- Email: [email protected]
Drugs
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Drugs NONSTEROIDAL ANTIINFLAMMATORY DRUGS Introduction In the early part of the 20th century it was first recognized that aspirin could precipitate asthma in susceptible individuals [1]. Similar asthmatic reactions were later shown to occur with other nonsteroidal anti-inflammatory drugs (NSAIDs) [2] and patients with aspirin-induced asthma were found to be sensitive to other cyclooxygenase (COX)-1 inhibitors. Various terms have been used to describe the sensitivity to NSAIDs, including aspirin-induced asthma, aspirin-sensitive asthma, aspirin hypersensitivity, idiosyncratic reaction to aspirin, aspirin intolerance, and nonallergic hypersensitivity reactions to aspirin and NSAIDs [3].
Prevalence The prevalence of hypersensitivity reactions to aspirin and NSAIDs in individuals with asthma is unclear, with estimates ranging from 4.3% to 21% [4–6]. The prevalence figures are higher when determined by oral provocation testing (e.g. 21% in adults and 5% in children [6]). Oral aspirin challenges undertaken in subgroups of patients with asthma, nasal polyps, and chronic sinusitis attending specialized allergy centers provide high positive rates of 30% or greater.
Clinical features Aspirin-induced asthma is characterized by the development of bronchoconstriction within
minutes to several hours after the ingestion of aspirin or other NSAIDs [2, 3]. The asthmatic reaction can be associated with other symptoms, including rhinorrhea, flushing, and loss of consciousness, and very rarely the attack may be fatal. In the typical case, symptoms of chronic rhinitis are present for many years before asthma develops. The rhinitis starts as intermittent watery rhinorrhea, which develops during the second or third decade of life. The rhinorrhea becomes progressively more severe and is complicated by nasal polyp formation and sinusitis. On average 2 years later symptoms of asthma appear associated with the development of acute asthma after the ingestion of COX-1 inhibitors. Although in this group drugs may precipitate asthma, these patients continue to have nasal and asthmatic symptoms in the absence of ingesting aspirin or other NSAIDs. Respiratory symptoms are often chronic, severe, and perennial in nature. Individuals with aspirininduced asthma are more commonly female. Skin tests to common external allergens are positive in a third to over a half of subjects. A small percentage of patients with aspirin-induced asthma also develop associated symptoms of urticaria and angioedema after ingestion of aspirin.
CHAPTER
Neil C. Thomson1 and Peter J. Barnes2 1
Department of Respiratory Medicine, Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, UK 2 National Heart and Lung Institute (NHLI), Clinical Studies Unit, Imperial College, London, UK
Diagnosis In most clinical circumstances, the diagnosis is based on a history of bronchoconstriction following the ingestion of a COX-1 inhibitor. It should be appreciated, however, that a history of either the presence or the absence of aspirininduced asthma may result in both a false positive and a false negative diagnosis. For example, patients with a history of aspirin-induced asthma have a positive oral aspirin challenge in approximately 60% to over 90% of cases. A negative oral 515
Asthma and COPD: Basic Mechanisms and Clinical Management challenge may occur in patients with a history of aspirininduced asthma due to changing responsiveness to aspirin, a high threshold to aspirin, or a misleading history. The only reliable method of establishing a diagnosis of aspirin-induced asthma is by aspirin challenge. Oral aspirin challenge is indicated in patients with adult asthma who require treatment with an NSAID. The oral challenge procedure has been reported to be safe, if a standardized protocol is used [3, 7]. An alternative but less widely used method of detecting aspirin-induced asthma involves administering aspirin-lysine by inhalation [7]. It is claimed that this method is safe and when compared to oral challenge the procedure is shorter and the reaction is localized to the respiratory tract. Aspirin-lysine administered as a nasal challenge has also been used to diagnose aspirin-sensitive asthma and this technique does not induce bronchoconstriction [8]. No in vitro test is currently available to detect aspirin-induced asthma. Tartrazine is a yellow dye used for coloring foods and drugs such as confectionery, soft drinks, antibiotics, and antihistamines. A number of earlier reports suggested that tartrazine caused bronchospasm in some patients with aspirin-induced asthma, but further research has failed to support any cross-reactivity between tartrazine and aspirin in patients with aspirin-induced asthma [9].
