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Ocular hypertensive drugs—Overview
X ICER Abstracts AQUFZOUSHUMOR DYNAMICS
Thursday, Sep 24, 1992 La Palms/A
CODE: AH-9
SEIVZMBER
24mHURSDAY
624
1
OCULAR
HYPERTENSIVE
Badbaker. Department USA
Ocular
Hvoerte
R. Brubaker
s’ve
Drugs
-
Overview
&%,
Aloha-2-Agonists: A.L. Robin (USA)
Present
and Future
10 the for the Desinn P.1.
Wistrand
(Sweden)
Clinicallv
Active
EA.
(USA)
Tooical
Anhvdrase
Carbonic
U&& Lippa
Lrsairallv 10 Exoerimental C.B. Camras (USA) ects of Tom Proslaelandin and PlpSLaelandin A. Aim and I. Willumsen (Sweden) The CtcJic
GMP
Fluid SWWQLI J.A. Nathanson
R.F.. of Ophthalmology,
Mayo
Clinic:
Rochester
NN,
Cholinergics, adrenergics, and carbonic anhydrase inhibitors have dominated the medical therapy of glaucoma. Cholinergics and fl-adrenergic agonists enhance the outflow of aqueous humor whereas @adrenergic antagonists and carbonic anhydrase inhibitors reduce the rate of aqueous humor formation. Current workers are engaged in studies of four new therapeutic approaches, each of which will be discussed at this symposium. 1) Alpha-2 selective adrenergic agonists have been shown to lower intraocular pressure by lowering the rate of aqueous formation. The effect is not additive to that of fi-adrenergic antagonists. Both of these drugs are presumed to inhibit the rate of synthesis of CAMP in the NPE cell. 2) Several carbonic anhydrase agents are being tested for their efficacy as topically-applied ocular hypotensive agents. CAIS may reduce IOP by their action not only on the pars plicata but also the RPE of the retina. 3) Several prostaglandins and prostaglandin derivatives have been shown to lower intraocular pressure without altering the rate of aqueous formation and without altering the blood-aqueous barrier. 4) Preliminary evidence has been published that activators of cGMP are ocular hypotensive agents. Some of these activators are small organic compounds that can be administered topically, such as nitroglycerin or hydralazine.
ALBERT ALM (SWEDEN) CARL B. CAMRAS (USA)
CHAIRPERSONS:
DRUGS--OVERVIEW
625
2 &-AGONISTS:
PRESENT
AND FUTURE
Analoeu~ Alan L. Robin. fvl& Department of Ophthalmology, 7.1205
Sm
Johns
Hopkins
Universitv,
Baltimore,
Maryland
In the Eve and Brain Both svstamic and topical clonidine lowar intraocular pmssura IIOPI. This is assoeistad with a dose-dapamlenl lowarin~ of systamic blood pmsswe. Because of thLs blood pressure sffwt and tha fear thn tzifmidb my impair optic narva haad pa&lion, ckmkfine’s usa in ophth&w&gy haa bean limited. Apraelonidlne is a &ativ& sdactivs cr,-agonist M only diffsmnce from clonidine is an amida group on the C, posit&. Thla char&al #ttaration makes apraclonidina mora polar and thwmticm it has loss B bar&r permaabilii. Apmdonidins dacmaar aqumus flow, wan in eyea mcalvin~ chronic ,9-blockws. It is t&a only topical mediwtiw which &so towers flow during slaap. Apmclanidins has no tit on outflow. It haa no dk&xlty significant affect on blood pressure, heart rata, or exwcisa induced tachvcardia.
(USA)
Discussion L. Bim (USA)
Apraclanidine is ths only madiiation known which si@ficantlV decreases both tha freqoanq and magilituds of tha poamprfativa IOP elevation associated with trabaculopkstY, iridotomy, and capsulotomy. It is mtlv better than other mpkxl and oral agants. It also decraasas ths IOP slevation associated with cataract surgary. Apraelonidina lowers the mean IOP up to 40% in nomjala and plaucomatous ayes when used alone. It also decmasas mean K)$ m addiiional 15% to 20%. compamd to dipivafrin. when added to timok# mulwa. Mare importantly, apsclonidins 0.26% pmducoa s a&t&ant &&t&al IOP reduction in evea of patients on maxim&v tabrstad~-gfwcwu thorapv. In owr 50% of eyss with basaliie IOPs over 23 m m lb, add&&al f&ring surgery was avoided for up to two years because of apraclonidine’s addition.
