Angioedema

Introduction

Background

Many types of angioedema are described in the literature: hereditary angioedema (HAE) types I, II, and III; acquired angioedema; drug-induced angioedema (associated with angiotensin-converting enzyme [ACE] inhibitors and angiotensin II receptor blockers [ARBs]); urticaria-associated angioedema; and idiopathic angioedema. Most forms of angioedema are considered idiopathic. In general, angioedema can be categorized as with urticaria or without urticaria. Urticaria and angioedema are similar in pathogenesis; however, angioedema manifests deeper in mucosal tissue. The reaction is mast cell mediated when both are evident during clinical presentation. In this case, the patient describes subjective pruritus, often associated with hypersensitivity to an offending agent.

Ten percent of angioedema cases occur without urticaria and is considered to be kinin-mediated rather than a hypersensitivity reaction. Hereditary angioedema and acquired angioedema are associated with insufficient or dysfunctional C1 esterase inhibitor, resulting in increased circulation of vasoactive substances. This type of angioedema can be induced spontaneously, or it can be due to stress or medications; this type is highly associated with ACE inhibitors.

In general, angioedema is described as deep, subcutaneous, submucosal edema due to increased vascular permeability. It can manifest as an episodic or self-limiting event but can often be described as recurrent. Acute episodes may involve the skin, larynx, and buccal and gastrointestinal (GI) mucosa.

Pathophysiology

Angioedema without urticaria can be classified as hereditary angioedema (HAE) or acquired C1 inhibitory deficiency (AAE/ACID). Hereditary angioedema results from a quantitative or qualitative deficiency of the C1 esterase inhibitor (C1-INH) due to a defective C1NH gene.³ Type I is described as C1 esterase inhibitor deficiency. Type II is believed to be a dysfunction of C1 esterase inhibitor with normal-to-high circulating levels of the molecule. These two forms are not distinguishable clinically.

An additional type III HAE, occurring only in females, has also been described. In this case, there is also an abnormal functioning protein. Abdominal attacks are seen less frequently in this variant. Orofacial involvement seems to be the most common presentation of the type III sensitivity, making it very difficult to distinguish from types I and II. This type has also been associated with exogenous estrogen administration and pregnancy.

C1 esterase is a serine protease that is involved in the regulation of bradykinin, a potent vasoactive substance. Low levels of this protease results in the activation of the kallikrein-kinin system, the complement cascade, and the fibrinolytic system and results in the release of vasoactive peptides such as bradykinin, considered to be the most important regulatory complement involved in many molecular cascades.Release of vasoactive substances causes vasodilatation of endothelial cells as well as smooth muscle bowel contraction. This ultimately manifests in the common clinical presentation of the disease.

In the setting of hereditary angioedema, AAE, and ACE inhibitor – induced angioedema, bradykinin levels are directly elevated in the blood. ACE is naturally one of the inhibitors of bradykinin. With ACE inhibition, bradykinin levels are increased.

Acquired angioedema (ACID) is classified as type I or type II. It is a result of autoantibodies that act on the protease, thus increasing consumption of C1-INH. Clinically, it presents like hereditary angioedema.

The type I variant of acquired angioedema is associated with B-cell proliferative disorders. In this disease, there is hypercatabolization of C1-INH. Immunocomplexes are formed between antibodies and abnormal immunoglobulins on the cell surface of B cells. The complement cascade hyperreacts, producing large amounts of C1. C1-INH is then consumed on attempts to prevent the activation of the continuously activated C1. The relative deficiency of C1 inhibitor causes increased activation of the kallikrein-kinin system.Enzymatic cleavage by kallikrein is increased with consumption of kininogen and subsequently the production of bradykinin increases. The end result of this intricate molecular cascade is vasodilatation meditated by the interaction of kinins with endothelial cell receptors, B1R and B2R.

The type II variant of acquired angioedema is associated with autoantibodies (immunoglobulin G [IgG] and less often immunoglobulin M [IgM]) directed against the C1-INH molecule.Depletion of C1-INH results in the production of large amounts of bradykinin and other vasoactive substances, which causes the signs and symptoms of angioedema.

Angioedema associated with urticaria is a hypersensitivity to an offending agent. Histamine is released into the bloodstream, resulting in an increase in endothelial cell permeability. Angioedema, generalized urticaria, and, in severe cases, anaphylaxis will occur. The allergen binds to the mast cell, causing degranulation and histamine and tryptase release. Degranulations of mast cells have also been shown to be a direct result of anesthetics, contrast mediums, and opiates.

Autoantibodies against the mast cell IgE receptor or mast cell-bound IgE (or basophils) is another common cause of histamine release. Additionally, proteases may activate the complement cascade associated with c3a, c4a, and c5a, which are considered anaphylactoids, and result in increased capillary permeability and extravasation of fluid.⁷

Frequency

United States

Eighty-five percent of patients who experience angioedema not associated with urticaria have type I HAE. Approximately 1 out of 10,000 patients have recurrent angioedema classified as type I. Type II HAE occurs in 1 out of 50,000 people. Angioedema induced by ACE inhibitors occurs at a frequency of 0.1-0.7%.

Mortality/Morbidity

Morbidity and mortality are directly related to the severity of airway obstruction. Asphyxiation due to laryngeal edema yields a 3-40% mortality rate.

Race

No specific racial predilection exists for angioedema.

Sex

Women tend to have more occurrences of angioedema than men.

Age

Persons who are predisposed to angioedema have an increase in frequency of attacks after adolescence, with the peak incidence occurring in the third decade of life.

Clinical

History

• Hereditary angioedema (HAE), idiopathic angioedema, and drug-induced angioedema^1,2
  • Episodes consist of relapsing, self-limiting edema. All edema episodes are self-limiting, last for 1-7 days and are followed by a disease-free interval.
  • Edema may occur in the subcutaneous tissue, wall of the intestine, and larynx.
  • Abdominal pain attacks may present with or without nausea, vomiting, and ascites.
  • Skin swelling most frequently affects the lips, face, hands, feet, and genitalia.
  • Urticaria is generally not a clinical symptom.
  • Rare symptoms include episodes of tongue edema and swelling of the soft palate.
  • Local trauma (eg, dental procedure, tonsillectomy) or stress may be present in the patient's history.
  • The frequency and severity of the clinical symptoms are highly variable from patient to patient and even in the same patient with recurrent episodes.
  • The patient's history may include use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), or nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Most of these edema episodes occur spontaneously without a recognizable external trigger.
• Urticaria-associated edema
  • Urticarial eruptions usually appear at intervals and are intensely pruritic.
  • Patients with angioedema or urticaria should be questioned in detail to identify the offending antigen (in cases of allergic angioedema).
  • History of atopy such as allergic rhinitis, asthma, and aspirin allergy should be sought, as these increase the risk of hypersensitivities.
  • Drugs associated with urticaria and angioedema include the following:
    • Radiocontrast agents
    • Opiates
    • Dextran
    • Aspirin
    • Nonsteroidal anti-inflammatory drugs
  • Common sources of antigens that cause urticaria and angioedema include the following:
    • Hymenoptera envenomations
    • Food allergies such as fresh berries, shellfish, fish, nuts, tomatoes, eggs, milk, chocolate, food additives, and preservatives, and exposure to water, sunlight, cold, or heat
    • Animal dander (from scales of shed skin)
  • Chronic urticaria (increasingly associated with Helicobacter pylori bacteria)

Physical

• General examination
  • Patients usually present with acute onset of well-demarcated cutaneous edema of distensible tissues (eg, lips, eyes, earlobes, tongue, uvula).
  • The face, extremities, and genitalia are most commonly affected.
• Airway assessment
  • First, determine airway patency.
  • Severe attacks can herald the onset of systemic anaphylaxis, characterized initially by dyspnea.
• Gastrointestinal (GI): Massive edema of the subcutaneous tissue in the abdominal region may present with abdominal distention and signs consistent with bowel obstruction.

Causes

• Mast cell–mediated angioedema/urticaria : This type of angioedema may be associated with antigen (allergy), food, drug, animal bites, stings (ie, Hymenoptera), preservatives, or food coloring. Note: Food coloring and preservatives may cause angioedema with or without urticaria.
• Hereditary angioedema
  • Hereditary angioedema (HAE) has an autosomal dominant pattern.
  • Types I and II are characterized by C1 esterase deficiency. The gene encoding for C1-INH is located in chromosome band 11q13.1.
  • Approximately 20–25% of cases are the result of spontaneous mutations without a family history of disease. In this disease, the gene is either nonfunctional and thus C1 esterase is not transcribed in adequate quantities, as in type I, or there is synthesis of normal quantities of an abnormally functioning C1-INH protein, as in type II.
  • Type III is characterized by C1 esterase dysfunction. Symptoms occur during the first 2 decades of life.
• Acquired angioedema
  • This type of angioedema usually occurs in the fourth decade of life.
  • Acquired angioedema is often associated with autoimmune diseases and lymphoproliferative disorders.
• Drug-induced angioedema
  • ACE inhibitors precipitate attacks by directly interfering with the degradation of bradykinin, thereby potentiating its biological effect.
  • Other drugs may precipitate attacks by effects on arachidonic acid metabolism (eg, aspirin, NSAIDs, ARBs, opiates, antibiotic, any compound that is a cyclooxygenase inhibitor).
• Physically induced angioedem
  • Physical agents, such as cold, heat pressure, vibration, and ultraviolet radiation, can cause angioedema. This manifestation may occur with or without urticaria.
  • Cold-induced angioedema and urticaria have been reported in association with cryoglobulins, cold agglutinin disease, cryofibrinogenemia, and paroxysmal cold hemoglobinuria.
• Idiopathic angioedema: Most commonly, the cause is idiopathic.

