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The Journal of Emergency Medicine, Vol. 50, No. 1, pp. 108–115, 2016 Copyright 2016 Elsevier
The Journal of Emergency Medicine, Vol. 50, No. 1, pp. 108–115, 2016 Copyright 2016 Elsevier

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

Pharmacology in Emergency Medicine

SUBLINGUAL VS. ORAL CAPTOPRIL IN HYPERTENSIVE 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

, Abstract—Background: There are confusing data in literature regarding oral and sublingual captopril effects over blood pressure (BP) decrease. Objectives: In our study we compared oral and sublingual captopril effectiveness over BP decrease in patients admitted to our Emergency Department with hypertensive urgency. Methods: Our study was conducted from January 2012 to January 2013 in patients with hypertensive urgency. In this cross- sectional study after two initial BP measurements, patients were identified as eligible for the study. An initial electrocar- diogram was obtained and blood samples were drawn. A to- tal of 212 patients were accepted as eligible for the study, and 25 mg of captopril was randomly given orally or sublin- gually; BP was measured at 10, 30, and 60 min. We selected the patients to the groups consecutively. A 25% reduction of initial BP 1 h after initiation of the treatment was accepted as an accomplishment. A second 25 mg of captopril 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 prominent in the sublingual captopril group ( p < 0.001). This decrease was statistically significant in the SBP and MBP at 30 min ( p < 0.001), and no statistical differ- ence 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; sub- lingual 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) . Hypertension is the most common underlying etiology of cardiovascular dis- eases. Hypertensive crisis, which is the most serious complication of hypertension, means acute increase of BP that threatens a patient’s life. This is defined as SBP levels of 180 mm Hg or more, or DBP levels of 120 mm Hg or more (2) . One component of this entity, hypertensive emergency, is presence of concomitant high BP levels with vital organ damage symptoms like angina, dyspnea, headache, acute neurologic disorders, oliguria, and anuria. The other component of hyperten- sive urgency is that there is no associated organ damage. Both entities need to be treated with BP-lowering drugs. Hypertensive emergency should be treated with intrave- nous drugs to achieve aimed BP levels within hours to diminish end-organ damage. Captopril is one of the most used oral or sublingual drugs in emergency

one of the most used oral or sublingual drugs in emergency R ECEIVED : 8 December

R ECEIVED : 8 December 2014; F INAL SUBMISSION RECEIVED : 4 July 2015;

ACCEPTED: 25 July 2015

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Sublingual vs. Oral Captopril in Hypertensive Crisis

109

departments (EDs) to decrease BP to aimed levels. It in- hibits angiotensin-converting enzyme (ACE) and de- creases angiotensin II (a potent vasoconstrictor), aldosterone, and increases bradykinin levels in tissue (3) . There are conflicting views about usage of this medi- cation 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 sur- gery 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, dys- pnea, 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 electrocardi- ography, chest X-ray study, and cardiac enzyme evalua- tion. There is a group of patients who were treated in the ED, and redirected to cardiology outpatient poly- clinics (high blood pressure, supraventricular dysrhyth- mias, 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 sublin- gual 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, myocar- dial infarction, cerebral symptoms suggesting hyperten- sive encephalopathy or stroke, acute dyspnea, acute renal failure, chronic kidney disease, on chronic dialysis treatment, known to have renal artery stenosis, in the ter- minal stage of a malignant disease, on cytotoxic therapy and long-term corticosteroid therapy, on oral contracep- tive therapy, cocaine and amphetamine overdose, and pregnancy were excluded. We excluded patients with hy- pertensive emergency because these patients need more rapid BP-lowering strategies. Intravenous drug adminis- tration 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

more without any end-organ damage symptoms, and find- ings 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 chemis- try. 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 accept-

ing 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 sublin- gually. We selected the patients to the groups consecu- tively. 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 Mer- cury 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 sphygmo- manometer is done by a technical service monthly as a routine. A 25% reduction of initial BP after 1 h of capto- pril 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 pa-

tients. 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 (Kolmo- gorov-Smirnov/Shapiro-Wilk’s test). Descriptive anal- ysis 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

