CardiovascularDrugs and Therapy4:97-991990 © KluwerAcademicPublishers. Printed in the U.S.A.
EFFECTSOFKETANSERINONINTRAOCULAR PRESSURE
SUMMARY. There is e v i d e n c e that some antihypertensive drugs, such as beta blockers, are effective in r e d u c i n g intraocular pressure (IOP) and are c o m m o n l y u s e d in the medical treatment of glaucoma. The aim of this s t u d y w a s to evaluate the effects of the anti-serotonergic agent ketanserin, w h i c h has associated alpha]-blocking properties, on IOP in n o r m o t e n s i v e and hypertensive eyes. The first part of the study w a s performed in six arterial h y p e r t e n s i v e patients (mean ± SD blood pressure 156/102 ± 10/6 mml'Ig) w i t h a pretreatment IOP in the normal range (15.7 ± I mmHg). Both blood pressure and IOP w e r e m e a s u r e d at baseline and at 1 h o u r intervals up to 3 hours f o l l o w i n g the oral administration of k e t a n s e r i n 20 m g or placebo, given in a r a n d o m i z e d manner. Three hours after ketanserin treatment, m e a n systolic and diastolic blood pressures dropped by 10/5 m m H g and m e a n IOP w a s reduced by 2.7 mml-lg;, after placebo, no change w a s observed in these variables. Thereafter, four n o r m o t e n s i v e patients w i t h chronic open-angle glaucoma (IOP = 22.8 mmHg) w e r e given 20 m g k e t a n s e r i n orally. Three hours after administration, a 22% reduction in m e a n IOP occurred (-5.8 mmtIg), w i t h a concomitant reduction in m e a n systolic blood pressure of 13.0 mmHg. These results indicate that k e t a n s e r i n treatment reduces IOP and systemic blood pressure. Further, long-term studies are n e e d e d in order to confirm the efficacy of ketanserin in the medical treatment of ocular hypertension. KEY WORDS. intraocular pressure, open-angle glaucoma, ketanserin
t0hmong antihypertensive agents, beta blockers are commonly used to lower intraocular pressure (IOP) in patients with open-angle glaucoma [1]. Ketanserin, the first selective 5HT2 receptor antagonist drug, has proven effective in reducing blood pressure (BP) in patients with mild-to-moderate arterial hypertension, alone or in combination [2-5]. In experimental studies, topically applied, this drug was able to reduce IOP in rabbits, cats, and monkeys [6, 7]; there is, however, no study to date regarding ketanserin t r e a t m e n t of elevated IOP in humans. The aims of this clinical trial were to evaluate the effects of oral ketanserin on a) intraocular pressure in hypertensive patients with normotensive eyes and b) IOP in normotensive patients affected by openangle glaucoma.
Ciro Costagliola, 1 Maria Lusia Fasano, 2 Giovanni Iuliano, 1 Liberato Aldo Ferrara 2 1Eye Clinic, 1st Medical School,University of Naples, Italy 2Institute of Internal Medicine and Metabolic Diseases, 2nd Medical School,University of Naples, Italy
Patients and Methods Two different groups of patients entered this study. Group A consisted of six patients (four male, two female), age range 28-51 years, with mild-to-moderate arterial hypertension (entry BP 156/102 _+ 10/6 mmHg) and normal intraocular pressure (15.7 _+ 1.5 mmHg). These patients discontinued any previous antihypertensive t r e a t m e n t for a 2-week washout period before the study commenced. Group B consisted of four patients (one male, three female), age range 30-54 years, with open-angle glaucoma (IOP = 22.8 _+1.3 mmHg) and arterial pressure in the normal range (BP = 140/80 _+12/5 mmHg). They had stopped their previous t r e a t m e n t (topically applied pilocarpine or beta blocker) for a 7-day washout period before the study commenced. The hypertensive group received, in a randomized order, ketanserin 20 mg or placebo at 1-week intervals. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and IOP were measured before treatment and at 1-hour intervals during the 3 hours following treatment. The group with open-angle glaucoma received 20 mg ketanserin only. Measurements of BP, HR, and IOP were performed according to the scheduled protocol as described for patients with normal intraocular pressure.
Statistical Procedures Data are expressed as mean _+ standard deviation. Significances were assessed using Student's paired
Address for correspondenceand reprint requests: L. Aldo Ferrara, MD, Assistant Professor, Clinica Medica, 2nd Medical School, University of Naples, Via S. Pansini 5, 80131 Napoli, Italy. 97
98
Costagliolaet al.
Table 1. SBP and DBP variations after ketanserin administration.
SBP mmHg (mean _+SD) 0 Group A Group B
1 hour
2 hours
DBP mmHg (mean + SD) 3 hours
156.0 _+10.5 141.2 + 13.2 142.3 _+12.1 144.3 _+12.3 140.5 _+12.3 132.5 _+12.5 128.8 + 11.7 127.5 _+11.2
t test. The strength of the correlations was evaluated by linear regression analysis.
