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Clinical pharmacology and toxicology of ipratropium bromide
Clinical Pharmacology and Toxicology of lpratropium Bromide
Anticholinergic drugs inhibit a variety of intrapulmonary events related to airflow obstructiqn. When administered as an inhaled aerosol, approximately 90 percent of ipratropium bromide (as with betaadrenergic aerosols) can @e assumed to be swallowed. Peak pharmacologic effects occur prior to any detectable plasma drug concentrations. lpratropium does not exhibit the well-known toxic effects of atropine, and doses many times those required for maximum therapeutic benefit do not produce any effects on the eye, urinary bladder, heart rate, or mucociliary function. lpratropium seems to act primarily on large- and intermediate-size ainnays; beta-adrenergic agents, on the other hand, appear to act primarily on the smaller airways. The drug is a promising addition to the therapeutic armamentarium, and may be especially use$~l in certain groups of patients whose condition is less responsive to other agents.
DAVID W. CUGELL, M.D. Chicago,
Illinois
Pharmacologically active anticholinergic alkaloids exist in the roots, seeds, and leaves of a variety of piants, and their use for the relief of respiratory symptoms originated thousands of years ago in India [l]. These and other substances were prepare@ as combustible powders, and the inhalation of the smoke they produced was a practice gradually incorporated into Western medicine during the early 19th century 111. Smoke from the leaves of the stramonium plant became the preparation of choice for the relief of bronchospasm. That the active principle of stramonium is atropine has been known since the 1830s [l]. Medical writings from those times clearly describe the signs and symptoms of atropine overdose with stramonium, and warn of stramonium’s narrow therapeutic range. With the introduction of ephedrine and epinephrine during the 20th century, the use of atropine and related substances for relief of bronchospasm declined and, except for unusual or obstinate cases, virtually disappeared from use. The development of the quaternaty methyl isopropyl derivative of atropine, ipratropium bromide, has awakened new interest in anticholinergic bronchodilation. Its unique advantage over other anticholinergic drugs is a high degree of bronchoselectivity in very small doses when delivered by inhalation. The basic pharmacology of this compound was studied 10 to 15 years ago; recent studies of ipratropium have been directed toward iden!ifying its site of action in human airways, side effects, potential toxicity, combined use with other bronchodilators, and clinical effectiveness. This article highlights these many aspects of the drug’s pharmacology and toxicology. From the Northwestern University Medical School, Chicago, Illinois. Requests for reprints should be addressed to Dr. David W. Cugell, Northwestern Memorial Hospital, 250 East Superior Street, Room 454, Chicago, Illinois 60611.
16
November
14,1986
The
Americen
Journal
ABSORPTION, ORGAN ACTIVITV, AND SPECIFICITY The spectrum of activity of ipratropium bromide when delivered systemitally is similar to that of atropine with respect to inhibition of salivation and gastric secretion, mydriasis, tachycardia, and urinary bladder function.
of Medicine
Volume
81
(suppl5A)
SYMPOSIUM
Significant differences between the two drugs are that the effectiveness of ipratropium is lacking in the central nervous system, and poor gastric absorption of the drug is demonstrated. The limited gastric absorption of ipratropium is clinically important. Studies with radiolabeled beta agonists have shown that, following aerosol administration, approximately 90 percent of the drug is swallowed [2]. Although no comparable studies have been done with aerosolized ipratropium, there seems little reason to doubt that a similar proportion of the administered dose is also swallowed. It is significant then that little ipratropium is absorbed from the stomach; what is absorbed is broken down to metabolites with essentially no pharmacologic effects, and within 24 hours, half of an aerosol dose (presumably, mostly swallowed drug) appears in the feces [3,4]. lpratropium is highly selective in its effect on bronchial smooth muscle. However, its efficacy differs markedly depending on the route of administration; this is clearly shown in Table I, which has been adapted from a report by Bauer and colleagues [5]. The amount of ipratropium required to inhibit acetylcholine-induced bronchoconstriction in dogs by 50 percent when the drug is administered intravenously is 10 times the dose that is required when the drug is given by inhalation. The most sensitive side effect of anticholinergic drugs is the inhibition of salivary secretions [5]. Fortunately, with ipratropium this and other side effects appear only at doses that are much higher than the therapeutic dose. When the drug is given intravenously, it takes IO times as much to inhibit salivary secretion as it takes to inhibit acetylcholine-induced bronchoconstriction. When ipratropium is given via the aerosol route, that same ratio is increased to almost 300 to one. The safety margin for tachycardia is even greater [5,6]. In their study, Bauer and co-workers administered equipotent doses of ipratropium-amounts sufficient to produce equivalent bronchodilation-via the oral, intravenous, and inhalation routes, and plasma drug levels were followed for the subsequent 12 hours. Figure 1 shows that the plasma levels recorded following oral and intravenous administration were three to four orders of magnitude higher than the plasma level following inhalation. In fact, plasma levels are so low following therapeutically effective aerosol doses that systematic pharmacokinetic studies cannot be done. The elimination half-life of ipratropium is 3.2 to 3.8 hours regardless of the route of administration [7]. MODE AND SITE OF ACTION
TABLE
OBSTRUCTIVE
AIRWAYS
DISEASE-CUGELL
Selectivity of lpratropium Administered Intravenously and by Inhalation
I
Intravenous
Bronchospasmolysis Inhibition of salivation Tachycardia*
inhalation EC5,, (percent
ED50 (/.@!!I*
0.15 1.5 15.0
aerosol)t
0.014 4.0 >lO.O
*EDs0 = effective dose needed to inhibit acetylcholine-induced bronchoconstriction or pilocarpine-induced salivation in anesthetized dogs by 50 percent. +ECSO = effective concentration of an aqueous aerosol that will produce a similar inhibition of bronchospasm and salivary secretions. *Values shown indicate dose that will produce an increase in heart rate of 10 to 20 beats per minute. Reproduced from [5].
