Adverse Drug Reactions

Function

ADRs are classified as Type A or Type B reactions. Both Type A and B reactions have several subcategories.[5]  Although signs, symptoms, and onset time can help differentiate between these types of reactions, some clinical overlap may exist.

Type A Reactions

ADRs that occur as the result of known pharmacological properties of the drug are called Type A reactions.[9] They can happen in any individual given a sufficient dose. Type A reactions are common and constitute 85% to 90% of ADRs. These reactions include the following categories:

Drug Overdoses

Overdose occurs when an excessive amount of a drug is consumed. Examples of ADRs due to drug overdoses include liver failure after an acetaminophen overdose, bleeding after a warfarin overdose, and respiratory depression after an oxycodone overdose.

Side Effects

A side effect is defined as a predictable or dose-dependent effect of a drug that is not the principal effect for which the drug was used. Side effects may be desirable, adverse, or inconsequential.[5] Examples of ADRs due to side effects include gastritis after the use of nonsteroidal anti-inflammatory drugs (NSAIDs), nephrotoxicity after aminoglycoside therapy, diarrhea after the use of antibiotics, phototoxicity due to doxycycline use, etc.

Drug Interactions

Drug interactions are reactions between a drug and other drugs, foods, beverages, supplements, or diseases.[NIH. Fact Sheet] Examples of ADRs due to drug interactions include increased theophylline exposure due to the use of macrolide antibiotics, a reduction in warfarin's anticoagulant effect as a result of increased vitamin K intake, and respiratory depression as the result of benzodiazepine and opioid coingestion.

Type B Reactions

ADRs that occur when the known pharmacological properties of the drug do not predict the reaction are called Type B reactions.[9] These reactions include the following categories:

Hypersensitivity reactions

The immunologic or inflammatory effects of a drug cause hypersensitivity reactions. These reactions constitute 6% to 10% of all ADRs.[5] Hypersensitivity reactions are categorized into the following types:

1. Type I reactions are mediated by immunoglobulin E (IgE), mast cells, and basophils and are immediate in onset. With initial exposure, drug-specific IgE is formed and occupies the surface receptors of mast cells and basophils. If reexposure occurs, the drug is bound by the preformed IgE antibodies, which results in the release of vasoactive and proinflammatory mediators from mast cells and basophils. This release can cause symptoms such as urticarial rash, pruritus, and flushing. In severe cases, the release can result in angioedema, hypotension, and anaphylaxis. Drugs commonly implicated in Type I hypersensitivity reactions include beta-lactams, quinolones, and platinum-containing chemotherapeutic agents.[10]
2. Type II hypersensitivity reactions occur when IgG or IgM binds cellular or extracellular matrix antigens. The resultant reaction can lead to cellular destruction and damage to tissues. Type II hypersensitivity reactions are late in onset, and symptoms typically appear 5 to 8 days after drug exposure. Examples of these reactions include drug-induced hemolytic anemia (cephalosporins, penicillin), drug-induced thrombocytopenia (heparin, apixaban, quinidine, sulfonamides), and drug-induced neutropenia (propylthiouracil, flecainide).[11] 
3. Type III hypersensitivity reactions are mediated by immune complexes and the activation of complement. Similar to type II reactions, they are delayed in onset. However, it can take weeks for symptoms to appear. In Type III reactions, a drug forms an immune complex by binding to drug-specific IgG, which activates complement. These reactions occur in various tissues, including joints, kidneys, and blood vessels. Examples of type III hypersensitivity reactions include serum sickness with equine-antitoxins and monoclonal antibodies, vasculitis with penicillins, cephalosporins, and phenytoin, and Arthus reactions with diphtheria and tetanus vaccines.[12]
4. Type IV hypersensitivity reactions are mediated by T cells and are delayed in onset. Depending on what cells are subsequently activated to release cytokines, type IV reactions are further divided into several subtypes, including IVa (macrophages), IVb (eosinophils), IVc (T cells), and IVd (neutrophils). Examples of Type IV reactions include contact dermatitis, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome (SJS), drug-induced hypersensitivity syndrome (DiHS), and drug reaction with eosinophilia and systemic syndrome (DRESS).[13]