626
3
DISTRIBUTION AND FUNCl’ION OF CARBONIC ANHYDRASE (CA) ISOZYMFS IN THE HUMAN EYE. RELEVANCE FOR THE DESIGN OF TOPICAL CA INHIBITORS Deptartment
of Ophthalmology,
University
Hospital,
Uppsala,
Sweden.
Of the hitherto known eight isozymes of CA, designed CA I-VIII, only the cytosolic CA I and CA II and the membrane-bound CA IV are found in the human eye. CA II and CA IV are located, probably together, in I-I’ and HCO,-secreting epitbelia, i.e. in eiliary epitbelium, comes1 endothelium, probably together with CA I, and possibly also in the cornea1 epitbelium. CA II and CA IV are also found in the lens epitbelium and fibem, and in the Miiller cells, pigment epithelium and in red- and green-sensitive cones of the retina. CA IV is moreover found (as the only isozyme?) in the endothelium of the vessels of the choroid and ciliary processes. CA 1 and CA II probably function as “house-keeping” enzymes, i.e. they provide an adequate supply of R, Off or HCO, by rapidly responding to perturbations of the CO&CO, equilibrium in the eytosol. Inhibition of these isozymes does not appear to give tWapautieally useful effects. Tlte function of CA IV, with its active site facing the exterior of the cell, is probably to dehydrate I&CO3 in order to avoid steep pH-gradients acmss the membrane. In analogy with other tissues, inhibition of CA IV seems to be important for lowering of the eye pressure, and perhaps also for axtain side effects. Tbe selective inhibition of CA IV in the base-lateral NPE membranes of the ciliary epithelium, should be the goal for topical CA inhibitors.
S.185
Thursday, Sep 24, 1992 La Palms/A
CODE: AH-9
SEIVZMBER
24mHURSDAY
624
1
OCULAR
HYPERTENSIVE
Badbaker. Department USA
Ocular
Hvoerte
R. Brubaker
s’ve
Drugs
-
Overview
&%,
Aloha-2-Agonists: A.L. Robin (USA)
Present
and Future
10 the for the Desinn P.1.
Wistrand
(Sweden)
Clinicallv
Active
EA.
(USA)
Tooical
Anhvdrase
Carbonic
U&& Lippa
Lrsairallv 10 Exoerimental C.B. Camras (USA) ects of Tom Proslaelandin and PlpSLaelandin A. Aim and I. Willumsen (Sweden) The CtcJic
GMP
Fluid SWWQLI J.A. Nathanson
R.F.. of Ophthalmology,
Mayo
Clinic:
Rochester
NN,
Cholinergics, adrenergics, and carbonic anhydrase inhibitors have dominated the medical therapy of glaucoma. Cholinergics and fl-adrenergic agonists enhance the outflow of aqueous humor whereas @adrenergic antagonists and carbonic anhydrase inhibitors reduce the rate of aqueous humor formation. Current workers are engaged in studies of four new therapeutic approaches, each of which will be discussed at this symposium. 1) Alpha-2 selective adrenergic agonists have been shown to lower intraocular pressure by lowering the rate of aqueous formation. The effect is not additive to that of fi-adrenergic antagonists. Both of these drugs are presumed to inhibit the rate of synthesis of CAMP in the NPE cell. 2) Several carbonic anhydrase agents are being tested for their efficacy as topically-applied ocular hypotensive agents. CAIS may reduce IOP by their action not only on the pars plicata but also the RPE of the retina. 3) Several prostaglandins and prostaglandin derivatives have been shown to lower intraocular pressure without altering the rate of aqueous formation and without altering the blood-aqueous barrier. 4) Preliminary evidence has been published that activators of cGMP are ocular hypotensive agents. Some of these activators are small organic compounds that can be administered topically, such as nitroglycerin or hydralazine.
ALBERT ALM (SWEDEN) CARL B. CAMRAS (USA)
CHAIRPERSONS:
DRUGS--OVERVIEW
625
2 &-AGONISTS:
PRESENT
AND FUTURE
Analoeu~ Alan L. Robin. fvl& Department of Ophthalmology, 7.1205
Sm
Johns
Hopkins
Universitv,
Baltimore,
Maryland
In the Eve and Brain Both svstamic and topical clonidine lowar intraocular pmssura IIOPI. This is assoeistad with a dose-dapamlenl lowarin~ of systamic blood pmsswe. Because of thLs blood pressure sffwt and tha fear thn tzifmidb my impair optic narva haad pa&lion, ckmkfine’s usa in ophth&w&gy haa bean limited. Apraelonidlne is a &ativ& sdactivs cr,-agonist M only diffsmnce from clonidine is an amida group on the C, posit&. Thla char&al #ttaration makes apraclonidina mora polar and thwmticm it has loss B bar&r permaabilii. Apmdonidins dacmaar aqumus flow, wan in eyea mcalvin~ chronic ,9-blockws. It is t&a only topical mediwtiw which &so towers flow during slaap. Apmclanidins has no tit on outflow. It haa no dk&xlty significant affect on blood pressure, heart rata, or exwcisa induced tachvcardia.
(USA)
Discussion L. Bim (USA)
Apraclanidine is ths only madiiation known which si@ficantlV decreases both tha freqoanq and magilituds of tha poamprfativa IOP elevation associated with trabaculopkstY, iridotomy, and capsulotomy. It is mtlv better than other mpkxl and oral agants. It also decraasas ths IOP slevation associated with cataract surgary. Apraelonidina lowers the mean IOP up to 40% in nomjala and plaucomatous ayes when used alone. It also decmasas mean K)$ m addiiional 15% to 20%. compamd to dipivafrin. when added to timok# mulwa. Mare importantly, apsclonidins 0.26% pmducoa s a&t&ant &&t&al IOP reduction in evea of patients on maxim&v tabrstad~-gfwcwu thorapv. In owr 50% of eyss with basaliie IOPs over 23 m m lb, add&&al f&ring surgery was avoided for up to two years because of apraclonidine’s addition.
626
3
DISTRIBUTION AND FUNCl’ION OF CARBONIC ANHYDRASE (CA) ISOZYMFS IN THE HUMAN EYE. RELEVANCE FOR THE DESIGN OF TOPICAL CA INHIBITORS Deptartment
of Ophthalmology,
University
Hospital,
Uppsala,
Sweden.
Of the hitherto known eight isozymes of CA, designed CA I-VIII, only the cytosolic CA I and CA II and the membrane-bound CA IV are found in the human eye. CA II and CA IV are located, probably together, in I-I’ and HCO,-secreting epitbelia, i.e. in eiliary epitbelium, comes1 endothelium, probably together with CA I, and possibly also in the cornea1 epitbelium. CA II and CA IV are also found in the lens epitbelium and fibem, and in the Miiller cells, pigment epithelium and in red- and green-sensitive cones of the retina. CA IV is moreover found (as the only isozyme?) in the endothelium of the vessels of the choroid and ciliary processes. CA 1 and CA II probably function as “house-keeping” enzymes, i.e. they provide an adequate supply of R, Off or HCO, by rapidly responding to perturbations of the CO&CO, equilibrium in the eytosol. Inhibition of these isozymes does not appear to give tWapautieally useful effects. Tlte function of CA IV, with its active site facing the exterior of the cell, is probably to dehydrate I&CO3 in order to avoid steep pH-gradients acmss the membrane. In analogy with other tissues, inhibition of CA IV seems to be important for lowering of the eye pressure, and perhaps also for axtain side effects. Tbe selective inhibition of CA IV in the base-lateral NPE membranes of the ciliary epithelium, should be the goal for topical CA inhibitors.
S.185