Chapter 40
Systemic Side Effects From Topical Application of ß-Blockers
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Systemic administration of ß-adrenergic receptor blocking agents is associated with multiple effects, some of them desirable and some not. The drugs have accepted value for treatment of angina pectoris, ventricular cardiac arrhythmias, systemic hypertension, hypertrophic cardiomyopathy, essential tremor, acute anxiety, and thyrotoxicosis and for prophylaxis of myocardial reinfarction and migraine headache. However, these drugs are also known to produce cardiac bradycardia and failure, systemic hypotension, and asthmatic attacks. They may promote hypoglycemia in diabetics and, arguably, may cause mental depression and hallucinations.

Topically applied ophthalmic ß-blockers are absorbed systemically. Case reports of undesirable side effects abound, but causality is often poorly documented. For example, 140 patients using topical ophthalmic timolol had their “adverse” cardiovascular and cerebrovascular episodes reported to one agency during a 2-year period.1 Without knowing the size of the patient pool or having an age-matched control group, it is difficult to interpret these findings. During this same period of time, the manufacturer of ophthalmic timolol, Merck Sharp and Dohme, reported only 13 verified strokes in users of timolol; 12 of the 13 were in patients 75 to 92 years old.2 Could not a strong argument be made that the relatively low number of strokes indicated that ophthalmic timolol was of prophylactic value in cerebrovascular disease? Because of the relative lack of value of case reports, emphasis in the ensuing discussion is on data collected from controlled studies.

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Hepatic metabolism reduces the blood level of active drug absorbed from the gastrointestinal tract. Absorption of a drug into the blood vessels serving the eye, conjunctiva, lacrimal drainage apparatus, and nasopharynx avoids this “first pass” effect of the liver. As a result, surprisingly high plasma levels may be achieved from an eye drop even though a large portion of the drop overflows onto the lids. The maximum level after oral timolol maleate, 5 mg, was 17 ng/ml of plasma.3 The amount of ß-blocker in a 40-μL eye drop is from 0.1 mg in a 0.25% solution (e.g., timolol maleate) to 0.4 mg in a 1% solution (e.g., carteolol). Two drops of timolol 0.5% given bilaterally twice a day for 2 weeks produced plasma concentrations of from less than 1 ng/ml to more than 5 ng/ml.4 Timolol could be detected in all the urine samples assayed. In another study, timolol 0.5%, two drops twice a day to both eyes, was given for 5 days; the maximum plasma level was 9.6 ng/ml.5 Since urine levels were the same after both the first and ninth dose, drug accumulation did not appear to occur. Timolol 0.5%, one drop to each eye, was given to patients being maintained on one drop of this drug bilaterally twice a day.6 Before the test set of drops the baseline mean timolol level was 0.34 ± 0.3 ng/ml plasma. One hour after the test set of drops, the maximum mean value of 1.39 ng/ml was reached; the single highest value was 2.45 ng/ml. Children on maintenance timolol 0.25% or 0.5% to one or both eyes had their blood samples drawn randomly during the course of the day. The lowest timolol level, 3.5 ng/ml, was in a 5-year-old child, and the highest, 34 ng/ml, was in a 3-week-old infant.

Levobunolol, 0.5%, one drop bilaterally, produced detectable blood levels within 1 hour, at which time the mean plasma levels were 0.3 ng/ml. The highest plasma level was 1.1 ng/ml.7

These levels of ß-blockers are capable of producing pharmacologic effects. The ß-adrenergic stimulatory effects of intravenous isoproterenol are inhibited by plasma timolol levels well below 1 ng/ml.8,9 Isoproterenol was infused in healthy volunteers at increasing rates until the heart rate was raised 25 beats per minute above baseline. The isoproterenol infusion was then discontinued. A single dose of timolol 0.25 mg was then infused during a 15-minute period. Plasma timolol levels were 2.3 ± 0.4 ng/ml at the end of the infusion and 0.7 ± 0.1 and 0.4 ± 0.1 ng/ml at 1 and 4 hours, respectively. The isoproterenol infusions were repeated. Timolol decreased the sensitivity to isoproterenol. The dose of isoproterenol had to be increased 6.4 ± 1.2-fold at 1 hour and 3.9 ± 0.9-fold at 4.5 hours after timolol to achieve the same pulse rate elevation of 25 beats per minute. By Schild's equation (log of isoproterenol infusion plotted against the minus log of timolol plasma concentration), 0.17 ng of timolol per milliliter of plasma was the pA2 (i.e., the plasma level of timolol requiring a doubling of the amount of isoproterenol infused to produce the same response as in timolol's absence).

