Medication Summary
The primary goal of medical therapy for angioedema is to reduce and prevent swelling. Reducing discomfort and minimizing complications are also extremely important goals. Most of the drugs used for urticaria and anaphylaxis are also used for many types of angioedema.
In histamine-mediated angioedema, second-generation antihistamines are often first-line treatment. Corticosteroids can be used in severe cases of this form of the disease, but long-term use of these agents should be avoided in outpatient treatment.
Antihistamines do not work for patients with bradykinin-mediated angioedema, and corticosteroids have limited or no value in this type of angioedema. However, fresh frozen plasma (FFP), antifibrinolytics, C1 esterase inhibitor (C1-INH), ecallantide, and icatibant can be used to manage bradykinin-mediated angioedema.
Limited small studies of anti-inflammatory agents have shown dapsone, sulfasalazine, hydroxychloroquine, and colchicine to provide clinical benefit in patients with chronic urticaria or angioedema. [7] This group of medications is associated with higher risk than antihistamines or H2 antagonists and leukotriene receptor antagonists. However, for those requiring corticosteroids, selecting one of these drugs may offer better side effect profile. Special safety monitoring is recommended for each individual medication.
Recalcitrant angioedema
Immunosuppressants such as calcineurin inhibitors (cyclosporine and tacrolimus), methotrexate, mycophenolate mofetil, cyclophosphamide, azathioprine, and sirolimus have been tried in treating antihistamine-resistant chronic urticaria or angioedema. Of these, cyclosporine has been most thoroughly studied in this setting. [62] Although clear benefit has been shown with cyclosporine, concerns for its side effects (which may outweigh the benefit) still pose a challenge for clinicians.
Intravenous immunoglobulin (IVIg) has also shown to be effective for some patients who are antihistamine-unresponsive. Evidence of its efficacy is limited to a few open-label case studies, and the appropriate dosage, dosing interval, and treatment duration have not been well established. At this time, IVIg use is limited to a carefully selected group of patients who do not have an adequate treatment response or do not tolerate alternative treatment.
Alpha/Beta-Adrenergic Agonists
Class Summary
Adrenergic agonist agents cause vasoconstriction and bronchodilation and reduce vascular permeability. They are vitally important in treating acute angioedema associated with an allergic reaction affecting the upper airways. Their benefit in other types of laryngeal edema (eg, acute hereditary angioedema [HAE]) is less certain.
Epinephrine (EpiPen, EpiPen Jr, Adyphren, Adrenaclick, EPIsnap, Adrenalin)
Use epinephrine in case of laryngeal edema. It has alpha-agonist effects that include increased peripheral vascular resistance and reduced vascular permeability.
Antihistamines, 1st-Generation
Class Summary
Antihistamines (H1 and H2) generally work well for urticaria. However, the great majority of angioedema cases, especially when not accompanied by urticaria, do not respond adequately to antihistamine treatment. In certain types of angioedema, such as hereditary angioedema (HAE), angiotensin-converting enzyme (ACE) inhibitor–acquired angioedema (AIIA), and acquired angioedema (AAE), antihistamines are ineffective and are not recommended for treatment.
The first-generation H1 antagonists (eg, diphenhydramine, hydroxyzine, doxepin, chlorpheniramine, and cyproheptadine) are inexpensive and effective in reducing pruritus, but drowsiness and anticholinergic effects can be troublesome. Because of the potential sedative effects, patients should be cautioned about driving and operating heavy machinery.
Diphenhydramine (Benadryl, Benadryl Dye-Free Allergy, PediaCare Children's Allergy, Pharbedryl, PediaCare Children's Allergy)
Diphenhydramine is used for the relief of symptoms caused by the release of histamine. It is the most commonly used first-generation antihistamine and is available without a prescription in the United States.
Chlorpheniramine (Chlor-Trimeton, Aller-Chlor, Pharbechlor, Allergy)
Chlorpheniramine is a first-generation agent. It competes with histamine for H1-receptor sites on effector cells in blood vessels and the respiratory tract. Chlorpheniramine is one of the safest antihistamines to use during pregnancy.
Cyproheptadine
Cyproheptadine is a first-generation agent. It is used for the symptomatic relief of allergic symptoms caused by histamine release. Cyproheptadine prevents histamine release in blood vessels and is more effective in preventing histamine response than in reversing it. It may be useful in patients with syndromes sustained by histamine-producing tumors.
Hydroxyzine hydrochloride (Vistaril)
Hydroxyzine hydrochloride antagonizes H1 receptors in the periphery. It may suppress histamine activity in the subcortical region of the central nervous system (CNS).
Antihistamines, 2nd Generation
Class Summary
The second-generation antihistamines have much lower sedative effects. Nevertheless, any patient who is taking a medication that has potential sedative effects should be cautioned about driving and operating heavy machinery.
Fexofenadine (Allegra Allergy, Mucinex Allergy)
Fexofenadine is a nonsedating second-generation antihistamine. It is tolerated very well, with a rate of sedation that does not differ significantly from that of placebo.
