DRUG EVALUATION

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Drugs & Aging 2 (I): 58-77, 1992 1170-229X/92/000I-0058/$IO.00/0 © Adis International Limited. All rights reserved. DAM 77

Ocular Carteolol A Review of its Pharmacological Properties, and Therapeutic Use in Glaucoma and Ocular Hypertension Paul Chrisp and Eugene M. Sorkin Adis International Limited, Auckland, New Zealand

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 Liege, Liege, Belgium; F.I. Fraun/elder, 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 Medecine Interne II, H6pital Laennec, 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 Medecine Interne II, H6pital Laennec, 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.

Contents 59 60 61 61 62 62 62 63 64 65 65 66 67 67 67 68 69 69 69 70 71 71 73 74 74

Summary 1. Pharmacodynamic Properties 1.1 Effect on Intraocular Pressure 1.1.1 Studies in Healthy Volunteers 1.1 .2 Studies in Patients with Glaucoma or Ocular Hypertension 1.2 Other Ocular Effects 1.2.1 Animal Studies 1.2.2 Studies in Humans 1.3 Systemic Activity 1.3.1 Bronchopulmonary Effects 1.3.2 Haemodynamic Effects 1.4 Mechanism of Action 2. Pharmacokinetic Properties 2.1 Absorption and Distribution 2.2 Metabolism and Excretion 3. Therapeutic Use 3.1 Noncomparative Trials 3.2 Comparative Trials 3.2.1 Comparison with Placebo 3.2.2 Comparisons with Timolol 4. Tolerability 4.1 Ocular Effects 4.2 Systemic Effects 5. Dosage and Administration 6. Place of Carteolol in Glaucoma and Ocular Hypertension

Ocular Carteolol: A Review

59

Summary Synopsis Carteolol is a relatively potent nonselective fJ-adrenoceptor antagonist with partial agonist activity. It is used topically to reduce elevated intraocular pressure (lOP) in patients with glaucoma or ocular hypertension. Twice-daily ocular administration of carteolol 1 or 2% lowers lOP 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 lOP. 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 {1-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 (lOP) by a mean of approximately 2 to 5mm Hg (14 to 38% of baseline value). The reduction in lOP 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 lOP decreases by 5 to IOmm Hg (about 20 to 25%) 4 hours after ocular administration of carteolol 1 or 2% in patients with open angle glaucoma or ocular hypertension (lOP> 21mm Hg), and persists for 24 to 48 hours, although lOP over 12 hours appears to be less well controlled than after timolol 0.5%. The mean decrease in lOP 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 lOP 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 lOP, 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 {1-blockade. Decreases in mean forced expiratory volume in 1 second (FEY \) 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 oftimolol (mean 18.2%). Systolic blood pressure may be decreased by ocular administration of carteolol (mean 6.5%) while, in common with other {1-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.

Drugs & Aging 2 (1) 1992

60

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 lOP, 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 carteololl or 2% twice daily reduced mean lOP by a mean of8.7mm 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 lOP 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 lOP was generally reduced by 2 to 4mm Hg (12 to 20%) by both drugs. Greater decreases of between 6 and IOmm 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. lOP was reduced slightly further in previously untreated patients, compared with those changed over from another ocular fJ-blocker.

Tolerability Acute eye irritation was reported by 25.8% of 609 patients in a muIticentre 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 fJ-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. Exerciseinduced 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 fJ-blocker therapy and those with conditions which may be exacerbated by systemic fJ-blockade.

1. Pharmacodynamic Properties Carteolol is a hydrophilic tJ-adrenoceptor antagonist structurally related to timolol, levobunol01, betaxolol and metipranolol (fig. 1). It is a nonselective antagonist with moderate partial agonist activity towards both tJl- and Ih-adrenoceptors, but

lacks local anaesthetic (membrane stabilising) activity (Frishman & Covey 1990; Hoh 1989). Carteolol is 10 times more potent than propranolol as a tJ-adrenoceptor blocker (Frishman & Covey 1990). This review focuses on the use of ocular carteo101 in the management of glaucoma and ocular

61

Ocular Carteolol: A Review

H

O~COI~ .0

CH3 I

OCH2CHCH2NHC-CHa • HCI

I

OH

I

CH3

Carteolol hydrochloride

oY

[>-CH20CH2CH2

1Ha

OCH2CHCH2NHCH • HCI 6H

Levobunolol hydrochloride

bHa

Betaxolol hydrochloride

Fig. 1. Chemical structures of carteolol hydrochloride, levobunolol hydrochloride, metipranolol and timolol maleate.

hypertension. The oral use of carteolol in essential hypertension and angina (see review by Frishman & Covey 1990) is thus beyond the scope of this review. 1.1 Effect on Intraocular Pressure Carteolol, along with other p-adrenoceptor blocking drugs possessing little or no local anaesthetic activity listed in table I, may be used topically to reduce intraocular pressure (lOP), and thus has a role in glaucoma management. The effects of carteolol on lOP have been investigated in healthy volunteers and in patients with ocular hypertension or chronic open angle glaucoma. 1.1.1 Studies in Healthy Volunteers Mean lOP was 1.7 to 1.8mm Hg (14 to 16%) lower in eyes instilled with carteolol 1% compared with placebo or untreated eyes in 3 groups of 5, 8

and 10 healthy volunteers (Araie & Takase 1985; Negishi et al. 1981; Wright et al. 1989). Four hours after single topical administration of carteolol 0.1, 0.25, 0.5, 1 and 2% ophthalmic solutions to 8 volunteers, mean lOP decreased by a maximum 2.5 (19% reduction), 2.9 (22.5%), 3.7 (27.5%), 4.4 (31%) and 5.2mm Hg (38.5%), respectively, in a double-blind crossover study (Negishi et al. 1981). Timolol 0.5% caused an lOP reduction of 4.6mm Hg (34%) and placebo l.3mm Hg (11%) [fig. 2J. A significant reduction in lOP was observed within 1 hour of administration of carteolol 0.5 and 1%, and within 30 minutes with the 2% solution, and the lower lOP persisted for 12 hours. In another study involving 3 groups of 10 healthy volunteers, carteolol 2% reduced lOP by a mean of 3.2mm Hg in both treated eyes, compared with 2.6mm Hg with timolol 0.5% and 1.95mm Hg witJt betaxolol 0.5% (Pillunat et al. 1988).

