Cardiovascular Journal of Africa: Vol 26 No 6 (November/December 2015)

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 26, No 6, November/December 2015

212

AFRICA

the patients with topical beta-blocker-induced AV block needed

pacemaker implantation during follow up.

Topical beta-blockers decrease intra-ocular pressure by

reducing the inflow of aqueous humour, which is controlled by

the adrenergic system in the ciliary epithelium.

However, only

two to 10% of the drugs may penetrate to the inner parts of

the eye and the periocular tissues.

The remainder of the drugs

(about 80% for timolol) enter the systemic circulation through

the conjunctival vessels and via the nasolacrimal duct through

the nasal mucosa, and reach peak plasma concentrations within

five to 30 minutes.

19,20

Quaranta

et al.

showed that timolol significantly reduced systolic

and diastolic blood pressures.

21,22

Beta-blockers decrease sinus node

automaticity, prolong sino-atrial, intra-atrial and atrioventricular

conduction times, and increase atrioventricular node refractoriness.

Orzalesi

et al

. reported that the level of cardiovascular risk was

significantly higher in glaucoma patients,

although in potentially

predisposed patients, topical beta-blockers may cause adverse

cardiovascular events secondary to systemic effects.

In a randomised trial conducted in glaucoma patients using

placebo, topical beta-blockers or dual therapy of topical and oral

beta-blockers, the pulse rate was significantly lower in the topical

beta-blocker group compared to the controls (70.3 vs 76 beats/

min). Heart rate was lowest in the dual-therapy group, which was

reported as 58 beats/min.

In our study, even though none of the

patients received dual beta-blocker therapy, severe conduction

disturbances were observed in patients using topical beta-

blockers. In most of the patients, even after discontinuation of

the drug, the conduction disturbances persisted and permanent

pacemaker implantation was required.

In a previous study by our group, permanent pacemaker

implantation rate was 48% in patients taking rate-limiting drugs

except topical beta-blockers.

However, in this cohort, the rate

of permanent pacemaker implantation was significantly higher

(84.6%,

0.01).

The mean age of patients in earlier and more recent articles

was similar (72.01 vs 71.7 years, respectively).

However, the level

of AV block was significantly different in two articles: 28 of 108

patients (25.9%) taking rate-limiting drugs except topical beta-

blockers had infra-nodal AV block, while eight of 13 patients

(61.5%) on topical beta-blockers had infra-nodal AV block.

In previous trials conducted on patients with drug-induced

AV block, it was shown that infra-nodal block was associated

with a higher rate of pacemaker implantation.

15,16

Topical beta-

blockers may not disturb electrical conduction as strongly as

oral rate-limiting drugs due to their lower dose and the route

of administration. However, topical beta-blockers may induce

AV block in susceptible patients, and there are case reports of

permanent pacemaker implantation in patients receiving them.

6-8

Edwards and Aronson classified adverse drug reactions into

six types: dose related (augmented), non-dose related (bizarre),

dose related and time related (chronic), time related (delayed),

withdrawal (end of use), and failure of therapy (failure).

In our

cohort, AV conduction fully recovered after drug withdrawal

in two patients who were on fixed-dose timolol for more than

four years. In 11 of 13 patients, AV conduction did not recover

after drug withdrawal, which means the dose and length of

time it was administered had no effect. According to the above

drug-reaction classification, we concluded that 11 of 13 of our

patients had non-dose-related (bizarre) drug reactions, and

two of 13 patients had time-related (delayed) drug reactions.

We suggest, however, that if AV block occurs during treatment

with ophthalmic beta-blockers, it may be an indicator of an

underlying severely damaged electrical pathway.

Lopez

et al

. evaluated the prognosis of 12 patients with

ophthalmic beta-blocker-induced AV block.

In their series,

seven of the 12 patients recovered during follow up and five

needed pacemaker implantation. They concluded that every

patient with AV block must be questioned about concomitant

use of eye drops. The pacemaker implantation rate in our series

was higher than in their series, but the percentage of patients

using topical beta-blockers was higher in their series (12 of 243

patients with AV block vs 13 of 1 122 patients with AV block in

our series). In their study the age, gender, presence of a bundle

branch block, escape rhythm on ECG, or dosage of the drugs

did not predict the risk for permanent pacemaker implantation.

Limitations

We evaluated elderly symptomatic patients who required

hospitalisation in a tertiary centre. We did not include out-patient

clinic patients, asymptomatic cases, those with mild symptoms or

patients with transient forms of conduction abnormalities in our

study. This may explain the high rate of pacemaker implantation

in our cohort, which included patients with more severe forms

of conduction abnormalities secondary to topical beta-blocker

therapy. Irrespective of the accuracy of the electrocardiographic

characteristics in defining the level of the AV block, His-bundle

recording was not performed during the course of this study and

we could also not determine a causal relationship.

Conclusion

This study and previous reports show that patients using topical

beta-blockers may suffer severe bradyarrhythmias secondary to

AV block, and a significant percentage of these cases required

pacemaker implantation. Patients with underlying pathology of

the sinus or AV node, or the conduction pathways may develop

AV block while on treatment with ophthalmic beta-blockers and

these drugs may reveal concealed AV block. It may therefore be

beneficial to search for pre-existing conduction abnormalities in

patients with glaucoma before initiation of this type of medication.

References

European Glaucoma Society. Treatment principles and options,

antiglaucoma drugs. In:

Terminology and Guidelines for Glaucoma

, 3rd

edn. Savona: Dogma, 2008: 121–134.

Zimmerman T. Topical ophthalmic beta-blockers: a comparative review.

J Ocul Pharmacol

1993;

(4): 373–384.

Gerber SL, Cantor LB, Brater DC. Systemic drug interactions with

topical glaucoma medications.

Surv Ophthalmol

1990;

(3): 205–218.

Dorigo MT, Cerin O, Fracasso G, Altafini R. Cardiovascular effects of

befunolol, betaxolol and timolol eye drops. I

nt J Clin Pharmacol Res

1990;

(3): 163–166.

Tattersall C, Vernon S, Singh R. Resting pulse rates in a glaucoma clinic:

the effect of topical and systemic beta-blocker usage.

Eye (Lond)

2006;

(2): 221–225.

Sharifi M, Koch JM, Steele RJ, Adler D, Pompili VJ, Sopko J. Third

degree AC block due to ophthalmic timilol solution. I

nt J Cardiol

2001;