Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD.
ABSTRACT In the lungs, parasympathetic nerves provide the dominant control of airway smooth muscle with release of acetylcholine onto M3 muscarinic receptors. Treatment of airway disease with anticholinergic drugs that block muscarinic receptors began over 2000 years ago. Pharmacologic data all indicated that antimuscarinic drugs should be highly effective in asthma but clinical results were mixed. Thus, with the discovery of effective β-adrenergic receptor agonists the use of muscarinic antagonists declined. Lack of effectiveness of muscarinic antagonists is due to a variety of factors including unwanted side effects (ranging from dry mouth to coma) and the discovery of additional muscarinic receptor subtypes in the lungs with sometimes competing effects. Perhaps the most important problem is ineffective dosing due to poorly understood differences between routes of administration and no effective way of testing whether antagonists block receptors stimulated physiologically by acetylcholine. Newer muscarinic receptor antagonists are being developed that address the problems of side effects and receptor selectivity that appear to be quite promising in the treatment of asthma and chronic obstructive pulmonary disease.
Current Medical Research and Opinion 02/1974; 2(5):281-7. · 2.38 Impact Factor
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ABSTRACT: To determine the site in the parasympathetic pathway responsible for the increased bronchial reactivity in 5 atopic subjects, we studied the effect of premedication with aerosols of hexamethonium, a ganglionic blocking agent, and atropine, a postganglionic blocking agent, on the bronchomotor responses to histamine and methacholine aerosols. After 7 mg of aerosolized atropine, baseline specific airway resistance (SRaw) decreased, and the increases in SRaw produced by histamine and by methacholine were prevented in each subject (p < 0.001). After 1 g of hexamethonium, baseline SRaw was decreased to a similar level, and the increase in SRaw produced by histamine was again Prevented in each subject (P < 0.001); However, the increase in SRaw produced by methacholine was not affected significantly in 3 subjects (p > 0.5) and was increased or decreased only slightly in 2 subjects (p < 0.05). These results suggest that bronchial hyperreactivity in atopic subjects may be due to a change in the characteristics of the efferent parasympathetic pathway at a site distal to the ganglion, possibly at the smooth muscle, and that bronchodilation caused by atropine and hexamethonium cannot, by itself, account for their effects on bronchomotor responses.The American review of respiratory disease 08/1980; 122(1):17-25. · 10.19 Impact Factor
Article: Integrated pharmacokinetics and pharmacodynamics of atropine in healthy humans. I: Pharmacokinetics.[show abstract] [hide abstract]
ABSTRACT: The pharmacokinetics of atropine in three healthy male volunteers after intravenous administration of 1.35 and 2.15 mg of the drug was determined. Pharmacodynamic effects of atropine were measured simultaneously. All the data were fitted to a novel integrated kinetic-dynamic model. Plasma concentrations of atropine and the amounts of atropine and its primary metabolite, tropine, excreted in the urine were measured by a sensitive gas chromatographic-mass spectrometric assay. The kinetics of elimination of atropine was first order. There was evidence that the kinetics of distribution of the drug was dose dependent. Two phases with apparent half-lives of 1 and 140 min were distinguishable in accordance with a linear two-compartment disposition model for atropine. The urinary excretion of unchanged drug was 57% of the dose. The steady-state volume of distribution was 210 L, implying extensive tissue binding and/or partitioning. Renal plasma clearance was 660 mL/min, suggesting significant tubular secretion. The renal clearance of atropine depended on urine flow. Urinary excretion of tropine amounted to 29% of the dose. The kinetics of the metabolite was first order.Journal of Pharmaceutical Sciences 08/1985; 74(7):703-10. · 3.06 Impact Factor