Original Article

CUTANEOUS REACTIONS DUE TO ANTIHYPERTENSIVE DRUGS

J B Upadhayai, Anup Kumar Nangia, R D Mukhija*, Mukum Misra**, Lalit Mohan*,
K K Singh***
Abstract
Out of a total of 1147 patients on antihypertensive drugs, 23 (2.04%) developed adverse cutaneous drug reactions
(ACDR). The commonest antihypertensive drug group causing ACDR was beta-blockers of which atenolol was the
commonest culprit. The second most common group was calcium channel blockers with amlodipine as the commonest
offender. The most common patterns of ACDR observed included urticaria followed by lichenoid drug eruption (LDE).
We noted 2 new patterns of reactions; (i) one patient developed brownish blue pigmentation of nails while on atenolol
for 3 years, which resolved in 4 months after withdrawal and (ii) another patient on amlodipine for 8 years developed
Schambergs like purpuric pigmentation, which resolved on withdrawal of drug within 3 months. These findings have not
been reported in the literature earlier. This study is presented for paucity of Indian data on ACDR due to
antihypertensive drugs, and remarkable advancement in area of cardiovascular and antihypertensive pharmacology and a
large number of population taking antihypertensive drugs.

m
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re w P m).
f
r noand Methods
o
Introduction
foMaterials
c
.
k was
e Theedstudy
w carried out in the Department of
An adverse cutaneous drug reaction (ACDR) is lan
o
b
undesirable or unintended change in structure or function
Dermatology,
BRD Medical College, Gorakhpur from
n
a
M
of the skin or its appendages, and mucous membrane
while
January
2002
to
May 2003. The study group consisted of
l
k
i
d
on medication. Adverse drug reactions are said ato be they all hypertensive
patients taking antihypertensive drugs,
e
v
b
inevitable price we pay for the benefits of modern
drug
attending
the cardiology unit of Department of Medicine.
a on the .m
therapy. It is difficult to obtain reliable information d
the patients on antihypertensive drugs who developed
is softelack of w All
incidence of drug reactions, possibly because
skin lesions were evaluated in the Department of
standardized coding for drug reactions.
F o ww Dermatology.
D
There is a large number of population on
or( other
h one
The patients in whom there was no improvement within 6
P widespread
antihypertensive drug. With the
use of these
months after withdrawal of antihypertensive drug, were
e
t
i
agents now-a-days, especially
newer
drugs,
reports
of
s
from the study. In patients with ACDR possibly
i enormously.
s However, pre- excluded
ACDRs have increased
h
due to other concomitantly administered drugs,
a before a new drug is
T conducted
marketing clinical trials
Key Words: Adverse cutaneous drug reaction, lichenoid drug eruption, antihypertensive drugs
Indian J Dermatol 2006:51(3):189-91

confirmation was done by provocative tests.

licensed do not identify ACDR occurring in less than 0.1 to

1% of patients, or those occurring only after prolonged
administration or with long latent period or occurring only
in susceptible patients or those occurring when the drug is
combined with other factors/drugs.
In view of large patients receiving antihypertensive agents
and absence of any study from India except sporadic case
reports, we evaluated the incidence and clinical profile of
ACDR due to antihypertensive drugs.

After confirmation of the reaction as drug reaction, we

searched
for
the
causative
drug
among
the
antihypertensives (by clinical evaluation, skin biopsy and
provocative tests). Oral challenge test is the gold standard
for the diagnosis of ACDR. This test was done after 6
weeks of subsidence of lesions following withdrawal of the
offending drug. The schedule of this test is as follows:
dose on day one, if no reaction dose on day 2, even if
no reaction then full dose on day 3. Even if no reaction
occurred, the daily full dose was given for one week. If no
reaction occurred, the test was considered negative and
next suspected drug was tested in the same manner.

Resident, Department of Skin & VD, *Professor, Department of

Skin & VD, **Associate Professor Cardiology, Department of
Medicine, ***Associate Professor, Department of Skin & VD
Institute of BRD Medical College, Gorakhpur - 273 013, UP,
India. Address correspondence to: Dr. Anup Kumar Nangia,
Department of Skin & VD, BRD Medical College, Gorakhpur,
India. E-mail: anupnangia@rediffmail.com

The patch test (topical provocation

alternative to oral challenge test. The
weeks after complete subsidence of
petrolatum was used as vehicle. Drug
189

test) is a safe
test was done 6
eruptions. White
was used in the

Indian J Dermatol 2006; 51(3)

CMYK 189

Upadhayai JB, et al.: Cutaneous reactions due to antihypertensive drugs

concentration of 1 and 10%. Upper back was preferred for

patch testing. The patches were removed after 2 days and
read on 2nd and 4th day. The reaction on 4th day was
regarded as conclusive.

challenge test or biopsy.

