|Year : 1954 | Volume
| Issue : 2 | Page : 33-44
Adrenergic blocking agents in glaucoma
Department of Ophthalmology, Medical College, Agra, India
S P Srivastava
Department of Ophthalmology, Medical College, Agra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Srivastava S P. Adrenergic blocking agents in glaucoma. Indian J Ophthalmol 1954;2:33-44
Sympathetic nervous system has long been incriminated in the a;tiology of primary glaucoma but its actual role in the mechanism remains obscure. Holtzke (1883) and Adamuk ( 1866) were the first workers to show a fall in intraocular pressure on section of the cervical sympathetic. Since then many experiments have been performed by different workers showing the effect of stimulation and sectioning of cervical sympathetic on intraocular pressure. Based on these observations earlier workers practised a resection of the cervical sympathetic for the treatment of glaucoma. It was thought therefore that similar effects would be operative if a "chemical sympathectomy" was accomplished pharmacologically.
The blockade of the sympathetic nervous system can be established at only one of the following three points : - [Figure - 1]
- Central axis.
- Ganglionic synapse, and
- The terminal nerve endings.
Barbiturates may conceivably effect a sympathetic blockade by their sedative action on either the cerebrum, hypothalamus, or medulla. Hydrallazine hydrochloride acts chiefly in the midbrain. Veratrum viride apparently depresses the vasomotor centres in the hind brain.
Tetraethylammonium chloride and hexamethonium act only on the galglionic synapse, blocking impulses at the synaptic point of transfer from pre-to-postganglionic fibres. Unfortunately these agents also block the parasympathetic impulses. They do not block the action of norepinephrine and may even potentiate pressor responses to epinephrine and norepinephrine with serious clinical consequences.
The third type of compounds are those which attack the post-ganglionic synapses. These are the "adrenergic blocking agents". They have been defined by Nickerson (1949) as agents which inhibit certain responses of effector cells to epinephrine, related amines and sympathetic nerve impulses. The action is not due to alteration or destruction of epinephrine nor to an effect on peripheral nerves, nor to interference with the contractile mechanism of the smooth muscle. Nickerson and Goodman (1945) conclude that they specifically block the receptor substances of the effector cells to sympathoadrenal stimuli in an unknown manner. Since these compounds do not lyse the nerve ending, the mediator or the effector cells the term sympatholytic or adrenolytic does not seem satisfactory and the term "adrenergic blocking agents" has been given to them. There are many types of adrenergic blocking agents examples of which are listed below : -
- Beta-halo-alkylamines e.g. Dibenamine and Dibenzyline.
- Imidazolines e.g. benzazoline (Priscol ).
- Benzodioxanes e.g. benodaine.
- Ergot alkaloids e.g. di-hydroergocornine.
- Yohimbines e.g. ethylyohimbine.
Thiel (1926) was the first to use ergotamine for this purpose followed by many others. With the introduction of newer hydrogenated ergot alkaloids, having greatly enhanced adreno-sympatholytic activity and the adrenergic blocking effects of dibenamine reported by Nickerson and Goodman, the use of these compounds was once more introduced in the treatment of glaucoma. Christenson, Swan and Gould (1948) were the first to report dramatic lowering of intraocular pressure following systemic administration of dibenamine in acute glaucoma, recalcitrant to usual medical treatment. This was followed by similar reports by a number of workers.
| Present Study|| |
The present study was undertaken with a view to study the role of adrenergic blockade in glaucoma, both as regards its part in the underlying mechanism of the production of glaucoma and its therapeutic applicability. With this idea in view it was done in two parts (a) Experimental, (b) Clinical.
This study consisted in determining (1) the effect of stimulation of cervical sympathetic on intraocular pressure in cats and (2) to compare what changes occur by a similar stimulation of the cervical sympathetic after an adrenergic blockade has been effected by an adrenergic blocking agent. The experiments were carried out in four normal cats.
| Methods|| |
Cats were anaesthetised with nembutal 12 gr. per 5 lbs. of body weight intraperitonially. The sympathetic nerve between the middle and superior cervical ganglion was dissected out on one side of the neck.