vagal neurotransmitter. Its rapid hydrolysis by naturally occurring cholinesterases and its action on multiple types of receptors make it impractical for use in clinical studies. On the other hand, the cholinergic agonist methacholine is resistant to hydrolysis, and it is a specific agonist for vagal postganglionic nerve fibers in the smooth muscle cells of the tracheobronchial tree. The judicious administration of methacholine in inhalation challenge tests provides a means of measuring the effects of increased vagal discharge and the protective effect of anticholinergic agents. (See also the “Comments” section of this article.) Anticholinergic drugs probably produce bronchodilation by antagonizing the action of acetylcholine at its receptor site [7]. They may also inhibit bronchoconstriction by limiting the release of mediators. By blocking the cholinergic receptors present on the surface of mast cells, the release of intracellular cyclic guanosine 3’,5’-monophosphate is inhibited, which in turn inhibits release of bronchoconstrictive mediators, such as histamine.
r
1
pgl g plasma 10’
103
102
c-----_
10’ RC
IN THE LUNG
--__
inhaled --w_
I
I
I
I
0.5
1
2
3
I
--
4
---IL
I I
I
5
12hr I
The vagus nerve mediates some or all of the following: resting bronchomotor tone; afferent signals from stretch receptors, irritant receptors, and J receptors; and vagal stimulation that produces bronchoconstriction and increases bronchial gland secretions. Acetylcholine is the
November
ON
14, 1986
F‘igure 1. Approximate
plasma levels following administration of ipratropium bromide by the intravenous (0.15 mg), oral (15 mg), and inhalation (0.04 mg) routes. These doses produced an approximately equivalent degree of “bronchospasmolysis” in human subjects. Reproduced from [5].
The American
Journal
of Medicine
Volume
81 (suppl
5A)
19
SYMPOSIUM
ON OBSTRUCTIVE
AIRWAYS
DISEASE-CUGELL
The exact site within the airway where ipratropium or other anticholinergic drugs act is uncertain. Numerous inferences have been drawn from studies of isolated airway segments, intact animals, and human subjects, plus the known anatomic distribution of postganglionic parasympathetic nerve terminals and irritant receptors. The postganglionic cholinergic fibers innervate respiratory smooth muscle down to the small bronchioles [8]. Studies of receptors [9] and the results of lung function tests purported to demonstrate the site of action within the tracheobronchial tree [lo] indicate that the primary site of cholinergicinduced bronchoconstriction is in the major airways. Thus, ipratropium appears to act mainly in the larger airways; beta-adrenergic agents, on the other hand, seem to act primarily on the smaller airways [ll]. Knowledge of the site of action of a drug should be useful for selecting specific drugs for individual patients. The so-called tests of small airway function and the measurement of flow-volume relationships with air and with a helium-oxygen mixture theoretically permit identification of the major site of airflow limitation, leading to selection of the drug best suited to correct that limitation. Unfortunately, such therapeutic objectivity has not been achievable in clinical practice. Optimal, sustained relief from airflow limitation often requires a trial-and-error selection of therapeutic agents. Studies of lung tissue obtained at the time of surgery and morphologic comparison with preoperative density-dependent lung function tests have shown poor correlation. A logical explanation for this poor correlation has been offered by Pare et al [12]: airflow limitation, particularly in abnormal airways, need not occur at morphologically abnormal locations, but can exist at other sites where the effects of gas density, cross-sectional area, and compliance of an airway combine to limit airflow. These sites are the “choke points” described by Dawson and Elliott [I 31 in their wave-speed theory of flow limitation. SIDE EFFECTS
AND TOXICITY
Because of their similarities to atropine, other anticholinergic drugs are also assumed to carry a substantial risk of precipitating urinary retention, thickening of bronchial secretions, cessation of tearing, tachycardia, or glaucoma until proved otherwise. Alterations in the properties of bronchial secretions and impaired mucociliary function are the potential adverse respiratory effects of greatest concern. Although the “drying effect” of atropine on bronchial secretions is well known, atropine has another effect that is less well known but has been fully described in the pharmacologic literature. Small doses of atropine, which are nonetheless sufficient to produce bronchodilation, can cause an increase, not a decrease, in bronchial secretions for up to three hours [5]. The same paradoxical effect follows the use of small doses of ipratropium [5]. Over a
20
November
14, 1986
The
American
Journal
of Medicine
concentration range of 0.001 to 1.0 mg percent, ipratropium was shown to produce an increase, not a decrease, in bronchial secretions [14]. Numerous studies of mucociliary function and tracheobronchial clearance in patients with chronic obstructive lung disease have shown either no effect or a slight increase in the rate at which radioactive particles are cleared from the lungs following a single dose of ipratropium [15,16]. The beta agonists have some advantages over the anticholinergics in this regard: they increase ciliary beat frequency, whereas ciliary movement is unaffected by ipratropium [7]. Impaired clearance is only one of many functional defects in patients with chronic obstructive lung disease, but it is definitely not aggravated by ipratropium. A similar clearance defect was noted by Pavia and co-workers [17] in eight asthmatic subjects while they were in complete remission with normal expiratory airflow. It appears that impaired mucociliary clearance is another clinically inapparent but physiologically persistent abnormality of asthmatic patients. Although there have been numerous “warnings” that longterm use of inhaled ipratropium in patients with abnormal bronchial secretions might have some adverse effects that could not be anticipated on the basis of acute, shortterm studies [18], the margin of safety is so large, the amount of drug reaching the lungs so small, and the lack of reports of any difficulty so striking that this concern seems unfounded. There are no significant cardiovascular effects of inhaled ipratropium. No significant change in pulse rate, compared with the effect of placebo, was noted in 21 patients with severe chronic bronchitis even though the dose given was twice that normally used [19]. The only side effects that have been reported with any regularity, and in only a small number of patients, are a bad taste and dry mouth after