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Ophthalmic beta-blockers since timolol
SURVEY OF OPHTHALMOLOGY
THERAPEUTIC
VOLUME
31
l
NUMBER
5.
MARCH-APRIL
1987
REVIEW
JOEL S. MINDEL AND SAIICHI MISHIMA, EDITORS
Ophthalmic Beta-blockers Since Timolol
GARY
D. NOVACK,
PH.D.
lniversifv of Calt$mia, Irvine, California
and Department of Ophthalmologv, Clinical Research, illlergan Pharmaceuticals,
Abstract. In the twenty years since beta-blockers were proposed for treatment of glaucoma. use of topical timolol has increased to account for 70% of all glaucoma medications used. The objective of this article is to review the “newer” beta-blockers, and to address the generalization that “all ophthalmic beta-blockers are the same.” The review concentrates on agents that have been studied as topical treatments for patients with elevated intraocular pressure. Sections on pharmacology and design of clinical trials are included to aid the ophthalmologist in evaluating new drugs and published clinical reports. The major questions to consider in evaluating the therapeutic potential of a new beta-blocker for the treatment of glaucoma involve efficacy and safety: Is the drug as effective as timolol? Does it have a duration of action at least as long as timolol? Does it have ocular toxicity? Is it comfortable? What are its systemic effects? (Surv Opbtbalmol 31:307-327, 1987)
Key words. glaucoma
l
beta-adrenergic antagonists intraocular pressure
l
beta-blockers
Nearly 20 years ago, Phillips suggested that systemic or topical beta-adrenergic-receptor antagonists (beta-blockers) might have a therapeutic ocular hypotensive effect. ‘I3 The efficacy of topical propranolol was reported by Bucci et al*’ in Italy and Merte and Merkle in Germany.8’ Concerns over cornea1 anesthesia following topical propranolol limited its general acceptance.3g Over the next several years, a host of beta-blockers, borrowed mainly from oral cardiovascular use, including practolol, nadolol and atenolol, were evaluated for topical ophthalmic use in the treatment of elevated intraocular pressure. The beta-blocker, timolol, became available for topical use nearly world-wide in the late 1970s and early 198Os, and by 1985, in the U.S.,
l
clinical
trials
l
timolol accounted for approximately 70% of all prescriptions in patients receiving medical therapy for glaucoma.“’ The efficacy, safety, and utility of topical timolol have been reviewed in myriad publications, including a special issue of this journalR8”~” The objective of this article is to review the “newer” beta-blockers - those explored for topical ophthalmic use in the late 1970s and 198Os, addressing the generalization that “all ophthalmic betablockers are the same.” The analogous proposition for systemic beta-blockers was addressed by Lowenthal et al and was found to be an over-simplification.‘” As the literature on ophthalmic betablockers is vast, this review concentrates on certain areas. 307
308
Surv Ophthalmol 31(5) March-April 1987
1. Emphasis is given to agents evaluated topically in humans with elevated intraocularpressure. Only articles in which a given patient was treated with a single drug (or vehicle) are referenced. Studies on timolol are referenced frequently as it is the prototype drug. 2. A pharmacology section describes the concepts of beta-receptor subtypes, intrinsic sympathomimetic activity, and mechanism of action. 3. A clinical trial design section is included, which is applicable not only to articles reviewed herein, but to appropriate interpretation of future reports of novel agents. 4. Publications available in literature data bases as of September 1985 are utilized. Some articles published in 1986, during the editorial review process, are included. Publications from non-American journals were particularly sought out to maximize information on investigational beta-blockers.
NOVACK
Lcvobunolol
Q 0
AlWlOlOl
CH,COO
CH2CONH2
HIC CH3
CH&HflCH& Betoxolol
Meloprolol OH
Bwrano~o~
Nodolol 0CHZFHCH2NHCKH&
0
OH
HN:N (C&In
Pharmacology CHEMICAL
STRUCTURES
OF BETA-BLOCKERS
Fig. 1 shows the structural formulae for selected beta-blockers. Common features include a ring system, (partially or completely aromatized and planar) and an alkyl side chain. On this side chain is an asymmetrical carbon atom. The levo (or S) form of the molecule is generally 10 to lOO-fold more potent than the dextro (or R) form in receptor-binding, at least at the cardio-pulmonary receptor.40aJ’2 In the heart, it is clear that receptor-binding potency of stereoisomers is directly related to the therapeutic effect. In the eye, however, the P-receptor may be different in that d-isomers are closer in potency to l-isomers in their receptor afftnity.g2 In a pilot clinical study using a high concentration, dtimolol was reported similar in ocular-hypotensive efficacy to the l-isomer. 62 Interestingly, some 15 years ago, Vale and Philips153 reported d-proprano101, injected intravenously, decreased elevated intraocular pressure in humans; however, on a mg-permg basis, d-propranolol was less active than d,l-propranolol. This is consistent with rabbit studies of ocular hypotensive effect, in which topical dtimolol was equi-effective to 1-timolol, but only l/ 10 the potency. That is, the intraocular pressure decreases seen with d-timolol were as great as with ltimolol, but approximately 10 times the concentration was required.73 Table 1 provides a cross-reference of generic and brand names of beta-blocker formulations. The formulation of a beta-blocker for ophthalmic use is an important part of developing the drug for general use by glaucoma patients. An ophthalmic formulation includes water to dissolve the drug and may
?”
Ccllprolol
0CH~CHCH2NHCHKH~)2
0CH2$HCH#HCKHs),
Propranolol
OH OH
Cctamalol
F”, Oi+Wi, NH
0
532-468
ICI 118.55I
Fig. 1. Chemical structures of selected beta-blockers.
contain a preservative to prevent bacterial growth, buffers and/or other agents to control pH and stability, and a vehicle, such as polyvinyl alcohol to transport the formulation into the eye. These are required to achieve a drop which is acceptable for ocular instillation and sufficient stability. The preservative in commercially available beta-blockers is generally benzalkonium chloride (BAK, Zephiran) in a concentration ranging from 0.004% to 0.010%) depending upon the product. Benzalkonium chloride is a relatively rare sensitizing agent.47 Recently, a “unit-dose” nonpreserved preparation of timolol was released in Sweden. Also shown in Table 1 is the regulatory status of various ophthalmic beta-blockers in America, Canada, and selected European countries. Germany has eight ophthalmic beta-blockers, the largest number of options. The complex regulatory situation as well as marketing priorities of pharmaceutical firms make the ophthalmic situation unique in each coun-
BETA-BLOCKERS
SINCE TIMOLOL
309 TABLE
1
Generic and Trade Names and Regulatov Status af Beta-Blockers
Generic
Name
ACC 9447 Arotinolol Atenolol Betaxolol Befunolol Bupranolol Carte0101 Celiprolol Cetamolol ICI-l 18,551 Labetalol Levobunolol Levomoprolol Metoprolol Metipranolol Nadolol Practolol Propranolol Pindolol S32-468 Timolol
Trade
Selected Countries Where Ophthalmic Preparation Approved*
Names
S-596
Tenormin Betoptic, Kerlone Glauconex, Bentos Ophtorenin, Betadrenol, Panimit Arteoptic, Endak, Teoptic, Mikelan
GER, USA, FRA** GER, JPN GER GER, FRA, UK, JPN
Normodyne, Trandate Betagan, Vistagan, Bunorit,
GER, USA, CAN, FRA**
Gotensin
Lopressor, Beloc Betamann, Betanol, Disorat, Beta-Ophthiole, Corgard Eraldin, Dalzic Inderal, Dociton Glauco-Visken, Durapindol, Visken Timoptic,
Timoptol,
Chibro-Timoptol,
Glaucoline
GER, FRA, UK
GER, FRA**
Blocadren
GER, UK, CAN, USA, FRA, JPN
.4s of February, 1986: *GER = Federal Republic ofGermany, FRA = France, UK = United Kingdom, USA = United States ofAmerica, C.4N = Canada, JPN = Japan. **Scientific approval. In France, new products must be assigned a reimbursement price by the government. This process is currently ongoing where noted, and must be completed prior to actual availability as a marketed product.
try. In America, timolol, levobunolol and betaxolol are available. Based upon cardiopulmonary studies, betablockers are divided into beta, and beta, subtypes. When stimulated, cardiac beta, receptors, acting via a second messenger, cyclic adenosine monophosphate (CAMP), elicit tachycardia, positive inotropism and/or increased conduction time (dromotropism). Beta, receptors in the liver have a glucagon-like effect and enhance the breakdown of stored triglycerides. It appears that memory functions may be /3,, rather than &-adrenergic events.48a When stimulated, pulmonary beta, receptors cause bronchodilation. Beta, receptors in the uterus elicit a relaxation of contractions, and in the blood vessels, mainly in skeletal muscle, elicit a vasodilation. Interestingly, elderly healthy volunteers have been reported to be less sensitive to the cardiovascular effects of isoproterenol, a /3,I& agonist, than young volunteers. However, these elderly volunteers had a similar sensitivity to timolol, a p,I& antagonist.63” Pharmacologically, agents such as timolol are correctly called beta-adrenergic antagonists. However, within this review, the more commonly used “beta-blocker” is used. Betashort-hand phrase
blockers, by definition, antagonize the effects of beta-agonists at the beta receptor. In the eye, timo101has been reported effective in decreasing aqueous humor flow only during the subjects’ waking hours when, presumably, there is greater endogenous adrenergic stimulation of aqueous humor production.‘4g Some beta-blockers, such as propranolol and timolol, are equipotent at beta, and beta, adrenergicreceptors. That is, they are not “selective” with respect to beta, or beta, adrenergic receptors. Other beta-blockers, such as practolol and betaxolol, are more potent at beta, than beta, sites and are called “/3,-adrenergic receptor selective.” Yet other betablockers, such as ICI-l 18,55 1, are more potent at beta., than beta, receptors. The importance of such relative affinity at beta subtype receptors is the object of much cardiovascular research and bears on the systemic safety of topically administered betablockers. The relative beta, and beta, selectivity of various ophthalmic drugs is shown in Table 2. Experiments using in vitro stereospecific receptor binding and cyclic AMP stimulation techniques as well as in vivo agonist/antagonist models of intraocular pressure in rabbits suggest that the ocular beta-
Surv Ophthalmol
31(5) March-April
NOVACK
1987 TABLE
2
Pharmacological Properties of Beta-Blockers
Agent ACC 9447 Atenolol Arotinolol Betaxolol Befimolol Bupranolol Carte0101 Celiprolol Cetamolol ICI-l 18,551 Labetalol Levobunolol Levomoprolol Metoprolol Metipranolol Nadolol Practolol Propranolol Pindolol S32-468 Timolol
P-Receptor Sub-Types Antagonized PI,
Lipophilicity
ISA+
P2
0.16 ;:, PI
Human Data Oral Potency
Cornea1 Anesthesia
0.2-4.0 4.0
4.0
0.5 0.25-0.5 0.05-0.5 1.o-2.0
0.5 4.0
+ +
1.0 50
2
P2
2.73*
;:: ;z
+
?
Ophthalmic Concentration (%)
p2
Pl P2
5:: ;: PI, P2 PI
2.40
;:: ;: PI
0.93
1.88
3.21
i32
+ +
;:: ;; ;:>
+ -
1.91
-
0.25-0.5 2.0 3.0 0.1-0.5 2.0 1.0 0.5-1.0 0.5-1.0 1.0 0.25-0.5
0.5 10.0 2.5 0.3 1.0 13.0 7.0
2
++ % I?
Table designed after Shanks et al., (1984), with additional data from Physician’s Desk Reference (1985), Rote Liste (1985), Wright (1975), Morselli et al. (1983), N a k as h’ima et al. (1985), Van Joost et al. (1979), Van Buskirk and Samples (1985), Duzman et al. (1983), Sugrue et al. (1985), and Gos and Stankiewica (1979). Lipophilicity expressed as Log P from Huang et al. (1983) and * for betaxolol, calculated from Manoury (1983). Oral potency is based on total daily oral human dose utilized for antihypertensive efficacy, with proprano101 = 1 (200 mg/d). Cornea1 anesthesia data from Draeger (1984), Berson et al. (1985), and Gorgone et al. (1983). + Intrinsic Sympathomimetic Activity (defined in in vivo cardiovascular studies): ( - ) = absent; ( + ) = present.
adrenoreceptor behaves like a beta,-adrenergic receptor. 58,9995,151,165a,169a Theoretically, the use of topical beta-blockers of various degrees of beta,/beta,-adrenergic receptor selectivity is interesting. If the ocular beta-adrenergic substrate is a &adrenergic receptor, then what is the mechanism of action of a drug with a relative &adrenergic selectivity? Several explanations are possible. One is that beta-blockers do not lower intraocular pressure via a beta-adrenergic mechanism, as suggested by Chiou et ahz8 and may work via dopamine antagonism. A second is that the concentrations achieved in the anterior chamber of a relatively beta,-selective agent will block both beta,and beta,-adrenergic receptors.‘50 Since this theory was initially suggested by Trope et a1,15’ there have been additional data published that support this theory in ocular tissues. Within the first hour after topical instillation in humans, the concentration of timolol in the anterior chamber is 1-2 ~M.“3aJ52
The concentration of timolol required to block either beta,- or beta,-adrenergic receptors is l-10 nM 96,118,151,165a approximately 3 log units less. The con:entration of betaxolol required to block beta,adrenergic receptors is l-10 nM, and 600 nM to block beta,-adrenergic receptors.“8 Thus, if one assumes that a drug such as betaxolol achieves aqueous humor concentrations similar to timolol’s, it is possible that ocular beta,-adrenergic blockade might occur with topical instillation of betaxolol. Additional theoretical concerns are also present. The in vitro selectivity of an agent, the value usually referenced, is generally greater than the in vivo selectivity.27s"%127 Many factors affect in vivo response, such as pharmacokinetics and penetration. The in vivo ocular potency and systemic specificity may be greater or less than the in vitro systemic value.g6 While on the average, beta,-adrenergic receptor “selective” beta-blockers are usually without pulmonary effects,4’J62 there are reports of reduced pul-
BETA-BLOCKERS
311
SINCE TIMOLOL
monary function in sensitive patients following systemic”‘~“” or topical instillation.jzb.“* Interestingly, 25% of beta receptors in the human lung are beta,, although their function is not clear.26 Thus, beta,adrenergic receptor “selectivity” should not be assumed to he absolute.‘“’ The oral and topical potency of ophthalmic betablockers is shown in Table 2.
-3.5 s .E
$
sx .% &v, E $ 6 n_b
INTRINSIC
SYMPATHOMIMETIC
ACTIVITY
The beta-antagonist molecule, similar to betaagonists such as isoproterenol, has an affinity for the receptor. The difference between agonist and antagonist is. however, that once bound to the receptor, the agonist stimulates adenylate cyclase to produce c&, while the antagonist does not. However, some beta-blockers, such as pindolol, in addition to their afftnity for the receptor, have some agonist activity, called “intrinsic sympathomimetic activity” (ISA). That is, the beta-blocker has agonistic actions similar to epinephrine. If this ISA were predominantly beta,, then a vasodilatory effect might be observed with these drugs.” However, a recent pharmacologic study suggests that the ISA of pindolol is not selectively beta,, but also beta,.8b Mekki et al”’ found topical pindolol to antagonize exercise-induced tachycardia to a degree similar to that reported for timolol, a beta-blocker without ISA.’ Bleckmann and Dorow”” found no difference between topical pindolol. an agent with ISA, and metipranolol, an agent without ISA, in pulmonary patients. Thus, the clinical importance of ISA in a topical agent is not entirely clear. LIPOPHILICITY In order to penetrate through the cornea and achieve therapeutic concentrations at the ciliary body, a topically applied beta-blocker must be lipophilic. Lipophilicity is expressed as the logarithm of the ratio ofpartitioning of the molecule in oil to its partitioning in water, or log P. The lipophilicity of various beta-blockers are given in Table 2. However. as shown in Fig. 2, the permeability coefficient of beta-blockers plateaus at log P values greater than 2.5.5b Theoretically, if an agent is too lipophilic, it remains in the epithelium, and does not pass through the stroma and endothelium into the anterior chamber. A similar relationship has been reported for steroids.‘“” LOCAL ANESTHETIC
ACTIVITY
As a lipophilic molecule, a beta-blocker can permeate the cell membrane of an axon, and in doing so stabilize the membrane and interfere with the mechanism of active propagation of the action POtential. This effect is not related to beta-blockade,“”
1
.z
4.5-
-550
E
1
-6.5
\ -1
I
0
I 1
I
2
I
3
I
4
I
5
Log Oil/\il/ater Partition Coefficient Fig. 2. Theoretical lipophilicity curve. Relationship of lipid solubility and cornea1 penetration for a series of betablockers. (Adapted from Huang HS5”).