63.2 6 12.9

63.6 6 11.3

0.83

Female gender, n (%)

59 (54.5%)

55 (52.9%)

0.89

Male gender, n (%) Diabetes mellitus, n (%)

49 (45.4%) 34 (31.5%)

49 (47.1%) 27 (26.0%)

0.44

Hypertension, n (%)

104 (96.3%)

103 (99.0%)

0.36

Hyperlipidemia, n (%)

22 (20.4%)

25 (24%)

0.62

Current smoker, n (%)

38 (35.2%)

32 (30.8%)

0.56

Stroke, n (%)

5 (4.6%)

6 (5.8%)

0.76

Obesity, n (%)

17 (15.7%)

19 (18.1%)

0.71

Congestive heart failure, n (%)

4 (3.7%)

5 (4.9%)

0.74

Coronary artery disease, n (%)

13 (12.0%)

17 (16.3%)

0.43

Heart rate, beats/min

83.0 6 17.9

86.4 6 16.5

0.15

Sinus rhythm, n (%)

89 (82.4%)

88 (84.6%)

0.71

Atrial fibrillation, n (%) Normal QRS duration, n (%) LBBB, n (%) RBBB, n (%)

19 (17.6%) 100 (92.6%) 3 (2.8%) 5 (4.6%)

16 (15.4%) 95 (91.3%) 7 (6.7%) 2 (1.9%)

0.22

LBBB = left bundle branch block; RBBB = right bundle branch block.

RESULTS

In this cross-sectional study, which compared the effi- ciency 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 fibril- lation, 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 be- tween 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 aspar- tate 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 10- min 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

Sublingual Captopril (n = 108)

Oral Captopril (n = 104)

p Value

WBC, 10 3 / m L

7.66 6 1.90

7.65 6 2.01

0.98

Hemoglobin, g/dL

13.3 6 1.59

14.5 6 11.6

0.29

Hematocrit, %

40.0 6 4.4

40.1 6 4.9

0.90

Platelet, 10 3 / m L

255.6 6 70.5

250.2 6 65.6

0.56

MCV, fL

86.0 6 5.9

86.5 6 4.1

0.49

RDW, %

14.2 6 1.5

14.0 6 1.2

0.43

MPV, fL

8.8 6 0.9

8.7 6 0.8

0.67

Glucose, mg/dL

123.1 6 45.8

122.9 6 46.2

0.97

Blood urea nitrogen, mg/dL

18.0 6 6.2

18.7 6 10.0

0.56

Creatinine, mg/dL

0.87 6 0.70

0.82 6 0.17

0.52

Aspartate aminotransferase, IU/L

24.8 6 9.1

24.7 6 8.7

0.92

Alanine aminotransferase, IU/L

23.6 6 13.8

22.3 6 10.4

0.44

Sublingual vs. Oral Captopril in Hypertensive Crisis

111

Table 3. Comparison of the Difference Between the Arrival BP Measurements and 10-Min Measurements and the 10-Min BP of Groups

Table 5. Comparison of the Difference Between Arrival BP Measurements and 60-Min Measurements of Groups

Variables

Sublingual

Oral

p Value

Variables

Sublingual

Oral

p Value

D SBP

16.4 6 4.9 172.9 6 7.92 14.1 6 4.9 101.8 6 5.5 15.6 6 3.8 149.2 6 5.7

12.3 6 4.2 178.6 6 9.5 10.3 6 10.3 105.9 6 10.4 11.6 6 4.6 154.4 6 7.6

<0.001

DSBP 60 th SBP DDBP 60 th DBP DMBP 60 th MBP

39.8 6 8.5 149.5 6 7.6 35.1 6 6.06 80.9 6 6.1 38.2 6 6.0 126.6 6 5.8

40.1 6 8.7 150.8 6 8.3 33.7 6 7.1 82.5 6 6.5 38.0 6 6.8 128.0 6 6.8

0.75

10-min SBP

<0.001

0.26

D DBP

0.001

0.12

10-min DBP

0.001

0.06

D MBP

<0.001

0.80

10-min MBP

<0.001

0.12

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 30- min 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 60- min 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 sta- tistical conclusion is shown in Figures 1 and 2 A, B, and C.

