Download The Risk of Atropine-Induced Acute Angle

藥物科學
The Risk of Atropine-Induced Acute Angle-Closure Glaucoma in Irinotecan User with History of Angle-Closure Glaucoma
The Risk of Atropine-Induced Acute AngleClosure Glaucoma in Irinotecan User with
History of Angle-Closure Glaucoma
Hung-Yi Chen
Department of Pharmacy, National Cheng Kung University Hospital
Abstract
Irinotecan was approved by FDA as the first line therapy in combination with fluorouracil
and leucovorin for metastatic colon or rectal cancer patients. Atropine is given for management
of irinotecan-induced cholinergic syndrome, however, it is contraindicated for patient with
angle-closure glaucoma. It is necessary to weigh the benefit before making a clinical decision.
In this article, we are going to discuss whether it is appropriate to use atropine in colon cancer
patients with history of angle-closure glaucoma before irinotecan therapy.
Keywords: colorectal cancer, irinotecan, atropine, angle-closure glaucoma
that can be ameliorate by atropine, this
Introduction
Irinotecan was approved by FDA as
the first line therapy in combination with
fluorouracil and leucovorin for metastatic colon
or rectal cancer patients. Irinotecan is also given
as off-lable use for esophageal cancer, gastric
suggests that irinotecan directly interacts
with acetylcholinesterase (AChE). And this
hypothesis was confirmed by a series of detail
2
kinetic analyses with irinotecan . Diarrhea
is one of the most concerned effect, the
cancer, pancreatic cancer, cervical cancer,
relationship between the pharmacokinetics of
ovarian cancer (recurrent), glioblastoma, Ewing
irinotecan and its metabolites (such as SN38)
sarcoma, rhabdomyosarcoma, non-small cell
and diarrhea is also quite complex. Both
1
lung cancer, and small cell lung cancer .
irinotecan and its metabolite, SN-38 undergo
One of the most well-known side effects
enterohepatic circulation, and the concentration
of irinotecan is cholinergic syndrome. Since a
of SN-38 has been correlated with diarrhea
cholinergic syndrome rapidly occurs following
in mice and in humans . These side effects
high dose of irinotecan administration
can be easily managed with atropine. Thus,
3
第 32 卷第 1 期
Mar. 31 2016
藥學雜誌
第126冊
49
藥物科學
Pharmaceutical Sciences
atropine is widely used in irinotecan-containing
affect the willingness of patients to receive the
chemotherapy regimens.
next course of chemotherapy.
Incidence rate of cholinergic syndrome
Incidence rate of cholinergic syndrome,
Literature review: Atropine induced
acute angle-closure glaucoma
such as early diarrhea, perspiration, abdominal
Several case reports have mentioned about
cramps, hiccup, visual accommodation
atropine induced acute angle-closure glaucoma
disturbances, and lacrimation, ranges from 1.4%
in precipitated patients . They cause our concern
4,5
to 60% in patients receiving irinotecan
.
of acute angle-closure glaucoma (AACG) when
These side effects usually occur just after
colon cancer patients are receiving atropine. A
irinotecan infusion are not life-threatening and
summary of these atropine-induced AACG case
can be managed well in hospital, however, can
reports are listed on Table 1.
