H2 receptor antagonists (H2RAs) act by competitive inhibition of histamine at the Gs-coupled H2 receptor on gastric parietal cells, reducing cyclic AMP (cAMP) generation and thereby decreasing proton pump (H+/K+-ATPase) activity and acid secretion. Although largely supplanted by proton pump inhibitors (PPIs) for most acid-related indications, H2RAs retain important clinical roles and remain high-yield pharmacology because of the markedly different interaction profiles among agents within the class, particularly cimetidine's broad cytochrome P450 (CYP) inhibitory activity compared to famotidine's essentially clean interaction profile.
All four clinically used H2RAs bind competitively to the parietal cell H2 receptor, reducing histamine-stimulated acid secretion. Because the gastric parietal cell is regulated by three convergent stimulatory pathways (histamine via H2, gastrin via cholecystokinin-2 (CCK2) receptors, and acetylcholine (ACh) via M3 muscarinic receptors), H2RAs provide partial but not complete acid suppression. PPIs, acting at the final common step of the H+/K+-ATPase proton pump, achieve superior and more sustained acid suppression regardless of the stimulatory pathway. H2RAs are, however, more rapid in onset than PPIs (effect within 1–3 hours versus the requirement for PPIs to be taken before meals to activate secreting pumps) and retain utility for immediate acid relief, nocturnal acid breakthrough in PPI users, and stress ulcer prophylaxis in patients in the intensive care unit where intravenous formulations are available.1
Cimetidine was the first clinically available H2RA and remains important primarily as a pharmacological landmark and as a teaching example of drug interactions through CYP inhibition. Its acid suppression efficacy is comparable to other H2RAs at equivalent doses, but its interaction profile is dramatically different. Cimetidine inhibits multiple CYP isoforms: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, through binding to the heme iron of cytochrome P450 via its imidazole ring nitrogen. This broad inhibitory activity means cimetidine can elevate plasma concentrations of warfarin (CYP2C9 substrate), phenytoin (CYP2C9/2C19), theophylline (CYP1A2), lidocaine (CYP3A4/1A2), metoprolol and other beta-blockers (CYP2D6), tricyclic antidepressants (TCAs) (CYP2D6), and numerous other drugs. Famotidine, nizatidine, and the withdrawn ranitidine all lack the imidazole ring and do not produce clinically meaningful CYP inhibition at therapeutic doses, making them far safer for patients on multiple medications.2
The pharmacokinetics of H2RAs show important differences across the class. Cimetidine has an oral bioavailability of approximately 60–70%, a half-life of 2 hours, and undergoes significant renal clearance with a smaller hepatic component; dose reduction is required in renal impairment (glomerular filtration rate (GFR) below 50 mL/min). Famotidine has oral bioavailability of approximately 40–50%, a half-life of 2.5–4 hours, and is primarily renally eliminated (65–70% unchanged); dose adjustment in renal impairment is mandatory and more stringent than for cimetidine because famotidine clearance falls proportionally with GFR, with accumulation risk in dialysis patients. Nizatidine has oral bioavailability exceeding 90% (the highest of the class), a half-life of 1–2 hours, and approximately 57% of the dose is excreted unchanged renally, also requiring dose adjustment in renal failure. All H2RAs cross the blood-brain barrier to varying degrees, and CNS adverse effects including confusion, agitation, and delirium occur most commonly with cimetidine in elderly patients with renal impairment due to drug accumulation.1
The role of H2RAs in the post-PPI era is primarily as adjunctive therapy rather than primary acid suppression. In gastroesophageal reflux disease (GERD), H2RAs are second-line to PPIs for maintenance therapy but are used as on-demand agents for breakthrough symptoms. In peptic ulcer disease, PPIs have superior healing rates and are the standard of care unless there is a specific reason to avoid them. H2RAs retain a distinct niche in stress ulcer prophylaxis in intensive care unit (ICU) patients: both H2RAs and PPIs reduce clinically significant stress ulcer bleeding in mechanically ventilated patients, and the choice between them is informed by bleeding risk, aspiration pneumonia risk (elevated gastric pH with PPIs may increase bacterial overgrowth), and route of administration availability. The combination of H1 and H2 antihistamines in anaphylaxis management is discussed in Section 3, where their complementary receptor targeting provides rational justification for combined use.