The male female ratio was 1.09: 1 and mean age of patients
was 52 12 years: The age difference between male and
female and their ratio were not significant. Maximum
number of patients 7 (30.43%) were in 37-46 year age group
which is followed by 6 (26.29%) in 64-73 year age group.

Observations
A total of 1986 patients attended the cardiology out
patients department (from July 2002 to August 2003) of
which 1147 were on antihypertensive drugs. Fifty-four (54)
patients had one or other type of skin reactions. Thirty-one
patients were excluded fromt he study (22 did not improve
on withdrawal and 9 patients dropped out). The remaining
23 patients who improved on withdrawal of drugs were
included. These were studied further.

Maximum number of patients with ACDR was seen with

atenolol followed by amlodipine. The most common type of
ACDR was found to be urticaria followed by Lichenoid
drug eruption (LDE) (Table 1). The average latent period
for urticaria was 38.93 days and for LDE 19.6 months.
Psoriasiform eruptions appeared after 2 years of exposure,
while maculopapular eruption occurred after 17.5 days and
vasculitis after 28.75 days (Table 2).

m
o
r
f
Out of these 23 patients skin biopsy was done in 6, 12
dpositivensin 8 out of 12 patients
were tested with oral challenge test and 4 patients
Oral challenge test was
a
underwent patch test; 7 patients refused to undergo
(66.67%) (Table 3).lo
The ACDR
io where latent period was
t
n
a
w drugs
Table 1. ACDR associated with antihypertensive
c
i
o
d ubl
e P .
e
r w m)
f
r
fo kno .co
le ed ow
b
la M dkn
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is ste w
F o ww
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P te h (
s si
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Th Tablea 2. Distribution of cases according to ACDR vs Latent period
Drugs

Type of ACDR

Atenolol

Amlodipine

Propranolol

Carbedilol

Prazosin

Ramipril

Enalapril

Furosemide/

Total

Percentage

7
5
5
2
2
1
1
1
1
1
23
100.0

30.43
21.74
21.74
08.69
08.69
04.35
04.35
04.35
04.35
04.35
100.0
-

Amiloride

Urticaria
1
Lichenoid drug eruptions 3
Maculopapular eruptions Vasculitis
1
Psoriasiform eruption
1
Schambergs like PP
Erythroderma
Photoallergic reaction
Fixed drug eruption
Nail pigmentation
1
Total
7
Total (%)
30.43

2
1
1
1
5
21.74

1
1
1
1
4
17.39

1
1
2
08.69

1
1
04.35

1
1
04.35

1
1
04.35

1
1
04.35

1
1
04.35

ACDR - Adverse cutaneous drug reaction

ACDR

Latent period

Urticarial

FDE

Maculopapular

Vasculitis

eruptions

0-5 days
5-10 days
10-15 days
15-30 days
1-3 months
3-6 months
6-12 months
1-3 years
3-6 years
6-9 years
Total
Average latent
period observed

01
01
03
01
01
07
38.93
days

01
04
05
19.6
months

01
01
04
17.5
days

01
01
02
28.75
days

Psoriasiform

like PP

02
02
2
years

01
01
8
years

ACDR - Adverse cutaneous drug reaction

Indian J Dermatol 2006; 51(3)

190 CMYK

Schamberg's Erythroderma Photoallergic

eruptions

190

01
01
1
month

Fixed drug

Nail

reaction

eruptions

pigmentation

01
01
3
months

01
01
2
months

01
01
3
years

Total

01
01
02
04
05
02
06
01
01
23

Upadhayai JB, et al.: Cutaneous reactions due to antihypertensive drugs

(19.6 months average) and the resolution time was 1 to 4

months. These observations are similar to a study of 17
patients with LDE by Halevy and Shai.8