Angioedema

Introduction

Background

Many types of angioedema are described in the literature: hereditary angioedema (HAE) types I, II, and III; acquired angioedema; drug-induced angioedema (associated with angiotensin-converting enzyme [ACE] inhibitors and angiotensin II receptor blockers [ARBs]); urticaria-associated angioedema; and idiopathic angioedema. Most forms of angioedema are considered idiopathic. In general, angioedema can be categorized as with urticaria or without urticaria. Urticaria and angioedema are similar in pathogenesis; however, angioedema manifests deeper in mucosal tissue. The reaction is mast cell mediated when both are evident during clinical presentation. In this case, the patient describes subjective pruritus, often associated with hypersensitivity to an offending agent.

Ten percent of angioedema cases occur without urticaria and is considered to be kinin-mediated rather than a hypersensitivity reaction. Hereditary angioedema and acquired angioedema are associated with insufficient or dysfunctional C1 esterase inhibitor, resulting in increased circulation of vasoactive substances. This type of angioedema can be induced spontaneously, or it can be due to stress or medications; this type is highly associated with ACE inhibitors.

In general, angioedema is described as deep, subcutaneous, submucosal edema due to increased vascular permeability. It can manifest as an episodic or self-limiting event but can often be described as recurrent. Acute episodes may involve the skin, larynx, and buccal and gastrointestinal (GI) mucosa.

Pathophysiology

Angioedema without urticaria can be classified as hereditary angioedema (HAE) or acquired C1 inhibitory deficiency (AAE/ACID). Hereditary angioedema results from a quantitative or qualitative deficiency of the C1 esterase inhibitor (C1-INH) due to a defective C1NH gene.³ Type I is described as C1 esterase inhibitor deficiency. Type II is believed to be a dysfunction of C1 esterase inhibitor with normal-to-high circulating levels of the molecule. These two forms are not distinguishable clinically.

An additional type III HAE, occurring only in females, has also been described. In this case, there is also an abnormal functioning protein. Abdominal attacks are seen less frequently in this variant. Orofacial involvement seems to be the most common presentation of the type III sensitivity, making it very difficult to distinguish from types I and II. This type has also been associated with exogenous estrogen administration and pregnancy.

C1 esterase is a serine protease that is involved in the regulation of bradykinin, a potent vasoactive substance. Low levels of this protease results in the activation of the kallikrein-kinin system, the complement cascade, and the fibrinolytic system and results in the release of vasoactive peptides such as bradykinin, considered to be the most important regulatory complement involved in many molecular cascades.Release of vasoactive substances causes vasodilatation of endothelial cells as well as smooth muscle bowel contraction. This ultimately manifests in the common clinical presentation of the disease.

In the setting of hereditary angioedema, AAE, and ACE inhibitor – induced angioedema, bradykinin levels are directly elevated in the blood. ACE is naturally one of the inhibitors of bradykinin. With ACE inhibition, bradykinin levels are increased.

Acquired angioedema (ACID) is classified as type I or type II. It is a result of autoantibodies that act on the protease, thus increasing consumption of C1-INH. Clinically, it presents like hereditary angioedema.

The type I variant of acquired angioedema is associated with B-cell proliferative disorders. In this disease, there is hypercatabolization of C1-INH. Immunocomplexes are formed between antibodies and abnormal immunoglobulins on the cell surface of B cells. The complement cascade hyperreacts, producing large amounts of C1. C1-INH is then consumed on attempts to prevent the activation of the continuously activated C1. The relative deficiency of C1 inhibitor causes increased activation of the kallikrein-kinin system.Enzymatic cleavage by kallikrein is increased with consumption of kininogen and subsequently the production of bradykinin increases. The end result of this intricate molecular cascade is vasodilatation meditated by the interaction of kinins with endothelial cell receptors, B1R and B2R.

The type II variant of acquired angioedema is associated with autoantibodies (immunoglobulin G [IgG] and less often immunoglobulin M [IgM]) directed against the C1-INH molecule.Depletion of C1-INH results in the production of large amounts of bradykinin and other vasoactive substances, which causes the signs and symptoms of angioedema.

Angioedema associated with urticaria is a hypersensitivity to an offending agent. Histamine is released into the bloodstream, resulting in an increase in endothelial cell permeability. Angioedema, generalized urticaria, and, in severe cases, anaphylaxis will occur. The allergen binds to the mast cell, causing degranulation and histamine and tryptase release. Degranulations of mast cells have also been shown to be a direct result of anesthetics, contrast mediums, and opiates.

Autoantibodies against the mast cell IgE receptor or mast cell-bound IgE (or basophils) is another common cause of histamine release. Additionally, proteases may activate the complement cascade associated with c3a, c4a, and c5a, which are considered anaphylactoids, and result in increased capillary permeability and extravasation of fluid.⁷

Frequency

United States

Eighty-five percent of patients who experience angioedema not associated with urticaria have type I HAE. Approximately 1 out of 10,000 patients have recurrent angioedema classified as type I. Type II HAE occurs in 1 out of 50,000 people. Angioedema induced by ACE inhibitors occurs at a frequency of 0.1-0.7%.

Mortality/Morbidity

Morbidity and mortality are directly related to the severity of airway obstruction. Asphyxiation due to laryngeal edema yields a 3-40% mortality rate.

Race

No specific racial predilection exists for angioedema.

Sex

Women tend to have more occurrences of angioedema than men.

Age

Persons who are predisposed to angioedema have an increase in frequency of attacks after adolescence, with the peak incidence occurring in the third decade of life.

Clinical

History

• Hereditary angioedema (HAE), idiopathic angioedema, and drug-induced angioedema^1,2
  • Episodes consist of relapsing, self-limiting edema. All edema episodes are self-limiting, last for 1-7 days and are followed by a disease-free interval.
  • Edema may occur in the subcutaneous tissue, wall of the intestine, and larynx.
  • Abdominal pain attacks may present with or without nausea, vomiting, and ascites.
  • Skin swelling most frequently affects the lips, face, hands, feet, and genitalia.
  • Urticaria is generally not a clinical symptom.
  • Rare symptoms include episodes of tongue edema and swelling of the soft palate.
  • Local trauma (eg, dental procedure, tonsillectomy) or stress may be present in the patient's history.
  • The frequency and severity of the clinical symptoms are highly variable from patient to patient and even in the same patient with recurrent episodes.
  • The patient's history may include use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), or nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Most of these edema episodes occur spontaneously without a recognizable external trigger.
• Urticaria-associated edema
  • Urticarial eruptions usually appear at intervals and are intensely pruritic.
  • Patients with angioedema or urticaria should be questioned in detail to identify the offending antigen (in cases of allergic angioedema).
  • History of atopy such as allergic rhinitis, asthma, and aspirin allergy should be sought, as these increase the risk of hypersensitivities.
  • Drugs associated with urticaria and angioedema include the following:
    • Radiocontrast agents
    • Opiates
    • Dextran
    • Aspirin
    • Nonsteroidal anti-inflammatory drugs
  • Common sources of antigens that cause urticaria and angioedema include the following:
    • Hymenoptera envenomations
    • Food allergies such as fresh berries, shellfish, fish, nuts, tomatoes, eggs, milk, chocolate, food additives, and preservatives, and exposure to water, sunlight, cold, or heat
    • Animal dander (from scales of shed skin)
  • Chronic urticaria (increasingly associated with Helicobacter pylori bacteria)

Physical

• General examination
  • Patients usually present with acute onset of well-demarcated cutaneous edema of distensible tissues (eg, lips, eyes, earlobes, tongue, uvula).
  • The face, extremities, and genitalia are most commonly affected.
• Airway assessment
  • First, determine airway patency.
  • Severe attacks can herald the onset of systemic anaphylaxis, characterized initially by dyspnea.
• Gastrointestinal (GI): Massive edema of the subcutaneous tissue in the abdominal region may present with abdominal distention and signs consistent with bowel obstruction.

Causes

• Mast cell–mediated angioedema/urticaria : This type of angioedema may be associated with antigen (allergy), food, drug, animal bites, stings (ie, Hymenoptera), preservatives, or food coloring. Note: Food coloring and preservatives may cause angioedema with or without urticaria.
• Hereditary angioedema
  • Hereditary angioedema (HAE) has an autosomal dominant pattern.
  • Types I and II are characterized by C1 esterase deficiency. The gene encoding for C1-INH is located in chromosome band 11q13.1.
  • Approximately 20–25% of cases are the result of spontaneous mutations without a family history of disease. In this disease, the gene is either nonfunctional and thus C1 esterase is not transcribed in adequate quantities, as in type I, or there is synthesis of normal quantities of an abnormally functioning C1-INH protein, as in type II.
  • Type III is characterized by C1 esterase dysfunction. Symptoms occur during the first 2 decades of life.
• Acquired angioedema
  • This type of angioedema usually occurs in the fourth decade of life.
  • Acquired angioedema is often associated with autoimmune diseases and lymphoproliferative disorders.
• Drug-induced angioedema
  • ACE inhibitors precipitate attacks by directly interfering with the degradation of bradykinin, thereby potentiating its biological effect.
  • Other drugs may precipitate attacks by effects on arachidonic acid metabolism (eg, aspirin, NSAIDs, ARBs, opiates, antibiotic, any compound that is a cyclooxygenase inhibitor).
• Physically induced angioedem
  • Physical agents, such as cold, heat pressure, vibration, and ultraviolet radiation, can cause angioedema. This manifestation may occur with or without urticaria.
  • Cold-induced angioedema and urticaria have been reported in association with cryoglobulins, cold agglutinin disease, cryofibrinogenemia, and paroxysmal cold hemoglobinuria.
• Idiopathic angioedema: Most commonly, the cause is idiopathic.