Other immunological reactions

1. Drug-induced autoimmunity may occur after drug exposure and lead to autoimmune diseases.[14] For example, lupus-like disease can develop after exposure to isoniazid, phenytoin, procainamide, or hydralazine. Additionally, IgA bullous dermatosis can develop after exposure to vancomycin or ceftriaxone, and a pemphigus-like disorder can develop with exposure to penicillamine.
2. Fixed drug eruptions are characterized by drug-induced lesions recurring at the same anatomical site. Typically, these lesions are erythematous plaques with a gray center that occur on the lips, tongue, genitalia, face, and acral areas. Intraepidermal CD8+ T cells are implicated in these reactions.[15] These T cells remain quiescent in the healed lesions; however, upon rechallenging with the culprit drug, they are activated and release interferon-gamma and cytotoxic granules, precipitating another eruption.[16][17] Sulfonamides and anticoagulants can cause fixed drug eruptions.[17]

Idiosyncratic Reactions

Type B reactions not mediated by immunological or inflammatory mechanisms are called idiosyncratic drug reactions. These reactions can arise because of genetic anomalies (eg, dapsone-induced hemolysis in a patient with G6PD deficiency) or exaggerated sensitivity at low doses (eg, tinnitus after a single dose of aspirin).

Pseudoallergic Reactions

Pseudoallergic drug reactions resemble allergic drug reactions; however, they are not initiated by immunologic mechanisms. Often referred to as "nonimmune hypersensitivity reactions," pseudoallergic reactions arise due to the direct activation of inflammatory cells. Specifically, the Mas-Related G-Protein Coupled Receptor Member X2 is implicated in direct mast cell stimulation without needing IgE-mediated activation.[18] Some medications, such as fluoroquinolones and neuromuscular blocking agents, can bind to these receptors and cause nonimmunogenic anaphylaxis. A commonly encountered example of a pseudoallergic reaction in the inpatient setting is vancomycin flushing syndrome. Vancomycin directly activates the degranulation of basophils and mast cells, leading to histamine release and flushing. Interestingly, this reaction may be avoided by slowing the infusion rate of vancomycin, which controls the release rate of histamine.[19]

Issues of Concern

Among the ADRs mentioned above, some specific reactions are of significant concern due to the risk of serious morbidity and mortality they carry.  These reactions include anaphylaxis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS).

Anaphylaxis

Anaphylaxis is a Type I hypersensitivity reaction and is potentially life-threatening. Anaphylaxis occurs within minutes to a few hours of exposure to a drug.[20] Symptoms common in anaphylaxis include hives, pruritis, swelling in the lips, tongue, and uvula, and low blood pressure due to vasodilation.[21][22] Airway narrowing or obstruction due to facial or pharyngeal swelling can lead to respiratory failure.  Underlying health conditions such as asthma, chronic obstructive pulmonary disease, coronary artery disease, and mastocytosis increase the risk of death due to anaphylaxis. A detailed history and understanding of the chronology of events is essential to establish the diagnosis of anaphylaxis and to identify the causative drug. Common drugs implicated in anaphylaxis include NSAIDs, antibiotics, and radiocontrast agents.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

SJS and TEN are examples of severe forms of type IV hypersensitivity reactions.[23] These conditions are specifically associated with extensive necrosis and detachment of the epidermis. Mucous membranes can be affected, as well.[24] The percentage of body surface area (BSA) detached determines the condition's classification. If less than 10% of BSA is detached, the condition is classified as SJS. If 10% to 30% of BSA is detached, the condition is classified as "SJS/TEN overlap." If more than 30% of BSA is detached, the condition is classified as TEN.[25]

Lesions usually start on the face as an erythematous rash and then spread to all other areas. Lesions typically appear as target-like lesions and flaccid bullae at first.  As the condition progresses, sheet-like detachment of the epidermis and erosions occur. The acute, progressive phase of the illness lasts for approximately 7 to 9 days from initial symptoms. Skin reepithelizes over 7 to 21 days after the acute phase ends. Drugs associated with SJS and TEN include carbamazepine, sulfamethoxazole, phenytoin, lamotrigine, and immune checkpoint inhibitors.

