The Journal of Emergency Medicine, Vol. 50, No. 1, pp.

108115, 2016
Copyright 2016 Elsevier Inc.
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http://dx.doi.org/10.1016/j.jemermed.2015.07.017

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

, AbstractBackground: 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.
, Keywordshypertensive 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 patients 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

RECEIVED: 8 December 2014; FINAL SUBMISSION RECEIVED: 4 July 2015;

ACCEPTED: 25 July 2015

108

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Sublingual vs. Oral Captopril in Hypertensive Crisis
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 (410).
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
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109
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-Wilks 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%.
110 A. Kaya et al.

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 (%) 49 (45.4%) 49 (47.1%)
Diabetes mellitus, n (%) 34 (31.5%) 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 (%) 19 (17.6%) 16 (15.4%)
Normal QRS duration, n (%) 100 (92.6%) 95 (91.3%) 0.22
LBBB, n (%) 3 (2.8%) 7 (6.7%)
RBBB, n (%) 5 (4.6%) 2 (1.9%)

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

3
WBC, 10 /mL 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, 103/mL 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

WBC = white blood cell count; MCV = mean corpuscular volume; RDW = reticulocyte distribution width; MPV = mean platelet volume.

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Sublingual vs. Oral Captopril in Hypertensive Crisis 111

Table 3. Comparison of the Difference Between the Arrival Table 5. Comparison of the Difference Between Arrival BP
BP Measurements and 10-Min Measurements and Measurements and 60-Min Measurements of
the 10-Min BP of Groups Groups

Variables Sublingual Oral p Value Variables Sublingual Oral p Value

DSBP 16.4 6 4.9 12.3 6 4.2 <0.001 DSBP 39.8 6 8.5 40.1 6 8.7 0.75
10-min SBP 172.9 6 7.92 178.6 6 9.5 <0.001 60th SBP 149.5 6 7.6 150.8 6 8.3 0.26
DDBP 14.1 6 4.9 10.3 6 10.3 0.001 DDBP 35.1 6 6.06 33.7 6 7.1 0.12
10-min DBP 101.8 6 5.5 105.9 6 10.4 0.001 60th DBP 80.9 6 6.1 82.5 6 6.5 0.06
DMBP 15.6 6 3.8 11.6 6 4.6 <0.001 DMBP 38.2 6 6.0 38.0 6 6.8 0.80
10-min MBP 149.2 6 5.7 154.4 6 7.6 <0.001 60th MBP 126.6 6 5.8 128.0 6 6.8 0.12

BP = blood pressure; SBP = systolic blood pressure; BP = blood pressure; SBP = systolic blood pressure;
DBP = diastolic blood pressure; MBP = mean 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 2A, 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
DSBP 31.6 6 7.3 29.6 6 7.5
30-min SBP 157.7 6 8.41 161.3 6 7.7
DDBP 28.7 6 6.8 27.2 6 7.0
30-min DBP 87.3 6 7.2 89.0 6 6.3
DMBP 30.6 6 5.7 28.8 6 5.7
30-min MBP 134.2 6 6.7 137.2 6 6.2
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 captoprils 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 captoprils decrease of
blood pressure is better than the oral method (2022).
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 captoprils 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
p Value
captopril blood concentration (21). In the second study,
0.052 maximum plasma concentration of captopril was reached
0.001 quickly in a sublingual group, which means short tmax
0.121
0.07 (time to reach maximum concentration) with the sublin-
0.022 gual method. There was no difference between other
0.001 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 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

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.
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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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