Cimetidine inhibits CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 via its imidazole ring nitrogen coordinating with the CYP heme iron. Clinically significant interactions include: warfarin (increased anticoagulation, INR monitoring required), phenytoin (toxicity at standard doses), theophylline (nausea, arrhythmia), metoprolol (bradycardia, hypotension), and TCAs (increased plasma levels). Famotidine lacks the imidazole ring and has no clinically meaningful CYP inhibitory activity. When an H2RA is clinically indicated in a patient on any of these drugs, famotidine is the correct choice. The same principle applies to nizatidine. Ranitidine is no longer available in the US due to N-nitrosodimethylamine (NDMA) contamination discovered in 2019.
Prophylactic allergy pharmacology encompasses agents that act upstream of histamine release, either by preventing mast cell degranulation or by eliminating the IgE-mediated sensitization pathway entirely. Cromolyn sodium and nedocromil are classical mast cell stabilizers with narrow clinical niches determined by their poor systemic bioavailability. Omalizumab represents a mechanistically distinct approach: a humanized monoclonal antibody that depletes free IgE, interrupting the sensitization pathway before allergen encounter.
Cromolyn sodium (cromoglicate) was among the first preventive treatments for asthma and allergic rhinitis and acts by stabilizing mast cells against degranulation, preventing both the early-phase and late-phase allergic responses. The precise molecular mechanism of cromolyn remains incompletely characterized; it appears to interfere with calcium ion flux across the mast cell membrane that is required for granule-plasma membrane fusion during exocytosis, and it may also reduce chloride channel conductance in sensory nerves that modulate mast cell activation. The key pharmacokinetic feature of cromolyn is its extremely poor oral bioavailability (less than 1%), meaning that inhaled formulations for asthma and rhinitis act topically at the airway mucosa rather than systemically, and oral cromolyn for mastocytosis-related gastrointestinal symptoms acts within the gut lumen without systemic exposure. Cromolyn is effective only when used prophylactically before allergen exposure; it has no utility in acute allergic reactions where mast cells have already degranulated. The inhaled formulation requires four-times-daily administration, which limits adherence compared to once-daily or twice-daily inhaled corticosteroids, and cromolyn has largely been displaced in asthma management by inhaled corticosteroids, leukotriene receptor antagonists (LTRAs), and combination therapies.3
Nedocromil sodium shares cromolyn's mechanism class but has a broader profile of anti-inflammatory activity, inhibiting mast cells, eosinophils, neutrophils, and macrophages at the airway mucosa. Like cromolyn, it is available in inhaled form (MDI) and ophthalmic form (for allergic conjunctivitis) and acts topically with minimal systemic absorption. Nedocromil is better tolerated than cromolyn by most patients because it does not cause the cough and throat irritation that cromolyn can provoke. Both agents retain modest use in exercise-induced bronchospasm (EIB) prophylaxis (taken 15–20 minutes before exercise), in patients unable to tolerate inhaled corticosteroids, and in certain pediatric allergy populations. Their clean safety profiles make them attractive in pregnancy when pharmacological allergy management is needed and the risks of inhaled corticosteroids are a concern for the clinician or patient, though inhaled corticosteroids remain the preferred agents in most pregnant women with persistent asthma.3
Omalizumab (Xolair) is a recombinant humanized IgG1 monoclonal antibody directed against the FcεIII domain of IgE, the region that binds to the high-affinity FcεRI receptor on mast cells and basophils. By binding free circulating IgE with high affinity (Ka approximately 10 nM), omalizumab prevents IgE from occupying FcεRI on mast cells and basophils. This interrupts the sensitization step of the IgE-mediated allergic cascade: without surface-bound IgE, allergen cannot cross-link receptors and trigger degranulation. Prolonged use additionally leads to down-regulation of FcεRI expression on mast cell and basophil surfaces because receptor expression is upregulated by surface IgE occupancy; as free IgE falls with treatment, surface IgE decreases and FcεRI density diminishes, further reducing allergic reactivity. This secondary effect develops over weeks to months of treatment.4
