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Allergy versus side effects: The Confusion Must Stop

1 Contact Hour including 1 Pharmacology Hour
This peer reviewed course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Nursing Student, Registered Nurse (RN)
This course will be updated or discontinued on or before Saturday, September 23, 2023

The purpose of this course is to enable the participants to distinguish between true allergic reactions versus side effects in prescribed medications. Additionally, prevention and management strategies for allergic reactions and side effects of prescribed medications will be discussed.


After completing this course, the learner will be able to:

  1. Describe how drugs and their metabolites become active allergens
  2. Differentiate between anaphylactic and anaphylactoid reactions
  3. Describe the cross reactivity between Penicillin and Cephalosporin allergies
  4. Identify the drugs most frequently involved in true allergic reactions
CEUFast Inc. did not endorse any product, or receive any commercial support or sponsorship for this course. The Planning Committee and Authors do not have any conflict of interest.

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To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
  2. Reflect on practice impact by completing self-reflection, self-assessment and course evaluation.
    (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)
Author:    Berthina Coleman (MD, BSN,RN)

Definition of terms

Side effects are the secondary and undesired effects of a drug. These are expected reactions that occur with the administration of a drug, and every patient receiving that drug is at risk for experiencing side effects. Examples of side effects include drowsiness with the administration of diphenhydramine and nausea with the administration of chemotherapeutic drugs.

Allergic reactions are aberrant immune responses to an antigen or an allergen. An antigen is defined as a toxin or substance that incites an allergic reaction in the body, especially one that leads to the production of antibodies. An allergen is defined as a substance that incites an allergic reaction.

It has been previously reported that true hypersensitivity reactions to drugs probably account for less than 10% of all adverse reactions to drugs.1 In general, most drugs are small organic molecules which are incapable of stimulating a full immune response independently. However, when these drug molecules or their metabolites become bound to proteins, they form drug-protein complexes which then act as allergens and stimulate an immune system response. The ability of a drug or a metabolite to sensitize the immune system depends on its ability to bind tissue proteins and become an allergen.2

The term allergy implies an immediate hypersensitivity reaction mediated by immunoglobulin E (IgE) antibody. However, many allergic reactions are not IgE mediated. The subsequent reaction produces a wide range of clinical symptoms ranging from itching to anaphylaxis. Anaphylaxis is the most severe form of an allergic reaction, and it can occur suddenly and may, eventually, lead to death.

Anaphylaxis occurs when the body’s immune system produces a substance called immunoglobin E. This substance binds to cells in the body called mast cells that then release chemicals that cause an allergic reaction, such as redness, swelling, or hives. After this process occurs once, it is likely to get more severe with each additional exposure.5

The anaphylactic reaction may occur within a few seconds to a few minutes. Allergic reactions after the administration of drugs orally tend to occur at unpredictable times. Anaphylactic reactions currently account for 1 out of every 2000 ambulance requests and are reported to be fatal in as many as 2% of all the cases. Some epidemiologic studies have shown that up to 5,100 hospitalizations have been linked to anaphylactic reactions.3

Anaphylactic versus Anaphylactoid reactions

Anaphylactic reactions are immunologically mediated reactions as opposed to reactions secondary to drug interactions, drug overdose, direct toxicity or pharmacologic idiosyncrasies. Anaphylaxis is a type 1 immediate hypersensitivity reaction. Type 1 reactions are IgE mediated and produce responses in end organs such as urticaria in the skin, angioedema and bronchospasm in the respiratory system, and vasodilation and increased capillary permeability in the cardiovascular system.3

Anaphylactoid reactions, on the other hand, can have an identical clinical response, but they are not mediated by IgE or by an antigen-antibody process. Examples of anaphylactoid reactions include hypersensitivity to radiocontrast dye and angiotensin-converting enzyme inhibitors. Anaphylactoid reactions tend to activate the complement system. The complement system is usually activated in one of two pathways, classical pathway and alternative pathway. The classical pathway is initiated through IgG or IgM. The alternative pathway is mediated by endotoxins, or directly by the allergen such as the drug in question. Anaphylactoid reactions cannot be predicted with pretesting; only IgE mediated reactions can be predicted with pretesting.3

Patients with a past medical history of atopic conditions such as eczema, asthma and seasonal allergies do not have an increased risk of anaphylactic reactions. However, they have an increased risk of having more severe reactions.

How are allergic reactions mediated?