Table 3. Distribution of patients according to ACDR vs

oral challenge test
Type of ACDR

Positive

Negative

Total

Urtidaria

03

02

05

LDE

02

01

03

FDE
MP eruption

01
01

01
01

01

01

Vasculitis
Psoriasiform eruption

01

01

Total

08

04

12

We observed an interesting finding in a patient on atenolol

for 3 years; he developed brownish blue pigmentation of
nails, which resolved in 4 months after drug withdrawal.
This observation has not been mentioned earlier in
literature with atenolol, but has the reported with timolol, a
beta-blocker, which was reported to cause brownish
pigmentation of nails.9
Another interesting observation was in a patient on
amlodipine for 8 years developing Schambergs like
purpuric pigmentation with ankle oedema, which resolved
on withdrawal of amlodipine within 3 months. the probable
explanation of Schambergs like purpuric pigmentation
could be prolonged ankle eema caused by amlodipine,
which may damage the normal permeability of capillaries,
thus causing subacute or chronic capillaritis, producing
purpuric pigmentation.

m
o
longer showed positive oral challenge test on full dose for
fr
longer duration, and where latent period was short showed
d ns
positive oral challenge test with lower dose of drug within
a
1 day. Six patients were subjected to histopathological
lo tio
examination of which 2 were conclusive and 4 were nonn
conclusive.
w lica
o
Four patients were patch tested; only one patient showed
d ub
equivocal results and other 3 were negative.
Conclusion
e
e P .
As fra large number ) of population is receiving
Discussion
m proper awareness of ACDR is
antihypertensive
drugs,
r n forw every
In our study, the incidence of ACDR was 2.04%. No exact onecessary o
o
for early diagnosis and
c ofphysician
incidence of ACDR from antihypertensive drugs is f better kmanagement
.
ACDR due to antihypertensive
e drugs.
d ow
available in literature. However, Danish National Board lof
e
b
Healths Committee on adverse drug reactions (ADR)
n
lafrom MReferences
showed that 10-60% of adverse drug reactions
k
i
a Theby ed
antihypertensive drugs were dermatological.
v
combination of amiloride (5 mg) and hydrochlorothiazide
a d of .m
(50 mg) had the highest number of recorded ADR; 59%
e w
is fromstManipal,
these were in the skin. One recent study
India shows 3.75% ACDR due to
drugs,
w
Fwerecardioactive
o
urticarial patterns of drug eruptions
excluded
in
the
w
D
study.
P te h (
s and sagei difference between
In our study, male: female iratio
male and female was nothsignificant. This may be because
T a
1

1.

Thestrup-Pedersen K. Adverse reactions in skin

antihypertensive drugs. Dan Med Bull 1987;34:3-5.

2.

Sehgal S, Balachandran C, Shenai SD. Clinical study of

cutaneous drug reactions in 80 patietns. Indian J Dermatol
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3.

Bolzano K, Arriaga J and Bernal R. The antihypertensive

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1997;9:543-7.

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Kitamura K, Kanasashi M, Suga C, Saito S, Yoshida S, Ikezawa

Z. Cutaneous reactions induced by calciumchannel blocker:
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5.

Stephen SA. Unwanted effect of propranolol. Am J Cardiol

1966;18:463-72.

6.

Stern R, Khalsa JH. Cutaneous adverse reactions: Association

with calcium channel blockers. Arch Intern Med
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7.

Sabroe RA, Kobza Black A. Angiotensin converting enzyme

(ACE) inhibitors and angioedema. Br J Dermatol
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8.

Halevy S, Shai A. Lichenoid drug eruption. J Am Acad

Dermatol 1993;29:249-55.

9.

Runne U, Orfando CE. The human nail: Structure, growth and

pathological changes. Curr Prob Dermatol 1981;9:102-49.

of the fact that prevalence of hypertension does not show

gender bias.

The commonest antihypertensive drug group causing

ACDR was beta-blockers in which atenolol was the most
common offender. Second most common group of
antihypertensives was calcium channel blockers with
amlodipine being the commonest offending drug. All the
groups of antihypertensive drugs have been documented
to show ACDR in earlier studies.3-6
In our study the commonest ACDR was urticaria with the
most common causative agent being amlodipine. The latent
period for urticaria was 3 days to 3 months, while the
resolution time was 4-14 days. Earlier workers have
published similar observations.7
LDE was the second common ACDR mostly caused by
atenolol. Latent period for LDE ranged from 1 to 24 months

from

Source of Support: Nil, Conflict of Interest: None declared.

191

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CMYK 191