Table of Contents  
Year : 2016  |  Volume : 9  |  Issue : 4  |  Page : 510-511  

Drugs inducing Kounis syndrome: The more drugs, the easier, the quicker, and the more severe anaphylaxis

Department of Medical Sciences, Western Highest Institute of Education and Technology, Patras, Achaia, Greece

Date of Web Publication12-Jul-2016

Correspondence Address:
Nicholas G Kounis
Queen Olgas Square, 7 Aratou Street, Patras 26221
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0975-2870.186063

Rights and Permissions

How to cite this article:
Kounis NG. Drugs inducing Kounis syndrome: The more drugs, the easier, the quicker, and the more severe anaphylaxis. Med J DY Patil Univ 2016;9:510-1

How to cite this URL:
Kounis NG. Drugs inducing Kounis syndrome: The more drugs, the easier, the quicker, and the more severe anaphylaxis. Med J DY Patil Univ [serial online] 2016 [cited 2024 Feb 24];9:510-1. Available from:

When two dangerous clinical entities, namely, the hypersensitivity inflammation and the acute coronary syndrome meet, merge or join each other, the result might be the hypersensitivity coronary syndrome, the so-called Kounis syndrome.[1] Kounis syndrome is defined [2] as the concurrence of acute coronary syndromes such as coronary spasm, acute myocardial infarction, and stent thrombosis, with conditions associated with mast cell and platelet activation involving interrelated and interacting inflammatory cells, including macrophages and T-lymphocytes, in the setting of allergic or hypersensitivity and anaphylactic or anaphylactoid insults. It is caused by inflammatory mediators such as histamine, neutral proteases, arachidonic acid products, platelet-activating factor, and a variety of cytokines and chemokines released during the activation process. A subset of platelets bearing FcγRI, FcγRII, FcεRI, and FcεRII receptors are also involved in the activation process. All these inflammatory cells participate in an inflammatory cycle and activate each other via multidirectional signals. Kounis like syndromes that affect the cerebral and mesenteric arteries have been described recently. It is anticipated that the heart and the entire arterial system is vulnerable to allergic, hypersensitivity, anaphylactic, and/or anaphylactoid events.[3] The discovery that the junctions between the endothelial cells which line and cover an arterial atheromatous plaque are open and are easily penetrated by inflammatory cells that release their contents, in contrast to junctions over the normal arterial intima which are normal and closed was made by the late Paris Constantinidis.[4] Paris Constantinidis, in 1995, was also the first who raised the possibility that “even ordinary allergic reactions could promote plaque erosion and rupture.”[5]

Mast cells are important contributors in allergy, atopy, and anaphylaxis and named as such by Paul Erlich in 1887 because of their numerous metachromatic granules that reminded him of “well-fed cells” (mastzellen in German). Mast cells enter the circulation, from bone marrow as, mononuclear cell precursors and circulate as mast cell precursors and bring in their surface KIT receptors for stem cell factor. Stem cell factor is a major cytokine which is essential for mast cell growth, differentiation, development, proliferation, survival, adhesion, and homing. They go to all human tissues even to the brain tissue which does not suffer from allergic reactions because immunoglobulin E (IgE) antibodies cannot cross the blood-brain barrier. There, they differentiate and mature. This takes several days, even weeks. On the contrary, basophils mature in bone marrow from granulocyte precursors and enter the circulation as mature cells, and they do not go into the tissues only during the late stage of an allergic reaction. The allergic inflammation takes place when allergens cross-bridge their corresponding, receptor-bound, IgE antibodies on the mast cell or basophil cell surface. When the critical number of bridged IgE antibodies reaches the order of 2000 out of a maximal number of some 500,000-1,000,000 IgE antibodies on the cell surface is reached then the degranulation takes place.[6] A total of approximately 1000 bridges are necessary to induced mast cell degranulation. However, recent findings indicate that mast cells can be activated by nonallergic triggers often without degranulation, but with selective release of potent and vasoactive compounds.[7]