Drugs & Aging 2 (1) 1992

62

Table I. Properties of some j3-adrenoceptor antagonists shown to lower lOP (after Buckley et al. 1990; Frishman & Covey 1990)

Drug

Betaxolol Carteolol Levobunolol Metipranolol Timolol

Partial agonist activity

Cardiosel8Ctivity

Membrane stabilising activity

+

1.0 10.0 14.6 1.8 4.7

+

- A further double-blind crossover study demonstrated comparable decreases in mean lOP of 2.2mm Hg and 2.3mm Hg, respectively, following administration of 2 drops of carteolol 2% or timolol 0.5% in 6 volunteers, significantly greater reductions than achieved with placebo (Brazier & Smith 1988). Again, the greatest effect occurred 4 hours after drug administration. Similarly, 3 hours after administration of single drops of carteolol 2%, timolol 0.5% and metipranolol 0.6%, respectively, mean lOP was 2.38, 2.44 and 3.6mm Hg lower than after placebo in 12 healthy volunteers (Berlin et al. 1987). Mean lOP also decreased by approximately 14 to 21% in the untreated eyes of healthy volunteers (Brazier & Smith 1988; Negishi et al. 1981), suggesting a crossover effect resulting from systemic absorption of carteolol (see also section 1.3). However, placebo administration also caused a 4 to 11 % decrease in mean lOP in untreated eyes. Carteolol 1% reduced lOP by 1.02mm Hg compared with a 0.38mm Hg reduction during placebo administration (p < 0.05) in the untreated eyes of 10 volunteers (Wright et al. 1989).

Relative j3-blocking potency (propranolol=1)

tazawa et al. 1981). Four hours after a single instillation of carteolol 1% eyedrops in 7 patients with open angle glaucoma, mean lOP decreased by 9.9mm Hg, and by 7.3mm Hg after carteolol 2% in 10 others (Negishi et al. 1981). lOP decreased within 1 hour of administration and was still significantly below pretreatment values 24 hours after the 1% solution and 48 hours after the 2% solution. However, in a double-blind crossover study Duff and Newcombe (1988) reported that 12-hourly administration of carteolol 2% for 7 days was significantly less effective than timolol 0.5% in maintaining a reduced lOP over a 12-hour period. lOP was 2.7mm Hg (14%) lower than during placebo 12 hours after the final carteolol dose, and 4.2mm Hg (21%) lower 12 hours after the last dose of tim0101. Stodtmeister et al. (1989) demonstrated an identical decrease of 4mm Hg in mean lOP following 3 days' administration of either carteolol 2% or timolol 0.5% in 60 eyes. Likewise, carteolol 2% and timolol 0.5% produced similar reductions in lOP of 6mm Hg (25.75%) and 6.4mm Hg, respectively, in 14 patients with ocular hypertension or open angle glaucoma (Flury et al. 1986). 1.2 Other Ocular Effects

1.1.2 Studies in Patients with Glaucoma or Ocular Hypertension Carteolol 0.5, 1 and 2% reduced mean lOP by 4.85mm Hg (20%), 4.9mm Hg (21%) and 5.5mm Hg (23.6%), respectively, 4 hours after ocular administration compared with a 2.7mm Hg (12%) decrease during placebo administration in a doubleblind crossover study involving 13 patients with ocular hypertension or open angle glaucoma (Ki-

1.2.1 Animal Studies Application of carteolol and, to a lesser extent its major metabolite 8-hydroxy-carteolol (section 2.2) to the endothelial surface of isolated porcine corneas caused a significant increase in opacity at concentrations of 0.5 mmol/L and above (Igarashi et al. 1990). Addition of the preservative benzalkonium chloride 0.005% to mimic the formulation

63

Ocular Carteolol: A Review

used clinically (benzalkonium chloride 0.05 gfL) caused a further significant increase in the opacifying effects of both carteolol (at concentrations ~ 0.5 mmol/L) and 8-hydroxy-carteolol (at a concentration of 50 mmol/L) when applied to the corneal epithelium and/or endothelium. In vivo, twice-daily administration of carteolol 1 or 2% for 2 months to rabbits produced no pathological changes in corneal epithelium, endothelium or parenchyma, whereas befunolol 0.5 and 1% and timolol 0.25 and 0.5% caused epithelial desquamation (Segawa et al. 1986). 8 months' administration of carteolol 2% 4 times daily was associated with slight changes in rat corneal endothelial ultrastructure limited to some small vacuoles in cell membranes; endothelial degeneration (numerous cell membrane holes, swollen endotholial cells) was more marked in animals given befunolol I % or timolol 0.5% (Matsuda et al. 1989). Fluorescein staining revealed that healing of scarred rabbit corneal epithelium was delayed by carteolol I and 2% eyedrops and, to a greater degree, timolol 0.5%, compared with normal saline (Tamagawa et al. 1983). Ocular administration of carteolol 0.25 to 4% had no effect on corneal reflex, pupil diameter, nictitation or irritation of the cornea, iris or conjunctiva in vivo (Tamagawa et al. 1983; Watanabe et al. 1983), and the eye structure, optic nerves and lacrymal glands of dogs were unaffected by oral administration of 3, 30 or 150 mg/kg, although mild

funduscopic changes (linear colour change, appearance of tapetum cells) occurred in 3 of 13 animals (Tanaka et al. 1983).

1.2.2 Studies in Humans In 35 healthy volunteers, corneal sensitivity was no different following a single administration of carteolol 2% or placebo (normal saline) eyedrops, in contrast to metipranolol 0.6% and betaxolol 0.5% which caused signiflcant decreases in sensitivity for 10 minutes (Hoh 1989). In 5 other volunteers, carteolol 1% decreased aqueous flow rate, accompanied by an increase in iris permeability and unchanged anterior chamber volume (Araie & Takase 1985). Aqueous humour flow (see section 1.4) was reduced 20.4% by carteolol, 23.8% by betaxolol and 39% by timolol in 40 patients with ocular hypertension (Coulangeon et al. 1990). In contrast to timolol 0.5% and befunolol 1%, a single carteolol 2% eyedrop did not significantly reduce tear secretion in 39 healthy volunteers over 3 to 4 hours (Hommura et al. 1988). Carteolol had no effect on visual acuity or pupil diameter (Horie et al. 1982; Kitazawa et al. 1981; Scoville et al. 1988). Disturbances in perfusion of the optic disc, as well as elevated lOP, may lead to optic nerve damage and visual field deterioration associated with glaucoma (Collignon-Brach 1989; James 1989; Pillunat & Stodtmeister 1988, 1989). There is an in-

Time after administration (hours)

+1 4

~

20

28

=.::

==.::.::..::.::- - - - - -- --.. .

'6i

§.

36

40

44

48

---- ----

:I:

E -1

32

•

24

.5

-6 Flg. 2. Mean change in lOP from baseline following single ocular administration of carteolol 1% (0) or 2% (0), timolol 0.5% (A) or placebo (e) in 8 healthy volunteers (after Negishi et al. 1981).

