Parameters of drug antagonism: re-examination of two modes of functional competitive drug antagonism on intraocular muscles

Abstract

There are two distinct kinetic functional pharmacological procedures by which the equilibrium affinity constant, KB, of a competitive reversible blocker is obtained. The classical method on an organ system requires the study of the parallel displacement of the agonist concentration-response curve in the presence of the blocker. In the second method, the agonist-evoked functional mechanical response is reduced to half by the blocker IC50 (the concentration required for 50% inhibition). In relation to these parameters the role of the ionization constant pKa and liposolubility log Pc or log D of blockers was examined. On the ciliary muscle from human eye, IC50/KB ratios for (+/-)-atropine, its quaternary analogue (+/-)-methylatropine, (-)-scopolamine, (+/-)-cyclopentolate, (-)-tropicamide, (+/-)-oxybutynin and pirenzepine were 15, 23, 4.4, 2.6, 1.66, 1.46 and 1.71, respectively. The ratios on the iris sphincter were comparable with those of ciliary muscle. When compared with large proportions of ionized molecules with water soluble properties of (+/-)-atropine and (+/-)-methylatropine, relatively high amounts of un-ionized and/or with greater partitioning of all other blockers in the lipoid barrier correlated well to low IC50/KB ratios, as predicted by the classical theory of competitive drug antagonism. It was hypothesized that due to receptor biophase access, the reduction of the mechanical response of the agonist by the highly ionized water-soluble antagonist at IC50 represented time-distorted "pseudoequilibrium" estimation, where a higher concentration of the blocker was needed. On the other cholinergic effectors, like that of rat anococcygeus muscle or frog rectus abdominus muscle, IC50/KB ratios of respective blockers atropine or (+)-tubocurarine and hexamethonium were close to 1. Thus physicochemical properties, which affect the distribution coefficient log D and the tissue morphology (where asymmetric distribution of receptors may occur), appeared to be a critical factor in the analysis of the affinity parameters of the competitive reversible blocker. On the intraocular muscles, two functional pharmacological procedures for obtaining KB and IC50 values were not kinetically equivalent.

Effects of tamsulosin and silodosin on isolated albino and pigmented rabbit iris dilators: Possible mechanism of intraoperative floppy-iris syndrome

“…6,7 Thus, the aim of the present study was to examine the binding affinity of tamsulosin and silodosin to a-receptors and melanin pigment, in vivo and in vitro, in a rabbit model in which an a-blocker was chronically administered. This study was performed on isolated albino and pigmented rabbit iris dilators using pharmacologic and morphologic examinations to determine the mechanism of IFIS.…”

“…Liposoluble drugs and chemicals, such as tamsulosin and silodosin, in the iris can bind to pigment, including that in the spindle cells, and can also be readily available for reaction with smooth muscle membrane receptors. 6,7 In the morphologic examinations (experiment 2), atrophy of the dilator muscles was obvious in the a-blocker administration model. In studies that used optical coherence tomography, patients using systemic a 1 -adrenergic receptor antagonists had significantly thinner dilator muscle regions.…”

The classical competitive antagonism of phentolamine on smooth muscle preparations, investigated by two procedures

“…When calculated, IC 50 / K ratios for atropine at 37.5 and 17.5 °C were 10 and 67 n m respectively (Patil, 1992, 1999). The ratios deviating from 1 were explained on the basis of the ionization constant and lipid solubility of the antagonist (Patil, 2004). According to classical receptor theory – if the drug–receptor interaction is relatively simple, and the kinetics of intracellular transduction for the mechanical response is instantaneous, the IC 50 / K ratio for a competitive antagonist can approach unity (Gaddum, 1937, 1957; Schild, 1947; Ariëns, 1954; Furchgott, 1964, 1972).…”

The Influence of the Autonomic Nervous System on the Human Choroid

“…We hypothesise that the observed phenomenon may represent a desensitization effect that is related to atropine's inverse agonism activity (pharmacokinetics) and/or a longer than expected decay of atropine due to it binding to ocular pigment. The time required for a drug to reach its plasma maximum concentration is equal to four to five times the half-life of the drug (Patil, 2004) and a total elimination time of a drug from the body (a washout period) is calculated as five-10 times the terminal elimination half-life (World Health Organization, 2004). Atropine has a plasma half-life of 2.5 ± 0.8 hours (Kaila et al, 1999) Therefore, it should not take longer than 16 hours, for atropine, to have its maximal effect on choroidal thickness, and another eight hours to be almost completely eliminated (96.9%-99.9% of the drug) from the body.…”

“…The drug dose of 0.01% was chosen based on effective dosage that was used in previous randomized, controlled clinical trials, since this dose is known to be efficacious in myopic control and to have a clinically less significant pharmacological effects on the iris and ciliary body function compared with higher doses of atropine (Chia et al, 2016). The 0.01% dose is also predicted to exceed the published ID50 values (concentration that binds 50% of the possible maximum to the target receptor) of atropine (Patil, 2004). To prevent contamination of a trial due to the residual action of a previously administered agent, a washout period of five to ten times the terminal elimination half-life of the drug was chosen (World Health Organization, 2004).…”