Omalizumab is approved for moderate-to-severe persistent allergic asthma (in patients aged 6 and older with documented allergen sensitization and inadequate control on inhaled corticosteroids), chronic spontaneous urticaria (CSU) refractory to antihistamines (in patients aged 12 and older), and chronic rhinosinusitis with nasal polyps (CRSwNP). For allergic asthma and CSU, dosing is weight-based and determined by baseline total IgE level: patients with very high IgE or large body weight require higher or more frequent doses to achieve free IgE suppression. The subcutaneous injection is administered every 2–4 weeks. Omalizumab's half-life is approximately 26 days, consistent with typical IgG1 pharmacokinetics. The principal safety concern is anaphylaxis, which occurs in approximately 0.1% of patients and can be delayed (occurring hours after injection), requiring a 30-minute observation period post-injection and patient education about delayed reaction recognition. Malignancy was initially a concern in early trials but has not been confirmed as a drug-related risk in subsequent large registry studies.4
The mechanism of omalizumab in chronic spontaneous urticaria (CSU) is not fully elucidated because CSU is not always IgE-mediated in the classical allergen-driven sense. Proposed mechanisms include: (1) reduction of free IgE and subsequent FcεRI down-regulation, reducing mast cell responsiveness even to autoimmune or autoallergic triggers; (2) reduction of IgE-mediated autoimmune activation in patients with IgE directed against FcεRI itself or IgE against thyroperoxidase; and (3) general mast cell stabilization independent of specific IgE-antigen interactions. Clinical trials (ASTERIA I, II; GLACIAL) established 300 mg subcutaneously every 4 weeks as the standard dose for CSU, with robust response rates and a favorable safety profile. Response occurs rapidly in many CSU patients (within 1–4 weeks), suggesting mechanisms beyond simple IgE depletion, since IgE-mediated receptor down-regulation requires weeks to months.
Anaphylaxis management is anchored by a single pharmacological principle: epinephrine is the only agent that addresses the multimediator, multisystem nature of anaphylactic shock simultaneously. All other agents, including antihistamines, corticosteroids, and bronchodilators, are adjuncts that treat specific manifestations or provide longer-term stabilization but cannot independently prevent or reverse cardiovascular collapse. Understanding why requires mechanistic clarity about which mediators cause which effects and which drugs address them.
The systemic vasodilation and hypotension of anaphylaxis are driven by a combination of histamine (H1-mediated endothelial nitric oxide and vascular smooth muscle effects, H2-mediated tachycardia), platelet-activating factor (PAF), prostaglandin D2 (PGD2), and leukotrienes. Bronchospasm is driven primarily by histamine (early), cysteinyl leukotrienes (LTC4, LTD4, LTE4, more sustained), and PGD2. Urticaria and angioedema are predominantly histamine-mediated (H1). Tryptase released from mast cell granules activates complement and the contact activation system, amplifying the cascade. Epinephrine addresses this multimediator profile through three simultaneous actions: alpha-1 adrenergic receptor-mediated vasoconstriction reverses distributive hypotension; beta-2 adrenergic receptor stimulation relaxes bronchial smooth muscle and reverses bronchospasm; and beta-2 receptor-mediated cAMP elevation in mast cells and basophils inhibits ongoing mediator release. No antihistamine, corticosteroid, or bronchodilator alone or in combination provides all three effects.5