Acute Generalized Exanthematous Pustulosis

AGEP is a rare type IV hypersensitivity skin reaction characterized by the rapid development of hundreds of sterile, pinhead-sized pustules on a background of edematous erythema.[26][27][28] After discontinuing the offending drug, skin symptoms can resolve without treatment in 1 to 2 weeks.[29] However, secondary skin infections can develop in immunocompromised or older patients.[27][28][30] Drugs implicated in AGEP include penicillins, macrolides, antimalarials, diltiazem, and antifungals.[30][31]  

Drug Reaction With Eosinophilia and Systemic Symptoms

DRESS is a severe form of type IV hypersensitivity reaction characterized by an extensive skin rash in association with visceral organ involvement, lymphadenopathy, eosinophilia, and atypical lymphocytosis. This condition typically develops 2 to 8 weeks after the initiation of a causative drug. Skin lesions develop and may include maculopapular eruptions, purpura, plaques, target-like lesions, bumps, and exfoliative dermatitis. Facial edema is commonly present, as well. Patients can also experience systemic symptoms like fever, lymphadenopathy, and eosinophilia. Eosinophilic infiltration can adversely affect organs such as the liver, kidney, and lungs, and lead to life-threatening organ failure.[32] Common drugs implicated in DRESS include phenytoin, carbamazepine, lamotrigine, trimethoprim-sulfamethoxazole, dapsone, vancomycin, rifampicin, ethambutol, isoniazid, and mexiletine.    

Clinical Significance

The management of ADRs depends on the type of reaction and severity. The questions that need to be answered when an ADR is suspected include:

• Is the reaction related to a drug? If so, which one?
• What kind of reaction is it: Type A, Type B, idiosyncratic, or pseudoallergic?
• How severe is the reaction, and what organs are involved?
• How urgently should the reaction be treated?
• Is there an alternative therapy that may be prescribed for the indication of the offending drug?

Recognition of Adverse Drug Reactions and Identification of the Offending Agent

Clinical and Medication Histories

A detailed clinical history is necessary to identify an ADR and its severity.[33][34] Determining if the patient experienced a reaction of significant concern is of particular importance. Simple open-ended questions to ask include but are not limited to:

• In your own words, what reaction did you have?
• Can you estimate when the reaction began? When did it resolve?
• What have you done, or what medications have you taken to treat your reaction?
• What types of medication reactions have you had in the past?

Obtaining an accurate medication history is also important. Questions to be considered include but are not limited to:

• What medications are you taking?
• How long after a medication administration did the reaction develop?
• What is/are the indication(s) for each drug?
• What dosage is prescribed, and have there been any recent changes in dosage?
• Have you used the medication(s) previously?
• Do you have a history of reaction to the medicine or similar medicines?

The medication history should be taken from the most reliable source(s). Often, patients are unreliable historians or unable to provide history due to illness. Thus, members must consider the use of multiple sources. Beyond the patient, a medication history may be obtained directly from a caregiver, the patient's preferred pharmacy, documentation in the electronic medical record, or a combination of these. Beware of relying on static "medication lists" as these are often outdated and may not appraise self-medication, supplement use, or recent changes. Consider employing a pharmacist, nurse, or other medical professional with special medication history training if this does not lead to a significant delay in obtaining the medication history.