Cetirizine (Zyrtec Allergy, All Day Allergy)
Cetirizine selectively inhibits histamine H1 receptor sites in blood vessels and in the gastrointestinal (GI) and respiratory tracts, and this action, in turn, inhibits the physiologic effects that histamine normally induces at H1 receptor sites. The once-daily dosing is convenient. Bedtime dosing may be useful if sedation is a problem.
Desloratadine (Clarinex)
Desloratadine is a long-acting, tricyclic histamine antagonist that is selective for the H1 receptor. It is a major metabolite of loratadine, which, after ingestion, is extensively metabolized to the active metabolite 3-hydroxydesloratadine.
Loratadine (Claritin, Alavert, Loradamed, Allergy Relief, QlearQuil 24 Hour Relief, Triaminic Allerchews)
Loratadine selectively inhibits peripheral histamine H1 receptors. It is tolerated very well, with a rate of sedation that does not differ significantly from that of placebo. The once-daily dosing makes it convenient.
Levocetirizine (Xyzal)
Levocetirizine is an H1-receptor antagonist that is an active enantiomer of cetirizine. This agent is available as a 5-mg breakable (scored) tab and a 0.5 mg/mL oral solution.
Histamine H2 Antagonists
Class Summary
These drugs are usually used to decrease gastric acid secretion. When used as a single agent for urticaria and angioedema, they are not effective. However, the combination of an H1 antagonist with an H2 antagonist has been shown to be more effective than an H1 antagonist alone. Any of the H2 blockers can be used. Two of the most commonly used agents are ranitidine and cimetidine.
Cimetidine (Tagamet)
Cimetidine is a nonprescription antihistamine H2-receptor antagonist. Its use can increase the serum concentration of hydroxyzine but not of cetirizine. [73]
Ranitidine (Zantac, GoodSense Acid Reducer, Acid Reducer, Deprizine FusePaq)
Ranitidine is a nonprescription antihistamine H2-receptor antagonist. It has a better safety profile, a longer duration of action, and considerably (10 times) stronger H2-receptor binding than cimetidine does, and it does not suppress cytochrome P450 isoenzymes. Its clinical efficacy as add-on therapy to antihistamine in urticaria has not been conclusively determined. [74, 75, 76]
Leukotriene Receptor Antagonists
Class Summary
Leukotriene receptor antagonists may be used as add-on therapy for histamine-mediated angioedema with or without urticaria. A subset of patients, especially those with sensitivity to aspirin or nonsteroidal anti-inflammatory agents (NSAIDs) or food additive intolerance, may benefit more from this treatment; however, this is not supported by strong clinical evidence. [77]
Montelukast (Singulair)
Montelukast blocks binding of leukotriene D4 to its receptor. It is used off label to treat chronic urticaria.
Zafirlukast (Accolate)
Zafirlukast is a competitive receptor antagonist of leukotrienes C4, D4, and E4.
Tricyclic Antidepressants
Class Summary
Tricyclic antidepressants (TCAs) have potent H1 antihistamine activity that may be beneficial in treating angioedema.
Doxepin
Doxepin is a TCA that has potent H1-blocking activity.
Corticosteroids
Class Summary
Despite the paucity of well controlled clinical studies, the efficacy of corticosteroids in histamine-mediated angioedema and some forms of idiopathic angioedema (IAE) appears to be evident. However, because of their well-recognized side effects, long-term use of corticosteroids is generally not advisable.
The optimal dosage and duration of treatment are not well established. Most experts are in favor of their short-term use, preferably with the lowest effective dosage over a limited time period (eg, 15 mg/day, reduced by 1 mg weekly). Corticosteroids should only be used when other treatments cannot provide adequate clinical benefits or symptom control.{ [14]
Corticosteroids may be used when antihistamines are inadequate or ineffective at controlling an acute episode of angioedema. These agents usually reduce inflammation and reduce vascular permeability in allergic angioedema and in some cases of idiopathic angioedema. However, they usually have very limited or no benefit in ACE inhibitor ̶ induced angioedema (AIIA), hereditary angioedema (HAE), and acquired angioedema (AAE).
Corticosteroids can be given as a short course of an oral agent (administered daily for 5-7 days, with or without a taper) or as a single dose of a long-acting, injectable agent. Such regimens are not usually associated with long-term sequelae.
Long-term corticosteroid use should be avoided in chronic angioedema, when possible. If angioedema is severe and cannot be safely controlled with other medications, low-dose therapy and/or alternate-day therapy can be considered.
Prednisone (Deltasone, Rayos, Prednisone Intensol)
Prednisone, a commonly used oral agent, may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. To have an effect, it must be metabolized to the active metabolite prednisolone. Conversion may be impaired in liver disease.
Prednisolone (Pediapred, Prelone, Veripred 20, Millipred)
Prednisolone, available in tablet and liquid forms, reduces vascular permeability.
Methylprednisolone (Medrol, Depo-Medrol, Solu-Medrol, A-Methapred)
Methylprednisolone, available in intravenous (IV)/intramuscular (IM) and oral forms, reduces vascular permeability.
