General anaesthetics - chloroform, ether, etc. *Atropine. *Belladonna.

Belladonnine.

Benzoyltropine.

Cocaine.

Daturine. *Duboisine.

Gelsemine locally. *Homatropine (oxytoluylic-acid-tropine).

Hyoscyamine.

Muscarine locally (?).

Narcissine. Piturine. Scopalein. Stramonium.

Myotics.

General anaesthetics chloroform, ether, etc. *Calabar bean.

Gelsemine internally. Jaborandi. Lobeline internally. Morphine internally. Muscarine internally.

,, locally. Nicotine locally. Opium. *Physostigmine (eserine). Pilocarpine. Thebaine.

Anaesthetics occur in both classes, because they cause contraction towards the commencement of their action, while later on they cause dilatation. The probable reason of this is that at first they lessen reflex action, so that the reflex dilatation of the pupil by stimulation of sensory nerves is abolished. Later on, when they begin to paralyse the respiration, the accumulation of venous blood causes irritation of the dilating centre and widens the pupil. Dilatation of the pupil during the administration of anaesthetics is therefore to be regarded as a sign of imperfect aeration of the blood, due either to embarrassed or failing respiration (p. 218) or failing circulation (p. 207).

The contraction caused by morphine is also central, and probably due to a similar cause.

It is possible that the local application of drugs to the eyes may have an action on the pupil due merely to their effect as irritants, and independent of any special action on the iris, for E. H. Weber l found that local irritation at the margin of the cornea causes partial dilatation. Irritation in the middle of the cornea causes rather contraction of the pupil. Localised irritation at the margin of the iris may cause dilatation at that part.

The reason why muscarine has been found by Ringer and Morshead to dilate the pupil when applied locally is probably that the solution they used was very irritating, either from its strength or for some other reason, while Schmiedeberg and Harnack found it to contract the pupil both when given internally and applied locally.

1 Quoted by Landois, Physiologie, 1880, p. 799.

The contraction of the pupil noticed by Rossbach in rabbits immediately after the application of atropine, may also have been due to local irritation. The occurrence of dilatation in one case and of contraction in the other may possibly have been due to the solution being dropped into the eye in a different way in the two cases.

The commonest and most important local mydriatic and myotic are respectively atropine and physostigmine (eserine).

From ten to twenty minutes after a solution of atropine has been dropped on the eye, the pupil dilates and the ciliary muscle becomes paralysed, so that the accommodation for near objects is no longer possible, and the eye remains focussed for distant objects. When a solution of physostigmine is dropped into the eye, the pupil contracts and the ciliary muscle becomes spasmodically contracted, so that the eye is accommodated for near objects.

It is very difficult to explain the mode of action of these drugs satisfactorily, and authorities are by no means agreed regarding it. That the action is local is shown by the fact that when either atropine or physostigmine is applied to one eye its action is limited to it and the other remains unaffected. If care be taken to limit the application of a solution of atropine to one side of the margin of the cornea, local dilatation of the corresponding part of the pupil may be produced.

Dilatation of the pupil may be due to

(1) Paralysis of the sphincter, or

(2) Excessive action of the dilator, or

(3) Both conditions combined.

Paralysis of the sphincter may be due to (a) imperfect action or paralysis of the oculo-motor centre in the corpora quadri-gemina, (b) to paralysis of the ends of the third nerve in the sphincter iridis, or (c) to the action of the drug upon the muscular fibres of the sphincter itself, or to a combination of two or more of these factors.

Along with the factors just mentioned might be associated excessive contraction of the dilator muscle, which may be due to stimulation (1) of the sympathetic centre in the medulla, (2) of the ends of the sympathetic in the dilator muscle, or (3) of the dilator muscle itself.

Excluding for the present the question of excessive action of the dilator muscle and confining ourselves to the causes of paralysis, we see that paralysis of the cerebral oculo-motor centre as a factor in dilatation of the pupil by atropine is excluded by the local action of the drug, by the experiments of Bernard and others, which show that dilatation occurs from the local action of atropine when the ciliary ganglion is extirpated and all the nerves of the eye have been divided, and by the mydriatic action of atropine even in the exsected eye. We can now limit its action either to paralysis of the ends of the oculo-motor nerve, or paralysis of the muscular fibres of the sphincter.

That the ends of the oculo-motor nerve in the sphincter iridis are paralysed is shown by the experiment that when the pupil is under the full action of atropine, irritation of the third nerve will not produce any contraction in it, although the sphincter will still contract when stimulated directly.

Here also we find the same relation between the action of atropine on nerves supplying striated and non-striated muscle that we have already noticed in the case of the oesophagus (p. 139), for in most animals the iris consists of unstriated muscular fibre, and atropine causes dilatation; but in birds the iris consists of striated muscular fibre, and atropine causes no dilatation. Paralysis of the ends of the oculo-motor nerve in the iris itself may be looked upon as one of the factors in dilatation by atropine, and similar paralysis of the fibres supplying the ciliary muscle may be regarded as the cause of loss of accommodation.

