SURVEY OF OPHTHALMOLOGY

VOLUME 35 - NUMBER 3. NOVEMBER-DECEMBER

THERAPEUTIC

1990

REVIEW

JOEL MINDEL AND SAIICHI MISHIMA, EDITORS

Systemic Drug Interactions with Topical Glaucoma Medications STEVE L. GERBER, M.D.,’ LOUIS B. CANTOR,

M.D.,’ AND D. CRAIG BRATER, M.D.’

Departments of ‘Ophthalmology and 2Medicine, Division of Clinical Pharmacolog?, Indiana University School of Medicine, Indianapolis, Indiana

Abstract. Topically administered ophthalmic medications are capable of attaining clinically important serum concentrations, as evidenced by the variety of systemic side effects they can produce. These drugs are therefore also capable of interacting with other drugs administered orally and intravenously. This is especially important when medications are administered to an elderly population, who are often receiving multiple medications. The PhysicianS Desk Refv-enca and the United States Pharmacopeia Drug tnfor~ti~n directory contain numerous warnings of potential interactions between topical glaucoma medications and systemically administered drugs. Unfortunately, literature supporting such interactions is limited, both in quantity and quality, being anecdotal in many cases. This report summarizes available information regarding the nonocular interactions between topical ophthalmic glaucoma medications and other systemically administered medications. Clinical evidence of these interactions is lacking in many cases. (Sure Ophthalmol 35:205-218, 1990)

adrenergic Key words. glaucoma medications

beta-adrenergic antagonist agonist parasympathomimetic agent l

l

There are few reports of interactions between topical ophthalmic drugs and systemic medications. This is in part due to a lack of awareness on the part of patients and even some physicians, because topical eye medications are often not considered to be capable of interaction with oral and intravenous medications. Topically applied ophthalmic medications can, however, attain sufficient serum levels via absorption into conjunctival, nasal, oropharyngeal and gastrointestinal mucosa to have systemic effects and thereby interact with other drugs. In fact, topical administration to the eye has been likened to intravenous rather than oral administration because a high percentage of the absorbed drug

l

drug interactions

l

avoids hepatic first-pass metabolism; thus, drugs administered by this route can attain higher levels relative to dose than if administered orally.4fi,57.77 The Physician’s Desk Reference (PDR) and the United States Pharmucopeia Drug Infownation directory (USPDI) are two frequently referenced sources of drug interaction information. The information reported in the PDR is the same as that in the Food and Drug Administration approved package insert and is supplied by the drug manufacturer. For each medication there is a “Drug Interaction” heading. The USPDZ is a three volume publication compiled through a review process by hundreds of health care professionals. Volume One, Drug Information ,for “05

206

Surv Ophthalmol

35 (3) November-December

the Health Care Professional includes a specific drug interaction section for all medications listed. This section reports the consensuses of specific nationwide committees assigned to each drug category, e.g., panel on ophthalmology, panel on pediatrics, etc. Neither the PDR nor the USPDI contains published references. We initiated a detailed search of the drug interactions listed in these two sources to determine the basis for their listing. This search was conducted using the Medline computerized system of all Index Medicus referenced sources from 1966 to 1989, communication with the drug manufacturers and two specific interaction references: Hansten’s Drug Interactions and Drug Interaction Facts and Comparisons. 3333 Of the reports and studies available, many are single case reports in which the addition of a topical medication to a systemic medication (or vice versa) resulted in an unwanted reaction. Few of these reports involved rechallenging the patient with the offending agent after the side effects had resolved. This rechallenge is the “gold standard” to determine whether the addition of the second medication or mere coincidence caused the reaction. A number of reported interactions are partially based upon pharmacologic studies in animals or in vitro. Whether their results can be applied to actual in vivo events is questionable. It is important to remember that even where the potential for drug interaction exists, there are methods to reduce systemic absorption. Nasolacrima1 occlusion, a technique in which digital pressure on the periphery of the nasolacrimal drainage system obstructs drainage to the nasopharyngeal mucosa, has been shown to significantly decrease systemic absorption. Eyelid closure for five minutes following drug application also achieves the same purpose by inhibiting nasolacrimal pump action.gs This review summarizes available information on the interaction between specific topical antiglaucoma medications and systemic medications. The interactions listed are as categorized in the PDR and USPDI with one exception. Literature reports on the interaction of timolol with cholinesterase inhibitors is reviewed, even though it is not listed in the PDR or USPDI. Included with the text is a summary table of reported interactions, which indicates whether the interactions are additive or antagonistic and offers our evaluation of the literature support for each report. We do not attempt to differentiate between additive and synergistic interactions, as the literature available does not allow such a distinction to be made. Although the amount of information is limited and anecdotal in many instances, physicians should be aware of documented and potential drug interactions of topical ophthalmic

GERBER

1990

ET AL

medications.

I. Ophthalmic Beta-adrenergic Antagonists A. CHARACTERISTICS

AND MECHANISMS

After instillation in the conjunctival sac, timolol (Timoptic@) is absorbed into the conjunctival, nasal, oropharyngeal and gastrointestinal mucosal capillaries. Measured peak plasma levels following topical administration have varied from undetectable to 9.6 ng/ml, with the average level recorded in the literature being approximately 1 ng/ml. Although these plasma levels are lower than the range of 2040 ng/ml noted in pharmacokinetic studies using a 10 mg oral dose of timolol, they approximate plasma concentrations present 6-8 hours after oral administration and are sufficient to cause a degree of systemic beta-adrenergic blockade.57*60 Much of the available information on timolol interactions is based upon propranolol studies because both are extensively metabolized in the liver and both have similar beta-blocking effects.5g However, a major difference is that propranolol stabilizes cell membranes, which is the reason it is a local anesthetic and is not suitable for chronic topical administration to the eye.60,g2 It has been estimated that a patient instilling a solution of timolol 0.5%, two drops twice per day, could receive the equivalent of four milligrams of propranolol intravenously twice per day. 3’ There are also differences in their pharmacokinetic properties. For example, blood levels of timolol tend to be greater than those of propranolol because of its slower systemic clearance. Although the exact reasons for this are unknown, it is probably due to a lower first-pass effect (hepatic metabolism) because of timolol’s lower lipophilicity and therefore slower transfer across hepatocyte membranes.“O,g” Regardless of the mechanism, one would expect an even greater potential for side effects with timolol. There is little available information on potential interactions of the newer beta-blockers used to treat glaucoma (levobunolol and betaxolol). Levobunolol 0.5%, which like timolol is a nonselective betaadrenergic antagonist, has been reported to achieve serum levels up to 0.21 ng/ml following ophthalmic administration.60s”’ Serum levels of 0.5% betaxolol, a beta-l selective antagonist, have been reported as undetectable following topical administration although detection limits for the assay are not available.” The lipophilicities of betaxolol and levobunolol are between those of timolol and propranolol. These may allow better cornea1 penetration than timolol and allow for increased transfer across hepatocyte membranes with resultant lower serum concentrations.60

SYSTEMIC DRUG INTERACTIONS

WITH TOPICAL

GLAUCOMA

TABLE Sumwuzq of Non-ocular

Beta-adrenergic antagonist

1

Interactions Between Topical Glaucoma Mrdirations and Systemic lhcp

Topical g 1aucoma medication

Interaction Systemic drug Anesthetic agents (inhalational) Hypoglycemic agents

Additive

Antagonistic

x

Phenothiazines

X X X

2) xanthines

x

3) beta-adrenergic agonists for the treatment of: a) heart failure b) bronchoconstriction

Cholinesterase inhibitors

Anesthetic agents (inhalational) Digitalis glycosides Monoamine oxidase (MAO) inhibitors Sympathomimetic amines

a) retard hypoglycemic rebound b) mask hypoglycemic symptoms c.) produce hypoglycemia increased toxic effects of beta-antagonists cardiac depression weakness of striated muscle systemic hypertensive rebound following clonidine withdrawal cardiac depression increased toxic effects of fentanyl increased serum levels of beta-blockers and phenothiazines with potential for toxic side effects cardiac depression cardiac depression

Digitalis glycosides Fentanyl derivatives

Quinidine Reserpine Sympathomimetic amines 1) sub-cutaneous epi

Potential result systemic hypotension

x

Beta-adrenergic antagonists Calcium channel blockers Cholinesterase inhibitors Clonidine

Adrenergic aponist

‘107

MEDICATIONS

x x

abrupt systemic hypertension a) bronchoconstriction h) reduced theophylline clearance

cardiac depression bronchoconstriction

x

cardiac arrhythmias

X

cardiac arrhythmias hypertensive crises refuted by literature systemic hypertension and cardiac arrhythmias cardiac arrhythmias

X X

Tri- and tetracyclic antidepressants Anesthetic agents (local: ester-type)

X

Cholinesterase inhibitors Succinylcholine

X

X

X

Documentation quality references poor .55 IlOIlc'

p”o1‘

87

poor 1, 87 poor 7, 9, 13

poor 67, x0 tilir- 75, 89 Poole 3

fair 4, 71, 96 none 11011e

good

17

110116‘

110116

good 14. 57, 73 IlOIlc’

good 29, 46, 57 good 54,57,66, 72, 73 poor 25, 82 none good 11, 2 1, 3X none none

prolonged anesthetic action with cardio-pulmonary depression cholinergic toxicity

fair

prolonged neuromuscular blockade

good 2.3, 64

99

none

208

Surv Ophthalmol

35 (3) November-December

Even though disparate serum concentrations are reported for the three ophthalmic beta-blockers, the many reports of systemic side effects are proof that all can achieve serum levels which are sufficient to cause systemic beta-blockade. The most widely studied and reported of these effects are on cardiovascular and pulmonary function. Stimulation of cardiac beta-l receptors elicits increases in heart rate, contractility and conduction velocity. Blocking these receptors can cause bradycardia, conduction disturbances and decreases in cardiac ouptut. Peripheral vascular stimulation of beta-2 receptors results in vasodilation. Blocking vasodilation might be expected to contradict the antihypertensive use of however, their blood pressure beta-antagonists; lowering action is primarily due to their cardiac effects.g’ Stimulation ofpulmonary beta-2 receptors results in relaxation of bronchial musculature. Therefore, beta-2 receptor antagonists can cause increased airway resistance and respiratory compromise, especially in susceptible individuals. While a beta-l selective blocker such as betaxolol is less likely to have pulmonary effects, its selectivity is not absolute, as proven by reports of reduced pulmonary function with its use.2g,6087’ Beta-blockers have complex effects on blood glucose control and metabolism. In the liver, stimulation of beta-2 receptors causes glycogenolysis and gluconeogenesis with resultant glucose release. The pancreatic islet cells which are responsible for the secretion of insulin also respond to beta-2 adrenergic stimulation. Although the effect ofbeta-blocking agents on glucose metabolism in normal patients is minimal, in the diabetic patient they have the POtential to slow recovery of the glucose concentration and prevent the usual rebound of plasma glucose in response to hypoglycemia. Signs of hypoglycemia are also masked.45v63 These issues will be discussed further in regard to the interaction between betablockers and antidiabetic agents. Beta-adrenergic effects on the central nervous system are poorly understood. Reports of depression, lethargy, confusion and hallucinations in patients taking both oral and ophthalmic betablockers have been described.2,5’“s57 Other studies, however, have shown improvement of mental test performance without any resultant lethargy or drowsiness.27,36 Also poorly understood are reports of timolol exacerbating myasthenia gravis, possibly because of a depressant effect ofbeta-antagonists on the neuromuscular junctiong3 While propranolol has membrane stabilization potential, this mechanism is less easilyjustified with the ophthalmic betaantagonists, which do not appear to have any significant membrane stabilization activity.60 More extensive discussions of beta-adrenergic pharma-

GERBER ET AL

1990

cology as well as listings of systemic side effects due to beta blockade are published elsewhere.26,46,g1.g2 Potential drug interactions with opthalmic beta-receptor antagonists discussed below are listed in the USPDI and/or PDR. B. INTERACTIONS

WITH OTHER DRUGS

1. Anesthetic Agents (Cyclopropane, Enflurane, Halothane, Isoflurane, Methoxyflurane, Trichloroethylene) Inhalational anesthetics are associated with hypotension due to direct depression of the heart with a decrease in cardiac output. These cardiovascular changes, however, elicit a reflex, compensatory increase in sympathetic nervous system activity with subsequent cardiac stimulation and increase in heart rate, contractility and cardiac output.” In the presence of beta-blocking medication the heart’s ability to respond to these sympathetic stimuli is reduced, resulting in potentially prolonged and seTopical ophthalmic betavere hypotension.“g*74 blockers have the potential to cause a similar effect. Documentation is limited. One report describes a 69-year-old man applying 0.5% timolol four times daily to his right eye and 2% pilocarpine twice daily to his left eye, who experienced bradycardia and hypotension during halothane anesthesia. Timolol was detected in a serum sample removed during surgery at a concentration consistent with partial beta-adrenergic blockade (2.6 ng/ml). The authors admit that the hemodynamic changes could also be attributed to underin cardiac conduction or lying abnormalities excessive sensitivity to halothane anesthesia.55 In addition, timolol should have been administered twice rather than four times daily in this patient. This one case does not provide sufftcient support to recommend removal of the ophthalmic medication prior to surgery. Antidiabetic

Agents

(Oral/Insulin)

The interaction between beta-blockers and glucose control is complex and still under study. The adrenergic nervous system, through beta-2 adrenergic effects on the liver, plays a major role in the counter-regulatory response to hypoglycemia induced by insulin and oral agents. Nonselective betaadrenergic antagonists can therefore retard blood glucose rebound following hypoglycemia. These agents also mask symptoms of hypoglycemia, such as tachycardia and palpitations, which serve as vital warning signs to the patient.45’6” More controversial - in terms of both hypo- and hyperglycemia - is the role of beta-blockers in effecting glucose homeostasis. Propranolol and other nonselective agents have been implicated in causing

SYSTEMIC DRUG INTERACTIONS

WITH TOPICAL

hypoglycemia, however, this is most likely related to the effects of retarding blood glucose rebound and masking hypoglycemic symptoms. Studies of normal and diabetic patients receiving beta-blocker therapy have shown no overall increase in the incidence of hypoglycemia.‘“.““,“5 In regard to hyperglycemia, the beta-2 adrenergic receptors in the pancreas respond to stimulation with the release of insulin. Antagonists with beta-2 blocking activity can inhibit this release, although the magnitude of this effect is rarely, if ever, of clinical significance. Most reports, however, advise the use of beta-l selective antagonists in diabetic patients.““,‘~~.“‘?.‘” There are two reports of timolol associated with hypoglycemia in diabetic patients. The first was a 72-year-old woman who had a thirteen-year history of insulin-treated diabetes mellitus, and a history of one to four hypoglycemic episodes weekly, which she terminated with dietary intervention. Three weeks after starting timololO.5% twice daily in both eyes, she had a two-hour hypoglycemic episode requiring hospitalization, at which time she reported a recent subjective increase in hypoglycemic episodes. She did well following discharge on a lower insulin dose, but the report does not indicate whether the timolol was continued.’ The second case reported was a 65-year-old male diabetic on insulin for 25 years. He usually experienced one hypoglycemic episode per month characterized by diaphoresis, anxiety and visual sensations. Approximately fifteen months after the patient began timolol 0.25% twice daily in both eyes, his wife noted an increase in the frequency of hypoglycemic episodes to two or three per month, with a change in symptoms. During these episodes the patient was no longer having diaphoresis and anxiety, but instead was experiencing mental status changes with staring and grunting. Following the discontinuation of timolol the patient continued to experience several hypoglycemic reactions per month, but with a return of the previous symptoms of anxiety and diaphoresis.” Two important facts that make the causal relationship of timolol eye drops unlikely in this case. First, the patient continued to experience multiple hypoglycemic reactions even after the discontinuation of timolol and, second, beta blockers have been previously shown not to affect hypoglycemic-induced diaphoresis.‘” In both cases, it is not possible to convincingly implicate timolol as the cause of the hypoglycemic episodes. Topical nonselective beta blockers can be safely given to diabetic patients if blood glucose levels and hypoglycemic symptoms are monitored. Cardioselective beta blockers may have less effect on blood glucose control and therefore be preferred.

GLAUCOMA

MEDICATIONS

“09

3. Beta-adrenergic Antagonists [Atenolol (Tenormin@), Metoprolol (LopressoP), Propranolol (Inderal@), Timolol (Blocadrenm) The concurrent use of oral and topical betablockers theoretically has the potential for causing an additive cardioinhibitory effect. Yet, in a double blind trial of 3 1 patients with open angle glaucoma, the use of topical timololO.5% bid for one week did not enhance the pulse and blood pressure-lowering effects of timolol20 mg bid.’ In another study, seven healthy patients receiving SO-160 mg proprano101 daily were treated once with timolol 0.5’% in a single eye, and showed no significant effect on pulse rate or blood pressure.” In a recently published letter, betaxololO.581 was instilled in the left eye of an 81 -year-old male on atenolol 25 mg qd, followed withm minutes by an acute inferior myocardial infarction. The patient had a history of hypertension and was also receiving indapamide an oral diuretic with anti-hypertensive activity, and potassium chloride.“’ It is impossible to conclude what caused this event. In patients tolerating ophthalmic or systemic beta-blocker therapy, the addition of a second agent can almost always be added safely although it is recommended that heart rate and blood pressure be monitored for changes. 4. Calcium Channel Blocking Agents [(Diltiazem, Cardkern@), Nifedipine (Procardiam), Verapamil (Calan@)] Because they have similar pharmacologic effects, concurrent use of calcium channel antagonists with ophthalmic beta-blockers may lead to depressed atrioventricular conduction, as well as left ventricular failure and hypotension in patients with impaired cardiovascular function. Two cases of severe bradycardia have been reported in patients on timolol eye drops and verapamil. In one case, a 64-year-old man was receiving both verapamil 160 mg and timolol 0.5%’ twice daily, as well as pilocarpine 2% four times daily. He had been on these medications over a year when he presented with a sinus bradycardia of 36, which responded well within 4X hours to a change from verapamil to nifedipine. In the second case, a 52year-old man was hospitalized with atypical chest pain while on timololO.5% twice daily in both eyes. Shortly after admission to the coronary care unit and after receiving intravenous nitroglycerin and oral verapamil 40 mg, the patient used his timolol drops. His heart rate decreased after approximately thirty minutes and he experienced a ten-second period of asystole. Treatment with verapamil was discontinued and bradycardia did not return on

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35 (3) November-December

1990

GERBER ET AL

timolol alone. It is impossible to rule out that the verapamil may have been solely responsible for the bradycardia in both cases.“‘*0 Nifedipine or nicardipine may be the best choice if a calcium channel antagonist is needed. They have the most potent peripheral vasodilating effect of the available calcium channel blockers, while their ability to decrease cardiac contractility and slow atrial-ventricular conduction of the heart is least. Diltiazem is intermediate in peripheral and cardiac effects. Verapamil would be the most potentially hazardous, because of its predominantly cardiac depressant action.47.62 Calcium channel blockers and ophthalmic beta blockers may be used concurrently with caution.

medication, such as clonidine, may lead to a severe rebound increase in blood pressure. Theoretically, the increased peripheral vascular resistance due to beta-2 receptor blockade could aggravate this hypertensive crisis.40 There is one report of a 60-yearold woman on clonidine for ten months who was given oral timolol, 5 mg per day. The patient mistakenly stopped the clonidine abruptly and experienced a severe hypertensive crisis. Although this crisis may have been exacerbated by the betablocker therapy, it could also be explained by abrupt withdrawal of the clonidine alone.3 No specific concerns seem indicated for the simultaneous use of topical beta-blocker therapy and clonidine.

5. Cholinesterase Inhibitors [e.g., Edrophonium (TensiloS+), Neostigmine (Prostigmin@), Pyridostigmine (Mestinon@)]

7. Digitalis Preparations [e.g., Digoxin (Lanoxin@), Digitoxin (Crystodigin@)]

Two reports of patients with myasthenia gravis receiving pyridostigmine, a cholinesterase inhibitor, cited the addition of timolol eye drops 0.5% as the cause of significant worsening of dysarthria and ptosis. The first involved a 70-year-old man with gradual deterioration of muscle function and worsening of diplopia and ptosis during his six months of timolol eyedrop therapy. Within days of switching to pilocarpine the symptoms markedly improved. The second case was even more striking. A 71-year-old man had the onset of dysphagia, dysarthria and worsening of diplopia and ptosis twenty-four hours following the initiation of timolol therapy. Within twenty-four hours of stopping the timolol he returned to his original clinical status. Neither patient was rechallenged with timolol after discontinuation.75l8g These followed one report of three patients in whom orally administered propranolol and oxprenolol worsened symptoms of myasthenia gravis.” The proposed mechanism involves a depressant effect of beta-blockers on the neuromuscular junction.“” Such a phenomenon with propranolol and oxprenolol is understandable since the lipophilicity of each of these compounds allows them to permeate the cell membrane and interfere with propagation of the action potential. The topical beta-blockers, however, have limited membrane-stabilizing properties and therefore would be less likely to act by this mechanism.“” Physicians with patients with myasthenia gravis receiving pyridostigmine or other cholinomimetic agents should be aware of a possible interaction rarely occurring with topical beta blockers. 6. Clonidine (Catapres@) The abrupt

withdrawal

of any antihypertensive

Toxic levels of cardiac glycosides alone or of betaantagonists alone can result in bradycardia and heart block. The simultaneous use of systemic betablockers with digitalis glycosides can lead to additive cardiac toxicity.““*48 There is also some potential for beta-blockers to displace serum protein bound glycosides and, thereby, increase the digitalis blood concentration.“’ However, this effect is not considered to be of clinical significance when topical betablocking drugs are being administered. There are three case reports implicating an interaction between ophthalmic beta-blockers and digoxin. The first was an 84-year-old woman who experienced a syncopal episode with sinus bradycardia at a rate of 36 beats per minute, one hour following instillation of timolol 0.5%. The patient was receiving diltiazem. More important, she had a toxic digoxin level of 3.1 ng/ml.“‘j In the second case a 91-year-old woman developed palpitations and shortness of breath while on digoxin, furosemide, and 0.5% pilocarpine qid and 0.25% timolol bid in her right eye. Her digoxin level was also in the toxic range. Her electrocardiogram revealed an irregular heart rate of 35-50 beats per minute with heart block.‘l The third patient was an SO-year-old man with a history of congestive heart failure, atria1 fibrillation and sick sinus syndrome previously well controlled on digoxin 0.125 milligrams and metolazone, a diuretic. Within one week after the initiation of betaxolol 0.5% twice daily, he experienced pulmonary and peripheral edema with a ventricular rate of 30 beats per minute. Following diuretic therapy and discontinuation of betaxolol he recovered to his previous state of health. Digoxin levels were not determined during this course.4 The cases suggest that patients can be safely placed on both these medications except when digitalis levels are at or near toxic levels.

SYSTEMIC

DRUG

INTERACTIONS

WITH

TOPICAL

8. Fentanyl Derivatives [Fentanyl (Sublimaze@), Alfentail (Alfenta@), Sufentanil (Sufenta@)] Through competition for pulmonary binding sites, chronic oral propranolol therapy can significantly decrease first-pass pulmonary uptake of fentanyl, an intravenous anesthetic, resulting in increased levels of the drug in the systemic circulation and prolonged systemic side effects such as bradycardia and hypotension.“” Propanolol’s pulmonary binding is related to its relatively high lipophilicity. The topical ophthalmic beta-antagonists are less lipophilic than propranolol and may not exhibit this same interaction. ” In addition, there are no studies available documenting an interaction between fentanyl and the topical ophthalmic beta-antagonists. There is no evidence that prior to a surgical procedure a recommendation to discontinue the topical ophthalmic beta-blockers should be made. 9. Hypotension-producing Appendix II)

Medications (USPDI

The CJSPDI contains a list of 42 hypotension-producing medications or categories of medications that have the potential to react additively with ophthalmic beta-blockers. Included on this list are general anesthetic agents, calcium channel blockers, beta-adrenergic antagonists and clonidine, which are all discussed elsewhere in this section. Of the other agents listed, none except quinidine (discussed elsewhere) has been implicated in case reports. While physicians should use caution, no specific contraindications to the combined use of an ocular beta blocker and a systemically administered hypotensive agent can be made based upon available literature. 10. Phenothiazines [e.g., Chlorpromazine (Thorazine@), Fluphenazine (Prolixin@), Thioridazine (Mellarilm), Trifluoperazine (Stelazine@)] Warnings of interaction between opthalmic beta blockers and phenothiazines are based upon limited studies showing that propranolol combined with chlorpromazine or thioridazine may result in elevated plasma levels of both the beta blocker and the neuroleptic agent.“5.7”.x” When two patients on longterm thioridazine treatment received propranolol in a controlled, prospective study, they experienced a three to fivefold increase in plasma thioridazine levels within two weeks, placing them in a potentially toxic range. The enhanced efficacy of chlorpromazine in treating schizophrenic patients receiving betablocking medication prompted further investigation of their interaction.“’ Both propranolol and

GLAUCOMA

MEDICATIONS

211

chlorpromazine blood levels were elevated in the presence of each other.65.xx Although no mechanism of interaction was proposed, it may be related to competition in the liver where both compounds are metabolized. An alternative mechanism, competitive displacement from plasma protein binding sites has been shown to be not involved.“” These patients did not manifest toxicity in terms of cardiac arrhythmias or pigmentary retinal changes, but such increases in serum concentration if maintained for prolonged periods, might lead to such events. Timolol, like propranolol is hepatically metabolized and may exhibit a similar interaction although there are no reports documenting this. Many of the neuroleptic agents share common metabolic pathways, but extrapolating thioridazine and chlorpromazine data to these may not be justified. One other point which bears mentioning is the reported central nervous system eflects of topical beta blockers, such as depression, lethargy, confusion and hallucinations.“‘“,” Both case reports and large scale studies have suggested a link between oral beta-blockers and depression.” However, not all the data supports a relationship.“,“” If increased depression were to occur it could conceivably have a great impact on patients with psychiatric disorders. Unfortunately, there is little clinical data available regarding the interaction of systemic or topical beta-blockers with the many available neuroleptic agents. Despite this lack of documentation, one of the beta-antagonists used to treat glaucoma, betax0101, advertises that it is less likely to cause psychiatric effects because it is relatively beta-l selective. The evidence that psychiatric effects are a beta-2 antagonist action is even more tenuous. Physicians should be aware that beta-blockers have been implicated as a cause of increased depression but no specific contraindication to their use with neuroleptic agents is warranted. 11. Quinidine (Quinaglute@, Cardioquin@) Timolol, in blocking beta-adrenergic cardiac receptors may exacerbate the cardiodepressant activity associated with quinidine. A 70-year-old man was initially placed on quinidine, 500 mg three times daily, because of atria1 premature beats. After three months of this therapy without complications, timololO.5% in both eyes twice daily was prescribed for primary open angle glaucoma. Twelve weeks later the patient was hospitalized with dizziness and a heart rate of 36. Symptoms abated following discontinuation of both drugs. One month later the patient was admitted for rechallenge while cardiac monitoring was performed. He experienced no adverse effects on timolol alone for six days, but thirty hours following the addition of quinidine, sinus

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Surv Ophthalmol

35 (3) November-December

bradycardia returned. Only when both medications were utilized together did the patient experience side effects, thereby confirming a drug interaction.” If these two medications are to be used together, cardiac monitoring is advisable to rule out medication-induced bradycardia or heart block. 12. Reserpine (Serpasil@) Reserpine is an infrequently used antihypertensive agent which acts by depleting stores of catecholamines. Following administration a transient sympathomimetic effect occurs followed by a fall in blood pressure often associated with bradycardia. Reserpine in combination with beta blockers has the potential to cause additive cardiac depression leading to atrioventricular conduction disturbances, left ventricular failure and hypotension.” There are no clinical reports of such an interaction with systemic or topical beta-blocking medications. Therefore, no specific contraindication to the use of these two medications together is warranted.

13. Sympathomimetic Amines: [Alpha and Beta Receptor Agonists - Epinephrine, Ephedrine; Beta Receptor Agonists - Dobutamine (Dobutrexe); Metaproterenol (Alupente), Isoproterenol (Isuprele), Albuterol (Ventolin@, Proventile), Terbutaline (Brethinee), Isoetharine (Bronkosole)]

a. Systemic Hypertension Patients receiving low subcutaneous doses of epinephrine, an alpha and beta agonist, can experience rapid, marked increases in systolic and diastolic blood pressure with significant decreases in heart rate in the presence of propranolo1.24~3”S86 The mechanisms responsible for this hypertension are not fully elucidated. This effect was previously attributed to unopposed alpha receptor stimulation in the presence of beta blockade, although more recent studies present compelling evidence against such a hypothesis.58,68 These hypertensive episodes are possibly attributable to the epinephrine alone rather than any interaction. Owing to the controversial evidence supporting this interaction and the lack of reports citing such a reaction with topical beta-blockers, no specific contraindication to their combined use is warranted.

b. Cardiac Failure Beta blockers are specifically contraindicated in patients with overt cardiac failure, sinus bradycardia and second and third degree atrioventricular block.‘6*2g*46,57Patients who are ill enough to warrant potent inotropic agents such as dopamine and do-

1990

GERBER ET AL

butamine should therefore beta blockers.

not be given ophthalmic

c. Obstructive Pulmonary

Disease

Timolol and levobunolol as nonselective beta blockers are contraindicated in patients with underlying chronic obstructive pulmonary disease and bronchial asthma, because they block endogenous stimulation of beta-2 receptors as well as exogenous stimulation by medications such as isoproterenol, metaproterenol, isoetharine, albuterol and terbutaline.54*57*66,72,73There are many reports of patients on bronchodilators experiencing respiratory distress due to ophthalmic beta blocker administration.‘4*3’,57,73 Betaxolol, a relatively beta- 1 selective antagonist may have a therapeutic role in glaucoma patients who have underlying pulmonary disease. Although it may provoke asthmatic attacks betaxo101does not exhibit the same degree of beta-2 blocking activity as the nonselective ophthalmic beta blockers.35*70 Betaxolol can therefore often be used in the presence of bronchodilating medications, although respiratory function must be closely monitored.72,85

d. The Xanthines [Theophylline Aminophyllin, Slophyllin)]

(Theodur,

The xanthines act indirectly to enhance beta adrenergic function by inhibiting the breakdown of cyclic AMP. Beta blocking agents, particularly the noncardioselective ones, reduce the pharmacologic effects of xanthines by inhibiting the beta-2 receptor induced increase in cyclic AMP. This leads to increased bronchial resistance.14,57,73 In addition, theophylline is metabolized by the hepatic mixedfunction oxidase system. Beta-blockers, both cardioselective and nonselective, can through this competition reduce clearance of theophylline by 30-50%. This leads to an increased potential for theophylline toxicity. 15,50,56 There is no documentation of such an effect occurring with ophthalmic beta-antagonists. Patients receiving theophylline generally have moderately severe underlying pulmonary disease for which nonselective beta blockers are contraindicated. If a patient on theophylline is also receiving betaxolol, pulmonary function along with drug levels should be monitored closely.

II. Ophthalmic Adrenergic Agonists A. CHARACTERISTICS AND MECHANISMS The potential cardiovascular effects of topical epinephrine preparations have long been known. The ophthalmic administration of two drops of a 2% epinephrine solution (.05 ml/drop) can provide

SYSTEMIC

DRUG

INTERACTIONS

WITH

TOPICAL

up to 2.0 mg of systemic epinephrine.6 This dose of epinephrine can cause significant cardiovascular effects including hypertension and dysrhythmias and has the potential for interaction with systemic medications.‘*” There is, however, only one report of ophthalmic epinephrine interacting with another medication; this is the inhalational anesthetic agent, halothane. Otherwise, the drug interaction warnings in the LTSPDI and PDR for topical epinephrine are all based upon the interaction of low dose subcutaneous and intravenous epinephrine. Potential interactions with topical epinephrine are only speculative. Dipivalyl epinephrine (DPE, Propine) is a prodrug which is more lipid soluble and therefore more readily absorbed through the cornea than epinephrine. Lower concentrations can be administered with a reduced amount available for systemic absorption.x,44 There are no drug interactions reported for dipivalyl epinephrine in the USPDI or the PDR or in our literature search. B. INTERACTIONS 1. Anesthetic Halothane,

WITH

Agents

Isoflurane,

OTHER

DRUGS

(Cyclopropane,

Enflurane,

Methoxyflurane,

Trichloroethylene)

Halothane is capable of increasing the automaticity of the myocardium and thereby rendering it more susceptible to arrhythmogenic influences such as epinephrine. The other anesthetic agents may have similar effects. although this is somewhat controversial.‘“.“.4” Thus, the potential for interaction with ophthalmic epinephrine exists although limited documentation is available. There is one report of a patient who developed transient ventricular fibrillation following the administration of the equivalent of one milligram of topical epinephrine in a 2% ophthalmic solution during halothane anesthesia.‘” However, in a series of patients undergoing cataract surgery with halothane anesthesia, the injection of0.04-0.7 milligrams of epinephrine into the vitreous caused no change in the incidence of’ cardiac arrhythmias compared to a control group.“’ It is advisable to notify the anesthesiologist of any topical medications administered prior to or during surgery. However, no specific recommendation to discontinue topical ocular adrenergic medications prior to surgery can be supported. 2. Digitalis Glycosides Digitoxin

[Digoxin

(Lanoxin@),

(Crystodigin@)]

Digoxin toxicity frequently results in cardiac arrhythmias. As epinephrine alone can also cause such a reaction, it is postulated that there is an additive risk of arrhythmia in patients on both these medications.7x However, this is speculative as there

GLAUCOMA

2 I3

MEDICATIONS

is no documentation available supporting sertion. Topical epinephrine preparations given to digitalized patients. 3. Monoamine

Oxidase

[Isocarboxazid

(Mar-plan@), Phenelzine

Pargyline

(MAO)

this ascan be

Inhibitors

(EutonylQ), Tramylpromine

(Nardilm), (Parnate@)]

Monoamine oxidase inhibitors are used as both antihypertensive and antidepressant therapy. Although epinephrine is a substrate for the enzyme monoamine oxidase, termination of its action is mainly due to uptake into adrenergic neurons and metabolism by the enzyme catechol-o-methyl transferase. Therefore, there is little potential for a significant interaction as monoamine oxidase inhibitors would not be expected to greatly potentiate the effects of small amounts of epinephrine absorbed from topical application to the eye. ’ ‘z’~9xThe hypertensive crises which are known to occur with monoamine oxidase inhibitors are due to the ingestion of tyramine. As a sympathomimetic amine, tyramine acts peripherally, primarily by releasing stores of catecholamines at the myoneural junction of vascular smooth muscle. The hypertensive crisis is then created hy the release of large quantities of norepinephrine.” An effect as massive and localized as the tyramine reaction is extremely unlikely to occur with topical application of epinephrine. 4. Sympathomimetic

Agents (Systemic or Local)*

Theoretically, if significant systemic absorption of ophthalmic epinephrines were to occur, concurrent use of systemic sympathomimetics could cause toxicity.‘,“” However, this is based upon the potential for this absorption rather than documented cases. As there is no evidence to the contrary, ophthalmic epinephrine can he used safely with systemic sympathomimetics. Warnings of side effects with the combined use of topical epinephrine and local anesthetics containing vasoconstrictors are also based upon theoretical synergism. In any injection of local anesthetic, the minimum effective concentration of vasoconstrictor should be used but there is no specific contraindication for patients receiving ophthalmic epinephrine. 5. Tricyclic [Doxepin

and

Tetracyclic

(Sinequa@),

Maptrotiline (Ludiamila), (Pamelor@), Protriptyline

Antidepressants

Imipramine

(TofraniF),

Nortriptyline (Vivactil@)]

The tricyclic and tetracyclic antidepressants inhibit the re-uptake of catecholamines in a mamrer similar to cocaine. The proposed interaction be-

*See previous

list in beta-adrenergic

antagonist

section.

214

Surv Ophthalmol

35 (3) November-December

tween ophthalmic epinephrine and these antidepressants is based upon the ability of imipramine and protriptyline to increase the sensitivity to intravenous infusions of epineprhine. This was shown in a study of four normal patients receiving imipramine 25 milligrams three times daily for five days who when given an infusion of epinephrine developed sinus arrhythmia along with atria1 and ventricular ectopy. The presumed mechanism was the prolongation of epinephrine action by the imipramine’s inhibition of uptake into adrenergic nerve endings.” No reports of interaction with ophthalmic epinephrine are available. Patients on maprotiline, a tetracycline antidepressant, can safely receive ophthalmic epinephrine as the effects of sympathomimetics such as epinephrine are not consistently altered by this drug.g0 Patients on tricyclic and teracyclic antidepressants can safely receive concomitant topical epinephrine therapy.

III. Cholinergic Agents A. CHARACTERISTICS

AND MECHANISMS

1. Direct Acting There are few reports describing systemic side effects following topical ophthalmic pilocarpine or carbachol administration.23*26~30*4g Systemic levels must therefore be low although there are no specific studies of the systemic concentration following ophthalmic application. However, when given excessively pilocarpine and carbachol can directly stimulate cholinergic receptors which are found throughout the body. Locations include interneurons and postganglionic neurons of sympathetic and parasympathetic ganglia as well as neurons in the central nervous system. Stimulation by nicotinic agonists causes skeletal muscle contraction. Stimulation by muscarinic agonists causes smooth muscle contraction, salivary and sweat gland stimulation, pulmonary bronchoconstriction and gastrointestinal stimulation with nausea, vomiting and diarrhea. Central nervous system effects include depression, anxiety, headache, tremor and ataxia. Effects on the cardiovascular system depend upon the interplay between cholinergic stimulation of the heart’s muscarinic receptors causing bradycardia, negative inotropy and vasodilation versus sympathetic response to these changes resulting in the release of epinephrine and norepinephrine with subsequent tachycardia, increased inotropy and vasoconstriction.*’ Thus, it is difficult to predict whether cholinergic side effects and toxicity will result in an increase or decrease in heart rate and blood pressure. Pilocarpine is a muscarinic agonist. One drop of pilocarpine 4% (20 drops/cc) contains approximate-

1990

GERBER ET AL

ly 2.0 mg of the drug, which is about 20% of the subcutaneous dose capable of causing diaphoresis.30 Such a toxicity has been reported following the repeated administration of pilocarpine during attacks of angle closure glaucoma.4g However, in routine use, systemic side effects due to pilocarpine are rare. This is reflected by the paucity of articles describing potential drug interactions. There is a report of one patient receiving pilocarpine 2% and timolol 0.5% the evening prior to surgery, who developed bradycardia and hypotension during halothane anesthesia. However, the patient had undetectable serum plasma levels of pilocarpine (below 2 ng/ml) during the surgery. Instead, halothane in combination with a detectable serum timolol level and pre-existing cardiovascular disease were the more likely culprits. 55 Carbachol, unlike pilocarpine is both a muscarinic and nicotinic agonist. Skeletal muscle stimulation with muscle cramps, fasciculations and eventual severe weakness and paralysis would be expected to occur in addition to the signs and symptoms of toxicity already discussed with a muscarinic agonist such as pilocarpine. Although the risk is small, ophthalmologists should at least be aware of the potential for interaction between direct acting cholinergic agents and medications affecting cardiovascular, pulmonary and gastrointestinal function.

2. Ophthalmic

Cholinesterase

Inhibitors

Ophthalmic cholinesterase inhibitors include physostigmine, demecarium, isoflurophate and echothiophate. Rather than directly stimulating cholinergic receptors these medications act by inhibiting the cholinesterase enzyme responsible for metabolism of acetylcholine in neural tissues and effector organs. Physostigmine is termed a reversible inhibitor because the chemical tie-up of the cholinesterase enzyme may be hydrolyzed by water in a matter of hours. Echothiophate, demecarium and isoflurophate are irreversible inhibitors because they form a bond with cholinesterase which may not be hydrolyzed with water for several days, after which the cholinesterase enzyme is permanently altered and rendered inactive.” Because acetylcholine is found at muscarinic and nicotinic receptors, these cholinesterase inhibitors can produce a variety of cardiovascular, pulmonary, central nervous system and gastrointestinal effects.lg When cholinesterase inhibitors are lethal (e.g., insecticides such as maiathion) they act by paralyzing the respiratory muscles, which have been overstimulated by the accumulation of acetylcholine. Central nervous system effects such as headache, anxiety, confusion and depression are more likely to occur with isoflurophate due

SYSTEMIC DRUG INTERACTIONS WITH TOPICAL GLAUCOMA MEDICATIONS to its high lipid solubility, which allows it to more easily cross the blood-brain barrier as compared to echothiophate which carries a positive charge and is more hydrophilic. “’ Following topical ophthalmic administration of any of these medications measured decreases in erythrocyte and plasma cholinesterase activity have been shown.‘“.“:’ These could result in interaction with systemically administered medications as described below. B. INTERACTIONS WITH OTHER DRUGS 1. Anesthetic Agents - local, Ester-derivative (Cocaine, Procaine, Tetracaine) Prolonged ophthalmic use of anticholinesterase medications leads to reduced cholinesterase activity and a subsequent decrease in procaine hydrolysis. Patients with inherited atypical plasma cholinesterase have developed severe reactions, including cardiovascular collapse and convulsion after the injection of procaine for local anesthesia.“” This may be due to a failure to de-esterify any procaine that is absorbed into the systemic circulation. Theoretically, a vasoconstrictor such as epinephrine in the anesthetic solution would retard systemic absorption and reduce the chance of toxicities such as cardiac depression, peripheral vasodilation and respiratory depression. Patients receiving these topical ophthalmic cholinesterase inhibitors should be given procaine with caution. However, a better alternative would be the use ofamide compounds (mepivaCaine, bupivacaine and lidocaine) for local anesthesia. These compounds, are not esters, and hence, are not hydrolyzed by serum cholinesterase. Instead, they are metabolized in the liver. In addition, amide local anesthetics have less intrinsic toxic potency than do ester compounds and would thereafter be safer overall to administer to patients receiving cholinesterase inhibitors.

Systemically administered cholinesterase inhibitors are most commonly used in the treatment of myasthenia gravis. Owing to the ability of topical ophthalmic preparations to reduce serum cholinesterase levels, there is a theoretical risk of additive toxicity when combined with systemic cholinesterase inhibitors. “‘L’ However, there is no available documentation of such an interaction in the literature. No specific contraindication to the use of these two tapes of medications together is warranted. 3. Succinylcholine (Anectine@, Quelicinm) is a

neuromuscular

agent which causes skeletal muscle paralysis. It has a short half-life; effects from a 30 milligram intravenous dose last approximately five minutes. Serum cholinesterase is the enzyme responsible for metabolizing succinylcholine, an ester compound, which structurally consists of two molecules of acetylcholine bonded together at their choline ends.“’ Topical ophthalmic cholinesterase inhibitors can cause profound and longlasting depression ofserum cholinesterase levels, especially with the irreversible inhibitors echothiophate and isoflurophate.‘“,” “’ Two cases of prolonged apnea due to succinylcholine-induced respiratory muscle paralysis have been reported with the administration of succinylcholine to patients receiving topical echothiophate therapy. In the first case, a 12-year-old boy with congenital glaucoma was administered 40 milligrams of succinylcholine to facilitate endotracheal intubation prior to cryotherapy of his left eye. H< had been using 0.125% echothiophate iodide twice daily in both eyes for nine months. He experienced a forty-five minute period of apnea following the succinylcholine administration.“’ In the second case, a 72-year-old woman received a total of 200 milligrams of succinylcholine during surgical exploration of a presumed small bowel obstruction. She experienced a five-hour period ofapnea following the procedure. The dosage and duration of previous echothiophate iodide therapy was not deTopical cholinesterase scribed in the report.‘” inhibitors should be discontinued, if possible, four to six weeks prior to the use of succinylcholine.X’ If the anesthetist is notified, reduced amounts of succinylcholine or a nondepolarizing neuromuscular blocking agent (atracurium, pancuronium and t,ubocurarine) can be used since the latter is not metabolized by serum cholinesterase.

IV. Conclusionss

2. Cholinesterase Inhibitors [Edrophonium (Tensilo@), Neostigmine (Prostigmin@), Pyridostigmine (Mestinon)]

Succ-inylrholine

I!I.:

blocking

The potential for interaction exists when applying topical glaucoma medications to patients, many of whom are elderly and are on multiple medications. We have stressed however, the lack of clinical evidence and documentation for many of the interactions stated in the PDR and LTSPDI. This supports the excellent track record for safety of these drugs. In addition, there exist methods to minimize systemic absorption, such as nasolacrimal occlusion and eyelid closure. Clinicians, however, should still be aware of these possible interactions and keep them in mind when prescribing medication. Communication with the patient and with the patient’s other physicians is also advisable when initiating topical therapy for the treatment of glaucoma.

216

Surv

Ophthalmol

35 (3) November-December

Acknowledgment We acknowledge Alcon, Dohme for their assistance tion. The authors have no the products discussed in

Allergan, and Merck Sharp & in providing product informaproprietary interest in any of

this manuscript.

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1990

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24. Foster CA, Aston SJ: Propranolol-epinephrine interaction: a potential disaster. Plast Reconstr Sure 72:74-78. 1983 25. ‘Franfois J, Verbraeken H: Danger”of collyrium with 2% levorenone (abstract). Bull Sot Belge Ophthalmol185:99-102, 1979 26. Fraunfelder FT, Meyer SM: Systemic adverse reactions to glaucoma medications. Int O~hthalmol Clin 29: 143-I 46,1989 27. Gengo FM, Fagan SC, de Padova A, et al: The effect of betablockers on mental performance on older hypertensive patients. Arch Intern Med 148:779-784, 1988 28. Gesztes T: Prolonged apnea after saxamethonium injection associated with eye drops containing an anticholinesterase agent. Br J Anaesthesiol 38:408-410, 1966 29. Giudicelli JF, Chauvin M, Thuillez C, et al: B-Adrenoceptor blocking effects and pharmacokinetics of betaxolol (SL 75212) in man. Br J Clin Phurmucol 10:41-49, 1980 30. Greco JJ, Kelman CD: Systemic pilocarpine toxicity in the treatment of angle-closure glaucoma. Ann Ophthulmol 5: 57-59, 1973 31. Guzman C: Exacerbation of bronchorrhea by topical timo101. Ann Rev Resb Dis 121:899-900, 1980 32 Hansbrough JF,‘Near A: Propranolol-epinephrine: antagonism with hypertension and stroke. Ann Intern Med 92:717, 1980 33. Hansten P: Drug Interactions. Philadelphia, Lea & Febiger, 1985, ed 5 34. Hansten PD: Beta-blocking agents and anti-diabetic drugs. Drug Int Clin Pharm 14:46-50, 1980 35. Harris L, Greenstein S, Bloom A: Respiratory difficulties with betaxolol. Am J Ophthalmol 102.274-275, 1986 36. Hartley LR, Ungaden S, Davie I. et al: The effect of betablocking drugs on speakers performance and memory. Br J Psychiatry 142:5 12-5 15, 1983 37. Herishanu Y, Rosenberg P: Beta blockers and myasthenia gravis. Ann Intern Med 83:834-835, 1975 38. Horwitz D, Goldberg LI, Sjoerdsma A: Increased blood pressure responses to dopamine and norepinephrine produced by monoamine oxidase inhibitors in* man.j L.ub’CIin Med 56:747-753. 1960 39. Hunter JM: Synergism between halothane and labetolol. 4naesthesia 34:257-259, 1979 40. Hunyon SH, Hansson L, Harrison T, et al: Effects of clonidine withdrawal: possible mechanisms and suggestions for management. Br Med J 2:209-2 11, 1973 41. Johnston RR, Eger EI, Wilson C: A comparative interaction of epinephrine with enflurane, isoflurane and halothane in man. Anesth Analg 55:709-712, 1976 42. Katz RL, Epstein RA: The interaction of anesthetic agents and adrenergic drugs to produce cardiac arrhythmias. Anesthesiology 29:763-784, 1968 43. Katz RL, Matte0 RS, Papper EM: The injection of epinephrine during general anesthesia. 2. Halothane. Anesthesiology 23:597-600, 1962 44. Kerr CR, Hass I, Drance SM, et al: Cardiovascular effects of epinephrine and dipivalyl epinephrine applied topically to the eye in patients with glaucoma. Br J Ophthalmol 66: 109-114, 1982 45. Larner J: Insulin and oral hypoglycemic drugs, in Gilman A, Goodman L, Rall T, Murad F (eds): The Pharmacological Bask of Therapeutics (7th Edition). New York, MacMillan Publishing Co, 1985, pp 1492-1493 46. Leier CV, Baker ND, Weber PA: Cardiovascular effects of ophthalmic timolol. Ann Intern Med 104:197-199, 1986 47. Leier CV, Patrick Tl, Hermiller 1. et al: Nifedivine in congestive heart failure: effects on r&ting and exircise hemodynamics and regional blood flow. Am Heart J 108: 1461-1468, 1984 48. LeWinter MW, Crawford MH, O’Rourke RA, et al: The effects of oral propranolol, digoxin and combination therapy on the resting and exercise electrocardiogram. Am Heart J 93:202-209, 1977 49. Littmann L, Kempler P, Rohla M, et al: Severe symptomatic AV block induced by pilocarpine eye drops. Arch Intern Med 147:586-587, 1987 50. Lombardi TP, Bertino JS, Goldberg A,et al: The effects of a

SYSTEMIC DRUG INTERACTIONS

5 1.

51a.

52.

53.

54. 55.

56.

57.

58.

59. 60. 61.

62. 63. 64.

65.

66. 67.

68.

69.

70. 7 1. 72.

73.

74.

75. 76.

WITH TOPICAL GLAUCOMA

beta-2 selective adrenergic agent and a beta-non-selective antagonist on theophylline clearance. J Clin Pharmaco/ 27: 523-529, 1987 Lowenthal DT, Porter S, Saris SD, et al: Clinical pharmacology, pharmacodynamics and interactions with esmolol. AmJ Cardud 56:14F-17F, 1985 Lynch MC, Whitson JT, Brown RH, et al: Topical betablorher therapy and central nervous system side effects. A preliminary study comparing betaxalol and timolol. Arch OphWmol 106:908-911, 1988 Massara F, Strumia E. Camanni F. et al: Depressed tolbutamide-induced insulin response in subjects treated with propranolol. Dinhrlologiu 7:287-299, 1971 McGdvi D: Depressed levels of serum pseudo-cholinesterase with echothiophate iodide eye drops. I_ancet 2:272-273, 1975 Middleton E, Finke SR: Metabolic response to epinephrine in bronchial asthma. J ,411~g~ 12:288-299, 1968 Mishra P, Calvey I‘N. Williams NE, et al: Intraoperative bradycardia and hypotension associated with timolol and pilocarpine eye drops. Hr,J .4nuesthesio/ 55;897-899, 1983 Mue S, Sasaki ~1’.Shibahara S, et al: Clinical pharmacokinetits of rhetjphylline and propranolol. Itti ,J C/in Phnrmacol Biophurm I7:346-350, t 97’1 Munroe WP, Rindone JP. Kershner RM: Systemic side ef fects associated with the ophthalmic administration of timoloI. Drrcg /n&l/ C/in Phalrn I9:85-89, 1985 Mters MC:: Beta-adrenoceptor antagonism and pressor response to phcnylephrine. (:11n Pharmacol Ther ?6:57-63, 1984 Nits A.J. Shand DC;: Clinical pharmacology of propranolol. Ci,.c&/ion 52%14, 1975 Novack (;D: Ophthalmic beta-blockers since timolol. S’ztnj Ophplrlhrrlmol31:307-327, 1987 Noback GD,Tang-Liu D, Kelley EP, et al: Plasma levobunolol levels litllowing topical administration with reference to systemic side cftects. Oph~hnlmolog~ra 194: 194-200, 1987 Opie LH. White DA: Adverse interaction between nifedipine and beta-blockade. R,- Med J 281; 1462, 1980 Postman J: Beta-adrenerglc blockade and diabetes mellitus. A review. .4cto Mrd Scnnd [~uppi] 672:69-77, 1983 Pantuck EJ: Echothiophate eve drops and prolonged re;c;se to suxamethonium. tlr / .4nae.~thesio/ 38:406-407. Peet M, Middlemiss DN, Yates RA, et al: Pharmacokinetic inttraction between propranolol and chlorpromazine in schizophrenic patients. I.orrcrl 2t978, 1980 Print-c DS, Carliner NH: Respiratory arrest following first d(tse ot timolol ophthalmic solution. (;hhp.\lKqr640-641, 1983 PI,ingle SD. MacEwen