Pharmacogenetic explanation for excessive beta-blockade following timolol eye drops. Potential for oral-ophthalmic drug interaction.

OBJECTIVE: To determine whether the effects of topically administered timolol in an individual would be dependent on the presence or absence in that individual of the P-450 enzyme CYP2D6 and whether the effects of topically administered timolol would be increased and its metabolism decreased by the oral administration of quinidine, a known inhibitor of CYP2D6. DESIGN: Single-blind randomized crossover comparison of topical timolol, placebo, and the effects of inhibition of timolol metabolism by oral quinidine. SETTING: Clinical research center of an academic medical center. PARTICIPANTS: Eight male extensive metabolizers (EMs) and five male poor metabolizers (PMs) of debrisoquin. INTERVENTION: Two drops of 0.5% timolol or artificial tears were administered into each nostril in random order, and placebo or 50 mg of quinidine was administered orally to the EMs in random order, followed 30 minutes later by either the timolol or placebo drops. MAIN OUTCOME MEASUREMENT: Plasma timolol concentrations were measured by high-pressure liquid chromatography, while the extent of beta-blockade was determined by the suppression of exercise-induced rise in heart rate. RESULTS: The exercise heart rate was reduced following timolol eye drops compared with placebo in both EMs (P < .001) and PMs (P < .001) with significantly greater heart rate reduction (P = .01) and higher plasma timolol concentration in PMs compared with EMs (P = .03). Administration of quinidine with timolol eye drops to EMs resulted in a further significant reduction in heart rate (P = .02) and increase in plasma timolol concentration (P = .04). CONCLUSIONS: An individual's debrisoquin phenotype is an important determinant of beta-blockade following timolol eye drops, and metabolism of timolol is inhibited and beta-blockade increased by coadministration of oral quinidine. Clinicians should be aware of the potential for drug interactions that occur when orally administered drugs inhibit the metabolism of a topically administered drug.

Catecholaminergic responses in vas deferens isolated from rats submitted to acute swimming stress.

The study was performed to examine the responses to catecholamines in vas deferens isolated from rats submitted to acute swimming-induced stress. It was demonstrated that acute stress induces a significant subsensitivity of rat vas deferens to norepinephrine. This subsensitivity was inhibited when the experiment was carried out in the presence of either cocaine (10-5 M) or timolol (10-5 M). On the other hand, the rat vas deferens sensitivity to methoxamine was significantly increased by acute swimming-induced stress. Thus, despite acute swimming stress inducing a reduction in response to norepinephrine, the alpha1-adrenoceptor-mediated contractile response was increased. Additionally there were increases in neuronal uptake and beta2-adrenoceptor activity that opposes the alpha1-adrenoceptor activity. Integrated, these phenomena are responsible for the rat vas deferens subsensitivity to norepinephrine which may be involved in body homeostasis in stressogenic situations.

Dopamine-2 receptor blockade does not affect the ocular hypotensive action of timolol.

We have shown that metoclopramide, a dopamine-2 antagonist, failed to antagonise the ocular hypotensive action of timolol. The practical implication of combining dopamine agonists with beta-adrenoceptor antagonists in the treatment of glaucoma is discussed.

Pharmacologic pupillary modulation in the perioperative period.

The perioperative management of the pupil is essential to the success of anterior segment surgery. A new dilating regimen was tested in 65 cases of cataract extraction and intraocular lens implantation. The alpha-adrenergic agonist, phenylephrine 2.5%, was used after pretreatment with the adrenergic beta-blocker, timolol 0.5%. This treatment successfully dilated the pupil in all but three cases, was maintained by intraoperative epinephrine infusion, and was readily reversed with intraocular acetylcholine. We conclude that this pharmacologic regimen provided a successful and easily reversible mydriasis during surgery.

Active transport of beta-adrenergic blocking agents in the anterior uvea of albino rabbit.