Anaphylaxis

Introduction

Background

Anaphylaxis is a severe allergic reaction that is rapid in onset and may cause death. There are usually prominent dermal and systemic signs and symptoms. The full-blown syndrome includes urticaria (hives) and/or angioedema with hypotension and bronchospasm. The classic form, described in 1902, involves prior sensitization to an allergen with later re-exposure, producing symptoms via an immunologic mechanism. An anaphylactoid reaction produces a very similar clinical syndrome but is not immune-mediated. Treatment for both conditions is similar, and this article uses the term anaphylaxis to refer to both conditions unless otherwise specified. A recent consensus report reviewed the definition and management of anaphylaxis.

Pathophysiology

Rapid onset of increased secretion from mucous membranes, increased bronchial smooth muscle tone, decreased vascular smooth muscle tone, and increased capillary permeability occur after exposure to an inciting substance. These effects are produced by the release of mediators, which include histamine, leukotriene C4, prostaglandin D2, and tryptase.

In the classic form, mediator release occurs when the antigen (allergen) binds to antigen-specific immunoglobulin E (IgE) attached to previously sensitized basophils and mast cells. The mediators are released almost immediately when the antigen binds. In an anaphylactoid reaction, exposure to an inciting substance causes direct release of mediators, a process that is not mediated by IgE. Increased mucous secretion and increased bronchial smooth muscle tone, as well as airway edema, contribute to the respiratory symptoms observed in anaphylaxis. Cardiovascular effects result from decreased vascular tone and capillary leakage. Histamine release in skin causes urticarial skin lesions.

The most common inciting agents in anaphylaxis are parenteral antibiotics (especially penicillins), IV contrast materials, Hymenoptera stings, and certain foods (most notably, peanuts). Oral medications and many other types of exposures also have been implicated. Anaphylaxis also may be idiopathic.

Frequency

United States

The true incidence of anaphylaxis is unknown, partly because of the lack of a precise definition of the syndrome. Some clinicians reserve the term for the full-blown syndrome, while others use it to describe milder cases. Fatal anaphylaxis is relatively rare; milder forms occur much more frequently. The frequency of anaphylaxis is increasing, and this has been attributed to the increased number of potential allergens to which people are exposed. Up to 500-1000 fatal cases of anaphylaxis per year are estimated to occur in the United States. A recent review concluded that the lifetime prevalence of anaphylaxis is 1-2% of the population as a whole.

The incidence of anaphylaxis appears to be increasing, especially cases in children attributed to food allergy.

International

Reactions to insects and other venomous plants and animals are more prevalent in tropical areas because of the greater biodiversity in these areas.

Exposure and therefore reactions to medications are more common in industrialized areas.

Mortality/Morbidity

Approximately 1 in 5000 exposures to a parenteral dose of a penicillin or cephalosporin antibiotic causes anaphylaxis. More than 100 deaths per year are reported in the United States. Fewer than 100 fatal reactions to Hymenoptera stings are reported each year in the United States but this is considered to be an underestimate. One to 2% of people receiving IV radiocontrast experience some sort of reaction. The majority of these reactions are minor, and fatalities are rare. Low molecular weight contrast causes fewer and less severe reactions.

Race

Well-described racial differences in the incidence or severity of anaphylaxis do not exist. Cultural and socioeconomic differences may influence exposure rates.

Sex

Differences have been reported in the incidence and prevalence of anaphylactic reactions between men and women. Overall, women have a higher incidence of anaphylaxis than men, but, in some series of children, males predominate.

Age

Anaphylaxis occurs in all age groups. Food allergies are more common in the young, whereas more drug reactions occur in adults, possibly due to greater exposure. Although prior exposure is essential for the development of true anaphylaxis, reactions occur even when no documented prior exposure exists. Thus, patients may react to a first exposure to an antibiotic or insect sting. Elderly persons have the greatest risk of mortality from anaphylaxis due to the presence of preexisting disease.

Clinical

History

• Anaphylactic reactions almost always involve the skin or mucous membranes. More than 90% of patients have some combination of urticaria, erythema, pruritus, or angioedema.
• The upper respiratory tract commonly is involved, with complaints of nasal congestion, sneezing, or coryza. Cough, hoarseness, or a sensation of tightness in the throat may presage significant airway obstruction.
• Eyes may itch and tearing may be noted. Conjunctival injection may occur.
• Dyspnea is present when patients have bronchospasm or upper airway edema. Hypoxia and hypotension may cause weakness, dizziness, or syncope. Chest pain may occur due to bronchospasm or myocardial ischemia (secondary to hypotension and hypoxia).
• GI symptoms of cramplike abdominal pain with nausea, vomiting, or diarrhea also occur but are less common, except in the case of food allergy.
• In a classic case of anaphylaxis, the patient or a bystander provides a history of possible exposures that may have caused the rapid onset of skin and other manifestations. This history often is partial; exposure may not be recalled, or it may not be considered significant by the patient or health care provider. For example, when queried about medications, a patient may not mention over-the-counter (OTC) products. The clinician may not realize that, while reactions are usually rapid in onset, they also may be delayed.
• For reasons that are not well understood, a lack of dermal findings is more common in children than in adults.

Physical

• General
  • Physical examination of patients with anaphylaxis depends on affected organ systems and severity of attack. Vital signs may be normal or significantly disordered with tachypnea, tachycardia, and/or hypotension.
  • Place emphasis on determining the patient's respiratory and cardiovascular status.
  • Frank cardiovascular collapse or respiratory arrest may occur in severe cases. Anxiety is common unless hypotension or hypoxia causes obtundation. Shock may occur without prominent skin manifestations or history of exposure; therefore, anaphylaxis is part of the differential diagnosis for patients who present with shock and no obvious cause.
  • General appearance and vital signs vary according to severity of attack and affected organ system(s). Patients commonly are restless due to severe pruritus from urticaria. Anxiety, tremor, and a sensation of cold may result from compensatory endogenous catecholamine release. Severe air hunger may occur when the respiratory tract is involved. If hypoperfusion or hypoxia occurs, the patient may exhibit a depressed level of consciousness or may be agitated and/or combative. Tachycardia usually is present, but bradycardia may occur in very severe reactions.
• Skin
  • The classic skin manifestation is urticaria (ie, hives). Lesions are red and raised, and they sometimes have central blanching. Intense pruritus occurs with the lesions. Lesion borders usually are irregular and sizes vary markedly. Only a few small or large lesions may become confluent, forming giant urticaria. At times, the entire dermis is involved with diffuse erythema and edema. Hives can occur anywhere on the skin.
  • In a local reaction, lesions occur near the site of a cutaneous exposure (eg, insect bite). The involved area is erythematous, edematous, and pruritic. If only local skin reaction (as opposed to generalized urticaria) is present, systemic manifestations (eg, respiratory distress) are less likely. Local reactions, even if severe, are not predictive of systemic anaphylaxis on reexposure.
  • Lesions typical of angioedema also may manifest in anaphylaxis. The lesions involve mucosal surfaces and deeper skin layers. Angioedema usually is nonpruritic and associated lesions are nonpitting. Lesions most often appear on the lips, palms, soles, and genitalia.
• Pulmonary
  • Upper airway compromise may occur when the tongue or oropharynx is involved. When the upper airway is involved, stridor may be noted. The patient may have a hoarse or quiet voice and may lose speaking ability as the edema progresses. Complete airway obstruction is the most common cause of death in anaphylaxis.
  • Wheezing is common when patients have lower airway compromise due to bronchospasm or mucosal edema.
  • In angioedema, due to ACE inhibitors, marked edema of the tongue and lips may obstruct the airway.
• Cardiovascular
  • Cardiovascular examination is normal in mild cases. In more severe cases, compensatory tachycardia occurs due to loss of vascular tone.
  • Intravascular volume depletion may take place as a consequence of capillary leakage. These mechanisms also lead to development of hypotension.
  • Relative bradycardia has been reported.

Causes

• A wide variety of substances can cause anaphylaxis. Drugs and foods are the most common causes. Peanuts, tree nuts, and shellfish are the most commonly implicated foods, while antibiotics (especially penicillins) and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs. Anaphylaxis also may be idiopathic.
• The most common cause (86% in one study) of anaphylaxis in children is food.
• In the classic form of anaphylaxis, a foreign protein is the inciting agent (eg, antigen). On initial exposure, the antigen elicits generation of an IgE antibody. The antibody residue binds to mast cells and basophils. On reexposure, the antigen binds to the antibody, and the receptors are activated. Clinical manifestations result from release of immune response mediators such as histamine, leukotrienes, tryptase, and prostaglandins. The same mechanism occurs when a nonimmunogenic foreign substance binds as a so-called hapten to a native carrier protein, creating an immunogenic molecule. Factors influencing severity of a reaction include degree of host sensitivity and dose, route, and rate of administration of the offending agent.
• Parenteral exposures tend to result in faster and more severe reactions. Most severe reactions occur soon after exposure. The faster a reaction develops, the more severe it is likely to be. While most reactions occur within hours, symptoms may not occur for as long as 3-4 days after exposure.

