AF-DX 116, a cardioselective muscarinic antagonist in humans: Pharmacodynamic and pharmacokinetic properties

Abstract

Effects of AF-DX 116, a cardioselective antagonist, on M cholinergic receptors (M-ChR) were studied in healthy volunteers. Occupancy of M-ChR subtypes by drug present in plasma samples (radioreceptor assay) was compared with these effects. After an intravenous dose of AF-DX 116 saturating greater than 90% of cardiac M2-ChR, an increase in heart rate by 25 beats/min was observed. This cardiac receptor occupancy and effect wore off with a parallel time course within 10 hours. No inhibition of salivary flow was observed, coinciding with a lack of M3-ChR blockade in the radioreceptor assay. Beta-adrenergic receptor blockade by propranolol did not affect either of the effects. No indication for active metabolites or stereoselective drug metabolism was found comparing HPLC and receptor assay for drug concentrations in plasma. We conclude that AF-DX 116 may be a useful drug for the treatment of bradycardia. Its lack of troublesome side effects is the result of its selectivity for cardiac M-ChR.

A Theoretical Appraisal of the Dependence of Respiratory Sinus Arrhythmia on Gradual Vagal Blockade

“…The choice of such an input signal reflects the fact that the binding of ACh to M 2 -cholinergic receptors of the SA node has an inhibitory effect on pacemaker activity while the interaction between NE and the β-adrenergic receptors accelerates the pacemakers' firing rate. Moreover, the functional pattern of the assigned input signal is supported by the results of previously published experimental studies [7][8][9].…”

Comparison of the effects of atropine in vivo and ex vivo (radioreceptor assay) after oral and intramuscular administration to man

“…This can only be done, however, when the concentration of antagonist in plasma corresponds to the concentration of antagonist in the effect compartment. This has been shown in investigations carried out with numerous antagonists at ~-adrenoceptors [11] and M-cholinoceptors [14]. The aim of our study was to investigate whether preoperative intramuscular administration of atropine 0.02 mg/kg body weight could be replaced by an oral dose of atropine 0.03 mg/kg body weight and whether the effects could be correlated with the M2-cholinoceptor occupancy.…”

“…M2-cholinoceptor-containing membranes were prepared from porcine atria and auricles [13]. For species comparison of affinities of atropine for M-cholinoceptors, slices from human cardiac right atria (obtained from cardiac surgery patients without clinical signs of cardiac insufficiency) were also prepared for receptor-binding studies [14]. The tissues were homogenized in sodium phosphate buffer (Buffer A: 310 mosm/I, 10 mM EDTA, pH 7.4 at 25°C) and centrifuged (27.000 x g, at 4°C for 10 min).…”

Muscarinic Receptor Agonists and Antagonists

“…This property of atropine ( 4 ) is used in the emergency treatment of acute myocardial infarction when the dominant autonomic influence on the heart is via the vagus nerve, causing sinus or nodal bradycardia. Selective M 2 receptor antagonists are therefore of potential value for this indication and AF-DX 116 (otenzepad) ( 18 ) is in the latter stages of development for bradycardia [ 39 ].…”