Intramuscular epinephrine in the mid-outer thigh (vastus lateralis) is the correct route and site of administration. The intramuscular vastus lateralis provides faster and more reliable peak plasma epinephrine concentrations than intramuscular deltoid injection (which has more variable absorption due to lower muscle mass and potentially higher subcutaneous fat) or subcutaneous injection (slower absorption due to epinephrine-induced local vasoconstriction). The standard dose is 0.3–0.5 mg (0.3–0.5 mL of 1:1000 solution) for adults and 0.01 mg/kg up to 0.3 mg for children. Intravenous epinephrine is reserved for patients with cardiovascular collapse refractory to intramuscular dosing and requires careful dilution (1:10,000 concentration) and continuous hemodynamic monitoring because of the risk of hypertensive crisis and arrhythmia with IV bolus administration. Auto-injectors (EpiPen 0.3 mg, EpiPen Jr 0.15 mg) are the standard of care for outpatient self-administration and should be prescribed in pairs because 15–20% of anaphylaxis cases are biphasic, with a second reaction occurring 1–72 hours after apparent resolution.5
The rationale for combined H1 plus H2 antihistamine therapy as adjunctive treatment in anaphylaxis rests on the complementary receptor coverage across the vascular histamine response. H1 receptors on vascular endothelium and smooth muscle mediate vasodilation, urticaria, and angioedema; H2 receptors on cardiac myocytes contribute to tachycardia and additionally mediate vasodilation in some vascular beds. Diphenhydramine (H1 blocker, 25–50 mg IV or IM) plus famotidine (H2 blocker, 20 mg IV) provides broader histamine receptor blockade than either alone, and observational evidence and mechanistic plausibility support this combination as a standard adjunct for cutaneous manifestations. However, clinical trial evidence for antihistamines reducing the duration of anaphylaxis or preventing biphasic reactions is limited; they remain adjuncts, not alternatives to epinephrine. Antihistamines do not affect leukotriene, PAF, or prostaglandin-mediated components of anaphylaxis, reinforcing why they cannot be the primary treatment.6
Systemic corticosteroids (methylprednisolone 1–2 mg/kg IV, or prednisone 40–60 mg orally) are used in anaphylaxis to suppress the late-phase inflammatory response and, theoretically, to reduce the risk of biphasic reactions, though randomized controlled trial evidence for the latter is limited. Corticosteroids have an onset of several hours and provide no benefit in the acute hemodynamic emergency; their role is primarily in the hours following initial stabilization to attenuate eosinophilic and Th2-mediated secondary inflammation. Beta-2 agonists (salbutamol/albuterol by nebulizer) are useful adjuncts for persistent bronchospasm refractory to epinephrine but address only the airway component and have no effect on systemic vasodilation. Glucagon (1–5 mg IV) is a specific antidote for epinephrine-refractory anaphylaxis in patients taking beta-blockers, whose beta-adrenergic signaling is pharmacologically blocked: glucagon activates adenylyl cyclase through a beta-receptor-independent mechanism, increasing cAMP in cardiac and smooth muscle cells and restoring positive inotropy and chronotropy despite beta-blockade.5
Patients on beta-blockers who develop anaphylaxis represent a high-risk scenario because beta-adrenergic receptor blockade prevents epinephrine's beta-1 and beta-2 effects (inotropy, chronotropy, bronchodilation), leaving only alpha-1 vasoconstriction active. The result is refractory bronchospasm, bradycardia, and hypotension that does not respond to standard epinephrine doses. Glucagon activates adenylyl cyclase in cardiac myocytes through its own G protein-coupled receptor, independent of beta-adrenergic signaling, increasing cAMP and restoring positive inotropy and chronotropy. The IV dose is 1–5 mg bolus followed by infusion at 5–15 mcg/min. Nausea and vomiting are common adverse effects; aspiration precautions are important in the obtunded patient. Atropine can address glucagon-unresponsive bradycardia by muscarinic blockade. All patients on beta-blockers with a history of anaphylaxis should have their allergist or immunologist reassess the risk-benefit of continued beta-blockade.
Bradykinin is a vasoactive nonapeptide autacoid generated locally at sites of tissue injury, inflammation, and vascular activation. Unlike histamine, which is stored preformed in granules and released by exocytosis, bradykinin is synthesized on demand from precursor proteins through a protease cascade and acts transiently before rapid degradation by peptidases. Its physiological roles in vasodilation, vascular permeability, pain sensitization, and bronchoconstriction parallel those of histamine in important ways but are mediated through distinct receptors and signaling mechanisms.