Drugs

• Penicillin and cephalosporin antibiotics are the most commonly reported medical agents in anaphylaxis. This prevalence is a function of the immunogenicity and frequent use of these agents. Although concern for cross-sensitivity has been present because of their molecular and immunologic similarity, there is growing evidence that this association is not significant and is based on historic data with early cephalosporins.
  • Prior reports, based on skin testing, indicated that about 10% of patients allergic to a penicillin antibiotic are allergic to cephalosporins.
    • One report suggested that the actual incidence of clinical cross-reactivity is lower (perhaps 1%), with most reactions considered mild.Another paper indicated that patients with a history of allergy to penicillin seem to have a higher risk (by a factor of about 3) of subsequent reaction to any drug and that the risk of an allergic reaction to cephalosporins in patients with a history of penicillin allergy may be up to 8 times as high as the risk in those with no history of penicillin allergy (ie, at least part of the observed "cross reactivity" may represent a general state of immune hyperresponsiveness, rather than true "cross-reactivity").
    • One retrospective study evaluated 606 hospitalized patients with a history of penicillin allergy who were given a cephalosporin. Only one patient (0.17%) had a reaction, and it was minor.
    • A review of the topic of penicillin and cephalosporin "cross-reactivity" concluded that the widely quoted 10% "cross-reactivity" is a myth.
    • In penicillin-allergic patients, cephalothin, cephalexin, cefadroxil, and cephazolin are more likely to precipitate an allergic reaction than cefprozil, cefuroxime, ceftazidime, or ceftriaxone. This increased reactivity with the older agents is due to greater antigenic similarity of the side chain not present with the newer second- and third-generation agents.
  • Patients with a history of positive skin tests for penicillin allergy are at high risk of subsequent reactions. However, approximately 85% of patients with a history of penicillin allergy have negative skin tests and a low risk of reactions.
    • When a drug in either class is the drug of choice for a patient with a life-threatening emergency, a number of options exist. When the history is indefinite, the drug may be administered under close observation; however, when possible, obtain the patient's informed consent. Immediate treatment measures for anaphylaxis should be available. Alternatively, when the history is more convincing, a desensitization or prophylactic pretreatment protocol may be instituted or another agent selected.
• Reactions to medications tend to be more severe and rapid in onset when the antibiotic is administered parenterally.
• A drug reaction may occur in a patient with no prior history of drug exposure.
• Aspirin and NSAIDs commonly are implicated in allergic reactions and anaphylaxis. Bronchospasm is common in patients with reactive airway disease and nasal polyps. Cross-reactivity often occurs between aspirin and the various NSAIDs.
• ACE inhibitors (ACEI), widely used in the treatment of hypertension, are associated with angioedema in 0.5-1.0% of patients who take them. Systemic anaphylaxis is rarely associated with these agents. The reaction is thought to be mediated by bradykinin and is considerably more common in African Americans.

Intravenous radiocontrast media

• IV administered radiocontrast media causes an anaphylactoid reaction that is clinically similar to true anaphylaxis and is treated in the same way. The reaction is not related to prior exposure. Shellfish or iodine allergy is not a contraindication to use of IV contrast and does not mandate a pretreatment regimen. As with any allergic patient, give consideration to use of low molecular weight (LMW) contrast.
  • The term iodine allergy is a misnomer. Iodine is an essential trace element present throughout the body. No one is allergic to iodine. Patients who report iodine allergy usually have had either a prior contrast reaction, a shellfish allergy, or a contact reaction to povidone-iodine (Betadine). Manage these patients as indicated earlier.
• Approximately 1-3% of patients who receive hyperosmolar IV contrast experience a reaction. Use of LMW contrast decreases incidence of reactions to approximately 0.5%. Personnel, medications, and equipment needed for treatment of allergic reactions always should be available when these agents are administered. Obtain consent before administration.
• Reactions to radiocontrast usually are mild (most commonly urticarial), with only rare fatalities reported. Risk of a fatal reaction has been estimated at 0.9 cases per 100,000 exposures.
• Mucosal exposure (eg, GI, genitourinary [GU]) to radiocontrast agents has not been reported to cause anaphylaxis; therefore, a history of prior reaction is not a contraindication to GI or GU use of these agents.
• Pretreatment with antihistamines or corticosteroids and use of LMW agents lead to lower rates of anaphylactoid reactions to IV contrast. Consider these measures for patients who have prior history of reaction, since rate of recurrence is estimated at 17-60%. Some institutions use only LMW agents. Patients who are atopic and/or asthmatic also are at increased risk of reaction. In addition, allergic reaction is more difficult to treat in those taking beta-blockers.

Hymenoptera stings

• Hymenoptera stings are a common cause of allergic reaction and anaphylaxis. An uncertain but enormous number of exposures occur; accurate reaction rates are therefore difficult to estimate. In the United States, Hymenoptera envenomations result in fewer than 100 reported deaths per year.
• Local reaction and urticaria without other manifestations of anaphylaxis are much more common than full-blown anaphylaxis. Generalized urticaria is a risk factor for subsequent anaphylaxis; but a local reaction, even if severe, is not a risk factor for anaphylaxis.
• Caution patients treated and released from the ED after an episode of anaphylaxis or generalized urticaria from Hymenoptera envenomation to avoid future exposure when possible. Consider referral to an allergist for desensitization, particularly when further exposure is likely. Additionally, consider prescribing a treatment kit with an epinephrine auto-injector and oral antihistamine. Both are effective measures in preventing or ameliorating future reactions.

Food and environmental allergies

• Food allergy is common. Symptoms usually are mild and limited to the GI tract, but full-blown anaphylaxis can occur. Fatalities are rare compared to number of exposures; however, the number of exposures is so high that foods may be the commonest cause of anaphylaxis. Anaphylaxis due to foods may be an underrecognized cause of sudden death and an unappreciated cause of diagnosed anaphylaxis. Commonly implicated foods include peanuts, tree nuts, legumes, fish and shellfish, milk, and eggs. Reports of severe allergic reactions to peanuts are increasing.
• Latex allergy is an increasingly recognized problem in medical settings, where use of gloves and other latex products is ubiquitous. Most reactions are cutaneous or involve the mucous membranes. Anaphylactic reactions occur and have been reported with seemingly benign procedures (eg, Foley catheter insertion, intraperitoneal exposure to gloves during surgery).

Anaphylaxis

Introduction

Background

Anaphylaxis is a severe allergic reaction that is rapid in onset and may cause death. There are usually prominent dermal and systemic signs and symptoms. The full-blown syndrome includes urticaria (hives) and/or angioedema with hypotension and bronchospasm. The classic form, described in 1902, involves prior sensitization to an allergen with later re-exposure, producing symptoms via an immunologic mechanism. An anaphylactoid reaction produces a very similar clinical syndrome but is not immune-mediated. Treatment for both conditions is similar, and this article uses the term anaphylaxis to refer to both conditions unless otherwise specified. A recent consensus report reviewed the definition and management of anaphylaxis.

Pathophysiology

Rapid onset of increased secretion from mucous membranes, increased bronchial smooth muscle tone, decreased vascular smooth muscle tone, and increased capillary permeability occur after exposure to an inciting substance. These effects are produced by the release of mediators, which include histamine, leukotriene C4, prostaglandin D2, and tryptase.

In the classic form, mediator release occurs when the antigen (allergen) binds to antigen-specific immunoglobulin E (IgE) attached to previously sensitized basophils and mast cells. The mediators are released almost immediately when the antigen binds. In an anaphylactoid reaction, exposure to an inciting substance causes direct release of mediators, a process that is not mediated by IgE. Increased mucous secretion and increased bronchial smooth muscle tone, as well as airway edema, contribute to the respiratory symptoms observed in anaphylaxis. Cardiovascular effects result from decreased vascular tone and capillary leakage. Histamine release in skin causes urticarial skin lesions.

The most common inciting agents in anaphylaxis are parenteral antibiotics (especially penicillins), IV contrast materials, Hymenoptera stings, and certain foods (most notably, peanuts). Oral medications and many other types of exposures also have been implicated. Anaphylaxis also may be idiopathic.

Frequency

United States

The true incidence of anaphylaxis is unknown, partly because of the lack of a precise definition of the syndrome. Some clinicians reserve the term for the full-blown syndrome, while others use it to describe milder cases. Fatal anaphylaxis is relatively rare; milder forms occur much more frequently. The frequency of anaphylaxis is increasing, and this has been attributed to the increased number of potential allergens to which people are exposed. Up to 500-1000 fatal cases of anaphylaxis per year are estimated to occur in the United States. A recent review concluded that the lifetime prevalence of anaphylaxis is 1-2% of the population as a whole.

The incidence of anaphylaxis appears to be increasing, especially cases in children attributed to food allergy.