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Timolol's plasma half-life is 4.1 ± 1.1 hours. The drug is metabolized extensively by the liver, primarily by microsomal oxidative reactions that result in the cleaving of its morpholino ring.10 Debrisoquin has been used as a probe to determine the genetic make-up of individuals with regard to oxidative metabolism of drugs. About 9% of the white British and North American populations are poor metabolizers of debrisoquin, and the defect is transmitted as an autosomal recessive trait.11 The abnormal phenotype has been found in less than 1% of Asians.12,13

Timolol metabolism is impaired in subjects with slow debrisoquin metabolism.14,15 These subjects, given a single oral dose of timolol, 20 mg, developed significantly higher plasma levels than normal metabolizers of debrisoquin. The maximum timolol plasma concentrations, timolol plasma concentrations at 24 hours and timolol plasma half lives, respectively, for slow and rapid debrisoquin metabolizers were 113.8 ± 20.6 versus 60.7 ± 38.6 ng/ml, 11.3 ± 9.6 ng/ml versus none detectable, and 7.5 ± 3 versus 3.7 ± 1.7 hours. Several other ß-blockers (e.g., alprenolol, metoprolol, and propranolol) have been identified as being inactivated primarily by oxidation reactions involving the same microsomal enzyme as debrisoquin.16 Furthermore, other drugs may compete for or otherwise alter this pathway, resulting in elevated and prolonged plasma drug levels in both normal and defective debrisoquin metabolizers. For example, quinidine inhibits the cytochrome P450 isoenzyme responsible for debrisoquin metabolism even though quinidine is not metabolized by this enzyme.17 Quinidine has been implicated in a toxicity reaction with ophthalmic timolol.18 Bradycardia (36 beats per minute) was found in a 70-year-old man taking oral quinidine bisulfite, 250-mg sustained-release tablets, and timolol, 0.5% eye drops. The serum quinidine level, 3.5 μg/ml, was at a therapeutic, not toxic, level. The bradycardia resolved when both drugs were discontinued, and it did not recur when ocular timolol alone was administered. However, when oral quinidine was added, the bradycardia returned; and when it was discontinued a second time, the bradycardia resolved. In a well-controlled study,8 the cardiac response to intravenous isoproterenol of healthy, normal debrisoquin metabolizers was compared after 0.25 mg of intravenous timolol with and without pretreatment with 100 mg of oral quinidine. Quinidine was shown to increase both the timolol plasma level and the timolol cardiac ß-blocking effect by 10% to 40%.