64

verse relationship between lOP and ocular perfusion pressure (Pillunat & Stodtmeister 1988). Furthermore, an autoregulatory mechanism normally present appears to be absent in patients with glaucoma (Pillunat & Stodtmeister 1989). Thus, a drug which lowers lOP and also jeopardises blood flow to the optic nerve head could actually have a deleterious effect (Collignon-Brach 1989; Pillunat & Stodtmeister 1988). In groups of 10 healthy volunteers, carteolol 2% caused a nonsignificant reduction in mean systolic retinal perfusion pressure of up to 2mm Hg (as assessed by oculo-oscillodynamography), and a significant (p < 0.02 vs baseline) decrease in ciliary pressure of 4.3mm Hg after twice-daily administration for 3 days (Pillunat & Stodtmeister 1988; Pillunat et al. 1988). In comparison, nonsignificant decreases of 1.2 and 2.5mm Hg, respectively, were achieved after timolol 0.5%, and a decrease of 0.3 and an increase of l.lmm Hg, respectively, with betaxolol 0.5%. Autoregulation was apparently not affected by any of these tJ-blockers (Pillunat & Stodtmeister 1989; Pillunat et al. 1988), although the critical perfusion pressure [equivalent to the artificially increased lOP at which visual function (determined by visually evoked cortical responses) is reduced by 80 or 90%] was decreased from 63 to 53mm Hg by carteolol 2% and from 62 to 57.5mm Hg by timolol 0.5% after 3 days in volunteers (Stodtmeister et al. 1989). Thus, the sensitivity of the optic nerve to damage occurs at a significantly lower perfusion pressure with carteolol than with timolol. Constriction of the larger orbital vessels due to tJ2-adrenoceptor blockade combined with dilatation of the smaller retinal and ciliary vessels because of partial tJ2agonist activity may be a possible explanation for the decrease in perfusion pressures observed in these studies (Pillunat & Stodtmeister 1988). Using fluoroscein video-angiography and image analysis in 7 healthy volunteers, Mihara et al. (1989) demonstrated that 1 drop of carteolol 2% increased mean ocular perfusion pressure from 46 to 51.5 mm Hg (p < 0.04), and decreased mean retinal circulation time from 4.6 to 4.1 seconds (p < 0.02). These changes were attributed to a decrease in mean lOP and a postulated dilatation of retinal capillaries, al-

Drugs & Aging 2 (1) 1992

though no changes in the diameters oflarger retinal vessels were detected. However, within 15 minutes of administration of a single drop of carteolol 2%, retinal blood flow increased by a mean of 18.1 1Ll/ min in 9 treated eyes compared with 11.6 ILl/min in 6 eyes treated with timolol 0.5% (p < 0.05), despite no significant change in lOP during this time, perhaps suggesting carteolol-induced dilatation of retinal capillaries (Yamazaki et al. 1992). Flammer and Etienne (1985) implicated enhanced retinal perfusion in a tendency toward visual field improvements (assessed by differential light sensitivity) achieved with twice-daily administration of carteolol 2% for 2 weeks, compared with no significant difference between timolol 0.5% and placebo in 30 patients (54 eyes) with open angle glaucoma. 1.3 Systemic Activity Following ocular administration, tJ-blockers may enter the systemic circulation via absorption through the nasal mucosa, which is reached by passage through the nasolacrimal ducts (Lesar 1987). Plasma concentrations may be sufficient to cause systemic tJ-blockade (see also sections 2.1 and 4.2). Theoretically, carteolol, with its partial tJ-agonist activity, should produce fewer systemic effects (e.g. fall in blood pressure, bradycardia, bronchoconstriction) than ocular tJ-blockers lacking this activity. In vivo. intravenous or intra-arterial carteo101 administration causes positive inotropic and chronotropic effects and dose-dependent vasodilatation through nonspecific partial agonist activity (Ueda et al. 1991; Yabuuchi & Kinoshita 1974). In 8 healthy volunteers, carteolol 15mg intravenously or 20mg orally produced a nonsignificant increase of 5.5 to 6.5 beats/min in resting heart rate within 4 hours, in contrast to the bradycardia usually observed following administration of tJ-blockers that do not possess partial agonist activity (Ishizaki et al. 1983). However, incubation of S49 lymphoma and BC3Hl smooth muscle cells with carteolol in vitro did not result in cyclic adenosine monophosphate (cAMP) accumulation, a measure of tJadrenoceptor stimulation (Jasper et al. 1990). In

Ocular Carteolol: A Review

contrast, the major metabolite of carteolol, 8-hydroxy-carteolol (see section 2.2), provoked fJadrenoceptor-mediated cAMP release. The partial fJ-agonist activity of carteolol in vivo therefore appears to be attributable to its metabolite 8-hydroxy-carteolol. 1.3.1 Bronchopulmonary Effects Administration of 1 or 2 drops of carteolol 1 or 2% eyedrops to 10 asthmatic individuals decreased the mean forced expiratory volume in 1 second (FEY I) by 7% within 45 minutes, compared with 11.4% following timolol 0.25 or 0.5% (n = 15), and 15.1 % with metipranolol 0.3 or 0.6% (n = 10) [Le Jeunne et al. 1989]. FEYI was reduced by >15% in 3 carteolol, 4 timolol and 6 metipranolol recipients (Hugues et al. 1987; Le Jeunne et al. 1989). Clinically insignificant reductions in mean vital capacity of 6 or 7% occurred 15 to 30 minutes after ocular carteolol and 30 to 45 minutes after metipranolol administration, and of approximately 2% with timolol after 30 minutes. The only significant individual falls in vital capacity were 29.2% with carteolol and 31.6% with metipranolol (Le Jeunne et al. 1989). Baseline vital capacity was re-established 60 minutes after carteolol and timolol administration. 1.3.2 Haemodynamic Effects Within 30 minutes, fJl-adrenoceptor-mediated tachycardia induced by isoprenaline (isoproterenol) was decreased considerably by ocular carteo101 (25% reduction), metipranolol (34%), timolol (32%), levobunolol (31%), bupranolol (26%), pindolol (24%) and befunolol (22.5%) but not betax0101 (4%) in monkeys (DeSantis et al. 1987). In 18 healthy volunteers the dose of isoprenaline which initially increased heart rate by 50% caused increases of only 8.2 and 8.5% following a single drop of carteolol 2% and timolol 0.5%, respectively, into each eye (Le Jeunne et al. 1990). Isoprenaline increased peripheral (right forearm) blood flow by about 57%, but this decreased to 6.6 and 5.3%, respectively, after administration of carteolol and timolol. The isoprenaline-induced increases in heart rate and blood flow were largely

65

unchanged after instillation ofbetaxolol 0.5%. The mean dose of isoprenaline required to increase heart rate by 50% was increased approximately 4-fold with carteolol and timolol. Berlin et al. (1987) reported that 39.2#,g of isoprenaline was required to increase heart rate by 25 beats/min 3 hours after a single carteolol 2% eyedrop in 12 healthy volunteers, compared with 1O.9#,g following timolol 0.5%, 5.2#,g following metipranolol 0.6% and 3.1#,g after placebo, indicating greater fJ-blockade with carteo101 (Berlin et al. 198"1). A single instillation or 3 days' administration of carteolol 2% or timolol 0.5% in 2 groups of 6 and 60 volunteers had no significant effect on resting blood pressure or heart rate (Brazier & Smith 1988; Stodtmeister et al. 1989). However, exercise heart rate was reduced by 22 beats/min 2 hours after carteolol administration and by 12 beats/min after timolol. More importantly, Le Jeunne et al. (1988) studied the haemodynamic effects of single ocular doses of carteolol 1 or 2%, timolol 0.25 or 0.5%, metipranolol 0.3 or 0.6% and betaxolol 0.5% in 60 healthy elderly volunteers (mean ages between 70 and 81 years). Carteolol caused a significant maximal decrease in mean resting heart rate of 16.7%, compared with 18.2% following timolol, 13.6% with metipranolol and a nonsignificant fall of 5.6% with betaxolol. Maximum bradycardia occurred 60 to 75 minutes after fJ-blocker administration. In 4 of 15 carteolol and 3 of 20 timolol recipients mean heart rate reduction was> 20%. Sinus rhythm was maintained. There was a significant decrease in systolic blood pressure of 6.5% 60 minutes after carteolol instillation and of 4.5% 45 minutes following metipranolol. A fall of 15 to 20% was observed in 3 of 15 carteolol, 2 of 15 metipranolol, 3 of 20 timolol and 1 of 10 betaxolol recipients. Diastolic blood pressure was not significantly reduced. Similarly, in 35 asthmatic patients (mean ages 40 to 49 years), maximum reductions in mean heart rate were 7.8, 16.3 and 13.2%, respectively, 45 to 60 minutes after administration of carteolol 1 or 2%, timolol 0.25 or 0.5% and metipranolol 0.3 or 0.6% (Le Jeunne et al. 1989). The difference between carteolol and the other 2 agents was signifi-