International

Reactions to insects and other venomous plants and animals are more prevalent in tropical areas because of the greater biodiversity in these areas.

Exposure and therefore reactions to medications are more common in industrialized areas.

Mortality/Morbidity

Approximately 1 in 5000 exposures to a parenteral dose of a penicillin or cephalosporin antibiotic causes anaphylaxis. More than 100 deaths per year are reported in the United States. Fewer than 100 fatal reactions to Hymenoptera stings are reported each year in the United States but this is considered to be an underestimate. One to 2% of people receiving IV radiocontrast experience some sort of reaction. The majority of these reactions are minor, and fatalities are rare. Low molecular weight contrast causes fewer and less severe reactions.

Race

Well-described racial differences in the incidence or severity of anaphylaxis do not exist. Cultural and socioeconomic differences may influence exposure rates.

Sex

Differences have been reported in the incidence and prevalence of anaphylactic reactions between men and women. Overall, women have a higher incidence of anaphylaxis than men, but, in some series of children, males predominate.

Age

Anaphylaxis occurs in all age groups. Food allergies are more common in the young, whereas more drug reactions occur in adults, possibly due to greater exposure. Although prior exposure is essential for the development of true anaphylaxis, reactions occur even when no documented prior exposure exists. Thus, patients may react to a first exposure to an antibiotic or insect sting. Elderly persons have the greatest risk of mortality from anaphylaxis due to the presence of preexisting disease.

Clinical

History

• Anaphylactic reactions almost always involve the skin or mucous membranes. More than 90% of patients have some combination of urticaria, erythema, pruritus, or angioedema.
• The upper respiratory tract commonly is involved, with complaints of nasal congestion, sneezing, or coryza. Cough, hoarseness, or a sensation of tightness in the throat may presage significant airway obstruction.
• Eyes may itch and tearing may be noted. Conjunctival injection may occur.
• Dyspnea is present when patients have bronchospasm or upper airway edema. Hypoxia and hypotension may cause weakness, dizziness, or syncope. Chest pain may occur due to bronchospasm or myocardial ischemia (secondary to hypotension and hypoxia).
• GI symptoms of cramplike abdominal pain with nausea, vomiting, or diarrhea also occur but are less common, except in the case of food allergy.
• In a classic case of anaphylaxis, the patient or a bystander provides a history of possible exposures that may have caused the rapid onset of skin and other manifestations. This history often is partial; exposure may not be recalled, or it may not be considered significant by the patient or health care provider. For example, when queried about medications, a patient may not mention over-the-counter (OTC) products. The clinician may not realize that, while reactions are usually rapid in onset, they also may be delayed.
• For reasons that are not well understood, a lack of dermal findings is more common in children than in adults.

Physical

• General
  • Physical examination of patients with anaphylaxis depends on affected organ systems and severity of attack. Vital signs may be normal or significantly disordered with tachypnea, tachycardia, and/or hypotension.
  • Place emphasis on determining the patient's respiratory and cardiovascular status.
  • Frank cardiovascular collapse or respiratory arrest may occur in severe cases. Anxiety is common unless hypotension or hypoxia causes obtundation. Shock may occur without prominent skin manifestations or history of exposure; therefore, anaphylaxis is part of the differential diagnosis for patients who present with shock and no obvious cause.
  • General appearance and vital signs vary according to severity of attack and affected organ system(s). Patients commonly are restless due to severe pruritus from urticaria. Anxiety, tremor, and a sensation of cold may result from compensatory endogenous catecholamine release. Severe air hunger may occur when the respiratory tract is involved. If hypoperfusion or hypoxia occurs, the patient may exhibit a depressed level of consciousness or may be agitated and/or combative. Tachycardia usually is present, but bradycardia may occur in very severe reactions.
• Skin
  • The classic skin manifestation is urticaria (ie, hives). Lesions are red and raised, and they sometimes have central blanching. Intense pruritus occurs with the lesions. Lesion borders usually are irregular and sizes vary markedly. Only a few small or large lesions may become confluent, forming giant urticaria. At times, the entire dermis is involved with diffuse erythema and edema. Hives can occur anywhere on the skin.
  • In a local reaction, lesions occur near the site of a cutaneous exposure (eg, insect bite). The involved area is erythematous, edematous, and pruritic. If only local skin reaction (as opposed to generalized urticaria) is present, systemic manifestations (eg, respiratory distress) are less likely. Local reactions, even if severe, are not predictive of systemic anaphylaxis on reexposure.
  • Lesions typical of angioedema also may manifest in anaphylaxis. The lesions involve mucosal surfaces and deeper skin layers. Angioedema usually is nonpruritic and associated lesions are nonpitting. Lesions most often appear on the lips, palms, soles, and genitalia.
• Pulmonary
  • Upper airway compromise may occur when the tongue or oropharynx is involved. When the upper airway is involved, stridor may be noted. The patient may have a hoarse or quiet voice and may lose speaking ability as the edema progresses. Complete airway obstruction is the most common cause of death in anaphylaxis.
  • Wheezing is common when patients have lower airway compromise due to bronchospasm or mucosal edema.
  • In angioedema, due to ACE inhibitors, marked edema of the tongue and lips may obstruct the airway.
• Cardiovascular
  • Cardiovascular examination is normal in mild cases. In more severe cases, compensatory tachycardia occurs due to loss of vascular tone.
  • Intravascular volume depletion may take place as a consequence of capillary leakage. These mechanisms also lead to development of hypotension.
  • Relative bradycardia has been reported.

Causes

• A wide variety of substances can cause anaphylaxis. Drugs and foods are the most common causes. Peanuts, tree nuts, and shellfish are the most commonly implicated foods, while antibiotics (especially penicillins) and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs. Anaphylaxis also may be idiopathic.
• The most common cause (86% in one study) of anaphylaxis in children is food.
• In the classic form of anaphylaxis, a foreign protein is the inciting agent (eg, antigen). On initial exposure, the antigen elicits generation of an IgE antibody. The antibody residue binds to mast cells and basophils. On reexposure, the antigen binds to the antibody, and the receptors are activated. Clinical manifestations result from release of immune response mediators such as histamine, leukotrienes, tryptase, and prostaglandins. The same mechanism occurs when a nonimmunogenic foreign substance binds as a so-called hapten to a native carrier protein, creating an immunogenic molecule. Factors influencing severity of a reaction include degree of host sensitivity and dose, route, and rate of administration of the offending agent.
• Parenteral exposures tend to result in faster and more severe reactions. Most severe reactions occur soon after exposure. The faster a reaction develops, the more severe it is likely to be. While most reactions occur within hours, symptoms may not occur for as long as 3-4 days after exposure.

Drugs

• Penicillin and cephalosporin antibiotics are the most commonly reported medical agents in anaphylaxis. This prevalence is a function of the immunogenicity and frequent use of these agents. Although concern for cross-sensitivity has been present because of their molecular and immunologic similarity, there is growing evidence that this association is not significant and is based on historic data with early cephalosporins.
  • Prior reports, based on skin testing, indicated that about 10% of patients allergic to a penicillin antibiotic are allergic to cephalosporins.
    • One report suggested that the actual incidence of clinical cross-reactivity is lower (perhaps 1%), with most reactions considered mild.Another paper indicated that patients with a history of allergy to penicillin seem to have a higher risk (by a factor of about 3) of subsequent reaction to any drug and that the risk of an allergic reaction to cephalosporins in patients with a history of penicillin allergy may be up to 8 times as high as the risk in those with no history of penicillin allergy (ie, at least part of the observed "cross reactivity" may represent a general state of immune hyperresponsiveness, rather than true "cross-reactivity").
    • One retrospective study evaluated 606 hospitalized patients with a history of penicillin allergy who were given a cephalosporin. Only one patient (0.17%) had a reaction, and it was minor.
    • A review of the topic of penicillin and cephalosporin "cross-reactivity" concluded that the widely quoted 10% "cross-reactivity" is a myth.
    • In penicillin-allergic patients, cephalothin, cephalexin, cefadroxil, and cephazolin are more likely to precipitate an allergic reaction than cefprozil, cefuroxime, ceftazidime, or ceftriaxone. This increased reactivity with the older agents is due to greater antigenic similarity of the side chain not present with the newer second- and third-generation agents.
  • Patients with a history of positive skin tests for penicillin allergy are at high risk of subsequent reactions. However, approximately 85% of patients with a history of penicillin allergy have negative skin tests and a low risk of reactions.
    • When a drug in either class is the drug of choice for a patient with a life-threatening emergency, a number of options exist. When the history is indefinite, the drug may be administered under close observation; however, when possible, obtain the patient's informed consent. Immediate treatment measures for anaphylaxis should be available. Alternatively, when the history is more convincing, a desensitization or prophylactic pretreatment protocol may be instituted or another agent selected.
• Reactions to medications tend to be more severe and rapid in onset when the antibiotic is administered parenterally.
• A drug reaction may occur in a patient with no prior history of drug exposure.
• Aspirin and NSAIDs commonly are implicated in allergic reactions and anaphylaxis. Bronchospasm is common in patients with reactive airway disease and nasal polyps. Cross-reactivity often occurs between aspirin and the various NSAIDs.
• ACE inhibitors (ACEI), widely used in the treatment of hypertension, are associated with angioedema in 0.5-1.0% of patients who take them. Systemic anaphylaxis is rarely associated with these agents. The reaction is thought to be mediated by bradykinin and is considerably more common in African Americans.