ipratropium inhalation. No effect on urinary flow was noted among 50 elderly men given substantial doses of ipratropium [20]. Ipratropium also has no effect on intraocular pressure or pupillary size, even in patients with glaucoma [21], unless the drug is actually sprayed into the eyes; that, however, can easily happen in semiconscious patients administered aerosolized ipratropium via a facemask [6,22]. Paradoxical responses to inhaled ipratropium solution resulting in severe bronchospasm were the subject of an interesting exchange of articles and letters in the British Medical Journal between 1982 and 1984 [23-271. Although originally attributed to the bromide portion of the drug, subsequent studies showed that the bronchospastic reaction occurred in response to the hypotonicity of the aerosol solution. After the tonicity was corrected, no further reports of any paradoxical bronchoconstrictor responses appeared. There has been some concern about aerosol drugs in general. In the 1970% an increase in mortality among pa-
Volume
61 (wppl
5A)
SYMPOSIUM
tients with asthma was noted in England; excessive use of beta*-agonist aerosols was blamed [28]. When stern warnings about overdosage were included with the canisters, mortality rates declined and the problem was considered solved. The belief that excessive use of beta2 agonists was the true culprit was not universally accepted, because no comparable mortality increases were noted in the United States. In fact, in two separate asthmatic mortality surveys by physician panels in Great Britain and in New Zealand, too little treatment rather than too much
was deemed a major factor in the patients’ deaths [29,30]. There does not appear to be any reason to fear the addition of another class of aerosol compounds, the anticholinergics, to the therapeutic arsenal available to patients with airflow limitation. On the contrary, the mortality sur-
veys just noted clearly demonstrate that the majority of patients
with bronchospastic
disease
needed
more treat-
ment, not less. CLINICAL There
APPLICATIONS
is a large body of literature
on the clinical
use of
ipratropium and related compounds, much of which is reviewed elsewhere in this supplement [31]. Both short- and long-term studies of ipratropium-administered to both children and adults, either alone or together with other bronchoactive drugs-have also been reviewed [7,11]. Clinical studies show that symptoms in patients with overt asthmatic bronchospasm are better controlled with beta,adrenergic
agents
than
with ipratropium.
On the other
hand, in patients with chronic bronchitis, ipratropium has been found in many studies to be at least as effective and sometimes superior to betag agonists. Side effects of ipratropium
are few and not serious.
In most studies,
ipratropium used in doses in excess of those that are recommended does not seem to produce any additional beneficial effect. Treatment of asthmatic patients with a combination
of either
ipratropium
and a beta2
agonist
or
ipratropium plus a theophylline preparation permits a re-
ON OBSTRUCTIVE
AIRWAYS
DISEASE-CUGELL
duction in the beta2 agonist and theophylline doses, thereby minimizing the likelihood of possible side effects 1321. There are specific groups of patients in whom anticholinergics such as ipratropium may be particularly advantageous. Non-atopic patients should benefit more from ipratropium than patients with obvious allergies. Among a group of age-matched patients with equivalent forced expiratory volume in one second (FEV,) improvement following aerosol bronchodilator therapy, those without eosinophilia and with a negative result on the skin prick test had a much better response to atropine than those with obvious allergies [33]. Elderly asthmatic patients have a better response than young asthmatic patients [34], perhaps because of their lesser degree of atopy. Among patients with a strong emotional component to their asthmatic episodes, in whom a measurable reduction in FEV, can be provoked by suggestion alone, ipratropium abolishes the bronchoconstrictor response [35]. Because of its wide margin of safety, ipratropium can be used in patients with cardiovascular disease in whom beta, agonists must be used sparingly, if at all, and in asthma-prone patients in need of beta-adrenergic blocking drugs. lpratropium should be evaluated for possible use in minimizing corti-
costeroid therapy and its myriad consequences; it will be of benefit for patients in whom full therapeutic doses of conventional bronchodilators (beta agonists or theophylline) cause intolerable side effects, such as tachycardia, tremor, nausea, or insomnia. COMMENTS The precise therapeutic niche that ipratropium bromide will fill among the array of drugs now available for the treatment of patients with airflow limitation has not yet been clearly defined. In view of its wide margin of safety
and proved efficacy, which are apparent from the other contributions to this symposium, enjoy widespread use.
it seems
destined
to
REFERENCES 1. Gandevia B: Historical review of the use of parasympatholytic agents in the treatment of respiratory disorders. Postgrad Med J 1975; 51 (suppl 7): 13-20. 2. Davies D: Pharmacokinetics of inhaled substances. Postgrad Med J 1975; 51 (suppl 7): 69-75. 3. Pakes G: Anticholinergic drugs. In: Buckle D, Smith H, eds. Development of antiasthma drugs. New York: Bulterworths, 1964. 4. Rominger K: Chemistry and pharmacokinetics of ipratropium bromide. Stand J Respir Dis 1979; (suppl 103): 116-129. 5. Bauer R, Banholzer R, Griben C, et al: lpratropium bromide. Pharmacol Biochem Prop Drug Subst 1979; 2: 469-515. 6. Pakes G, Cayton R, Mashhoudi N: Nebulised ipratropium bromide and salbutamol causing closed-angle glaucoma (letter). Lancet 1964; II: 691. 7. Pakes G, Brogden R, Heel R, Speight T, Avery G: lpratropium bromide: a review of its pharmacological properties and thera-
November
14,1966
peutic efficacy in asthma and chronic bronchitis. Drugs 1960; 20: 237-266. 6.
9.
10.
11. 12.
Richardson JB: Nerve supply to the lungs. Am Rev Respir Dis 1979; 119: 765-602. Barnes PJ, Basbaum CB, Nadel JA: Autoradiographic localization of automatic receptors in airway smooth muscle: marked differences between large and small airways. Am Rev Respir Dis 1963; 127: 756-762. Ingram RH, Wellman JJ, McFadden ER, Mead J: Relative contribution of large and small airways to flow limitations in normal subjects before and after atropine and isoproterenol. J Clin Invest 1977; 59: 696-703. Gross N, Skorodin MS: Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 1964; 129: 656-670. Pare P, Brooks L, Coppin C, et al: Density dependence of maximal expiratory flow and its correlations with small airway disease in smokers. Am Rev Respir Dis 1965; 131: 521-526.