The kallikrein-kinin system generates bradykinin through a sequential proteolytic cascade. The substrate is high-molecular-weight kininogen (HMWK), a plasma protein that circulates as a complex with plasma prekallikrein. When factor XII (Hageman factor) is activated by contact with negatively charged surfaces (damaged subendothelium, foreign surfaces such as dialysis membranes, lipopolysaccharide), it converts prekallikrein to plasma kallikrein. Plasma kallikrein then cleaves HMWK at two specific sites, releasing bradykinin (a nine-amino-acid peptide, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) from the central portion of HMWK. A parallel pathway in peripheral tissues involves tissue kallikrein (glandular kallikrein), which cleaves low-molecular-weight kininogen (LMWK) to release kallidin (Lys-bradykinin), a decapeptide with the same nine terminal amino acids as bradykinin plus an N-terminal lysine. Kallidin can be converted to bradykinin by aminopeptidase cleavage of the terminal lysine residue. Both bradykinin and kallidin act on the same receptor subtypes.7
Bradykinin is degraded extremely rapidly, with a plasma half-life of approximately 15–30 seconds under normal physiological conditions. The principal degrading enzyme is angiotensin-converting enzyme (ACE, also called kininase II), which cleaves a dipeptide from the C-terminus of bradykinin, rendering it inactive. A second degrading enzyme, kininase I (carboxypeptidase N), removes the C-terminal arginine, generating des-Arg9-bradykinin, which is the primary endogenous agonist of the B1 receptor rather than an inactive metabolite. The physiological importance of ACE as a bradykinin-degrading enzyme directly explains the mechanism by which ACE inhibitors (ACEIs) cause bradykinin accumulation and their associated adverse effects, which are discussed fully in Section 5.7
The B2 receptor is the constitutively expressed, widely distributed bradykinin receptor that mediates the majority of bradykinin's acute physiological and pathophysiological effects. It couples to Gq (activating phospholipase C-beta and generating IP3 and DAG, with downstream intracellular calcium release and arachidonic acid mobilization), Gi (reducing cAMP), and Gs in some contexts. B2 receptor activation on vascular endothelium stimulates eNOS via calcium-calmodulin, generating nitric oxide that diffuses to smooth muscle and produces potent vasodilation; simultaneously, prostacyclin (PGI2) is generated via phospholipase A2 and COX-1, contributing to vasodilation and inhibiting platelet aggregation. B2 receptor activation also increases vascular permeability through interendothelial gap formation, complementing the histamine-mediated permeability increase. On bronchial smooth muscle, B2 receptor activation produces bronchoconstriction through IP3-mediated calcium release. On sensory C-fibers (nociceptors), bradykinin is among the most potent endogenous algogens, directly depolarizing pain fibers and sensitizing them to other stimuli through PKC-dependent phosphorylation of TRPV1 and other transient receptor potential (TRP) channels, a mechanism underlying the pain and hyperalgesia of inflammatory states.8
The B1 receptor is normally expressed at very low levels in most tissues but is dramatically upregulated in response to tissue injury, inflammation, and cytokines (particularly interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha)). Its primary endogenous agonist is des-Arg9-bradykinin, the carboxypeptidase N cleavage product of bradykinin that would otherwise be considered an inactivation step. B1 receptor activation shares many downstream signaling pathways with B2, including Gq coupling and phospholipase C activation, but its pharmacological and temporal profile differs: whereas B2 receptors desensitize rapidly with continuous agonist exposure, B1 receptors do not desensitize, allowing sustained activation during prolonged inflammatory states. The B1 receptor is considered a mediator of chronic rather than acute pain and inflammation; it is under active investigation as a therapeutic target for chronic pain, diabetes-related vascular complications, and inflammatory conditions where B2-directed pharmacology has proved insufficient.8
Both bradykinin and histamine produce vasodilation, increased vascular permeability, bronchoconstriction, and pain sensitization, yet the pharmacology of their blockade differs entirely. H1 antihistamines effectively block histamine-mediated vascular permeability, urticaria, and itch; they have no effect on bradykinin-mediated angioedema, which is mechanistically distinct. Epinephrine reverses histamine-mediated anaphylaxis; it has variable and often inadequate efficacy against bradykinin-mediated angioedema because the permeability increase is NO- and prostaglandin-driven rather than reversible by adrenergic vasoconstriction alone. Clinicians must distinguish the two autacoids based on clinical context because failure to do so leads to treating bradykinin-mediated emergencies with drugs that are ineffective, while the correct agents (icatibant, ecallantide, C1 inhibitor concentrate) are delayed or withheld.
