Drug Interactions between Betagan C-Cap and Extendryl PEM

MONITOR: The pressor response to phenylephrine may be potentiated by the vagolytic effect of atropine, which inhibits the reflex bradycardia that would normally accompany any increases in blood pressure induced by phenylephrine. Other antimuscarinic agents may also participate in this interaction, although clinical data are lacking. In one report, pseudo-pheochromocytoma (i.e., significant increases in blood pressure and tachycardia) occurred in seven patients who underwent eye surgery and were given phenylephrine 10% ophthalmic solution and systemic atropine, three of whom subsequently developed left ventricular failure and pulmonary edema that required intensive care monitoring. Two patients had preexisting hypertension, while others had no known history of cardiovascular disease. All had received general anesthesia with propofol, phenoperidine, and vecuronium. Since phenylephrine use alone may be associated with cardiovascular toxicities including hypertension, arrhythmia, myocardial infarction and cardiac failure, the extent of involvement by atropine is uncertain. The authors reported no further cardiovascular events following implementation of various measures that reduced phenylephrine dosage and systemic exposure, including: use of a milder strength of phenylephrine ophthalmic solution; swabbing to minimize drainage into the nasolachrymal duct to the nasal mucosa; and use of a cannula to reduce drop size. In a study of six healthy volunteers, diastolic and systolic blood pressure increased by 4 mmHg following administration of phenylephrine (0.42 mcg/kg/min), compared to 17 mmHg when phenylephrine was given after three doses of atropine (0.02, 0.01 and 0.01 mg/kg at 30 minute intervals).

MANAGEMENT: Caution is advised if phenylephrine (systemic or ophthalmic) is used in combination with atropine or other antimuscarinic agents. Cardiovascular status, including blood pressure and heart rate, should be closely monitored. When using ophthalmic formulations, measures to minimize systemic absorption should be employed, such as digital compression of the lacrimal sac or lid closure after instillation. A milder strength (< 10%) is preferable if phenylephrine ophthalmic solution is given.

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MONITOR: A case report suggests that beta-blockers may enhance the pressor response to phenylephrine. The proposed mechanism involves blockade of beta-2 adrenergic receptors in the peripheral vasculature, resulting in unopposed alpha-adrenergic effect of phenylephrine that is responsible for vasoconstriction. Additionally, beta-blockers may desensitize baroreceptors that normally modulate heart rate in response to blood pressure elevations by increasing vagal activity on the sinoauricular node. In the case report, a woman with a history of hypertension treated with hydrochlorothiazide (50 mg twice a day) and propranolol (40 mg four times a day) developed sudden bitemporal pain and became unconscious shortly after she was given one drop of a 10% phenylephrine solution in each eye during an ophthalmic examination. She subsequently died of intracerebral hemorrhage due to rupture of a berry aneurysm. The authors noted that the patient had received the same eye drop without incident on two previous occasions when she was not receiving blood pressure or other medications. Nevertheless, an interaction between phenylephrine and beta-blockers is not well established. Phenylephrine acts predominantly on alpha-adrenergic receptors and has little or no direct effect on beta-2 adrenergic receptors, although it may affect them indirectly by enhancing release of norepinephrine from adrenergic nerve terminals. In a study of 12 patients with hypertension, mean phenylephrine doses required to increase systolic blood pressure by 25 mmHg were not significantly different following 2 weeks on propranolol, metoprolol, and placebo (4.8 mcg/kg, 4.7 mcg/kg, and 5.3 mcg/kg, respectively). Baroreceptor-mediated decreases in heart rate during phenylephrine infusion were also in the same range on propranolol, metoprolol, and placebo over baseline heart rate values. In another study, no changes in blood pressure or heart rate were observed in hypertensive patients treated with metoprolol who were given 0.5 to 4 mg doses of phenylephrine intranasally every hour up to a total of 7.5 to 15 mg, or 4 to 30 times the usual recommended dose, compared to placebo or baseline values. These results support the lack of a significant interaction between beta-blockers and phenylephrine.

MANAGEMENT: Until more information is available, caution should be exercised when phenylephrine is used in combination with beta-blockers including ophthalmic formulations, which may be systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Monitoring of blood pressure should be considered, particularly when phenylephrine is administered intravenously or intraocularly. Although an interaction is not likely to occur with cardioselective beta-blockers, caution may be advisable when high dosages are used, since cardioselectivity is not absolute and may be lost with larger doses. A beta-blocker such as propranolol may be used to treat cardiac arrhythmias that occur during administration of phenylephrine.

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