Temporal Association

Clinicians should investigate the temporal association(s) between the administered medication(s) and the reaction. They should also use available literature to assist in determining the likelihood of the drug causing the reaction.

Diagnostic Algorithms

When an ADR diagnosis is in doubt, several decision aids and algorithms can be employed. Available tools include the Naranjo algorithm, the Begaud algorithm, the Yale algorithm, the Jones algorithm, the Karch algorithm, the ADRAC, the WHO-UMC16, and the quantitative approach algorithm.[35][36][37][38][39][40] The Naranjo algorithm uses a scoring system to indicate the likelihood of an ADR. A score of ≥9 strongly indicates an ADR. A score of 5 to 8 indicates a probable ADR, while a score of 1 to 4 indicates a possible ADR. A score of 0 indicates that an ADR is in doubt.[35]  Though these algorithms can help with assessing the causality of ADRs, they cannot prove or disprove such an association. 

Diagnostic Testing

Despite detailed evaluation and use of the algorithms, it may be challenging to identify whether the reaction is related to a medication. In such cases, additional diagnostic testing may help determine an ADR diagnosis.

1. Tryptase is a peptidase released by mast cells and basophils that can also be elevated in patients with systemic mastocytosis and other myeloid neoplasms.[41] Tryptase levels may be elevated after IgE-mediated type I hypersensitivity reactions; however, normal levels do not exclude a diagnosis. Following anaphylaxis, tryptase levels may also be elevated.[42] They should be obtained within 1 to 3 hours of anaphylaxis to diagnose the condition. As people have varying baseline levels of serum tryptase, it is essential to collect serial samples to confirm a true elevation. For example, in a patient with features of anaphylaxis, a "normal" tryptase level could diagnose anaphylaxis if the patient's baseline tryptase level is below normal.
2. Histamine levels may also be elevated after IgE-mediated Type I hypersensitivity reactions. The sensitivity of histamine levels is higher than tryptase sensitivity, but their reliability is questionable as histamine levels are only elevated for a short time after the reaction itself.
3. Intradermal skin tests can detect IgE-mediated type I hypersensitivity reactions to a drug. The test is performed by administering a nonirritating concentration of the suspect drug into the intradermal space.[43] A wheal-and-flare response within 15 to 20 minutes after administration indicates a relevant reaction. 
4. Patch testing is used to test for T-cell–mediated Type IV hypersensitivity reactions. A patch containing a prespecified concentration of a culprit drug is applied to a small skin area under occlusion for 48 hours.[44] The site is examined 48 to 96 hours after placement for the development of a reaction.
5. Intradermal testing with delayed readout also tests for T-cell–mediated type IV hypersensitivity reactions. This test is used for the same indications as the patch test but is more sensitive.[45] A nonirritating drug concentration is administered intradermally, and the site is examined 24 to 48 hours later for the reaction.[44]
6. If the skin tests are not diagnostic or there is a clinical need to use a drug suspected of causing ADR in the future, a drug challenge may be considered. This testing should not be performed on a patient with an allergic response in any prior drug allergy test. Challenge testing should be done under close supervision due to the risk of precipitating the reaction. In a challenge test, the patient is subjected to a graded exposure to the drug orally, subcutaneously, intravenously, or in a combination of routes. Challenge testing should generally be considered only in IgE-mediated reactions and is not recommended in patients who have experienced type II, III, or IV reactions (eg, TEN, SJS, DRESS, AGEP, etc).[46]

Treatment of Adverse Drug Reactions

Modifying the dosage or discontinuing the offending agent is the most crucial step in treating an ADR. The basic treatment plan for some of the common ADRs is as follows:

Drug Overdose

Drug overdose can be accidental or intentional, and symptoms depend on the medication(s) used, the amount of drug taken, whether the toxicity is acute or chronic, and the influence of underlying medical conditions. In case of severe reactions, one must ensure that the airway and circulation are maintained. An appropriate antidote (for example, N-acetyl cysteine for acetaminophen toxicity, naloxone for opioid toxicity) needs to be administered. Consulting with poison control or a toxicologist, especially in an overdose of an unknown amount or combination of medications, is critical in the management of drug overdose.