Drugs & Aging 2 (J) 1992

66

cant (p < 0.05). The mean maximum decrease in systolic blood pressure was 6.8% 60 minutes after giving carteolol; reductions> 10% occurred in 3 of 10 patients, compared with 2 of 15 timolol and 4 of 10 metipranolol recipients. Diastolic blood pressure was again largely unaffected by any of the (3blockers. 1.4 Mechanism of Action The lOP-lowering effect of ocular carteolol and other (3-blockers arises through inhibition of aqueous humour production in the ciliary body, rather than promotion of aqueous outflow (see reviews by Hurvitz et al. 1991; Lesar 1987). Since aqueous humour is formed through a combination of blood ultrafiltration and osmotic activity resulting from active secretory processes, (3-adrenoceptor antagonists could affect either of these mechanisms, although the precise details remain unresolved. Blockade of the predominantly (32adrenoceptors in the ciliary body epithelium responsible for the active secretory component of aqueous humour formation is generally assumed to contribute (Lesar 1987). However, a number of observations do not support this mechanism: there is apparently no sympathetic innervation of the ciliary body; blockade of (3-mediated cAMP production is not related to lOP reduction; d-timolol effectively lowers lOP despite having poor (3-blocking potency compared with its commonly used stereoisomer l-timolol; and betaxolol, a relatively selective (32-blocker, is effective in reducing lOP (Buckley et aI. 1990; Cotton 1990; Lesar 1987). Thus, the (32-adrenoceptors of the ciliary body epithelium must have different unexpected characteristics from (3-receptors elsewhere if they are indeed the main site of (3-blocker activity in decreasing lOP (Lesar 1987). The second component of aqueous production, ultrafiltration in the ciliary process, may be affected by ocular (3-blockers such as carteolol. The microvascular bed in this region possesses (3-adrenoceptors and sympathetic innervation (Buckley et aI. 1990). Decreases in lOP have been shown to be related to ciliary blood flow decreases (Lesar 1987). Reduced ciliary perfusion

was associated with a reduction in tissue dopamine levels. Carteolol 1% eyedrops however increased the transfer coefficient for diffusion across the blood-aqueous barrier in 11 volunteers, perhaps reflecting its partial agonist activity since this value is also increased by 'pure' (3-agonists (Araie & Takase 1980, 1985). The aqueous flow rate was nevertheless lowered by carteolol. Ocular perfusion may playa part in the development of ocular nerve damage and subsequent visual field loss associated with glaucoma (see section 1.2). An ocular (3-blocker which reduced lOP but led to local vasoconstriction could have a potentially deleterious effect. Theoretically, an agent with partial agonist activity may perhaps preserve ocular perfusion through local (3-mediated vasodilatation, or at least minimisation of vasoconstriction. Indeed, there is evidence that carleolol may improve retinal perfusion (Mihara et al. 1989; Yamazaki et al. 1992). This has been attributed partly to partial agonist activity, and to a relaxant effect on endothelial vasculature mediated via stimulation ofprostacyclin secretion, facilitation of endothelium-derived relaxing factor (particularly when endothelial a2-adrenoceptors are stimulated), and inhibition of endothelium-derived contraction factor release (Rigeade 1990; Vanhoutte 1990). There is evidence that 8-hydroxy-carteolol, the main metabolite of carteolol (see section 2.2), contributes significantly to the ocular antihypertensive activity of the drug. In rabbits, waterload-induced increases in lOP were significantly attenuated by 1.1 and 2mm Hg, respectively, by single drops of carteolol 1 and 2% compared with saline administration, and by 3.6 and 2.4mm Hg using 8-hydroxy-carteolol 0.01 and 0.1 % (Sugiyama et al. 1989). Similarly, single drops of carteolol 2% did not significantly decrease rabbit lOP compared with significant reductions of 3 to 3.5mm Hg obtained with (3-hydroxy-carteolol om to 1% (Hirota et al. 1991). Comparable decreases in lOP were achieved with carteolol 2% and 8-hydroxy-carteolol 0.1 % in monkeys, implying that the metabolite was more potent on an equimolar basis. Furthermore, the

67

Ocular Carteolol: A Review

partial agonist activity of 8-hydroxy-carteolol is greater than that of carteolol (Jasper et al. 1990).

2. Pharmacokinetic Properties Instillation of eyedrops containing J3-blockers into the conjunctival sac does result in the intended absorption through the cornea into the aqueous humour, however most of the administered dose is absorbed into conjunctival capillaries or drains through the puncta lacrimale to nasal mucosa (Lesar 1987). From here, and from absorption into oropharyngeal and gastrointestinal mucosal capillaries, the J3-blocker may reach the systemic circulation (Gerber et al. 1990; Lesar 1987). Thus, although there appear to be very few published data investigating the disposition of carteolol following ocular administration, some pharmacokinetic data after oral or intravenous administration are relevant. The extent of absorption during ocular instillation warrants further investigation to determine the probability of systemic effects. 2.1 Absorption and Distribution Plasma carteolol concentrations were below assay detection limits « 5 ~gJL) following a single ocular administration of carteolol 2% eyedrops in 6 healthy volunteers (Gregory & Martin 1986). Approximately 25% of the topically applied dose was absorbed. In healthy human volunteers approximate peak plasma carteolol concentrations (C max ) of between 46 and 88 ~g/L were achieved within 1 or 2 hours of single oral doses of 15 or 20mg (Ishizaki et al. 1983b; Lorenz 1983; Morita et al. 1977; Odomi et al. 1989a) and 113 ~g/L 1 to 3 hours after 30mg (Hasenfuss et al. 1985). Bioavailability was 83% after oral administration, with only about 15% undergoing first-pass metabolism (Ishizaki et al. 1983b), although enterohepatic circulation would most likely be circumvented following conjunctival and nasal absorption of ocularly administered drug. The plasma concentration profile of carteolol is

