Medication Summary
The primary goal of medical treatment for angioedema is to reduce and prevent swelling. To reduce discomfort and complication are equally important. Most medicine used in treating urticaria and anaphylaxis is also used in the management of many types of angioedema.
In histamine-mediated angioedema, antihistamines are often used as the first-line treatment. Corticosteroids can be used in severe cases of this form of the disease. (Outpatient treatment should avoid long-term corticosteroid use.)
Antihistamines do not work for patients with bradykinin-mediated angioedema, and cortical steroids have limited or no value. Agents used in the treatment of this form of edema include fresh frozen plasma, antifibrinolytics, C1-INH, ecallantide, and icatibant.
Adrenergic Agonist Agents
Class Summary
These 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, Adrenalin, Twinject)
Use epinephrine in case of laryngeal edema. It has alpha-agonist effects that include increased peripheral vascular resistance and reduced vascular permeability.
Antihistamines
Class Summary
Antihistamines (H1 and H2) generally work well for urticaria. However, the great majority of angioedema, especially when not accompanied by urticaria, does not respond adequately to antihistamine. In certain cases, such as hereditary angioedema (HAE), 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, cyproheptadine) are inexpensive and effective in reducing pruritus, but drowsiness and anticholinergic effects can be troublesome. The second-generation antihistamines (loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine) have much lower sedative effects. Any patient who is taking a medication that has potential sedative effects should be cautioned about driving and operating heavy machinery.
Fexofenadine (Allegra)
Fexofenadine is a nonsedating, second-generation antihistamine. It is tolerated very well, with a rate of sedation that is not significantly different from placebo.
Cetirizine (Zyrtec)
Cetirizine selectively inhibits histamine H1 receptor sites in blood vessels and in the GI and respiratory tracts, which in turn inhibits 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.
Diphenhydramine (Benadryl, Aler-Dryl, Anti-Hist)
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..
Hydroxyzine hydrochloride (Vistaril)
This agent antagonizes H1 receptors in the periphery. It may suppress histamine activity in the subcortical region of the central nervous system (CNS).
Loratadine (Claritin, Alavert, Loradamed)
Loratadine selectively inhibits peripheral histamine H1 receptors. It is tolerated very well, with a rate of sedation that is not significantly different from that of placebo. The once-daily dosing makes it convenient.
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 active metabolite 3-hydroxydesloratadine.
Levocetirizine (Xyzal)
Levocetirizine is an H1-receptor antagonist. It is a second generation, prescription antihistamine and is an active enantiomer of cetirizine. Levocetirizine is available as a 5-mg breakable (scored) tab and a 0.5 mg/mL oral solution.
Chlorpheniramine (Ahist, Aller-Chlor, Chlor-Trimeton, Chlor Hist)
Chlorpheniramine is a first-generation agent. It competes with histamine or 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.
Antihistamines 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.
Ranitidine (Zantac)
Ranitidine is a nonprescription antihistamine H2-receptor antagonist.
Cimetidine (Tagamet)
Cimetidine is a nonprescription antihistamine H2-receptor antagonist.
Tricyclic Antidepressants
Class Summary
These are agents with H1 antihistamine activity that may be beneficial.
Doxepin
Doxepin is a tricyclic antidepressant that has potent H1-blocking activity.
Corticosteroids
Class Summary
In some instances of acute or chronic angioedema, especially when antihistamines do not help or are not able to adequately control swelling, corticosteroids are used. This usually works well for allergic or certain idiopathic angioedema. However, in ACE inhibitor ̶ induced angioedema (AIIA), hereditary angioedema (HAE), and acquired angioedema (AAE), corticosteroids most of the time have very limited benefit or are not effective.
Corticosteroids may help to reduce inflammation and reduce vascular permeability. A short course of an oral corticosteroid (administered daily for 5-7 d, with or without a taper) or a single dose of a long-acting, injectable steroid is not usually associated with long-term sequelae and can be helpful when used for an acute episode of angioedema that is nonresponsive to antihistamines.
Because of adverse effects of chronic or recurrent use of systemic corticosteroids, the long-term use of these agents 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.
A large number of preparations are available. Representative examples are prednisone, prednisolone, methylprednisolone, and triamcinolone.
Prednisone
Prednisone, a commonly used oral agent, may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It must be metabolized to the active metabolite prednisolone for it to have an effect. Conversion may be impaired in liver disease.
Methylprednisolone (Solu-Medrol, Depo-Medrol, A-Methapred)
Methylprednisolone, available in IV/IM and oral form, reduces vascular permeability.
Prednisolone (Pediapred, Prelone, Orapred, Millipred)
Prednisolone, available in tablet and liquid forms, reduces vascular permeability.
Androgen Derivatives
Class Summary
These agents are particularly useful in patients with hereditary angioedema (HAE) and perhaps in some patients with AAE. They are not useful in angioedema due to allergic reaction or drug sensitivity/intolerance. There is limited experience with these drugs in idiopathic angioedema. 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 pediatric indication. It is used primarily in HAE prophylaxis.
Hemostatic Agents
Class Summary
The exact mechanism of action of these agents in the treatment of angioedema is uncertain, but most likely it is related to the inhibition of plasmin and subsequently affects bradykinin metabolism. Hemostatic agents have shown benefit in treating hereditary angioedema (HAE), acquired angioedema (AAE), and certain idiopathic angioedemas. They are not indicated in the treatment of allergic angioedema.
Aminocaproic acid (Amicar)
Aminocaproic acid inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. It may be used in hereditary angioedema (HAE) and acquired angioedema (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.
Serine Proteinase Inhibitors (serpins)
Class Summary
These agents are used for treating acute hereditary angioedema (HAE) attacks and as routine prophylaxis against HAE attacks.
C1 inhibitor, human (Cinryze, Berinert)
C1-INH is serine protease inhibitors (serpins) and a normal constituent of human blood that regulates activation of the complement pathway, intrinsic coagulation system, and fibrinolytic system.. It binds to and neutralizes substrates that activate these systems, thereby suppressing activity. It suppresses the conversion of tissue high ̶ molecular weight kininogen to bradykinin, therefore reducing bradykinin-mediated angioedema. In the United States, Cinryze is currently approved for prophylaxis of HAE attacks. Berinert is available as a pasteurized, lyophilized preparation derived from purified human plasma. One unit corresponds to the mean quantity of C1 INH present in 1 mL of normal, fresh plasma.[44] Berinert is indicated for acute laryngeal, abdominal, and facial angioedema attacks in adolescents and adults with HAE.
Kallikrein Inhibitors
Class Summary
This agent elicits specific activity that results in bradykinin reduction. It is useful for treating acute, episodic attacks.
Ecallantide (Kalbitor)
Ecallantide is a potent, selective, reversible inhibitor of plasma kallikrein. It treats acute, episodic attacks of hereditary angioedema (HAE) by binding to plasma kallikrein and blocking its binding site, in this way inhibiting the conversion of high ̶ molecular weight kininogen to bradykinin.
Bradykinin Receptor Antagonists
Class Summary
Bradykinin receptor antagonists such as icatibant inhibit bradykinin from binding the B2 receptor and thereby treat the clinical symptoms of an acute attack. Recommended dose of icatibant is 30 mg SC in the abdominal area. It is available as a single-use, prefilled syringe, which delivers a dose of 30 mg (10 mg/mL).
Icatibant (Firazyr)
Icatibant is a bradykinin B2 receptor antagonist indicated for acute attacks of hereditary angioedema (HAE).
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