Urticaria

Urticaria is usually treated with antihistamines such as diphenhydramine, cetirizine, levocetirizine, and loratadine.[47][48] Histamine 2 receptor antagonists such as ranitidine may also be beneficial. Additionally, corticosteroids such as prednisone may also be beneficial.[49][50]

Exanthematous Drug Eruptions

Topical corticosteroids and oral antihistamines are effective for treating exanthematous drug eruptions. Systemic corticosteroids can be considered in case of a widespread reaction.[51]

Acute Generalized Exanthematous Pustulosis

AGEP is a self-limiting disease with a favorable prognosis. The recommended management of AGEP includes withdrawal of the offending drug, supportive care, and symptomatic treatment of pruritus and skin inflammation with topical corticosteroids.[52][53]

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

SJS and TEN are severe ADRs and should be managed in a tertiary care facility that can treat burns patients.[54][55] These reactions are characterized by widespread detachment of skin, a high risk for fluid and electrolyte imbalances, sepsis, organ dysfunction, and death. Depending on the extent of the disease, organ involvement, the patient's age, and other comorbidities, the mortality rate is about 10% to 50%.[56][57] In addition to stopping the offending agent, management should focus on supportive care and preventing short- and long-term complications. The patient will need wound care, fluid management, pain control, and management of other complications such as sepsis. Besides supportive care, pharmacotherapy with cyclosporin or etanercept might be beneficial in cases of severe skin involvement.[58][59] The role of systemic corticosteroids is unclear.[56][60]

Drug Reaction With Eosinophilia and Systemic Symptoms

This condition has various manifestations involving skin and other organ systems. Management of the condition is based on the extent and severity of skin and organ involvement. Mild symptoms may be managed in the outpatient setting, but severe symptoms require hospitalization.[61][62][63] Topical corticosteroids can be used for mild skin reactions. For severe symptoms, in addition to supportive therapy, systemic corticosteroids are considered to be the first-line therapy.[64] Second-line treatment options include immunosuppressive therapies like cyclosporine and intravenous immunoglobulin.[65][66]

Anaphylaxis

Anaphylaxis constitutes a medical emergency. The offending agent should be immediately stopped, and IM epinephrine should be administered promptly.[67] Simultaneous oxygen administration, fluid resuscitation, and albuterol nebulization should be provided. Adjunctive therapies include intravenous antihistamines (histamine 1 and 2 receptor antagonists) and intravenous corticosteroids. If there is evidence of impending airway obstruction or compromise, intubation is required. In the case of anaphylactic shock, the patient may require additional fluid and vasopressor administration.

Desensitization

Drug desensitization is a procedure by which drug hypersensitivity is altered, resulting in temporary tolerance. Tolerance will last as long as the drug is administered without interruption. With interruptions, hypersensitivity reactions may precipitate, necessitating treatment followed by a repeat desensitization. Desensitization is considered when there is no effective and safe substitute for treatment (eg, IV penicillin and Treponema pallidum infection in pregnancy). The process is indicated in patients with drug-specific IgE-mediated hypersensitivity reactions. Under close monitoring, a small amount of very low drug concentration is administered, followed by increasing concentrations. Specific protocols for desensitization are available for antibiotics such as penicillin, cefepime, and several other drugs.[68][69][70]

Other Issues

Preventing Adverse Drug Reactions

The patient and multidisciplinary healthcare team members should be vigilant in watching for and identifying ADRs. Some of the ways by which patients and healthcare providers can prevent ADRs include:

Medical History Review

Gaining a detailed medical history is crucial to identifying any existing drug allergies or previous ADRs. The patient's family and others involved in their care may also provide helpful information. The involvement of professionals specifically trained to gather medication and allergy histories, such as pharmacists, will also improve patient outcomes.[71]

