Summary
Synopsis
Carteolol is a relatively potent nonselective β-adrenoceptor antagonist with partial agonist activity. It is used topically to reduce elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension. Twice-daily ocular administration of carteolol 1 or 2% lowers IOP by approximately 32% on average in patients with these conditions, an efficacy equivalent to that of timolol 0.25 or 0.5%. Carteolol eyedrops lack local anaesthetic activity, appear to cause less local irritation than timolol, and produce less pronounced decreases in heart rate or dyspnoea, possibly due to partial agonist activity. The latter activity may also improve retinal perfusion.
Thus, although additional comparative trials are needed to accurately assess the precise place of carteolol in therapy, this drug offers a useful alternative to timolol in the management of conditions associated with a raised IOP, and may have advantages in older patients with regard to its tolerability profile, although careful monitoring is still wise.
Pharmacodynamic Properties
Carteolol is a nonselective β-adrenoceptor antagonist with partial agonist activity and no local anaesthetic activity.
In healthy volunteers, single ocular administration of carteolol 1 or 2% reduces intraocular pressure (IOP) by a mean of approximately 2 to 5mm Hg (14 to 38% of baseline value). The reduction in IOP lasts for up to 12 hours, with peak effects occurring 4 hours after eyedrop instillation. A crossover effect in the untreated eye is also apparent. Mean IOP decreases by 5 to 10mm Hg (about 20 to 25%) 4 hours after ocular administration of carteolol 1 or 2% in patients with open angle glaucoma or ocular hypertension (IOP > 21mm Hg), and persists for 24 to 48 hours, although IOP over 12 hours appears to be less well controlled than after timolol 0.5%. The mean decrease in IOP is similar following twice-daily ocular administration of carteolol 1 or 2%, or timolol 0.5% after 4 to 10 weeks. 8-Hydroxy-carteolol, the main metabolite of carteolol, appears to be more potent in lowering IOP and possesses greater partial agonist activity.
Studies in volunteers have variously shown that retinal blood perfusion pressure is not significantly decreased, and mean ocular perfusion pressure and retinal blood flow rate may be increased by carteolol. Partial agonist activity and possibly a relaxant effect on endothelial vasculature, as well as the reduced IOP, may contribute to these findings.
In vivo, carteolol elicits fewer pathological changes in the cornea and less readily inhibits epithelial healing than timolol 0.25 and 0.5%, or befunolol 0.5 and 1%. Aqueous humour flow is reduced by carteolol in volunteers, but visual acuity, pupil diameter and anterior chamber volume do not change.
Sufficient carteolol concentrations are achieved systemically following ocular administration to produce systemic β-blockade. Decreases in mean forced expiratory volume in 1 second (FEV1) are less after 1 or 2 carteolol eyedrops (7%) than after timolol (11%) or metipranolol (15%) in patients with asthma. Resting heart rate is unaffected or reduced (mean 16.7%) by single ocular doses of carteolol 1 or 2%, an effect slightly less than that of timolol (mean 18.2%). Systolic blood pressure may be decreased by ocular administration of carteolol (mean 6.5%) while, in common with other β-blocker eyedrops, diastolic pressure is generally unaffected.
Pharmacokinetic Properties
There are very few published data regarding the disposition of carteolol eyedrops in humans, but since most of the ocular dose eventually reaches the systemic circulation, some pharmacokinetic parameters following oral and intravenous delivery are relevant.
First-pass metabolism, about 15% following oral carteolol administration, is bypassed by the ocular route. Total clearance and half-life of carteolol correlate linearly with creatinine clearance. Adjustment of oral dosage is therefore necessary in patients with renal dysfunction, although no data concerning this relevance to the ocular administration of carteolol have been reported.
In humans with normal renal function, 63 to 87% of an oral or intravenous dose of carteolol in total is recovered unchanged in the urine, with the major metabolite, 8-hydroxy-carteolol, comprising 4 to 10%. The volume of distribution of an intravenous dose of carteolol was 4 L/kg in 8 healthy volunteers.