Table 1. Summary of atropine induced acute angle-closure glaucoma-case reports
Age & Sex
History
Routine drugs
Chief complain
62 y/o, Female
Obstructive pulmonary disease,
routine ophthalamic examination of
shallow anterior chambers, angleclosure glaucoma, laser iridotomy in
the right eye only
4% pilocarpine, 0.1% dipivefrin (to
increase humor outflow)
Decompensation obstructive lung
disease
Aerosolized atropine, 2.5 mg q4h
57 y/o, Female
Long-standing, steroid
dependent, obstructive
pulmonary disease,
routine eye examination of
shallow anterior chambers
-
6,7
66 y/o, Male
Acute myocardial infarction
with thrombolytic therapy,
Ballon angioplasty was
performed for recurred chest
pain
-
Acute respiratory failure
Bradycardia during
requiring intubation
angioplasty
Suspected drug
Aerosolized atropine, 2 mg q4h IV atropine 0.5 mg, 0.5 mg,
0.3 mg in a 40-mins time
period
AACG onset time 3rd hospital day
5th hospital day
Shortly after administration
Symptoms and
Hyperemia with corneal edema in
Hyperemic left eye with
Right eye pain, blurred
signs
left eye, Increasing pain in her left mild photophobia, ocular
vision of the right eye,
of AACG
eye, an intense, unilateral, left-side surface pain, and a discharge. headache, conjunctival
headache; blurred vision and nausea. (Misdiagnosis as conjunctivitis, hyperemia, dilated and fixed
Left pupil was mildly dilated at 5
then 10% sulfacetamide
right pupil
mm, with minimal reaction to light. solution for 4 days)
IOP 32 mmHg
IOP 10/28 mmHg
Management
IV acetazolamide 500 mg , 2%
2% pilocarpine HCl QID OS, Laser iridotomy was
pilocarpine HCl, 0.5% Timolol,
laser iridotomy was performed performed
20% mannitol 1 g/kg x 2 doses; 2% in the left eye
pilocarpine Q3H、1% prednisolone
QID until iridectomy was performed
*AACG = acute angle-closure glaucoma；IOP = intraocular pressure
50
THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.1 Mar. 31 2016
藥物科學
The Risk of Atropine-Induced Acute Angle-Closure Glaucoma in Irinotecan User with History of Angle-Closure Glaucoma
It is noteworthy that, an acute ACG attack
was triggered in one patient by aerosolized
atropine and oxybutynin caused another
ACG attack, even though the patient received
pilocarpine HCl miotic therapy routinely.
Dosing regimen of atropine for
cholinergic syndrome
In Taiwan, atropine is used when patients
suffer from cholinergic syndrome. In some
hospitals, while it could be routinely prescribed
at the first time and subsequent courses of
chemotherapy. There are two administration
routes to deliver atropine, intravenous and
subcutaneous route. There are not any
dosage difference in each route. The most
consentaneous dosage of atropine is 0.5 mg and
0.25 mg. Though atropine dosage ranges from
0.2 mg to 2 mg regardless of administration
route in literatures
9,10
. Should we use atropine
for colon cancer patients receiving irinotecan
with history of angle-closure glaucoma?
We proposed several reasons to support
the use of atropine in colon cancer with history
of angle closure glaucoma, and some reasons
to hold atropine in these patients. These
considerations are listed on Table 2.
Table 2. Factors should be considered in
colon cancer patients going to use
atropine with history of angle-closure
glaucoma.
Use atropine before irinotecan
Diarrhea may cause dehydration, electrolyte imbalance
which maybe fetal
Incidence of irinotecan induced cholinergic syndrome
(1.4-60%) is higher than atropine induced AACG (<
0.1%)9.
Patient may delayed chemotherapy regimen because of
displeasure cholinergic syndrome.
It is unclear if low dose systemic atropine (< 0.6 mg)
cause ocular effects. Conventional systemic dose of
atropine (0.6 mg) have little ocular effect.
Pilocarpine eye drops could be given to patient before
subcutaneous atropine to reduce the possibility of
ocular events.
There is no case report of single dose of subcutaneous
atropine induced acute glaucoma.
Do not use atropine before irinotecan
AACG is serious and could lead to irreversible loss of
vision.
The premedication, diphenydramine is also with
anticholinergic effect, to combine with atropine may
increase risk of AACG which may cause visual loss.
Cholinergic symptoms are reversible.
Atropine is labled as contraindication in angle-closure
glaucoma patients in package insert.
*AACG=acute angle closure glaucoma
Alternative agents
Cheng et al. conducted a retrospective,
single-center, nonrandomized, cohort study
of adult patients (N = 80) treated with oral
atropine 0.025 mg-diphenoxylate 0.25 mg or
hyoscyamine as premedication before receiving
irinotecan (total 532 cycles). Incidence of
cholinergic syndrome did not differ between
atropine-diphenoxylate and hyoscyamine
groups after the first cycle or after the
entire treatment course. There was a higher
percentage of diarrhea but less abdominal
pain or cramping and diaphoresis reported in
the hyoscyamine group compared with the
atropine-diphenoxylate group among patients
who developed cholinergic syndrome. It is
worth noting that additional premedications
with intravenous atropine 0.5 mg were not
required for subsequent irinotecan cycles in
第 32 卷第 1 期
Mar. 31 2016
藥學雜誌
第126冊
51
藥物科學
Pharmaceutical Sciences
the hyoscyamine group, compared with the
atropine routinely if the patient suffers from
23.3% of patients in the atropine-diphenoxylate
cholinergic syndrome which may impede him
11
group . Theoretically, atropine-diphenoxylate
to receive further courses of chemotherapy. We
and hyoscyamine both could result in enlarged
recommend that pilocarpine 2% eye drops could
pupils of the eyes and elevate ocular pressure.