but is a physiochemical interaction related to the concentration of the beta-blocker, its membranestabilizing activity, its lipophilicity, and the exposed area of the cell membrane. The membrane-stabilizing effect of beta-blockers can be measured in an isolated frog axon.13’ In the eye, a topical beta-blocker may stabilize the unmyelinated pain fibers of the cornea to produce cornea1 anesthesia. Clinically, case reports of significant cornea1 anesthesia produced by timolol were first published by Van Buskirk,‘“” after testing by touching a cotton-tipped applicator to the cornea. Subsequent longterm controlled clinical trials using similar techniques” have failed to find such an effect with timolol or levobunolol, suggesting that if present, it is either very mild or rare in occurrence. Table 2 shows the relative cornea1 anesthetic potentials of selected beta-blockers. MECHANISM
OF ACTION
Timolol decreases aqueous humor production’0,1’“.‘70”with little or no significant effect on episoutflow facility or uveocleral venous pressure,” scleral flo~.“~.” Thus, the mechanism of the ocular hypotensive action of timolol appears to be solely a decrease in aqueous humor production. Betaxolol,“” levobunolol,“’ carteolol’ and metipranolol”” have also been reported to decrease aqueous humor production. Similar to timolol. levobunolol has been reported to have no effect on uveoscleral flow, outflow facility, or episcleral vehas no effect on total nous pressure. I” Carteolol are outflow facility. 5oWhether all new beta-blockers similar to timolol in solely affecting aqueous humor production must be determined through research using both fluorophotometry and outflow measuremerits.*** ‘72
312
Surv Ophthalmol
3 l(5) March-April
NOVACK
1987
Design of Clinical Trials In the practice of their specialty, clinical ophthalmologists desire to treat the patient. In the evaluation of a new ophthalmic drug, clinical pharmacologists desire to test the drug. While these two objectives seem congruous, the perspectives of these individuals are indeed different with regard to the design of a study. 68 Should one design a trial from the clinician’s perspective, one would want the option of maximum individuality of treatment and open-ended duration of treatment. An example of such a study is a report of bupranolol.35 A five-fold range of concentrations of bupranolol was used, as well as concomitant medications, such as pilocarpine. One might suppose the patients in this study received the maximum degree of individualized therapy. However, due to the noncomparative design, the efficacy of bupranolol is not clearly demonstrated, especially vis-a-vis timolol. Also, the non-masked nature of the trial allows for the confounding influence of any biases of the patient or ophthalmologist. Should one design a trial from the clinical pharmacologist’s perspective, one would want to standardize patient treatment, compare the new drug to a standard currently acceptable therapy, and minimize any investigator or patient biases. One such study was done on levobunolol. With regard to levobunolol, patients were divided into three groups, and randomly received double-masked levobunolol, 0.5% or 1.O%, or timolol 0.5%. If the assigned medication was insufficient to control intraocular pressure, the treatment was judged ineffective. In this study, a clear evaluation of the efficacy of levobunolol vis-a-vis timolol was accomplished. While patient safety was not compromised, the individuality of patient treatment was minimized. The exposure of patients to experimental protocols and drugs demands maximizing benefits both to the patient and to society as a whole. One editor has suggested that study design is a major part of the benefit-risk relationship in any drug study.2 Study design concerns are important to consider when reading and interpreting a clinical report or when designing a study.‘7s4s The size ofthe study population is another important consideration in the design of a study. One might deduce that relatively few patients would be needed to differentiate between a drug as effective as timolol and an inactive placebo in glaucomatous patients. On the other hand, a relatively large number of patients would be needed to detect the small difference in activity between timolol and a slightly less active drug. Statistically, this concept is called power, (beta or Type II error).37 Power is the
strength of a clinical trial to detect a difference between two treatment groups, given that such a difference exists. When evaluating changes in intraocular pressure, power is a function of the sample size, the difference between the mean changes in intraocular pressures in the treatment groups, the alpha level, and the standard deviation.* The greater the number of patients per treatment group (N), the greater the power. Similarly, the greater the putative difference between the two treatment groups (AIOP), i.e., 6 mm Hg, rather than 2 mm Hg, the greater the power. Inversely, the greater the standard deviation of the group (SD), and the smaller the cx (critical significance level, i.e., p = 0.01) the smaller the power. Note that power is critical only when claiming an equivalence - that is, finding no difference between groups. If a difference was seen, then the power to have found that difference is not germane. Biostatisticians and most regulatory agencies require a power of at least 0.80 - that is, a study powerful enough to have an 80% chance to detect differences between two treatments. What is often surprising to the clinical investigator is the large number of patients required to achieve this level of power. The power of a placebo-controlled study relative to the number of patients is shown in Fig. 3. Clinically, one might say that NEWDRUG might be useful only if there were a 6 mm Hg difference in intraocular pressure from placebo. In order to reach 80% power, eight patients per group, or a total of 16 patients are required for a parallel study. A similar power curve is shown in Fig. 4, for a study of NEWDRUG compared with timolol. One might say that there must be a 2 mm Hg difference in efficacy between the two drugs to state that there is a clinically significant difference between the drugs. As the expected difference is much less in this situation, one needs 30 subjects per group, or 60 patients to obtain a power of 80%. A study of low power is analogous to a pre-presidential election poll on only 20 people - the results are interesting, but not necessarily a powerful prediction of the outcome of the real election with 60 million voters. As will be seen in the clinical studies detailed in the efficacy section, the power of most timolol-con-
*Mathematically, power, or the probability significant difference is: 1-p = Probability
to find a statistically
(Z > z,,,((AO~(20)))
where P = p-error; Z denotes a random variable having the standard normal distribution; zuj2 = Z-value for chosen alpha level; A0 = the difference between the mean changes from baseline in intraocular pressure37,48c; n = sample size; and u = standard deviation.
BETA-BLOCKERS
bz
SINCE TIMOLOL
313
100
100
80
80
60
0
R
!
1
I
1
IJ
5
10
15
A = 6 mm
Hg,
trolled
studies
?
20
N/Group SD = 4,a = 0.05, 2 toii
Fig. 3. Projected power curve for ocular hypotensive cal trial: Placebo-controlled.
0
A = 2 mm clini-
of beta-blockers is much less than reason for this is that at any one study site, it is difficult to locate and recruit more than 30 suitable patients within a six-month period. Power may be increased by using several cooperative study sites. I7 Such studies involve cooperation of ophthalmologists and biostatisticians from different geographical areas, where concepts of disease treatment vary, as does the prevalence and nature of the disease. As the costs and labor of such projects are high, they are generally undertaken only with government or corporate sponsorship. The exposure of patients to various treatment(s) in a study can be of several designs. In a parallel study, patients are randomly assigned to receive one of the treatments for the duration of the study. In a cross-over study, each patient receives, sequentially, each treatment. Masking ofthe treatment(s) may be open, where both physician and patient know the treatment, single-masked, where only one party, generally the physician, knows the treatment, or doublemasked, where neither the physician nor the patient knows the treatment. In a titration study, patients begin treatment at a given regimen. If uncontrolled (i.e., intraocular pressure is too high), the concentration or frequency of instillation is increased. Cross-over studies, in which each patient receives both treatments sequentially, are an attractive design and may increase power. The assumptions of a cross-over study are: 1) each patient must complete both phases of the study; 2) there is no carry-over effect of the first treatment; and 3) the disease remains constant throughout both periods. Crossover designs are most easily applied to single-drop studies in patients with mild disease, where disease constancy and completion of both phases of the study are more likely. In longer-term studies, not all patients successfully respond to the beta-blocker. Statistically, the investigator may average intraocular pressure at each
80%. The primary
60
25
50
Hg. SD =
N / Group 3,a = 0.05, 2 taii
Fig. 4. Projected power curve for ocular hypotensive cal trial: Timolol-controlled.
75
clini-
visit for all patients or completely delete failed patients from the analysis. Clearly, the latter method would result in greater apparent mean intraocular pressure decreases, as only “responders” would be included. In a patient treated bilaterally, both eyes tend to respond similarly to a test medication or “covary.” Thus, it is inappropriate to analyze eyes separately as independent events. 44Alternate methods, such as averaging eyes’ should be used to correct for the covariance. The issue of compliance is frequently discussed in the use ofglaucoma drugs.‘58b From monitoring data of four-times-daily pilocarpine52,60*6’a~‘“o and twicedaily timolol,‘33 we know that compliance in a population of patients unaware that compliance is being tested is quite poor. In a study of patients inadequately controlled by timolol b.i.d., patients were randomized to receive timolol again or levobunolol in a masked study. lo3 The control rate at three months for 0.5%) 1.O% levobunolol and 0.5% timo101was 31%) 43% and 38%) respectively. This suggests improved compliance. Similarly, when patients taking a combination of medications switched their timolol for befunolol, an average intraocular pressure decrease of 2 mm Hg was seen.‘46 It is possible that the newer beta-blockers may be more effective than timolol in this population. However, a more likely explanation is the “Hawthorne effect”: when aware that they are being tested, people im76We also know that ophprove their performance. thalmologists’ estimation of compliance, at least with pilocarpine, is poor.6’ If compliance is critical, as in a one-drop study, then it is best to have the investigator instill the test medication. Compliance might be enhanced by patient instructions and encouragement. In theory, one would like to measure the efficacy of a drug without the issue of compliance. In reality, one measures the combination of the two in a study, which is
TABLE
3: Single-Instillation Studies of Egicacy of Beta-Blockers IOP at Baseline
Design*
Study VanBuskirk’%
DMX
Nakashima”
OX
Ros’*’
DMP
Tanei4’
nl Group 17 6 11
Treatment 1 Eye O.U. 1 Eye
9
Kitazawa63
DMX
Negishi”
DMP
Bonomit6
OP
13
7-10 18
1 Eye
l-2 Eyes 1 Eye
DMP
6
1 Eye
DMP
8
1 Eye
Dausch3*
DMP
10
1 Eye
Kruse6’ Krieglsteins“
0 DMP
9 7
O.U. 1 Eye
Duzman43
Partamian’
to
Ros’**
DMX
13
1 Eye
Nielsot?
SMX
11
O.U.
DMP
10
1 Eye
DMP
15
0.u
DauschM
0
GOP
Vale’54 Zimmerman
‘74
30
DMX
8
DMX
20
1 Eye
1 Eye
Groups Vehicle ACC 9447 1.5% Arotinolol 0.5% Timolol 0.5% Vehicle Atenolol 4% Befimolol 0.2% Befunolol 0.5% Befunolol 1% Vehicle Carte0101 0.5% Carteolol 1% Carte0101 2% Carte0101 1% Carte0101 2% Vehicle Labetalol 0.5% Labetalol 1% Vehicle Levobunolol 0.5% Levobunolol 1% Timolol 0.5% Vehicle Levobunolol 0.03% Levobunolol 0.3% Levobunolol 0.6% Levobunolol 1% Levobunolol 2% Vehicle Metipranolol 0.3% Metipranolol 0.25% Vehicle (Fellow Eye) Metoprolol 0.1% Metoprolol 0.5% Metoprolol 1% Metoprolol 3% Vehicle Metoprolol 1% Metoprolol 2% Metoprolol 4% No treatment Metoprolol 220 pg rods Timolol 0.5% Vehicle (Fellow Eye) Nadolol 2% Labetalol 1% Vehicle Pindolol 0.17% Pindolol 0.35% Pindolol 0.50% Pindolol 0.72% Pindolol 1% Vehicle Practolol 1% Practolol 10% Propranolol 1% Vehicle Timolol 0.1% Timolol 0.25% Timolol 0.5% Timolol 1.O%
(mm Hg) 15.0x 15.5 13.5” 14.0 25.6 28.3 25.1 25.1 24.5 22.4 24.0 23.4 23.5 24.0 22.0 33.0 29.5 33.5 29.3 27.6 27.4 26.7 25.6 24.9 25.1 26.0 25.6 25.4 20.5 27.0 29.0 32.0 29.0 27.0 23.8 28.5 26.5 26.0 26.8
30.0 31.0 32.0 24.6 23.8 24.2 23.7 24.4 24.5 18.7 18.3
SD
4.0t 5.0 2.0 2.0
2.5
3.0 3.0
2.2
3.0
4.07 3.0
3.0t
3.0t
4.0
4.0
- 1.5 -1.5 -4.lll - 5.oll - 1.0 -5.0 -3 -7 -7 -0.5 - 3.6 -3.9 -5.1 - 7.0 -5.0 -1.0 - 7.0 -6.0 - 1.0 -8.3 -6.3 -7.1 - 4.4 -5.4 -8.3 -9.2 -9.4 -11.2 - 1.0 -11.0 - 3.0 0.5 -2.0 -3.0 - 7.0 -9.0 1.0 -6.0 - 2.0 - 3.5 -0.0 -6.4 -6.1 - 1.0 -3.0 -2.0 -2.6 - 3.8 -4.6 - 4.6 -5.5 -4.9
2.0 4.0+
22.0 26.2 23.7 28.0 25.3
2 Hours
3.0 +
IOP Changes 6-8 Hours
(mm Hg) 24 Hours
Power5
- 2.0 - 1.5 -
+2 +2 -
99%
-0.8 -0.6 -2 -6 -6 -0.6 -2.2 - 1.7
-
99%
-
52%
-2.2 -5.0 - 1.0 - 1.0 -0.3 -5.8 - 2.9 -4.2 - 5.8 -6.3 - 7.4 - 7.9 -9.5 - 10.5 - 3.0 -11.0 -3.5 0.0 -9.0 -9.0 + 1.0 - 4.0 - 3.5 -5.5 -2.2 -4.0 -3.7 -2.0 - 10.0 -5.0 -
9%
99%
-3
14%
-1 -
99%
-0.8 - 3.4 - 3.8 -3.3 -3.1 - 2.9 -3.5 -3.2 -6.8 -5.8 - 1.0 -8.0
99%
96%
89% 32% 94%
-1 -
99%
-
99%
-0 -0 -0 - 1.2 -2.5 - 2.9 - 1.9 -2.5 -4.5
89%
98%
+0.1 -0.4 - 1.0 -8.5 - 7.8 -8.7 -9.5
4.1 4.4 4.0 -9.7 -9.5 -9.7 - 7.6
t= SD. estimate; not given in report. ll= At 3 Hours. x Normal, rather than hypertensive patients. *Design abbreviations SM = single-masked, DM = double-masked, 0 = open, P = parallel, X §Power calculated by review author using formulae stated by Dixon and Massey3’ as (Y = 0.05, two-tailed, Hg for vehicle-controlled and 2 mm Hg for active-controlled studies.
99% -
16%
-2.0 -6.6 - 6.6 -11.1 -8.0
99%
= cross-over. and AIOP
of6 mm
BETA-BLOCKERS
SINCE
TIMOLOL
315
similar to the “real world” where the most effective drug is of no use if the patient does not take it. Attempts to decrease the required frequency of instillations of antiglaucoma medication has resulted in devices such as the OCUSERT+8 and a oncedaily pilocarpine gel.” An alternative to drops, ophthalmic plastic rods, has been reported effective for metoprolol.“H Once-daily timolol and levobunolol have been reported effective for some patients,~‘.l”‘.l’ ( 17’1.1 Many studies do not state the interval between instillation and measurement of intraocular pressure. In clinical practice, ophthalmologists generally see a patient within one to eight hours after the instillation of their beta-blocker. Most consider this appropriate for clinical practice, as it estimates the efficacy of treatment during the day. In a clinical study, however, the efficacy of the drug may be overestimated if measured immediately after instillation, or underestimated if measured 12 hours after the last dose. Given that patients are likely to take their medicine on the day they are to visit their doctor.<” it may be more appropriate to take the worst possible intraocular pressure rather than the best. For beta-blockers with a duration of action longer than 12 hours, such as timolol’7’ and levobunolol.““it has been reported that during longterm T:!BLE
4: Open-Label
therapy, the intraocular pressure is similar at 1 hour and 12 hours following instillation.“” Similarly, this has been reported for oral nadolol after four week’s therapy. IhRHowever, such is not the case for shorteracting agents, such as metoprolol.“’
Results
Stud!
N/ Group
Sterk””
30
Single-drop
Medium- to Long-term Studies Selected open-label evaluations of various betablockers are listed in Table 4. As noted in the cliniStudies of Beta-Blocker
Mertr”
3
4
Brpwitt”
3
162
Berrospi” i? LWy
12 24
Demmler”
Baseline Groups
(mm
4%
Studies
In Table 3, the results are compiled ofsingle-drop clinical studies on the efficacy of various betablockers. On a one-drop basis, befunolol, carteolol, levobunolol, metipranolol, and pindolol are effective. The cardioselective agents atenolol and metopro101 are not of sufficient duration to allow b.i.d. therapy. ACC-9447, designed to be short-acting systemically, appears ineffective. AArotinolol appears similar to timolol in efficacy, although only data in normals have been reported. At this time, there is no published dose-response. time-response studv on betaxolol.
r\fedium to Lorqterm
Atenolol
H,~I
(mm
Hg)
Variablr
\.ariahle
0.2% 0.5% 0.25% 0.5%
24.5 24.0 22.9 2.5.1
20.0 20.0 18.3 19.3
12 70
Betaxolol Betaxolol
0.25% 0.5%**
32.6 25.0
21.3 19.0
6
10
Bupranolol
Variable
\‘ariahle
13
102
Levomoprolol
25.0
16.0
6
47
Metipranolol
27.3
18.6
Krieglsrein”’
4
10
Metoprolol
24.5
18.0
Andreasson” stryz’+’
1 12
8 33
Pindolol Pindolol
0.25% 1%
29.0 24.0
20.0 18.1
Dausch”
12
74
Timolol
0.
I%
25.4
19.3
Virno Von
IO0
Dentfer””
2.0% 0.3-0.6%
4%
.E/jicacy*
IOP at Follow-Up
Befunolol Befunolol Befunolol Befunolol
O.l-0.5%
Trials
EFFICACY
IOP at Duration (months)
of Clinical
Comments :1pproximatrly half of patients taking concomitant medications. 50% failure rate within tirst month, 82% at 2.5 years. Diurnal IOPs indicatr rfflcacv 2 8 Hours. Combined data from nrw and transferred patients. Approximately 20% failure ratr. Follow-up IOP includes effect of concomitant medications. 6 month efficacy. mainly with concomitant medications. No significant stinging or cornea1 anesthesia. Stinging in up to 45% of patients, not abating \\ith timr. Follow-up IOP at 2 Hours. Diurnal IOPs indicate duration > 4 and < 24 Hours. Diurnal IOPs 2 8 Hours. Approximately
indicate
efficacy
30% failure
rate.
*All reports are O.U., b.i.d. treatment, except for atenolol (Sterk, 1979) which is O.U., Cd. and levomoprolol (Virno, 1986) which was q.d. to t.i.d. dosage. form without quantitative data, reports eflicacy and safety of0.5% betaxolol in several hundred **Beasley et al, ha in abstract patients, of which Levy’s appear to be a subset.