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Studies in the ophthalmic literature tend to evaluate cardiac ß1-blocking activity by monitoring the pulse at rest. The result is that systemic absorption of eye drops seems to produce little or no effect. At rest, healthy individuals have low levels of circulating epinephrine and of sympathetic neural activity; as a result the heart rate is controlled primarily by vagal tone. When the heart is stressed, a reversal of this situation occurs. Only then may the degree of ß-blockade become evident. ß-Blocking effects that appear trivial in healthy subjects at rest may be of serious consequence in the sick and elderly when they are stressed. A single oral dose of timolol maleate, 10 mg, will reduce the pulse rate in healthy volunteers by 13 to 16 beats per minute.19 Healthy male volunteers given timolol 0.5% twice a day bilaterally showed no changes in their resting pulses after the first and ninth doses.5 However, exercise tachycardias were significantly reduced. Approximately 1 and 4 hours after the first and ninth drops, exercise resulted in mean pulse rates of 153 (placebo, 1 hour after first drop) versus 143 (timolol, 1 hour after first drop), 158 (placebo, 4 hours after first drop) versus 150 (timolol, 4 hours after first drop), 149 (placebo, 1 hour after ninth drop) versus 141 (timolol, 1 hour after ninth drop), and 152 (placebo 4 hours after ninth drop) versus 147 (timolol 4 hours after ninth drop). In other studies, 15 months of timolol 0.5% or levobunolol 0.5%, twice daily bilaterally,20 produced significant reductions in the resting pulses of 5 to 10 beats per minute; betaxolol 0.25% eye drops twice a day for 6 weeks did not change resting pulses21; metipranolol 0.3%, twice a day bilaterally for 6 weeks, did not significantly alter resting pulse rates,22 and after a 3-month trial of timolol 0.5% or carteolol 1% there were no significant reductions in pulse rate from pretreatment levels.23 No significant differences were found in the resting pulse effects of betaxolol 0.5% and levobunolol 0.5%24 or between timolol 0.25% and carteolol 1%.25 In a crossover, masked, placebo-controlled study, a single drop of timolol 0.5% or betaxolol 1% had no effect on the resting pulse.26 However, after a 10-minute stress test on the treadmill, the mean pulse rate was 141 beats per minute after the placebo and betaxolol drop but was significantly reduced to 132 beats per minute by the timolol drop. In another crossover study,27 one drop of bilateral timolol 0.5%, betaxolol 0.5%, and carteolol 2% was given in at least three different sessions. Forty-five minutes later, the ß-agonist isoproterenol was infused. The ß-blockade by timolol and carteolol was sufficient to require that a fourfold higher dose of isoproterenol was needed to produce the same increase in heart rate as when the placebo drop had been given. The betaxolol drop had no more effect than placebo. Timolol 0.5%, carteolol 2%, or metipranolol 0.6% was given once to each eye at different times.28 Although there were no changes in the resulting blood pressure or pulse, the doses of intravenous isoproterenol needed to increase the pulse 25 beats per minute were increased significantly for all three drugs: after placebo, 3.1 ± 0.5 μg isoproterenol; after timolol, 10.9 ± 1.9 μg isoproterenol; after carteolol, 39.6 ± 5.4 μg isoproterenol; and after metipranolol, 5.2 ± 0.9 μg isoproterenol.
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The mechanisms by which ß-blocking agents reduce blood pressure are not clearly understood. ß1-Blocking agents reduce not only the rate of cardiac contraction but also the force of cardiac contraction; this could contribute to a hypotensive effect. Blood vessel smooth muscles relax when stimulated by ß2-agonists, so a ß2-antagonist would be expected to increase, not decrease, blood pressure. ß-Blockers affect plasma renin levels and prejunctional sympathetic receptors modulating norepinephrine release. These have been investigated without conclusive results.

Nearly all the studies on the effects of systemic absorption of ophthalmic ß-blockers monitor the resting blood pressure rather than testing changes produced by exercise. Single drops given bilaterally of timolol 0.5%, carteolol 2%, or metipranolol 0.6% produced no changes in the resting blood pressures of healthy volunteers.28 One drop of timolol 0.5%, betaxolol 1%, or placebo did not affect the blood pressure at rest or during treadmill testing.26 Six weeks of metipranolol 0.3% twice a day bilaterally did not affect resting mean systemic systolic or diastolic blood pressures.22 Six weeks of betaxolol 0.25% eye drops twice a day also failed to alter the resting blood pressure.21 Three months of timolol 0.5% or carteolol 1% or 2% eye drops failed to cause a significant difference in resting blood pressure.23 Fifteen months of timolol 0.5% or levobunolol 0.5% twice a day bilaterally reduced the resting systolic and diastolic blood pressures by less than 4 mm Hg.20 Bilateral timolol 0.5% drops failed to significantly alter the postexercise systolic or diastolic blood pressure after the first or ninth dose.5 Bilateral application of one drop of timolol 0.5%, carteolol 2%, or betaxolol 0.5% was given in a crossover study in which peripheral blood flow was measured by veno-occlusive plethysmography.27 Forty-five minutes after drop application, isoproterenol was infused. Compared with placebo, four times the dose of isoproterenol was needed to produce the same increase in peripheral blood flow after the timolol and carteolol drops. The response after the betaxolol drops was the same as that after the placebo.

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Oral administration of ß-blocking drugs does not affect the respiratory indices of patients unless there is pre-existing pulmonary disease. Thus, in healthy males given single drops of bilateral timolol 0.5% twice a day, there was no change in the postexercise forced expiratory volume at 1 second (FEV1) when tested 70 and 255 minutes after the first and ninth doses.5 Single intravenous doses of betaxolol 0.6% also did not affect the vital capacity, peak expiratory flow rate, or forced expiratory volumes at rest and after exercise in normal volunteers.29 However, in those patients with asthma and other obstructive airway diseases, systemic absorption of ophthalmic ß-blockers can be sufficient to trigger bronchoconstriction. In a placebo-controlled 4-hour study of nine asthmatic patients, bilateral single drops of timolol 0.5% or betaxolol 1% were given.30 Timolol produced a significant mean reduction in the FEV1 of approximately 25% at 30 minutes and 1, 3, and 4 hours (Fig. 1). The ratio of FEV1 to vital capacity was significantly reduced at 1, 2, and 4 hours. Although as a group there was no significant effect from betaxolol, a relatively selective ß1-antagonist, one of the subjects had a marked response to the drug and his subsequent reaction to timolol was so severe he had to be terminated from the study early. Of 101 subjects with glaucoma with chronic obstructive pulmonary disease, asthma, or timolol-induced bronchoconstruction treated with betaxolol 0.5% twice a day for up to 2 years, 9 subjects developed respiratory symptoms possibly attributable to the betaxolol and had to be withdrawn from the study.31

Fig. 1. Effect of eyedrops on forced expiratory volume in 1 second expressed as a percent change from control values. (Schoene RB, Abvan T, Ward RL, Beasley CH: Effects of topical betaxolol, timolol and placebo on pulmonary function in asthmatic bronchitis. Am J Ophthalmol 97:86, 1984)

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Controversy surrounds the issue of whether systemic ß-blockers can produce psychiatric symptoms. One review of the subject concluded32: “However, although the results of available clinical studies are inconsistent, it is reasonable to conclude that all beta-blockers pass the blood brain barrier and may cause CNS-related subjective symptoms.” The abstract of the article showed a similar lack of conviction about the mechanism of the psychiatric effects: “Although it cannot be claimed with certainty, nonselective beta-blockers seem to cause CNS-related side effects to a greater extent than beta-1 selective blockers.” One subsequent study claimed an increased prescribing of antidepressants in subjects receiving oral ß-blocker therapy (6.4% of 3218 new ß-blocker users versus 2.8% of non-ß-blocker users)33 while another study denied such a relationship.34 Data can also be found supporting an improvement in mental status from taking oral ß-blockers; standardized psychometric tests used in this study consisted of trails-A trail making, critical flash-fusion threshold measurements, and the visual analogue scale for subjective lethargy.35

Multiple case reports associate psychiatric side effects with ophthalmic ß-blocker use.36 Although the majority are in patients using timolol, the most frequently prescribed ophthalmic ß-blocker, they also exist for betaxolol.37,38 Several small masked studies have compared the central nervous system effects of timolol and betaxolol. Forty-four normal volunteers received either timolol eye drops or betaxolol eye drops for 5 weeks and were evaluated by the Hamilton Anxiety Rating Scale and the Montgomery-Asberg, Global Summary and Minnesota Multiphasic Personality Inventory tests.39 There was a nonsignificant trend for central nervous system side effects to be less using betaxolol. When seven patients with central nervous system symptoms presumably from timolol eye drops were rechallenged in a double-masked crossover study comparing timolol 0.5% and betaxolol 0.5%, twice daily for 1 month each, five patients preferred betaxolol and two preferred timolol.40

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In general, oral administration of ß-blockers results in elevated serum triglyceride levels and lowered higher-density lipoproteins.41 Nonselective ß-blockers have more pronounced effects than ß1-selective blockers such as betaxolol.29 Nonselective ß-blockers with intrinsic sympathomimetic activity produce variable changes.42,43 The biochemical mechanisms are only partially understood.44 Hepatic lipoprotein lipase and lecithin cholesterol acyltransferase activities are inhibited by ß2-blockers. This results in reduced conversion of very low-density lipoprotein into high-density lipoprotein. On the other hand, ß2-adrenergic stimulation increases this conversion rate, perhaps explaining why ß-blockers with partial ß2-agonist activity are less likely to reduce high-density lipoprotein levels. With regard to cholesterol elevation, the proposed mechanisms at work are more speculative.

The beneficial cardiovascular effects from orally administered ß-blockers easily outweigh their negative blood lipid effects. For example, long-term treatment with timolol 10 mg orally twice a day significantly reduces the sudden death rate (7.7% in timolol group versus 13% in placebo group) and reinfarction rate (14.4% in timolol group versus 20.1% in placebo group) in patients with prior myocardial infarctions treated over a 33-month period.45 However, it is not clear that the cardiovascular effects from systemic absorption of ophthalmic ß-blockers would outweigh a negative effect on blood lipids. When bilateral timolol eyes drops, 0.5%, were given twice daily for an average of 76 days, the mean cholesterol and low-density lipoprotein levels did not change.46 However, the triglycerides increased 12% and the high-density lipoproteins decreased 9%. In another study,47 lasting 105 days, bilateral timolol eye drops twice daily did not significantly affect any of the lipid fractions.

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Oral administration of ß-blockers can lower intraocular pressure. In one study, propranolol, 80 mg, was ingested during a 24-hour period by subjects with normal intraocular pressures. When the intraocular pressures were taken the next day, 2 hours after a 20-mg dose, the mean ± SD intraocular pressure had fallen from a baseline value of 16 ± 1.5 mm Hg to 12.9 ± 2.6 mm Hg.48 This reduction was not the maximum possible because topical application of 2 drops of timolol 0.5% produced an additional mean reduction in intraocular pressure of 3 mm Hg. If systemic levels of ß-blockers from oral therapy can lower the intraocular pressure, it would seem likely that systemic levels from unilateral topical treatment could affect the contralateral eye. In 30 patients with open-angle glaucoma treated unilaterally for a mean length of 34 weeks with timolol 0.5% twice daily, the treated eyes had a mean ± SD change in intraocular pressure of 7.5 ± 4.29 mm Hg, going from a pretreatment level of 28.5 ± 4.54 mm Hg to 21 ± 2.85 mm Hg.49 The contralateral untreated eyes also had a significant reduction in intraocular pressure, of 4.5 ± 4.69 mm Hg, going from a pretreatment level of 26.4 ± 4.83 mm Hg to 21.9 ± 3.84 mm Hg. Topical application of as little as a single unilateral drop of either timolol 0.5% or levobunolol 0.5% in patients with ocular hypertension and glaucoma50 has been reported as producing bilateral effects. The timing and magnitude of the contralateral responses paralleled those of the treated eyes. The mean ± SD baseline intraocular pressures and the pressure reductions 2 and 4 hours after treatment were as follows:

  Treated eyes
  Placebo drop: 29.3 ± 2.8, -1 ± 3.7, and -0.4 ± 3.3

  Timolol 0.5%: 26.7 ± 2.1, -7 ± 3.3, and -5.8 ± 3.7
  Levobunolol 0.5%: 27.6 ± 1.3, -8.3 ± 3.5, and -6.9 ± 3.5

  Untreated eyes

  Placebo drop: 29.6 ± 3.5, 0 ± 2.4, and 0 ± 2.9
  Timolol 0.5%: 27.2 ± 2.2, -3.8 ± 2.5, and -2.8 ± 1.3
  Levobunolol 0.5%: 28.3 ± 1.5, -3.8 ± 2.8, and -3.3 ± 3.2

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Stimulation of α1-adrenergic receptors in arteriolar smooth muscle fibers results in vasoconstriction and elevation of the blood pressure. Normally, there is a compensatory ß2-mediated vasodilation.51 If the degree of ß2-blockade is sufficient, vasodilation will not occur and the blood pressure might reach dangerously high levels.52 The primary protective response remaining then becomes a carotid baroreceptor-to-vagal bradycardia, which could be profound.

There are two sources of α1-stimulants in the blood: exogenous and endogenous. A patient receiving ß-blocking eye drops for glaucoma might be given phenylephrine, an α-agonist, to dilate the pupils as part of a routine examination. Or the same patient might be placed on epinephrine eye drops or its prodrug, dipivefrin, for additional ocular hypotensive effect. Epinephrine is a potent α- as well as ß-agonist. Clinically, simultaneous use of epinephrine and ß-blocking eye drops usually results either in predominance of the systemic effects of the ß-blocker or no effect at all. In four patients with glaucoma using dipivefrin eye drops, the addition of the relatively selective ß1-antagonist betaxolol resulted in wheezing.53 When the betaxolol was discontinued, this symptom resolved. In another study, patients with glaucoma who at baseline had been taking bilateral dipivefrin 0.1% eye drops twice daily for more than 6 months received 2 months of treatment with bilateral dipivefrin plus bilateral timolol 0.25% twice daily.54 There was a significant reduction in the pulse rate, from 83 ± 12 to 70 ± 6 beats per minute. When the order of the eye drops was reversed (i.e., baseline cardiovascular evaluation took place after more than 6 months of bilateral timolol 0.25% twice a day and then the patients were treated with 2 months of bilateral timolol plus dipivefrin 0.1% twice daily) there was no significant elevation in the heart rate when dipivefrin was added.

Endogenous plasma levels of catecholamines are acutely elevated by stress. Patients with mild systemic hypertension had mean ± SD levels at rest of 489 ± 254 pg/ml of norepinephrine and 73 ± 55 pg/ml of epinephrine.55 Mental stress, consisting of timed subtractions of 2-digit numbers from a 4-digit number for 5 minutes, produced significant elevations in the levels of norepinephrine, 610 ± 304 pg/ml, and epinephrine, 97 ± 54 pg/ml. Isometric hand grips, sustained for 3 minutes at 50% of the maximum predetermined hand grip strength, produced even higher levels of norepinephrine, 734 ± 271 pg/ml, and epinephrine, 156 ± 117 pg/ml. The highest levels were produced by a treadmill test: 2717 ± 1505 pg/ml of norepinephrine and 185 ± 94 pg/ml of epinephrine. An additional long-term elevation in plasma catecholamines is produced by ß-blockers. ß-Blockers, despite their well-known ability to lower blood pressure, elevate plasma catecholamine levels56 and reduce clearance of plasma catecholamines.57

Acute and chronic elevations of catecholamines might create adverse cardiovascular events in patients treated with ophthalmic ß-blockers. The appropriate factors seem in place for adverse events to occur. A well-controlled, and reassuring, study has been performed.58 Systemic hypertensive volunteers were enrolled in a double-masked crossover study in which propranolol, metoprolol, and placebo were given orally in random sequence for 2-week periods. Propranolol was given as either 80 or 160 mg twice daily, and metoprolol was given as either 50 or 100 mg twice daily, the study doses approximating the amounts of medication the volunteers had been receiving therapeutically. At the end of each 2-week period, 1 to 2 hours after dosing, phenylephrine was infused intravenously in increasing doses until a rise in systolic blood pressure of at least 30 mm Hg or until a reflex bradycardia of 35 beats per minute occurred. The number of subjects involved was sufficient to detect a difference of 23% in the sensitivities to intravenous phenylephrine. Neither the increases in blood pressure produced by phenylephrine nor the subsequent reductions in pulse rate were significantly different whether subjects were ingesting ß-blocker or placebo. Thus, it appears that while the systemic hypertensive response to phenylephrine may vary markedly from subject to subject, co-administration of ß-blocker is probably not causally related to adverse cardiovascular events.

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Tremor is a ß2-adrenergic function; that is, finger tremor is increased by intravenous isoproterenol, a nonselective ß-stimulant.59 This tremor increase is not reduced by prior oral ingestion of a drug with little or no ß2-blocking activity (e.g., betaxolol, 10 mg). Carteolol is a nonselective ß-blocker with partial ß1- and ß2- agonist activity. This last activity causes a dose-related increase in resting finger tremor. However, if the more potent selective ß2-agonist terbutaline is given first, the ß-blocking activity of carteolol will predominate and will reduce the resting finger tremor.60

In a randomized masked, crossover, placebo-controlled study, bilateral single eye drops of timolol 0.5%, metipranolol 0.6%, and betaxolol 0.5% were tested for their effect on the finger tremor induced by inhaled isoproterenol.61 Timolol and metipranolol eye drops significantly reduced the tremor while betaxolol and placebo did not (Table 1).


TABLE ONE. Comparison of Effects of Timolol,Metipranolol, and Betaxolol on Finger Tremor Inducedby Inhaled Isoproterenol

 Tremor Amplitude (cm/s)
Placebo56.56 5 1.4955.69 5 1.49
Timolol62.13 5 2.1356.44 5 2.88
Metipranolol58.25 5 1.7953.13 5 2.03
Betaxolol55.5 5 1.5555.31 5 2.47


Because ß-blockers reduce tremor, they are banned and tested for in many Olympic events (e.g., shooting, diving, ski jumping, figure skating and gymnastics).62 ß-Blockers are banned by the National Collegiate Athletic Association but tested for in only one sport, rifle shooting. The regulatory bodies for these sports require relatively simple and uniform criteria for enforcement of their drug rules. The urine test has become the gold standard for this enforcement. The sensitivity of urine assays has reached the point at which systemically absorbed eye drop medications can be detected. When the test is positive, there is no simple way to determine whether the intent and effect were medical or cheating. To some extend it may not matter. Should a patient taking ß-blocking eye drops for therapeutic reasons be given a competitive sports advantage? The United States Pharmacopeia Drug Information, an important drug compendium, places warning of the Olympic and NCAA bans in its descriptions of ophthalmic timolol, levobunolol, metipranolol, carteolol, and even the relatively ß-selective betaxolol. The penalties for their use are severe and are the same as those for anabolic steroids: Olympic eligibility is lost for 2 years after the first offense and for life after the second offense. An athlete may, at the discretion of the Olympic Committee, be allowed to use a banned substance if a letter from the contestant's physician is sent stating there is a medical need for use of the drug. However, this mechanism has been abused in the past, and permission to use a banned substance is not granted automatically.

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Breast milk of mothers given oral timolol, 5 or 10 mg three times a day, had mean ± SD milk-to-plasma drug ratios of 0.80 ± 0.21 and 0.83 ± 0.18, respectively.63 This suggests that the drug is not concentrated in the milk. However, the timolol levels in the milk and plasma of a nursing mother who 1 1/2 hours earlier had applied one eye drop of timolol 0.5% to one eye suggested that the drug was secreted in a concentrated form.64 The milk level was 5.6 ng/ml while the plasma level was 0.93 ng/ml. In mothers given oral doses of betaxolol, 10 to 40 mg, umbilical cord levels indicated that a rapid equilibrium was reached with the maternal circulation within a few hours65; the umbilical blood levels were about 90% those of the mothers' levels. However, the milk betaxolol concentrations were three times those in the maternal blood. The clinical significance of these data is not clear since the newborn's abilities to absorb, metabolize, and excrete these drugs are largely unknown.
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1. Van Buskirk EM, Fraunfelder FT: Timolol and glaucoma (letter). Arch Ophthalmol 99:696, 1981

2. Katz IM: Side effects of topical ocular timolol (letter). Am J Ophthalmol 96:552, 1983

3. Vermeij P, el Sherbini-Schepers M, Van Zwietaen PA: The disposition of timolol in man. J Pharm Pharmacol 30:53, 1978

4. Alvan G, Calissendorff B, Seideman P et al: Absorption of ocular timolol. Clin Pharmacokinet 5:95, 1980

5. Affrime MB, Lowenthal DT, Tobert JA et al: Dynamics and kinetics of ophthalmic timolol. Clin Pharmacol Ther 27:471, 1980

6. Passo MS, Palmer EA, van Buskirk EM: Plasma timolol in glaucoma patients. Ophthalmology 91:1361, 1984

7. Novack GD, Tang-Liu DD-S, Kelley EP et al: Plasma levobunolol levels following topical administration with reference to systemic side effects. Ophthalmologica 194:194, 1987

8. Kaila T, Huupponen R, Karhuvaara S et al: ß-Blocking effects of timolol at low plasma concentrations. Clin Pharmacol Ther 49:53, 1991

9. Achong MR, Piafsky KM, Ogilvie RI: Comparison of cardiac effects of timolol and propranolol. Clin Pharmacol Ther 18:278, 1975

10. Wasson BK, Scheiyetz J, Rooney CS et al: Urinary metabolites of timolol from humans and laboratory animals: Syntheses and beta adrenergic blocking activities. J Med Chem 23:1178, 1980

11. Kalow W: The metabolism of xenobiotics in different populations. Can J Physiol Pharmacol 60:1, 1982

12. Gonzalez J: The molecular biology of cytochrome P450s. Pharmacol Rev 40:243, 1989

13. Wang SL, Huang J, Lai MD et al: Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects: Polymorphism in RFLP and DNA sequence of CYP2D6. Clin Pharmacol Ther 53:410, 1993

14. McGourty JC, Silas JH, Fleming JJ et al: Pharcacokinetics and beta-blocking effects of timolol in poor and extensive metabolizers of debrisoquin. Clin Pharmacol Ther 38:409, 1985

15. Lewis RV, Lennard MS, Jackson PR et al: Timolol, atenolol: Relationships between oxidation phenotype, pharmacokinetics and pharmacodynamics. Br J Clin Pharmacol 19:329, 1985

16. Eichelbaum M, Gross AS: The genetic polymorphism of delrisoquine/sparteine metabolism: Clinical aspects. Pharmacol Ther 46:377, 1990

17. Mikus G, Ha HR, Vozeh S et al: Pharmacokinetics and metabolism of quinidine in extensive and poor metabolisers of sparteine. Eur J Clin Pharmacol 31:69, 1986

18. Dinai Y, Sharir M, Naveh N, Halkin H: Bradycardia induced by interaction between quinidine and ophthalmic timolol. Ann Intern Med 103:890, 1985

19. Lowenthal DT, Pitone JM, Afrime MB et al: Pharmacokinetics of timolol maleate in chronic renal insufficiency. Clin Pharmacol Ther 23:606, 1978

20. Berson FG, Cohen HB, Foerster RJ et al: Levobunolol compared with timolol for the long-term control of elevated intraocular pressure. Arch Ophthalmol 103:379, 1985

21. Feghali JG, Kaufman PL: Decreased intraocular pressure in the hypertensive human eye with betaxolol, a ß1-adrenergic antagonist. Am J Ophthalmol 100:777, 1985

22. Serle JB, Lustgarten JS, Podos SM: A clinical trial of metipranolol, a concardioselective beta-adrenergic antagonist, in ocular hypertension. Am J Ophthalmol 112:302, 1991

23. Stewart WC, Shield MB, Allen RC et al: A 3-month comparison of 1% and 2% carteolol and 0.5% timolol in open-angle glaucoma. Graefes Arch Klin Exp Ophthalmol 229:258, 1991

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