Comparison of the airway response to eye drops of timolol and its isomer L‐714,465 in asthmatic subjects.

Abstract

1 The inadvertent administration of timolol to asthmatic patients continues to cause occasional severe and even fatal attacks of asthma. The (R)-entantiomer of timolol, L-714,465, is four times less potent than timolol in reducing intraocular pressure in man. It is 49 times less potent than timolol on 132-adrenoceptors in animals and 13 times less potent on the airways of normal subjects. These findings suggested that L-714,465 might be a safer alternative for the treatment of glaucoma. 2 Ten subjects with mild asthma who bronchoconstricted to timolol eye drops (0.25 or 0.5%) were studied. Airway dose-response curves to timolol (0-2%), L-714,465 (0-4%), and placebo (methyl cellulose) eye drops were performed in a double-blind randomised study in which airway response was measured as change in FEV1 and specific airway conductance (sGaw). 3 L-714,465 and timolol caused dose dependent falls in sGaw and FEV1 with L-714,465 being approximately four times less potent than timolol. The geometric mean dose ratio was 3.89 for FEV1 (95% confidence interval (CI) 1.7-8.7) and 3.93 (95% CI 2-7.8) for sGaw. Since the difference in potency is similar to the reported difference in potency of the two drugs on intraocular pressure we conclude that L-714,465 would not have a greater safety margin than timolol. 4 After completion of the dose-response study eight subjects inhaled ipratropium bromide (72,ug) and this caused an increase in FEV1 from 74% to 80% of baseline. There was no further increase in FEV1 after a further 72 ,ug in seven patients though the FEV1 returned to baseline values after inhaled salbutamol (0.2-2.5 mg). ,B-adrenoceptor antagonist-induced bronchoconstriction is only partially reversed by conventional doses of antimuscarinic drugs.

Preventive effect of lacrimal occlusion on topical timolol‐induced bronchoconstriction in asthmatics

“…As demonstrated in Table 3, the administration of timolol drop into the eye resulted in significant decreases in FVC, FEV1, FEV1/FVC, and FEF 25‐75 when measured after 60 min of drug application. The mean percentages of the decrement in these parameters were –9.61 ± 9.57, –12.15 ± 10.25, –4.30 ± 5.46, and –11.0 ± 8.64, respectively, similar to the previous studies 6,14,15 . Table 3 also indicates that the lacrimal occlusion by intracanalicular plugs significantly reduced the decrease in spirometric values induced by timolol drop ( P = 0.638, 0.807, 0.789, 0.485 for FVC, FEV1, FEV1/FVC, and FEF 25‐75 , respectively).…”

Assessment of bronchial effects following topical administration of butylamino‐phenoxy‐propanol‐acetate, an oculoselective beta‐ adrenoceptor blocker in asthmatic subjects.

“…Our results show a good coincidence with those of other authors concerning bronchoconstriction following ophthalmic timolol in selected asthmatics (Cervantes et al, 1986;Dunn et al, 1986;Richards & Tattersfield, 1987;Schoene et al, 1984;Spiritus & Casciari, 1985).…”

“…The very low flow and quasi-static conditions of sGaw measurements (Tattersfield & Keeping, 1979) (Kaback et al, 1976), and the o-pivalyl ester of a carbonic anhydrase inhibitor (Sugrue et al, 1985). In asthmatic subjects the (R)-enantiomer of timolol caused falls in sGaw and FEV1 being approximately four times less potent than timolol (Richards & Tattersfield, 1987). Since the difference in potency is similar to that in IOP the (R)-enantiomer of timolol would not have a greater safety margin than timolol (Richards & Tattersfield, 1987).…”

“…In asthmatic subjects the (R)-enantiomer of timolol caused falls in sGaw and FEV1 being approximately four times less potent than timolol (Richards & Tattersfield, 1987). Since the difference in potency is similar to that in IOP the (R)-enantiomer of timolol would not have a greater safety margin than timolol (Richards & Tattersfield, 1987). Recently it has been suggested that betaxolol should be preferred to any other ophthalmic P-adrenoceptor blocker in case of positive contraindications (LeJeunne et al, 1990).…”

Drugs used in ophthalmology—anti-glaucoma drugs

“…Because it was originally considered possible to separate the ocular hypotensive effects from the systemic effects of beta-blockers by making use of different stereo isomers, Richards and Tattersfield (1987) compared timolol to its D isomer. The isomer is four times less potent in reducing IOP and is four times less potent in causing bronchoconstriction.…”