Interaction between timolol eyedrops and oral nicardipine or oral diltiazem in healthy Japanese subjects.
OBJECTIVE
Timolol is widely used for the topical therapy of glaucoma. Adverse cardiovascular effects include slowing of the heart rate and weakening of myocardial contractility. We investigated pharmacodynamic interactions with respect to cardiovascular and ocular responses between timolol ophthalmic solution and either nicardipine, which does not directly inhibit cardiac conduction, or diltiazem, which does.


METHODS
Two studies utilized a randomized, double-blind, Latin-square, placebo-controlled design involving four separate treatments given at least 1 week apart. Eight healthy male Japanese volunteers received a single drop of 0.5% timolol or artificial tears in each eye with or without a single oral dose of nicardipine (40 mg), and with or without a single oral dose of diltiazem (60 mg). Subjects exercised on a bicycle ergometer before and 1.5 and 3 h after dosing. At these times, heart rate and blood pressure were measured at rest and after exercise. The intraocular pressure was measured at rest.


RESULTS
One drop of 0.5% timolol per eye significantly reduced the exercise-induced increase in heart rate and blood pressure, and intraocular pressure at rest. The timolol ophthalmic solution suppressed the reflex sympathetic cardiac stimulation that resulted from the primarily vasodilative action of nicardipine. No additional reduction in heart rate occurred when the ophthalmic timolol solution was administered in conjunction with diltiazem. The concomitant use of timolol and nicardipine or diltiazem did not induce an additional reduction in intraocular pressure. Oral nicardipine or diltiazem did not reduce intraocular pressure. Care should be taken when using topical timolol in patients with cardiovascular or respiratory diseases.
Yatsuka
Y I
YI
Department of Clinical Pharmacology and Therapeutics, Oita Medical University, Japan.
Tsutsumi
K
K
Kotegawa
T
T
Nakamura
K
K
Nakano
S
S
Nakatsuka
K
K
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D044466:Asian People; D001794:Blood Pressure / Q000187:drug effects; D004110:Diltiazem / Q000037:antagonists & inhibitors*; D004311:Double-Blind Method; D005080:Exercise Test; D005901:Glaucoma / Q000188:drug therapy; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D007564:Japan; D008297:Male; D009529:Nicardipine / Q000037:antagonists & inhibitors*; D009883:Ophthalmic Solutions; D012016:Reference Values; D013999:Timolol / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors*
D000319:Adrenergic beta-Antagonists; D009883:Ophthalmic Solutions; D014665:Vasodilator Agents; D013999:Timolol; D009529:Nicardipine; D004110:Diltiazem