0
102.1 _+6.3 98.8 _+5.2 80.0 + 5.1 80.0 _+2.5
Discussion Ketanserin, the first antiserotonergic agent commonly used in the treatment of arterial hypertension, has been shown to reduce ocular pressure in experimental models when applied topically. However, no observations had been made in h u m a n s regarding
2 hours
3 hours
96.3 -+5.5 80.0 -+5.2
96.5 _+4.5 80.0 _+3.5
Table 2. lOP variations after ketanserin administration.
IOP mmHg (mean _+SD) 0
1 hour
15.7 _+1.5 22.8_+1.3
13.6_+1.4 20.0_+1.5
Results Patients with arterial hypertension showed significant reductions in mean BP after ketanserin administration, from 156/102 _+ 10/6 m m H g before treatment to 141/99 _+ 13/5 mmHg, 142/96 _+ 12/5 mmHg, and 144/96 _+ 12/5 m m H g 1, 2, and 3 hours after dosing, respectively. No concomitant change in HR was observed during treatment (mean HR varied from 80 _+2 beats/min to 81 _+2 beats/min). IOP was reduced by 13% of the baseline value 1 hour after dosing and even more markedly (by 17%) in the examinations following. Changes in BP and IOP are shown in Tables 1 and 2. The decreases in systolic blood pressure were significantly related to decreases in intraocular pressure (r = 0.996, p < 0.001). For normotensive patients with open-angle glaucoma, mean BP changed only slightly, from 140/80 _+ 12/5 m m H g before ketanserin administration to 132/80 _+ 12/2 m m H g after 1 hour, 129/80 + 12/5 m m H g after 2 hours, and 127/80 _+ 11/3 m m H g after 3 hours. No concomitant change occurred in mean HR. IOP was reduced significantly, from 22.8 _+ 1.3 m m H g before ketanserin administration to 20.0 _+1.5 1 hour after dosing, 17.5 _+ 1.2 m m H g after 2 hours, and 17.0 _+ 1.1 after 3 hours. Changes in SBP, DBP, and IOP were shown in Tables 1 and 2. In this group also, the decreases in IOP were significantly related to SBP reductions (r = 0.996, p < 0.001).
1 hour
Group A Group B
2 hours
3 hours
13.1 _+1.5 13.0 _+1.3 17.5 _+1.2 17.0 + 1.1
IOP = intraocular pressure.
a possible hypotensive effect of ketanserin on ocular pressure when given orally. In this clinical trial, ketanserin treatment lowered IOP acutely in both normotensive and hypertensive eyes after a single dose of 20 mg. This effect might be related to the vasodilating properties of the drug, which also involve the episcleral venous system. Moreover, the alphal-blocking property of ketanserin may contribute to the fall in IOP by decreasing aqueous humor production or facilitating its outflow [8]. F u r t h e r studies are obviously needed in order to clarify the mechanism of action of ketanserin, to confirm its hypotensive effect on ocular pressure after chronic treatment, and to evaluate its efficacy and safety in h u m a n s when applied topically.
References 1. Phillips CI, Howitt G, Rowlands DJ. Propanolol as ocular hypotensive agent. Br J Ophthalmol 1967;51:222-228. 2. Riemann IW, Frolich JC. Mechanisms of antihypertensive action of ketanserin in man. Br Med J 1983;287:381-383. 3. Ferrara LA, Fasano ML, Soro S, Rubba P, Iannuzzi A. Cardiovascular effectsof ketanserin, a new antiserotonergic agent, in the treatment of arterial hypertension. J Clin Pharmacol 1985;25:187-192. 4. Ferrara LA, Fasano ML, Soro S, Pasanisi F, Mancini M. Antihypertensive efficacyof a combination of ketanserin + thiazide in hypertensives older than 50 years. J Cardiovasc Pharmacol 1987;10(Suppl 3):124-125.
Ketanserin and Intraocular Pressure
5. Fagard R, Fiocchi R, Lijnen P, et al. Haemodynamic and humoral responses to chronic ketanserin treatment in essential hypertension. Br Heart J 1984;51:149-156. 6. Chang FW, Burke JA, Potter DE. Mechanism of the ocular hypotensive action of ketanserin. J Ocul Pharmaco11985;l: 137-147.
99
7. Conway JL, Lewis RA. Ocular hypotensive action ofketanserin. Invest Ophthalmol Vis Sci 1989;30:24. 8. Mittag TW, Tormay A, Severin C, Podos SM. Alpha adrenergic antagonists: Correlation of the effect on intraocular pressure and on alpha-adrenergic receptor binding specifically in the rabbit eye. Exp Eye Res 1985;40:591-600.