The American
Journal
of Medlclne
Volume
61
(suppl 6A)
21
SYMPOSIUM
13.
14.
15.
16.
17.
18. 19.
20.
21.
22.
ON OBSTRUCTIVE
AIRWAYS
DISEASE-CUGELL
Dawson S, Elliott E: Use of the choke point in the prediction of flow limitation in elastic tubes. Fed Proc 1980; 39: 27652770. Engelhardt A, Klupp H: The pharmacology and toxicology of a new tropane alkaloid derivative. Postgrad Med 1975; 51 (suppl 7): 82-84. Pavia D, Bateman J, Sheahan N, Clarke S: Effect of ipratropium bromide on mucociliary clearance and pulmonary function in reversible airways obstruction. Thorax 1979; 34: 501-507. Ruffin R, Wolff P, Dolovich M, Rossman C, Fitzgerald J, Newhouse M: Aerosol therapy with SCH 1000. Short term mucociliary clearance in normal and bronchitic subjects and toxicology in normal subjects. Chest 1978; 73: 501-600. Pavia D, Bateman D, Sheahan N, Agnew J, Clarke S: Tracheobronchial mucociliary clearance in asthma: impairment during remission. Thorax 1985; 40: 171-175. Crompton G: Sputum viscosity and long-term ipratropium bromide nebuliser therapy (letter). Lancet 1982; II: 1243. Douglas N, Davidson I, Sudlow M, Flenley D: Bronchodilatation and the site of airway resistance in severe chronic bronchitis. Thorax 1979; 34: 51-55. Molkenboer J, Lardenoye J: The effect of Atrovent in micturition function, double blind cross-over study. Stand J Respir Dis 1979 (suppl 103): 154-158. Thumm H: Ophthalmic effects of high doses of SCH 1000 MDI in healthy volunteers and patients with glaucoma. Postgrad Med J 1975; 51 (suppl 7): 132-133. Malani J, Robinson G, Seneviratne E: lpratropium bromide induced angle closure glaucoma (letter). NZ Med J 1982; 95: 749.
23. 24. 25. 26.
27.
28.
29. 30.
31. 32.
33. 34. 35.
Jolobe 0: Adverse reaction to ipratropium bromide (letter). Br Med J 1982; 285: 1425-1426. Pate1 K, Tullett W: Bronchoconstriction in response to ipratropium bromide. Br Med J 1983; 286: 1318. Connolly C: Adverse reaction to ipratropium bromide. Br Med J 1982; 285: 934-935. Mann J, Howarth P, Holgate ST: Bronchoconstriction induced by ipratropium bromide in asthma: relation to hypotonicity. Br Med J 1984; 289: 469. Dewhurst J: Bronchoconstriction induced by ipratropium bromide in asthma: relation to hypotonicity (letter). Br Med J 1984; 289: 833. Speizer F, Doll R, Heaf P, Strang L: Investigation into use of drugs preceding death from asthma. Br Med J 1968; 1: 339343. British Thoracic Society: Death from asthma in two regions of England. Br Med J 1982; 285: 1251-1255. Sears M, Rae H, Beaglehole R, et al: Asthma mortality in New Zealand: a national study (abstr). In: Proceedings of the American Thoracic Society 1985; A55. Data on file, Boehringer Ingelheim. Elwood R, Abboud R: The short-term bronchodilator effects of fenoterol and ipratropium in asthma. Allergy Clin lmmunol 1982; 69: 453-467. Jolobe 0: Impaired atropine responsiveness in asthma: role of atopy. Respiration 1983; 44: 97-102. Rebuck A, Chapman K, Baude M: Anticholinergic therapy of asthma. Chest 1982; 82 (suppl): 55S-575. Nield J, Cameron I: Bronchoconstriction in response to suggestion. Br Med J 1985; 290: 674.
Discussion Dr. Edward Bergofsky: Dr. Cugell, you said that about 90 percent of an inhaled drug dose is swallowed. Does this figure vary depending on the inhalation device used? For instance, is it more or less with a metered-dose inhaler, as compared with a spacer device? Dr. David Cugell: There may be a difference between how much drug gets into the lungs after direct inhalation from a metered-dose inhaler or after a spacer is used. It may be that in an older, clumsier individual who has repeated difficulty handling a metered-dose inhaler, a spacer should be used; most patients, however, will get sufficient drug into their lungs with a metered-dose inhaler. Dr. Morton Skorodin: Dr. Cugell, you emphasized ipratropium’s bronchoselectivity in comparison to atropine. The drug tends to confine its effects to the lungs when given via inhalation, whereas inhaled atropine has many systemic effects. Is the bronchoselectivity of inhaled ipratropium due solely to the combination of local deposition and the drug’s poor systemic absorption, or is bronchoselectivity a feature of the ipratropium molecule itself?
22
November
14, 1986
The American
Journal
of Medicine
Dr. Cugell: The literature implies that bronchoselectivity is a feature of the drug molecule itself. However, bronchoselectivity is greatly enhanced by inhalation and by the drug’s poor absorption from the stomach. Therefore, the patient benefits both ways. Dr. Bergofsky: I would like to add something, based on our work on the effects of ipratropium on mucociliary clearance. Clearance can be influenced, of course, by a variety of pharmacologic agents. If an oral atropine dose is administered to a normal individual, mucus clearance can actually be stopped completely. And if atropine is given and clearance is stopped, clearance can resume rapidly and completely if a beta agonist, such as isoproterenol, is administered. So a question posed by this relatively simple finding is: Does the lack of effect of newer atropine congeners, like ipratropium, on mucociliary clearance depend on aerosol administration? Dr. Cugell: I think that we have to expect what has already been found: ipratropium’s effect on mucociliary clearance appears to be less than that of atropine, and in clinically useful dosages, the effect on clearance is not measurable.