When an allergen binds IgE antibodies on the surface of basophils and mast cells, eosinophilic chemotactic factors and histamine are released from storage granules in the cell. Once this happens, other chemical mediators are rapidly synthesized and released, such as kinins, platelet activating factors, adenosine and leukotrienes which are slow acting reactants involved in anaphylaxis. Clinically, the patient experiences the first wave of symptoms which is usually vasodilation and a sense of imminent doom.3 In a sensitized patient, the onset of signs and symptoms can be experienced almost immediately, but it may be delayed by 2 to 15 minutes. Occasionally the allergic reactions can be delayed by up to two and a half hours after exposure to the allergen. Mast cell activation and proliferation promote the production of cytokines which perpetuate the allergic reaction even after the allergen is no longer present lasting up to 6 to 8 hours.3 The clinical symptoms of an allergic reaction to a drug may vary widely. A generalized allergic reaction may appear similar to serum sickness reactions or immune-complex reactions.

Serum sickness

Serum sickness and serum sickness-like reactions occur approximately 7-10 days after primary exposure to an allergen, in this case, the drug, and are characterized by urticaria (hives), polyarthralgia (joint pain involving multiple joints), fever, and lymphadenopathy (swollen lymph nodes). Occasionally the patients may have systemic venalities’ (inflammation of the veins during intravenous drug administration) which may progress into full blown systemic vasculitis. Serum sickness and serum sickness-like reactions can also occur after secondary exposure to heterologous proteins (classic serum sickness) or after secondary exposure to non-protein drugs such as sulfa based drugs or penicillin based antibiotics (serum sickness like reactions).

Most transfusion reactions occur as a result of the formation of immune complexes which usually result in serum sickness. Transfusion based allergic reactions usually occur secondary to IgE and IgG antibodies against IgA as well as mast cell mediated reactions. Angioedema is initiated by histamine release, but its effects are sustained by peptide kinins which are unaffected by antihistamines.4

Some patients are more susceptible to the release of histamines and other immunologic mediators with the administration of certain drugs. Some believe there are environmental and hereditary factors which contribute to this predisposition to allergic reactions.3

Allergic reactions to specific medications

Allergic reactions to penicillin

Penicillin remains the drug most commonly involved in true allergic reactions. It accounts for almost 90% of all reported allergic reactions to drugs. It is also implicated in at least 75% of all fatal anaphylactic drug reactions. Penicillin based allergies are the primary cause of allergic reactions in hospitalized patients. There is a difference between a history of a penicillin allergy and a witnessed and documented allergic reaction to penicillin. Up to 90% of the patients who report a history of a penicillin allergy do not demonstrate IgE antibodies to penicillin.

It is important to point out that fatal allergic reactions can occur without a history of prior allergic reactions. In cases of fatal penicillin induced anaphylactic reactions, less than a quarter of the patients who died reported a previous allergic reaction to penicillin. In general, intravenous administration of penicillin is associated with two times the risk of a fatal allergic reaction when compared to oral administration of the drug. Cephalosporins have a 10% cross-reactivity with a penicillin allergy. As such, patients with a previous anaphylactic reaction to penicillin should not be administered cephalosporins.2

Sulfa allergic reactions

Sulfa products are contained in several drugs. However, allergic reactions to non-antibiotic sulfa medications are uncommon relative to sulfa containing antibiotics. The exact mechanism of serum sickness-like reactions is unclear. However, it is not related to immune complex formation or complement activation.

Management of allergic reactions

First generation antihistamines are over the counter drugs commonly used for the management of allergic conditions. However, they commonly have sedative effects therefore, second-generation antihistamines are increasing in their frequency of use.4

Antihistamines are often the first drugs used to prevent or treat allergic reactions. In allergic rhinitis, the H1 antagonists are used after the administration of intranasal steroids. In urticaria, histamines are responsible for mediating the allergic response for that reason antihistamines are the drug of choice. In urticaria, the antihistamines tend to be more effective if they are administered before exposure to the allergen.4 In the case of asthma, there are multiple mediators of the allergic reactions therefore antihistamines are mostly ineffective. In patients with atopic dermatitis, antihistamines are usually administered for their sedative effects in order to reduce the patient’s awareness of itching.

Learning Break

Intravenous contrast agents are the most frequently used drugs that cause anaphylactoid reactions.

In some cases, such as anaphylactoid reactions to intravenous contrast agents, pretreatment with antihistamines (diphenhydramine) has been shown to be helpful in preventing or ameliorating the reaction.

Minimize a patient’s risk to anaphylactic reactions

  • Obtain a thorough medical history, including an updated allergies list with the reported reaction.
  • Premedicated patients with any risk of an anaphylactoid reaction. (antihistamines, steroids and iv fluids)
  • In cases when the diagnosis is unclear, blood levels of chemical mediators, especially tryptase, can be used to clarify the diagnosis.