EFFECTSOFKETANSERINONINTRAOCULAR PRESSURE
SUMMARY. There is e v i d e n c e that some antihypertensive drugs, such as beta blockers, are effective in r e d u c i n g intraocular pressure (IOP) and are c o m m o n l y u s e d in the medical treatment of glaucoma. The aim of this s t u d y w a s to evaluate the effects of the anti-serotonergic agent ketanserin, w h i c h has associated alpha]-blocking properties, on IOP in n o r m o t e n s i v e and hypertensive eyes. The first part of the study w a s performed in six arterial h y p e r t e n s i v e patients (mean ± SD blood pressure 156/102 ± 10/6 mml'Ig) w i t h a pretreatment IOP in the normal range (15.7 ± I mmHg). Both blood pressure and IOP w e r e m e a s u r e d at baseline and at 1 h o u r intervals up to 3 hours f o l l o w i n g the oral administration of k e t a n s e r i n 20 m g or placebo, given in a r a n d o m i z e d manner. Three hours after ketanserin treatment, m e a n systolic and diastolic blood pressures dropped by 10/5 m m H g and m e a n IOP w a s reduced by 2.7 mml-lg;, after placebo, no change w a s observed in these variables. Thereafter, four n o r m o t e n s i v e patients w i t h chronic open-angle glaucoma (IOP = 22.8 mmHg) w e r e given 20 m g k e t a n s e r i n orally. Three hours after administration, a 22% reduction in m e a n IOP occurred (-5.8 mmtIg), w i t h a concomitant reduction in m e a n systolic blood pressure of 13.0 mmHg. These results indicate that k e t a n s e r i n treatment reduces IOP and systemic blood pressure. Further, long-term studies are n e e d e d in order to confirm the efficacy of ketanserin in the medical treatment of ocular hypertension. KEY WORDS. intraocular pressure, open-angle glaucoma, ketanserin
t0hmong antihypertensive agents, beta blockers are commonly used to lower intraocular pressure (IOP) in patients with open-angle glaucoma [1]. Ketanserin, the first selective 5HT2 receptor antagonist drug, has proven effective in reducing blood pressure (BP) in patients with mild-to-moderate arterial hypertension, alone or in combination [2-5]. In experimental studies, topically applied, this drug was able to reduce IOP in rabbits, cats, and monkeys [6, 7]; there is, however, no study to date regarding ketanserin t r e a t m e n t of elevated IOP in humans. The aims of this clinical trial were to evaluate the effects of oral ketanserin on a) intraocular pressure in hypertensive patients with normotensive eyes and b) IOP in normotensive patients affected by openangle glaucoma.
Ciro Costagliola, 1 Maria Lusia Fasano, 2 Giovanni Iuliano, 1 Liberato Aldo Ferrara 2 1Eye Clinic, 1st Medical School,University of Naples, Italy 2Institute of Internal Medicine and Metabolic Diseases, 2nd Medical School,University of Naples, Italy
Patients and Methods Two different groups of patients entered this study. Group A consisted of six patients (four male, two female), age range 28-51 years, with mild-to-moderate arterial hypertension (entry BP 156/102 _+ 10/6 mmHg) and normal intraocular pressure (15.7 _+ 1.5 mmHg). These patients discontinued any previous antihypertensive t r e a t m e n t for a 2-week washout period before the study commenced. Group B consisted of four patients (one male, three female), age range 30-54 years, with open-angle glaucoma (IOP = 22.8 _+1.3 mmHg) and arterial pressure in the normal range (BP = 140/80 _+12/5 mmHg). They had stopped their previous t r e a t m e n t (topically applied pilocarpine or beta blocker) for a 7-day washout period before the study commenced. The hypertensive group received, in a randomized order, ketanserin 20 mg or placebo at 1-week intervals. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and IOP were measured before treatment and at 1-hour intervals during the 3 hours following treatment. The group with open-angle glaucoma received 20 mg ketanserin only. Measurements of BP, HR, and IOP were performed according to the scheduled protocol as described for patients with normal intraocular pressure.
Statistical Procedures Data are expressed as mean _+ standard deviation. Significances were assessed using Student's paired
Address for correspondenceand reprint requests: L. Aldo Ferrara, MD, Assistant Professor, Clinica Medica, 2nd Medical School, University of Naples, Via S. Pansini 5, 80131 Napoli, Italy. 97
98
Costagliolaet al.
Table 1. SBP and DBP variations after ketanserin administration.
SBP mmHg (mean _+SD) 0 Group A Group B
1 hour
2 hours
DBP mmHg (mean + SD) 3 hours
156.0 _+10.5 141.2 + 13.2 142.3 _+12.1 144.3 _+12.3 140.5 _+12.3 132.5 _+12.5 128.8 + 11.7 127.5 _+11.2
t test. The strength of the correlations was evaluated by linear regression analysis.