Volume
81
(suppl 5A)
Anticholinergic drugs inhibit a variety of intrapulmonary events related to airflow obstructiqn. When administered as an inhaled aerosol, approximately 90 percent of ipratropium bromide (as with betaadrenergic aerosols) can @e assumed to be swallowed. Peak pharmacologic effects occur prior to any detectable plasma drug concentrations. lpratropium does not exhibit the well-known toxic effects of atropine, and doses many times those required for maximum therapeutic benefit do not produce any effects on the eye, urinary bladder, heart rate, or mucociliary function. lpratropium seems to act primarily on large- and intermediate-size ainnays; beta-adrenergic agents, on the other hand, appear to act primarily on the smaller airways. The drug is a promising addition to the therapeutic armamentarium, and may be especially use$~l in certain groups of patients whose condition is less responsive to other agents.
DAVID W. CUGELL, M.D. Chicago,
Illinois
Pharmacologically active anticholinergic alkaloids exist in the roots, seeds, and leaves of a variety of piants, and their use for the relief of respiratory symptoms originated thousands of years ago in India [l]. These and other substances were prepare@ as combustible powders, and the inhalation of the smoke they produced was a practice gradually incorporated into Western medicine during the early 19th century 111. Smoke from the leaves of the stramonium plant became the preparation of choice for the relief of bronchospasm. That the active principle of stramonium is atropine has been known since the 1830s [l]. Medical writings from those times clearly describe the signs and symptoms of atropine overdose with stramonium, and warn of stramonium’s narrow therapeutic range. With the introduction of ephedrine and epinephrine during the 20th century, the use of atropine and related substances for relief of bronchospasm declined and, except for unusual or obstinate cases, virtually disappeared from use. The development of the quaternaty methyl isopropyl derivative of atropine, ipratropium bromide, has awakened new interest in anticholinergic bronchodilation. Its unique advantage over other anticholinergic drugs is a high degree of bronchoselectivity in very small doses when delivered by inhalation. The basic pharmacology of this compound was studied 10 to 15 years ago; recent studies of ipratropium have been directed toward iden!ifying its site of action in human airways, side effects, potential toxicity, combined use with other bronchodilators, and clinical effectiveness. This article highlights these many aspects of the drug’s pharmacology and toxicology. From the Northwestern University Medical School, Chicago, Illinois. Requests for reprints should be addressed to Dr. David W. Cugell, Northwestern Memorial Hospital, 250 East Superior Street, Room 454, Chicago, Illinois 60611.
16
November
14,1986
The
Americen
Journal
ABSORPTION, ORGAN ACTIVITV, AND SPECIFICITY The spectrum of activity of ipratropium bromide when delivered systemitally is similar to that of atropine with respect to inhibition of salivation and gastric secretion, mydriasis, tachycardia, and urinary bladder function.
of Medicine
Volume
81
(suppl5A)
SYMPOSIUM
Significant differences between the two drugs are that the effectiveness of ipratropium is lacking in the central nervous system, and poor gastric absorption of the drug is demonstrated. The limited gastric absorption of ipratropium is clinically important. Studies with radiolabeled beta agonists have shown that, following aerosol administration, approximately 90 percent of the drug is swallowed [2]. Although no comparable studies have been done with aerosolized ipratropium, there seems little reason to doubt that a similar proportion of the administered dose is also swallowed. It is significant then that little ipratropium is absorbed from the stomach; what is absorbed is broken down to metabolites with essentially no pharmacologic effects, and within 24 hours, half of an aerosol dose (presumably, mostly swallowed drug) appears in the feces [3,4]. lpratropium is highly selective in its effect on bronchial smooth muscle. However, its efficacy differs markedly depending on the route of administration; this is clearly shown in Table I, which has been adapted from a report by Bauer and colleagues [5]. The amount of ipratropium required to inhibit acetylcholine-induced bronchoconstriction in dogs by 50 percent when the drug is administered intravenously is 10 times the dose that is required when the drug is given by inhalation. The most sensitive side effect of anticholinergic drugs is the inhibition of salivary secretions [5]. Fortunately, with ipratropium this and other side effects appear only at doses that are much higher than the therapeutic dose. When the drug is given intravenously, it takes IO times as much to inhibit salivary secretion as it takes to inhibit acetylcholine-induced bronchoconstriction. When ipratropium is given via the aerosol route, that same ratio is increased to almost 300 to one. The safety margin for tachycardia is even greater [5,6]. In their study, Bauer and co-workers administered equipotent doses of ipratropium-amounts sufficient to produce equivalent bronchodilation-via the oral, intravenous, and inhalation routes, and plasma drug levels were followed for the subsequent 12 hours. Figure 1 shows that the plasma levels recorded following oral and intravenous administration were three to four orders of magnitude higher than the plasma level following inhalation. In fact, plasma levels are so low following therapeutically effective aerosol doses that systematic pharmacokinetic studies cannot be done. The elimination half-life of ipratropium is 3.2 to 3.8 hours regardless of the route of administration [7]. MODE AND SITE OF ACTION
TABLE
OBSTRUCTIVE
AIRWAYS
DISEASE-CUGELL
Selectivity of lpratropium Administered Intravenously and by Inhalation
I
Intravenous
Bronchospasmolysis Inhibition of salivation Tachycardia*
inhalation EC5,, (percent
ED50 (/.@!!I*
0.15 1.5 15.0
aerosol)t
0.014 4.0 >lO.O
*EDs0 = effective dose needed to inhibit acetylcholine-induced bronchoconstriction or pilocarpine-induced salivation in anesthetized dogs by 50 percent. +ECSO = effective concentration of an aqueous aerosol that will produce a similar inhibition of bronchospasm and salivary secretions. *Values shown indicate dose that will produce an increase in heart rate of 10 to 20 beats per minute. Reproduced from [5].