be given before starting atropine to reduced risk
This article gave us a hint that two medications
of AACG in colon cancer patients with history
sharing similar mechanism could result in
of angle-closure glaucoma as shown in Figure
different side effect profile. Though the risk
1
4,6,7
.
of atropine, diphenoxylate and hyoscyamineinduced AACG are still unknown. To date,
there is not any research could answer which
premedication is the best for patient with
history of ACG before irinotecan infusion.
Conclusion
In summary, we didn't find any case report
of subcutaneously administered atropineinduced AACG. However, it is unclear if low
dose systemic atropine (< 0.6 mg) could cause
ocular effects. Since incidence of cholinergic
syndrome in not high, we recommend to hold
atropine in colon cancer patient with history of
angle-closure glaucoma who are going to for
receive irinotecan, and to give a lower dose of
Figure 1. Flow chart of atropine use in colon
cancer patients receiving irinotecan with
history of angle-closure glaucoma
有閉鎖性青光眼病人接受 irinotecan 時
使用 atropine 而誘發 AACG 的風險
成大醫院藥劑部藥師 陳弘益
摘要
美國 FDA 核准 irinotecan 與 fluorouracil 和 leucovorin 用於轉移性大腸直腸癌之第
一線治療，atropine 則被用於緩解 irinotecan 引起的膽鹼症候群，然而 atropine 對於閉
52
THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.1 Mar. 31 2016
藥物科學
The Risk of Atropine-Induced Acute Angle-Closure Glaucoma in Irinotecan User with History of Angle-Closure Glaucoma
鎖性青光眼的病人而言屬於禁忌，使用前應評估好壞處的風險效益，本文我們將討論
有閉鎖性青光眼病史的大腸直腸癌病人，預計接受 irinotecan 治療時，是否應該使用
atropine。
Reference:
1.
Irinotecan: Drug information In: UpToDate, Post TW
glaucoma complicating systemic atropine use in the car-
(Ed), UpToDate, Waltham, MA. (Accessed on January 19,
diac catheterization laboratory. Cathet Cardiovasc Diagn.
2015.)
2.
3.
Hyatt JL, Tsurkan L, Morton CL et al: Inhibition of ace-
1996; 39:262-264.
8.
Koch P, Grothaus-Pinke B, Hiddemann W, et al: Primary
tylcholinesterase by the anticancer prodrug CPT-11. Chem
lymphoma of the stomach: three-year results of a prospec-
Biol Interact. 2005;157-158:247-52.
tive multicenter study. The German Multicenter Study
Hecht JR. Gastrointestinal toxicity or irinotecan. Oncology (Williston Park). 1998;12(8 Suppl 6):72-8.
Group on GI-NHL. Ann Oncol. 1997; 8 Suppl 1:85-8.
9.
Gandia D, Abigerges D, Armand JP, et al: CPT-11-induced
4.
Package insert of Campto (irinotecan).
cholinergic effects in cancer patients. J Clin Oncol. 1993;
5.
Abigerges D, Chabot GG, Armand JP, et al: Phase I and
11(1):196-7.
pharmacologic studies of the camptothecin analog irinote-
10.
can administered every 3 weeks in cancer patients. J Clin
Oncol. 1995; 13(1):210-21.
6.
7.
Lai JS, Gangwani RA. Medication-induced acute angle
closure attack. Hong Kong Med J 2012; 18:139-45.
11.
Cheng C, Lau JE, Earl MA. Use of atropine-diphenox-
Berdy GJ, Berdy SS, Odin LS, et al: Angle closure glau-
ylate compared with hyoscyamine to decrease rates of
coma precipitated by aerosolized atropine. Arch Intern
irinotecan-related cholinergic syndrome. J Community
Med 1991; 151:1658-1660.
Support Oncol. 2015(1):3-7.
Mandak JS, Minerva P, Wilson TW, et al: Angle closure
第 32 卷第 1 期
Mar. 31 2016
藥學雜誌
第126冊
53