affected by age. Mean Cmax following a single oral dose of carteolol 2.5mg was significantly higher in 18 healthy volunteers aged 56 to 69 years compared with 12 younger volunteers aged between 21 and 53 years (9.1 vs 6.2 ~g/L) [Ringham et al. 1987]. The area under the plasma concentration-time curve (AUC) was also significantly greater following administration of carteolol 2.5mg orally (106.4 vs 66.4 ~gJL' h) or intravenously (104.4 vs 80.9 ~g/ L· h) in the older group. These differences were attributed to diminished renal function, and therefore clearance, in the older subjects (see section 2.2). This indeed seems likely since mean AUCO-oo after an oral dose of carteolol 30mg was 993 ~g/L • h in healthy volunteers compared with 3550 ~g/L' h (range 873 to 8971 ~g/L' h) in 9 patients with varying degrees of renal impairment (creatinine clearance 0.3 to 3 L/h) [Hasenfuss et al. 1985]. The relevance of renal impairment in the ocular use of carteolol has yet to be determined, although it is unlikely to be significant because of the small doses used in glaucoma. The drug is rapidly and extensively distributed out of the plasma following intravenous injection, with an absorption half-life of 7 minutes and apparent volume of distribution (Vd) of 4 L/kg in 8 volunteers (Ishizaki et al. 1983b). Age correlated significantly with Vd (Ringham et al. 1987), with a lower value expected for the hydrophilic carteolol in older patients (Ritschel 1988). The degree of plasma protein binding is small, approaching 15% in humans (Lang 1983). In rats, the highest concentrations of [l4c]carteolol1 to 12 hours after oral administration were in the liver, kidneys and lungs (Lang 1983). Very little activity was found in the brain. Decreasing concentrations of radioactivity were detected in the cornea, iris, anterior sclera and ciliary body 30 minutes after ocular administration of 1O~1 of [I4C] carteolol 2% in rabbits (Fujio & Kitazawa 1984). 2.2 Metabolism and Excretion In healthy human volunteers, between 63 and 87% of an oral or intravenous dose of carteolol is recovered unchanged in the urine (Hasenfuss et al.

Drugs & Aging 2 (1) 1992

68

1985; Ishizaki et al. 1983b; Koch 1983; Lorenz 1983). The major metabolite, 8-hydroxy-carteolol, represents about 4 to 10% of this amount, and a glucuronide conjugate of carteolol accounts for an additional 17% (Hasenfuss et al. 1985; Lorenz 1983). The proportion of a given dose detected in the urine as unchanged drug and metabolites within 24 hours after oral dosing was 62 to 76% (Morita et al. 1977; Odomi et al. 1978) and 84% in total (Hasenfuss et al. 1985). Most urinary excretion occurred in the first 12 hours following drug administration (Ishizaki et al. 1983b). Total plasma clearance (CL) of carteolol in subjects with normal renal function was 28 L/h after 5 days' oral administration of 10 mg/day (Ringham et al. 1985) and 0.61 L/h/kg following 15mg intravenously (Ishizaki et al. 1983b).' Renal clearance was 15 L/h after a single oral 30mg dose (Hasenfuss et al. 1985), representing 65% of the total (Ishizaki et al. 1983b). Since the renal contribution exceeded both glomerular filtration rate and creatinine clearance, renal tubular secretion was probably involved (Hasenfuss et al. 1985; Ishizaki et al. 1983b). Nonrenal clearance (0.2 L/h/kg) was significantly less than liver blood flow, suggesting metabolic clearance (Ishizaki et al. 1983b). The elimination half-life (toh/l) of carteolol has ranged between approximately 5 and 7 hours after single or repeated oral administration in humans with normal renal function (Hasenfuss et al. 1985; Ishizaki et al. 1983b; Lorenz 1983; Morita et al. 1977; Odomi et al. 1978, 1989a,b; Ringham et al. 1987; Wellstein et al. 1984). The t'12/1 of 8-hydroxycarteolol was 17.3 hours in 6 volunteers, about 2to 3-fold greater than that of carteolol (Wellstein et al. 1984). The elimination of carteolol is thus biphasic. The extended elimination of the active metabolite may contribute to the long duration of i3-blockade following oral carteolol administration. Consistent with the predominantly renal clearance of carteolol, total clearance was reduced to a mean of 3.4 L/h and t'l2/1 prolonged to 24 hours (range, 16 to 41 hours) in 9 patients with renal impairment (creatinine clearance ~ 3 L/h) [Hasenfuss et al. 1985]. Both CL and t'l2/1 were inversely related to creatinine clearance (Ringham et al. 1985). In

18 older volunteers (aged 56 to 69 years), mean t'l2/1 was 6.3 hours compared with 5.5 hours in younger subjects, and 24-hour urinary excretion of the drug was significantly lower, reflecting the decreased renal function in the older group (Ringham et al. 1987). Although oral dosage adjustment according to creatinine clearance is therefore required in patients with renal impairment and in some older individuals (Ishizaki et al. 1983b; Ringham et al. 1985), it is not clear if this recommendation also applies to ocular carte'olol administration.

3. Therapeutic Use Since glaucoma is progressive, the elderly have an increased risk of developing the condition. It has been estimated that 3% of the population aged over 65 years have glaucoma (Hurvitz et al. 1991; Rich 1990), and it is the leading cause of blindness in the United States (Rich 1990). Glaucoma is characterised by elevated lOP (~ 21mm Hg), cupping of the optic disc and atrophy of the optic nerve which results in visual field defects (Hurvitz et al. 1991; Kupfer 1990; Lesar 1987; Rich 1990; Steffmsson 1990). An increased lOP alone is not indicative of glaucoma, since many patients with elevated lOP do not demonstrate visual loss and up to 1 in 6 patients with glaucoma have a 'normal' « 21mm Hg) lOP (CollignonBrach 1989; Cotton 1990; Hurvitz et al. 1991; Kupfer 1990; Lesar 1987; Pillunat & Stodtmeister 1989). Changes in the microcirculation of the optic nerve may also be implicated in visual field loss (see section 1.2; Bienfang et al. 1990; Cotton 1990; Pillunat & Stodtmeister 1989). Raised lOP should be regarded as one risk factor in a multifactorial disease. Ocular hypertension describes an lOP above 21mm Hg but without optic nerve damage or loss of visual field (Kupfer 1990; Lesar 1987). Despite the lack of absolute correlation between visual defects and lOP, the usual aim of glaucoma therapy is to lower lOP and thus eliminate one risk factor. Few trials investigating the efficacy of ocular carteolol have been published, and the majority are noncomparative, with very few comparisons with placebo or timolol. Reduction in lOP was used as