The intraocular pressure was recorded by inserting into the anterior chamber No. 12 hypodermic needle connected by narrow pressure tubing to an optical manometer prepared as described by Davson and Purvis (1950) which allows a continuous recording giving a deflection of some 3 to 4" of light spot on a scale 5 ft. away in response to a rise of pressure of 10 cms. of H 2 O. [Figure - 2] Anaethaine 1 % was instilled into the eye before inserting the needle as a rapid rise of intraocular pressure is seen if it is not used. The manometer system was filled with normal saline and at the moment of the insertion of the needle a reservoir connected to the manometer was adjusted to give a head-pressure of 20 cms. of saline-the tap being closed again as soon as the needle was in place.
The movement of the beam of light reflected from the mirror of the manometer was received on a white scale placed at a distance of 5 ft. When the intraocular pressure had reached a steady level the sympathetic nerve was stimulated by a faradic current of 4-5 volts of 50 cycles frequency generated in a pantostat. The duration of the stimulation was 10 seconds. At the same time the deflection of the spot of light on the scale was recorded till the I.O.P. reached the original level. Thereafter adrenergic blockade was effected by giving hydergine (a mixture of methanesulphonates of 3 hydrogenated ergot alkaloids). After 5 minutes of giving hydergine the I.O.P. was again noted and then the cervical sympathetic was again stimulated and the reading on the scale recorded.
| Results|| |
[Table - 1],[Table - 2],[Table - 3] and [Figure - 3] show the results obtained on stimulating the cervical sympathetic before and after giving hydergine.
The following points are clearly brought out of this experimental study:
- There was a definite rise in I.O.P. on stimulation of cervical sympathetic in all the 4 cats.
- There was no change in the I.O.P. after administration of hydergine.
- On stimulation of the cervical sympathetic after adrenergic blockade (a) the rise in I.O.P. was much less as compared to the rise before it. (b) the peak pressure was reached in a longer time. (c) the pressure came back to original level in a shorter time. [Table - 3].
This was carried out in 59 eyes, with primary glaucoma having acute congestive glaucoma in 21 eyes, chronic congestive glaucoma in 18 eyes and chronic simple glaucoma in 20 eyes. A careful history of the patients was taken with special reference to emotional upsets. Thereafter a detailed local examination of the eyes was conducted and the blood pressure and tension recorded. It was made certain that the patient was not under any miotic treatment and if so the miotics were discontinued 24 hours before starting the adrenergic blocking agents. During their administration no other treatment was given. Three adrenergic blocking agents were used in the present study viz. hydergine, dihydroergotamine and dibenzylin. Cases of each type of glaucoma were divided into three groups, each group receiving one adrenergic blocking agent.
| Method and Dose of Administration|| |
1. Hydergine (Sandoz) :- It was given in doses of 0.3 mg. in 1 c.c. intravenously 3 times a day usually for a period of 2-3 days, followed by sublingual tablets of hydergine of 0.25 mg. each, one tablet 3-4 times a day.
2. Dihydroergotamine (D.H.E. 45 Sandoz):- This was given in doses of 1 mg. in 1 c.c. intravenously, 3 times a day for a period of 2-3 days followed by oral administration of a solution of the same 20-30 drops 3-4 times a day (20 drops = 2 mgs.).
3. Dibenzyline (Smith, Kline & French Labs.): - is a congener of dibenamine in the p-alkylamine family. It is capable of producing a chemical sympathectomy by oral administration. The drug was started usually with two capsules of 10 mg. each on the first day and was daily increased by 20 mg. till the effect of adrenergic blockade viz. stuffy nose and slight orthostatic hypotension appeared, after which the patient was maintained on that very dosage for the rest of the period he was under observation. Medication should begin at a low level as some individuals show postural changes with as little as 20 mgs. of dibenzyline.
The administration of these drugs was undertaken for a period varying from 2-7 days depending on the effect produced. If with the administration of the drug tension was not lowered, the drug was discontinued on the third day. If a fall in tension was observed the drug was given till that period when either the tension rose again inspite of the drug being continued or after a maximum lowering a steady state was reached.