vagal neurotransmitter. Its rapid hydrolysis by naturally occurring cholinesterases and its action on multiple types of receptors make it impractical for use in clinical studies. On the other hand, the cholinergic agonist methacholine is resistant to hydrolysis, and it is a specific agonist for vagal postganglionic nerve fibers in the smooth muscle cells of the tracheobronchial tree. The judicious administration of methacholine in inhalation challenge tests provides a means of measuring the effects of increased vagal discharge and the protective effect of anticholinergic agents. (See also the “Comments” section of this article.) Anticholinergic drugs probably produce bronchodilation by antagonizing the action of acetylcholine at its receptor site [7]. They may also inhibit bronchoconstriction by limiting the release of mediators. By blocking the cholinergic receptors present on the surface of mast cells, the release of intracellular cyclic guanosine 3’,5’-monophosphate is inhibited, which in turn inhibits release of bronchoconstrictive mediators, such as histamine.
r
1
pgl g plasma 10’
103
102
c-----_
10’ RC
IN THE LUNG
--__
inhaled --w_
I
I
I
I
0.5
1
2
3
I
--
4
---IL
I I
I
5
12hr I
The vagus nerve mediates some or all of the following: resting bronchomotor tone; afferent signals from stretch receptors, irritant receptors, and J receptors; and vagal stimulation that produces bronchoconstriction and increases bronchial gland secretions. Acetylcholine is the
November
ON
14, 1986
F‘igure 1. Approximate
plasma levels following administration of ipratropium bromide by the intravenous (0.15 mg), oral (15 mg), and inhalation (0.04 mg) routes. These doses produced an approximately equivalent degree of “bronchospasmolysis” in human subjects. Reproduced from [5].
The American
Journal
of Medicine
Volume
81 (suppl
5A)
19
SYMPOSIUM
ON OBSTRUCTIVE
AIRWAYS
DISEASE-CUGELL
The exact site within the airway where ipratropium or other anticholinergic drugs act is uncertain. Numerous inferences have been drawn from studies of isolated airway segments, intact animals, and human subjects, plus the known anatomic distribution of postganglionic parasympathetic nerve terminals and irritant receptors. The postganglionic cholinergic fibers innervate respiratory smooth muscle down to the small bronchioles [8]. Studies of receptors [9] and the results of lung function tests purported to demonstrate the site of action within the tracheobronchial tree [lo] indicate that the primary site of cholinergicinduced bronchoconstriction is in the major airways. Thus, ipratropium appears to act mainly in the larger airways; beta-adrenergic agents, on the other hand, seem to act primarily on the smaller airways [ll]. Knowledge of the site of action of a drug should be useful for selecting specific drugs for individual patients. The so-called tests of small airway function and the measurement of flow-volume relationships with air and with a helium-oxygen mixture theoretically permit identification of the major site of airflow limitation, leading to selection of the drug best suited to correct that limitation. Unfortunately, such therapeutic objectivity has not been achievable in clinical practice. Optimal, sustained relief from airflow limitation often requires a trial-and-error selection of therapeutic agents. Studies of lung tissue obtained at the time of surgery and morphologic comparison with preoperative density-dependent lung function tests have shown poor correlation. A logical explanation for this poor correlation has been offered by Pare et al [12]: airflow limitation, particularly in abnormal airways, need not occur at morphologically abnormal locations, but can exist at other sites where the effects of gas density, cross-sectional area, and compliance of an airway combine to limit airflow. These sites are the “choke points” described by Dawson and Elliott [I 31 in their wave-speed theory of flow limitation. SIDE EFFECTS
AND TOXICITY
Because of their similarities to atropine, other anticholinergic drugs are also assumed to carry a substantial risk of precipitating urinary retention, thickening of bronchial secretions, cessation of tearing, tachycardia, or glaucoma until proved otherwise. Alterations in the properties of bronchial secretions and impaired mucociliary function are the potential adverse respiratory effects of greatest concern. Although the “drying effect” of atropine on bronchial secretions is well known, atropine has another effect that is less well known but has been fully described in the pharmacologic literature. Small doses of atropine, which are nonetheless sufficient to produce bronchodilation, can cause an increase, not a decrease, in bronchial secretions for up to three hours [5]. The same paradoxical effect follows the use of small doses of ipratropium [5]. Over a
20
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The
American
Journal
of Medicine
concentration range of 0.001 to 1.0 mg percent, ipratropium was shown to produce an increase, not a decrease, in bronchial secretions [14]. Numerous studies of mucociliary function and tracheobronchial clearance in patients with chronic obstructive lung disease have shown either no effect or a slight increase in the rate at which radioactive particles are cleared from the lungs following a single dose of ipratropium [15,16]. The beta agonists have some advantages over the anticholinergics in this regard: they increase ciliary beat frequency, whereas ciliary movement is unaffected by ipratropium [7]. Impaired clearance is only one of many functional defects in patients with chronic obstructive lung disease, but it is definitely not aggravated by ipratropium. A similar clearance defect was noted by Pavia and co-workers [17] in eight asthmatic subjects while they were in complete remission with normal expiratory airflow. It appears that impaired mucociliary clearance is another clinically inapparent but physiologically persistent abnormality of asthmatic patients. Although there have been numerous “warnings” that longterm use of inhaled ipratropium in patients with abnormal bronchial secretions might have some adverse effects that could not be anticipated on the basis of acute, shortterm studies [18], the margin of safety is so large, the amount of drug reaching the lungs so small, and the lack of reports of any difficulty so striking that this concern seems unfounded. There are no significant cardiovascular effects of inhaled ipratropium. No significant change in pulse rate, compared with the effect of placebo, was noted in 21 patients with severe chronic bronchitis even though the dose given was twice that normally used [19]. The only side effects that have been reported with any regularity, and in only a small number of patients, are a bad taste