TABLE
Study
Design*
NJ Group
5: Chronic-Treatment, Controlled Studies on Beta-Blocker @j%acy Duration (months)
Berry to
DMP
Caldwe11z4
DMP
5
1.5
Feghali&
DMP
9-10
1.5
Radius’ts”
DMP
10
1.5
Levy72
DMP
20
6
Stewarti4’
DMP
14-15
6
Allenta
DMP
12-15
6
F1~r-y~~
DMX
14
0.25
Levobunolol Study Group7’*
DMP
130
24
Bensingers
DMP
16
3
Long74
DMP T
24-26
3
Kruse’jg
DMP
18
1
Mertzss
DMX
27
0.75
Mills@
DMX
10
1
Krieglstei&&
DMP
21-25
Bucheliz2
DMP
Nielsengg
DMXX
Duzman42
20-26
6
8
1
19
1
DMP
8
3
DMPC
9
1
17
1
OP
Andriasson3
DMP
9
1
Dausch34
DMP
21
1
Merte@
DMP
40
6
MillsE7
DMP
15
12
Uusitalo152A
DMP
13-15
6
Groups
IOP at Baseline (mm Hg)
Betaxolol 0.5% Timolol 0.5% Betaxolol 0.25% Vehicle Betaxolol 0.25% Vehicle Betaxolol 0.125% Vehicle Betaxolol 0.5% Timolol 0.5% Betaxolol 0.5% Timolol 0.5%
29.8 29.8 27.2 29.0 31.8 29.9 31.2 28.7 30.6 28.6 29.0 27.6
Betaxolol 0.25% Timolol 0.25% Carte0101 2% Timolol 0.5% Levobunolol 0.5% Levobunolol 1% Timolol 0.5% Levobunolol 0.5% Levobunolol 1% Vehicle Levobunolol 0.25% Timolol 0.125% Metipranolol 0.25% Timolol 0.25% Metipranolol 0.25% Timolol 0.25% Metipranolol 0.3% Timolol 0.25% Metipranolol 0.6% Levobunolol 0.5% Metoprolol 1% Metoprolol 2% Metoprolol 4% Metoprolol 8% Metoprolol 3% Timolol 0.5% Nadolol 2% Diacetyl NadololO.5% Diacetyl Nadolol 2% Timolol 0.5% Nadolol 2% Timolol 0.25%
27.2 26.6 23.3 23.3 26.8 26.8 27.1 27.3 27.2 27.3 29.5 27.8 23.5 24.5 25.8 29.0 23.3 26.0 25.0 24.0 24.0 24.0 24.0 27.5 28.8 26.6 27.3 26.6 27.6 27.0 27.0
Nadolol Nadolol Nadolol Timolol Pindolol Timolol Pindolol Timolol Pindolol Timolol Timolol Timolol Timolol Timolol
28.6 28.1 27.0 26.7 25.0 27.0 24.5 25.0 23.5 23.5 26.9 24.8 25.8 23.2
20 mg p.o. 40 mg p.o. 80 mg p.o. 0.25% 0.25% 0.5% 1% 0.5% 1% 0.5% 0.25% 0.5% 0.25% 0.5%
SD
4t 0.8 1.8 3.5 2.2 2.3 4.0 2.0 3.7 1.2 2.4 2.8 3.7
3.5
4.9 4.0 5.0 2.2 3.6 2.2 4.07
2.2
4t
3.0 3.0
4t
4t 2.8 3.4 4.6 2.6
IOP Changes (mm Hg)
Power5
-7.8 -6.4 - 7.5 -2.5 -4.2 -0.5 -5.5 - 1.6 -11.1 - 10.6 -7.2 -8.2
37%**
-5.7 - 7.4 -6.0 - 6.4 - 7.2 - 7.3 -7.1 -9.0 -9.1 -0.5 -6.9 - 7.2 -4.5 -6.0 - 6.3 -6.5 -3.7 -2.9
56%
99% 99% 99% 50% 46%
46% 99%
99%
29% 32% 30% 49% 46%
- 5.0 -5.0 - 5.0 - 5.0 -5.9 -8.9 - 2.0 - 7.0 -6.0 - 7.0 - 11.0 - 12.0 -6.0 -8.0 -6.0 -9.0 -8.3 -6.4 -5.0 - 9.0 - 6.5 - 7.0 -5.5 -5.5 -7.1 -5.5 -5.5 -4.6
15%
78% 15%
27%
29%
17% 62% 73% 21% 28%
Failures A 65% 54% 0% 0% ? ? 0% 0% 40% 30% 0% 0% 40% 6% 0% 0% 17% 15% 19% 14% 8% 40% 38% 15% 44% 32% 0% 0% 0% 0% 4% 0% 15% 15%
53% 40% 100% 63% 13% 29% At 1 Day At 1 Day At 4 Wks - 0% At 4 Wks - 0% 24% 6% 19% 25% 0% 0% 0% 0% 3% 5% 20% 33% 0% 23%
All treatments were O.U. and b.i.d. except nadolol/timolol (Krieglstein, 1982) and nadolol p.o., which was q.d. (Williamson et al, 1985). *Design abbreviations - SM = single-masked, DM = double-masked, 0 = open, P = parallel, X = cross-over, PC = paired comparison, T = Titration study. **Power calculated by review author based upon difference of 2 mm Hg. Using a difference of 4 mm Hg, the authors found a power greater than 80%. t = S.D. Estimate; Not given in report.
TABLE
5
(Continued)
Comments IOP changes for successful patients only. Burning 30% for Betaxolol vs 9% for Timolol.
Burning
22% (2/9) for betaxolol
Only successful
patients
vs. 0% for vehicle.
were analyzed.
Note 0% failures in both P-blocker groups in 6 months. Burning 40% (6/15) for betaxolol and 30% (4/14) for timolol. Burning 70% (l-1-/20) for betaxolol and 0% for timolol.
Burning at < 10% of patients visits (see Cinotti 1985). IOP 12 hours after instillation. Burning
58% for metoprolol
et al.,
vs 26% for timolol
Additional 13% of levobunolol and 4% of timolol patients controlled with higher concentrations. Burning 44% for metipranolol and 32% for timolol. Stinging
67”/0 for metipranolol
and 11% for timolol.
Stinging
20% for metipranolol
and 0% for timolol.
Burning complaints for 2,4 & 8%. Diurnals for up to 8 hours.
show efficacy
IOP at 5 hours after instillation. Periorbital
dermatitis
in 28 2% diacetyl
nadolol patients.
IOP at 3 hrs. Patients in fellow eye.
received nadolol in 1 eye and timolol
13% (5/41) pindolol tions.
patients
terminated
for allergic reac-
§Power calculated b review author using formulae stated by Dixon and Massey” Yas cy = 0.05, two-tailed, and AIOP of 6 mm Hg for vehicle-controlled and 2 mm Hg for activecontrolled studies. A Treatment Failures: Failure to be controlled with initial concentration of beta-blocker as sole medication; i.e., if patient required additional medication for control, review author considered as failure.
cal design section, such trials are limited due to the lack of a control group for comparison. These studies do provide qualitative information about patient tolerance, side effects and intrapatient efficacy. Selected longer-term controlled comparative studies of various beta-blockers are presented in Table 5. The important comparison points are the duration of treatment, relative intraocular pressure changes, treatment failure rate, and the statistical power. In studies with a vehicle-control group, if equivalency is found, power is the strength of the statement that the new beta-blocker is equivalent to vehicle. Using this criterion, both betaxolol and levobunolol have been evaluated in studies of sufftcient size. Caldwell et al’” found betaxolol 0.2.5% to be 3.0 mm Hg better than vehicle. Feghali and Kauftnant6 found betaxololO.25% to be 3.7 mm Hg better than vehicle, although this difference was not statistically significant. Radiusiix” found betaxolol 0.125% to be 3.9 mm Hg better than vehicle at most visits. Bensinger et al” found levohunolol 0.5% to be 8.5 mm Hg better than vehicle. Allen et al’” evaluated betaxolol and timolol in a double-masked, parallel study. They found both agents eff‘ective; however, the decrease in intraocular pressure with betaxolol, approximately 5.7 mm Hg, was statistically significantly less than with timolol, 7.4 mm Hg. The failure rate on a betablocker alone was 40% (8/20) with betaxolol and 6% (l/18) with timolol. Allen et al“ reported on a larger comparison of betaxolol and timolol. of which his above study is a subset, most likely- along with the studies of Berry,“’ Levy’? and Stewart.“” In the differlarger study, Allen at al” report no statistical ence in IOP between betaxolol O.S%, and timolol 0.5% over 6 months, although neither the IOPs nor the statistical methods are mentioned in the abstract. Theoretically, decreasing the number of’ daily doses might increase adherence to a regimen.“” Handel et al’“” evaluated the efficacy of once-daily levobunololO.5% and 1.O%, and timololO.5%. The control rate for the three treatment groups was 72%, 79%) and 64%, respectively. From a baseline intraocular pressure of 28.2 mm Hg, 26.9 mm Hg and 26.4 mm Hg, the overall decrease for the three months of the study was 7 mm Hg (29% ), 6.5 mm Hg (25%) and 4.5 mm Hg (20%), respectively. The 0.5% levobunolol group was statistically, different from the timolol group with respect to overall intraocular pressure, using analysis of variance techniques. 141though the groups were not statistically significant at baseline, an analysis of variance was performed on percent change from baseline, which statistically adjusts for baseline differences. Similar to overall intraocular pressure change, overall percent change was also greater for the 0.5% levobunolo1 group. The reason for this may be pharmacokinetic. Levobunolol has a longer half-life than timolol after oral administration.“,‘“.‘t”’ .Additionally. the major ocular and systemic metabolite of Icvobuno-
318
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3 l(5)
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NOVACK
1987
101, dihydro-levobunolol, has a half-life of seven hom-s.36J48 Dihydrolevobunolol has been reported to be similar in beta-blocker potency and efficacy in several systems. Given intravenously to dogs, dihydrolevobunolol is equipotent and equieffective to levobunolol in blockade of isoproterenol-induced tais similar chycardia. ‘ObIn vitro, dihydrolevobunolol to levobunolol in competition for beta-blocker sites in rat lung.1’s Ocularly, dihydrolevobunolol is a potent and effective antagonist of isoproterenol-induced ocular hypotension in rabbits.16’” In human iris ciliary body tissue, the affinity of the beta-adrenoceptor for dihydrolevobunolol and levobunolol is 6.7 nM and 3.9 nM, respectively, similar to that for timolol.‘65” To date, only one study has been published on once-daily levobunolol. The concept of utilizing once-a-day levobunolol may be quite adequate in many patients, and should be further evaluated in controlled studies and individual patients. Timolol appears to have no active ocular metabolites.“7s’65 Betaxolol, at least systemically administered, appears to be metabolized to inactive compounds.8a,8ga Metipranolol, a PI/p2 adrenoceptor antagonist, has been used extensively in Europe, and proceedings of a symposium on its ophthalmic use have appears similar to been published. 82 Metipranolol timolol or levobunolol in efficacy studies of up to three months treatment.68a,6gJ5~** However, comfort appears to be a concern.85’06 In studies with a timolol-control group, if equivalency is found, power is the strength of the statement that the new beta-blocker is equivalent to timolol. A power of 80% or greater is generally accepted as the minimum criterion required for a powerful equivalency statement. Using this criterion, levobunolol, and perhaps metoprolol and pindolol, have been evaluated in sufficiently large studies to state they have an efficacy equivalent to timolol. Levobunolol (0.5% and l.O%), as well as timolol (0.5%), lowered intraocular pressure by 7-8 mm Hg, with a failure rate of 5-10% per year in a two-year study with 99% power. ” Metoprolol (3%) lowered intraocular pressure by 6 mm Hg, and timolol (0.5%) 9 mm Hg in a one-month study with 78% power.gg Pindolol (1%) and timolol (0.5%) lowered pressure by 5.5 mm Hg in a six-month study with 73% power.84 There are controlled clinical trials on other beta-blockers. Betaxolol (0.5%) lowered pressures by 7.8 mm Hg and timolol (0.5%) by 6.4 mm Hg in a six-month controlled study of 37% power.‘O In a similar study of 46% power, betaxolol lowered intraocular pressure by 7.2mm Hg and timolol by 8.2 mm Hg. 14’ However, the interpretation of equivalence to timolol must be tempered by their limited statistical power.
In the studies presented here, it is often difficult to establish a clear difference in efficacy among various concentrations of beta-blockers in chronic use. No difference between 0.25% and 0.5% timolol was found over the course of six to twelve months.87s 15” Similarly, little difference in efficacy was observed between various concentrations of metoprolo12* or nadolo15’ in one- or three-month studies, respectively. The efficacy of oral nadolol (20-80 mg, q.d.) was reported to be similar to topical 0.25% timolol b.i.d.“j* Oral propranolol (40-60 mg, p.o.) was found similar in efficacy to topical timolol (0.5%, b.i.d.) when used in combination with pilocarpine (2%, t.i.d.).‘O’ TOLERANCE A rapidly developing tolerance, over the course of a few days in up to one-third of patients, has been reported with timolol. lo8 Of greater concern is that the ocular hypotensive efficacy of timolol may decrease by up to 25% with longterm treatment.‘5.‘40 Calissendorff and Marenz5 observed a greater degree of tolerance in patients with glaucoma than in patients with ocular hypertension over the course of year-long timolol treatment. In a large, well-controlled two-year study, less than 10% ofpatients per year were uncontrolled with timolol or levobunolol as sole antiglaucoma medication.” The apparent discrepancy between these studies, and clinical anecdotal experience of tolerance, might be due to difference in disease severity. In a progressive disease, it is difficult to separate the worsening of disease from a dimunition in efficacy of the medications. EFFECT
ON VISUAL
FIELDS
Glaucoma is a disease characterized by progressive loss of visual field over many years. Efficacy of a new beta-blocker is generally assessed by its ocular hypotensive effects, since decreasing intraocular pressure is assumed to prevent visual field loss. Intraocular pressure has the advantage of being a single dimensional, “objective” measurement. It also is labile; that is, it may be changed by a new treatment within hours. True efficacy of any glaucoma treatment demands the longterm preservation of visual fields. Shin et a1’32atreated 19 patients with ocular hypertension unilaterally with epinephrine for up to five years. Glaucomatous visual field defects were observed in 32% (6/19) ofthe untreated eyes and none of the treated eyes. In a report from the same institution, Becker and Morton’ treated 50 glaucoma-suspect patients unilaterally with epinephrine for up to
BETA-BLOCKERS
SINCE
TIMOLOL
319
five years. Two of 50 epinephrine eyes developed glaucomatous field loss in contrast to seven of 50 untreated eyes. In a more recent preliminary report after two years of study, Palmer et aliog reported timolol treatment in 27 ocular hypertensives more effective than no treatment in 32 patients.‘“’ In a two-year evaluation of levobunolol and timolol in 400 patients, no significant field progression was reported with either drug.” In two recent abstracts, Crick et al’“” and Sponsel et al’jga have reported longterm (up to four years) treatment with timolol more effective in preservation of visual field than pilocarpine. although both had similar effects on intraocular pressure. In another recent abstract, Alexander et al’ reported timolol to be more effective than epinephrine on intraocular pressure and/ or visual field parameters over a l-2 year treatment period. One must use caution in comparing various studies, as the study populations may not be similar with respect to visual field status at entry. The effect of acute ocular hypotensive therapy on visual field performance has been investigated by several researchers. Heilmannj” reported that acute oral acetazolamide decreased intraocular pressure in 24 glaucomatous patients similarly to topical clonidine. Goldmann field performance increased (i.e., thresholds for stimuli decreased) in the acetazolamide group, but remained unchanged in the clonidine group. Holmin and Kraka+ evaluated the acute effects of timolol and vehicle in a crossover study of 15 glaucomatous patients using the COMPETER. Following placebo instillation, visual field performance decreased by 7.8 P-units, compared with a decrease of 12.3 P-units with timolol. In a similar study, Drance and Flammer’“’ evaluated the acute effects of timolol and vehicle in 28 eyes of glaucoma suspects using a special OCTOPUS central 30”-threshold, automated-perimetric test. They found a decrease in retinal sensitivity with timolol (0.7 dB decrease) in contrast to a 0.1 dB decrease with vehicle. That beta-blockers may be vasoactive has lead some researchers to correlate this with vasopathology in glaucoma patients.“s.“ja Interestingly, topical timolol increases retinal blood flow in normal human eyes, probably via decreasing autoHowever, these preliminary studies regulation.“” suggest that the acute lowering of intraocular pressure with topical beta-blockers does not acutely enhance visual field performance. The clinical significance of a small acute decrease on longterm field preservation has not been determined.
SAFETY The attraction of timolol has been lack of ocular side effects. Hand-in-hand
the relative with this
enhanced previously
ocular safety is a systemic toxicity experienced by ophthalmologists.
not
Ocular Safety and Comfort Timolol is relatively devoid of the obvious ocular side effects of pilocarpine. Miosis or accommodative problems are not a major problem with timolol. Initially, the major ocular concerns about timolol were cornea1 anesthesia and reduced tear production.‘“6 While both problems have been documented in several case reports, their incidence appears to be relatively rare, as they have not been found a significant concern in longterm, double-masked,” or open-label studies.“” Strempel”3 reported both timolol and metiprano101 decreased tear break-up time (BUT) within the first 20 minutes after instillation. In a subsequent study, she reported that a similar decrease in BUT (up to 40%) was seen with timolol, metipranolol and pindolol. Levobunolol and saline decreased BUT approximately 11% .i$ZidMeasured five hours after timolol or metoprolol instillation, Nielsen and Eriksengg observed no significant changes in tear BUT, tear osmolarity, cornea1 sensitivity, or Schirmer I (unanesthetized) values. In Germany, carteolol has a warning against use in sicca syndrome. “+ Allergy to topical beta-blockers, as evidenced by a blepharoconjunctivitis, occurs in some patients after longterm use of timolol. Similar reactions have also been reported to occur after nadolol,” levobun0101,‘“~ and metoprolol.‘jg Cross-reactivity among beta-blockers is not complete,‘“” suggesting that sensitivity is related to chemical structure, not to conformation of beta-blockers per se. Thus, as more topical beta-blockers become available for general use, patients developing intolerance to one betablocker may be switched to an alternate one. The relative paucity of ocular problems with timolol has the lure of suggesting that all new betablockers are similar in their ocular safety. One need only recall the oculomucocutaneous syndrome from systemic practolol, wherein a pemphygoid reaction followed its use’3’.“o to realize that ocular safety of each new molecule needs to be assessed. This process entails longterm (one year or greater) treatment of large numbers of patients whose eyes are regularly examined. Discomfort upon instillation is an undesirable side effect of a beta-blocker and, thus, an important part of its ocular profile. Additionally, the more uncomfortable a medication, the less likely a patient is to use it. Timolol has a low rate of discomfort, as noted in Table 5. Levobunolol, in a longterm study, had a rate of discomfort similar to timolol’s.‘g Metipranolol has been reported to sting more than timo-
320
Surv Ophthalmol
3 l(5)
March-April
NOVACK
1987 TABLE
6
Comparative Heart-Rate Effects of Beta-Blockers
Study
Design*
N/Group
Groups
Treatment
Nakashimag’
ox
Rosn”
DMP
11
Levy72
DMP
6
Berry lo
DMP
20
q.d. X 1 Eye X 1D b.i.d. X O.U. X 6 mos b.i.d. X l-2 Eyes
Stewar+
DMP
14-15
b.i.d.
