LaserVision.gr | Systemic Calcium Channel Blockers and Glaucoma

Anastasios John Kanellopoulos, M.D., Kristine A. Erickson, Ph.D.,
and Peter A. Netland, M.D., Ph.D.

Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, U.S.A.

Calcium channel blockers are a group of drugs that were initially developed for use in the management of patients with angina pectoris (1). Since their introduction, calcium channel blockers have had a major impact in the therapy of patients with cardiac and vascular disease, including vasospastic and chronic angina pectoris, supraventricular tachyarrhythmias, and essential hypertension. These agents alter calcium uptake across cell membranes, affecting intracellular calcium uptake or release. This affects blood vessels, by reducing their resis- tance and preventing vasospasm. Potential applications for calcium channel blockers include Raynaud's syndrome and migraine headaches as well as disorders such as asthma and esophageal spasm.

Verapamil, nifedipine, and diltiazern can be considered the first generation of calcium channel blockers. Many of the newer agents exhibit a greater degree of selectivity for cerebral, coronary, and peripheral vasculature (2). Nimodipine is selective for the cerebral vasculature and has been shown to reverse cerebral vasospasm and increase cerebral blood flow (3). Nicardipine is more selective for vascular smooth muscle than nifedipine. Felodipine, nisolpidine, isradipine, and nitrendipine are potent vasodilators for peripheral vasculature (4).

The potential clinical role of calcium channel blockers in the management of glaucoma is of current interest. This review summarizes the ocular effects of systemic calcium channel blockers that may have applications in glaucoma therapy.

The most common form of glaucoma is associated with elevated intraocular pressure, optic nerve damage, and progressive visual field loss. Low-tension glaucoma is increasingly recognized as a relatively common disorder, present in one-fifth to one-half of all open-angle glaucoma patients (5). Low-tension glaucoma is associated with glaucomatous optic nerve and visual field damage in the absence of elevated intraocular pressure. This entity has also been called "normal-tension glaucoma," because the intraocular pressure is generally in the normal range.

Although the pathogenesis of low-tension glaucoma remains obscure, several hypotheses have been proposed (5). One advocates the mechanical susceptibility of the optic nerve to intraocular pressure levels considered normal. Another possibility is that inadequate blood perfusion of the optic nerve is the cause. Optic nerve ischemia can result from either sustained reduction in the blood flow to the optic nerve head or vasospastic episodes causing intermittent ischemia.

Traditional ocular hypotensive therapy has been often unsatisfactory in halting the progression of optic nerve damage and visual field loss in low-tension glaucoma (6). In a study of low-tension glaucoma patients followed for an average of 5 years, all patients had received con- ventional medical treatment and two-thirds had undergone at least one surgical procedure. Despite these efforts, 62% continued to lose visual field over the 5-year period (7). It appears that alternative means of treatment for low-tension glaucoma may be necessary to prevent deterioration in visual fields and optic nerve damage. Theoretically, the ideal medication for low-tension glaucoma patients would decrease intraocular pressure and facilitate optic nerve perfusion. Because of their effects on blood vessels and intraocular pressure, calcium chan- nel blockers may have clinical application in the therapy of low-tension glaucoma patients.

Harino and co-workers (8) studied the effect of intravenous nicardipine on optic nerve head blood flow in cats using laser Doppler flowmetry. Systemic nicardipine produced a significant increase in optic nerve head blood flow despite a drop in systemic blood pressure. Measurements with an oxygen-sensitive microelectrode placed in the vitreous just anterior to the optic disc showed a significant increase in the partial pressure of oxygen that paralleled the increase in optic nerve head blood flow. In rabbit retinal vessels, an average dilation of retinal vessels of up to 22% was found after intravenous administration of nicardipine (9). In the retinal vessels with angiospasm due to retinal detachment, retinal arterioles dilated up to 97% over the caliber prior to nicardipine. Similarly, Nielson and Nyborg (10) have shown that nitrendipine and D600, a verapamil analogue, cause relaxation of the prostaglandin-induced constriction of isolated calf retinal vessels (10). Both diltiazern and verapamil have been shown to cause relaxation of cat ophthalmociliary artery ring segments in vitro (II).

In normal human subjects studied using color Doppler ultrasonography, topical verapamil was found to reduce the resistive index in the central retinal artery (12). The change in the vascular resistance resulted primarily from an increased end-diastolic velocity in the central retinal artery (Fig. 1). Color Doppler ultrasound is a noninvasive technique that can measure hemodynamic changes in relatively large retrobulbar vessels, whereas the laser Dopper technique examines directly the capillary blood speed in the anterior optic nerve head. Using the laser Doppler technique, Netland and co-workers (13) found an increased capillary blood speed in the optic nerve head in normal subjects following topical verapamil administration. In a study using fluorescein angiography, tissue perfusion in ischemic areas of the retina and optic nerve was improved following systemic administration of the calcium channel blockers cinnarizine and flunarizine, although there were no controls for comparison (14). In a study of 17 low-tension glaucoma patients using color Doppler ultrasound, contrast sensitivity was improved and retrobulbar blood velocities were increased in 8 patients (47%) following 6 months of therapy with oral nifedipine (15).

