Pharmacodynamic Similarity To Prenylamine

Pharmacologically, too, terodiline resembles pre-nylamine. Although prenylamine has been labelled as a calcium antagonist, it is not a true antagonist since it does not act selectively at the membrane-associated, voltage-dependent calcium channels. However, it is a potent inhibitor of calmodulin-dependent enzymes, relaxes smooth muscle and reduces slow inward current. It has been shown to depress peak sodium conductance (Hashimoto et al., 1978; Bayer et al., 1988). Hashimoto et al. (1978) have also shown that prenylamine increased the duration of action potential, indicating that the drug may interfere with the late outward current. Thus, prenylamine has potassium channels blocking activity in addition to its negative inotropic and sodium channel blocking effects.

Terodiline not only blocks the uptake of calcium but, in addition, it blocks the utilistion of some intracellular stores of calcium. Some data suggest that the drug also has local anaesthetic activity comparable to that of lignocaine. Additional recent studies have confirmed that terodiline (>1-2 mM) leads to the blockade of the sodium and calcium channels as well as muscarinic receptors in canine cardiac tissues. Terodiline (>2 mM) also depressed the action potential plateau but did not significantly alter the action potential duration at concentrations <10 mM (Pressler et al., 1995). In another study in anaesthetised dogs, terodiline (10 mg/kg given intravenously) significantly prolonged the QTc interval by 6%-8%, an effect thought to be associated with torsades de pointes (Natsukawa et al., 1998). The primary pharmacological activities of terodiline are potent calcium antagonistic and non-selective antimuscarinic effects within the same concentration range. Although both activities probably contribute to the therapeutic effect to a variable extent, the anticholinergic effect predominates at low concentrations and the calcium entry blocking action at high concentrations (Andersson, 1984), suggesting the dominance of (+)-(R)-terodiline at low daily doses of 2550 mg.

As with prenylamine, the pharmacological activities of terodiline are enantioselective. (—)-(S)-terodiline is almost ten times more potent than its antipode as a calcium antagonist, while (+)-(R)-terodiline is almost ten times more potent than (—)-(S)-terodiline in its anticholinergic activity (Larsson-Backstrom et al., 1985; Andersson et al., 1988). In a later study, the affinity and selectivity of racemic terodiline for muscarinic receptor subtypes was determined from functional responses of rabbit vas deferens (M1), guinea pig atria (M2) and bladder detrusor muscle (M3). The results suggest that the in vivo actions of racemic terodiline at (M3) receptors mediating bladder contraction may not be separable from its actions at receptors mediating mydriasis and salivation. Moreover, its effects on the pupil and salivary glands are apparently not mediated through M1 receptors (Noronha-Blob et al., 1991).

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