Kitazawa63
DMX
13
q.d.
Levobunolol Study Group7’
DMP
130
Kruse”
DMP
18
Mertza5
DMX
27
Nielson’*
SMX
11
DMP
7
DMP
10
Krieglstein’”
6
q.d. x O.U. x 1 D
X X
X
l-2 Eyes
1 Eye X 1 D
b.i.d. X O.U. 24 mos
X
b.i.d. X O.U. X 1 mo O.U. X b.i.d. X 0.75 mo q.d.xO.U. 1D
q.i.d. X 1 Eye X 1D
q.d.xl
Eyexl
D
Arotinolol 0.5% Timolol 0.5% Vehicle Atenolol 4% Betaxolol 0.5% Timolol 0.5% Betaxolol 0.5% Timolol 0.5% Betaxolol 0.5% Timolol 0.5% Vehicle Carte0101 0.5% Carte0101 1.O% Carte0101 2.0% Levobunolol 0.5% Levobunolol 1.O% Timolol 0.5% Metipranolol 0.25% Timolol 0.25% Metipranolol 0.25% Timolol 0.25% No treatment Metoprolol 220 pg rods Timolol 0.5% Metoprolol 0.1% Metoprolol 0.5% Metoprolol 1% Metoprolol 3% Nadolol 2% Labetalol 1%
Heart Rate at Baseline (beats/ min) 68 69 73.7 71.7 78.7 73.3 73.2 76.2 77.7 75.6 76.8 83.4 81.7 77.5 74 74 74 74 73 71.5 69.5 78
88 94 80 79 80 80
t = SD. Estimate - Not given in report. Design abbreviations - SM = single-masked, DM = double-masked, 0 = open, P = parallel, paired comparison, Power calculated as a = 0.05, two-tailed, and Aheart rate of 6 beats per minute.
1oP5J* or levobunolol.106 Metoprolol, at concentrations of 1% to 8%, has been reported to elicit burning. 22 Betaxolol was reported to elicit stinging in 30-40% ofpatients in studies where the incidence of timolol stinging was 6-9% .laJO in a comfort study designed along methods used for evaluating analgesics, Scoville et a1130reported carteolol more comfortable than timolol. As most beta-blockers have a similar formulation, it is most likely the betablocker molecule itself that elicits the discomfort. Systemic Safety The major safety concern with the use of topical beta-blockers is systemic beta-blockade. As previously noted in the pharmacology section, systemic beta-blockade of beta,-receptors might decrease heart rate, and blockade of beta,-receptors might increase respiratory resistance.
SD
Heart Rate at Follow-Up (beats/ min)
12 8t 10.3 8.9 11 4.8 6.6 12.6
8
11.1 3 8 - 6.0
8t
8+
X = cross-over,
-5 - 10 - 2.0 -6.6 0.6 - 1.6 - 1.9 -0.5 - 1.4 - 3.0 -3.2 -8.6 -6.4 -5.9 -4 -5 -4 -4 +2 -0.5 -2 0 -6.0 -11 -12 -1 -1 -2 -5
PC =
Table 6 shows the effect of various topical betablockers on resting heart rate. Note that the effect of timolol ranged from a two-beat per minute (bpm) increase to a 10 bpm decrease. The more difficult it is then to assess the degree of&-blockade elicited by a novel agent, as the @,-blockade of timolol is not always demonstrable. In addition, no longterm studies, save those with levobunolol,” have sufficient power to detect a difference from timolol as small as 5 bpm (see Table 6). In healthy normals, controlled exercise may elevate heart rate to approximately 140 bpm. Systemic beta-blockers may allow a maximum heart rate of only 90-100 bpm, a decrease of 40-50 bpm. 23~164 A single instillation of topical 0.5% timolol decreases maximal heart rate by 7-18 bpm. 5,jq In a separate study, a single instillation of 0.5% timolol decreased time to exhaustion from 40.3 to 9.7 minutes. 38 In studies of similar de-
BETA-BLOCKERS
SINCE TIMOLOL TABLE
321
6
(Continued)
Power
Comments
9%
29%
At 4 Hours
13% 33%
Changes
62%
Note 0% failures 6 months. At 2 Hrs.
16%
include patients
on concomitant
in both beta-blocker
therapy. groups
in
99%
20%
At 4 Wks.
95%
First phase of cross-over.
29%
At 1 Hour.
13%
sign, topical 1% betaxolol had either no effect5 or a 3 bpm decrease54 on maximal heart rate. Pindolol, lo/o,decreased maximal heart rate by 14 bpmTO and 1% levobunolol by 11 bpm.54 As pointed out previously,“’ the clinical relevance of mean heart rate differences of 5-10 bpm (4%-3X0) is open to debate. It is unclear if such differences in healthy normals can reliably predict the incidence of severe bradycardia in glaucoma patients. The precipitation of acute pulmonary crises by topical timolol is a serious adverse reaction of glaucoma therapy. ‘57Van Buskirk et a1158aadded betaxo101 therapy to the regimen of 11 patients with asthma and severe glaucoma. They found an additional pressure lowering effect of 4.6 mm Hg and no objective or subjective pulmonary effects. Schoene et alIz evaluated the potential for betaxolol, a P,-blocker, to produce bronchoconstriction in nine patients with pulmonary disease who had demonstrated bronchoconstriction to timolol. Patients were evaluated for four hours after instillation of the beta-
blocker. On the average, placebo and 1% betaxolol had no effect on forced expiratory volume (FEV,), while 0.5% timolol elicited a 25% decrease in FEV,. Two other studies demonstrating the relative safety of betaxolol in patients with reactive airway disease have been reported in abstracts.J7a,‘58C This data would suggest that in glaucoma patients betaxolol would have little potential for pulmonary problems. However, as pointed out by Spiritus and Casciari,13’ more than half of the patients had a 15% decrease in FEV, at one or more time points following betaxo101. In a similarly designed study, Dunn et al” evaluated topical betaxolol or vehicle in patients with documented pulmonary effects of timolol. As with the study by Schoene et al I28there was little decrease in the average FEV, following betaxolol. However, live of the eight patients had a decrease in FEV, of 15% or greater at one or more time points following betaxolol. Harris et alYJb reported live cases of patients who experienced symptoms of pulmonary distress with topical betaxolol. Recently, topical 1% d-timolol was reported to have one-tenth the pulmonary blocking potency of 1% I-timolol in normal volunteers.‘20 As with systemic &-blockade, it may be difficult to predict the relevance of systemic 0, blockade in a controlled study to the clinical experience. Scharrer and 0bern5 evaluated the safety of timo101 in 26 patients with relative cardiovascular and pulmonary contraindications to timolol. While 58% of the patients showed untoward reactions to timo101, 42% did not. This study demonstrates that not all patients who are expected to have a negative response to timolol actually do when challenged. Thus, when “timolol-responders” are given a new medication, and show no untoward effects,16’ it does not necessarily demonstrate absolute safety of the new medication. Newer agents with pharmacology similar to timo101, such as levobunolol or metipranolol, have similar propensities to elicit pulmonary problems in sensitive patients. The relative lack of reports of bronchospasm with such agents, in contrast to timo101, is most likely due to the novelty of their use or caution exercised by prescribing ophthalmologists, rather than to a lower risk than timolol. Many patients receiving glaucoma medications also have systemic hypertension, which may be treated with oral beta-blockers. Certainly, in this subgroup of patients treated with systemic betablockers, topical beta-blockers are not absolutely contraindicated. BLOOD LEVELS Blood levels following topical instillation of betablockers are shown in Table 7. On the average, the
Surv Ophthalmol
322
3 l(5) March-April
NOVACK
1987 TABLE 7
Blood Levels of Topical Beta-Blockers %
Study
N/ Group
Nakashimag’
6
1 Drop x O.U.
BloomL3+
-
-
(Abstract) Azuma6 Novack102
10 6
1 Drop x O.U. 1 Drop X 2 Eyes
Andreasson3 Kaila5’ Alvanlb Zimmerman’76
8 6 8
Groups
Treatment
1 1 2 1
Dropx O.U. Dropx 1 Eye Drops X O.U. Drop X O.U.
Passor ’ ’
10
1 Drop X O.U.
Leier””
10
1 Drop X O.U.
Arotinolol 0.5% Timolol 0.5% Betaxolol 0.5% Befunolol 1% Levobunolol 0.5% Levobunolol 1% Pindolol 0.25% Timolol 0.5% Timolol 0.5% Timolol 0.5% Timolol 0.5% + EC Timolol 0.5% + NLO Timolol 0.5% Timolol 0.5% + NLO Timolol 0.5%
All measurements at 1 hour after dosing. EC = eyelid closure. NLO = nasolacrimal duct occlusion. + = the data on betaxolol from Bloom et al., are based upon preliminary
plasma level of 0.5% timolol reported in the literature is approximately 1 ng/ml. The plasma level for 0.5% levobunolol is reported to be less than this (0.21 ng/ml), arotinolol 0.5%, similar or slightly and befunolol 1% significantly higher (2.9 ng/ml), higher (40 ng/ml). Pindolol 0.25% was reported to have no detectable plasma levels after topical instillation3 although detection limits were 10 ng/m13 In an abstract, Bloom et al3 reported finding no detectable betaxolol in blood after topical instillation of betaxolol 0.5%.3 At this time, detection limits for that assay are not published. Plasma levels of topical timolol can be higher in newborns (up to 20 ng/ml)“O and lower with punctal occlusion or eyelid closure (0.4 ng/ml) .“‘j Oral timolol results in levels of 5-50 ng/ml, in which the cardiac beta-blockade is log-linear.‘4 As topical timolol results in plasma levels less than 5 ng/ml on the average, it is somewhat puzzling that bradycardia is a frequently discussed side effect of topical timolol. It apears that average plasma levels are not necessarily meaningful indicators of systemic effect following ophthalmic instillation,16’j and physiological parameters must be used. CONSENSUAL EFFECT Topically-instilled beta-blockers lower intraocular pressure not only in the treated eye, but also in the fellow eye up to 30-40% of the ipsilateral response, as has been reported for timolol,‘38 levobun0101,‘~~carteolol,63 bupranolol,‘24 and metoprolol.‘22
Mean (ng/ml)
With No Detectable Levels
Individual Peak Sensitivity (ng/ml) (ng/ml)
2.9 3.5 0
100% -
40.0 0.21 0.42 0 0.54 0.88 1.28 0.46 0.41 1.39 0.90 0.78
100% 66% 33% 100% 0% 50% -
90.8 0.6 1.2 0 1.4 5.0 -
60%
2.5 1.4 2.0
-
1.0 2.0 0.3 10.0 0.2 1.0 -
0.2 0.5
abstract.
This is called “consensual” effect. This consensual effect following unilateral topical instillation of a beta-blocker may be due to several factors: 1) systemic absorption and delivery of the beta-blocker to the contralateral eye, where it can have a direct hypotensive effect, 2) systemic absorption and a systemic hypotensive effect which secondarily decreases intraocular pressure, or 3) a neural mechanism wherein decrease in pressure in one eye results in a reflex lowering of pressure in the contralateral eye. The effect of beta-blockers on the eye contralateral to treatment appears to occur at doses greater than that required for ipsilateral ocular hypotension and at doses similar to that eliciting decreased heart rate, at least for levobunolol.‘04 Thus, consensual effects are a possible measure of systemic absorption. In rabbits, the level of timolol in aqueous humor contralateral to treatment, 19.5 pg/ml, while less than ipsilateral, 318 pg/ml,‘j2 is more than that required for adenylate cyclase inhibition, 0.8 pg/m1.g4 This study supports the first and simplest of the three theories noted above - that sufficient timolol is delivered to the contralateral eye to have a direct effect.
Summary Are all beta-blockers tainly not, as potencies vary.
the same in efficacy? and duration of action
Cermay
BETA-BLOCKERS
SINCE TIMOLOL
323
Are all beta-blockers the same in safety? No, as some beta-blockers appear relatively safer than timolol, but they still elicit problems in some patients. The objective of this review is to encourage the ophthalmologist to carefully assess the published literature on new compounds. Efficacy can be “proven,” but only in studies of appropriate design and significant power. Since absolute safety does not exist, safety is relative, but differences between drugs can be demonstrated. The ophthalmologist needs to recognize that all beta-blockers, especially those still undergoing Phase III evaluation, are new antiglaucoma agents relative to the traditional agents pilocarpine and epinephrine, and must be used with caution. Acknowledgments The author gratefully acknowledges the extensive literature search performed by Dona Novack, the statistical consultation of John Lue and Josh Burke, the technical assistance of Bev McCarrell, Mary-Jane Branin, and Douglass Frapwell. III, the helpful suggestions from research colleagues and to P.C. for inspiration.
1. Alexander DW, Berson F, Hertzmark E, Epstein DL: Longterm eficacy of timolol vs. epinephrine in open-anglr glaucoma. Inoest Ophthal 27 ([Suppl 3]:43, 1986 la. Allen R. Hertzmark E. walker Ahl, Epstein DL: A doublcmasked comparison of hetaxolol vs. timolol in the treatment open-angle glaucoma. ilm J Ophthalmol 101:535-,541. 1986 1 b. Alvan G, Calissendorff BM, Seideman P, ct al: Absorption ocular timolol. Clin Pharmacokin 5:95-100, 1980
The first major review of beta-adrenergic blocking agents appeared in a special issue of this journal in 1979 [GLAUCOMA SYMPOSIUM, Volume 23 (6), May-June 19791. There, Drs. Thorn Zimmerman and William Boger (page 347) wrote, “Testing to date has shown timolol to be a promising medication for the treatment ofglaucoma. It appears to be more effective in lowering intraocular pressure than any of the other topical agents and seems to be better tolerated than these agents.” Timolol’s success resulted in the marketing of many other beta-antagonists worldwide, a trend amply documented in Dr. Novack’s current review. What has lagged behind is an understanding of how these agents act. In the paper immediately following Zimmerman and Boger’s, Dr. Arthur Neufeld (page 363) reviewed the experimental studies on the mrchanism of action of timolol, concluding that, “Although the usefulness of timolol for the treatment ofglaucoma has excited many ophthalmologists, the cellular mechanism of action of the drug is largely unknown.” This assessment, unfortunately, remains valid today. There are three competing brands of beta antagonists available in the United States; Dr. Novack is employed by the manufacturer of one of them. Thus, to minimize any unintentional or unjustified bias, the Editor-in Chief of this journal and I imposed stringent demands for peer review. Dr. Novack’s paper was reviewed by us, two universitybased ophthalmologists chosen by me, and two ophthalmologists suggested by the manufacturers of the products competing with that of Dr. Novack’s company. Dr. Novack accepted this burden of double or, more accurately, triple jeopardy without complaint. responding promptly and thoroughly to all suggestions. I want to express my thanks for his understanding, mv admiration for his equanimity, and my appreciation for this timely update on beta antagonists in the treatmrnt of glaucoma. REVIL\VS
of of
Ic. Allen
RC, Cagle GD, Bruce LA: Controlled clinical evaluation ofhetaxolol (0.5%) ophthalmic solution intraocular pressure and adjunctive therapy. Program anddbttracts. Glaucoma .Soc .lftg Turin (X.YI’Int Coq Oph). :Ma~a 19R6. p 20 Editorial: Therapeutic trials Rrsnonsibilit\ 2. .\nonymous: and Accountability. Pharmaceut Med !:81-83, 198;’ 3. AndrCasson S, ,Jensen K-M: Effect of pindolol on intraocular pressure in glaucoma: pilot study and a randomized comparison with timolol. 5r J Ophthalmol 67:228-230. 1983 4. ;\raie \I. Takase M: Effects of S-596 and carteolol. new betaadrenergic blockers. and flurbiprofen on the human eye: 3 fluorophotometric study. Gmcfi‘t .irrh C/zn b:lr/, Ophthalmnl ZZ:25!)-262, 1985 Pugh BR, Timewell RM: Cardiovascular effects of 5. Atkins,JM, topical beta-hlorkers during esrrrlsr. :IIN ,/ Oph~hnlmol 99: 173-l 7.5. 1985 6. Azuma I. Yamamoto I: Study of plasma concrntrations of hefunolol following topical application to the eyes. in: Proc 171 Cq L’urop Sot Ophthalmol. Yliopistopaino. Finland. 1985, pp 1174-1.57.5 6a. Beasley H, Cagle GD. McDonald TO: Longterm &cary and safety of hetaxolol 0.5% ophthalmic solution. Program and ilb-
&acts, 7. Brckrr
Editor’s Note
Jot,~. &IIND~.I.,h’I.D., PH.D. SEVI.IOS EI)I-IC)R, THERAPEUTIC:
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BETA-BLOCKERS
SINCE TIMOLOL
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with once-daily
Arch Clin Exp Ophthalmol
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Reprint requests should be addressed to Gary D. Novack, 2525 DuPont Drive. Irvine. CA 9271.5.