Intravenous radiocontrast media

• IV administered radiocontrast media causes an anaphylactoid reaction that is clinically similar to true anaphylaxis and is treated in the same way. The reaction is not related to prior exposure. Shellfish or iodine allergy is not a contraindication to use of IV contrast and does not mandate a pretreatment regimen. As with any allergic patient, give consideration to use of low molecular weight (LMW) contrast.
  • The term iodine allergy is a misnomer. Iodine is an essential trace element present throughout the body. No one is allergic to iodine. Patients who report iodine allergy usually have had either a prior contrast reaction, a shellfish allergy, or a contact reaction to povidone-iodine (Betadine). Manage these patients as indicated earlier.
• Approximately 1-3% of patients who receive hyperosmolar IV contrast experience a reaction. Use of LMW contrast decreases incidence of reactions to approximately 0.5%. Personnel, medications, and equipment needed for treatment of allergic reactions always should be available when these agents are administered. Obtain consent before administration.
• Reactions to radiocontrast usually are mild (most commonly urticarial), with only rare fatalities reported. Risk of a fatal reaction has been estimated at 0.9 cases per 100,000 exposures.
• Mucosal exposure (eg, GI, genitourinary [GU]) to radiocontrast agents has not been reported to cause anaphylaxis; therefore, a history of prior reaction is not a contraindication to GI or GU use of these agents.
• Pretreatment with antihistamines or corticosteroids and use of LMW agents lead to lower rates of anaphylactoid reactions to IV contrast. Consider these measures for patients who have prior history of reaction, since rate of recurrence is estimated at 17-60%. Some institutions use only LMW agents. Patients who are atopic and/or asthmatic also are at increased risk of reaction. In addition, allergic reaction is more difficult to treat in those taking beta-blockers.

Hymenoptera stings

• Hymenoptera stings are a common cause of allergic reaction and anaphylaxis. An uncertain but enormous number of exposures occur; accurate reaction rates are therefore difficult to estimate. In the United States, Hymenoptera envenomations result in fewer than 100 reported deaths per year.
• Local reaction and urticaria without other manifestations of anaphylaxis are much more common than full-blown anaphylaxis. Generalized urticaria is a risk factor for subsequent anaphylaxis; but a local reaction, even if severe, is not a risk factor for anaphylaxis.
• Caution patients treated and released from the ED after an episode of anaphylaxis or generalized urticaria from Hymenoptera envenomation to avoid future exposure when possible. Consider referral to an allergist for desensitization, particularly when further exposure is likely. Additionally, consider prescribing a treatment kit with an epinephrine auto-injector and oral antihistamine. Both are effective measures in preventing or ameliorating future reactions.

Food and environmental allergies

• Food allergy is common. Symptoms usually are mild and limited to the GI tract, but full-blown anaphylaxis can occur. Fatalities are rare compared to number of exposures; however, the number of exposures is so high that foods may be the commonest cause of anaphylaxis. Anaphylaxis due to foods may be an underrecognized cause of sudden death and an unappreciated cause of diagnosed anaphylaxis. Commonly implicated foods include peanuts, tree nuts, legumes, fish and shellfish, milk, and eggs. Reports of severe allergic reactions to peanuts are increasing.
• Latex allergy is an increasingly recognized problem in medical settings, where use of gloves and other latex products is ubiquitous. Most reactions are cutaneous or involve the mucous membranes. Anaphylactic reactions occur and have been reported with seemingly benign procedures (eg, Foley catheter insertion, intraperitoneal exposure to gloves during surgery).

Alfuzosin

U.S. BRAND NAMES — Uroxatral®

PHARMACOLOGIC CATEGORY
Alpha 1 Blocker

DOSING: ADULTS — Benign prostatic hyperplasia (BPH): Oral: 10 mg once daily

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT — Bioavailability and maximum serum concentrations are increased by ~50% with mild, moderate, or severe renal impairment.

Note: Safety has not been evaluated in patients with creatinine clearances <30 mL/minute.

DOSING: HEPATIC IMPAIRMENT
Mild hepatic impairment: Use has not been studied.

Moderate or severe hepatic impairment (Child-Pugh class B and C): Clearance is decreased 1/3 to 1/4 and serum concentration is increased three- to fourfold; use is contraindicated.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, extended release, as hydrochloride:
Uroxatral®: 10 mg

DOSAGE FORMS: CONCISE
Tablet, extended release:
Uroxatral®: 10 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Tablet should be swallowed whole; do not crush or chew. Administer once daily (with a meal); should be taken at the same time each day.

USE — Treatment of the functional symptoms of benign prostatic hyperplasia (BPH)

ADVERSE REACTIONS SIGNIFICANT
1% to 10%:
Central nervous system: Dizziness (6%), fatigue (3%), headache (3%), pain (1% to 2%)
Gastrointestinal: Abdominal pain (1% to 2%), constipation (1% to 2%), dyspepsia (1% to 2%), nausea (1% to 2%)
Genitourinary: Impotence (1% to 2%)
Respiratory: Upper respiratory tract infection (3%), bronchitis (1% to 2%), pharyngitis (1% to 2%), sinusitis (1% to 2%)

<1% (Limited to important or life-threatening): Angina pectoris (pre-existing CAD), angioedema, chest pain, cholestatic liver injury, diarrhea, edema, flushing, hepatocellular injury, intraoperative floppy iris syndrome (with cataract surgery), jaundice, priapism, pruritus, rash, rhinitis, tachycardia, urticaria

CONTRAINDICATIONS — Hypersensitivity to alfuzosin or any component of the formulation; moderate or severe hepatic insufficiency (Child-Pugh class B and C); concurrent use with potent CYP3A4 inhibitors (eg, itraconazole, ketoconazole, ritonavir)

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Angina: Discontinue if symptoms of angina occur or worsen. Floppy iris syndrome: Intraoperative floppy iris syndrome has been observed in cataract surgery patients who were on or were previously treated with alpha1-blockers; causality has not been established and there appears to be no benefit in discontinuing alpha-blocker therapy prior to surgery. Orthostatic hypotension/syncope: May cause significant orthostatic hypotension and syncope, especially with first dose; anticipate a similar effect if therapy is interrupted for a few days, if dosage is rapidly increased, or used with antihypertensives (particularly vasodilators), PDE-5 inhibitors, nitrates or other medications which may result in hypotension. Patients should be cautioned about performing hazardous tasks when starting new therapy or adjusting dosage upward.

Disease-related concerns: Hepatic impairment: Use with caution in patients with mild hepatic impairment; contraindicated in moderate-to-severe impairment. Prostate cancer: Rule out prostatic carcinoma before beginning therapy (many symptoms of BPH and prostate cancer are similar). QT prolongation: Alfuzosin has been shown to prolong the QT interval alone (minimal) and with other drugs with comparable effects on the QT interval (additive). Use with caution in patients with known QT prolongation (congenital or acquired). Renal impairment: Use with caution in patients with renal impairment.

Special populations: Pediatrics: Not indicated for use in children.

Other warning/precautions: Antihypertensive agent: Not intended for use as an antihypertensive drug.

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP3A4 (major)

DRUG INTERACTIONS
Alpha1-Blockers: May enhance the antihypertensive effect of Alfuzosin. Risk of orthostatic hypotension or syncope may be increased. Alfuzosin may enhance the antihypertensive effect of Alpha1-Blockers. Risk X: Avoid combination

Beta-Blockers: May enhance the orthostatic effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Exceptions: Levobunolol; Metipranolol. Risk D: Consider therapy modification

Calcium Channel Blockers: Alpha1-Blockers may enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Alfuzosin. Risk X: Avoid combination

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Alpha1-Blockers. Management: Ensure patient is stable on alpha 1 blocker before starting PDE5 inhibitor; initiate PDE5 inhibitor at lowest possible dose. If patient stable on PDE5 inhibitor, initiate alpha 1 blocker at lowest dose. Risk D: Consider therapy modification

QTc-Prolonging Agents: Alfuzosin may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Silodosin: Alpha1-Blockers may enhance the adverse/toxic effect of Silodosin. Of particular concern are the risk of postural hypotension, syncope, and/or hypotension. Silodosin may enhance the hypotensive effect of Alpha1-Blockers. Of particular concern are the risk of postural hypotension, syncope, and/or hypotension. Risk X: Avoid combination

Tamsulosin: Alpha1-Blockers may enhance the antihypertensive effect of Tamsulosin. Risk of orthostatic hypotension or syncope may be increased. Tamsulosin may enhance the antihypertensive effect of Alpha1-Blockers. Risk X: Avoid combination

ETHANOL / NUTRITION / HERB INTERACTIONS
Food: Food increases the extent of absorption.

Herb/Nutraceutical: Avoid St John's wort (may decrease alfuzosin levels).

PREGNANCY RISK FACTOR — B (show table)

PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies; however, alfuzosin is not indicated for use in women.

LACTATION — Not indicated for use in women

DIETARY CONSIDERATIONS — Take following a meal at the same time each day.