In this issue of Medical Journal of Dr. D. Y. Patil University, an interesting case of coronary vasospasm manifesting as Kounis syndrome in a patient with moderate mitral stenosis is described [8] and concerns a 50-year-old male patient that occurred 1 h following paracetamol, phenylephrine hydrochloride, and chlorpheniramine maleate administration. All these three substances have been incriminated as inducing mild or severe allergic reactions. Indeed, paracetamol has been incriminated of inducing hypersensitivity reactions in a series of 13 cases.[9] Furthermore, the combination of paracetamoland phenylephrine oral therapy has potential to increase blood pressure more than phenylephrine alone in those with cardiovascular compromise.[10] Phenylephrine is a sympathomimetic drug used mainly for its vasoconstrictor properties, such as for nasal congestion, or as a mydriatic agent. Although it is used widely, type I allergic reactions can occur but not so often.[11] Chlorpheniramine is the most classical H1-antihistamine and the first-generation alkylamine antihistamineused for the prevention of thesymptomsof allergicconditions such asrhinitisandurticaria but paradoxically can itself induce allergic reactions.[12] It seems that paracetamol, chlorpheniramine, and phenylephrine constitute a dangerous allergic triplet that physicians should be aware of Clinical studies indicate that allergic patients simultaneously exposed to several allergens have more symptoms than monosensitized individuals.[13] On the other hand, IgE antibodies with different specificities can have additive effects and small, even subthreshold numbers of them can join forces and trigger the cells to release their mediators. This can happen when the patient is simultaneously exposed to the corresponding antigens.[14] This data suggest that a possible sensitization should not be clinically evaluated as a consequence of exposure to a single drug but rather viewed in the context of potential sensitization to multiple drugs.

Several natural paradigms of how to treat but also several paradoxes of how not to treat have been given to us, on several occasions, by mother nature. Physicians should always remember that commonly used, generally safe life-saving substances may occasionally cause serious anaphylactic effects. Such substances may also join forces to do their deleterious effect. Thus, careful patient history and consideration for drug side effects and allergy should be taken into account before use. The decision to prescribe a drug, when a previous history of allergy or any other adverse reaction exists, requires careful assessment of the risks and potential benefits. We all as physicians should always have in mind the ancient Greek dictum expressed by philosopher Aristotle (384-322 B.C.):

“Not many is the good, but in the good, the many”

  References Top

Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): A natural paradigm? Int J Cardiol 2006;110:7-14.  Back to cited text no. 1
Kounis NG, Mazarakis A, Tsigkas G, Giannopoulos S, Goudevenos J. Kounis syndrome: A new twist on an old disease. Future Cardiol 2011;7:805-24.  Back to cited text no. 2
Kounis NG. Coronary hypersensitivity disorder: The Kounis syndrome. Clin Ther 2013;35:563-71.  Back to cited text no. 3
Constantinides P, Harkey M. Electron microscopic exploration of human endothelium in step-serial sections of early and advanced atherosclerotic lesions. Ann N Y Acad Sci 1990;598:113-24.  Back to cited text no. 4
Constantinides P. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995;92:1083.  Back to cited text no. 5
Wickman M. When allergies complicate allergies. Allergy 2005;60 Suppl 79:14-8.  Back to cited text no. 6
Theoharides TC, Kalogeromitros D. The critical role of mast cells in allergy and inflammation. Ann N Y Acad Sci 2006;1088:78-99.  Back to cited text no. 7
Osken A, Aydin E, Kocayigit I, Osken S, Oz TK, Zehir R, et al. Chlorpheniramine and phenylephrine induced coronary vasospasm manifesting as Kounis syndrome in a patient with moderate mitral stenosis. Med J DY Patil Univ 2016;9:507-9.  Back to cited text no. 8
  Medknow Journal  
Rojas-Pérez-Ezquerra P, Sánchez-Morillas L, Gómez-Traseira C, Gonzalez-Mendiola R, Alcorta Valle AR, Laguna-Martinez J. Selective hypersensitivity reactions to acetaminophen: A 13-case series. J Allergy Clin Immunol Pract 2014;2:343-5.  Back to cited text no. 9
Atkinson HC, Potts AL, Anderson BJ. Potential cardiovascular adverse events when phenylephrine is combined with paracetamol: Simulation and narrative review. Eur J Clin Pharmacol 2015;71:931-8.  Back to cited text no. 10
Rojas-Hijazo B, Garcés MM, Segura N, Ferrer L, Sobrevía M. Anaphylactic reaction after intake of phenylephrine and tolerance of other sympathomimetic drugs. J Investig Allergol Clin Immunol 2007;17:421-2.  Back to cited text no. 11
Lee HS, Song WJ, Lee JW, Cho YY, Park HK, Kang MG, et al. Chlorpheniramine-induced anaphylaxis diagnosed by basophil activation test. Asia Pac Allergy 2015;5:177-80.  Back to cited text no. 12
MacGlashan DW Jr, Bochner BS, Adelman DC, Jardieu PM, Togias A, McKenzie-White J, et al. Down-regulation of Fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997;158:1438-45.  Back to cited text no. 13
Nopp A, Johansson SG, Lundberg M, Oman H. Simultaneous exposure of several allergens has an additive effect on multisensitized basophils. Allergy 2006;61:1366-8.  Back to cited text no. 14


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article

 Article Access Statistics
    PDF Downloaded176    
    Comments [Add]    

Recommend this journal