8.3 Adverse Drug Reactions, Pharmacovigilance & Allergy Verification

8.3 Adverse Drug Reactions, Pharmacovigilance & Allergy Verification

Adverse Drug Reactions (ADRs) represent a substantial source of patient morbidity, extended hospitalizations, and healthcare expenditures. In the Emirate of Abu Dhabi, the Department of Health (DOH) mandates strict clinical protocols for allergy verification, early identification of life-threatening immune reactions, rapid resuscitation during anaphylactic collapse, and institutional reporting to the national pharmacovigilance surveillance registry.

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Classification of Adverse Drug Reactions (Rawlins & Thompson)

The World Health Organization (WHO) defines an Adverse Drug Reaction (ADR) as any noxious, unintended, and undesired response to a pharmaceutical product that occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy. The Rawlins and Thompson Classification divides ADRs into two primary fundamental categories:

1. Type A Reactions (Augmented)

• Characteristics: Predictable, dose-dependent, and directly related to the known primary pharmacological mechanism of the drug. Type A reactions account for approximately 80% to 90% of all reported ADRs.
• Examples:
  • Orthostatic hypotension and syncope secondary to antihypertensive agents (e.g., amlodipine, prazosin).
  • Hypoglycemia secondary to sulfonylureas or exogenous insulin therapy.
  • Pathological bleeding secondary to anticoagulant therapy (e.g., heparin, warfarin, apixaban).
  • Gastrointestinal mucosal ulceration and gastritis secondary to non-steroidal anti-inflammatory drugs (NSAIDs).
  • Respiratory depression secondary to opioid analgesics.
• Management: Typically managed by reducing the prescribed dose, withholding single doses, adjusting administration timing, or substituting with a less potent agent.

2. Type B Reactions (Bizarre / Idiosyncratic)

• Characteristics: Unpredictable from the drug's usual pharmacology and conventionally classified as dose-independent. These reactions include immunologic allergy and nonimmunologic idiosyncrasy in susceptible individuals; severity ranges from mild reactions to life-threatening emergencies.
• Examples:
  • IgE-mediated anaphylaxis from penicillin or cephalosporins.
  • Malignant Hyperthermia triggered by volatile halogenated anesthetics or succinylcholine.
  • Aplastic anemia secondary to chloramphenicol.
  • Severe Cutaneous Adverse Reactions (SCAR) including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).
  • Acute hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency triggered by rasburicase, primaquine, or sulfonamides.
• Management: Withhold the suspected culprit and assess severity promptly. Provide emergency care for anaphylaxis or other severe reactions. Document the exact drug, reaction and avoidance advice in the EHR; distinguish allergy from nonallergic reactions and obtain specialist guidance about future exposure.

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Coombs & Gell Classification of Drug Allergies

Drug-induced hypersensitivity reactions are immunologically mediated responses classified under the Coombs and Gell Framework into four distinct pathophysiological types:

Severe Cutaneous Adverse Reactions (SCAR): SJS & TEN

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) represent medical-dermatologic emergencies characterized by extensive epidermal detachment, epidermal full-thickness necrosis, and mucocutaneous sloughing mediated by cytotoxic CD8+ T-lymphocytes and natural killer (NK) cells releasing granulysin.

Clinical Spectrum & Body Surface Area (BSA) Staging

• Stevens-Johnson Syndrome (SJS): Epidermal detachment involving less than 10% of total body surface area (TBSA).
• SJS / TEN Overlap: Epidermal detachment involving 10% to 30% of total body surface area.
• Toxic Epidermal Necrolysis (TEN): Epidermal detachment involving greater than 30% of total body surface area (associated with mortality rates exceeding 30% to 50%).

Common High-Risk Culprit Pharmaceuticals

• Allopurinol (frequently associated with HLA-B*5801 genotype)
• Aromatic Anticonvulsants (Carbamazepine, Phenytoin, Lamotrigine, Phenobarbital; associated with HLA-B*1502 genotype)
• Sulfonamide Antimicrobials (Trimethoprim-sulfamethoxazole [TMP-SMX])
• Non-Steroidal Anti-Inflammatory Drugs (Oxicam derivatives: Piroxicam, Meloxicam)
• Antiretrovirals (Nevirapine)

Diagnostic Hallmark: Nikolsky's Sign

During physical assessment of erythematous macules, the application of gentle, oblique, tangential shear pressure to normal-appearing perilesional skin results in immediate sliding and detachment of the epidermis from the underlying dermal bed (positive Nikolsky's sign). This sign supports epidermal fragility but is not specific for SJS/TEN; it can also occur in pemphigus vulgaris and staphylococcal scalded skin syndrome. Interpret it with the drug history, mucosal findings, clinical course and specialist assessment.