0
102.1 _+6.3 98.8 _+5.2 80.0 + 5.1 80.0 _+2.5
Discussion Ketanserin, the first antiserotonergic agent commonly used in the treatment of arterial hypertension, has been shown to reduce ocular pressure in experimental models when applied topically. However, no observations had been made in h u m a n s regarding
2 hours
3 hours
96.3 -+5.5 80.0 -+5.2
96.5 _+4.5 80.0 _+3.5
Table 2. lOP variations after ketanserin administration.
IOP mmHg (mean _+SD) 0
1 hour
15.7 _+1.5 22.8_+1.3
13.6_+1.4 20.0_+1.5
Results Patients with arterial hypertension showed significant reductions in mean BP after ketanserin administration, from 156/102 _+ 10/6 m m H g before treatment to 141/99 _+ 13/5 mmHg, 142/96 _+ 12/5 mmHg, and 144/96 _+ 12/5 m m H g 1, 2, and 3 hours after dosing, respectively. No concomitant change in HR was observed during treatment (mean HR varied from 80 _+2 beats/min to 81 _+2 beats/min). IOP was reduced by 13% of the baseline value 1 hour after dosing and even more markedly (by 17%) in the examinations following. Changes in BP and IOP are shown in Tables 1 and 2. The decreases in systolic blood pressure were significantly related to decreases in intraocular pressure (r = 0.996, p < 0.001). For normotensive patients with open-angle glaucoma, mean BP changed only slightly, from 140/80 _+ 12/5 m m H g before ketanserin administration to 132/80 _+ 12/2 m m H g after 1 hour, 129/80 + 12/5 m m H g after 2 hours, and 127/80 _+ 11/3 m m H g after 3 hours. No concomitant change occurred in mean HR. IOP was reduced significantly, from 22.8 _+ 1.3 m m H g before ketanserin administration to 20.0 _+1.5 1 hour after dosing, 17.5 _+ 1.2 m m H g after 2 hours, and 17.0 _+ 1.1 after 3 hours. Changes in SBP, DBP, and IOP were shown in Tables 1 and 2. In this group also, the decreases in IOP were significantly related to SBP reductions (r = 0.996, p < 0.001).
1 hour
Group A Group B
2 hours
3 hours
13.1 _+1.5 13.0 _+1.3 17.5 _+1.2 17.0 + 1.1
IOP = intraocular pressure.
a possible hypotensive effect of ketanserin on ocular pressure when given orally. In this clinical trial, ketanserin treatment lowered IOP acutely in both normotensive and hypertensive eyes after a single dose of 20 mg. This effect might be related to the vasodilating properties of the drug, which also involve the episcleral venous system. Moreover, the alphal-blocking property of ketanserin may contribute to the fall in IOP by decreasing aqueous humor production or facilitating its outflow [8]. F u r t h e r studies are obviously needed in order to clarify the mechanism of action of ketanserin, to confirm its hypotensive effect on ocular pressure after chronic treatment, and to evaluate its efficacy and safety in h u m a n s when applied topically.
References 1. Phillips CI, Howitt G, Rowlands DJ. Propanolol as ocular hypotensive agent. Br J Ophthalmol 1967;51:222-228. 2. Riemann IW, Frolich JC. Mechanisms of antihypertensive action of ketanserin in man. Br Med J 1983;287:381-383. 3. Ferrara LA, Fasano ML, Soro S, Rubba P, Iannuzzi A. Cardiovascular effectsof ketanserin, a new antiserotonergic agent, in the treatment of arterial hypertension. J Clin Pharmacol 1985;25:187-192. 4. Ferrara LA, Fasano ML, Soro S, Pasanisi F, Mancini M. Antihypertensive efficacyof a combination of ketanserin + thiazide in hypertensives older than 50 years. J Cardiovasc Pharmacol 1987;10(Suppl 3):124-125.
Ketanserin and Intraocular Pressure
5. Fagard R, Fiocchi R, Lijnen P, et al. Haemodynamic and humoral responses to chronic ketanserin treatment in essential hypertension. Br Heart J 1984;51:149-156. 6. Chang FW, Burke JA, Potter DE. Mechanism of the ocular hypotensive action of ketanserin. J Ocul Pharmaco11985;l: 137-147.
99
7. Conway JL, Lewis RA. Ocular hypotensive action ofketanserin. Invest Ophthalmol Vis Sci 1989;30:24. 8. Mittag TW, Tormay A, Severin C, Podos SM. Alpha adrenergic antagonists: Correlation of the effect on intraocular pressure and on alpha-adrenergic receptor binding specifically in the rabbit eye. Exp Eye Res 1985;40:591-600.