69

Ocular Carteolol: A Review

study end-point, generally after I or 2 months' treatment in patients with open angle glaucoma (based on the appearance of the anterior chamber angle with gonioscopy) or ocular hypertension. Patients with asthma or chronic obstructive airways disease, heart failure, heart block or conditions requiring concomitant systemic fj-blocker therapy were excluded from study. 3.1 Noncomparative Trials In a I-month double-blind crossover study with a 2-week washout period, Duff (1987) demonstrated no significant difference in the lOP-lowering effects of carteo101 I or 2% in 18 patients with ocular hypertension (table II). The difference between the lOPs achieved with carteo101 I or 2% was 0.32mm Hg after 2 weeks and 0.24mm Hg after 4 weeks. Both concentrations reduced mean lOP by about 5.4 to 5.75mm Hg, with an overall reduction at the end of the 100week trial (including the 2-week washout between treatments) of 5.9mm Hg (25%). The use of I or 2% eyedrops by other investigators in the studies summarised in table II should therefore not confound the results. One or 2 months' twice (or occasionally thrice) daily treatment with carteolol caused a mean lOP reduction of between approximately 5 and 15mm Hg (mean 8.7mm Hg), representing a 19 to 47% (mean 32%) decrease from pretreatment values in patients with ocular hypertension, open angle glaucoma or glaucoma secondary to uveitis (table II). A significant reduction in lOP was noted within 2 weeks (Duff 1987; Ohno et al. 1989; Schnaudigel et al. 1988; van Husen 1986), and was maintained for up to 14 months (Schnaudigel et al. 1988; van Husen 1986) [fig. 3], suggesting that long term 'drift' of lOP back towards pretreatment values, a problem with other ocular fj-blockers (Hurvitz et aI. 1991), did not occur. lOP was better controlled in 24 patients with open angle glaucoma secondary to uveitis than in 4 with closed angle disease, and carteolol was ineffective in 5 patients with sarcoidosis-induced glaucoma (Ohno et al. 1989). The decrease in lOP also appeared to be slightly greater

in previously untreated patients compared with those switched from other ocular fj-blockers (Schnaudigel et al. 1988; table II). Nevertheless, in a multicentre study involving 609 patients from 80 general practices, satisfactory lOP control « 21mm Hg) was maintained in 73% of patients crossed over from another fj-blocker (timolol 0.25 or 0.5%; metipranolol 0.3 or 0.6%; befunolol 0.25 or 0.5%; pindolol 1%) to carteolol 1% (n = 394) or 2% (n = 215) and improved further (~ 3mm Hg additional lOP reduction) in 18% more (Schnarr 1988). 80% of the general practitioners participating in this study judged the efficacy of carteolol to be 'good' or 'very good' and 62% of both general practitioners and patients preferred carteolol over the previous treatment, with 2 and 4%, respectively, preferring another fj-blocker, and 27.5 and 29% undecided. 3.2 Comparative Trials To date few comparative studies of the efficacy of carteolol have been published. The trials were, however, reasonably well-designed (randomised, double- or single-blind) and included a 2-week washout between treatment periods (Duff & Graham 1988) and/or a 1- or 2-week washout between stopping previous therapy and starting the study medication. 3.2.1 Comparison with Placebo

In 12 patients at risk of developing glaucoma (raised lOP, family history or optic disc cupping), 2 weeks' treatment with carteolol 2% eyedrops twice daily reduced mean lOP 2.2mm Hg further than 2 weeks' placebo administration (Duff & Graham 1988; table III). At the end of I week's treatment the difference in lOP reduction between carteolol and placebo was 2.8mm Hg in favour of the active drug. The crossover design used in the study involved instillation of carteolol to one eye and placebo to the other in each patient, with treatments switching after the 2-week washout phase. This method assumes a lack of effect of carteolol on the placebo-treated eye, an assumption which may not be valid (see section 1.1.1). Thus, the difference in .

Drugs & Aging 2 (1) 1992

70

Table II. Some noncomparative studies of ocular carteolol in patients with glaucoma or ocular hypertension

Reference

Patient group (number of evaluable eyes)

Dosage [duration (weeks)]

Duff (1987)

180H

Gorgone et al. (1983)

150AG (25) 30 U (37)8

1% bid 2% bid [4] 1% tid

Ohno et al. (1989)

14 GCU (14)

Results mean baseline lOP (mm Hg)

mean lOP reduction (mm Hg) [%]

23.5

5.4 [23]** 5.7 [24]**

27.6

9.4 [34]

27

10 [37]**c

32

15 [47]*c

27.5

10 [36]**

25.3

5.3 [21]**

22.1

4.3 [19]**

30

13 [43]C

[~4]

1% or 2% bid b [>8] 1% or 2% bid b [~4]

Schnaudigel et al. (1988)

89 OH or OAG 14 OH or OAG 75 OH or OAGd

Van Husen (1986)

140AG

1%9 [8] 2%9 [8] 1%9 [8] 1% bid [~60]

a b

Includes 24 patients (30 eyes) with OAG and 4 patients (5 eyes) with CAG. Other medication (epinephrine eyedrops, carbonic anhydrase inhibitors) allowed if carteolol ineffective; number of patients receiving additional medication not stated. c Results presented graphically; extrapolations only. d Patients previously treated with ocular /3-blockers (befunolol 0.25 or 0.5%; metipranolol 0.3 or 0.6%; timolol 0.25 or 0.5%; pindolol 1%). e Frequency of administration not stated. Abbreviations and symbols: OH = ocular hypertension; OAG = open angle glaucoma; CAG = closed angle glaucoma; U = uveitis; GCU = glaucomatocyclitic crisis uveitis; bid = twice daily; tid = 3 times daily; • = p < 0.05 vs baseline; * * = p < 0.01 vs baseline.

lOP between carteolol and placebo-treated eyes in this study is probably an underestimate.

3.2.2 Comparisons with Tim%/ There were no significant differences between the lOP-lowering effects of carteolol 1% or timolol 0.25% administered twice daily in an uncontrolled crossover study in 10 patients with ocular hypertension and 3 with primary open angle glaucoma (Horie et al. 1982) [fig. 4]. From a baseline of 22.7mm Hg, mean lOP decreased by 15% to 19.3mm Hg after 4 weeks' carteolol 1% or timolol 0.25% administration, and to 20.5mm Hg (a 9.5% reduction) and 19.9mm Hg (12%), respectively, after 6 weeks. A further uncontrolled crossover

study demonstrated decreases of 9.6 and 7%, respectively, after 4 and 6 weeks of twice-daily carteolol 2% administration, significantly less than the corresponding 15 and 16% decreases achieved with timolol 0.5% twice daily in 8 patients with ocular hypertension and 9 with primary open angle glaucoma with a baseline mean lOP of 24.8mm Hg (Horie et al. 1982). However, this significant difference in efficacy was not continued in a subsequent double-blind crossover study in another 20 patients with ocular hypertension or open angle glaucoma (Horie et al. 1982). Carteolol 2% and timolol 0.5% reduced lOP by an almost identical degree after 4 weeks (table III). In a larger group of patients with ocular hyper-

71

Ocular Carteolol: A Review

tension successfully pretreated with timolol, Scoville et al. (1988) revealed no significant differences between the mean lOPs obtained with twicedaily administration of carteolol 1% (n = 50; 19.9mm Hg) or timolol 0.25% (n = 47; 19.7mm Hg) after 4 weeks (table III). Visual field defects (assessed by perimetry) were similar in both groups. Treatment was deemed 'good' by investigators in 39 or 50 carteolol recipients (78%) and 26 of 46 timolol-treated patients (56%) after 4 weeks, a statistically significant difference (p = 0.03). Although not reaching such significance, patients also favoured carteolol over timolol. Longer term studies confirm the results of short term trials, with both carteolol and timolol eyedrops possessing equivalent lOP-lowering efficacy over 3 months to I year (table III). Again carteolol 2% appeared comparable to timolol 0.5%, with carteolol I % and timolol 0.25% equivalent. 29% of carteolol recipients required additional treatment within 6 months to reduce lOP compared with 22% of timolol-treated patients in one study (Mills et al. 1987), contrasting with results from noncomparative trials that long term 'drift' does not occur with carteolol (section 3.1). Tsuchisaka et al. (1991) reported no significant difference between the effects of carteolol and timolol treatment on visual

30

Week 2

Week 4

Oi 0

Week 6

:z:

E

Sl 0..

