1. Principles of Acute Pharmacotherapy

Prompt treatment of anaphylaxis aims to reverse life-threatening vasodilation and bronchoconstriction while maintaining airway patency and end-organ perfusion. The primary goals are rapid symptom reversal, mortality reduction, and prevention of biphasic reactions.

• Mechanism of Action: The cornerstone of therapy, epinephrine, provides potent α1-mediated vasoconstriction to counter hypotension, β1-mediated inotropy and chronotropy to improve cardiac output, and β2-mediated bronchodilation and mast cell stabilization to relieve respiratory distress.
• Pharmacokinetic Considerations: In shock states, an increased volume of distribution and potential hypoalbuminemia can elevate free drug fractions, altering drug effects. Renal replacement therapy (RRT) may clear hydrophilic drugs, requiring dose adjustments.
• Clinical Implications: Intramuscular (IM) epinephrine absorption remains consistent despite fluid shifts. Dosing of adjuncts like antihistamines and steroids may need adjustment around RRT sessions.

2. First-Line Agents

Epinephrine is the single most important, life-saving intervention and must be administered immediately. Antihistamines and corticosteroids serve as adjuncts for symptom relief and management of late-phase inflammation but do not replace epinephrine.

A. Epinephrine

The nonselective adrenergic agonism of epinephrine directly counters the pathophysiology of anaphylaxis. It is indicated for any patient with acute skin or mucosal signs accompanied by respiratory or cardiovascular compromise.

• Dosing: Use a 1:1,000 (1 mg/mL) solution for IM injection. The dose is 0.01 mg/kg, with a maximum of 0.5 mg per dose. Repeat every 5–15 minutes as needed based on clinical response.
• Monitoring: Continuous ECG and blood pressure monitoring are essential to detect potential tachyarrhythmias and severe hypertension.
• Warnings: Use with caution in patients with known coronary artery disease, as it can precipitate myocardial ischemia.

B. H1 and H2 Antihistamines

These agents are second-line and primarily treat cutaneous symptoms like urticaria and pruritus. H1 inverse agonists (e.g., diphenhydramine, cetirizine) reduce itching and vasodilation, while H2 blockers (e.g., ranitidine, famotidine) may help limit vascular permeability. Their onset is 15–30 minutes, and they have no effect on airway edema or hemodynamics. Administer only after epinephrine.

C. Corticosteroids

Corticosteroids work via genomic mechanisms to reduce inflammation and stabilize endothelial membranes. Their onset is delayed (4–6 hours), making them unsuitable for acute symptom reversal. They are administered to potentially prevent the late-phase or biphasic reaction of anaphylaxis.

• Dosing: A typical dose is methylprednisolone 1–2 mg/kg IV once, followed by an oral prednisone taper if the patient is stable.
• Monitoring: Monitor blood glucose every 4–6 hours, especially in diabetic patients.

3. Adjunctive & Second-Line Therapies

When first-line therapy is insufficient, adjunctive agents should be tailored to the patient’s specific symptoms, response, and comorbidities. This often occurs in cases of refractory hypotension or severe bronchospasm.

• Bronchodilators: For persistent wheezing despite epinephrine, administer nebulized albuterol (2.5 mg every 20 minutes) or a continuous infusion (10–15 mg/hour). Monitor for tachycardia and hypokalemia.
• Glucagon: Indicated for refractory hypotension in patients on beta-blockers, as it bypasses the beta-receptor to increase cardiac inotropy. Administer a 1–5 mg IV bolus over 1 minute, followed by an infusion at 5–15 mcg/min. Monitor for vomiting and hyperglycemia.
• IV Fluids & Vasopressors: For persistent hypotension, administer an initial crystalloid bolus of 20 mL/kg. If hypotension continues, initiate a norepinephrine infusion. Vasopressin can be considered as an adjunct in refractory distributive shock.

4. Route of Administration & Delivery Devices

The choice of route is critical. IM epinephrine is the standard for initial therapy due to its rapid and reliable absorption. IV routes are reserved for refractory cases or peri-arrest scenarios and require intensive monitoring.

• IM vs. IV: IM injection is preferred for all initial doses. An IV infusion should only be started by experienced personnel in a monitored setting (e.g., ICU, ED) to carefully titrate the dose and avoid overdose, which can cause life-threatening arrhythmias and hypertension.
• IV Infusion Setup: A standard concentration is 1 mg of epinephrine in 100 mL of normal saline (10 mcg/mL). Start the infusion at 1 mcg/min and titrate by 1–2 mcg/min every 5 minutes to maintain a systolic blood pressure ≥90 mmHg. Always label the bag and line as a “High-Alert” medication.
• Safety: Always prime tubing completely to prevent an inadvertent bolus of the drug. Use smart pumps with dose error reduction software (DERS) whenever possible.

5. Dosing Adjustments for Organ Dysfunction

Dosing modifications are crucial in patients with renal or hepatic impairment to ensure both efficacy and safety, primarily for adjunctive medications.

6. Monitoring & Toxicity Surveillance

Vigilant monitoring is essential to track therapeutic efficacy and detect drug-related complications early.

• Cardiovascular: Continuous ECG and vital signs are mandatory for at least 4 hours after the last dose of epinephrine to observe for arrhythmias, ischemia, and rebound hypotension.
• Laboratory: Check blood glucose every 4–6 hours during corticosteroid therapy. Monitor serum electrolytes, particularly potassium, after frequent beta-2 agonist (albuterol) administration.
• Observation Period: Extend monitoring to at least 8 hours in patients with a history of severe or biphasic reactions, or those who required multiple doses of epinephrine.

7. Pharmacoeconomic Considerations

Effective management involves balancing drug acquisition costs with overall resource utilization and clinical outcomes.

• Epinephrine Cost: The acquisition cost of IM epinephrine from a vial is very low, making it highly cost-effective given its profound impact on reducing mortality and morbidity.
• Autoinjectors: While having a higher per-unit cost, autoinjectors may reduce downstream costs by preventing dosing errors and treatment delays that could lead to longer hospital stays or worse outcomes.
• Resource Utilization: Escalation to IV infusions and continuous monitoring significantly increases demands on staffing, pharmacy, and ICU bed resources.
• Desensitization: For necessary but allergenic drugs (e.g., chemotherapy), formal desensitization protocols are resource-intensive but can be cost-effective by enabling the use of first-line, high-value therapies and avoiding more expensive, less effective alternatives.