Ph.D..
THERAPEUTIC
VOLUME
31
l
NUMBER
5.
MARCH-APRIL
1987
REVIEW
JOEL S. MINDEL AND SAIICHI MISHIMA, EDITORS
Ophthalmic Beta-blockers Since Timolol
GARY
D. NOVACK,
PH.D.
lniversifv of Calt$mia, Irvine, California
and Department of Ophthalmologv, Clinical Research, illlergan Pharmaceuticals,
Abstract. In the twenty years since beta-blockers were proposed for treatment of glaucoma. use of topical timolol has increased to account for 70% of all glaucoma medications used. The objective of this article is to review the “newer” beta-blockers, and to address the generalization that “all ophthalmic beta-blockers are the same.” The review concentrates on agents that have been studied as topical treatments for patients with elevated intraocular pressure. Sections on pharmacology and design of clinical trials are included to aid the ophthalmologist in evaluating new drugs and published clinical reports. The major questions to consider in evaluating the therapeutic potential of a new beta-blocker for the treatment of glaucoma involve efficacy and safety: Is the drug as effective as timolol? Does it have a duration of action at least as long as timolol? Does it have ocular toxicity? Is it comfortable? What are its systemic effects? (Surv Opbtbalmol 31:307-327, 1987)
Key words. glaucoma
l
beta-adrenergic antagonists intraocular pressure
l
beta-blockers
Nearly 20 years ago, Phillips suggested that systemic or topical beta-adrenergic-receptor antagonists (beta-blockers) might have a therapeutic ocular hypotensive effect. ‘I3 The efficacy of topical propranolol was reported by Bucci et al*’ in Italy and Merte and Merkle in Germany.8’ Concerns over cornea1 anesthesia following topical propranolol limited its general acceptance.3g Over the next several years, a host of beta-blockers, borrowed mainly from oral cardiovascular use, including practolol, nadolol and atenolol, were evaluated for topical ophthalmic use in the treatment of elevated intraocular pressure. The beta-blocker, timolol, became available for topical use nearly world-wide in the late 1970s and early 198Os, and by 1985, in the U.S.,
l
clinical
trials
l
timolol accounted for approximately 70% of all prescriptions in patients receiving medical therapy for glaucoma.“’ The efficacy, safety, and utility of topical timolol have been reviewed in myriad publications, including a special issue of this journalR8”~” The objective of this article is to review the “newer” beta-blockers - those explored for topical ophthalmic use in the late 1970s and 198Os, addressing the generalization that “all ophthalmic betablockers are the same.” The analogous proposition for systemic beta-blockers was addressed by Lowenthal et al and was found to be an over-simplification.‘” As the literature on ophthalmic betablockers is vast, this review concentrates on certain areas. 307
308
Surv Ophthalmol 31(5) March-April 1987
1. Emphasis is given to agents evaluated topically in humans with elevated intraocularpressure. Only articles in which a given patient was treated with a single drug (or vehicle) are referenced. Studies on timolol are referenced frequently as it is the prototype drug. 2. A pharmacology section describes the concepts of beta-receptor subtypes, intrinsic sympathomimetic activity, and mechanism of action. 3. A clinical trial design section is included, which is applicable not only to articles reviewed herein, but to appropriate interpretation of future reports of novel agents. 4. Publications available in literature data bases as of September 1985 are utilized. Some articles published in 1986, during the editorial review process, are included. Publications from non-American journals were particularly sought out to maximize information on investigational beta-blockers.
NOVACK
Lcvobunolol
Q 0
AlWlOlOl
CH,COO
CH2CONH2
HIC CH3
CH&HflCH& Betoxolol
Meloprolol OH
Bwrano~o~
Nodolol 0CHZFHCH2NHCKH&
0
OH
HN:N (C&In
Pharmacology CHEMICAL
STRUCTURES
OF BETA-BLOCKERS
Fig. 1 shows the structural formulae for selected beta-blockers. Common features include a ring system, (partially or completely aromatized and planar) and an alkyl side chain. On this side chain is an asymmetrical carbon atom. The levo (or S) form of the molecule is generally 10 to lOO-fold more potent than the dextro (or R) form in receptor-binding, at least at the cardio-pulmonary receptor.40aJ’2 In the heart, it is clear that receptor-binding potency of stereoisomers is directly related to the therapeutic effect. In the eye, however, the P-receptor may be different in that d-isomers are closer in potency to l-isomers in their receptor afftnity.g2 In a pilot clinical study using a high concentration, dtimolol was reported similar in ocular-hypotensive efficacy to the l-isomer. 62 Interestingly, some 15 years ago, Vale and Philips153 reported d-proprano101, injected intravenously, decreased elevated intraocular pressure in humans; however, on a mg-permg basis, d-propranolol was less active than d,l-propranolol. This is consistent with rabbit studies of ocular hypotensive effect, in which topical dtimolol was equi-effective to 1-timolol, but only l/ 10 the potency. That is, the intraocular pressure decreases seen with d-timolol were as great as with ltimolol, but approximately 10 times the concentration was required.73 Table 1 provides a cross-reference of generic and brand names of beta-blocker formulations. The formulation of a beta-blocker for ophthalmic use is an important part of developing the drug for general use by glaucoma patients. An ophthalmic formulation includes water to dissolve the drug and may
?”
Ccllprolol
0CH~CHCH2NHCHKH~)2
0CH2$HCH#HCKHs),
Propranolol
OH OH
Cctamalol
F”, Oi+Wi, NH
0
532-468
ICI 118.55I
Fig. 1. Chemical structures of selected beta-blockers.
contain a preservative to prevent bacterial growth, buffers and/or other agents to control pH and stability, and a vehicle, such as polyvinyl alcohol to transport the formulation into the eye. These are required to achieve a drop which is acceptable for ocular instillation and sufficient stability. The preservative in commercially available beta-blockers is generally benzalkonium chloride (BAK, Zephiran) in a concentration ranging from 0.004% to 0.010%) depending upon the product. Benzalkonium chloride is a relatively rare sensitizing agent.47 Recently, a “unit-dose” nonpreserved preparation of timolol was released in Sweden. Also shown in Table 1 is the regulatory status of various ophthalmic beta-blockers in America, Canada, and selected European countries. Germany has eight ophthalmic beta-blockers, the largest number of options. The complex regulatory situation as well as marketing priorities of pharmaceutical firms make the ophthalmic situation unique in each coun-
BETA-BLOCKERS
SINCE TIMOLOL
309 TABLE
1
Generic and Trade Names and Regulatov Status af Beta-Blockers
Generic
Name
ACC 9447 Arotinolol Atenolol Betaxolol Befunolol Bupranolol Carte0101 Celiprolol Cetamolol ICI-l 18,551 Labetalol Levobunolol Levomoprolol Metoprolol Metipranolol Nadolol Practolol Propranolol Pindolol S32-468 Timolol
Trade
Selected Countries Where Ophthalmic Preparation Approved*
Names
S-596
Tenormin Betoptic, Kerlone Glauconex, Bentos Ophtorenin, Betadrenol, Panimit Arteoptic, Endak, Teoptic, Mikelan
GER, USA, FRA** GER, JPN GER GER, FRA, UK, JPN
Normodyne, Trandate Betagan, Vistagan, Bunorit,
GER, USA, CAN, FRA**
Gotensin
Lopressor, Beloc Betamann, Betanol, Disorat, Beta-Ophthiole, Corgard Eraldin, Dalzic Inderal, Dociton Glauco-Visken, Durapindol, Visken Timoptic,
Timoptol,
Chibro-Timoptol,
Glaucoline
GER, FRA, UK
GER, FRA**
Blocadren
GER, UK, CAN, USA, FRA, JPN
.4s of February, 1986: *GER = Federal Republic ofGermany, FRA = France, UK = United Kingdom, USA = United States ofAmerica, C.4N = Canada, JPN = Japan. **Scientific approval. In France, new products must be assigned a reimbursement price by the government. This process is currently ongoing where noted, and must be completed prior to actual availability as a marketed product.
try. In America, timolol, levobunolol and betaxolol are available. Based upon cardiopulmonary studies, betablockers are divided into beta, and beta, subtypes. When stimulated, cardiac beta, receptors, acting via a second messenger, cyclic adenosine monophosphate (CAMP), elicit tachycardia, positive inotropism and/or increased conduction time (dromotropism). Beta, receptors in the liver have a glucagon-like effect and enhance the breakdown of stored triglycerides. It appears that memory functions may be /3,, rather than &-adrenergic events.48a When stimulated, pulmonary beta, receptors cause bronchodilation. Beta, receptors in the uterus elicit a relaxation of contractions, and in the blood vessels, mainly in skeletal muscle, elicit a vasodilation. Interestingly, elderly healthy volunteers have been reported to be less sensitive to the cardiovascular effects of isoproterenol, a /3,I& agonist, than young volunteers. However, these elderly volunteers had a similar sensitivity to timolol, a p,I& antagonist.63” Pharmacologically, agents such as timolol are correctly called beta-adrenergic antagonists. However, within this review, the more commonly used “beta-blocker” is used. Betashort-hand phrase
blockers, by definition, antagonize the effects of beta-agonists at the beta receptor. In the eye, timo101has been reported effective in decreasing aqueous humor flow only during the subjects’ waking hours when, presumably, there is greater endogenous adrenergic stimulation of aqueous humor production.‘4g Some beta-blockers, such as propranolol and timolol, are equipotent at beta, and beta, adrenergicreceptors. That is, they are not “selective” with respect to beta, or beta, adrenergic receptors. Other beta-blockers, such as practolol and betaxolol, are more potent at beta, than beta, sites and are called “/3,-adrenergic receptor selective.” Yet other betablockers, such as ICI-l 18,55 1, are more potent at beta., than beta, receptors. The importance of such relative affinity at beta subtype receptors is the object of much cardiovascular research and bears on the systemic safety of topically administered betablockers. The relative beta, and beta, selectivity of various ophthalmic drugs is shown in Table 2. Experiments using in vitro stereospecific receptor binding and cyclic AMP stimulation techniques as well as in vivo agonist/antagonist models of intraocular pressure in rabbits suggest that the ocular beta-
Surv Ophthalmol
31(5) March-April
NOVACK
1987 TABLE
2
Pharmacological Properties of Beta-Blockers
Agent ACC 9447 Atenolol Arotinolol Betaxolol Befimolol Bupranolol Carte0101 Celiprolol Cetamolol ICI-l 18,551 Labetalol Levobunolol Levomoprolol Metoprolol Metipranolol Nadolol Practolol Propranolol Pindolol S32-468 Timolol
P-Receptor Sub-Types Antagonized PI,
Lipophilicity
ISA+
P2
0.16 ;:, PI
Human Data Oral Potency
Cornea1 Anesthesia
0.2-4.0 4.0
4.0
0.5 0.25-0.5 0.05-0.5 1.o-2.0
0.5 4.0
+ +
1.0 50
2
P2
2.73*
;:: ;z
+
?
Ophthalmic Concentration (%)
p2
Pl P2
5:: ;: PI, P2 PI
2.40
;:: ;: PI
0.93
1.88
3.21
i32
+ +
;:: ;; ;:>
+ -
1.91
-
0.25-0.5 2.0 3.0 0.1-0.5 2.0 1.0 0.5-1.0 0.5-1.0 1.0 0.25-0.5
0.5 10.0 2.5 0.3 1.0 13.0 7.0
2
++ % I?
Table designed after Shanks et al., (1984), with additional data from Physician’s Desk Reference (1985), Rote Liste (1985), Wright (1975), Morselli et al. (1983), N a k as h’ima et al. (1985), Van Joost et al. (1979), Van Buskirk and Samples (1985), Duzman et al. (1983), Sugrue et al. (1985), and Gos and Stankiewica (1979). Lipophilicity expressed as Log P from Huang et al. (1983) and * for betaxolol, calculated from Manoury (1983). Oral potency is based on total daily oral human dose utilized for antihypertensive efficacy, with proprano101 = 1 (200 mg/d). Cornea1 anesthesia data from Draeger (1984), Berson et al. (1985), and Gorgone et al. (1983). + Intrinsic Sympathomimetic Activity (defined in in vivo cardiovascular studies): ( - ) = absent; ( + ) = present.
adrenoreceptor behaves like a beta,-adrenergic receptor. 58,9995,151,165a,169a Theoretically, the use of topical beta-blockers of various degrees of beta,/beta,-adrenergic receptor selectivity is interesting. If the ocular beta-adrenergic substrate is a &adrenergic receptor, then what is the mechanism of action of a drug with a relative &adrenergic selectivity? Several explanations are possible. One is that beta-blockers do not lower intraocular pressure via a beta-adrenergic mechanism, as suggested by Chiou et ahz8 and may work via dopamine antagonism. A second is that the concentrations achieved in the anterior chamber of a relatively beta,-selective agent will block both beta,and beta,-adrenergic receptors.‘50 Since this theory was initially suggested by Trope et a1,15’ there have been additional data published that support this theory in ocular tissues. Within the first hour after topical instillation in humans, the concentration of timolol in the anterior chamber is 1-2 ~M.“3aJ52
The concentration of timolol required to block either beta,- or beta,-adrenergic receptors is l-10 nM 96,118,151,165a approximately 3 log units less. The con:entration of betaxolol required to block beta,adrenergic receptors is l-10 nM, and 600 nM to block beta,-adrenergic receptors.“8 Thus, if one assumes that a drug such as betaxolol achieves aqueous humor concentrations similar to timolol’s, it is possible that ocular beta,-adrenergic blockade might occur with topical instillation of betaxolol. Additional theoretical concerns are also present. The in vitro selectivity of an agent, the value usually referenced, is generally greater than the in vivo selectivity.27s"%127 Many factors affect in vivo response, such as pharmacokinetics and penetration. The in vivo ocular potency and systemic specificity may be greater or less than the in vitro systemic value.g6 While on the average, beta,-adrenergic receptor “selective” beta-blockers are usually without pulmonary effects,4’J62 there are reports of reduced pul-
BETA-BLOCKERS
311
SINCE TIMOLOL
monary function in sensitive patients following systemic”‘~“” or topical instillation.jzb.“* Interestingly, 25% of beta receptors in the human lung are beta,, although their function is not clear.26 Thus, beta,adrenergic receptor “selectivity” should not be assumed to he absolute.‘“’ The oral and topical potency of ophthalmic betablockers is shown in Table 2.
-3.5 s .E
$
sx .% &v, E $ 6 n_b
INTRINSIC
SYMPATHOMIMETIC
ACTIVITY
The beta-antagonist molecule, similar to betaagonists such as isoproterenol, has an affinity for the receptor. The difference between agonist and antagonist is. however, that once bound to the receptor, the agonist stimulates adenylate cyclase to produce c&, while the antagonist does not. However, some beta-blockers, such as pindolol, in addition to their afftnity for the receptor, have some agonist activity, called “intrinsic sympathomimetic activity” (ISA). That is, the beta-blocker has agonistic actions similar to epinephrine. If this ISA were predominantly beta,, then a vasodilatory effect might be observed with these drugs.” However, a recent pharmacologic study suggests that the ISA of pindolol is not selectively beta,, but also beta,.8b Mekki et al”’ found topical pindolol to antagonize exercise-induced tachycardia to a degree similar to that reported for timolol, a beta-blocker without ISA.’ Bleckmann and Dorow”” found no difference between topical pindolol. an agent with ISA, and metipranolol, an agent without ISA, in pulmonary patients. Thus, the clinical importance of ISA in a topical agent is not entirely clear. LIPOPHILICITY In order to penetrate through the cornea and achieve therapeutic concentrations at the ciliary body, a topically applied beta-blocker must be lipophilic. Lipophilicity is expressed as the logarithm of the ratio ofpartitioning of the molecule in oil to its partitioning in water, or log P. The lipophilicity of various beta-blockers are given in Table 2. However. as shown in Fig. 2, the permeability coefficient of beta-blockers plateaus at log P values greater than 2.5.5b Theoretically, if an agent is too lipophilic, it remains in the epithelium, and does not pass through the stroma and endothelium into the anterior chamber. A similar relationship has been reported for steroids.‘“” LOCAL ANESTHETIC
ACTIVITY
As a lipophilic molecule, a beta-blocker can permeate the cell membrane of an axon, and in doing so stabilize the membrane and interfere with the mechanism of active propagation of the action POtential. This effect is not related to beta-blockade,“”
1
.z
4.5-
-550
E
1
-6.5
\ -1
I
0
I 1
I
2
I
3
I
4
I
5
Log Oil/\il/ater Partition Coefficient Fig. 2. Theoretical lipophilicity curve. Relationship of lipid solubility and cornea1 penetration for a series of betablockers. (Adapted from Huang HS5”).