Angiotensin-converting enzyme inhibitors are among the most widely prescribed medications in cardiovascular medicine, and their two bradykinin-mediated adverse effects, cough and angioedema, are among the most clinically consequential drug adverse effects encountered in primary care and emergency medicine. The pharmacological basis is straightforward: ACE is both the enzyme that converts angiotensin I to angiotensin II and the enzyme (kininase II) that degrades bradykinin. When ACE is inhibited, bradykinin accumulates locally in tissues that express ACE, particularly the lung and vasculature.
ACE inhibitor-induced cough occurs in approximately 5–20% of patients depending on ethnicity, with the highest rates reported in populations of East Asian ancestry (up to 30–40% in some Chinese and Japanese cohorts) compared to patients of European ancestry (approximately 5–15%). The mechanism is bradykinin and substance P accumulation in the bronchial mucosa, where ACE normally degrades these pro-tussive mediators. Bradykinin sensitizes bronchial sensory C-fibers via B2 receptor-mediated prostaglandin release and direct TRPV1 activation, producing the characteristic dry, nonproductive cough that begins within days to weeks of starting the ACE inhibitor and resolves within days to weeks of stopping it. The cough does not respond to antitussives, antihistamines, or corticosteroids; the only effective management is switching to an angiotensin receptor blocker (ARB), which blocks the renin-angiotensin system downstream of bradykinin accumulation without affecting ACE activity. ARBs do not inhibit bradykinin degradation and therefore do not cause ACEI-type cough in most patients.9
ACE inhibitor-induced angioedema is a less common but potentially life-threatening adverse effect, occurring in approximately 0.1–0.7% of patients treated with ACEIs. It is caused by bradykinin accumulation at the level of the dermal and submucosal microvasculature, producing B2 receptor-mediated endothelial NO and prostacyclin generation that increases vascular permeability and causes tissue edema. The angioedema characteristically involves the face, lips, tongue, pharynx, and larynx; gastrointestinal involvement (abdominal angioedema) is underrecognized and can present with acute abdominal pain and vomiting that mimics surgical emergencies. Unlike histamine-mediated angioedema, ACEI angioedema does not occur with urticaria, does not respond reliably to epinephrine, and does not respond to antihistamines or corticosteroids because histamine is not the mediator. Laryngeal involvement requires emergency airway management; the swelling is not rapidly reversible with standard anaphylaxis agents, and clinicians who mistake ACEI angioedema for histamine-mediated anaphylaxis and administer only epinephrine and antihistamines may find the airway continues to compromise.9
Risk factors for ACEI-induced angioedema include African American race (three- to fivefold higher incidence than White patients, attributed to differences in bradykinin metabolism and ACE genotype), female sex, a history of idiopathic angioedema prior to ACEI initiation, and concurrent use of neprilysin inhibitors (sacubitril). Sacubitril-valsartan (Entresto) contains a neprilysin inhibitor alongside an ARB; neprilysin is one of the enzymes that degrades bradykinin, and its inhibition raises bradykinin levels. When combined with an ACE inhibitor, the risk of angioedema is substantially increased, which is why sacubitril-valsartan is absolutely contraindicated within 36 hours of ACEI use. ARBs alone, by contrast, carry a very low risk of angioedema (estimated at approximately 10% of the risk associated with ACEIs) because they do not inhibit bradykinin degradation, though isolated case reports of ARB-associated angioedema exist and are attributed to residual angiotensin II-mediated effects on bradykinin metabolism.10