The patients receiving this therapy were made strict bed cases as in some cases orthostatic hypotension was observed to be of a considerable degree. A small degree of orthostatic hypotension with little giddiness on long standing was considered to be the effect of the drug and was a sign that adrenergic blockade has been produced. With the administration of the drug the progress of the cases was duly charted. The tension was recorded with Schiotz X tonometer. The same tonometer was used throughout the study and was taken by the same person. The tension and blood-pressure were recorded four times a day.
Acute Congestive Glaucoma
Out of the twenty-one cases, three cases gave a history of emotional upset before the onset of attack. Many cases were evacuees from Pakistan who had suffered many privations and much mental anxiety. The tension in the affected eyes ranged from 35 to 90 mm. Hg.
Tension. As can be seen from the table in all the cases the tension began to rise again after the initial fall by about the third day, in spite of the treatment being continued except in one case where it remained stationary after the maximum fall,
Blood Pressure. In 14 cases the systemic blood pressure kept on falling till the last day even though the tension rose again after the initial fall. In three cases treated with hydergine and two cases treated with dibenzyline, the bloodpressure fell and rose with the tension. In one case treated with hydergine and one treated with D.H.E.45 very little change was seen in the blood-pressure although there was a drop in the tension from 65 to 50 mm. Hg. and from 75 to 55 mm. Hg. respectively.
Pain. In all the cases, except two treated with D.H.E.45 there was considerable relief of pain irrespective of the fall in tension. In those cases where it started again with the rise of tension, it was not as great as initially.
Ciliary Congestion. In all the cases there was no change in the ciliary congestion.
Side effects : No side effects were seen in any case except for slight giddiness with a little orthostatic hypotension on standing which was due to adrenergic blockade.
Chronic Congestive Glaucoma
The tension in the affected eyes ranged from 35 to 70 mm. Hg. (Schiotz).
The tension rose again after the initial fall in all except one case in spite of continuation of treatment. In one case it did not rise after the initial fall.
Blood pressure : In 10 out of 18 cases it kept on falling till the last day of treatment. In four cases it rose and fell with the tension and in 3 cases there was no significant change in the blood-pressure.
Pupil: No change was seen in 12 eyes. In 5 eyes it got constricted by 0.5 mm. and in 1 by 2.5 mm., with the fall in tension.
Pain : Relieved in all the cases who complained of it, except in 3 cases that were treated with hydergine.
Ciliary congestion : No change was noticed.
Chronic Simple Glaucoma
Tension in the affected eyes varied from 32 to 75 mm. Hg. (Schiotz).
Tension : It began to rise in all the eyes inspite of the treatment being continued.
Blood-pressure : In 12 cases it went on falling till the end of treatment even though the tension rose. In 6 of them there was no significant change, whereas in 2 there was a rise and fall in blood-pressure corresponding with the rise and fall in intraocular tension.
Pupils : In 18 eyes there was no change in the size of pupils. In the two cases where there was slight miosis the contraction was not bigger than 0.5 mm.
| Conclusions|| |
Following is a list of actual conclusions arrived at from the study. Undoubtedly we would have liked to have a larger number of observations to make the study statistically more correct. While observations 3-8 concern the effect of individual drugs in smaller groups, which may not be called conclusive, observations 1, 2, 9 to 13 cover all the cases, and so may be considered more accurate. They form the more important group of observations and form the basis for discussion.
- In no case was the systolic blood-pressure more than what may be normal for the age of that case.
- Adrenergic blocking agents were most effective in congestive type of glaucoma while there was little effect in chronic simple glaucoma.
- Hydergine and Dibenzyline were equally effective in acute congestive glaucoma while D.H.E. had comparatively little effect.
- Hydergine was more effective than Dibenzyline in chronic congestive glaucoma.
- Hydergine, Dibenzyline and D.H.E. were very slightly effective in chronic simple glaucoma.
- With Hydergine the effect started in a shorter time while with dibenzyline it started after a longer time. D.H.E.45 occupied an intermediate position.