but is a physiochemical interaction related to the concentration of the beta-blocker, its membranestabilizing activity, its lipophilicity, and the exposed area of the cell membrane. The membrane-stabilizing effect of beta-blockers can be measured in an isolated frog axon.13’ In the eye, a topical beta-blocker may stabilize the unmyelinated pain fibers of the cornea to produce cornea1 anesthesia. Clinically, case reports of significant cornea1 anesthesia produced by timolol were first published by Van Buskirk,‘“” after testing by touching a cotton-tipped applicator to the cornea. Subsequent longterm controlled clinical trials using similar techniques” have failed to find such an effect with timolol or levobunolol, suggesting that if present, it is either very mild or rare in occurrence. Table 2 shows the relative cornea1 anesthetic potentials of selected beta-blockers. MECHANISM
OF ACTION
Timolol decreases aqueous humor production’0,1’“.‘70”with little or no significant effect on episoutflow facility or uveocleral venous pressure,” scleral flo~.“~.” Thus, the mechanism of the ocular hypotensive action of timolol appears to be solely a decrease in aqueous humor production. Betaxolol,“” levobunolol,“’ carteolol’ and metipranolol”” have also been reported to decrease aqueous humor production. Similar to timolol. levobunolol has been reported to have no effect on uveoscleral flow, outflow facility, or episcleral vehas no effect on total nous pressure. I” Carteolol are outflow facility. 5oWhether all new beta-blockers similar to timolol in solely affecting aqueous humor production must be determined through research using both fluorophotometry and outflow measuremerits.*** ‘72
312
Surv Ophthalmol
3 l(5) March-April
NOVACK
1987
Design of Clinical Trials In the practice of their specialty, clinical ophthalmologists desire to treat the patient. In the evaluation of a new ophthalmic drug, clinical pharmacologists desire to test the drug. While these two objectives seem congruous, the perspectives of these individuals are indeed different with regard to the design of a study. 68 Should one design a trial from the clinician’s perspective, one would want the option of maximum individuality of treatment and open-ended duration of treatment. An example of such a study is a report of bupranolol.35 A five-fold range of concentrations of bupranolol was used, as well as concomitant medications, such as pilocarpine. One might suppose the patients in this study received the maximum degree of individualized therapy. However, due to the noncomparative design, the efficacy of bupranolol is not clearly demonstrated, especially vis-a-vis timolol. Also, the non-masked nature of the trial allows for the confounding influence of any biases of the patient or ophthalmologist. Should one design a trial from the clinical pharmacologist’s perspective, one would want to standardize patient treatment, compare the new drug to a standard currently acceptable therapy, and minimize any investigator or patient biases. One such study was done on levobunolol. With regard to levobunolol, patients were divided into three groups, and randomly received double-masked levobunolol, 0.5% or 1.O%, or timolol 0.5%. If the assigned medication was insufficient to control intraocular pressure, the treatment was judged ineffective. In this study, a clear evaluation of the efficacy of levobunolol vis-a-vis timolol was accomplished. While patient safety was not compromised, the individuality of patient treatment was minimized. The exposure of patients to experimental protocols and drugs demands maximizing benefits both to the patient and to society as a whole. One editor has suggested that study design is a major part of the benefit-risk relationship in any drug study.2 Study design concerns are important to consider when reading and interpreting a clinical report or when designing a study.‘7s4s The size ofthe study population is another important consideration in the design of a study. One might deduce that relatively few patients would be needed to differentiate between a drug as effective as timolol and an inactive placebo in glaucomatous patients. On the other hand, a relatively large number of patients would be needed to detect the small difference in activity between timolol and a slightly less active drug. Statistically, this concept is called power, (beta or Type II error).37 Power is the
strength of a clinical trial to detect a difference between two treatment groups, given that such a difference exists. When evaluating changes in intraocular pressure, power is a function of the sample size, the difference between the mean changes in intraocular pressures in the treatment groups, the alpha level, and the standard deviation.* The greater the number of patients per treatment group (N), the greater the power. Similarly, the greater the putative difference between the two treatment groups (AIOP), i.e., 6 mm Hg, rather than 2 mm Hg, the greater the power. Inversely, the greater the standard deviation of the group (SD), and the smaller the cx (critical significance level, i.e., p = 0.01) the smaller the power. Note that power is critical only when claiming an equivalence - that is, finding no difference between groups. If a difference was seen, then the power to have found that difference is not germane. Biostatisticians and most regulatory agencies require a power of at least 0.80 - that is, a study powerful enough to have an 80% chance to detect differences between two treatments. What is often surprising to the clinical investigator is the large number of patients required to achieve this level of power. The power of a placebo-controlled study relative to the number of patients is shown in Fig. 3. Clinically, one might say that NEWDRUG might be useful only if there were a 6 mm Hg difference in intraocular pressure from placebo. In order to reach 80% power, eight patients per group, or a total of 16 patients are required for a parallel study. A similar power curve is shown in Fig. 4, for a study of NEWDRUG compared with timolol. One might say that there must be a 2 mm Hg difference in efficacy between the two drugs to state that there is a clinically significant difference between the drugs. As the expected difference is much less in this situation, one needs 30 subjects per group, or 60 patients to obtain a power of 80%. A study of low power is analogous to a pre-presidential election poll on only 20 people - the results are interesting, but not necessarily a powerful prediction of the outcome of the real election with 60 million voters. As will be seen in the clinical studies detailed in the efficacy section, the power of most timolol-con-
*Mathematically, power, or the probability significant difference is: 1-p = Probability
to find a statistically
(Z > z,,,((AO~(20)))
where P = p-error; Z denotes a random variable having the standard normal distribution; zuj2 = Z-value for chosen alpha level; A0 = the difference between the mean changes from baseline in intraocular pressure37,48c; n = sample size; and u = standard deviation.
BETA-BLOCKERS
bz
SINCE TIMOLOL
313
100
100
80
80
60
0
R
!
1
I
1
IJ
5
10
15
A = 6 mm
Hg,
trolled
studies
?
20
N/Group SD = 4,a = 0.05, 2 toii
Fig. 3. Projected power curve for ocular hypotensive cal trial: Placebo-controlled.
0
A = 2 mm clini-
of beta-blockers is much less than reason for this is that at any one study site, it is difficult to locate and recruit more than 30 suitable patients within a six-month period. Power may be increased by using several cooperative study sites. I7 Such studies involve cooperation of ophthalmologists and biostatisticians from different geographical areas, where concepts of disease treatment vary, as does the prevalence and nature of the disease. As the costs and labor of such projects are high, they are generally undertaken only with government or corporate sponsorship. The exposure of patients to various treatment(s) in a study can be of several designs. In a parallel study, patients are randomly assigned to receive one of the treatments for the duration of the study. In a cross-over study, each patient receives, sequentially, each treatment. Masking ofthe treatment(s) may be open, where both physician and patient know the treatment, single-masked, where only one party, generally the physician, knows the treatment, or doublemasked, where neither the physician nor the patient knows the treatment. In a titration study, patients begin treatment at a given regimen. If uncontrolled (i.e., intraocular pressure is too high), the concentration or frequency of instillation is increased. Cross-over studies, in which each patient receives both treatments sequentially, are an attractive design and may increase power. The assumptions of a cross-over study are: 1) each patient must complete both phases of the study; 2) there is no carry-over effect of the first treatment; and 3) the disease remains constant throughout both periods. Crossover designs are most easily applied to single-drop studies in patients with mild disease, where disease constancy and completion of both phases of the study are more likely. In longer-term studies, not all patients successfully respond to the beta-blocker. Statistically, the investigator may average intraocular pressure at each
80%. The primary
60
25
50
Hg. SD =
N / Group 3,a = 0.05, 2 taii
Fig. 4. Projected power curve for ocular hypotensive cal trial: Timolol-controlled.
75
clini-
visit for all patients or completely delete failed patients from the analysis. Clearly, the latter method would result in greater apparent mean intraocular pressure decreases, as only “responders” would be included. In a patient treated bilaterally, both eyes tend to respond similarly to a test medication or “covary.” Thus, it is inappropriate to analyze eyes separately as independent events. 44Alternate methods, such as averaging eyes’ should be used to correct for the covariance. The issue of compliance is frequently discussed in the use ofglaucoma drugs.‘58b From monitoring data of four-times-daily pilocarpine52,60*6’a~‘“o and twicedaily timolol,‘33 we know that compliance in a population of patients unaware that compliance is being tested is quite poor. In a study of patients inadequately controlled by timolol b.i.d., patients were randomized to receive timolol again or levobunolol in a masked study. lo3 The control rate at three months for 0.5%) 1.O% levobunolol and 0.5% timo101was 31%) 43% and 38%) respectively. This suggests improved compliance. Similarly, when patients taking a combination of medications switched their timolol for befunolol, an average intraocular pressure decrease of 2 mm Hg was seen.‘46 It is possible that the newer beta-blockers may be more effective than timolol in this population. However, a more likely explanation is the “Hawthorne effect”: when aware that they are being tested, people im76We also know that ophprove their performance. thalmologists’ estimation of compliance, at least with pilocarpine, is poor.6’ If compliance is critical, as in a one-drop study, then it is best to have the investigator instill the test medication. Compliance might be enhanced by patient instructions and encouragement. In theory, one would like to measure the efficacy of a drug without the issue of compliance. In reality, one measures the combination of the two in a study, which is
TABLE
3: Single-Instillation Studies of Egicacy of Beta-Blockers IOP at Baseline
Design*
Study VanBuskirk’%
DMX
Nakashima”
OX
Ros’*’
DMP
Tanei4’
nl Group 17 6 11
Treatment 1 Eye O.U. 1 Eye
9
Kitazawa63
DMX
Negishi”
DMP
Bonomit6
OP
13
7-10 18
1 Eye
l-2 Eyes 1 Eye
DMP
6
1 Eye
DMP
8
1 Eye
Dausch3*
DMP
10
1 Eye
Kruse6’ Krieglsteins“
0 DMP
9 7
O.U. 1 Eye
Duzman43
Partamian’
to
Ros’**
DMX
13
1 Eye
Nielsot?
SMX
11
O.U.
DMP
10
1 Eye
DMP
15
0.u
DauschM
0
GOP
Vale’54 Zimmerman
‘74
30
DMX
8
DMX
20
1 Eye
1 Eye
Groups Vehicle ACC 9447 1.5% Arotinolol 0.5% Timolol 0.5% Vehicle Atenolol 4% Befimolol 0.2% Befunolol 0.5% Befunolol 1% Vehicle Carte0101 0.5% Carteolol 1% Carte0101 2% Carte0101 1% Carte0101 2% Vehicle Labetalol 0.5% Labetalol 1% Vehicle Levobunolol 0.5% Levobunolol 1% Timolol 0.5% Vehicle Levobunolol 0.03% Levobunolol 0.3% Levobunolol 0.6% Levobunolol 1% Levobunolol 2% Vehicle Metipranolol 0.3% Metipranolol 0.25% Vehicle (Fellow Eye) Metoprolol 0.1% Metoprolol 0.5% Metoprolol 1% Metoprolol 3% Vehicle Metoprolol 1% Metoprolol 2% Metoprolol 4% No treatment Metoprolol 220 pg rods Timolol 0.5% Vehicle (Fellow Eye) Nadolol 2% Labetalol 1% Vehicle Pindolol 0.17% Pindolol 0.35% Pindolol 0.50% Pindolol 0.72% Pindolol 1% Vehicle Practolol 1% Practolol 10% Propranolol 1% Vehicle Timolol 0.1% Timolol 0.25% Timolol 0.5% Timolol 1.O%
(mm Hg) 15.0x 15.5 13.5” 14.0 25.6 28.3 25.1 25.1 24.5 22.4 24.0 23.4 23.5 24.0 22.0 33.0 29.5 33.5 29.3 27.6 27.4 26.7 25.6 24.9 25.1 26.0 25.6 25.4 20.5 27.0 29.0 32.0 29.0 27.0 23.8 28.5 26.5 26.0 26.8
30.0 31.0 32.0 24.6 23.8 24.2 23.7 24.4 24.5 18.7 18.3
SD
4.0t 5.0 2.0 2.0
2.5
3.0 3.0
2.2
3.0
4.07 3.0
3.0t
3.0t
4.0
4.0
- 1.5 -1.5 -4.lll - 5.oll - 1.0 -5.0 -3 -7 -7 -0.5 - 3.6 -3.9 -5.1 - 7.0 -5.0 -1.0 - 7.0 -6.0 - 1.0 -8.3 -6.3 -7.1 - 4.4 -5.4 -8.3 -9.2 -9.4 -11.2 - 1.0 -11.0 - 3.0 0.5 -2.0 -3.0 - 7.0 -9.0 1.0 -6.0 - 2.0 - 3.5 -0.0 -6.4 -6.1 - 1.0 -3.0 -2.0 -2.6 - 3.8 -4.6 - 4.6 -5.5 -4.9
2.0 4.0+
22.0 26.2 23.7 28.0 25.3
2 Hours
3.0 +
IOP Changes 6-8 Hours
(mm Hg) 24 Hours
Power5
- 2.0 - 1.5 -
+2 +2 -
99%
-0.8 -0.6 -2 -6 -6 -0.6 -2.2 - 1.7
-
99%
-
52%
-2.2 -5.0 - 1.0 - 1.0 -0.3 -5.8 - 2.9 -4.2 - 5.8 -6.3 - 7.4 - 7.9 -9.5 - 10.5 - 3.0 -11.0 -3.5 0.0 -9.0 -9.0 + 1.0 - 4.0 - 3.5 -5.5 -2.2 -4.0 -3.7 -2.0 - 10.0 -5.0 -
9%
99%
-3
14%
-1 -
99%
-0.8 - 3.4 - 3.8 -3.3 -3.1 - 2.9 -3.5 -3.2 -6.8 -5.8 - 1.0 -8.0
99%
96%
89% 32% 94%
-1 -
99%
-
99%
-0 -0 -0 - 1.2 -2.5 - 2.9 - 1.9 -2.5 -4.5
89%
98%
+0.1 -0.4 - 1.0 -8.5 - 7.8 -8.7 -9.5
4.1 4.4 4.0 -9.7 -9.5 -9.7 - 7.6
t= SD. estimate; not given in report. ll= At 3 Hours. x Normal, rather than hypertensive patients. *Design abbreviations SM = single-masked, DM = double-masked, 0 = open, P = parallel, X §Power calculated by review author using formulae stated by Dixon and Massey3’ as (Y = 0.05, two-tailed, Hg for vehicle-controlled and 2 mm Hg for active-controlled studies.
99% -
16%
-2.0 -6.6 - 6.6 -11.1 -8.0
99%
= cross-over. and AIOP
of6 mm
BETA-BLOCKERS
SINCE
TIMOLOL
315
similar to the “real world” where the most effective drug is of no use if the patient does not take it. Attempts to decrease the required frequency of instillations of antiglaucoma medication has resulted in devices such as the OCUSERT+8 and a oncedaily pilocarpine gel.” An alternative to drops, ophthalmic plastic rods, has been reported effective for metoprolol.“H Once-daily timolol and levobunolol have been reported effective for some patients,~‘.l”‘.l’ ( 17’1.1 Many studies do not state the interval between instillation and measurement of intraocular pressure. In clinical practice, ophthalmologists generally see a patient within one to eight hours after the instillation of their beta-blocker. Most consider this appropriate for clinical practice, as it estimates the efficacy of treatment during the day. In a clinical study, however, the efficacy of the drug may be overestimated if measured immediately after instillation, or underestimated if measured 12 hours after the last dose. Given that patients are likely to take their medicine on the day they are to visit their doctor.<” it may be more appropriate to take the worst possible intraocular pressure rather than the best. For beta-blockers with a duration of action longer than 12 hours, such as timolol’7’ and levobunolol.““it has been reported that during longterm T:!BLE
4: Open-Label
therapy, the intraocular pressure is similar at 1 hour and 12 hours following instillation.“” Similarly, this has been reported for oral nadolol after four week’s therapy. IhRHowever, such is not the case for shorteracting agents, such as metoprolol.“’
Results
Stud!
N/ Group
Sterk””
30
Single-drop
Medium- to Long-term Studies Selected open-label evaluations of various betablockers are listed in Table 4. As noted in the cliniStudies of Beta-Blocker
Mertr”
3
4
Brpwitt”
3
162
Berrospi” i? LWy
12 24
Demmler”
Baseline Groups
(mm
4%
Studies
In Table 3, the results are compiled ofsingle-drop clinical studies on the efficacy of various betablockers. On a one-drop basis, befunolol, carteolol, levobunolol, metipranolol, and pindolol are effective. The cardioselective agents atenolol and metopro101 are not of sufficient duration to allow b.i.d. therapy. ACC-9447, designed to be short-acting systemically, appears ineffective. AArotinolol appears similar to timolol in efficacy, although only data in normals have been reported. At this time, there is no published dose-response. time-response studv on betaxolol.
r\fedium to Lorqterm
Atenolol
H,~I
(mm
Hg)
Variablr
\.ariahle
0.2% 0.5% 0.25% 0.5%
24.5 24.0 22.9 2.5.1
20.0 20.0 18.3 19.3
12 70
Betaxolol Betaxolol
0.25% 0.5%**
32.6 25.0
21.3 19.0
6
10
Bupranolol
Variable
\‘ariahle
13
102
Levomoprolol
25.0
16.0
6
47
Metipranolol
27.3
18.6
Krieglsrein”’
4
10
Metoprolol
24.5
18.0
Andreasson” stryz’+’
1 12
8 33
Pindolol Pindolol
0.25% 1%
29.0 24.0
20.0 18.1
Dausch”
12
74
Timolol
0.
I%
25.4
19.3
Virno Von
IO0
Dentfer””
2.0% 0.3-0.6%
4%
.E/jicacy*
IOP at Follow-Up
Befunolol Befunolol Befunolol Befunolol
O.l-0.5%
Trials
EFFICACY
IOP at Duration (months)
of Clinical
Comments :1pproximatrly half of patients taking concomitant medications. 50% failure rate within tirst month, 82% at 2.5 years. Diurnal IOPs indicatr rfflcacv 2 8 Hours. Combined data from nrw and transferred patients. Approximately 20% failure ratr. Follow-up IOP includes effect of concomitant medications. 6 month efficacy. mainly with concomitant medications. No significant stinging or cornea1 anesthesia. Stinging in up to 45% of patients, not abating \\ith timr. Follow-up IOP at 2 Hours. Diurnal IOPs indicate duration > 4 and < 24 Hours. Diurnal IOPs 2 8 Hours. Approximately
indicate
efficacy
30% failure
rate.
*All reports are O.U., b.i.d. treatment, except for atenolol (Sterk, 1979) which is O.U., Cd. and levomoprolol (Virno, 1986) which was q.d. to t.i.d. dosage. form without quantitative data, reports eflicacy and safety of0.5% betaxolol in several hundred **Beasley et al, ha in abstract patients, of which Levy’s appear to be a subset.