and dry mouth after ipratropium inhalation. No effect on urinary flow was noted among 50 elderly men given substantial doses of ipratropium [20]. Ipratropium also has no effect on intraocular pressure or pupillary size, even in patients with glaucoma [21], unless the drug is actually sprayed into the eyes; that, however, can easily happen in semiconscious patients administered aerosolized ipratropium via a facemask [6,22]. Paradoxical responses to inhaled ipratropium solution resulting in severe bronchospasm were the subject of an interesting exchange of articles and letters in the British Medical Journal between 1982 and 1984 [23-271. Although originally attributed to the bromide portion of the drug, subsequent studies showed that the bronchospastic reaction occurred in response to the hypotonicity of the aerosol solution. After the tonicity was corrected, no further reports of any paradoxical bronchoconstrictor responses appeared. There has been some concern about aerosol drugs in general. In the 1970% an increase in mortality among pa-
Volume
61 (wppl
5A)
SYMPOSIUM
tients with asthma was noted in England; excessive use of beta*-agonist aerosols was blamed [28]. When stern warnings about overdosage were included with the canisters, mortality rates declined and the problem was considered solved. The belief that excessive use of beta2 agonists was the true culprit was not universally accepted, because no comparable mortality increases were noted in the United States. In fact, in two separate asthmatic mortality surveys by physician panels in Great Britain and in New Zealand, too little treatment rather than too much
was deemed a major factor in the patients’ deaths [29,30]. There does not appear to be any reason to fear the addition of another class of aerosol compounds, the anticholinergics, to the therapeutic arsenal available to patients with airflow limitation. On the contrary, the mortality sur-
veys just noted clearly demonstrate that the majority of patients
with bronchospastic
disease
needed
more treat-
ment, not less. CLINICAL There
APPLICATIONS
is a large body of literature
on the clinical
use of
ipratropium and related compounds, much of which is reviewed elsewhere in this supplement [31]. Both short- and long-term studies of ipratropium-administered to both children and adults, either alone or together with other bronchoactive drugs-have also been reviewed [7,11]. Clinical studies show that symptoms in patients with overt asthmatic bronchospasm are better controlled with beta,adrenergic
agents
than
with ipratropium.
On the other
hand, in patients with chronic bronchitis, ipratropium has been found in many studies to be at least as effective and sometimes superior to betag agonists. Side effects of ipratropium
are few and not serious.
In most studies,
ipratropium used in doses in excess of those that are recommended does not seem to produce any additional beneficial effect. Treatment of asthmatic patients with a combination
of either
ipratropium
and a beta2
agonist
or
ipratropium plus a theophylline preparation permits a re-
ON OBSTRUCTIVE
AIRWAYS
DISEASE-CUGELL
duction in the beta2 agonist and theophylline doses, thereby minimizing the likelihood of possible side effects 1321. There are specific groups of patients in whom anticholinergics such as ipratropium may be particularly advantageous. Non-atopic patients should benefit more from ipratropium than patients with obvious allergies. Among a group of age-matched patients with equivalent forced expiratory volume in one second (FEV,) improvement following aerosol bronchodilator therapy, those without eosinophilia and with a negative result on the skin prick test had a much better response to atropine than those with obvious allergies [33]. Elderly asthmatic patients have a better response than young asthmatic patients [34], perhaps because of their lesser degree of atopy. Among patients with a strong emotional component to their asthmatic episodes, in whom a measurable reduction in FEV, can be provoked by suggestion alone, ipratropium abolishes the bronchoconstrictor response [35]. Because of its wide margin of safety, ipratropium can be used in patients with cardiovascular disease in whom beta, agonists must be used sparingly, if at all, and in asthma-prone patients in need of beta-adrenergic blocking drugs. lpratropium should be evaluated for possible use in minimizing corti-
costeroid therapy and its myriad consequences; it will be of benefit for patients in whom full therapeutic doses of conventional bronchodilators (beta agonists or theophylline) cause intolerable side effects, such as tachycardia, tremor, nausea, or insomnia. COMMENTS The precise therapeutic niche that ipratropium bromide will fill among the array of drugs now available for the treatment of patients with airflow limitation has not yet been clearly defined. In view of its wide margin of safety
and proved efficacy, which are apparent from the other contributions to this symposium, enjoy widespread use.
it seems
destined
to
REFERENCES 1. Gandevia B: Historical review of the use of parasympatholytic agents in the treatment of respiratory disorders. Postgrad Med J 1975; 51 (suppl 7): 13-20. 2. Davies D: Pharmacokinetics of inhaled substances. Postgrad Med J 1975; 51 (suppl 7): 69-75. 3. Pakes G: Anticholinergic drugs. In: Buckle D, Smith H, eds. Development of antiasthma drugs. New York: Bulterworths, 1964. 4. Rominger K: Chemistry and pharmacokinetics of ipratropium bromide. Stand J Respir Dis 1979; (suppl 103): 116-129. 5. Bauer R, Banholzer R, Griben C, et al: lpratropium bromide. Pharmacol Biochem Prop Drug Subst 1979; 2: 469-515. 6. Pakes G, Cayton R, Mashhoudi N: Nebulised ipratropium bromide and salbutamol causing closed-angle glaucoma (letter). Lancet 1964; II: 691. 7. Pakes G, Brogden R, Heel R, Speight T, Avery G: lpratropium bromide: a review of its pharmacological properties and thera-
November
14,1966
peutic efficacy in asthma and chronic bronchitis. Drugs 1960; 20: 237-266. 6.
9.
10.
11. 12.
Richardson JB: Nerve supply to the lungs. Am Rev Respir Dis 1979; 119: 765-602. Barnes PJ, Basbaum CB, Nadel JA: Autoradiographic localization of automatic receptors in airway smooth muscle: marked differences between large and small airways. Am Rev Respir Dis 1963; 127: 756-762. Ingram RH, Wellman JJ, McFadden ER, Mead J: Relative contribution of large and small airways to flow limitations in normal subjects before and after atropine and isoproterenol. J Clin Invest 1977; 59: 696-703. Gross N, Skorodin MS: Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 1964; 129: 656-670. Pare P, Brooks L, Coppin C, et al: Density dependence of maximal expiratory flow and its correlations with small airway disease in smokers. Am Rev Respir Dis 1965; 131: 521-526.