Factors that affect the extent to which an allergic reaction manifests include the following: the amount of the allergen, the route of entry (oral versus dermic versus intravenous), the persistence of the antigen, and the end organ response to vasoactive mediators.

Other signs and symptoms of allergic reactions include: nausea, vomiting, diarrhea and colicky abdominal pain (gastrointestinal manifestations), dyspnea, wheezing and chest tightness (respiratory manifestations), peripheral vasodilation, and hypotension and tachycardia (cardiovascular manifestations).

Triage decisions in patients with allergic reactions rely upon both the severity of the reaction and the initial response to treatment. Patients presenting with mild-to-moderate symptoms (urticaria and/or angioedema with stable airway and hemodynamics) can be treated in the emergency department and discharged home. Patients with more severe reactions require hospitalization for further monitoring.3

How to triage patients with allergic reactions

Patients who present with severe wheezing, hypotension, stridor, hoarseness of voice and shortness of breath should be treated as a medical emergency with the primary focus being to secure the airway and cardiopulmonary resuscitation. Patients who respond to treatment immediately should be observed as inpatients for 24 hours. Those who respond to therapy more slowly or inadequately should be observed in an intensive care unit, especially those intubated for severe laryngeal edema. Occasionally the patients may have severe hypotension refractory to treatment thereby warranting intensive care mentoring.

Allergic reactions in the hospital setting

Although the mechanism of allergic reactions remains the same in outpatient and inpatient settings, there are certain triggers which are specific to a hospital setting such as latex. Additionally, in the hospital setting, intravenous medications are more frequently administered, and they have been linked to more severe allergic reactions compared to oral ingestions.

Case study

Mrs. T is admitted to a medical/surgical unit with Congestive heart failure and pneumonia. You are the nurse completing the admission and initial assessment. Upon review of her medical record, you note that she has an allergy to sulfa drugs and morphine. What are the missing components of her allergy history? How would you proceed to clarify her allergy history?


When obtaining an allergy history, it is important to obtain the specific allergen, the specific allergic reaction and the last time the allergic reaction occurred. In addition, the nurse obtaining the history should clarify allergies to broad categories and should aim to characterize them as specifically as possible.

In Mrs. T’s case, first, we should focus on the sulfa drug which caused the allergy. In her case, she had an allergy to Trimethoprim/Sulfamethoxazole (Bactrim) which caused a mild rash on her hands that resolved 3 days later spontaneously. Since then she has received other sulfa based non-antibiotics which did not elicit a response. The allergic response happened once 6 years prior.

Upon clarification of her allergies, the clinical providers were able to order Lasix intravenously for the management of her congestive heart failure. Even though Lasix is a sulfa containing drug, the clinicians felt comfortable administering it given that she only showed a mild reaction to a sulfa based antibiotic.

The documented reaction to morphine was somnolence which occurred after the administration of 10 mg of morphine while she had on a fentanyl patch. The patient was educated about the difference between allergic reactions and side effects, and the allergy to morphine was removed from her records.


Nurses play a critical role in obtaining and verifying allergy histories, as such, a thorough and detail approach is necessary. In some cases, the patient may need to be educated about the difference between side effects and allergies as detailed in the case above. It is important to enter a note in the medical record explaining details in the allergy history prior to updating the clinical record.

Select one of the following methods to complete this course.

Take TestPass an exam testing your knowledge of the course material.
Reflect on Practice ImpactDescribe how this course will impact your practice.   (No Test)


  1. Joint Task Force on Practice Parameters;American Academy of Allergy, Asthma and Immunology;American College of AllergyAsthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug Allergy: An Updated Practice Parameter. Annals of Allergy, Asthma & Immunology. 2010; 105(4) 259-273. doi:10.1016/j.anai.2010.08.002
  2. Rowe BH, Gaeta TJ. Anaphylaxis, Allergies, and Angioedema. In: Tintinalli JE, Stapczynski J, Ma O, Yealy DM, Meckler GD, Cline DM. eds. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e New York, NY: McGraw-Hill; 2016.
  3. Cosco DL, Winawer NH, Murali MR. Allergy and Anaphylaxis. In: McKean SC, Ross JJ, Dressler DD, Scheurer DB. eds. Principles and Practice of Hospital Medicine, 2e New York, NY: McGraw-Hill;
  4. Katzung BG. Histamine, Serotonin, & the Ergot Alkaloids. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13e New York, NY: McGraw-Hill; 2015
  5. Seitz, S. (2019) Dog Anaphylaxis: What It Looks Like and What to Do If It Happens to Your Dog, June 11, 2019 retrived 9/17/19 from