From Dr W. S. Wilson, MRPharmS
SIR,—I write to comment on the article by L. C. Titcomb "Mydriatic-cycloplegic drugs and corticosteroids" (PJ, December 4, 1999, p900).
Atropine is indeed the most potent of the antimuscarinic drugs mentioned, but the implication that this explains its long duration of action is misleading. In fact, potency has only an indirect influence on duration of action, hence the later statement that clinical applications in ophthalmology vary according to the drug's potency is incorrect. Their variation in use largely depends on their duration of action, which depends on their different affinity for iris pigment (melanin). The extreme duration of atropine's mydriatic effect is remarkable and is due to the very high degree of binding which occurs between atropine and melanin, as is evinced by the common observation that eyes with heavy pigmentation (dark brown to black) require a higher topical dose than brown eyes, which in turn require a bigger dose than blue eyes.
Mrs Titcomb mentions "mechanical blockade by chromatophores (melanin-containing cells) which hinder drug molecules from reaching the receptor sites". In fact, the smooth muscle of the sphincter pupillae lies anterior to the pigment layer where the bulk of the melanin is located and so the drug molecules advancing largely from the direction of the cornea (following topical administration and transcorneal absorption) will not be mechanically hindered by chromatophores. Rather, atropine is bound to the melanin and very slowly released over a period of many days, during which time it continually renews the blockade of muscarinic receptors in the sphincter pupillae and the ciliary muscles.
This process also leads to prolongation of the cycloplegic effect, but for most antimuscarinic drugs this tends to happen to a smaller extent than for mydriasis, presumably because the ciliary muscle is relatively more distant from the drug depot in the iris. Furthermore, drug molecules released from the iris are being steadily washed into the anterior chamber by the continual tide of aqueous humour being secreted by the ciliary body, thus making their access to the ciliary muscle (to produce cycloplegia) more difficult.
One further practical point that is of interest to pharmacists relates to atropine and its considerable toxicity: since the danger of accidential poisoning with the ointment is negligble, this formulation is far preferable to eyedrops, especially for use by patients who may have children at home.
William S. Wilson
Lecturer in Pharmacology, Ocular Pharmacology Laboratory, Institute of Biomedical and Life Sciences, Glasgow University
Mrs TITCOMB replies: I thank Dr Wilson for his interest in my article and agree with him that mydriatic-cycloplegic drugs may be selected on the basis of their duration of action. For example, tropicamide is chosen to dilate the pupil for routine ophthalmoscopy because it has a rapid onset and brief duration of action. However, I cannot agree that potency, which I would define as the ability of the drug to cause a certain desired effect, is unimportant. Optometrists select atropine for cycloplegic refraction because of its potency. The use of atropine completely paralyses the ciliary muscle while varying degrees of residual cycloplegia remain with other cycloplegics.1 It is certainly not chosen for this use for its prolonged duration of action, and parents of patients undergoing cycloplegic refraction with atropine must be counselled that the adverse effects of the drug on the child's vision can last for up to two weeks after the test.
My article quotes Lovasik's proposal that the deeper cycloplegia of faster onset seen in eyes with blue irides "may be attributable to mechanical blockade by chromatophores".2
Dr Wilson talks about the site of the smooth muscle of the sphincter pupillae but it is not this muscle but the ciliary muscle, sited posterior to the iris, which is paralysed to produce cycloplegia.
Although I agree that the majority of the iris pigment is sited in the pigment epithelial layer which is posterior to the iris musculature, the anterior border layer also contains pigmented uveal melanocytes.
It is this layer which is responsible for the colour of the iris, being thin in the blue iris and thick and deeply pigmented in the brown iris.3
Therefore, it is possible that this mechanism may also contribute to the more rapid and greater degree of mydriasis seen in patients with light irides.4 However, I did include the alternative explanation for this observation: "Binding of the drug by pigment cells, which occur in greater density in dark irides."
I agree with Dr Wilson on his point that atropine eye ointment is the preferred drug delivery system for use in children. Unfortunately, supplies of the ointment formulation have, of late, been extremely erratic and I would be grateful to hear from readers who have found a reliable source of this product.