TABLE
Study
Design*
NJ Group
5: Chronic-Treatment, Controlled Studies on Beta-Blocker @j%acy Duration (months)
Berry to
DMP
Caldwe11z4
DMP
5
1.5
Feghali&
DMP
9-10
1.5
Radius’ts”
DMP
10
1.5
Levy72
DMP
20
6
Stewarti4’
DMP
14-15
6
Allenta
DMP
12-15
6
F1~r-y~~
DMX
14
0.25
Levobunolol Study Group7’*
DMP
130
24
Bensingers
DMP
16
3
Long74
DMP T
24-26
3
Kruse’jg
DMP
18
1
Mertzss
DMX
27
0.75
Mills@
DMX
10
1
Krieglstei&&
DMP
21-25
Bucheliz2
DMP
Nielsengg
DMXX
Duzman42
20-26
6
8
1
19
1
DMP
8
3
DMPC
9
1
17
1
OP
Andriasson3
DMP
9
1
Dausch34
DMP
21
1
Merte@
DMP
40
6
MillsE7
DMP
15
12
Uusitalo152A
DMP
13-15
6
Groups
IOP at Baseline (mm Hg)
Betaxolol 0.5% Timolol 0.5% Betaxolol 0.25% Vehicle Betaxolol 0.25% Vehicle Betaxolol 0.125% Vehicle Betaxolol 0.5% Timolol 0.5% Betaxolol 0.5% Timolol 0.5%
29.8 29.8 27.2 29.0 31.8 29.9 31.2 28.7 30.6 28.6 29.0 27.6
Betaxolol 0.25% Timolol 0.25% Carte0101 2% Timolol 0.5% Levobunolol 0.5% Levobunolol 1% Timolol 0.5% Levobunolol 0.5% Levobunolol 1% Vehicle Levobunolol 0.25% Timolol 0.125% Metipranolol 0.25% Timolol 0.25% Metipranolol 0.25% Timolol 0.25% Metipranolol 0.3% Timolol 0.25% Metipranolol 0.6% Levobunolol 0.5% Metoprolol 1% Metoprolol 2% Metoprolol 4% Metoprolol 8% Metoprolol 3% Timolol 0.5% Nadolol 2% Diacetyl NadololO.5% Diacetyl Nadolol 2% Timolol 0.5% Nadolol 2% Timolol 0.25%
27.2 26.6 23.3 23.3 26.8 26.8 27.1 27.3 27.2 27.3 29.5 27.8 23.5 24.5 25.8 29.0 23.3 26.0 25.0 24.0 24.0 24.0 24.0 27.5 28.8 26.6 27.3 26.6 27.6 27.0 27.0
Nadolol Nadolol Nadolol Timolol Pindolol Timolol Pindolol Timolol Pindolol Timolol Timolol Timolol Timolol Timolol
28.6 28.1 27.0 26.7 25.0 27.0 24.5 25.0 23.5 23.5 26.9 24.8 25.8 23.2
20 mg p.o. 40 mg p.o. 80 mg p.o. 0.25% 0.25% 0.5% 1% 0.5% 1% 0.5% 0.25% 0.5% 0.25% 0.5%
SD
4t 0.8 1.8 3.5 2.2 2.3 4.0 2.0 3.7 1.2 2.4 2.8 3.7
3.5
4.9 4.0 5.0 2.2 3.6 2.2 4.07
2.2
4t
3.0 3.0
4t
4t 2.8 3.4 4.6 2.6
IOP Changes (mm Hg)
Power5
-7.8 -6.4 - 7.5 -2.5 -4.2 -0.5 -5.5 - 1.6 -11.1 - 10.6 -7.2 -8.2
37%**
-5.7 - 7.4 -6.0 - 6.4 - 7.2 - 7.3 -7.1 -9.0 -9.1 -0.5 -6.9 - 7.2 -4.5 -6.0 - 6.3 -6.5 -3.7 -2.9
56%
99% 99% 99% 50% 46%
46% 99%
99%
29% 32% 30% 49% 46%
- 5.0 -5.0 - 5.0 - 5.0 -5.9 -8.9 - 2.0 - 7.0 -6.0 - 7.0 - 11.0 - 12.0 -6.0 -8.0 -6.0 -9.0 -8.3 -6.4 -5.0 - 9.0 - 6.5 - 7.0 -5.5 -5.5 -7.1 -5.5 -5.5 -4.6
15%
78% 15%
27%
29%
17% 62% 73% 21% 28%
Failures A 65% 54% 0% 0% ? ? 0% 0% 40% 30% 0% 0% 40% 6% 0% 0% 17% 15% 19% 14% 8% 40% 38% 15% 44% 32% 0% 0% 0% 0% 4% 0% 15% 15%
53% 40% 100% 63% 13% 29% At 1 Day At 1 Day At 4 Wks - 0% At 4 Wks - 0% 24% 6% 19% 25% 0% 0% 0% 0% 3% 5% 20% 33% 0% 23%
All treatments were O.U. and b.i.d. except nadolol/timolol (Krieglstein, 1982) and nadolol p.o., which was q.d. (Williamson et al, 1985). *Design abbreviations - SM = single-masked, DM = double-masked, 0 = open, P = parallel, X = cross-over, PC = paired comparison, T = Titration study. **Power calculated by review author based upon difference of 2 mm Hg. Using a difference of 4 mm Hg, the authors found a power greater than 80%. t = S.D. Estimate; Not given in report.
TABLE
5
(Continued)
Comments IOP changes for successful patients only. Burning 30% for Betaxolol vs 9% for Timolol.
Burning
22% (2/9) for betaxolol
Only successful
patients
vs. 0% for vehicle.
were analyzed.
Note 0% failures in both P-blocker groups in 6 months. Burning 40% (6/15) for betaxolol and 30% (4/14) for timolol. Burning 70% (l-1-/20) for betaxolol and 0% for timolol.
Burning at < 10% of patients visits (see Cinotti 1985). IOP 12 hours after instillation. Burning
58% for metoprolol
et al.,
vs 26% for timolol
Additional 13% of levobunolol and 4% of timolol patients controlled with higher concentrations. Burning 44% for metipranolol and 32% for timolol. Stinging
67”/0 for metipranolol
and 11% for timolol.
Stinging
20% for metipranolol
and 0% for timolol.
Burning complaints for 2,4 & 8%. Diurnals for up to 8 hours.
show efficacy
IOP at 5 hours after instillation. Periorbital
dermatitis
in 28 2% diacetyl
nadolol patients.
IOP at 3 hrs. Patients in fellow eye.
received nadolol in 1 eye and timolol
13% (5/41) pindolol tions.
patients
terminated
for allergic reac-
§Power calculated b review author using formulae stated by Dixon and Massey” Yas cy = 0.05, two-tailed, and AIOP of 6 mm Hg for vehicle-controlled and 2 mm Hg for activecontrolled studies. A Treatment Failures: Failure to be controlled with initial concentration of beta-blocker as sole medication; i.e., if patient required additional medication for control, review author considered as failure.
cal design section, such trials are limited due to the lack of a control group for comparison. These studies do provide qualitative information about patient tolerance, side effects and intrapatient efficacy. Selected longer-term controlled comparative studies of various beta-blockers are presented in Table 5. The important comparison points are the duration of treatment, relative intraocular pressure changes, treatment failure rate, and the statistical power. In studies with a vehicle-control group, if equivalency is found, power is the strength of the statement that the new beta-blocker is equivalent to vehicle. Using this criterion, both betaxolol and levobunolol have been evaluated in studies of sufftcient size. Caldwell et al’” found betaxolol 0.2.5% to be 3.0 mm Hg better than vehicle. Feghali and Kauftnant6 found betaxololO.25% to be 3.7 mm Hg better than vehicle, although this difference was not statistically significant. Radiusiix” found betaxolol 0.125% to be 3.9 mm Hg better than vehicle at most visits. Bensinger et al” found levohunolol 0.5% to be 8.5 mm Hg better than vehicle. Allen et al’” evaluated betaxolol and timolol in a double-masked, parallel study. They found both agents eff‘ective; however, the decrease in intraocular pressure with betaxolol, approximately 5.7 mm Hg, was statistically significantly less than with timolol, 7.4 mm Hg. The failure rate on a betablocker alone was 40% (8/20) with betaxolol and 6% (l/18) with timolol. Allen et al“ reported on a larger comparison of betaxolol and timolol. of which his above study is a subset, most likely- along with the studies of Berry,“’ Levy’? and Stewart.“” In the differlarger study, Allen at al” report no statistical ence in IOP between betaxolol O.S%, and timolol 0.5% over 6 months, although neither the IOPs nor the statistical methods are mentioned in the abstract. Theoretically, decreasing the number of’ daily doses might increase adherence to a regimen.“” Handel et al’“” evaluated the efficacy of once-daily levobunololO.5% and 1.O%, and timololO.5%. The control rate for the three treatment groups was 72%, 79%) and 64%, respectively. From a baseline intraocular pressure of 28.2 mm Hg, 26.9 mm Hg and 26.4 mm Hg, the overall decrease for the three months of the study was 7 mm Hg (29% ), 6.5 mm Hg (25%) and 4.5 mm Hg (20%), respectively. The 0.5% levobunolol group was statistically, different from the timolol group with respect to overall intraocular pressure, using analysis of variance techniques. 141though the groups were not statistically significant at baseline, an analysis of variance was performed on percent change from baseline, which statistically adjusts for baseline differences. Similar to overall intraocular pressure change, overall percent change was also greater for the 0.5% levobunolo1 group. The reason for this may be pharmacokinetic. Levobunolol has a longer half-life than timolol after oral administration.“,‘“.‘t”’ .Additionally. the major ocular and systemic metabolite of Icvobuno-
318
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NOVACK
1987
101, dihydro-levobunolol, has a half-life of seven hom-s.36J48 Dihydrolevobunolol has been reported to be similar in beta-blocker potency and efficacy in several systems. Given intravenously to dogs, dihydrolevobunolol is equipotent and equieffective to levobunolol in blockade of isoproterenol-induced tais similar chycardia. ‘ObIn vitro, dihydrolevobunolol to levobunolol in competition for beta-blocker sites in rat lung.1’s Ocularly, dihydrolevobunolol is a potent and effective antagonist of isoproterenol-induced ocular hypotension in rabbits.16’” In human iris ciliary body tissue, the affinity of the beta-adrenoceptor for dihydrolevobunolol and levobunolol is 6.7 nM and 3.9 nM, respectively, similar to that for timolol.‘65” To date, only one study has been published on once-daily levobunolol. The concept of utilizing once-a-day levobunolol may be quite adequate in many patients, and should be further evaluated in controlled studies and individual patients. Timolol appears to have no active ocular metabolites.“7s’65 Betaxolol, at least systemically administered, appears to be metabolized to inactive compounds.8a,8ga Metipranolol, a PI/p2 adrenoceptor antagonist, has been used extensively in Europe, and proceedings of a symposium on its ophthalmic use have appears similar to been published. 82 Metipranolol timolol or levobunolol in efficacy studies of up to three months treatment.68a,6gJ5~** However, comfort appears to be a concern.85’06 In studies with a timolol-control group, if equivalency is found, power is the strength of the statement that the new beta-blocker is equivalent to timolol. A power of 80% or greater is generally accepted as the minimum criterion required for a powerful equivalency statement. Using this criterion, levobunolol, and perhaps metoprolol and pindolol, have been evaluated in sufficiently large studies to state they have an efficacy equivalent to timolol. Levobunolol (0.5% and l.O%), as well as timolol (0.5%), lowered intraocular pressure by 7-8 mm Hg, with a failure rate of 5-10% per year in a two-year study with 99% power. ” Metoprolol (3%) lowered intraocular pressure by 6 mm Hg, and timolol (0.5%) 9 mm Hg in a one-month study with 78% power.gg Pindolol (1%) and timolol (0.5%) lowered pressure by 5.5 mm Hg in a six-month study with 73% power.84 There are controlled clinical trials on other beta-blockers. Betaxolol (0.5%) lowered pressures by 7.8 mm Hg and timolol (0.5%) by 6.4 mm Hg in a six-month controlled study of 37% power.‘O In a similar study of 46% power, betaxolol lowered intraocular pressure by 7.2mm Hg and timolol by 8.2 mm Hg. 14’ However, the interpretation of equivalence to timolol must be tempered by their limited statistical power.
In the studies presented here, it is often difficult to establish a clear difference in efficacy among various concentrations of beta-blockers in chronic use. No difference between 0.25% and 0.5% timolol was found over the course of six to twelve months.87s 15” Similarly, little difference in efficacy was observed between various concentrations of metoprolo12* or nadolo15’ in one- or three-month studies, respectively. The efficacy of oral nadolol (20-80 mg, q.d.) was reported to be similar to topical 0.25% timolol b.i.d.“j* Oral propranolol (40-60 mg, p.o.) was found similar in efficacy to topical timolol (0.5%, b.i.d.) when used in combination with pilocarpine (2%, t.i.d.).‘O’ TOLERANCE A rapidly developing tolerance, over the course of a few days in up to one-third of patients, has been reported with timolol. lo8 Of greater concern is that the ocular hypotensive efficacy of timolol may decrease by up to 25% with longterm treatment.‘5.‘40 Calissendorff and Marenz5 observed a greater degree of tolerance in patients with glaucoma than in patients with ocular hypertension over the course of year-long timolol treatment. In a large, well-controlled two-year study, less than 10% ofpatients per year were uncontrolled with timolol or levobunolol as sole antiglaucoma medication.” The apparent discrepancy between these studies, and clinical anecdotal experience of tolerance, might be due to difference in disease severity. In a progressive disease, it is difficult to separate the worsening of disease from a dimunition in efficacy of the medications. EFFECT
ON VISUAL
FIELDS
Glaucoma is a disease characterized by progressive loss of visual field over many years. Efficacy of a new beta-blocker is generally assessed by its ocular hypotensive effects, since decreasing intraocular pressure is assumed to prevent visual field loss. Intraocular pressure has the advantage of being a single dimensional, “objective” measurement. It also is labile; that is, it may be changed by a new treatment within hours. True efficacy of any glaucoma treatment demands the longterm preservation of visual fields. Shin et a1’32atreated 19 patients with ocular hypertension unilaterally with epinephrine for up to five years. Glaucomatous visual field defects were observed in 32% (6/19) ofthe untreated eyes and none of the treated eyes. In a report from the same institution, Becker and Morton’ treated 50 glaucoma-suspect patients unilaterally with epinephrine for up to
BETA-BLOCKERS
SINCE
TIMOLOL
319
five years. Two of 50 epinephrine eyes developed glaucomatous field loss in contrast to seven of 50 untreated eyes. In a more recent preliminary report after two years of study, Palmer et aliog reported timolol treatment in 27 ocular hypertensives more effective than no treatment in 32 patients.‘“’ In a two-year evaluation of levobunolol and timolol in 400 patients, no significant field progression was reported with either drug.” In two recent abstracts, Crick et al’“” and Sponsel et al’jga have reported longterm (up to four years) treatment with timolol more effective in preservation of visual field than pilocarpine. although both had similar effects on intraocular pressure. In another recent abstract, Alexander et al’ reported timolol to be more effective than epinephrine on intraocular pressure and/ or visual field parameters over a l-2 year treatment period. One must use caution in comparing various studies, as the study populations may not be similar with respect to visual field status at entry. The effect of acute ocular hypotensive therapy on visual field performance has been investigated by several researchers. Heilmannj” reported that acute oral acetazolamide decreased intraocular pressure in 24 glaucomatous patients similarly to topical clonidine. Goldmann field performance increased (i.e., thresholds for stimuli decreased) in the acetazolamide group, but remained unchanged in the clonidine group. Holmin and Kraka+ evaluated the acute effects of timolol and vehicle in a crossover study of 15 glaucomatous patients using the COMPETER. Following placebo instillation, visual field performance decreased by 7.8 P-units, compared with a decrease of 12.3 P-units with timolol. In a similar study, Drance and Flammer’“’ evaluated the acute effects of timolol and vehicle in 28 eyes of glaucoma suspects using a special OCTOPUS central 30”-threshold, automated-perimetric test. They found a decrease in retinal sensitivity with timolol (0.7 dB decrease) in contrast to a 0.1 dB decrease with vehicle. That beta-blockers may be vasoactive has lead some researchers to correlate this with vasopathology in glaucoma patients.“s.“ja Interestingly, topical timolol increases retinal blood flow in normal human eyes, probably via decreasing autoHowever, these preliminary studies regulation.“” suggest that the acute lowering of intraocular pressure with topical beta-blockers does not acutely enhance visual field performance. The clinical significance of a small acute decrease on longterm field preservation has not been determined.
SAFETY The attraction of timolol has been lack of ocular side effects. Hand-in-hand
the relative with this
enhanced previously
ocular safety is a systemic toxicity experienced by ophthalmologists.
not
Ocular Safety and Comfort Timolol is relatively devoid of the obvious ocular side effects of pilocarpine. Miosis or accommodative problems are not a major problem with timolol. Initially, the major ocular concerns about timolol were cornea1 anesthesia and reduced tear production.‘“6 While both problems have been documented in several case reports, their incidence appears to be relatively rare, as they have not been found a significant concern in longterm, double-masked,” or open-label studies.“” Strempel”3 reported both timolol and metiprano101 decreased tear break-up time (BUT) within the first 20 minutes after instillation. In a subsequent study, she reported that a similar decrease in BUT (up to 40%) was seen with timolol, metipranolol and pindolol. Levobunolol and saline decreased BUT approximately 11% .i$ZidMeasured five hours after timolol or metoprolol instillation, Nielsen and Eriksengg observed no significant changes in tear BUT, tear osmolarity, cornea1 sensitivity, or Schirmer I (unanesthetized) values. In Germany, carteolol has a warning against use in sicca syndrome. “+ Allergy to topical beta-blockers, as evidenced by a blepharoconjunctivitis, occurs in some patients after longterm use of timolol. Similar reactions have also been reported to occur after nadolol,” levobun0101,‘“~ and metoprolol.‘jg Cross-reactivity among beta-blockers is not complete,‘“” suggesting that sensitivity is related to chemical structure, not to conformation of beta-blockers per se. Thus, as more topical beta-blockers become available for general use, patients developing intolerance to one betablocker may be switched to an alternate one. The relative paucity of ocular problems with timolol has the lure of suggesting that all new betablockers are similar in their ocular safety. One need only recall the oculomucocutaneous syndrome from systemic practolol, wherein a pemphygoid reaction followed its use’3’.“o to realize that ocular safety of each new molecule needs to be assessed. This process entails longterm (one year or greater) treatment of large numbers of patients whose eyes are regularly examined. Discomfort upon instillation is an undesirable side effect of a beta-blocker and, thus, an important part of its ocular profile. Additionally, the more uncomfortable a medication, the less likely a patient is to use it. Timolol has a low rate of discomfort, as noted in Table 5. Levobunolol, in a longterm study, had a rate of discomfort similar to timolol’s.‘g Metipranolol has been reported to sting more than timo-
320
Surv Ophthalmol
3 l(5)
March-April
NOVACK
1987 TABLE
6
Comparative Heart-Rate Effects of Beta-Blockers
Study
Design*
N/Group
Groups
Treatment
Nakashimag’
ox
Rosn”
DMP
11
Levy72
DMP
6
Berry lo
DMP
20
q.d. X 1 Eye X 1D b.i.d. X O.U. X 6 mos b.i.d. X l-2 Eyes
Stewar+
DMP
14-15
b.i.d.
