Mydriatic activity

Homatropine (mandelyltropine) being a useful mydriatic it is surprising that of nine esters of mandelic acid tried, none showed mydriatic activity though three were local anaesthetics, two of them being described as good. Only one of the tropic acid esters tried showed local anaesthetic action and that was poor. ... 

Mydriatic activity on rabbits and humans, and cycloplegic activity on humans were tested. It was found that tropicamide bioavailability, both in rabbits and in humans, was not decreased by micellar solubilization. The conclusion was that some poloxamers perform satisfactorily as solubilizing vehicles for tropicamide, producing neutral 1.0-1.5% drug solutions that are better tolerated and more effective than the standard aqueous eyedrops. 

Many of the methods of obtaining experimental evidence for the antispasmodic, antiulcer, and mydriatic activities do not measure precisely and selectively only one type of pharmacological activity. However, the techniques that are available (19,20), if used with an understanding of their scope and limitations, can provide useful information in the development of anticholinergicagents and their structure-activity relationships. 

The presence of an epo group seems to increase the mydriatic activity (Table 3.13). However, scopolamine (7), which contains an epoxy group, is a central depressant, as indicated by drowsiness, euphoria, amnesia, and dreamless sleep. Atropine (4), which does not contain an epoxy group, stimulates the medulla and higher cerebral centers. In clinical doses (0.5-1.0 mg), this effect is usually confined to mild vagal excitation. Toxic doses of atropine cause restlessness, disorientation, hallucinations, and delirium. 

Three tropic acid esters, ( )-tropoyltropan-3/ -ol (3), ( )-tropoylgranatan-3-/ -ol (4), and its C-3 epimer, have been synthesized and characterized for evaluation as mydriatics and spasmolytics.20 Another group21 has prepared 26 diarylacrylic esters of tropine for pharmacological evaluation all are potent spasmolytics (in mice) but devoid of mydriatic activity. The activities of these esters have been correlated with their structures,22 and a certain degree of success is claimed in this very limited field it may therefore prove possible to predict approximately the activity of hitherto unprepared compounds, and therefore increase the effectiveness of this particular area of pharmaceutical research. 

Dioscorine, like tropine, shows a mydriatic activity when injected into monkeys. Other physiological properties are similar to, but weaker than, those of picrotoxin and in some instances they reflect those of the cardiac glycosides (vagal excitation, etc.). 

Atropine itself is a relatively strong base with a pfc, at 15-20° C. of about 10 (31), i.e., its mineral salts are about 99.9 % ionized at pH 7. However, when an atropine salt is applied locally to the eye, it mil be somewhat less well ionized, because the eye temperature will be near 37° C. and bases become weaker as the temperature rises, and because tears, which normally bathe the cornea, are slightly alkaline (pH 7-8), so that we shall probably not be far wrong in assuming that in the eye about 99% of atropine is present as atropinium cations. If un-ionized atropine base is able to penetrate cell membranes much more easily than the atropinium cation, and only 1 % is present as such, we should expect absorption to be slow, and, as already mentioned, atropine does not achieve its full effect in the human eye under an hour. In conformity with this idea, alkalization of atropine salt solutions increases both the speed and the intensity of their mydriatic activity. Thus, whereas a 1 10,000 solution of atropine sulfate produced no effect in a cat s eye in 10 min. and a barely perceptible dilatation in 50 min., a similar solution made 0.5 N with respect to sodium bicarbonate began to act in 10 min. and had produced full dilatation in 50 min. (32). The alkalinized solution was judged by indicators to have a pH of 8-9, so that the concentration of un-ionized atropine was probably increased about tenfold by the addition of sodium bicarbonate. 

More far-reaching modifications of the tropane nucleus must now be considered. The tropic ester of homotropine (III) is said to act qualitatively like atropine on the eye and the heart, but to stimulate intestinal muscle and to antagonize atropine in that tissue. Its mandelic ester was said to be devoid of mydriatic activity (34). 

Fig. 2. Factor analysis of the Keasling/Moffett [48] data plot of the tests in the space spanned by the three orthogonally varimax-rotated common factors. Groups of variables are toxicity ( ) simple reflexes ( ) — traction (2), chimney (3), dish (4) anticonvulsant activity (o) — thiosemi carbazide (5) and nicotine antagonism (6), electroshock (7) anticholinergic actions (A) — central (8) and peripheral tremorine antagonism (9), mydriatic activity (10) fighting (A) (11).

These compounds possess potent physiological effects in animals and have long been of interest in medicine. Many have mydriatic activity (i.e., they cause dilation of the pupil of the eye). Others, such as cocaine, are anesthetics (Leete, 1990). 

Mydriatic activity in mice i.p. administration. Doses in mg, causing 5-fold pupil dilatation (upper line). Relative potency (lower line)... 

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