PRICING — (data from drugstore.com)
Tablet, 24-hour (Uroxatral)
10 mg (30): $111.79

MONITORING PARAMETERS — Urine flow; blood pressure

CANADIAN BRAND NAMES — Apo-Alfuzosin; Sandoz-Alfuzosin; Xatral

INTERNATIONAL BRAND NAMES — Alfetim (HN); Alfusin (IN); Benestan (PT); Benestan OD (PT); Dalfaz (AR, ES, PL); Lafuzo (TW); Uroxatral (CN); Uroxatral OD (AR, UY); Uroxatral uno (CH, DE); Xatral (AT, BE, BF, BJ, CH, CI, CL, CZ, DK, ET, FI, FR, GB, GH, GM, GN, GR, IE, IL, IT, KE, LR, MA, ML, MR, MU, MW, NE, NG, NL, NO, SC, SD, SE, SL, SN, TN, TZ, UG, ZA, ZM, ZW); Xatral LP (FR, HK); Xatral OD (BR, CO, CR, DO, EC, GT, HN, MX, NI, PA, PE, PH, PY, SE, SV, VE); Xatral SR (AT, BG, EE, EG, IL, PK, SG); Xatral XL (ID, IL, KP, SG, TH, TW); Xatral XR 10 (SG)

MECHANISM OF ACTION — An antagonist of alpha1-adrenoreceptors in the lower urinary tract. Smooth muscle tone is mediated by the sympathetic nervous stimulation of alpha1-adrenoreceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoreceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in BPH symptoms.

PHARMACODYNAMICS / KINETICS
Absorption: Decreased 50% under fasting conditions

Distribution: Vd: 3.2 L/kg

Protein binding: 82% to 90%

Metabolism: Hepatic, primarily via CYP3A4; metabolism includes oxidation, O-demethylation, and N-dealkylation; forms metabolites (inactive)

Bioavailability: 49% following a meal

Half-life elimination: 10 hours

Time to peak, plasma: 8 hours following a meal

Excretion: Feces (69%); urine (24%; 11% as unchanged drug)

PATIENT INFORMATION — Do not take any new medication during therapy without consulting prescriber. Take exactly as directed, with a meal at the same time each day. Swallow tablet whole; do not crush or chew. May cause drowsiness, dizziness, impaired judgment (use caution when driving or engaging in tasks that require alertness until response to drug is known), or postural hypotension (use caution when rising from sitting or lying position or when climbing stairs). Report unusual chest pain, respiratory difficulty, or any persistent adverse reactions.

Alfuzosin

U.S. BRAND NAMES — Uroxatral®

PHARMACOLOGIC CATEGORY
Alpha 1 Blocker

DOSING: ADULTS — Benign prostatic hyperplasia (BPH): Oral: 10 mg once daily

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT — Bioavailability and maximum serum concentrations are increased by ~50% with mild, moderate, or severe renal impairment.

Note: Safety has not been evaluated in patients with creatinine clearances <30 mL/minute.

DOSING: HEPATIC IMPAIRMENT
Mild hepatic impairment: Use has not been studied.

Moderate or severe hepatic impairment (Child-Pugh class B and C): Clearance is decreased 1/3 to 1/4 and serum concentration is increased three- to fourfold; use is contraindicated.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, extended release, as hydrochloride:
Uroxatral®: 10 mg

DOSAGE FORMS: CONCISE
Tablet, extended release:
Uroxatral®: 10 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Tablet should be swallowed whole; do not crush or chew. Administer once daily (with a meal); should be taken at the same time each day.

USE — Treatment of the functional symptoms of benign prostatic hyperplasia (BPH)

ADVERSE REACTIONS SIGNIFICANT
1% to 10%:
Central nervous system: Dizziness (6%), fatigue (3%), headache (3%), pain (1% to 2%)
Gastrointestinal: Abdominal pain (1% to 2%), constipation (1% to 2%), dyspepsia (1% to 2%), nausea (1% to 2%)
Genitourinary: Impotence (1% to 2%)
Respiratory: Upper respiratory tract infection (3%), bronchitis (1% to 2%), pharyngitis (1% to 2%), sinusitis (1% to 2%)

<1% (Limited to important or life-threatening): Angina pectoris (pre-existing CAD), angioedema, chest pain, cholestatic liver injury, diarrhea, edema, flushing, hepatocellular injury, intraoperative floppy iris syndrome (with cataract surgery), jaundice, priapism, pruritus, rash, rhinitis, tachycardia, urticaria

CONTRAINDICATIONS — Hypersensitivity to alfuzosin or any component of the formulation; moderate or severe hepatic insufficiency (Child-Pugh class B and C); concurrent use with potent CYP3A4 inhibitors (eg, itraconazole, ketoconazole, ritonavir)

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Angina: Discontinue if symptoms of angina occur or worsen. Floppy iris syndrome: Intraoperative floppy iris syndrome has been observed in cataract surgery patients who were on or were previously treated with alpha1-blockers; causality has not been established and there appears to be no benefit in discontinuing alpha-blocker therapy prior to surgery. Orthostatic hypotension/syncope: May cause significant orthostatic hypotension and syncope, especially with first dose; anticipate a similar effect if therapy is interrupted for a few days, if dosage is rapidly increased, or used with antihypertensives (particularly vasodilators), PDE-5 inhibitors, nitrates or other medications which may result in hypotension. Patients should be cautioned about performing hazardous tasks when starting new therapy or adjusting dosage upward.

Disease-related concerns: Hepatic impairment: Use with caution in patients with mild hepatic impairment; contraindicated in moderate-to-severe impairment. Prostate cancer: Rule out prostatic carcinoma before beginning therapy (many symptoms of BPH and prostate cancer are similar). QT prolongation: Alfuzosin has been shown to prolong the QT interval alone (minimal) and with other drugs with comparable effects on the QT interval (additive). Use with caution in patients with known QT prolongation (congenital or acquired). Renal impairment: Use with caution in patients with renal impairment.

Special populations: Pediatrics: Not indicated for use in children.

Other warning/precautions: Antihypertensive agent: Not intended for use as an antihypertensive drug.

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP3A4 (major)

DRUG INTERACTIONS
Alpha1-Blockers: May enhance the antihypertensive effect of Alfuzosin. Risk of orthostatic hypotension or syncope may be increased. Alfuzosin may enhance the antihypertensive effect of Alpha1-Blockers. Risk X: Avoid combination

Beta-Blockers: May enhance the orthostatic effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Exceptions: Levobunolol; Metipranolol. Risk D: Consider therapy modification

Calcium Channel Blockers: Alpha1-Blockers may enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Alfuzosin. Risk X: Avoid combination

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Alpha1-Blockers. Management: Ensure patient is stable on alpha 1 blocker before starting PDE5 inhibitor; initiate PDE5 inhibitor at lowest possible dose. If patient stable on PDE5 inhibitor, initiate alpha 1 blocker at lowest dose. Risk D: Consider therapy modification

QTc-Prolonging Agents: Alfuzosin may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Silodosin: Alpha1-Blockers may enhance the adverse/toxic effect of Silodosin. Of particular concern are the risk of postural hypotension, syncope, and/or hypotension. Silodosin may enhance the hypotensive effect of Alpha1-Blockers. Of particular concern are the risk of postural hypotension, syncope, and/or hypotension. Risk X: Avoid combination

Tamsulosin: Alpha1-Blockers may enhance the antihypertensive effect of Tamsulosin. Risk of orthostatic hypotension or syncope may be increased. Tamsulosin may enhance the antihypertensive effect of Alpha1-Blockers. Risk X: Avoid combination

ETHANOL / NUTRITION / HERB INTERACTIONS
Food: Food increases the extent of absorption.

Herb/Nutraceutical: Avoid St John's wort (may decrease alfuzosin levels).

PREGNANCY RISK FACTOR — B (show table)

PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies; however, alfuzosin is not indicated for use in women.

LACTATION — Not indicated for use in women

DIETARY CONSIDERATIONS — Take following a meal at the same time each day.

PRICING — (data from drugstore.com)
Tablet, 24-hour (Uroxatral)
10 mg (30): $111.79

MONITORING PARAMETERS — Urine flow; blood pressure

CANADIAN BRAND NAMES — Apo-Alfuzosin; Sandoz-Alfuzosin; Xatral

INTERNATIONAL BRAND NAMES — Alfetim (HN); Alfusin (IN); Benestan (PT); Benestan OD (PT); Dalfaz (AR, ES, PL); Lafuzo (TW); Uroxatral (CN); Uroxatral OD (AR, UY); Uroxatral uno (CH, DE); Xatral (AT, BE, BF, BJ, CH, CI, CL, CZ, DK, ET, FI, FR, GB, GH, GM, GN, GR, IE, IL, IT, KE, LR, MA, ML, MR, MU, MW, NE, NG, NL, NO, SC, SD, SE, SL, SN, TN, TZ, UG, ZA, ZM, ZW); Xatral LP (FR, HK); Xatral OD (BR, CO, CR, DO, EC, GT, HN, MX, NI, PA, PE, PH, PY, SE, SV, VE); Xatral SR (AT, BG, EE, EG, IL, PK, SG); Xatral XL (ID, IL, KP, SG, TH, TW); Xatral XR 10 (SG)

MECHANISM OF ACTION — An antagonist of alpha1-adrenoreceptors in the lower urinary tract. Smooth muscle tone is mediated by the sympathetic nervous stimulation of alpha1-adrenoreceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoreceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in BPH symptoms.