Systemic administration of calcium channel blockers has either had no effect or caused mild reduction of intraocular pressure in both experimental and clinical studies (Table 1). In rabbits, intravenous administration of verapamil or nifedipine caused a reduction of the intraocular pressure (16,17). Oral administration of verapamil in rabbits, however, had no effect on the intraocular pressure (18). This lack of effect may have been due to lower concentrations in the eye following oral compared with intravenous administration.

Monica and co-workers (19) found a significant reduction of intraocular pressure after oral nitrendipine in patients with systemic hypertension. Similarly, Schnell (20) reported significant reduction of intraocular pressure up to 13% in open-angle glaucoma patients following a single sublingual administration of nifedipine. In contrast, oral verapamil (18), oral or intravenous nifedipine (21), and oral diltiazern (22) did not have significant effect on intraocular pressure in normal human subjects.

Topical administration of calcium channel blockers has been found to have a moderate ocular hypotensive effect, with a more consistent reduction of intraocular pressure than has been observed following systemic administration (23). This may be due to a more optimal local concentration of calcium channel blocker following topical compared with systemic administration. Topical administration of 0.125% verapamil in rabbits produced peak aqueous humor levels in the 10-6 M range, which was 200-fold higher than the peak drug levels following high-dose systemic administration (24). Verapamil causes a dose-related increase in outflow facility in human eyes, which may explain the mechanism of the effect on intraocular pressure following topical adminis- tration of this calcium channel blocker (25).

In rabbits, Segarra and co-workers (26) found that topical verapamil and nifedipine lowered intraocular pressure. In this study, topical verapamil had a greater effect than nifedipine on intraocular pressure. Payne and associates (17), however, found no significant effect of topical nifedipine, verapamil, or diltiazern on intraocular pressure. In contrast, topical administration of 1.5 and 5% verapamil in rabbits resulted in transient elevation of intraocular pressure (18). This finding suggests a dose-dependent, biphasic response at higher concentrations of topical verapamil. Calcium channel blockers have multiple nonspecific effects at higher concentrations, which may produce unexpected results (23).

Topical administration of one dose of 0.125% verapamil caused up to 15% reduction of intraocular pressure in ocular hypertensive subjects (27). Significant reduction of intraocular pressure was sustained in ocular hypertensive subjects following topical administration of 0.125% verapamil three times daily for 2 weeks (28). In normal subjects, topical administration of 0.125 and 0.25% verapamil resulted in significant reduction of intraocular pressure (12,13). Beatty and co-workers (18) found, however, that higher concentrations of topical verapamil (2%) did not reduce intraocular pressure in normal subjects (18). Although they are currently for investigational use only, these findings indicate a potential role for topical calcium channel blockers in the management of glaucoma.

In patients with digital vasospasm documented by a local capillary cooling test, visual fields worsened after placing one hand in cold water and improved after treatment with systemic nifedipine (29,30). Kitazawa and coworkers (31) treated 25 patients with low-tension glaucoma with systemic nifedipine for a period of 6 months. Although this study had no control group for comparison, six patients showed sustained improvement in visual fields during the course of the study. Similarly, contrast sensitivity was significantly improved 2 h after a single dose of oral nimodipine in 14 patients with low-tension glaucoma and 17 control subjects (32). We have observed anecdotal examples of visual field stabilization or improvement in low-tension glaucoma patients following treatment with systemic calcium channel blockers (Fig. 2).

In a study of the neuroretinal rim area of the optic nerve, 10 patients with low-tension glaucoma who were treated with nifedipine were compared with II treated with acetazolamide and 11 patients on no therapy (33). There was no statistically significant difference in progressive loss of optic nerve rim area among the three groups, although progressive changes of optic nerve contour and visual fields were not evaluated.

Fifty-six patients with either open-angle or low-tension glaucoma who were concurrently taking calcium channel blockers were retrospectively compared with similar control groups not taking such medications for a mean follow-up of 3.4 years (34). In the low-tension glaucoma patients, there were significantly fewer progressive changes of visual fields and optic nerve contour in patients using calcium channel blockers than in controls (Fig. 3). These results indicate that systemic use of calcium channel blockers can be associated with slowed progression of low-tension glaucoma. The more stable course of low-tension glaucoma in patients on calcium channel blockers may be related to the inhibition of vasospasm, enhancement of ocular blood flow, or a neuroprotective effect caused by these drugs.

The short-term influence of nifedipine was evaluated in 59 patients with visual field defects: 38 with optic nerve head pathology and 21 with normal-appearing optic nerves (35). A statistically significant improvement of the visual fields was observed following treatment with systemic nifedipine. This effect was more pronounced in younger patients and those with normal-appearing optic nerve heads. In patients with visual field improvement, the changes were observed in scotomatous and nonscotomatous areas.