Kitazawa63
DMX
13
q.d.
Levobunolol Study Group7’
DMP
130
Kruse”
DMP
18
Mertza5
DMX
27
Nielson’*
SMX
11
DMP
7
DMP
10
Krieglstein’”
6
q.d. x O.U. x 1 D
X X
X
l-2 Eyes
1 Eye X 1 D
b.i.d. X O.U. 24 mos
X
b.i.d. X O.U. X 1 mo O.U. X b.i.d. X 0.75 mo q.d.xO.U. 1D
q.i.d. X 1 Eye X 1D
q.d.xl
Eyexl
D
Arotinolol 0.5% Timolol 0.5% Vehicle Atenolol 4% Betaxolol 0.5% Timolol 0.5% Betaxolol 0.5% Timolol 0.5% Betaxolol 0.5% Timolol 0.5% Vehicle Carte0101 0.5% Carte0101 1.O% Carte0101 2.0% Levobunolol 0.5% Levobunolol 1.O% Timolol 0.5% Metipranolol 0.25% Timolol 0.25% Metipranolol 0.25% Timolol 0.25% No treatment Metoprolol 220 pg rods Timolol 0.5% Metoprolol 0.1% Metoprolol 0.5% Metoprolol 1% Metoprolol 3% Nadolol 2% Labetalol 1%
Heart Rate at Baseline (beats/ min) 68 69 73.7 71.7 78.7 73.3 73.2 76.2 77.7 75.6 76.8 83.4 81.7 77.5 74 74 74 74 73 71.5 69.5 78
88 94 80 79 80 80
t = SD. Estimate - Not given in report. Design abbreviations - SM = single-masked, DM = double-masked, 0 = open, P = parallel, paired comparison, Power calculated as a = 0.05, two-tailed, and Aheart rate of 6 beats per minute.
1oP5J* or levobunolol.106 Metoprolol, at concentrations of 1% to 8%, has been reported to elicit burning. 22 Betaxolol was reported to elicit stinging in 30-40% ofpatients in studies where the incidence of timolol stinging was 6-9% .laJO in a comfort study designed along methods used for evaluating analgesics, Scoville et a1130reported carteolol more comfortable than timolol. As most beta-blockers have a similar formulation, it is most likely the betablocker molecule itself that elicits the discomfort. Systemic Safety The major safety concern with the use of topical beta-blockers is systemic beta-blockade. As previously noted in the pharmacology section, systemic beta-blockade of beta,-receptors might decrease heart rate, and blockade of beta,-receptors might increase respiratory resistance.
SD
Heart Rate at Follow-Up (beats/ min)
12 8t 10.3 8.9 11 4.8 6.6 12.6
8
11.1 3 8 - 6.0
8t
8+
X = cross-over,
-5 - 10 - 2.0 -6.6 0.6 - 1.6 - 1.9 -0.5 - 1.4 - 3.0 -3.2 -8.6 -6.4 -5.9 -4 -5 -4 -4 +2 -0.5 -2 0 -6.0 -11 -12 -1 -1 -2 -5
PC =
Table 6 shows the effect of various topical betablockers on resting heart rate. Note that the effect of timolol ranged from a two-beat per minute (bpm) increase to a 10 bpm decrease. The more difficult it is then to assess the degree of&-blockade elicited by a novel agent, as the @,-blockade of timolol is not always demonstrable. In addition, no longterm studies, save those with levobunolol,” have sufficient power to detect a difference from timolol as small as 5 bpm (see Table 6). In healthy normals, controlled exercise may elevate heart rate to approximately 140 bpm. Systemic beta-blockers may allow a maximum heart rate of only 90-100 bpm, a decrease of 40-50 bpm. 23~164 A single instillation of topical 0.5% timolol decreases maximal heart rate by 7-18 bpm. 5,jq In a separate study, a single instillation of 0.5% timolol decreased time to exhaustion from 40.3 to 9.7 minutes. 38 In studies of similar de-
BETA-BLOCKERS
SINCE TIMOLOL TABLE
321
6
(Continued)
Power
Comments
9%
29%
At 4 Hours
13% 33%
Changes
62%
Note 0% failures 6 months. At 2 Hrs.
16%
include patients
on concomitant
in both beta-blocker
therapy. groups
in
99%
20%
At 4 Wks.
95%
First phase of cross-over.
29%
At 1 Hour.
13%
sign, topical 1% betaxolol had either no effect5 or a 3 bpm decrease54 on maximal heart rate. Pindolol, lo/o,decreased maximal heart rate by 14 bpmTO and 1% levobunolol by 11 bpm.54 As pointed out previously,“’ the clinical relevance of mean heart rate differences of 5-10 bpm (4%-3X0) is open to debate. It is unclear if such differences in healthy normals can reliably predict the incidence of severe bradycardia in glaucoma patients. The precipitation of acute pulmonary crises by topical timolol is a serious adverse reaction of glaucoma therapy. ‘57Van Buskirk et a1158aadded betaxo101 therapy to the regimen of 11 patients with asthma and severe glaucoma. They found an additional pressure lowering effect of 4.6 mm Hg and no objective or subjective pulmonary effects. Schoene et alIz evaluated the potential for betaxolol, a P,-blocker, to produce bronchoconstriction in nine patients with pulmonary disease who had demonstrated bronchoconstriction to timolol. Patients were evaluated for four hours after instillation of the beta-
blocker. On the average, placebo and 1% betaxolol had no effect on forced expiratory volume (FEV,), while 0.5% timolol elicited a 25% decrease in FEV,. Two other studies demonstrating the relative safety of betaxolol in patients with reactive airway disease have been reported in abstracts.J7a,‘58C This data would suggest that in glaucoma patients betaxolol would have little potential for pulmonary problems. However, as pointed out by Spiritus and Casciari,13’ more than half of the patients had a 15% decrease in FEV, at one or more time points following betaxo101. In a similarly designed study, Dunn et al” evaluated topical betaxolol or vehicle in patients with documented pulmonary effects of timolol. As with the study by Schoene et al I28there was little decrease in the average FEV, following betaxolol. However, live of the eight patients had a decrease in FEV, of 15% or greater at one or more time points following betaxolol. Harris et alYJb reported live cases of patients who experienced symptoms of pulmonary distress with topical betaxolol. Recently, topical 1% d-timolol was reported to have one-tenth the pulmonary blocking potency of 1% I-timolol in normal volunteers.‘20 As with systemic &-blockade, it may be difficult to predict the relevance of systemic 0, blockade in a controlled study to the clinical experience. Scharrer and 0bern5 evaluated the safety of timo101 in 26 patients with relative cardiovascular and pulmonary contraindications to timolol. While 58% of the patients showed untoward reactions to timo101, 42% did not. This study demonstrates that not all patients who are expected to have a negative response to timolol actually do when challenged. Thus, when “timolol-responders” are given a new medication, and show no untoward effects,16’ it does not necessarily demonstrate absolute safety of the new medication. Newer agents with pharmacology similar to timo101, such as levobunolol or metipranolol, have similar propensities to elicit pulmonary problems in sensitive patients. The relative lack of reports of bronchospasm with such agents, in contrast to timo101, is most likely due to the novelty of their use or caution exercised by prescribing ophthalmologists, rather than to a lower risk than timolol. Many patients receiving glaucoma medications also have systemic hypertension, which may be treated with oral beta-blockers. Certainly, in this subgroup of patients treated with systemic betablockers, topical beta-blockers are not absolutely contraindicated. BLOOD LEVELS Blood levels following topical instillation of betablockers are shown in Table 7. On the average, the
Surv Ophthalmol
322
3 l(5) March-April
NOVACK
1987 TABLE 7
Blood Levels of Topical Beta-Blockers %
Study
N/ Group
Nakashimag’
6
1 Drop x O.U.
BloomL3+
-
-
(Abstract) Azuma6 Novack102
10 6
1 Drop x O.U. 1 Drop X 2 Eyes
Andreasson3 Kaila5’ Alvanlb Zimmerman’76
8 6 8
Groups
Treatment
1 1 2 1
Dropx O.U. Dropx 1 Eye Drops X O.U. Drop X O.U.
Passor ’ ’
10
1 Drop X O.U.
Leier””
10
1 Drop X O.U.
Arotinolol 0.5% Timolol 0.5% Betaxolol 0.5% Befunolol 1% Levobunolol 0.5% Levobunolol 1% Pindolol 0.25% Timolol 0.5% Timolol 0.5% Timolol 0.5% Timolol 0.5% + EC Timolol 0.5% + NLO Timolol 0.5% Timolol 0.5% + NLO Timolol 0.5%
All measurements at 1 hour after dosing. EC = eyelid closure. NLO = nasolacrimal duct occlusion. + = the data on betaxolol from Bloom et al., are based upon preliminary
plasma level of 0.5% timolol reported in the literature is approximately 1 ng/ml. The plasma level for 0.5% levobunolol is reported to be less than this (0.21 ng/ml), arotinolol 0.5%, similar or slightly and befunolol 1% significantly higher (2.9 ng/ml), higher (40 ng/ml). Pindolol 0.25% was reported to have no detectable plasma levels after topical instillation3 although detection limits were 10 ng/m13 In an abstract, Bloom et al3 reported finding no detectable betaxolol in blood after topical instillation of betaxolol 0.5%.3 At this time, detection limits for that assay are not published. Plasma levels of topical timolol can be higher in newborns (up to 20 ng/ml)“O and lower with punctal occlusion or eyelid closure (0.4 ng/ml) .“‘j Oral timolol results in levels of 5-50 ng/ml, in which the cardiac beta-blockade is log-linear.‘4 As topical timolol results in plasma levels less than 5 ng/ml on the average, it is somewhat puzzling that bradycardia is a frequently discussed side effect of topical timolol. It apears that average plasma levels are not necessarily meaningful indicators of systemic effect following ophthalmic instillation,16’j and physiological parameters must be used. CONSENSUAL EFFECT Topically-instilled beta-blockers lower intraocular pressure not only in the treated eye, but also in the fellow eye up to 30-40% of the ipsilateral response, as has been reported for timolol,‘38 levobun0101,‘~~carteolol,63 bupranolol,‘24 and metoprolol.‘22
Mean (ng/ml)
With No Detectable Levels
Individual Peak Sensitivity (ng/ml) (ng/ml)
2.9 3.5 0
100% -
40.0 0.21 0.42 0 0.54 0.88 1.28 0.46 0.41 1.39 0.90 0.78
100% 66% 33% 100% 0% 50% -
90.8 0.6 1.2 0 1.4 5.0 -
60%
2.5 1.4 2.0
-
1.0 2.0 0.3 10.0 0.2 1.0 -
0.2 0.5
abstract.
This is called “consensual” effect. This consensual effect following unilateral topical instillation of a beta-blocker may be due to several factors: 1) systemic absorption and delivery of the beta-blocker to the contralateral eye, where it can have a direct hypotensive effect, 2) systemic absorption and a systemic hypotensive effect which secondarily decreases intraocular pressure, or 3) a neural mechanism wherein decrease in pressure in one eye results in a reflex lowering of pressure in the contralateral eye. The effect of beta-blockers on the eye contralateral to treatment appears to occur at doses greater than that required for ipsilateral ocular hypotension and at doses similar to that eliciting decreased heart rate, at least for levobunolol.‘04 Thus, consensual effects are a possible measure of systemic absorption. In rabbits, the level of timolol in aqueous humor contralateral to treatment, 19.5 pg/ml, while less than ipsilateral, 318 pg/ml,‘j2 is more than that required for adenylate cyclase inhibition, 0.8 pg/m1.g4 This study supports the first and simplest of the three theories noted above - that sufficient timolol is delivered to the contralateral eye to have a direct effect.
Summary Are all beta-blockers tainly not, as potencies vary.
the same in efficacy? and duration of action
Cermay
BETA-BLOCKERS
SINCE TIMOLOL
323
Are all beta-blockers the same in safety? No, as some beta-blockers appear relatively safer than timolol, but they still elicit problems in some patients. The objective of this review is to encourage the ophthalmologist to carefully assess the published literature on new compounds. Efficacy can be “proven,” but only in studies of appropriate design and significant power. Since absolute safety does not exist, safety is relative, but differences between drugs can be demonstrated. The ophthalmologist needs to recognize that all beta-blockers, especially those still undergoing Phase III evaluation, are new antiglaucoma agents relative to the traditional agents pilocarpine and epinephrine, and must be used with caution. Acknowledgments The author gratefully acknowledges the extensive literature search performed by Dona Novack, the statistical consultation of John Lue and Josh Burke, the technical assistance of Bev McCarrell, Mary-Jane Branin, and Douglass Frapwell. III, the helpful suggestions from research colleagues and to P.C. for inspiration.
1. Alexander DW, Berson F, Hertzmark E, Epstein DL: Longterm eficacy of timolol vs. epinephrine in open-anglr glaucoma. Inoest Ophthal 27 ([Suppl 3]:43, 1986 la. Allen R. Hertzmark E. walker Ahl, Epstein DL: A doublcmasked comparison of hetaxolol vs. timolol in the treatment open-angle glaucoma. ilm J Ophthalmol 101:535-,541. 1986 1 b. Alvan G, Calissendorff BM, Seideman P, ct al: Absorption ocular timolol. Clin Pharmacokin 5:95-100, 1980
The first major review of beta-adrenergic blocking agents appeared in a special issue of this journal in 1979 [GLAUCOMA SYMPOSIUM, Volume 23 (6), May-June 19791. There, Drs. Thorn Zimmerman and William Boger (page 347) wrote, “Testing to date has shown timolol to be a promising medication for the treatment ofglaucoma. It appears to be more effective in lowering intraocular pressure than any of the other topical agents and seems to be better tolerated than these agents.” Timolol’s success resulted in the marketing of many other beta-antagonists worldwide, a trend amply documented in Dr. Novack’s current review. What has lagged behind is an understanding of how these agents act. In the paper immediately following Zimmerman and Boger’s, Dr. Arthur Neufeld (page 363) reviewed the experimental studies on the mrchanism of action of timolol, concluding that, “Although the usefulness of timolol for the treatment ofglaucoma has excited many ophthalmologists, the cellular mechanism of action of the drug is largely unknown.” This assessment, unfortunately, remains valid today. There are three competing brands of beta antagonists available in the United States; Dr. Novack is employed by the manufacturer of one of them. Thus, to minimize any unintentional or unjustified bias, the Editor-in Chief of this journal and I imposed stringent demands for peer review. Dr. Novack’s paper was reviewed by us, two universitybased ophthalmologists chosen by me, and two ophthalmologists suggested by the manufacturers of the products competing with that of Dr. Novack’s company. Dr. Novack accepted this burden of double or, more accurately, triple jeopardy without complaint. responding promptly and thoroughly to all suggestions. I want to express my thanks for his understanding, mv admiration for his equanimity, and my appreciation for this timely update on beta antagonists in the treatmrnt of glaucoma. REVIL\VS
of of
Ic. Allen
RC, Cagle GD, Bruce LA: Controlled clinical evaluation ofhetaxolol (0.5%) ophthalmic solution intraocular pressure and adjunctive therapy. Program anddbttracts. Glaucoma .Soc .lftg Turin (X.YI’Int Coq Oph). :Ma~a 19R6. p 20 Editorial: Therapeutic trials Rrsnonsibilit\ 2. .\nonymous: and Accountability. Pharmaceut Med !:81-83, 198;’ 3. AndrCasson S, ,Jensen K-M: Effect of pindolol on intraocular pressure in glaucoma: pilot study and a randomized comparison with timolol. 5r J Ophthalmol 67:228-230. 1983 4. ;\raie \I. Takase M: Effects of S-596 and carteolol. new betaadrenergic blockers. and flurbiprofen on the human eye: 3 fluorophotometric study. Gmcfi‘t .irrh C/zn b:lr/, Ophthalmnl ZZ:25!)-262, 1985 Pugh BR, Timewell RM: Cardiovascular effects of 5. Atkins,JM, topical beta-hlorkers during esrrrlsr. :IIN ,/ Oph~hnlmol 99: 173-l 7.5. 1985 6. Azuma I. Yamamoto I: Study of plasma concrntrations of hefunolol following topical application to the eyes. in: Proc 171 Cq L’urop Sot Ophthalmol. Yliopistopaino. Finland. 1985, pp 1174-1.57.5 6a. Beasley H, Cagle GD. McDonald TO: Longterm &cary and safety of hetaxolol 0.5% ophthalmic solution. Program and ilb-
&acts, 7. Brckrr
Editor’s Note
Jot,~. &IIND~.I.,h’I.D., PH.D. SEVI.IOS EI)I-IC)R, THERAPEUTIC:
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SINCE TIMOLOL
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Reprint requests should be addressed to Gary D. Novack, 2525 DuPont Drive. Irvine. CA 9271.5.
Ph.D..