Abstract
Synopsis
Ipratropium bromide1 is an anticholinergic bronchodilator administered by inhalation. Although producing bronchodilation in most patients with obstructive airways disease, it is somewhat less effective than β2-adrenoceptor agonist drugs such as salbutamol or fenoterol in patients with asthma, but is at least as effective as these agents in bronchitis. As with the β2-adrenoceptor agonists, the onset of maximum effect with ipratropium (about 1.5 to 2 hours) is slower than with isoprenaline (although significant bronchodilation usually occurs within seconds or minutes of ipratropium inhalation), and the duration of effect (about 4 to 6 hours) is longer. Studies of concomitant use of ipratropium and other agents such as β2-adrenoceptor agonists, theophylline, or sodium cromoglycate, have usually shown a greater response in many patients than with single drug therapy, as might be expected from the different mechanisms of action of these groups of drugs. Usual inhaled doses of ipratropium were well tolerated in all studies.
Ipratropium thus appears to be a suitable alternative to β2-adrenoceptor agonist drugs in patients not fully responding to these agents, and combined therapy with ipratropium and other bronchodilating drugs may prove to be an important area of use in patients failing to respond adequately to a single drug regimen. (Nevertheless, in asthma patients in whom a ‘non-responsive’ state is developing, initiation of corticosteroid therapy should not be delayed). Ipratropium may also be useful in the occasional patient in whom side effects such as palpitations or tremor are troublesome with usual inhaled doses of β2-adrenoceptor agonists.
Pharmacodynamic Studies
Ipratropium is an anticholinergic agent which produces bron-chodilation probably by inhibiting cholinergic bronchomotor tone. In studies to measure the protective effect of ipratropium against experimental bronchospasm, it was most effective against cholinergic challenges (as might be expected), providing little protection against serotonin or histamine-induced bronchospasm, and moderate protection against bronchospasm induced by propranolol or common allergens. The protective effect against exercise-induced bronchospasm was variable, probably at least partially depending on the extent of cholinergic involvement in the disease process in individual patients. Although some bron-chodilator response occurs rapidly following ipratropium inhalation (50% of the eventual maximum response within the first few minutes), the onset of maximum effect is relatively slow (about 1.5 to 2 hours). The duration of significant bronchodilation is about 4 to 6 hours with usual doses. The maximum bronchodilator response occurs with a dose of 20 to 40 or 80μg, higher doses providing no increase in response in most studies. Neither mucociliary clearance nor the volume or viscosity of respiratory secretions were altered by usual doses of ipratropium in short term studies. As with usual doses of other inhaled bronchodilator drugs, the effects of bronchodilating doses of inhaled ipratropium are confined primarily to the respiratory tract. No cardiovascular changes have occurred following inhalation of usual doses in patients or after up to 280μg in healthy subjects; intravenous administration increases heart rate, arterial blood pressure, cardiac output and peripheral blood flow while decreasing central venous pressure. Oxygen saturation of arterial blood does not seem to be altered by ipratropium inhalation in usual dosage, but such studies have not been done in already severely hypoxic patients which comprise the ‘at risk’ population for this paradoxical effect which may occur with isoprenaline.
Pharmacokinetic Studies
About 30 % of an oral dose of ipratropium bromide is absorbed, and a lesser fraction when the drug is given by inhalation. Peak plasma concentrations are attained after both dosage forms at 3 hours; plasma concentrations with equi-effective (bronchodilation) doses are about 1000 times lower after inhalation than after oral administration. Inhaled ipratropium is metabolised to 8 metabolites, and is excreted in approximately equal proportions in the faeces and urine. The metabolites have little or no anticholinergic activity in vitro. The elimination half-life of ipratropium is 3.2 to 3.8 hours by all routes of administration.
Therapeutic Trials
Most trials with ipratropium have made reasonable attempts to minimise the effects of natural variability of obstructive airways disease through standard study design principles, but many studies did not clearly differentiate between asthma and bronchitic conditions. In single dose or short term studies ipratropium aerosol (usually 40 or 80μg) was an effective bronchodilator in most patients, but in patients with asthma its maximum bronchodilator effect on the whole was somewhat less than that achieved with usual inhaled doses of β2drenoceptor agonist drugs such as salbutamol or fenoterol. However, unlike the β2-adrenoceptor agonists, which may be most effective in atopic asthma, ipratropium had a similar effect in both atopic and nonatopic patients. In patients with chronic bronchitis ipratropium and β2-agonist drugs were usually about equally effective, although in a few studies ipratropium produced greater bronchodilation. As occurs with other inhaled bronchodilators, systemic corticosteroid requirements in steroid-dependent patients were usually reduced during ipratropium therapy. In a small number of longer term studies ipratropium remained effective during continuous administration for up to several years. Indeed, in some studies the response appeared to improve after several months of treatment. Ipratropium has been successfully used in children with obstructive airways diseases, but may be less effective than salbutamol in preventing exercise-induced bronchospasm in such patients. Studies of combined treatment with ipratropium and (β2-adrenoceptor agonists, or other agents such as theophylline or sodium cromoglycate, have generally found a greater response in many patients than with single drug treatment, but such differences were not always statistically significant. Further well designed studies are needed to confirm the apparent increased effect of combined therapy, and to identify those types of patients who might benefit most from such treatment.
Side Effects
Usual inhaled doses of ipratropium are well tolerated, and do not appear to exert important systemic effects. With the exception of transient local effects reported in about 20 to 30 % of patients in some studies (but not mentioned in most reports), such as dryness in the mouth, ‘scratching’ in the trachea, or a ‘bad’ taste in the mouth, no adverse effects have occurred.
Dosage
The recommended prophylactic inhaled dose of ipratropium in adults or children is 20 to 40μg (1 to 2 puffs of the metered aerosol) 3 times daily. For an acute attack of bronchospasm, 2 to 3 additional puffs may be inhaled. However, the relatively gradual onset and late peak of bronchodilation with ipratropium suggest that it is more suitable for regular prophylactic use than for rapid symptomatic relief of acute bronchospasm. As with other aerosol bronchodilators, the correct administration technique is most important; the physician and pharmacist should ensure that the patient clearly understands the method of administration.
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Various sections of the manuscript reviewed by: W. Baigelman, Pulmonary Service, Carney Hospital, Boston, USA; H. Chai, National Jewish Hospital and Research Center, Institute for Respiratory and Immune Diseases, Denver, Colorado, USA; G. Kaik, Institut Medizinische, Universitatsklinik, Vienna, Austria; K.N. Leiter, Merritt Island, Florida, USA; J.B. McKay, Wellington Hospital, Wellington, New Zealand; A. Minette, Modische Instituut St.-Barbara, Lanaken, Belgium; G.R. Petrie, Kircaldy, Fife, Scotland; J.C. Petrie, Department of Therapeutics and Clinical Pharmacology, Aberdeen Royal Infirmary, Aberdeen, Scotland; A.S. Rebuck, Toronto General Hospital, Toronto, Ontario, Canada; J.M. Verstraeten, St.-Vincentiuskliniek, Gent, Belgium; E.G. Weinberg. Red Cross Memorial Children’s Hospital, Cape Town, South Africa; H.J. Wittig. Ochsner Clinic, New Orleans, USA.
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Pakes, G.E., Brogden, R.N., Heel, R.C. et al. Ipratropium Bromide: A Review of its Pharmacological Properties and Therapeutic Efficacy in Asthma and Chronic Bronchitis. Drugs 20, 237–266 (1980). https://doi.org/10.2165/00003495-198020040-00001
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DOI: https://doi.org/10.2165/00003495-198020040-00001