Sawada et al. (36) described the effect of the calcium channel blocker brovincamine fumarate on visual field changes in low-tension glaucoma in a prospective, placebo-controlled study. Brovincamine dilates intracranial vessels more selectively than does nifedipine, thereby minimizing adverse effects of peripheral vasodilation, including facial flushing and orthostatic hypotension. After a minimum follow-up of 2.5 years, Humphrey Statpac 2 linear regression analysis indicated that 6 of 14 brovincamine-treated eyes had improved visual fields, with no significant change in the remaining 8 patients. In contrast, none of the control patients had visual field im- provement, 2 had visual field deterioration, and 12 had r) unchanged visual fields. Analysis with )( of the visual field outcomes showed a statistically significant difference of the brovincamine-treated group compared with controls, indicating an association between improved visual field prognosis and brovincamine use. Better recovery of skin temperature after cold exposure and higher systolic blood pressure were identified as factors that may be related to a favorable response to brovincamine.

Systemic calcium channel blockers and topical P-blockers should be used concurrently with caution, especially in patients with impaired cardiovascular function. There have been two reports of severe bradycardia with concomitant use of timolol eye drops and oral verapamil (37,38). It is possible that calcium channel blockers other than verapamil with less cardiac and more specific vascular activity would be less likely to cause cardiac side effects. Calcium channel blockers appear to have a favorable ocular safety profile. In patients treated with high doses of oral verapamil for hypertrophic cardiomyopathy, there was no significant effect on lens transparency compared with controls following 1year of therapy (39).

Adverse effects of systemically administered calcium channel blockers may occur, but are generally not serious and rarely require discontinuation of therapy or dosage adjustment. Side effects may include peripheral edema, palpitations, transient hypotension, dizziness or lightheadedness, nausea, constipation or diarrhea, headache, weakness, nasal or chest congestion, and muscle cramps. A short-term meta-analysis of calcium antagonists has suggested a possible increased mortality in patients with coronary heart disease (40), but this possible relationship has been debated (41).

In patients with low-tension glaucoma, calcium channel blockers are potentially helpful in preventing pro- gression of the disease. Calcium channel blockers may be the drug of first choice for antihypertensive therapy in patients with systemic hypertension and low-tension glaucoma. In addition, after considering the risks, potential benefits, and surgical alternatives, low-tension glaucoma patients who continue to demonstrate disease pro- gression despite maximal tolerated medical therapy may elect treatment with systemic calcium channel blockers. Future clinical experience with systemic calcium channel blockers may suggest an expanded role for these drugs in the management of low-tension glaucoma patients. Because of their consistent moderate ocular hypotensive effect, topical calcium channel blockers may also have a role in the therapy of elevated intraocular pressure. Topical calcium channel blockers are currently under investigation for potential clinical use.

Calcium channel blockers currently available in the United States for the management of hypertension and their usual systemic doses are shown in Table 2. These drugs are generally prescribed by the ophthalmologist in collaboration with the patient's internist. Because there is no readily apparent clinical end-point, normotensive low-tension glaucoma patients are usually treated with the lowest recommended systemic dose to minimize complications. This differs from the use of calcium channel antagonists in the treatment of systemic hypertension, in which the blood pressure response can be monitored. Patients treated with calcium channel blockers may re- port subjective changes, such as increased warmth of the skin.

In low-tension glaucoma patients treated with systemic calcium channel blockers, the blood pressure should be monitored closely, especially in normotensive patients. Nocturnal reduction of blood pressure can be associated with progressive visual field loss in patients with glaucoma (42,43). Calcium antagonists, particularly when administered at night, can increase the magnitude of the nocturnal reduction of systemic blood pressure (44). Marked deterioration of the visual field has been reported in one patient with low systemic blood pressure (35). Although 24-h ambulatory blood pressure monitoring is often not practical clinically, patients or their partners may be able to measure the blood pressure at night, which can provide helpful information. In normotensive patients, it may be preferable to avoid sustained release formulations and even to avoid the evening dose of the calcium channel blocker.

Calcium channel blockers have ocular effects that may benefit glaucoma patients, particularly patients with lowtension glaucoma. Although less consistent compared with topical administration, systemic treatment with calcium channel blockers can cause a mild reduction of intraocular pressure. In some low-tension glaucoma patients, calcium channel blockers slow the rate of glaucomatous progression, possibly by increasing optic nerve blood flovrr; reducing vasospasm, or a neuroprotective effect. The blood pressure should be monitored in patients treated with these drugs, and arterial hypotension avoided by adjusting the dosing of the medication. Systemic calcium channel blocker therapy is potentially useful in select patients with low-tension glaucoma.

Acknowledgment: This work was supported in part by grants from Research to Prevent Blindness and the Massachu- setts Lions Eye Research Fund. The authors have no propri- etary interest in any product mentioned in this article.

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