Q:

12/19/2013
Pt with h/o insect sting allergy. On beta-blocker eye drops (Timolol). 1) If pt would have anaphylactic reaction, would Epi Pen be effective? 2) Should pt be on different eye drop? Pt also on ace inhibitor for hypertension (Lisinopril). Should pt be switched to different medication if venom immunotherapy would be started?

A:

Thank you for your inquiry.

We have dealt with both of these issues previously on our website. I have copied for you below previous responses to: 1) a question concerning beta-blocker eye drops, 2) a question about angiotensin-converting enzyme (ACE) inhibitors in patients with hymenoptera allergy, 3 ) a link to a very nice article on potential side effects of the administration of epinephrine in a patient on a beta-blocker, and 4) an abstract about the potential adverse effect of a beta-blocker in patients who are subject to anaphylaxis. These sources will give further and more detailed rationale to support the direct answers to your questions. These direct answers are:

1. Beta-blocker eye drops are absorbed systemically and have been known to be associated with adverse systemic reactions similar to those seen with oral beta-adrenergic blockers. Therefore it is always best, in a person who is at risk for anaphylaxis, to discontinue beta-blockers in any form.

2. ACE inhibitors are considered a risk factor for the production of anaphylactic episodes to hymenoptera stings, and theoretically can make these events worse by blocking the endogenous compensatory response manifested by the increased secretion of angiotensin-converting enzymes and by preventing the destruction of kinins produced during the anaphylactic episode. Therefore, if at all possible, the ACE inhibitor should be discontinued as well.

As noted above, our previous responses plus the additional references that are copied below will help substantiate these responses to your inquiry and present more detail about the rationale underlying the responses.

Thank you again for your inquiry and we hope this response is helpful to you.

"Anaphylaxis potentiated by eye drops containing beta-blockers"
Question:
11/29/2011
On what clinical/real-life basis was the recommendation that patients on beta-blocker eye drops should stop using those eye drops if patient is at high-risk for anaphylaxis, such as the case of someone with idiopathic anaphylaxis? Is there any real evidence that enough beta-blocker med from eye drops are absorbed into systemic circulation to make anaphylaxis more severe and/or harder to treat?

Just today, I had TWO instances that this situation occurred in:

#1) An older lady with a h/o "penicillin allergy". I told her to refrain from using her AM beta-blocker eye drop dose so she could undergo oral challenge to PCN today. She forgot to hold the AM eye drop dose, so I had to re-schedule her for the oral challenge.

#2) Saw a 55 yo man with two episodes of apparent anaphylaxis-- had documented hypotension and hives, lost consciousness several times during one of the episodes, cut his face during the fall to the ground. My working dx is idiopathic anaphylaxis, but am checking tryptase and may discuss him with doctors at NIH. (he already had one allergist see him and tryptase was wnl, but apparently pt. was unsatisfied with his experience with that allergist).

This patient is on TIMOLOL eye drops for glaucoma. Before I pick up the phone and call his ophthalmologist and request beta-blocker drops never be given to him the rest of his life and that an alternative eye drop med be used (in-addition to the latanoprost eye drop that he is already using), I need to know if there is any EVIDENCE that beta-blocker eye drops have enough systemic absorption to make a difference in anaphylaxis/a'laxis treatment.

(I told an ophthalmologist buddy of mine that we tell people to stop beta-blocker eye drops in certain situations, and he laughed at that notion and said that is completely unnecessary b/c so little of it is absorbed.)

Answer:
There is abundant evidence that beta-blocker eye drops have systemic effects. There are definitive pharmacokinetic and pharmacodynamic studies which have looked at this issue. In addition, as you know, beta-blocker eye drops have clearly been shown to exacerbate asthma, and have even caused acute fatalities in asthmatics shortly after their administration. There are numerous references in this regard. For your convenience, I have copied below six of these (1-6).

In addition, the systemic absorption of contents of eye drops have directly caused anaphylaxis (see reference copied below of anaphylaxis to benzalkonium contained in eye drops).