Hereditary angioedema (HAE) is the paradigm disorder of pathological bradykinin excess. The most common forms are caused by deficiency or dysfunction of C1 inhibitor (C1-INH), a serine protease inhibitor (serpin) that normally restrains the contact activation system by inhibiting activated factor XII (factor XIIa), plasma kallikrein, and factor XI. In C1-INH deficiency (HAE types I and II), unregulated plasma kallikrein activity generates bradykinin continuously from HMWK, causing episodic attacks of subcutaneous and submucosal edema that are not histamine-mediated. HAE attacks involve the extremities, abdomen, face, and upper airway; abdominal attacks cause severe pain and vomiting that frequently leads to unnecessary surgical exploration; upper airway attacks are potentially fatal. The complete absence of urticaria distinguishes HAE from allergic angioedema. The pharmacological management of HAE, including icatibant (B2 receptor antagonist), ecallantide (kallikrein inhibitor), C1-INH concentrates (plasma-derived and recombinant), and lanadelumab (prophylactic anti-kallikrein monoclonal), is covered in detail in Module 4.7
Angioedema without urticaria in a patient taking an ACE inhibitor should be presumed bradykinin-mediated until proven otherwise. Key clinical points: (1) Epinephrine, antihistamines, and corticosteroids have limited and unpredictable efficacy because histamine is not the primary mediator; they may provide partial symptomatic relief but should not be relied upon for airway management. (2) Airway assessment is the immediate priority: if the tongue is involved or stridor is present, early definitive airway management (intubation or surgical airway) is required before the swelling progresses to complete obstruction. (3) The ACEI must be permanently discontinued; rechallenge is absolutely contraindicated. (4) Icatibant (30 mg subcutaneously, licensed for HAE but used off-label for ACEI angioedema in some centers) has been studied in small trials with mixed results; its use is guided by institutional protocol and specialist consultation. (5) The next antihypertensive should be an ARB, not another ACEI or a neprilysin inhibitor.
Schubert ML, Peura DA. Control of gastric acid secretion in health and disease. Gastroenterology. 2008;134(7):1842–1860.
doi:10.1053/j.gastro.2008.05.021Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev. 1997;29(1–2):413–580.
doi:10.3109/03602539709037591Ghadersohi S, Tan BK. Contemporary pharmacotherapy for allergic rhinitis and chronic rhinosinusitis. Otolaryngol Clin North Am. 2017;50(6):1135–1151.
doi:10.1016/j.otc.2017.08.009Chang TW, Chen C, Lin CJ, Metz M, Church MK, Maurer M. The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol. 2015;135(2):337–342.
doi:10.1016/j.jaci.2014.04.036Simons FE, Ardusso LR, Bilo MB, et al. World Allergy Organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J. 2011;4(2):13–37.
doi:10.1097/WOX.0b013e318211496cLieberman P, Nicklas RA, Randolph C, et al. Anaphylaxis: a practice parameter update 2015. Ann Allergy Asthma Immunol. 2015;115(5):341–384.
doi:10.1016/j.anai.2015.07.019Moreau ME, Garbacki N, Molinaro G, Brown NJ, Marceau F, Adam A. The kallikrein-kinin system: current and future pharmacological targets. J Pharmacol Sci. 2005;99(1):6–38.
doi:10.1254/jphs.srj05001xCouture R, Harrisson M, Vianna RM, Cloutier F. Kinin receptors in pain and inflammation. Eur J Pharmacol. 2001;429(1–3):161–176.
doi:10.1016/s0014-2999(01)01318-8Sica DA, Gehr TWB. Angiotensin-converting enzyme inhibitors. In: Oparil S, Weber MA, eds. Hypertension: A Companion to Brenner and Rector's The Kidney. 2nd ed. Philadelphia, PA: Elsevier Saunders; 2005:509–519.
Haymore BR, Yoon J, Mikita CP, Klote MM, DeZee KJ. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting enzyme inhibitors: a meta-analysis. Ann Allergy Asthma Immunol. 2008;101(5):495–499.
doi:10.1016/S1081-1206(10)60288-8