In addition to this, however, when the dose of atropine is large, the muscular fibres of the sphincter themselves become paralysed, and fail to contract even when directly irritated.

The question now arises whether in addition to paralysis of the oculo-motor nerve there is not also excessive action of the dilator muscle. That such action of the dilator is actually present appears to be shown by the following fact, viz. that the dilatation caused by atropine does not appear to be merely passive, but occurs with such force as to tear the iris away from the lens, and break down inflammatory adhesions which may have formed between them. This conclusion has been considered to be supported also by the facts :- (a) That when the oculo-motor nerve is divided the pupil does not dilate nearly to the same extent as it does from the application of atropine. This is shown both by a comparison of measurements of the eye under the two conditions and by the observation that after the nerves have been divided and partial dilatation produced, atropine causes the pupil to dilate still more. And similarly in dilatation due to paralysis atropine increases the mydriasis. (b) When the pupil is dilated by atropine, section of the sympathetic in the neck lessens the dilatation.

We may consider, then, with tolerable certainty, that dilatation caused by atropine is due to increased action of the dilator as well as diminished action of the sphincter muscles of the iris.

Contraction of the pupil may be due to

(1) Excessive action of the sphincter, or

(2) Paralysis of the dilator.

That the contraction caused by physostigmine is not due to paralysis of the dilator is shown by the pupil dilating somewhat when shaded, even when the drug is exerting a well-marked action. Excessive action of the sphincter must therefore be regarded as the cause of the myosis. Such action may be due to stimulation (1) of the oculo-motor cerebral centre, (2) of the ends of the oculo-motor nerve in the sphincter, or (3) to increased action of the muscular fibres in the sphincter from the direct effect of the drug upon them. The local action of physostigmine upon the eye excludes the cerebral centre, and leaves for our consideration stimulation of the ends of the nerves and of the muscular fibres themselves.

These two structures seem to be specially affected by different drugs - so that local myotics may be divided into two classes 1 1st. Those which act upon the peripheral ends of the oculomotor nerve.

2nd. Those which affect the muscular fibre of the sphincter iridis.

The first class includes muscarine, pilocarpine,1 and nicotine, whereas physostigmine belongs to the second.

Muscarine, pilocarpine, and nicotine, when applied to the eye, cause contraction of the pupil and spasm of accommodation. Atropine, as we have already seen, not only paralyses the ends of the oculo-motor nerve, which these drugs stimulate, but has also an action on the muscular fibre itself. Its subsequent application will therefore remove the effect of these drugs, and they will not act when atropine has been applied first. As physostigmine stimulates the muscular fibre itself, it will cause contraction in an eye which is dilated by atropine unless the action of the atropine has been carried to such an extent as to paralyse the muscular fibre.

The contraction produced by muscarine in the eye of the cat is so great as to reduce the pupil to a mere slit, and is much greater than that caused by physostigmine, for muscarine, acting only on the ends of the oculo-motor, produces spasm in the sphincter without affecting the dilator, while physostigmine, acting on the muscular fibres, is said to stimulate those of the dilator as well as the sphincter, and thus to render the contraction less complete.2

It has already been pointed out, however, that the action of atropine is not confined to the ends of the oculo-motor nerve, but affects the muscular fibre itself, and thus it will counteract the effect of physostigmine, which it would not do if it acted only on the nerves.

Atropine consists of the combination of a base, tropine, with tropic acid. Tropine itself has no mydriatic action, but when an atom of hydrogen in it is displaced by an acid residue it acquires this action. A number of combinations of tropine with different acids have been artificially prepared by Ladenberg, who terms them tropeines. Amongst these are homatropine, in which the tropine is combined with oxytoluylic acid, and also benzoyl-tropine. Atropine appears to be identical with daturine. Hyoscyamine is also a combination of tropine with tropic acid, but it appears to be only isomeric with and not identical with atropine, though it seems to be identical with duboisine.

1 Schmiedeberg, Arzncimittellehre, p. 71. 2 Schmiedeberg, op. cit.

Action Of Drugs On Accommodation

The accommodation of the eye depends upon the ciliary muscle. When the eye is at rest the lens is flattened by the elastic tension of the zonule of Zinn. During accommodation for near objects the ciliary muscle draws the zonule forward and allows the lens to become more convex. The ciliary muscle is innervated by the third nerve: the centre for it appears to be in the posterior part of the floor of the third ventricle. Those drugs which affect the iris, also affect the power of accommodation. Their action on the iris and on accommodation do not, however, always begin at the same time, nor have they the same duration. The action of physostigmine and atropine on accommodation usually begins after, and passes away long before, the affection of the pupil.