I am sure that you are aware that beta-blockers themselves clearly can predispose to anaphylaxis and exacerbate episodes. If you would like to read further on that topic, please see the excellent article by Toogood. The reference is copied for you below. This article can be obtained online without charge. The link is also copied below.

These references are of course somewhat indirect. However, there are case reports as well of beta-blocker eye drops associated with severe anaphylactic episodes (see two abstracts copied below - Moneret-Vautrin, et al. and Vinti, et al.).

I have also personally witnessed a severe episode of asthma occurring minutes of the administration of a beta-adrenergic blocker eye drop.

In summary, based upon these studies, I think we can conclude the following:

The contents of eye drops have clearcut systemic effects, and can themselves cause anaphylaxis. These systemic effects have been demonstrated definitively in regards to beta-adrenergic blocker eye drops worsening asthma.

Beta-adrenergic blockade can worsen anaphylactic episodes.

Episodes of severe anaphylaxis have been associated with the administration of beta-blocker eye drops.

Beta Blockers and Asthma

1. Diggory, P, Heyworth. P Chau, G, et at. Improved lung function tests on changing from topical non-selective beta blockade impairs lung function tests in elderly. Eye, 1993:7: 661-63.

2. Confalonieri, M, Aiolfi, S. Patrini G, et al. evere bronchial spasm crises induced by topical administration of eye drops with timolol base, a non-selective beta blocking agent]. Recent. Prograd. Med., 1991:82:402-4.

3. Odeh. M, Oliven A, Bassan H. Timolol eye drop-induced fatal bronchospasm in all asthmatic patient J. Fam. l’ract., 1991:32:97-8.

4. Le-Jeunne, CL, Hugues FC, Duller JL, et at. Bronchial and cardiovascular effects of ocular topical B-antagonists in asthmatic subjects: comparison of timolol, carteolol and metipranolol J. Clin. Pharmacol., 1989:29:97-101

5. Taniguchi M, Kino, H. Moo, M. et at IA case of fatal asthma induced by timolol eye drops]. Nippon. Kyobu. Shikkan. Gakkai. Zasshi 1990:28:156-9.

6. Inamizu, T. Yoshikawa, M, Murai, H. IA case of severe bronchial asthma following first use of timolol ophthalmic solution]. Nippou.Kyohu.Shikkan. Gakkai. Zasshi. 1993:31:385-89.

Clin Exp Optom. 2009 Sep;92(5):444-6. Epub 2009 Jun 22.
Anaphylaxis with use of eye-drops containing benzalkonium chloride preservative.
Anderson D, Faltay B, Haller NA.
Source
Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, Ohio, USA

CMAJ. 1987 May 1; 136(9): 929–933.
Beta-blocker therapy and the risk of anaphylaxis.
J H Toogood

Rev Med Interne. 1993 Feb;14(2):107-11.
[Severe anaphylactic shock with heart arrest caused by coffee and gum arabic, potentiated by beta-blocking eyedrops].
[Article in French]
Moneret-Vautrin DA, Kanny G, Faller JP, Levan D, Kohler C.
Source
Service de Médecine D Médecine Interne, Immunologie Clinique et Allergologie, CHU de Nancy, Hôpitaux de Brabois, Vandceuvre-Les-Nancy.
Abstract
The case of a male patient who experienced four allergic accidents after drinking coffee is reported. Two serious anaphylactic reactions with cardiac arrest occurred after a continuous treatment with beta-blocking eye drops (timolol) was prescribed. Dual sensitivation to coffee and to the gum arabic coating roasted coffee beans was demonstrated by skin prick tests and by human basophil degranulation tests. Occupational allergy to green coffee has been widely described, but food sensitization to these two allergens has not yet been reported. This case also draws attention to the risk, inherent in beta-blockers, of immuno-allergic reactions. These drugs produce a loss of compensatory cardiovascular mechanisms and make those who take them resistant to the conventional treatment of anaphylactic shocks, which explains the serious accidents that occurred in this patient. The authors stress the usefulness of a thorough investigation for food allergy to a rare allergen in patients with idiopathic anaphylaxis.