Transport of timolol and befunolol in the anterior uvea of the albino rabbit was studied in vitro. Also, the mode of timolol elimination from the living eye was investigated. The isolated iris-ciliary body incubated at 37 degrees C accumulated 14C-timolol and 14C-befunolol against the concentration gradient, and the tissue-to-medium ratio was 5.45 +/- 0.29 and 5.46 +/- 0.44, respectively. The accumulation of both drugs was significantly suppressed by incubation at 0 degrees C and also by pretreatment with ouabain or cyanine but not with probenecid. The relationship between the initial velocities of accumulation and medium drug concentrations conformed with saturation kinetics, indicating the presence of mediated transport of these drugs. The apparent Km was 1.08 X 10(-6) mole per liter for timolol and 8.00 X 10(-7) for befunolol, and the Vmax was 5.46 X 10(-9) mole per g per hour for timolol and 1.52 X 10(-8) for befunolol. A mixture of 14C-timolol and 3H-sucrose was injected into the center of the vitreous cavity of the living rabbit. Timolol was lost from the vitreous at a rapid rate of about 36% per hour, while sucrose was lost very slowly, at about 5% per hour. Thus it was thought that an energy-requiring carrier-mediated transport system is operative in the anterior uvea of the albino rabbit, and that this would account for the rapid removal of the beta-blockers out of the eye.

Calcium interferes with the cardiodepressive effects of beta-blocker overdose in isolated rat hearts.

Propranolol, timolol and sotalol were compared with respect to their cardiotoxic properties in isolated, spontaneously beating rat hearts. Propranolol and timolol induced a dose-dependent decrease in myocardial contractility. A high dose of sotalol had only modest negative inotropic effects. Similar reductions in myocardial contractility were observed in isolated, ventricle-stimulated rat hearts. These observations were similar to those in a previous study in which spontaneously beating and ventricle-stimulated reserpinized rat hearts were investigated. Spontaneously beating rat hearts were perfused with a high-, a normal- and a low-Ca++ medium, each with and without propranolol, timolol and sotalol. Addition of each beta-blocker to a normal-Ca++ medium induced a decrease of myocardial contractility and of heart rate and an increase of AV-conduction time when compared with the drug-free medium. In a high-Ca++ medium containing the same concentration of each beta-blocker, a less pronounced decrease of myocardial contractility was observed. Heart rate decreased and AV-conduction time increased to the same extent as after perfusion with the drug containing normal-Ca++ medium. With respect to the corresponding drug-free medium perfusion with a low-Ca++ medium with each beta-blocker enhanced the decline in myocardial contractility, most pronounced in propranolol and timolol containing media. For propranolol and sotalol the decrease in heart rate and increase in AV-conduction time were similar to the results after administration of the same beta-blocker in a high- and a normal-Ca++ perfusion media. Timolol caused an electromechanical dissociation. It was concluded that in beta-blocker intoxication the negative-inotropic phenomena cannot be explained by an action of the drugs on the beta-receptor since the results in reserpinized and non-reserpinized rat hearts were similar. Other effects have to be responsible for the observed cardiotoxic phenomena. The present results indicate that these phenomena can be influenced by Ca++ and or can be attributed to differences in lipophilicity.

Interaction of timolol and caffeine on intraocular pressure.

The clinical interaction of 0.5% timolol maleate and 400 mg of oral caffeine on the intraocular pressure of 20 normotensive volunteers was studied. Caffeine administration did not significantly alter the reduction in intraocular pressure in timolol treated eyes. An antagonism, however, was observed in the fellow timolol untreated eyes with caffeine. The crossover reduction in intraocular pressure noted in the control group was significantly depressed in the caffeine group. A proposed mechanism for these observations is discussed.

Effect of indomethacin on the ocular hypotensive action of timolol maleate.

A randomized, double-masked, cross-over study of nine healthy normal subjects was conducted to determine whether indomethacin affected the ocular hypotensive action of timolol maleate. A significant decrease in intraocular pressure occurred with timolol maleate 0.5% eyedrops (used twice a day) alone. Indomethacin (25 mg three times a day, given orally) administered concurrently had no effect on timolol's hypotensive action. No subjective or objective side effects occurred and there were no significant changes in blood pressure, pulse rate, or respiratory rate with either treatment.

Timolol and epinephrine: a clinical study of ocular interactions.

In a crossover design study, we assessed effects on intraocular pressure, pupillary diamter, pulse rate, and blood pressure over six hours of one drop of 0.5% timolol maleate and 2% epinephrine hydrochloride in one eye. Both eyes of each patient had been pretreated for one week with twice-daily applications pf epinephrine or timolol, respectively. In random sequence, 20 patients (40 eyes) participated in both phases of the study. Pretreatment with timolol significantly reduced the ocular hypotensive effect of epinephrine (from 15.3% to 4.6%); epinephrine pretreatment did not affect the pressure reduction of timolol. Pretreatment with timolol enhanced the mydriatic effect of epinephrine (from 35.8% to 71.9% pupillary dilation); pretreatment with epinephrine resulted in an apparent mydriatic effect for timolol.