DISCUSSION

Hypertensive crisis is characterized by a sudden onset of increased BP and represents more than 25% of all medi- cal 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 BP- lowering 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

Sublingual

Oral

p Value

D SBP

31.6 6 7.3 157.7 6 8.41 28.7 6 6.8 87.3 6 7.2 30.6 6 5.7 134.2 6 6.7

29.6 6 7.5 161.3 6 7.7 27.2 6 7.0 89.0 6 6.3 28.8 6 5.7 137.2 6 6.2

0.052

30-min SBP

0.001

D DBP

0.121

30-min DBP

0.07

D MBP

0.022

30-min MBP

0.001

BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; MBP = mean blood pressure.

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 emer- gency (15) . The U.S. Food and Drug Administration does not recommend this drug nowadays in this indica- tion 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 pas- sive 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 max (time to reach maximum concentration) with the sublin- gual 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

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112

A. Kaya et al.

200 180 160 140 120 100 80 60 40 20 0 Arrival BP 10 th
200
180
160
140
120
100
80
60
40
20
0
Arrival BP
10 th minute BP
30 th minute BP
60 th minute BP
Sublingual SP
Oral SP
Sublingual DP
Oral DP
Sublingual MAP
Oral MAP

Figure 1. The effects of oral and sublingual captopril on blood pressure. BP = blood pressure; SP = systolic blood pressure; DP = diastolic blood pressure; MAP = mean blood pressure.

pharmacological effect when compared with oral admin- istration (20) . The patients in our study showed the same results. Patients in the sublingual group had more BP decrease at 10- and 30-min BP measurements and this was statistically significant, and the difference in BP decrease vanished at 60-min measurements.

Limitations

Limitations of our study included a relatively small sam- ple size, single-center data, and manual sphygmomanom- eter BP measurements. Unfortunately, the patients’

medications were not recorded. Swallowing of the sublin- gual captopril could not be predicted despite appropriate patient education.

CONCLUSION

Hypertensive crisis requires immediate evaluation and treatment due to life-threatening end-organ damage po- tentiality without treatment. Hypertensive emergency is treated with intravenous drugs to gain rapid BP reduction, and hypertensive urgency is treated less aggressively. Captopril, a popular drug for use in hypertensive urgency,

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Sublingual vs. Oral Captopril in Hypertensive Crisis

113

Sublingual vs. Oral Captopril in Hypertensive Crisis 113 Figure 2. Box plot graphs shows the effect

Figure 2. Box plot graphs shows the effect of oral and sublingual captopril on systolic blood pressure (A), on diastolic blood pres- sure (B) and on mean blood pressure (C).

is an ACE inhibitor and used in both oral and sublingual methods. In our study, sublingual captopril was found to decrease BP more efficiently in the first 30 min, but this difference equalized at 60 min. When immediate BP decrease is desired, the sublingual way should be preferred. When there is no need for immediate BP reduc- tion, either method can be used.

REFERENCES

36.

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14. Varon J, Elliott WJ. Management of severe asymptomatic hypertension (hypertensive urgencies) in adults. UpToDate. Available at: http://www.uptodate.com/contents/management-of- severe-asymptomatic-hypertension-hypertensiveurgencies-in-adults. Accessed August 4, 2015.

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Sublingual vs. Oral Captopril in Hypertensive Crisis

115

ARTICLE SUMMARY

1. Why is this topic important? Hypertensive urgency is a life-threatening medical con-

dition if not treated. Captopril is one of the best oral and sublingual drugs for effective blood pressure (BP) control in this indication.

2. What does this study attempt to show? This study attempted to show if there is any beneficial

effect of sublingual captopril over oral captopril in the first hour after ingestion (especially in the first 30 min).

3. What are the key findings?

Sublingual captopril is found to lower BP more effi- ciently in the first 30 min than oral captopril. But this dif- ference is equalized at 60 min.

4. How is patient care impacted?

Either oral captopril use or sublingual captopril use could be preferred in hypertensive urgency. When a fast BP decrease is wanted, it is advised to administer this drug sublingually.

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