Rev Med Interne. 1989 Jan-Feb;10(1):41-4.
[Systemic complications of beta-blocking eyedrops. Apropos of 6 cases].
[Article in French]
Vinti H, Chichmanian RM, Fournier JP, Pesce A, Taillan B, Fuzibet JG, Cassuto JP, Dujardin P.
Source
Service de médecine interne I, hématologie, hôpital de Cimiez, Nice.
Abstract
Six cases of systemic reactions to topical treatment with beta-blocking eyedrops are reported, bradycardia and faintness due to an over dosage of ophthalmic timolol; decompensated heart failure one month after the prescription of carteolol eyedrops: bronchospasm after two weeks of treatment with metipranolol eyedrops; crippling Raynaud's phenomenon of otherwise unknown origin, which had begun with timolol eyedrops, continued with carteolol eyedrops and regressed after discontinuation of ophthalmic beta-blockers; aggravation of an anaphylactoid shock in a patient treated with ophthalmic timolol, and myocardial infarction possibly due to the abrupt withdrawal of timolol eyedrops. It cannot be overstressed that the rules governing the prescription of oral beta-blockers also apply to ophthalmic preparations of these drugs: respect of contra-indications, strict adherence to the dosage recommended, gradual drug withdrawal and regular supervision. Only controlled studies and long-term follow-up will be able to demonstrate differences in safety between the five beta-blockers commercialized as eyedrops in this country.

"Patient on an angiotensin-converting enzyme inhibitor"
Question:
In the updated immunotherapy guidelines, it is described that patients on ACEI are at greater risk of severe reaction with VIT. What are the recommendation for patients on ACEI and inhalant IT? Thank you.

Answer:
I have copied for you below the answer to your inquiry in the form of a similar response to a question posted on the Academy website May 11, 2010.

Thank you again for your inquiry and we hope this response is helpful to you.

Patients taking ACE inhibitors on immunotherapy

5/11/2010
Question:
What is the current recommendation about patients on ACE inhibitors receiving immunotherapy?

Answer:
The issue differs as to the type of immunotherapy employed. For hymenoptera immunotherapy, there is a caution. I have copied for you below two abstracts. One is from a recent study of patients experiencing anaphylaxis to insect stings, and the other is a metaanalysis. I have also copied below excerpts taken from the package insert supplied with insect venom.

However, there is no such caution in regards to patients on ACE inhibitors taking immunotherapy to aeroallergens.

Abstract 1:
J Allergy Clin Immunol. 2009 Nov;124(5):1047-54.
Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase-a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity.
Ruëff F, Przybilla B, Biló MB, Müller U, Scheipl F, Aberer W, Birnbaum J, Bodzenta-Lukaszyk A, Bonifazi F, Bucher C, Campi P, Darsow U, Egger C, Haeberli G, Hawranek T, Körner M, Kucharewicz I, Küchenhoff H, Lang R, Quercia O, Reider N, Severino M, Sticherling M, Sturm GJ, Wüthrich B.
Department of Dermatology and Allergology, Ludwig-Maximilians-Universität, Munich, Germany.
Background: Severe anaphylaxis to honeybee or vespid stings is associated with a variety of risk factors, which are poorly defined.
Objective: Our aim was to evaluate the association of baseline serum tryptase concentrations and other variables routinely recorded during patient evaluation with the frequency of past severe anaphylaxis after a field sting.
Methods: In this observational multicenter study, we enrolled 962 patients with established bee or vespid venom allergy who had a systemic reaction after a field sting. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, and the number of preceding minor systemic reactions before the index field sting. A severe reaction was defined as anaphylactic shock, loss of consciousness, or cardiopulmonary arrest. The index sting was defined as the hitherto first, most severe systemic field-sting reaction. Relative rates were calculated with generalized additive models.
Results: Two hundred six (21.4%) patients had a severe anaphylactic reaction after a field sting. The frequency of this event increased significantly with higher tryptase concentrations (nonlinear association). Other factors significantly associated with severe reactions after a field sting were vespid venom allergy, older age, male sex, angiotensin-converting enzyme inhibitor medication, and 1 or more preceding field stings with a less severe systemic reaction.
Conclusion: In patients with honeybee or vespid venom allergy, baseline serum tryptase concentrations are associated with the risk for severe anaphylactic reactions. Preventive measures should include substitution of angiotensin-converting enzyme inhibitors.