Androgens
Class Summary
Androgens are particularly useful in patients with HAE and perhaps in some patients with AAE. They are not useful in angioedema due to allergy or to drug sensitivity or intolerance. There is limited experience with these drugs in IAE. They may induce the synthesis of messenger ribonucleic acid (mRNA) in the liver and directly increase C1-INH.
Danazol
Danazol increases levels of C4 and C1-INH and reduces attacks associated with angioedema.
Oxandrolone (Oxandrin)
Oxandrolone is a synthetic androgen derivative with a pediatric indication. It is used primarily in HAE prophylaxis.
Antifibrinolytic Agents
Class Summary
The exact mechanism by which hemostatic agents act against angioedema is uncertain, but it is most likely related to the inhibition of plasmin, with subsequent effects on bradykinin metabolism. Hemostatic agents have shown benefit in treating HAE, AAE, and certain forms of IAE. They are not indicated in the treatment of allergic angioedema.
Aminocaproic acid (Amicar)
Aminocaproic acid inhibits fibrinolysis through inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. It may be used in HAE and AAE as prophylaxis and to relieve acute attacks. The clinical benefit is marginal.
Tranexamic acid (Cyklokapron, Lysteda)
Tranexamic acid is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin. In Europe, it is used primarily for HAE prophylaxis, though some authors believe that it is also helpful for treating acute HAE attacks.
Immunomodulators
Class Summary
Immunomodulating agents are used for treating acute HAE attacks and as routine prophylaxis against HAE attacks.
Ecallantide (Kalbitor)
Ecallantide is a potent, selective, reversible inhibitor of plasma kallikrein. It treats acute, episodic attacks of HAE by binding to plasma kallikrein and blocking its binding site, thus inhibiting the conversion of high-molecular-weight kininogen to bradykinin.
Icatibant (Firazyr)
Icatibant inhibits the binding of bradykinin to the B2 receptor and thereby treats the clinical symptoms of an acute attack of angioedema. The recommended dose is 30 mg subcutaneously in the abdominal area. The drug is available in a single-use prefilled syringe, which delivers a dose of 30 mg (10 mg/mL). Syringes can be carried and stored at room temperature, and the medication can be self-injected by the patient.
C1 inhibitor, human (Cinryze, Berinert, Haegarda)
C1-INH is a serine protease inhibitor (serpin) and a normal constituent of human blood that regulates activation of the complement pathway, the intrinsic coagulation system, and the fibrinolytic system. It binds to and neutralizes substrates that activate these systems, suppressing conversion of tissue high- molecular-weight kininogen to bradykinin and thereby reducing bradykinin-mediated angioedema. Pharmacologic preparations of C1-INH are pasteurized, lyophilized products derived from purified human plasma.
Cinryze is approved by the US Food and Drug Administration (FDA) for prophylaxis of HAE attacks in adolescents and adults. It is available as a freeze-dried powder that is reconstituted for IV administration. Haegarda is indicated for routine prophylaxis in adults and adolescents and is administered as a twice weekly SC injection. Berinert is indicated for the treatment of acute laryngeal, abdominal, and facial angioedema attacks in children and adults with HAE. It is approved for patient self-administration after proper training by a healthcare professional.
C1 esterase inhibitor recombinant (Ruconest)
Recombinant C1 esterase inhibitor is from the milk of genetically modified (transgenic) rabbits. It restores the level of functional C1 esterase inhibitor in a patient's plasma, thereby treating the acute attack of swelling. It is indicated for adolescents and adults to treat acute attacks of hereditary angioedema (HAE). Efficacy for treatment of laryngeal attack was not established.
Monoclonal Antibodies, Anti-asthmatics
Class Summary
Monoclonal anti-IgE antibodies may greatly improve the severity of angioedema in patients recalcitrant to standard doses of H1 antihistamines.
Omalizumab (Xolair)
Omalizumab has been reported to be an effective treatment option for patients with angioedema who are unresponsive to high doses of antihistamine treatment. It binds to free IgE and thereby prevents IgE from binding to mast cells and basophils. As the binding of IgE decreases, the activation and release of mediators in an allergic response is minimized.
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Photographic documentation of swelling.
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Bradykinin production and metabolism.
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Classification of angioedema without urticaria based on clinical or etiopathologic features. AAE = acquired angioedema; ACEI = angiotensin-converting enzyme inhibitors; HAE = hereditary angioedema; Specific triggers = food, drug, insect bite, environmental allergen, or other physical stimulus. Based on data from Zingale LC, Beltrami L, Zanichelli A, et al. Angioedema without urticaria: a large clinical survey. CMAJ. Oct 24 2006; 175(9): 1065–70.
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Angioedema secondary to angiotensin-converting enzyme (ACE) inhibitors.
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Types of angioedema.
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Pathways for production of prostaglandins and leukotrine from mobilized arachidonic acid.
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Medication
- Medication Summary
- Alpha/Beta-Adrenergic Agonists
- Antihistamines, 1st-Generation
- Antihistamines, 2nd Generation
- Histamine H2 Antagonists
- Leukotriene Receptor Antagonists
- Tricyclic Antidepressants
- Corticosteroids
- Androgens
- Antifibrinolytic Agents
- Immunomodulators
- Monoclonal Antibodies, Anti-asthmatics
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