Mechanisms Alterations in the arachidonic acid pathway A characteristic feature of patients with aspirin-induced asthma is the occurrence of airway obstruction following the ingestion of drugs which inhibit COX-1, the enzyme that converts arachidonic acid into prostaglandins (PG) and
thromboxane. An abnormality in the arachidonic acid pathway in the respiratory tract of patients with aspirin-induced asthma seems to be central to the development of an asthmatic attack after the ingestion of NSAIDs (Fig. 40.1). In support of this hypothesis, the severity of bronchoconstriction induced by aspirin or other NSAIDs, such as indomethacin, flufenamic acid, and naproxen, is directly proportional to their ability to inhibit COX in vitro. Furthermore, specimens of nasal polyps removed from patients with aspirininduced asthma are more sensitive to the inhibition effects of aspirin on the COX-1 pathway. The influence of PG on bronchomotor tone may differ between patients with or without aspirin-induced asthma. The control of airway caliber in the latter group could be more dependent on the effects of PG, such as PGE2, either due to its direct bronchodilator activity or indirectly by suppression of the release of bronchoconstrictor mediators. Alternately, the production of PGE2 may be impaired in these individuals. In support of this later mechanism, peripheral blood mononuclear cells release reduced amounts of PGE2 in patients with aspirin-induced asthma [10], although a recent clinical challenge study with aspirin found that urinary metabolites of PGE2 were not altered in patients with aspirin-induced asthma [11]. The expression of the E-prostanoid (EP) 2 receptor for PGE2 is reduced in nasal tissue of patients with aspirin-induced asthma [12] and polymorphisms in the promoter region of the gene coding for the EP2 gene are associated with sensitivity to aspirin [13]. The lipoxygenase pathway also appears to be abnormal in these individuals, since the synthesis of leukotriene (LT) E4 is frequently increased in aspirin-induced asthma [14], the expression of cys LT1 receptors is increased in nasal inflammatory cells [15], and leukotriene C4 synthase
Membrane phospholipids Aspirin Arachidonic acid
5-LO and FLAP
Cox-1 and Cox-2
LTA4 LTA2 hydrolase
LTB4
PGH2
TBxA2 synthase PG synthase, Isomerase and reductase
LTC4 synthase ↑
LTC4, LTD4, LTE4 2
TBxA2
PGI2
PGD2
PGE2
PGF2
1
cys LT1 receptor
EP2 receptor
Bronchoconstriction
Bronchodilation
FIG. 40.1 Biosynthetic pathways leading to the production of LT and PG. Possible mechanisms by which aspirin and NSAIDs inhibit COX-1 to induce bronchoconstriction: (1) Impaired PGE2 synthesis and/or reduced PGE2 receptor function. (2) Increased cys LT synthesis and/or increased cys LT1 receptor function. 5-LO: 5-lipoxygenase; FLAP: 5-lipoxygenase-activating protein; TBxA2: thromboxane A2; PGI2: prostacyclin.
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Drugs (LTC4S), an enzyme involved in the synthesis of LTs, is often overexpressed in eosinophils and in bronchial tissue [16]. Furthermore, genetic polymorphisms of LTC4S promoter region have been found in some patients with aspirinsensitive asthma [17], but this has not been confirmed in other populations [18]. Taken together, these findings point to abnormalities in the arachidonic acid pathway in patients sensitive to NSAIDs in particular impaired PGE2 synthesis and actions and excessive LT synthesis and effects. There is, however, an overlap in some of the defects in the arachidonic acid pathway found in patients with aspirin-induced asthma when compared with individuals without sensitivity to NSAIDs, suggesting that the exact mechanisms underlying aspirininduced asthma are not yet fully elucidated.
Other mechanisms There is no convincing evidence that aspirin-induced asthma is due to IgE-mediated mechanisms. For example, specific anti-aspiryl IgE antibodies are generally absent and skin tests to aspiryl-polylysine are negative in these patients. Basal and post-aspirin challenge complement levels are not altered in patients with aspirin-induced asthma. Inflammatory mediators are released following aspirin challenge, such as neutrophil chemotactic factor, but this is thought to be secondary to the primary biochemical events.
Management Avoidance Patients with a history of acute bronchoconstrictor response after the ingestion of NSAIDs must be warned to avoid these drugs. If they require a simple analgesic, then acetaminophen (paracetamol) is usually safe in doses up to 500 mg. Cross-reactivity can occur with high doses of acetaminophen (paracetamol), which is a weak inhibitor of COX-1, although the respiratory reaction tends to be mild. There is considerable data to indicate that COX-2 inhibitors do not induce bronchoconstriction in individuals sensitive to aspirin [19], although a few case reports of reactions have been published. If a patient with aspirin-induced asthma should require an NSAID for the treatment of another condition, such as arthritis, then the patient can be desensitized to aspirin. This procedure should be undertaken by doctors with experience in aspirin challenge.
Treatment of respiratory disease These patients often have severe chronic asthma and nasal disease, which should be treated along similar lines to that of patients with chronic asthma who are not sensitive to NSAIDs. Pretreatment with a number of drugs, including sodium cromoglycate, the H1 receptor antagonist clemastine, and ketotifen, can inhibit the bronchoconstrictor response to aspirin ingestion in patients with aspirin-induced asthma. A small percentage of patients with aspirin-induced asthma develop bronchoconstriction after an intravenous injection of hydrocortisone, and occasionally the bronchoconstriction can be severe. These patients do not react adversely to other intravenous steroids such as methylprednisolone, dexamethasone,
40
or betamethasone. Although cys LTs have been implicated in the pathogenesis of aspirin-induced asthma, LT receptor antagonists and a 5 -lipoxygenase’ inhibitor have not been found to be any more effective than in nonsensitive asthmatic patients [20].
Desensitization Following the administration of oral or inhaled aspirin to patients with aspirin-induced asthma there is a refractory period to further aspirin challenge, which lasts for 2–5 days. Continued administration of aspirin on a daily basis will maintain this refractory state, and this effect has been termed desensitization. The process of outpatient desensitization is safe [21] and results in desensitization not only to aspirin but also to other NSAIDs. Those patients who react to small doses of aspirin require several aspirin challenges before desensitization is accomplished, whereas less aspirin-sensitive patients are more quickly desensitized. The process by which aspirin ingestion causes desensitization is unknown.
β-BLOCKERS Nonselective and cardioselective β-blockers Nonselective β-adrenergic receptor antagonists precipitate acute bronchoconstriction in asthma, even in individuals with mild disease [22], and attacks can be fatal. The dose of βblockers that causes bronchospasm may be low and there are case reports of severe asthma attacks induced by eye drops of timolol, a nonselective β-blocker used to treat glaucoma [23]. Compared to individuals with asthma, patients with chronic obstructive airways disease (COPD) are less likely to develop deterioration in lung function after a nonselective β-adrenergic receptor antagonist [24], although there are a few case reports of acute bronchospasm induced by nonselective β-blockers [25]. In patients with COPD who have acute exacerbations there is no evidence that β-blockers are detrimental and may even reduce mortality [26]. A meta-analysis of 19 studies on single-dose treatment and 10 studies on continued treatment with cardioselective β1-blockers concluded that this group of drugs does not precipitate bronchospasm in patients with mild to moderate reactive airway disease [27]. Nevertheless there are case reports of individuals with asthma who have developed bronchospasm due to cardioselective β-blockers [28]. Thus despite the recommendation that cardioselective β-blockers should not be withheld from patients with mild to moderate asthma [27] it seems prudent to administer these drugs with great care to patients with moderate persistent asthma and to avoid their use in individuals with severe persistent asthma [28]. A recent systematic review of 20 studies of cardioselective β-blockers given to patients with COPD found no evidence of adverse effects on lung function or on the response to β2-agonists [25, 29]. Acute bronchospasm induced by a nonselective β-blocker should be treated with an inhaled anticholinergic bronchodilator such as ipratropium or oxitropium [30]. 517
Asthma and COPD: Basic Mechanisms and Clinical Management Any fall in lung function due to a cardioselective β1-blocker can be reversed by an inhaled short-acting β2-agonist.
Normal
Adrenaline β-blocker
Possible mechanisms β-blocker-induced bronchoconstriction occurs in individuals with asthma, but not in healthy subjects, which suggests that endogenous activation of β-receptors is important in maintaining airway tone in asthma against neural and inflammatory bronchoconstrictor stimuli.
β2
Cholinergic nerve
M3 M2 Adrenaline Asthma β-blocker
Circulating catecholamines β-blockers could antagonize the bronchodilator effect of circulating catecholamines in patients with asthma but not in normal subjects. However, against this suggestion, circulating catecholamines are not elevated in asthmatic subjects, even in those subjects who have demonstrable bronchoconstriction after propranolol and the concentrations of adrenaline in plasma (0.3 nmol/l) are too low to have a direct effect on human airway smooth muscle tone [31, 32]. β-Blockers may inhibit the action of catecholamines on some other target cell, such as airway mast cells or cholinergic nerves. Mediator release from human lung mast cells is potently inhibited by β-agonists [33]. The effect of β-blockers may, therefore, be an increase in mediator release, which may be more marked in the “ leaky ” mast cells of asthmatic individuals. This idea is supported by the observation that cromolyn sodium, a mast cell “stabilizer,” prevents the bronchoconstriction produced by inhaled propranolol. However after intravenous propranolol, no increase in plasma histamine has been detected [34].
Neural pathways A more likely explanation for β-blocker-induced asthma is that there is an increase in neural bronchoconstrictor mechanisms. β2-adrenergic receptors on cholinergic nerves in human airways may be tonically activated by adrenaline to modulate acetylcholine (ACh) release [35] and therefore to dampen cholinergic tone. Blockage of these receptors would therefore increase the amount of ACh released tonically, but this would be compensated for by the increased stimulation of prejunctional M2-autoreceptors, which would act homeostatically to inhibit any increase in ACh release and therefore no increase in airway tone would occur, even with high doses of a β-blocker. By contrast, in patients with asthma β-blockers inhibit prejunctional β-receptors in the same way, increasing the release of ACh [36]; however, there may be a defect in M2-receptor function in asthmatic airways, so that the increased release in ACh cannot be compensated. Thus increased ACh reaches M3 receptors on airway smooth muscle. In addition, bronchoconstrictor responses to ACh are exaggerated in asthma, a manifestation of airway hyperresponsiveness, and thus two interacting amplifying mechanisms may lead to marked bronchoconstriction (Fig. 40.2). Evidence to support this hypothesis is provided by the inhibitory effect of an inhaled anticholinergic drug oxitropium bromide on β-blocker-induced asthma [30]. In patients with more severe asthma there may be an additional neural mechanism by which β-blockers may 518
No effect
ACh
ACh
Autoreceptor dysfunction
Bronchoconstriction
Cholinergic hyperresponsiveness
FIG. 40.2 Possible mechanisms of β-blocker-induced asthma. Blockade of prejunctional β2-receptors on cholinergic nerves in normal individuals results in increased release of acetylcholine (ACh), but this is compensated by stimulation of prejunctional muscarinic M2 receptors to inhibit any increase in ACh. In patients with asthma, prejunctional M2 receptors are dysfunctional, so that there is a net release of ACh; ACh also has a greater bronchoconstrictor effect on the airways due to airway hyperresponsiveness.
cause bronchoconstriction. β2-adrenergic receptors inhibit the release of tachykinins from airway sensory nerves [37], thus β-blockers may increase the release of these neuropeptides, thereby increasing bronchoconstriction and airway inflammation. While this mechanism may not be relevant in patients with mild asthma, in whom cholinergic mechanisms appear to account for the bronchoconstrictor response to β-blockers [30], it may be relevant in more severely affected asthmatic patients in whom cholinergic mechanisms do not appear to be as important.
Inverse agonism Another possible mechanism may be related to the recently recognized phenomenon of inverse agonism [38]. It has been found that some mutants of the β-receptor have constitutive activity and activate the coupling protein Gs, even in the absence of occupation by agonist. In this situation β-blockers function as inverse agonists and have an inhibitory effect on baseline function. It is possible that in asthmatic patients β2-receptors are constitutively active, so that β-blockers result in adverse effects. Different β-blockers have differing potencies as inverse agonists that are unrelated to their β-blocking potency. Thus, propranolol is a potent inverse agonist whereas pindolol is not and this may relate to the different tendency of these two agents to induce asthma. It has recently been suggested that some β-blockers with inverse agonist activity may even be beneficial in asthma when used chronically [39]. In murine models β-blockers with inverse agonist activity (nadolol and carvedilol) increased β2-receptor expression and caused bronchodilation [40]. In a pilot open study nadolol has been reported to be safe in asthmatic patients and to reduce airway
Drugs hyperresponsiveness [41]. Further controlled studies may therefore be indicated.
ANGIOTENSIN CONVERTING ENZYME INHIBITORS A retrospective cohort study suggested that bronchospasm was twice as common in patients treated with angiotensin converting enzyme (ACE) inhibitors (5.5%) compared to the reference group treated with lipid-lowering drugs (2.3%) [42]. However, the prevalence of a past history of bronchospasm in patients reporting ACE inhibitorinduced bronchospasm was not significantly different from the prevalence in patients on ACE inhibitors without an adverse reaction [42]. In a controlled trial in asthmatic and hypersensitive patients (with and without cough), there was no change in lung function following administration of captopril and no increase in reactivity to histamine or bradykinin [43]. Similar findings were obtained in a group of 21 patients with asthma given ACE inhibitors for 3 weeks, although one subject developed a slight wheeze [44]. Administration of a potent ACE inhibitor (ramipril) to a group of individuals with mild asthma showed no change in lung function or bronchial reactivity to inhaled histamine, nor was there any increase in bronchoconstrictor response to inhaled bradykinin [45]. Taken together these findings suggest that ACE inhibitors are unlikely to worsen asthma in the majority of patients, although there may be occasional patients in whom this occurs. When there is a possibility that asthma has been worsened or precipitated by an ACE inhibitor, the drug should be withdrawn and an alternative agent selected. As many as 20% of hypertensive patients treated with ACE inhibitors may develop an irritant cough, although this is unrelated to the presence of underlying airway disease or atopic status.
ADDITIVES Several chemicals used as additives in drug preparations and food have been associated with worsening of asthma and should, where possible, be avoided. Bisulphites and metabisulphites (E220, E221, E222, E226, and E227) are antioxidants used as preservatives in several foods, including wines (especially sparkling wines), beer, fruit juices, salads, and medications. Characteristically, they produce bronchoconstriction within 30 min of ingestion and this may account for several cases of “food allergy.” The mechanism of metabisulphite-induced asthma is probably explained by release of sulfur dioxide (SO2) after ingestion that is then inhaled, since nebulized metabisulphite solutions generate SO2 in sufficient quantities to provoke bronchoconstriction in asthmatic subjects [46]. Tartrazine (E102), a yellow dye, is used as a coloring in many foods, beverages (such as orange squash), and pharmaceutical preparations. Tartrazine
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sensitivity is relatively common and may affect 4% of asthmatic individuals, especially children [9]. Ingestion of tartrazine may result in urticarial rashes and bronchoconstriction. The mechanism may depend upon mediator release from mast cells. Monosodium glutamate (MSG, E621) is added to food as a flavor enhancer. It is found in soy sauce, spices, stock cubes, hamburgers, and in Chinese restaurant food. Some people react with sweating, flushing, and numbness of the chest; in patients with asthma this may be accompanied by wheezing, which may begin several hours after the ingestion (“Chinese restaurant asthma syndrome”) [47] Precipitation of asthma symptoms by MSG is uncommon, however.
LOCAL ANESTHETICS Aerosols of the local anesthetics, such as bupivacaine and lignocaine (lidocaine), cause bronchoconstriction in a proportion of asthmatic patients [48, 49]. The degree of bronchial reactivity to histamine does not predict the development or extent of bronchoconstriction following lignocaine inhalation [49]. The mechanism of local anesthetic-induced bronchoconstriction is unclear. Pretreatment with anticholinergic drugs partially attenuates the bronchoconstrictor response to aerosols of local anesthetics, suggesting that they may be acting in part via a vagal reflex pathway. Inhaled local anesthetics may selectively inhibit nonadrenergic noncholinergic bronchodilator nerves and so allow unopposed vagal tone. Some evidence for this is provided by the demonstration that lignocaine inhalation blocks nonadrenergic noncholinergic reflex bronchodilation in human subjects, leading to a reflex bronchoconstrictor response [50]. It is important to be aware that some patients with asthma may develop bronchoconstriction with topical local anesthetics during fiber optic bronchoscopy. All patients with asthma should receive premedication with a bronchodilator prior to bronchoscopy.
OTHER DRUGS Many other drugs have been reported to lead to exacerbation of asthma in occasional patients. Bronchoconstriction may constitute part of an anaphylactic reaction to a drug, such as penicillin or to intravenous dextran or to contrast media. Other drugs, such as opiates, may cause direct degranulation of mast cells. Bronchodilator aerosols may occasionally cause a paradoxical bronchoconstriction. This is presumed to be due to the propellant (Freon) or other additives (such as oleic acid, which is used as a surfactant). The mechanism of bronchoconstriction may be via a cholinergic reflex. The treatment of paracetamol poisoning with intravenous N-acetylcysteine has been reported to exacerbate asthma. Cholinergic agents such as pilocarpine, used for the treatment of dry mouth and pyridostigmine, used to treat myasthenia gravis can induce attacks of asthma. 519
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Drugs NONSTEROIDAL ANTIINFLAMMATORY DRUGS Introduction In the early part of the 20th century it was first recognized that aspirin could precipitate asthma in susceptible individuals [1]. Similar asthmatic reactions were later shown to occur with other nonsteroidal anti-inflammatory drugs (NSAIDs) [2] and patients with aspirin-induced asthma were found to be sensitive to other cyclooxygenase (COX)-1 inhibitors. Various terms have been used to describe the sensitivity to NSAIDs, including aspirin-induced asthma, aspirin-sensitive asthma, aspirin hypersensitivity, idiosyncratic reaction to aspirin, aspirin intolerance, and nonallergic hypersensitivity reactions to aspirin and NSAIDs [3].
Prevalence The prevalence of hypersensitivity reactions to aspirin and NSAIDs in individuals with asthma is unclear, with estimates ranging from 4.3% to 21% [4–6]. The prevalence figures are higher when determined by oral provocation testing (e.g. 21% in adults and 5% in children [6]). Oral aspirin challenges undertaken in subgroups of patients with asthma, nasal polyps, and chronic sinusitis attending specialized allergy centers provide high positive rates of 30% or greater.
Clinical features Aspirin-induced asthma is characterized by the development of bronchoconstriction within
minutes to several hours after the ingestion of aspirin or other NSAIDs [2, 3]. The asthmatic reaction can be associated with other symptoms, including rhinorrhea, flushing, and loss of consciousness, and very rarely the attack may be fatal. In the typical case, symptoms of chronic rhinitis are present for many years before asthma develops. The rhinitis starts as intermittent watery rhinorrhea, which develops during the second or third decade of life. The rhinorrhea becomes progressively more severe and is complicated by nasal polyp formation and sinusitis. On average 2 years later symptoms of asthma appear associated with the development of acute asthma after the ingestion of COX-1 inhibitors. Although in this group drugs may precipitate asthma, these patients continue to have nasal and asthmatic symptoms in the absence of ingesting aspirin or other NSAIDs. Respiratory symptoms are often chronic, severe, and perennial in nature. Individuals with aspirininduced asthma are more commonly female. Skin tests to common external allergens are positive in a third to over a half of subjects. A small percentage of patients with aspirin-induced asthma also develop associated symptoms of urticaria and angioedema after ingestion of aspirin.
CHAPTER
Neil C. Thomson1 and Peter J. Barnes2 1
Department of Respiratory Medicine, Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, UK 2 National Heart and Lung Institute (NHLI), Clinical Studies Unit, Imperial College, London, UK
Diagnosis In most clinical circumstances, the diagnosis is based on a history of bronchoconstriction following the ingestion of a COX-1 inhibitor. It should be appreciated, however, that a history of either the presence or the absence of aspirininduced asthma may result in both a false positive and a false negative diagnosis. For example, patients with a history of aspirin-induced asthma have a positive oral aspirin challenge in approximately 60% to over 90% of cases. A negative oral 515
Asthma and COPD: Basic Mechanisms and Clinical Management challenge may occur in patients with a history of aspirininduced asthma due to changing responsiveness to aspirin, a high threshold to aspirin, or a misleading history. The only reliable method of establishing a diagnosis of aspirin-induced asthma is by aspirin challenge. Oral aspirin challenge is indicated in patients with adult asthma who require treatment with an NSAID. The oral challenge procedure has been reported to be safe, if a standardized protocol is used [3, 7]. An alternative but less widely used method of detecting aspirin-induced asthma involves administering aspirin-lysine by inhalation [7]. It is claimed that this method is safe and when compared to oral challenge the procedure is shorter and the reaction is localized to the respiratory tract. Aspirin-lysine administered as a nasal challenge has also been used to diagnose aspirin-sensitive asthma and this technique does not induce bronchoconstriction [8]. No in vitro test is currently available to detect aspirin-induced asthma. Tartrazine is a yellow dye used for coloring foods and drugs such as confectionery, soft drinks, antibiotics, and antihistamines. A number of earlier reports suggested that tartrazine caused bronchospasm in some patients with aspirin-induced asthma, but further research has failed to support any cross-reactivity between tartrazine and aspirin in patients with aspirin-induced asthma [9].
Mechanisms Alterations in the arachidonic acid pathway A characteristic feature of patients with aspirin-induced asthma is the occurrence of airway obstruction following the ingestion of drugs which inhibit COX-1, the enzyme that converts arachidonic acid into prostaglandins (PG) and
thromboxane. An abnormality in the arachidonic acid pathway in the respiratory tract of patients with aspirin-induced asthma seems to be central to the development of an asthmatic attack after the ingestion of NSAIDs (Fig. 40.1). In support of this hypothesis, the severity of bronchoconstriction induced by aspirin or other NSAIDs, such as indomethacin, flufenamic acid, and naproxen, is directly proportional to their ability to inhibit COX in vitro. Furthermore, specimens of nasal polyps removed from patients with aspirininduced asthma are more sensitive to the inhibition effects of aspirin on the COX-1 pathway. The influence of PG on bronchomotor tone may differ between patients with or without aspirin-induced asthma. The control of airway caliber in the latter group could be more dependent on the effects of PG, such as PGE2, either due to its direct bronchodilator activity or indirectly by suppression of the release of bronchoconstrictor mediators. Alternately, the production of PGE2 may be impaired in these individuals. In support of this later mechanism, peripheral blood mononuclear cells release reduced amounts of PGE2 in patients with aspirin-induced asthma [10], although a recent clinical challenge study with aspirin found that urinary metabolites of PGE2 were not altered in patients with aspirin-induced asthma [11]. The expression of the E-prostanoid (EP) 2 receptor for PGE2 is reduced in nasal tissue of patients with aspirin-induced asthma [12] and polymorphisms in the promoter region of the gene coding for the EP2 gene are associated with sensitivity to aspirin [13]. The lipoxygenase pathway also appears to be abnormal in these individuals, since the synthesis of leukotriene (LT) E4 is frequently increased in aspirin-induced asthma [14], the expression of cys LT1 receptors is increased in nasal inflammatory cells [15], and leukotriene C4 synthase
Membrane phospholipids Aspirin Arachidonic acid
5-LO and FLAP
Cox-1 and Cox-2
LTA4 LTA2 hydrolase
LTB4
PGH2
TBxA2 synthase PG synthase, Isomerase and reductase
LTC4 synthase ↑
LTC4, LTD4, LTE4 2
TBxA2
PGI2
PGD2
PGE2
PGF2
1
cys LT1 receptor
EP2 receptor
Bronchoconstriction
Bronchodilation
FIG. 40.1 Biosynthetic pathways leading to the production of LT and PG. Possible mechanisms by which aspirin and NSAIDs inhibit COX-1 to induce bronchoconstriction: (1) Impaired PGE2 synthesis and/or reduced PGE2 receptor function. (2) Increased cys LT synthesis and/or increased cys LT1 receptor function. 5-LO: 5-lipoxygenase; FLAP: 5-lipoxygenase-activating protein; TBxA2: thromboxane A2; PGI2: prostacyclin.
516
Drugs (LTC4S), an enzyme involved in the synthesis of LTs, is often overexpressed in eosinophils and in bronchial tissue [16]. Furthermore, genetic polymorphisms of LTC4S promoter region have been found in some patients with aspirinsensitive asthma [17], but this has not been confirmed in other populations [18]. Taken together, these findings point to abnormalities in the arachidonic acid pathway in patients sensitive to NSAIDs in particular impaired PGE2 synthesis and actions and excessive LT synthesis and effects. There is, however, an overlap in some of the defects in the arachidonic acid pathway found in patients with aspirin-induced asthma when compared with individuals without sensitivity to NSAIDs, suggesting that the exact mechanisms underlying aspirininduced asthma are not yet fully elucidated.
Other mechanisms There is no convincing evidence that aspirin-induced asthma is due to IgE-mediated mechanisms. For example, specific anti-aspiryl IgE antibodies are generally absent and skin tests to aspiryl-polylysine are negative in these patients. Basal and post-aspirin challenge complement levels are not altered in patients with aspirin-induced asthma. Inflammatory mediators are released following aspirin challenge, such as neutrophil chemotactic factor, but this is thought to be secondary to the primary biochemical events.
Management Avoidance Patients with a history of acute bronchoconstrictor response after the ingestion of NSAIDs must be warned to avoid these drugs. If they require a simple analgesic, then acetaminophen (paracetamol) is usually safe in doses up to 500 mg. Cross-reactivity can occur with high doses of acetaminophen (paracetamol), which is a weak inhibitor of COX-1, although the respiratory reaction tends to be mild. There is considerable data to indicate that COX-2 inhibitors do not induce bronchoconstriction in individuals sensitive to aspirin [19], although a few case reports of reactions have been published. If a patient with aspirin-induced asthma should require an NSAID for the treatment of another condition, such as arthritis, then the patient can be desensitized to aspirin. This procedure should be undertaken by doctors with experience in aspirin challenge.
Treatment of respiratory disease These patients often have severe chronic asthma and nasal disease, which should be treated along similar lines to that of patients with chronic asthma who are not sensitive to NSAIDs. Pretreatment with a number of drugs, including sodium cromoglycate, the H1 receptor antagonist clemastine, and ketotifen, can inhibit the bronchoconstrictor response to aspirin ingestion in patients with aspirin-induced asthma. A small percentage of patients with aspirin-induced asthma develop bronchoconstriction after an intravenous injection of hydrocortisone, and occasionally the bronchoconstriction can be severe. These patients do not react adversely to other intravenous steroids such as methylprednisolone, dexamethasone,
40
or betamethasone. Although cys LTs have been implicated in the pathogenesis of aspirin-induced asthma, LT receptor antagonists and a 5 -lipoxygenase’ inhibitor have not been found to be any more effective than in nonsensitive asthmatic patients [20].
Desensitization Following the administration of oral or inhaled aspirin to patients with aspirin-induced asthma there is a refractory period to further aspirin challenge, which lasts for 2–5 days. Continued administration of aspirin on a daily basis will maintain this refractory state, and this effect has been termed desensitization. The process of outpatient desensitization is safe [21] and results in desensitization not only to aspirin but also to other NSAIDs. Those patients who react to small doses of aspirin require several aspirin challenges before desensitization is accomplished, whereas less aspirin-sensitive patients are more quickly desensitized. The process by which aspirin ingestion causes desensitization is unknown.
β-BLOCKERS Nonselective and cardioselective β-blockers Nonselective β-adrenergic receptor antagonists precipitate acute bronchoconstriction in asthma, even in individuals with mild disease [22], and attacks can be fatal. The dose of βblockers that causes bronchospasm may be low and there are case reports of severe asthma attacks induced by eye drops of timolol, a nonselective β-blocker used to treat glaucoma [23]. Compared to individuals with asthma, patients with chronic obstructive airways disease (COPD) are less likely to develop deterioration in lung function after a nonselective β-adrenergic receptor antagonist [24], although there are a few case reports of acute bronchospasm induced by nonselective β-blockers [25]. In patients with COPD who have acute exacerbations there is no evidence that β-blockers are detrimental and may even reduce mortality [26]. A meta-analysis of 19 studies on single-dose treatment and 10 studies on continued treatment with cardioselective β1-blockers concluded that this group of drugs does not precipitate bronchospasm in patients with mild to moderate reactive airway disease [27]. Nevertheless there are case reports of individuals with asthma who have developed bronchospasm due to cardioselective β-blockers [28]. Thus despite the recommendation that cardioselective β-blockers should not be withheld from patients with mild to moderate asthma [27] it seems prudent to administer these drugs with great care to patients with moderate persistent asthma and to avoid their use in individuals with severe persistent asthma [28]. A recent systematic review of 20 studies of cardioselective β-blockers given to patients with COPD found no evidence of adverse effects on lung function or on the response to β2-agonists [25, 29]. Acute bronchospasm induced by a nonselective β-blocker should be treated with an inhaled anticholinergic bronchodilator such as ipratropium or oxitropium [30]. 517
Asthma and COPD: Basic Mechanisms and Clinical Management Any fall in lung function due to a cardioselective β1-blocker can be reversed by an inhaled short-acting β2-agonist.
Normal
Adrenaline β-blocker
Possible mechanisms β-blocker-induced bronchoconstriction occurs in individuals with asthma, but not in healthy subjects, which suggests that endogenous activation of β-receptors is important in maintaining airway tone in asthma against neural and inflammatory bronchoconstrictor stimuli.
β2
Cholinergic nerve
M3 M2 Adrenaline Asthma β-blocker
Circulating catecholamines β-blockers could antagonize the bronchodilator effect of circulating catecholamines in patients with asthma but not in normal subjects. However, against this suggestion, circulating catecholamines are not elevated in asthmatic subjects, even in those subjects who have demonstrable bronchoconstriction after propranolol and the concentrations of adrenaline in plasma (0.3 nmol/l) are too low to have a direct effect on human airway smooth muscle tone [31, 32]. β-Blockers may inhibit the action of catecholamines on some other target cell, such as airway mast cells or cholinergic nerves. Mediator release from human lung mast cells is potently inhibited by β-agonists [33]. The effect of β-blockers may, therefore, be an increase in mediator release, which may be more marked in the “ leaky ” mast cells of asthmatic individuals. This idea is supported by the observation that cromolyn sodium, a mast cell “stabilizer,” prevents the bronchoconstriction produced by inhaled propranolol. However after intravenous propranolol, no increase in plasma histamine has been detected [34].
Neural pathways A more likely explanation for β-blocker-induced asthma is that there is an increase in neural bronchoconstrictor mechanisms. β2-adrenergic receptors on cholinergic nerves in human airways may be tonically activated by adrenaline to modulate acetylcholine (ACh) release [35] and therefore to dampen cholinergic tone. Blockage of these receptors would therefore increase the amount of ACh released tonically, but this would be compensated for by the increased stimulation of prejunctional M2-autoreceptors, which would act homeostatically to inhibit any increase in ACh release and therefore no increase in airway tone would occur, even with high doses of a β-blocker. By contrast, in patients with asthma β-blockers inhibit prejunctional β-receptors in the same way, increasing the release of ACh [36]; however, there may be a defect in M2-receptor function in asthmatic airways, so that the increased release in ACh cannot be compensated. Thus increased ACh reaches M3 receptors on airway smooth muscle. In addition, bronchoconstrictor responses to ACh are exaggerated in asthma, a manifestation of airway hyperresponsiveness, and thus two interacting amplifying mechanisms may lead to marked bronchoconstriction (Fig. 40.2). Evidence to support this hypothesis is provided by the inhibitory effect of an inhaled anticholinergic drug oxitropium bromide on β-blocker-induced asthma [30]. In patients with more severe asthma there may be an additional neural mechanism by which β-blockers may 518
No effect
ACh
ACh
Autoreceptor dysfunction
Bronchoconstriction
Cholinergic hyperresponsiveness
FIG. 40.2 Possible mechanisms of β-blocker-induced asthma. Blockade of prejunctional β2-receptors on cholinergic nerves in normal individuals results in increased release of acetylcholine (ACh), but this is compensated by stimulation of prejunctional muscarinic M2 receptors to inhibit any increase in ACh. In patients with asthma, prejunctional M2 receptors are dysfunctional, so that there is a net release of ACh; ACh also has a greater bronchoconstrictor effect on the airways due to airway hyperresponsiveness.
cause bronchoconstriction. β2-adrenergic receptors inhibit the release of tachykinins from airway sensory nerves [37], thus β-blockers may increase the release of these neuropeptides, thereby increasing bronchoconstriction and airway inflammation. While this mechanism may not be relevant in patients with mild asthma, in whom cholinergic mechanisms appear to account for the bronchoconstrictor response to β-blockers [30], it may be relevant in more severely affected asthmatic patients in whom cholinergic mechanisms do not appear to be as important.
Inverse agonism Another possible mechanism may be related to the recently recognized phenomenon of inverse agonism [38]. It has been found that some mutants of the β-receptor have constitutive activity and activate the coupling protein Gs, even in the absence of occupation by agonist. In this situation β-blockers function as inverse agonists and have an inhibitory effect on baseline function. It is possible that in asthmatic patients β2-receptors are constitutively active, so that β-blockers result in adverse effects. Different β-blockers have differing potencies as inverse agonists that are unrelated to their β-blocking potency. Thus, propranolol is a potent inverse agonist whereas pindolol is not and this may relate to the different tendency of these two agents to induce asthma. It has recently been suggested that some β-blockers with inverse agonist activity may even be beneficial in asthma when used chronically [39]. In murine models β-blockers with inverse agonist activity (nadolol and carvedilol) increased β2-receptor expression and caused bronchodilation [40]. In a pilot open study nadolol has been reported to be safe in asthmatic patients and to reduce airway
Drugs hyperresponsiveness [41]. Further controlled studies may therefore be indicated.
ANGIOTENSIN CONVERTING ENZYME INHIBITORS A retrospective cohort study suggested that bronchospasm was twice as common in patients treated with angiotensin converting enzyme (ACE) inhibitors (5.5%) compared to the reference group treated with lipid-lowering drugs (2.3%) [42]. However, the prevalence of a past history of bronchospasm in patients reporting ACE inhibitorinduced bronchospasm was not significantly different from the prevalence in patients on ACE inhibitors without an adverse reaction [42]. In a controlled trial in asthmatic and hypersensitive patients (with and without cough), there was no change in lung function following administration of captopril and no increase in reactivity to histamine or bradykinin [43]. Similar findings were obtained in a group of 21 patients with asthma given ACE inhibitors for 3 weeks, although one subject developed a slight wheeze [44]. Administration of a potent ACE inhibitor (ramipril) to a group of individuals with mild asthma showed no change in lung function or bronchial reactivity to inhaled histamine, nor was there any increase in bronchoconstrictor response to inhaled bradykinin [45]. Taken together these findings suggest that ACE inhibitors are unlikely to worsen asthma in the majority of patients, although there may be occasional patients in whom this occurs. When there is a possibility that asthma has been worsened or precipitated by an ACE inhibitor, the drug should be withdrawn and an alternative agent selected. As many as 20% of hypertensive patients treated with ACE inhibitors may develop an irritant cough, although this is unrelated to the presence of underlying airway disease or atopic status.
ADDITIVES Several chemicals used as additives in drug preparations and food have been associated with worsening of asthma and should, where possible, be avoided. Bisulphites and metabisulphites (E220, E221, E222, E226, and E227) are antioxidants used as preservatives in several foods, including wines (especially sparkling wines), beer, fruit juices, salads, and medications. Characteristically, they produce bronchoconstriction within 30 min of ingestion and this may account for several cases of “food allergy.” The mechanism of metabisulphite-induced asthma is probably explained by release of sulfur dioxide (SO2) after ingestion that is then inhaled, since nebulized metabisulphite solutions generate SO2 in sufficient quantities to provoke bronchoconstriction in asthmatic subjects [46]. Tartrazine (E102), a yellow dye, is used as a coloring in many foods, beverages (such as orange squash), and pharmaceutical preparations. Tartrazine
40
sensitivity is relatively common and may affect 4% of asthmatic individuals, especially children [9]. Ingestion of tartrazine may result in urticarial rashes and bronchoconstriction. The mechanism may depend upon mediator release from mast cells. Monosodium glutamate (MSG, E621) is added to food as a flavor enhancer. It is found in soy sauce, spices, stock cubes, hamburgers, and in Chinese restaurant food. Some people react with sweating, flushing, and numbness of the chest; in patients with asthma this may be accompanied by wheezing, which may begin several hours after the ingestion (“Chinese restaurant asthma syndrome”) [47] Precipitation of asthma symptoms by MSG is uncommon, however.
LOCAL ANESTHETICS Aerosols of the local anesthetics, such as bupivacaine and lignocaine (lidocaine), cause bronchoconstriction in a proportion of asthmatic patients [48, 49]. The degree of bronchial reactivity to histamine does not predict the development or extent of bronchoconstriction following lignocaine inhalation [49]. The mechanism of local anesthetic-induced bronchoconstriction is unclear. Pretreatment with anticholinergic drugs partially attenuates the bronchoconstrictor response to aerosols of local anesthetics, suggesting that they may be acting in part via a vagal reflex pathway. Inhaled local anesthetics may selectively inhibit nonadrenergic noncholinergic bronchodilator nerves and so allow unopposed vagal tone. Some evidence for this is provided by the demonstration that lignocaine inhalation blocks nonadrenergic noncholinergic reflex bronchodilation in human subjects, leading to a reflex bronchoconstrictor response [50]. It is important to be aware that some patients with asthma may develop bronchoconstriction with topical local anesthetics during fiber optic bronchoscopy. All patients with asthma should receive premedication with a bronchodilator prior to bronchoscopy.
OTHER DRUGS Many other drugs have been reported to lead to exacerbation of asthma in occasional patients. Bronchoconstriction may constitute part of an anaphylactic reaction to a drug, such as penicillin or to intravenous dextran or to contrast media. Other drugs, such as opiates, may cause direct degranulation of mast cells. Bronchodilator aerosols may occasionally cause a paradoxical bronchoconstriction. This is presumed to be due to the propellant (Freon) or other additives (such as oleic acid, which is used as a surfactant). The mechanism of bronchoconstriction may be via a cholinergic reflex. The treatment of paracetamol poisoning with intravenous N-acetylcysteine has been reported to exacerbate asthma. Cholinergic agents such as pilocarpine, used for the treatment of dry mouth and pyridostigmine, used to treat myasthenia gravis can induce attacks of asthma. 519
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