Abstract 2:
Ann Pharmacother. 2006 Apr;40(4):699-703. Epub 2006 Mar 28.
Safety of Angiotensin-converting enzyme inhibitors in patients with insect venom allergies.
Stumpf JL, Shehab N, Patel AC.
University of Michigan Health System and College of Pharmacy, Ann Arbor, MI 48109, USA.
Objective: To review the literature with respect to the safety of angiotensin-converting enzyme (ACE) inhibitors in patients allergic to insect venom and those undergoing venom immunotherapy (VIT).
Data Sources: A MEDLINE search was conducted (1966-March 2006) using the following search terms: bee sting, venom, insect stings, ACE inhibitors, angiotensin II receptor blockers, immunotherapy, and desensitization. The bibliographies of qualifying articles were also searched for relevant references.
Data Synthesis: Several case reports have described severe allergic reactions, including anaphylaxis, in patients taking ACE inhibitors subsequent to being stung or receiving VIT. Exacerbation of the allergic response by ACE inhibitors is thought to be related to accumulation of bradykinin and inhibition of the formation of angiotensin II. Similar reactions have not been described with angiotensin-receptor blockers, but are theoretically possible.
Conclusions: epinephrine should be provided, as with any person with venom allergy. In patients in whom VIT is appropriate, temporary discontinuation of the ACE inhibitor prior to each venom injection may prevent subsequent adverse reactioACE inhibitors may exacerbate the response to insect venom, resulting in potentially life-threatening allergic reactions to insect stings or VIT. Although this risk is difficult to quantify based only on data from case reports, it seems prudent that patients with documented allergic reactions to insect venom avoid ACE inhibitor therapy, if possible. If, after careful consideration of the risks and benefits, ACE inhibitor therapy is deemed warranted, education regarding measures to minimize exposure to insect stings and training on self-administration of ns.

QUOTE: SOURCE, PACKAGE INSERT FOR VENOM I.T.
“Patients with hypersensitivity to insect venom who undergo desensitization treatment while under concomitant therapy with ACE (angiotensin-converting enzyme) inhibitors, may have an increased risk of life-threatening anaphylactic reactions.(9) Patients without insect venom hypersensitivity, who take ACE inhibitors, and are stung by insects, such as bee or wasp, can show such reactions as well.(10)

Two patients undergoing desensitization treatment with Hymenoptera Venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.”

Eur J Emerg Med. 2006 Dec;13(6):358-60.
Paradoxical reaction to epinephrine induced by beta-blockers in an anaphylactic shock induced by penicillin.
Goddet NS, Descatha A, Liberge O, Dolveck F, Boutet J, Baer M, Fletcher D, Templier F.
Author information
SAMU 92-SMUR Garches bOccupational Health Department, Raymond Poincaré teaching hospital, AP-HP, Garches, France.
Abstract
Increased risk of severe and resistant anaphylactic shock is a rare and not widely known adverse effect of beta-blocker treatment. It is illustrated in a case of refractory anaphylactic shock occurring in a 47-year-old woman who received beta-blockers. Actually, beta-blockers increase the release of anaphylactic mediators, decrease the cardiovascular compensatory changes to the anaphylactic shock and promote paradoxical reflex vagotonic effects when using epinephrine.

Epinephrine-containing test dose during beta-blockade

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology