of ECG devices and mercury sphygmomanometer is done by a technical service monthly as a routine. A 25% reduction of initial BP after 1 h of captopril was considered to be responsive to the treatment, and after adjustment of oral BP treatment, the patients were discharged. After a response of a <25% reduction in BP, one more 25-mg captopril tablet was given to the patients. When the target of 25% of reduction was achieved, the patients were discharged and enrolled in the study. In other circumstances, intravenous drugs were initiated and the patients were excluded from the study. Informed consent was taken from all the patients prior to enrollment, and the study protocol was confirmed with ethical guidelines of the Helsinki Declaration, 1975 (11). The local ethics committee of the hospital approved the study. Statistical Analysis
Statistical analysis was performed using SPSS 15.0 (SPSS Inc., Chicago, IL) software. Conformity to the normal distribution of the variable was examined using images (histogram) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk’s test). Descriptive analysis for normally distributed variables was given by using mean and SD. SBP, DBP, and mean blood pressure (MBP) changes in the effect of captopril by sublingual or oral method were analyzed using repeated-measures analysis of variance. Total type-1 error level for statistical significance was set at 5%.
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Table 1. Clinical and Demographic Properties of Patients With Sublingual Captopril and Oral Captopril Groups
Variables
Sublingual Captopril (n = 108)
Oral Captopril (n = 104)
p Value
Age, years Female gender, n (%) Male gender, n (%) Diabetes mellitus, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Current smoker, n (%) Stroke, n (%) Obesity, n (%) Congestive heart failure, n (%) Coronary artery disease, n (%) Heart rate, beats/min Sinus rhythm, n (%) Atrial fibrillation, n (%) Normal QRS duration, n (%) LBBB, n (%) RBBB, n (%)
63.2 6 12.9 59 (54.5%) 49 (45.4%) 34 (31.5%) 104 (96.3%) 22 (20.4%) 38 (35.2%) 5 (4.6%) 17 (15.7%) 4 (3.7%) 13 (12.0%) 83.0 6 17.9 89 (82.4%) 19 (17.6%) 100 (92.6%) 3 (2.8%) 5 (4.6%)
63.6 6 11.3 55 (52.9%) 49 (47.1%) 27 (26.0%) 103 (99.0%) 25 (24%) 32 (30.8%) 6 (5.8%) 19 (18.1%) 5 (4.9%) 17 (16.3%) 86.4 6 16.5 88 (84.6%) 16 (15.4%) 95 (91.3%) 7 (6.7%) 2 (1.9%)
0.83 0.89 0.44 0.36 0.62 0.56 0.76 0.71 0.74 0.43 0.15 0.71 0.22
LBBB = left bundle branch block; RBBB = right bundle branch block.
RESULTS
In this cross-sectional study, which compared the efficiency of oral vs. sublingual captopril, a total of 212 consecutive patients with mean age 6 SD of 63.4 6 12.2 years were enrolled, and 98 of these were men (46.2%). When all the participants were studied, 28.8% of patients had diabetes mellitus (DM), 97.6% of patients had hypertension (HT), 22.2% of patients had hyperlipidemia (HL), and 33% of patients were smokers. The patients were divided into two groups, as shown in Table 1. There was no statistically significant difference in the proportions of subjects with oral and sublingual captopril in relation to age and gender. There were also no statistically significant differences between the two groups in relation to incidence of DM ( p > 0.05), HT ( p > 0.05), HL ( p > 0.05), smoking ( p > 0.05), stroke ( p > 0.05), obesity ( p > 0.05), heart failure ( p > 0.05), and coronary artery disease ( p > 0.05). The admission
heart rate, ECG with sinus rhythm, ECG with atrial fibrillation, and bundle branch block did not differ between the two groups. The patients’ laboratory data were shown in Table 2, and there were no statistically significant differences between the two groups in relation to admission white blood cell count ( p > 0.05), hemoglobin ( p > 0.05), hematocrit ( p > 0.05), thrombocyte ( p > 0.05), mean cell volume ( p > 0.05), red cell distribution width ( p > 0.05), mean platelet volume ( p > 0.05), glucose ( p > 0.05), blood urea nitrogen ( p > 0.05), creatinine ( p > 0.05), and aspartate transaminase ( p > 0.05) and alanine transaminase ( p > 0.05) levels. Statistical analysis showed a significant difference in BP decrease between arrival BP measurements and 10min measurements (Table 3). In the group of sublingual captopril administration, decrease at 10 min was more than in the orally administered group, and this level of decrease was statistically significant for SBP, DBP, and MBP ( p < 0.001).
Table 2. Comparison of Laboratory Parameters of Sublingual Captopril and Oral Captopril Groups
Variables WBC, 103 / mL Hemoglobin, g/dL Hematocrit, % Platelet, 10 3 / mL MCV, fL RDW, % MPV, fL Glucose, mg/dL Blood urea nitrogen, mg/dL Creatinine, mg/dL Aspartate aminotransferase, IU/L Alanine aminotransferase, IU/L
Sublingual Captopril (n = 108) 7.66 13.3 40.0 255.6 86.0 14.2 8.8 123.1 18.0 0.87 24.8 23.6
1.90 1.59 6 4.4 6 70.5 6 5.9 6 1.5 6 0.9 6 45.8 6 6.2 6 0.70 6 9.1 6 13.8 6 6
Oral Captopril (n = 104) 7.65 14.5 40.1 250.2 86.5 14.0 8.7 122.9 18.7 0.82 24.7 22.3
2.01 11.6 6 4.9 6 65.6 6 4.1 6 1.2 6 0.8 6 46.2 6 10.0 6 0.17 6 8.7 6 10.4 6 6
p Value
0.98 0.29 0.90 0.56 0.49 0.43 0.67 0.97 0.56 0.52 0.92 0.44
WBC = white blood cell count; MCV = mean corpuscular volume; RDW = reticulocyte distribution width; MPV = mean platelet volume.