- The maximum effect was produced in the shortest time by D.H.E.45. Dibenzyline took a longer time while Hydergine occupied an intermediate position.
- The lowering effect on I.O.P. lasted for the shortest period with D.H.E.45, longest with dibenzyline while Hydergine occupied the intermediate, position.
- In 94.9% cases the tension rose again after the initial fall, inspite of the drug being continued.
- In 79.6% of cases there was no change in the size of pupil irrespective of fall in tension.
- In 66% of cases the Blood Pressure went on falling gradually till the last day of treatment though the tension rose again.
- Pain was relieved in all congestive cases irrespective of the amount of lowering of I.O.P. Hydergine was most effective in this respect.
- There was no change in ciliary congestion in the congestive groups.
| Discussion|| |
From the clinical observation of this study, primary glaucoma can be definitely grouped into two types, the congestive and the non-congestive varieties differing entirely in their signs, symptoms and clinical course. That the episodic attacks of congestive glaucoma are associated with neurovegetative imbalance and vascular instability is quite evident from the fact that congestive glaucoma was seen to be more common in sympathotonic individuals, usually women, between the ages of 40-50 years, giving evidence of emotional upsets. The sudden and acute rise of tension, associated with congestion, stasis and oedema also points to the same fact. That the rise in tension is not the primary cause of these congestive attacks is evident from the observation that tension as high as 70-75 mm. of Hg. in chronic simple glaucoma was not associated with congestion, while tension as low as 35-40 mm. of Hg. was associated with congestion, stasis and vascular instability.
The underlying causes of this vascular instability may be a hyperexcitability of the sympathetic nervous system, whether central, diencephalic or peripheral. The results of the present experimental study definitely showed that there is a rise in intraocular pressure on stimulating the sympathetic and that it was much less when the sympathetic was blocked. Similarly the results of the clinical study showing a definite lowering of tension in congestive glaucoma by adrenergic blocking agents point to the association between the sympathetic nervous system and intraocular pressure as to be more than mere coincidence. The sympathetic nervous system may alter the intraocular pressure (1) by its effect on the general blood pressure, (2) by its effect on intraocular arterioles and capillaries and (3) by its effect on the venous pressure.
The results of the present study show that both the general blood pressure and the intraocular pressure started falling on administration of adrenergic blocking agents but the blood pressure went on falling while the intraocular pressure rose again after the initial fall. This shows clearly that though both are under the influence of sympathetic nervous system, the initial fall in tension was not due to the fall in blood pressure, as otherwise, with the fall in blood pressure continuing the tension should not have risen again. Further, the observation that in no case, in the present series was the blood pressure more than what was normal for that age establishes that a high blood pressure in itself is not an essential, not even an important factor in the etiology of primary glaucoma.
Considering the second factor of intraocular arterioles and capillaries, the tension lowering effect of adrenergic blocking agents may be due to the fact that the sympathetic blockade causes a dilatation of the arteriolar and capillary system of the eye. This will result either in a rise or fall of the capillary pressure and so of the intraocular pressure depending on the fact whether the entry of blood into these minute vessels is increased or decreased which in turn depend on a rise or fall of general blood pressure. On giving adrenergic blocking agents the general blood pressure falls (on account of the arteriolar and capillary dilatation in vascular beds in other parts of the body), and therefore the entry of blood into the dilated intraocular vessels is decreased resulting in a lower capillary pressure which leads to a lowering of the intraocular pressure.
Coming to the third factor of venous pressure, it is, claimed that a section of the sympathetic leads to a dilatation of veins (Wagner 1931; Wright 1952) and consequently to a fall in venous pressure. As the venous pressure in its variations is more closely connected with the intraocular pressure than is the arterial, (because the former is less adequately damped down by a vaso-motor mechanism) a facility in the venous return of the eye by a fall in venous pressure will give rise to a fall in I.O.P. Thomassen (1946-49) who actually measured the pressure in episcleral vessels found that the venous pressure showed changes comparable to those of intraocular pressure and that these venous changes preceded the changes in the tension of the eye.
The precise mechanism whereby adrenergic blocking agents effect the I.O.P. is not clear, but whatever the exact mechanism may be, the fall in I.O.P is most probably due to the potent adrenergic blockade, producing a dilatation of the minute intraocular vessels of the eye (with an associated fall in general blood pressure) on the one hand and dilatation of the episcleral veins on the other; the first effect causing a decrease in I.O.P. by producing a fall in capillary pressure and the second effect facilitating the outflow of aqueous. A fall in venous pressure will be ineffective in causing a lowering of I.O.P. if there is an organic blockage, partial or complete between the anterior chamber and episcleral veins. This probably accounts for the little effect which these drugs had in chronic simple glaucoma, where, as has been shown by Grant (1951), the facility and rate of outflow are reduced to a considerable degree.
The hypotensive effect produced by these agents in the present study was not dependent on the miosis that should occur as an effect of adrenergic blockade, is shown by the fact that in 79.6 of cases there was no change in the size of the pupil. Even in those cases where a slight constriction occurred, the fall in tension was much more as compared to the miosis. This fact throws much light on the etiologic mechanism of primary congestive glaucoma. We can conclude that in these cases the rise in tension was not primarily due to a dilatation of the pupil causing a blockage at the angle, but due to some other factor thus excluding the mechanical basis for the onset of congestive glaucoma.
Pain was constantly relieved in almost all cases of congestive glaucoma. It may be that pain in congestive glaucoma is mediated via the sympathetic nerves and is relieved by a sympathetic blockade. It may be of interest that ergot alkaloids are also effective in relieving migrainoid headaches and pain associated with herps zoster ophthalmicus.
The point that remains to be explained is as to why the intra-ocular tension went up again after the initial fall inspite of the adrenergic blockade being well maintained. This opens up a new field for further research in order to find as to how the eye accommodates again to achieve the same conditions which were operative previous to the sympathetic blockade.
Regarding the therapeutic applicability of these agents though they do not oust the use of miotics at all, the chief indication is in congestive glaucoma, especially acute, to reduce the I.O.P. to safer level prior to operative treatment and to alleviate pain. To achieve this it is advisable to start Hydergine about 12-24 hrs. and Dibenzyline about 48 hrs. before operation. It is advisable not to continue these drugs further, but to operate within this time as otherwise the hypotensive effect will wear off and the tension will rise again inspite of the treatment being continued.
| Summary|| |
- On stimulation of cervical sympathetic in cats a rise in intraocular pressure was observed which was much less when sympathetic was blocked by Hydergine.
- A therapeutic study with Hydergine, Dihydroergotamine and Dibenzyline was carried out in acute congestive, chronic congestive and chronic simple glaucoma and their effect in lowering the tension was observed.They were most effective in acute congestive glaucoma and it is suggested that they can be used preoperatively for lowering the tension.
- Role of sympathetic hypertonia in glaucoma and the mode of action of adrenergic blocking agents is discussed.
| References|| |
Adamuk ( 1866 ), Quoted from, Duke Elder, Text book of Ophthalmology Vol. 1, p. 522.
Christienson, Swan and Gould, ( 1948) Northwest Med. 46,
Davson & Purvis ( 1950). J. Physical. Lond. 71, 1.
Grant, W. M., ( 1950), A.M.A. Arch of Ophth. 46,
Holtzke ( 1883 ). Quoted from, Duke Elder, Text book of Ophthalmology Vol. 1, p. 522.
Nickerson ( 1949) J Pharmacol and Expt Therap 95, 27
Nickerson and Goodman, ( 1945) Proc. Am. Fed. Clin. Research 2, 109.
Thiel, R. (1926), Klin. Monatsbl. f. Augenh. 77, 753.
(a) Thomassen, T. L., ( 1947) Acta. Ophthal. 25, 369. (b) ( 1949) Acta. Ophthal. 27, 413.
Wagner, H. P., ( 1931) Surg. Clin. N. Amer. 11, 867.
Wright, S., ( 1952 ), Applied Physiology 9th Ed. p. 318.
[Figure - 1], [Figure - 2], [Figure - 3]
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6], [Table - 7], [Table - 8], [Table - 9], [Table - 10]