Timely and Accurate Documentation of Allergies

Once identified, drug allergies and a detailed account of the type and severity of the ADR should be promptly and accurately documented in the medical record to inform future care. Efforts should be made to ensure that drug allergies are known to providers and allied health professionals participating in the patient's care. Adjunct information surrounding allergies should be documented where appropriate to guide future care (eg, in the setting of a well-documented IgE-mediated penicillin allergy, documenting tolerance to cephalosporins will guide future antibiotic prescribing).

Appropriate Medication Use

Medications should only be used when necessary and for the correct indications. For instance, avoiding the use of antibiotics for a confirmed viral infection will minimize antibiotic-related ADRs. Additionally, tailoring drug dosages to individual patients based on factors such as indication, age, creatinine clearance, renal and hepatic function, and genetic attributes helps to mitigate adverse reactions. Finally, encouraging patients to adhere to medication directions minimizes the occurrence of ADRs.

Early ADR Identification 

Swift discontinuation of a culprit drug at the first sign of a severe ADR is essential. If the ADR is mild and continuation of the culprit drug is necessary, dosage modification with close monitoring for worsening of the ADR may be considered.

Avoidance of Drug Interactions

Identifying and avoiding potential drug interactions will reduce the risk of ADRs. Drug interactions propagate or mitigate the effect of drugs by altering drug absorption, distribution, metabolism, or excretion. Pharmacists are well-trained in identifying drug interactions and can help patients avoid them in all phases of medical care.

Patient-Specfic Information

Providing information to patients that details potential ADRs and their risks empowers them to be vigilant and proactive in reporting issues or reactions to the healthcare team. Additionally, educating patients at risk for anaphylaxis about the proper use of epinephrine injections ensures they are prepared for emergent treatment.

Referral for Specialized Care

Patients with suspected or confirmed cases of anaphylaxis should be referred to allergy specialists for management to prevent future ADRs.

Reporting to Regulatory Agencies

ADR reporting requirements may vary by institution or practice setting. Many care sites are required by accrediting or regulatory bodies, such as the Centers for Medicare and Medicaid Services, to have policies and procedures in place to prevent and report ADRs. In general, it is best practice for healthcare team members to promptly report ADRs.[5] Special focus should be given to serious events leading to death, life-threatening situations, persistent disability, and congenital anomalies.[5] For newly marketed drugs, the FDA encourages reporting of all adverse events.[5][72] 

ADRs can be reported to the FDA utilizing the MedWatch voluntary reporting system.[MedWatch] Approximately 1% of serious and unexpected ADRs are reported to the FDA.[5][73] Underreporting significantly delays the dissemination of critical information about such reactions, which could impede timely awareness and necessary interventions.

Enhancing Healthcare Team Outcomes

A study assessing ADRs in hospitalized patients revealed that physicians often overlook a significant portion of these reactions.[74] The data recorded by nursing staff may help identify up to 40% of all ADRs that physicians could miss.[75] Overlooking an ADR could result in the provision of inappropriate treatment for such reactions.[76] Thus, maintaining vigilance in identifying and diagnosing ADRs is critical.  Such vigilance is achieved through the collaborative efforts of a multidisciplinary healthcare team. 

Continuous education and training for healthcare professionals are essential to identifying and diagnosing ADRs. Staying up-to-date on the latest drug information, potential interactions, and ADR profiles can aid in the early recognition of ADRs. Additional benefits may come from regular ADR case reviews. Effective communication within the multidisciplinary healthcare team is also essential to ADR identification and diagnosis. Sharing patient information, including medication history, comorbidities, and previous ADRs, helps in accurate diagnosis and decision-making. Finally, team members should encourage patients to report any unusual symptoms or adverse effects they experience during medication therapy to ensure early recognition.