Sublingual vs. Oral Captopril in Hypertensive Crisis
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Table 3. Comparison of the Difference Between the Arrival BP Measurements and 10-Min Measurements and the 10-Min BP of Groups
Variables DSBP
10-min S BP DDBP 10-min D BP DMBP 10-min MBP
Sublingual 16.4 6 172.9 6 14.1 6 101.8 6 15.6 6 149.2 6
4.9 7.92 4.9 5.5 3.8 5.7
Oral 12.3 178.6 10.3 105.9 11.6 154.4
4.2 9.5 6 10.3 6 10.4 6 4.6 6 7.6 6 6
p Value
Variables
<0.001 <0.001 0.001 0.001 <0.001 <0.001
DSBP
BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; MBP = mean blood pressure.
Statistical analysis showed a significant difference in BP decrease between arrival BP measurements and 30min measurements (Table 4). In the group of sublingual captopril administration, decrease at 30 min was more than in the orally administered group, and this level of decrease was statistically significant on SBP ( p = 0.050) and MBP ( p = 0.022), whereas decrease in DBP ( p = 0.121) was not statistically significant. Statistical analysis showed no significant difference in BP decrease between arrival BP measurement and 60min measurement between the two groups (Table 5). These statistical data could be concluded as sublingual administration of captopril decreases BP early, in 10 min, more effectively than oral administration, but this effect of BP decrease is equalized at 60 min. This statistical conclusion is shown in Figures 1 and 2A,B,andC. DISCUSSION
Hypertensive crisis is characterized by a sudden onset of increased BP and represents more than 25% of all medical urgencies/emergencies, often threatening patients’ lives (12). Because different treatment approaches are required, drawing a line between hypertensive emergency and urgency is crucial. Checking end-organ damage symptoms and findings should be the priority of the physician whenever a patient presents to an ED with high BP. Immediate administration of intravenous BPlowering drugs should be kept in mind to protect vital Table 4. Comparison of the Difference Between the Arrival BP Measurements and 30-Min Measurements and 30-Min BP of Groups
Variables DSBP
30-min SBP DDBP 30-min DBP DMBP 30-min MBP
Sublingual 31.6 157.7 28.7 87.3 30.6 134.2
7.3 8.41 6 6.8 6 7.2 6 5.7 6 6.7 6 6
Oral 29.6 161.3 27.2 89.0 28.8 137.2
7.5 7.7 6 7.0 6 6.3 6 5.7 6 6.2 6 6
Table 5. Comparison of the Difference Between Arrival BP Measurements and 60-Min Measurements of Groups
p Value
0.052 0.001 0.121 0.07 0.022 0.001
BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; MBP = mean blood pressure.
60th SBP DDBP 60th DBP DMBP 60th MBP
Sublingual 39.8 149.5 35.1 80.9 38.2 126.6
8.5 7.6 6 6.06 6 6.1 6 6.0 6 5.8 6 6
Oral 40.1 150.8 33.7 82.5 38.0 128.0
8.7 8.3 6 7.1 6 6.5 6 6.8 6 6.8 6 6
p Value
0.75 0.26 0.12 0.06 0.80 0.12
BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; MBP = mean blood pressure.
organs like the heart, the brain, and the kidneys when diagnosis of hypertensive emergency is made. On the other hand, slow BP decrease with oral or sublingual drugs over 24 to 48 h is advised in hypertensive urgency (13,14). Sublingual nifedipine is one of the several drugs to decrease BP fast and effectively in a hypertensive emergency (15). The U.S. Food and Drug Administration does not recommend this drug nowadays in this indication due to a wide variety of side effects like palpitations, flushing, tachycardia, and headache (16). Some studies found that captopril’s BP-lowering effect is as effective as that of nifedipine, with fewer side effects (17,18). Bad taste and local mucosal trauma limit sublingual drug usage vs. oral usage, which is more safe and agreeable. The sublingual method could be used when the patient cannot swallow. There are conflicting results about the sublingual use of captopril in literature. Whereas one study showed low absorption of captopril from the sublingual cavity of rabbits, some others found no difference in proportion of BP decrease, plasma rennin activity inhibition, and ACE inhibition (9,12,19). On the other hand, many studies found that sublingual captopril’s decrease of blood pressure is better than the oral method (20–22). In this study, sublingual administration of captopril was found more effective in decreasing BP than oral in the first 30 min, and this effect equalized at 60 min. Our study is in accordance with two previous studies investigating sublingual captopril’s pharmacokinetic and pharmacodynamic effect. The first study found a passive diffusion permeation mechanism in a porcine model where sublingual steady-state flux was harmonic with captopril blood concentration (21). In the second study, maximum plasma concentration of captopril was reached quickly in a sublingual group, which means short t (time to reach maximum concentration) with the sublingual method. There was no difference between other pharmacokinetic parameters. The study concluded that sublingual captopril administration brings more rapid plasma captopril concentration and so, a more rapid max