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SYMPOSIUM
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14.
15.
16.
17.
18. 19.
20.
21.
22.
ON OBSTRUCTIVE
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Dawson S, Elliott E: Use of the choke point in the prediction of flow limitation in elastic tubes. Fed Proc 1980; 39: 27652770. Engelhardt A, Klupp H: The pharmacology and toxicology of a new tropane alkaloid derivative. Postgrad Med 1975; 51 (suppl 7): 82-84. Pavia D, Bateman J, Sheahan N, Clarke S: Effect of ipratropium bromide on mucociliary clearance and pulmonary function in reversible airways obstruction. Thorax 1979; 34: 501-507. Ruffin R, Wolff P, Dolovich M, Rossman C, Fitzgerald J, Newhouse M: Aerosol therapy with SCH 1000. Short term mucociliary clearance in normal and bronchitic subjects and toxicology in normal subjects. Chest 1978; 73: 501-600. Pavia D, Bateman D, Sheahan N, Agnew J, Clarke S: Tracheobronchial mucociliary clearance in asthma: impairment during remission. Thorax 1985; 40: 171-175. Crompton G: Sputum viscosity and long-term ipratropium bromide nebuliser therapy (letter). Lancet 1982; II: 1243. Douglas N, Davidson I, Sudlow M, Flenley D: Bronchodilatation and the site of airway resistance in severe chronic bronchitis. Thorax 1979; 34: 51-55. Molkenboer J, Lardenoye J: The effect of Atrovent in micturition function, double blind cross-over study. Stand J Respir Dis 1979 (suppl 103): 154-158. Thumm H: Ophthalmic effects of high doses of SCH 1000 MDI in healthy volunteers and patients with glaucoma. Postgrad Med J 1975; 51 (suppl 7): 132-133. Malani J, Robinson G, Seneviratne E: lpratropium bromide induced angle closure glaucoma (letter). NZ Med J 1982; 95: 749.
23. 24. 25. 26.
27.
28.
29. 30.
31. 32.
33. 34. 35.
Jolobe 0: Adverse reaction to ipratropium bromide (letter). Br Med J 1982; 285: 1425-1426. Pate1 K, Tullett W: Bronchoconstriction in response to ipratropium bromide. Br Med J 1983; 286: 1318. Connolly C: Adverse reaction to ipratropium bromide. Br Med J 1982; 285: 934-935. Mann J, Howarth P, Holgate ST: Bronchoconstriction induced by ipratropium bromide in asthma: relation to hypotonicity. Br Med J 1984; 289: 469. Dewhurst J: Bronchoconstriction induced by ipratropium bromide in asthma: relation to hypotonicity (letter). Br Med J 1984; 289: 833. Speizer F, Doll R, Heaf P, Strang L: Investigation into use of drugs preceding death from asthma. Br Med J 1968; 1: 339343. British Thoracic Society: Death from asthma in two regions of England. Br Med J 1982; 285: 1251-1255. Sears M, Rae H, Beaglehole R, et al: Asthma mortality in New Zealand: a national study (abstr). In: Proceedings of the American Thoracic Society 1985; A55. Data on file, Boehringer Ingelheim. Elwood R, Abboud R: The short-term bronchodilator effects of fenoterol and ipratropium in asthma. Allergy Clin lmmunol 1982; 69: 453-467. Jolobe 0: Impaired atropine responsiveness in asthma: role of atopy. Respiration 1983; 44: 97-102. Rebuck A, Chapman K, Baude M: Anticholinergic therapy of asthma. Chest 1982; 82 (suppl): 55S-575. Nield J, Cameron I: Bronchoconstriction in response to suggestion. Br Med J 1985; 290: 674.
Discussion Dr. Edward Bergofsky: Dr. Cugell, you said that about 90 percent of an inhaled drug dose is swallowed. Does this figure vary depending on the inhalation device used? For instance, is it more or less with a metered-dose inhaler, as compared with a spacer device? Dr. David Cugell: There may be a difference between how much drug gets into the lungs after direct inhalation from a metered-dose inhaler or after a spacer is used. It may be that in an older, clumsier individual who has repeated difficulty handling a metered-dose inhaler, a spacer should be used; most patients, however, will get sufficient drug into their lungs with a metered-dose inhaler. Dr. Morton Skorodin: Dr. Cugell, you emphasized ipratropium’s bronchoselectivity in comparison to atropine. The drug tends to confine its effects to the lungs when given via inhalation, whereas inhaled atropine has many systemic effects. Is the bronchoselectivity of inhaled ipratropium due solely to the combination of local deposition and the drug’s poor systemic absorption, or is bronchoselectivity a feature of the ipratropium molecule itself?
22
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Dr. Cugell: The literature implies that bronchoselectivity is a feature of the drug molecule itself. However, bronchoselectivity is greatly enhanced by inhalation and by the drug’s poor absorption from the stomach. Therefore, the patient benefits both ways. Dr. Bergofsky: I would like to add something, based on our work on the effects of ipratropium on mucociliary clearance. Clearance can be influenced, of course, by a variety of pharmacologic agents. If an oral atropine dose is administered to a normal individual, mucus clearance can actually be stopped completely. And if atropine is given and clearance is stopped, clearance can resume rapidly and completely if a beta agonist, such as isoproterenol, is administered. So a question posed by this relatively simple finding is: Does the lack of effect of newer atropine congeners, like ipratropium, on mucociliary clearance depend on aerosol administration? Dr. Cugell: I think that we have to expect what has already been found: ipratropium’s effect on mucociliary clearance appears to be less than that of atropine, and in clinically useful dosages, the effect on clearance is not measurable.
Volume
81
(suppl 5A)