Mydriatic

Review Problem 8 Suggest a synthesis of the mydriatic (dilates the pupils of tlie eyes) cyclopentolate, TM 110. 

The names, formulae and structures of these alkaloids are given in the following table. The esters of tropine or -tropine are known as tropeines or -tropeines respectively. The first eleven items in the table are sometimes called the solanaceous alkaloids, but they are not the only alkaloids, or even the only type of alkaloid, found in the botanical family Solanaceas. They are also sometimes referred to as the mydriatic alkaloids though other alkaloids also exert this action. 

For the detection and microchemical estimation of these alkaloids, the precipitation, crystalline form and melting-points of the perbromides, periodides, aurichlorides or picrates and the mydriatic test have been used. ... 

Phenylglycollyltropeine Mandelyltropeine, homatropine), CigHjiOjN. This is largely used as a substitute for atropine. It crystallises in prisms, m.p. 95-5-98-5°. The hydrobromide, the salt usually employed in medicine, is a crystalline powder, m.p. 217-8° (dec.) the hydrochloride, m.p. 224-5°, and the salicylate are also used. All tl ee are freely soluble in water. The methobromide has m.p. 192-6°. The aurichloride, B. HAUCI4, forms prisms and is sparingly soluble in water. Homatropine, unlike atropine, does not give the Vitali colour reaction (p. 70). Its mydriatic effect is more rapid and transient than that of atropine. 

Cocaine. This lias a bitter taste, is mydriatic, produces local anaesthesia and is toxic. After absorption, or when taken internally, it acts chiefly by stimulation of the central nervous system, succeeded by depression. Since the two phases may be present in different areas simultaneously, a mixed result may ensue. With large doses the chief symptoms are those of medullary depression. Death is due to paralysis of the respiratory centre. The main use of cocaine in medicine is as a local anaesthetic. 

Neither tropine nor 4-tropine is mydriatic, though the former is stated to produce mydriasis in cats when injected in large doses. The pharmacological properties of these two bases have been compared by Hazard, who points out that these cis-trans isomerides show qualitative differences in pharmacological action, whereas among optical isomerides there are usually only quantitative differences in activity. It has been stated that rabbits are immune from poisoning by belladonna and, in that connection,... 

According to Nyman the pharmacological action of hyoscine is considerably modified in the quaternary compounds of the alkaloid, e.g., the inhibiting action on salivary secretion is greatly increased in the methonitrate, as is also the spasmolytic activity, but the mydriatic action is unchanged and the central sedative activity disappears. 

Whilst tropyltropine (atropine) is mydriatic, this property is of a low order in benz yltropine and is absent in benzoyl- -tropine. The former is a weak and the latter a potent local anaesthetic. This parallelism in the influence of the tropyl and benzoyl radicals in developing mydriatic and local aniesthetic action respectively, has been shown by von Braun and his co-workers to occur through an extensive series of hydroxyalkylamines in addition to tropine. Considerable modification may be made in the structure of tropine without impairing its capacity for yielding mydriatics anaesthetics. Thus von Braun, Muller and Rath found that e tropyl- and benzoyl-esters respectively of liomotropine (I) and of N-hydroxyalkylnortropanes (III) are comparable with atropine and tropacocaine (derived from tropine (II) and 4-tropine (II) ), respectively... 

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. ... 

These results indicate that in these new ester mydriatics, the structural factors, which influence the development of this type of pharmacological action are similar to those made evident by the chemical investigations of Jowett and Pyman and the pharmacological work of Marshall, Dale, Laidlaw and Cushny on the tropeines. The nature of the basic component is obviously important since mydriasis is produced by simple bases such as ephedrine. As regards the nature of the esterifying acid, Jowett and Pyman drew the following conclusions — ... 

I. Tropeines of aliphatic acids exert no mydriatic effect. 

II. The replacement of the benzene residue by that of pyridine in the acyl group of a mydriatic tropeine does not cause the activity to vanish. 

III. In tropeines containing a disubstituted benzene ring, those in which the replacing groups occupy the pam-position have the least mydriatic action thus 0- and m-hydroxybenzoyltropeines are active, but not the p-isomeride. 

IV. No generalisation as to the relation between the mydriatic action and chemical constitution of the tropeines can be made which will explain the observed facts. 

Both Cushny and Dale found the amorphous gelsemium alkaloids represented by such fractions as gelseminine much more active than gelsemine. Cushny stated that gelseminine resembled coniine in action and showed a greater depressant effect on the central nervous system, but unlike coniine it exerted no pressor effect. It was also a powerful mydriatic. Dale found that 0-001 gm. of the hydrochlorides of the amorphous alkaloids injected into rabbits caused death from respiratory failure in 25 minutes, preceded by convulsions. These results are explained by the subsequent isolation from such amorphous fractions, of the potent alkaloids sempervirine and gelsemicine. 

Cycloplegic mydriatics cause mydriasis and cyclople-gia (paralysis of the ciliary muscle, resulting in an inability to focus the eye). These drugs (see Chap. 25) are used in the treatment of inflammatory conditions of the iris and uveal tract of the eye and for examination of the eye... 

Local adverse reactions associated with administration of tiie cycloplegic mydriatics include increased IOP, transient stinging or burning, and irritation with prolonged use (eg, conjunctivitis, edema, exudates). Systemic adverse reactions include dryness of the mouth and skin, blurred vision, photophobia, corneal staining, tachycardia, headache, parasympathetic stimulation, and somnolence. 

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