Q c:

Sl

2

-----*

E

.s

-

3l 3

.,'" u .,

o 4

t---

**

**

-----

'---

**

** **

o o

Timolol Carteolol

Fig. 4. Decrease in mean lOP from baseline (22.7mm Hg) in 10 patients with ocular hypertension and 3 with primary open angle glaucoma (26 treated eyes) receiving carteolol I% or timolol 0.25% twice daily for 6 weeks in an uncontrolled crossover study; * = p < 0.01 vs baseline; ** = p < 0.001 vs baseline (from Horie et al. 1982).

fields after 6 months in 62 patients, a finding substantiated by an interim analysis of an ongoing study specifically investigating visual field changes (Hammer et al. 1990). In 2 groups of 6 and 36 patients with lOP poorly controlled (recurrent lOP ~ 21 mm Hg) by timolol 0.25 or 0.5%, substitution of carteolol I or 2% elicited a fall of between 3 and 4 mm Hg (p < 0.05) in mean lOP within I month, whereas the converse switch in a total of 35 patients had no significant effect (Itoh et al. 1989; Tsuchisaka & Kin 1990).

Oi

:z: 25 E

4. Tolerability

Q.

4.1 Ocular Effects

S

Q c:

al 20

::E

15

~~~--~----~----~i--------~i

o

2

3:5

7

14

Time (months) Fig. 3. Reduction in mean lOP in 103 previously untreated patients with ocular hypertension or open angle glaucoma receiving ocular carteolol I or 2% for up to 14 months (adapted from Schnaudigel et al. 1988).

The subjective tolerability of carteolol 2% and timolol 0.5% did not differ significantly from placebo (normal saline) in 35 healthy volunteers, but metipranolol 0.6% and betaxolol 0.5% were significantly and similarly less well tolerated (Hoh 1989). Using a visual analogue scale of 0 (not irritating) to 100 (extremely irritating) 36 volunteers rated timolol 0.5% eyedrops more irritating than carteolol I or 2%, or placebo (mean scores 30.1 vs 10.2, 16.2 and 8.8, respectively (Scoville et al. 1985).

-..I

Table III. Some randomised studies comparing carteolol (C) with placebo (PI) or timolol (T) in patients with glaucoma or ocular hypertension Reference

Patient group

Treatment [duration (weeks))

Study design

12 GR

C 2% bid PI bid [2]

10 OH, OAG 10 OH, OAG 180AG 170AG

C 2% bid T 0.5% bid C2% TO.5% [52] C 1% T 0.25% [26] C 1% bid T 0.25% bid [4] C 1% bid C 2% bid T 0.5% bid [12] C 1% bid C 2% bid T 0.5% bid [26]

N

Efficacy

Results mean baseline lOP (mm Hg)

mean lOP change (mm Hg) [%]

db, r, co, wo

21

~

db, r, co

23.25 23.7 30 30

~ 3.1-3.5 [13.3-14.8]***

25.1 24.2

~ 4.6 [18]***

22.75c 23.75c

~

25.3 25.3 24.8

~ 6.3 [24]***

20.7 21 21

~

Comparison with placebo Duff

8. Graham (1988)

2.2-2.8 [11-14]8

C>PI

Comparisons with timolol Horie et al. (1982) Maclure et al. (1988)

Mills et al. (1987)

Scoville et al. (1988)

Stewart et al. (1991)

Tsuchisaka et al. (1991)

190AG 17 OAG 500Hb 470Hb 33 OH, OAG 39 OH. OAG 33 OH. OAG 200H,OAG 23 OH. OAG 19 OH. OAG

sb, r, p

sb, r, p. wo

db, r, p. wo

db, r. p. wo

r. p, wo

C=T

~ 3.2 [13.7]** ~ 10 [33]C

C=T

~ 10 [33]C

C=T

~ 4.3 [17.7]***

2.8 [12]C

C=T

~ 4 [17]C

C=T

~ 5.8 [23]***

~ 6.5 [28]***

1.4 [7]**c.d

C=T

~ 2.5 [12]**c.d.

!

2 [9.5]*c.d

tl

a Reduction compared with placebo. b All patients previously treated with timolol. c Results presented graphically; extrapolations only. d Compared with lOP after 4 weeks' treatment with timolol 0.5% twice daily. Abbreviations and symbols: GR = glaucoma risk (raised lOP. family history, or optic disc cupping); OH = ocular hypertension; OAG = open angle glaucoma; bid = twice daily; db = double-blind; r = randomised; co = crossover; p = parallel group; wo = washout period before treatment; sb = single-blind; ! = decrease; t = increase; > indicates significantly greater efficacy (p .. 0.01); = indicates equivalent efficacy; * = p < 0.05 vs baseline; ** = p < 0.01 vs baseline; *** = p < 0.001 vs baseline.

~ '" At>

~

~

2'" .... ~

Ocular Carteolol: A Review

Subjective tolerability of timolol was significantly worse than either carteolol solutions immediately after eyedrop instillation, and 3 and 10 minutes later. Similarly, using the same scale Flury et a1. (1986) reported mean scores of 5.9 and 9 for carteolol 2% and timolol 0.5%, respectively, in 14 patients with ocular hypertension or chronic open angle glaucoma. Significantly more carteolol than timolol recipients (6 vs I) gave a score of 0, indicating ideal local tolerability. In another study, eye pain was significantly (p = 0.02) more common after 4 weeks' treatment with timolol 0.25% [9 of 47 patients (19%)] than carteo101 1% [2 of 50 patients (4%)] (Scoville et al. 1988). Two-thirds of another group of 75 patients uncontrolled by, or experiencing adverse effects of, previous therapy preferred carteolol, and 33% had no preference; 93% of 103 previously untreated patients rated the local tolerability of carteolol as 'good', 6% as satisfactory and I % as worse (Schnaudigel et a1. 1988). Acute eye irritation was noted by 25.8% of 609 patients participating in a multicentre general practice study before crossing over to treatment with ocular carteolol I or 2%, inflamed eyelids by 11.6%, and conjunctival oedema by 4.1 % (Schnarr 1988). After 2 months' treatment, the incidence of these local adverse effects had decreased to 1.7,0.8 and 0.4%, respectively. 4.2 Systemic Effects

As discussed earlier (section 1.3) systemic absorption of ocular ,8-blockers may result in systemic ,8-blockade and thus induce or exacerbate bronchospasm, heart block or bradycardia (see review by Everitt & Avom 1990). These adverse effects occurred rarely (if ever) in studies investigating the efficacy of carteolol, but this may be because patients at risk of developing distressing respiratory or cardiovascular symptoms were excluded from study populations (see section 3). Resting heart rate was not significantly decreased by carteolol 2% eyedrops in 37 patients with ocular hypertension or open angle glaucoma, in contrast to significant reductions of approximately 10 to 14 beats/min during timolol 0.5% adminis-

73

