Drug Interactions between chlorpheniramine / epinephrine and Timoptic-XE

MONITOR CLOSELY: Noncardioselective beta-blockers can significantly enhance the pressor response to epinephrine. The mechanism involves blockade of beta-2 adrenergic receptors in the peripheral vasculature, resulting in unopposed alpha-adrenergic effect of epinephrine that is responsible for vasoconstriction. Severe hypertension accompanied by bradycardia has been reported in patients who were treated with a noncardioselective beta-blocker like propranolol or nadolol prior to receiving epinephrine. In rare cases, cardiac arrest and stroke have occurred. This interaction has not been reported with cardioselective beta-blockers, which generally have little effect on beta-2 adrenergic receptors at therapeutic dosages. In studies of hypertensive patients, treatment with propranolol was associated with significant increases in blood pressure and peripheral vascular resistance and decreases in heart rate and forearm blood flow in response to epinephrine administration, while metoprolol had only minor effects on epinephrine-induced cardiovascular changes compared to placebo. Similarly, in 24 healthy subjects treated with nadolol, atenolol, or placebo for one week prior to epinephrine administration, mean arterial pressure and calf vascular resistance increased significantly in the nadolol group but not in the atenolol group, and marked bradycardia also occurred in the former but not latter group. Theoretically, the interaction may also occur with noncardioselective beta-blocker ophthalmic preparations, since they may be systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels.

MONITOR CLOSELY: Beta-blockers may attenuate the response to epinephrine in the treatment of anaphylactic reactions. Noncardioselective beta-blockers, in particular, can antagonize the bronchodilating effects of epinephrine by blocking beta-2 adrenergic receptors in smooth muscles of the bronchial tree. All beta-blockers can antagonize the cardiostimulatory effects of epinephrine by blocking beta-1 adrenergic receptors in the heart. Some investigators have suggested that the use of beta-blockers in itself is associated with an increased incidence and severity of anaphylaxis due to modulation of adenylate cyclase, which can influence release of anaphylactogenic mediators. However, data are limited and conflicting.

MANAGEMENT: Extreme caution and close monitoring of cardiovascular status are indicated when epinephrine is administered to patients treated with noncardioselective beta-blockers. A dosage reduction of epinephrine may be necessary. Withdrawal of beta-blockers before anesthesia may increase the risk of myocardial ischemia and is not recommended. The interaction is not expected to occur with local anesthetics used in dental surgery that contain very low concentrations of epinephrine.

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MONITOR: Coadministration with inhibitors of CYP450 2D6 may increase the systemic effects of topically administered timolol, which is metabolized by the isoenzyme. Following ocular administration, timolol is systemically absorbed and can reach plasma levels associated with adverse beta-adrenergic blocking effects such as bronchospasm, depression, bradycardia, and hypotension. The risk may be increased if clearance of the drug is significantly diminished by concomitant CYP450 2D6 inhibitors. In one case report, a 70-year-old man experienced dizziness secondary to sinus bradycardia after 12 weeks of treatment with a 0.5% timolol eye drop while also taking quinidine sulfate 500 mg three times a day. The symptoms subsided and sinus rhythm returned to normal a day after discontinuation of both drugs. However, symptoms returned within 30 hours after restarting both drugs a month later. Quinidine was discontinued, and the patient did not experience further problems. In a study of 13 healthy volunteers, extensive metabolizers of CYP450 2D6 administered quinidine (50 mg single oral dose) 30 minutes before 0.5% timolol eye drop (2 drops in each nostril) demonstrated significantly greater reductions in exercise heart rate and had higher plasma timolol concentrations than when given timolol alone. The changes resulted in values that were similar to those observed in poor metabolizers given the timolol eye drop without quinidine. In another study, 12 healthy volunteers given cimetidine (400 mg orally twice a day for 7 doses) and 0.5% timolol eye drop (0.05 mL in each eye 30 minutes after last dose of cimetidine) demonstrated additional reductions in resting heart rate and intraocular pressure relative to administration of the timolol eye drop alone, although there were no additional reductions of exercise heart rate or systolic blood pressure (at rest or after exercise) compared to timolol alone.

MANAGEMENT: Patients should be monitored for systemic beta-adrenergic blocking effects of topical timolol during coadministration with CYP450 2D6 inhibitors such as cimetidine, quinidine, and certain selective serotonin reuptake inhibitors. Particular caution is warranted in elderly patients, since they are generally more susceptible to adverse effects of topically administered beta blockers.

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