PHARMACODYNAMICS / KINETICS
Absorption: Decreased 50% under fasting conditions

Distribution: Vd: 3.2 L/kg

Protein binding: 82% to 90%

Metabolism: Hepatic, primarily via CYP3A4; metabolism includes oxidation, O-demethylation, and N-dealkylation; forms metabolites (inactive)

Bioavailability: 49% following a meal

Half-life elimination: 10 hours

Time to peak, plasma: 8 hours following a meal

Excretion: Feces (69%); urine (24%; 11% as unchanged drug)

PATIENT INFORMATION — Do not take any new medication during therapy without consulting prescriber. Take exactly as directed, with a meal at the same time each day. Swallow tablet whole; do not crush or chew. May cause drowsiness, dizziness, impaired judgment (use caution when driving or engaging in tasks that require alertness until response to drug is known), or postural hypotension (use caution when rising from sitting or lying position or when climbing stairs). Report unusual chest pain, respiratory difficulty, or any persistent adverse reactions.

Alfentanil

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Alfentanil may be confused with Anafranil®, fentanyl, remifentanil, sufentanil
Alfenta® may be confused with Sufenta®

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

U.S. BRAND NAMES — Alfenta®

PHARMACOLOGIC CATEGORY
Analgesic, Opioid
Anilidopiperidine Opioid

DOSING: ADULTS — Doses should be titrated to appropriate effects; wide range of doses is dependent upon desired degree of analgesia/anesthesia

Anesthesia: I.V.: Dose should be based on ideal body weight as follows (see table).

Adult Dosage Adjustments

Incremental injection in anesthesia ≤ 30 minutes: Initial dose (induction period): 8-20 mcg/kg Maintenance period (increments/infusion): 3-5 mcg/kg or 0.5-1 mcg/kg/minute Total dose: 8-40 mcg/kg Appropriate effects: Spontaneously breathing or assisted ventilation when required

Incremental injection in anesthesia of 30-60 minutes: Initial dose (induction period): 20-50 mcg/kg Maintenance period (increments/infusion): 5-15 mcg/kg Total dose: Up to 75 mcg/kg Appropriate effects: Assisted or controlled ventilation required. Attenuation of response to laryngoscopy and intubation.

Continuous infusion >45 minutes: Initial dose (induction period): 50-75 mcg/kg Maintenance period (increments/infusion): 0.5-3mcg/kg/minute; average infusion rate: 1-1.5 mcg/kg/minute Total dose: Dependent on duration of procedure Appropriate effects: Assisted or controlled ventilation required. Some attenuation of response to intubation and incision, with intraoperative stability.

Anesthetic induction >45 minutes: Initial dose (induction period): 130-245 mcg/kg Maintenance period (increments/infusion): 0.5-1.5 mcg/kg/minute or general anesthetic Total dose: Dependent on duration of procedure Appropriate effects: Assisted or controlled ventilation required. Administer slowly (over 3 minutes). Concentration of inhalation agents reduced by 30% to 50% for initial hour.

DOSING: PEDIATRIC

(For additional information see "Alfentanil: Pediatric drug information")
Children <12 years: Dose has not been established.

Children ≥ 12 years: Refer to adult dosing.

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution [preservative free]: 500 mcg/mL (2 mL, 5 mL)
Alfenta®: 500 mcg/mL (2 mL, 5 mL, 10 mL, 20 mL)

DOSAGE FORMS: CONCISE
Injection, solution [preservative free]: 500 mcg/mL (2 mL, 5 mL)
Alfenta®: 500 mcg/mL (2 mL, 5 mL, 10 mL, 20 mL)

GENERIC EQUIVALENT AVAILABLE — Yes

ADMINISTRATION — Administer I.V. slowly over 3-5 minutes or by I.V. continuous infusion.

COMPATIBILITY — Stable in D5W, NS, LR, D5NS.

Y-site administration: Compatible: Cisatracurium, etomidate, gatifloxacin, linezolid, propofol, remifentanil. Incompatible: Amphotericin B cholesteryl sulfate complex, thiopental.

Compatibility in syringe: Compatible: Atracurium, midazolam, ondansetron.

USE — Analgesic adjunct for the induction and maintenance of general anesthesia; analgesic component for monitored anesthesia care (MAC)

ADVERSE REACTIONS SIGNIFICANT
>10%:
Cardiovascular: Bradycardia, peripheral vasodilation
Central nervous system: Drowsiness, sedation, intracranial pressure increased
Endocrine & metabolic: Antidiuretic hormone release
Gastrointestinal: Nausea, vomiting, constipation
Ocular: Miosis

1% to 10%:
Cardiovascular: Cardiac arrhythmia, orthostatic hypotension
Central nervous system: Confusion, CNS depression
Ocular: Blurred vision

<1% (Limited to important or life-threatening): Convulsions, mental depression, paradoxical CNS excitation or delirium, dizziness, dysesthesia, rash, urticaria, itching, biliary tract spasm, urinary tract spasm, respiratory depression, bronchospasm, laryngospasm, physical and psychological dependence with prolonged use; cold, clammy skin

CONTRAINDICATIONS — Hypersensitivity to alfentanil hydrochloride, to narcotics, or any component of the formulation; increased intracranial pressure, severe respiratory depression

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Hypotension: May cause hypotension; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Opioid agonist toxicities: Shares the toxic potentials of opiate agonists, and precautions of opiate agonist therapy should be observed.

Disease-related concerns: Bradyarrhythmias: Use with caution when administering to patients with bradyarrhythmias. Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use. Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur. Obesity: Use with caution in patients who are morbidly obese. Respiratory disease: Use with caution in patients with pre-existing respiratory compromise (hypoxia and/or hypercapnia), COPD or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function.

Special populations: Neonates: Hypotension has occurred in neonates with respiratory distress syndrome. Pediatrics: Safety and efficacy have not been established in children <12 years old.

Other warnings/precautions: Rapid infusion: Inject slowly over 3-5 minutes; rapid I.V. infusion may result in skeletal muscle and chest wall rigidity, impaired ventilation, or respiratory distress/arrest; nondepolarizing skeletal muscle relaxant may be required. Trained individuals: Due to the high incidence of apnea, hypotension, tachycardia and muscle rigidity; it should be administered by individuals specifically trained in the use of anesthetic agents and should not be used in diagnostic or therapeutic procedures outside the monitored anesthesia setting; resuscitative and intubation equipment should be readily available.

RESTRICTIONS — C-II

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP3A4 (major)

DRUG INTERACTIONS
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

Ammonium Chloride: May increase the excretion of Analgesics (Opioid). Risk C: Monitor therapy

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Risk C: Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Alfentanil. Risk D: Consider therapy modification

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy

Beta-Blockers: Anilidopiperidine Opioids may enhance the bradycardic effect of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): Anilidopiperidine Opioids may enhance the bradycardic effect of Calcium Channel Blockers (Nondihydropyridine). Anilidopiperidine Opioids may enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Alfentanil. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Diltiazem: May increase the serum concentration of Alfentanil. Risk C: Monitor therapy

Fluconazole: May decrease the metabolism of Alfentanil. Risk D: Consider therapy modification

Fospropofol: Alfentanil may enhance the adverse/toxic effect of Fospropofol. Specifically, the development of opisthotonus (severe hyperextension and spasticity resulting in arching or bridging position) and/or grand mal seizures. Risk C: Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of Alfentanil. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. Risk D: Consider therapy modification

MAO Inhibitors: Anilidopiperidine Opioids may enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Management: Avoid use of fentanyl (and other anilidopiperidine opioids when possible) in patients who have used a monoamine oxidase inhibitor within the past 14 days due to reports of unpredictable but severe adverse effects. Risk X: Avoid combination

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

Propofol: Alfentanil may enhance the adverse/toxic effect of Propofol. Specifically the development of opisthotonus (severe hyperextension and spasticity resulting in arching or bridging position) and/or grand mal seizures. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Alfentanil. Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Risk C: Monitor therapy

Thiazide Diuretics: Analgesics (Opioid) may enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy

PREGNANCY RISK FACTOR — C (show table)

MONITORING PARAMETERS — Respiratory rate, blood pressure, heart rate

REFERENCE RANGE — 100-340 ng/mL (depending upon procedure)

CANADIAN BRAND NAMES — Alfentanil Injection, USP; Alfenta®

INTERNATIONAL BRAND NAMES — Alfast (BR); Brevafen (AR); Fanaxal (ES); Fentalim (IT); Rapifen (AE, AT, AU, BE, BG, BH, BR, CH, CN, CY, CZ, DE, DK, EG, ES, FI, FR, GB, GR, HK, HN, HR, HU, IE, IL, IQ, IR, IT, JO, KW, LB, LU, LY, NL, NO, OM, PL, PT, PY, QA, RU, SA, SE, SG, SY, TR, TW, UY, VE, YE, ZA)

MECHANISM OF ACTION — Binds with stereospecific receptors at many sites within the CNS, increases pain threshold, alters pain perception, inhibits ascending pain pathways; is an ultra short-acting narcotic

PHARMACODYNAMICS / KINETICS
Onset of action: Rapid

Duration (dose dependent): 30-60 minutes

Distribution: Vd: Newborns, premature: 1 L/kg; Children: 0.163-0.48 L/kg; Adults: 0.46 L/kg

Half-life elimination: Newborns, premature: 5.33-8.75 hours; Children: 40-60 minutes; Adults: 83-97 minutes