Acute Nursing & Medical Management

1. Immediate Discontinuation: Cease all suspected and non-essential pharmaceuticals immediately. Prompt withdrawal of the suspected culprit is a priority and may reduce mortality.
2. Burn Center Transfer: Transfer the patient immediately to an accredited Intensive Care Burn Unit equipped with specialized laminar air flow and environmental temperature regulation (ambient room temperature maintained at 30°C to 32°C to prevent hypothermia).
3. Reverse Isolation & Infection Prevention: The loss of protective epidermal barriers leaves patients vulnerable to fatal systemic sepsis (predominantly Pseudomonas aeruginosa and Staphylococcus aureus). Enforce strict sterile barrier nursing precautions.
4. Wound Care & Dressing Management: Avoid mechanical scrubbing or surgical debridement. Apply sterile non-adherent dressings impregnated with petrolatum, silicone mesh, or biological biosynthetic skin substitutes. Never apply adhesive tapes directly to patient skin.
5. Aggressive Fluid & Electrolyte Resuscitation: Massive transdermal fluid loss requires intravenous crystalloid replacement titrated to maintain adequate end-organ perfusion and urine output (0.5 to 1.0 mL/kg/hr).
6. Multidisciplinary Ophthalmology Consultation: Severe bilateral conjunctival inflammation, pseudomembranes, and corneal epithelial sloughing can lead to permanent cicatricial blindness. Nurses must administer preservative-free ocular lubricating drops every hour and ensure daily lysis of fibrous conjunctival synechiae.

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Anaphylaxis Emergency Clinical Protocol

Anaphylaxis is an acute, life-threatening, multi-systemic hypersensitivity reaction that demands instantaneous recognition and decisive pharmacological intervention.

Clinical Presentation & Multi-System Criteria

• Respiratory: Dyspnea, tachypnea, severe bronchospasm with expiratory wheezing, laryngeal edema with audible high-pitched inspiratory stridor, feeling of throat tightness, hoarseness, and progressive hypoxemia.
• Cutaneous & Mucosal: Generalized urticaria (erythematous pruritic wheals), intense pruritus, warm flushing, and severe non-pitting angioedema involving the periorbital tissues, lips, tongue, uvula, and soft palate.
• Cardiovascular & Hemodynamic: Profound hypotension (systolic BP < 90 mmHg or a > 30% decline from baseline), reflex tachycardia (or paradoxical vagal bradycardia), diaphoresis, pallor, dizziness, syncope, and cardiac arrest.
• Gastrointestinal: Severe crampy abdominal pain, nausea, projectile vomiting, and involuntary watery diarrhea (triggered by gastrointestinal smooth muscle contraction).

First-Line Life-Saving Intervention: Intramuscular (IM) Epinephrine

Epinephrine is the absolute first-line drug for anaphylaxis. There are no absolute contraindications to epinephrine in a life-threatening anaphylactic emergency.

• Concentration: Epinephrine 1:1,000 (1 mg/mL).
• Adult Dosing: 0.3 to 0.5 mg (0.3 to 0.5 mL) administered Intramuscularly (IM).
• Pediatric Dosing: 0.01 mg/kg IM; the usual maximum is 0.3 mg in prepubertal children and 0.5 mg in adolescents/adults. Follow the age/weight-specific emergency protocol.
• Anatomical Site: Inject into the anterolateral aspect of the middle third of the thigh (Vastus Lateralis muscle).

• Dosing Frequency: If clinical manifestations do not improve or continue to deteriorate, repeat the IM epinephrine dose every 5 to 15 minutes in the opposite thigh.
• Intravenous Epinephrine Warning: Pure IV boluses of epinephrine 1:1,000 are strictly prohibited in non-arrest patients due to the extreme danger of inducing fatal ventricular fibrillation, myocardial infarction, and severe intracranial hemorrhage. Continuous intravenous infusions (0.1 to 0.5 mcg/kg/min) titrated under continuous invasive arterial monitoring are reserved exclusively for refractory shock that fails to respond to multiple IM injections and fluid boluses.

Secondary & Adjunctive Resuscitation Interventions

Once epinephrine has been administered, initiate secondary supportive interventions:

1. Patient Positioning: Place the patient in a flat recumbent (supine) position with the lower extremities elevated to optimize venous return. If dyspnea is severe, allow the patient to sit in semi-Fowler's position. Never allow an anaphylactic patient to stand or sit upright suddenly, as acute gravitational venous pooling in distributive shock precipitates the fatal "empty ventricle / empty heart" syndrome.
2. High-Flow Oxygen: Administer 100% oxygen via a non-rebreather mask at 10 to 15 L/min. If laryngeal stridor or progressive facial angioedema is present, alert the airway team for immediate endotracheal intubation or surgical cricothyroidotomy before complete airway occlusion occurs.
3. Aggressive IV Fluid Boluses: Establish two large-bore peripheral IV lines (16-gauge or 18-gauge). Infuse rapid boluses of 1 to 2 Liters of isotonic crystalloids (0.9% Normal Saline or Lactated Ringer's) in adults (20 mL/kg in children) to treat profound distributive vasodilation and vascular permeability.
4. Nebulized Beta-Agonists: Administer nebulized albuterol 2.5 to 5 mg for persistent lower airway bronchospasm.
5. Adjunctive Second-Line Pharmacotherapy:
   • H1 and H2 Antihistamines: IV Diphenhydramine (25 to 50 mg) plus IV Famotidine (20 mg) to alleviate cutaneous urticaria and gastric acid hypersecretion. Antihistamines do not relieve airway obstruction or shock and must never delay epinephrine.
   • Systemic Corticosteroids: Do not rely on steroids to prevent biphasic anaphylaxis; routine use is not recommended. They may be prescribed for a separate indication such as persistent asthma after initial resuscitation. They must never delay epinephrine or fluids.
   • Observation: Continue observation in an area able to treat recurrent anaphylaxis. Duration and admission depend on severity, treatment response, repeat epinephrine needs, ongoing allergen absorption and access to emergency care; use the facility protocol rather than a universal telemetry stay.

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Allergy Verification & DOH Pharmacovigilance Mandates

Preventing medication-induced harm requires meticulous clinical assessment at the bedside combined with institutional regulatory reporting across the Emirate of Abu Dhabi.

Clinical Distinction: True IgE Allergy vs. Drug Intolerance

A critical nursing assessment priority is distinguishing true immunologic allergies from expected adverse pharmacological side effects or intolerances:

• True Immunologic Allergy: Involves immune sensitization (IgE or cell-mediated). Manifests with urticaria, diffuse flushing, facial angioedema, wheezing, stridor, hypotension, or blistering skin desquamation. Strictly contraindicates future administration of the drug and cross-reactive pharmacological classes.
• Drug Intolerance / Non-Allergic Side Effect: Expected, non-immunologic physical symptoms such as mild nausea, epigastric fullness, mild non-bloody diarrhea (e.g., from oral erythromycin or amoxicillin), lightheadedness, or sedation (e.g., from codeine). The drug is not contraindicated if clinically indicated, and symptoms can be managed using antiemetics, dose titrations, or taking the drug with meals.

Clinical Safety Workflows & EHR Hard Stops

• Comprehensive Allergy Reconciliation: Upon patient admission to any DOH-licensed facility, the nurse must conduct an in-depth allergy history: recording the specific drug name, the exact clinical manifestations experienced, the approximate onset after ingestion, and what interventions were required.
• Visual & Digital Safeguards: Affix a standardized red allergy identification wristband to the patient's arm. Ensure the patient allergy profile is updated in the Electronic Health Record (EHR).
• Electronic Allergy Decision Support: DOH requires electronic screening for allergy alerts and verification/documentation of allergies before dispensing. Check the recorded reaction and resolve alerts with the prescriber/pharmacist using the approved process. Do not assume software will completely lock every unsafe order or replace bedside verification.
• Malaffi Health Information Exchange Integration: Abu Dhabi operates Malaffi (the centralized health information exchange platform). Documented drug allergies and severe ADRs recorded at one healthcare facility (e.g., Cleveland Clinic Abu Dhabi) are instantly synchronized and visible to clinicians treating the patient at any other public (SEHA) or private facility across the emirate, preventing duplicate cross-facility exposure.

DOH Abu Dhabi & MOHAP Pharmacovigilance Reporting

Use the DOH pharmacovigilance reporting process and facility safety workflow for suspected ADRs/AEFI; follow the separate current medication-error/product-quality reporting requirements for those events. Report a suspected association without waiting for certainty:

1. Reportable Events:
   • Any serious, unexpected, or fatal Adverse Drug Reaction.
   • Any adverse reaction resulting in persistent disability, congenital anomaly, or prolonged hospitalization.
   • Suspected counterfeit, degraded, contaminated, or substandard pharmaceuticals.
   • Adverse Events Following Immunization (AEFI).
   • Clinically significant medication administration errors resulting in patient harm.
2. Reporting Timelines & Protocols:
   • Serious ADRs/AEFI: Report as soon as possible, no later than 24 hours after the healthcare provider first receives the information. This includes non-fatal serious reactions.
   • Other ADRs/AEFI: Report as early as possible, no later than 30 days. Submit medically relevant follow-up information promptly under the same standard.
   • The clinical report must include patient demographic details, suspected drug brand/generic name, manufacturer lot/batch number, expiration date, concomitant medications, clinical management provided, and final patient outcome.