A COMPLEX INTERACTION BETWEEN TOPICAL VERAPAMIL AND TIMOLOL ON INTRAOCULAR-PRESSURE IN CONSCIOUS RABBITS

Calcium channel blockers have complex actions on aqueous humour dynami cs that seem to depend on the route of drug administration. When appli ed topically, verapamil and nifedipine effectively lower intraocular p ressure. However, these drugs also produce a slight reduction in aqueo us humor outflow through the trabecular meshwork whereby they could mo dify the effect of other drugs on intraocular pressure. As calcium cha nnel blockers could be effective in the management of ocular hypertens ion and low-tension glaucoma, the aim of the present work was to asses s the interaction between verapamil and timolol when both drugs are to pically applied to the eye of albino rabbits. Intraocular pressure was measured with a manual applanation tonometer. The effects of 5-6 diff erent doses of each drug alone and the effects of five mixtures of bot h drugs at fixed concentration ratios (timolol: verapamil 4:1, 2:1, 1: 1, 1:2 and 1:4) were evaluated. After measuring baseline intraocular p ressure, one 50 mu l drop of the different solutions was instilled in the left eye. Measures of the intraocular pressure were repeated at in tervals of 30 min until the maximal effect was reached. Each set of ex periments was carried out in a group of 9-11 rabbits. Dose-response cu rves were fitted with a nonlinear regression microcomputer programme. The median effect plot was constructed as proposed by Chou and Talalay (1981, 1983, 1984). In order to analyse the nature of the interaction between both drugs, the observed effect was compared with the theoret ically expected one and the combination indices, that relate the doses of verapamil and timolol present in the mixtures with the doses of bo th drugs separately which are equieffective with the-combination, were calculated. The effects of verapamil and timolol followed the princip le of the mass action law when administered alone. Nevertheless, no ad equate dose-response relationship was obtained when the mixtures of bo th drugs were applied. In general, the observed effects were lower tha n the expected ones. Combination indices also indicate the presence of antagonism, except for the lowest concentrations of mixtures where ve rapamil predominates. In this case, combination indices suggest summat ion of effects or synergy. Both drugs seem to decrease intraocular pre ssure by reducing aqueous humor secretion through different mechanisms . However, due to the reduction of aqueous humor outflow caused by ver apamil, the ocular hypotensive effect of timolol may be antagonized wh en high doses of verapamil are administered.