tration (Horie et a1. 1982). Nevertheless, Flury et a1. (1986) demonstrated that carteolol 2% reduced mean heart rate in 8 patients with a baseline rate above 70 beats/min (from 74.6 to 69.7 beats/min) but not in 6 others with a rate of 70 or below; the converse was true of timolol 0.5%. Mean blood pressure was usually decreased slightly, but not significantly, during ocular carteolol therapy (Horie et a1. 1982; Ohno et a1. 1989; Schnarr 1988; Schnaudigel et a1. 1988). Carteolol, through its partial agonist activity, may have a beneficial effect on plasma lipid profiles (particularly a reduction in triglycerides and increase in high density lipoprotein [HDL]-cholesterol) [van Brummelen 1983]. Indeed, these changes have been demonstrated with oral carteo101 (Kochar et al. 1983; Nakajima & Abe 1983). Ocular administration of the drug may also be expected to influence plasma lipids in a similar manner but perhaps smaller degree. Timolol 0.5% eyedrops twice daily have been shown to increase triglycerides by 12% and decrease HDL-cholesterol levels by 9%, which may increase coronary heart disease risk by 21% (Coleman et a1. 1990). Single cases of decompensated heart failure after I month's administration of carteolol eyedrops, and the development of disabling Raynaud's disease during ocular timolol treatment persisting during carteolol therapy have been reported (Vinti et a1. 1989), as has an isolated case of moderate asthma within 4 days of starting carteolol I % therapy (Duff 1987). Exercise-induced dyspnoea, present in 8.7% of 609 patients during previous treatment with timolol, metipranolol, befunolol or pindolol, occurred in 5.7% during subsequent carteolol I or 2% administration (Schnarr 1988). Headache, tiredness and dizziness also tended to be less frequent with carteolol than other ,8-blockers (Schnarr 1988; Scoville et al. 1988). Adverse drug effects were reported less frequently (41 vs 95 reports; p < 0.001) and by a smaller proportion of patients [13/50 (26%) vs 23/ 47 (49%); p < 0.02] during treatment with carteolol I % compared with timolol 0.25% (Scoville et al. 1988) [fig. 5]. Subjective systemic tolerability was 'good' in 98% and satisfactory in 2% of 103 pre-

Drugs & Aging 2 (1) 1992

74

o o 60

..

Timolol Carteolol

p = 0.03

,---,

50-

p

= 0.019 ,---,

-

E 40 ~ c: Q) "0

'u 30

.E

20

-

10

Week 1

Week 4

Fig. 5. Percentage of patients reporting adverse effects during

twice daily ocular treatment with carteolol 1% (n = 50) or timolol 0.25% (n = 147) [from Scoville et al. 1988).

viously untreated patients, and 42% of 75 patients given prior therapy preferred carteolol with 58% noting no difference (Schnaudigel et al. 1988). Tolerability of carteolol 1 or 2% was better (at least 2 fewer adverse effects) than previous timolol, metipranolol, befunolol or pindolol in 11.6% of 609 patients, similar in 32.7% and worse in I % in a 2month multicentre study (Schnarr 1988). Since systemic absorption of ocular {:1-blockers may result in plasma concentrations capable of manifesting extraocular {:1-blockade, then interactions commonly associated with oral {:1-blocker administration may be expected. In particular, caution should be exercised when giving ocular {:1blockers such as carteolol to patients receiving concomitant xanthines or {:12-agonists for bronchodilatation, or recipients of the antiarrhythmic drugs quinidine, amiodarone, diltiazem and digoxin (for a review of potential drug interactions with topical drugs commonly used in glaucoma management, see Gerber et al. 1990).

5. Dosage and Administration The recommended starting dosage of ocular carteolol in the treatment of glaucoma and ocular hypertension is 1 drop of the 1% solution into the

affected eye(s) twice daily. The dosage may be increased to 1 drop of carteolol 2% eyedrops twice daily if the initial response is inadequate. Dosage adjustment in the elderly is not necessary. Carteolol should theoretically produce less bronchoconstriction, bradycardia and vasoconstriction than other ocular {:1-blockers because of its partial agonist activity. However, its use is contraindicated in patients with poorly controlled cardiac insufficiency, and asthma or obstructive airways disease, and it should be used cautiously in recipients of systemic {:1-blocker therapy, and in those with conditions likely to be exacerbated by systemic {:1-adrenoceptor blockade (e.g. sinus bradycardia, atrioventricular block, right ventricular insufficiency, poorly controlled diabetes mellitus). Systemic absorption may be reduced by digital pressure on the periphery of the nasolacrimal drainage system in the corner of the eye and by closing the eyes for 5 minutes after instillation of {:1-blocker eyedrops (Gerber et al. 1990).

6. Place of Carteolol in Glaucoma and Ocular Hypertension Successful treatment of patients with glaucoma using topically administered {:1-adrenoceptor blocking agents such as timolol, levobunolol (Gonzalez & Clissold 1987), metipranolol (Battershill & Sorkin 1988) and betaxolol (Buckley et al. 1990) is now commonplace. Carteolol is another ocular {:1-blocker which has been shown to effectively reduce lOP in patients with glaucoma or ocular hypertension for up to 14 months. The few available comparative data indicate that carteolol has an equivalent efficacy to timolol, but may be associated with less local eye irritation and systemic side effects such as heart rate reduction, possibly because of its partial agonist activity. Longer term studies with visual field changes as an end-point, as well as lOP reduction, would be welcome to shed further light on the contribution of partial agonist activity to the efficacy of carteo101. In theory, this feature of the drug should preserve optic nerve perfusion better than a 'pure' {:1-

Ocular Carteolol: A Review

blocker such as timolol, despite similar decreases in lOP, which is after all just one risk factor for nerve damage. Published trials have excluded patients with obstructive pulmonary disease or heart failure, but carefully monitored studies in such patients may be justified to further define any safety advantages in using carteolol. Caution would nevertheless appear to be justified when using carteolol in some elderly patients with glaucoma, for example those with congestive heart failure, heart block, severe peripheral vascular disease or those at risk from cerebral hypoperfusion (Le Jeunne et al. 1990). Comparisons with the {j I-selective antagonist betaxolol would be of particular interest. Thus, ocular carteolol is a viable alternative to timolol with an apparently better tolerability profile, in the treatment of patients with open angle glaucoma or ocular hypertension.

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Drugs & Aging 2 (1) 1992

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Ocular Carteolol: A Review

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Correspondence: Paul Chrisp. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand.