Biphasic anaphylaxis occurs in 1-20% of anaphylactic episodes when a second wave of mediator release triggers recurrent symptoms hours after apparent resolution. The initial IgE-mediated mast cell degranulation releases histamine, tryptase, prostaglandins, and leukotrienes causing the acute phase. The late phase is driven by newly synthesized mediators (LTC4, LTD4, PGD2) and recruited inflammatory cells (eosinophils, basophils, neutrophils) that release cytokines (TNF-alpha, IL-4, IL-13), amplifying vascular permeability and bronchospasm without re-exposure to the allergen. Risk factors for biphasic reactions include delayed epinephrine administration, severe initial presentation, wide pulse pressure during the first episode, and unknown trigger. Epinephrine's pharmacology is central to management: alpha-1 agonism causes arteriolar vasoconstriction reversing hypotension and reducing mucosal edema; beta-1 agonism increases cardiac inotropy and chronotropy; beta-2 agonism relaxes bronchial smooth muscle and stabilizes mast cell membranes preventing further degranulation. IM administration into the vastus lateralis achieves peak plasma concentration in 8-10 minutes versus 34 minutes subcutaneously. IV epinephrine infusion (1-10 mcg/min titrated) is reserved for refractory anaphylaxis unresponsive to repeated IM doses.