Therapeutic Use
Because of its ability to lower elevated IOP, ocular carteolol has been used clinically to treat patients with ocular hypertension or glaucoma, primarily of the open angle type. Noncomparative trials have shown that carteolol 1 or 2% twice daily reduced mean IOP by a mean of 8.7mm Hg (range 5 to 15mm Hg), a reduction of 32% (19 to 47%) from pretreatment values for up to 14 months in patients with ocular hypertension or glaucoma.
The decrease in IOP during carteolol administration is significantly greater than occurs during placebo use, although open crossover trials have suggested a lesser efficacy of twice-daily carteolol 1% compared with timolol 0.25%, and carteolol 2% compared with timolol 0.5%, this has not been borne out in randomised studies of up to 1 year’s duration. In these trials, carteolol 2% twice daily was equivalent to timolol 0.5%, and carteolol 1% comparable to timolol 0.25%, in that mean IOP was generally reduced by 2 to 4mm Hg (12 to 20%) by both drugs. Greater decreases of between 6 and 10mm Hg (24 to 33%) were also reported. Each drug appears to preserve visual fields to a similar extent. Nevertheless, patients and investigators tended to favour carteolol over timolol based on efficacy and tolerability. IOP was reduced slightly further in previously untreated patients, compared with those changed over from another ocular β-blocker.
Tolerability
Acute eye irritation was reported by 25.8% of 609 patients in a multicentre study before receiving carteolol 1 or 2%, eyelid inflammation by 11.6% of patients and conjunctival oedema by 4.1%; these rates decreased to 1.7, 0.8 and 0.4%, respectively after 2 months’ treatment. Local tolerability of carteolol 2% is better than timolol 0.5%, betaxolol 0.5% and metipranolol 0.6%.
Adverse effects due to systemic absorption of β-blocking concentrations of ocular carteolol are rare in clinical trials, possibly due to selection criteria. Isolated decompensated heart failure, disabling Raynaud’s syndrome, and asthma have been reported during carteolol treatment of glaucoma. Resting heart rates are reduced to a lesser degree than with ocular timolol. Exercise-induced dyspnoea, headache, tiredness and dizziness tended to be less common with ocular carteolol compared with timolol, metipranolol, befunolol or pindolol. Overall incidence of adverse effects was smaller in carteolol (26%) versus timolol recipients (49%) in 1 study.
Dosage and Administration
The manufacturer’s recommended starting dosage of carteolol in the treatment of patients with glaucoma or ocular hypertension is 1 drop of 1% solution into the affected eye(s) twice daily, increasing to the 2% eyedrops twice daily if the initial response is inadequate.
Carteolol eyedrops are contraindicated in patients with cardiac failure or obstructive airways disease, and should be used with caution in those taking systemic β-blocker therapy and those with conditions which may be exacerbated by systemic β-blockade.
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Various sections of the manuscript reviewed by: A.M.V. Brooks, Glaucoma Investigation and Research Unit, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia; J. Collignon-Brach, Service d’Ophthalmologie, Centre Hospitalier Universitaire de Liège, Liège, Belgium; F.I. Fraunfelder, Casey Eye Institute, Oregon Health Sciences University School of Medicine, Portland, Oregon, USA; D.E. Gaasterland, Glaucoma and Laser Service and Worthen Center for Eye Care Research, Georgetown University Medical Center, Washington, D.C., USA; F.-C. Hugues, Service de Médecine Interne II, Hôpital Laënnec, Paris, France; E.U. Keates, Northern Ophthalmic Associates Inc., Jenkintown, Pennsylvania, USA; Y. Kitazawa, Department of Ophthalmology, School of Medicine, Gifu University, Gifu, Japan; Cl. Le Jeunne, Service de Médecine Interne II, Hôpital Laënnec, Paris, France; I.H. Leopold, Department of Ophthalmology, University of California, Irvine, California, USA; K. Segawa, Department of Ophthalmology, Shinshu University School of Medicine, Ngano-Ken, Japan.
An erratum to this article is available at http://dx.doi.org/10.1007/BF03257456.
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Chrisp, P., Sorkin, E.M. Ocular Carteolol. Drugs & Aging 2, 58–77 (1992). https://doi.org/10.2165/00002512-199202010-00007
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DOI: https://doi.org/10.2165/00002512-199202010-00007