Epinephrine prodrugs

In ophthalmic research, a prodrug is designed to be inactive with some degree of biphasic solubility as the cornea is a biphasic tissue in structure. It will be transformed into the active drug by either an enzymatic or a chemical processes in the eye. Dipivefrin is an epinephrine prodrug. Due to its increased lipophilicity,... 

Ocular inserts (epinephrin prodrug) Alginic acid Ocusert Alza... 

Hussain A, Truelove JE. Prodrug approaches to enhancement of physicochemical properties of drugs IV novel epinephrine prodrug. J Pharm Sci 1976 65 1510-1512. 

Numerous reports of prodrugs in the literature show improved drug effects. Prodrugs that have shown some measure of success for site-specific delivery include L-3,4-dihydroxyphenylalanine (L-dopa) to the brain [56], dipivaloyl derivative of epinephrine to the eye [57], /-glutamyl-L-dopa to the kidney [58], fi-n-glucoside dexamethasone and prednisolone derivatives to the colon [59], thiamine-tetrahydrofuryldisulfide to red blood cells, and various amino acid derivatives of antitumor agents such as daunorubicin [61,62], acivicin [63], doxorubicin [63], and phenylenediamine [63] to tumor cells. 

Pilocarpine and dipivefrin, a prodrug of epinephrine, are used as third-line therapies because of adverse events or reduced efficacy as compared with newer agents. 

Pharmacology Dipivefrin is a prodrug of epinephrine. Dipivefrin, converted to epinephrine in the eye by enzymatic hydrolysis, appears to act by decreasing aqueous production and enhancing outflow facility. It has the same therapeutic effects as epinephrine with fewer local and systemic side effects. 

FIGURE 9.10 The prodrug dipivalylepinephrine enters the cornea of the eye to allow esterase to produce epinephrine in the eye to alleviate high pressure in glaucoma. 

Use of the prodrug dipivefrin allows use of lower concentrations secondary to improved intraocular absorption (10- to 15-fold higher). The 0.1% dipivefrin produces equivalent lOP reduction to 1% to 2% epinephrine. Dipivefrin therefore may be tolerated by patients unable to tolerate epinephrine solutions, and it is often chosen over other epinephrine products when this class of drugs is indicated. 

Prodrugs have been designed to improve corneal absorption. This approach has been applied with epinephrine (226-230), terbutaline (231), various prostaglandins (232), phenylephrine (233-235), and pilocarpine (236-241). For some pilocarpine derivatives the double prodrug approach has been used to overcome eye irritation and improve on poor water solubility (240,241) (Section 5.4). 

Drugs containing hydroxyl groups are often converted into prodrugs to achieve better absorption properties. For example, consider the structure of epinephrine, wrhich is used in the treatment of glaucoma ... 

A prodrug form of epinephrine has been developed in which the aromatic hydroxyl groups are acylated to form ester moieties. This prodrug is called dipivefrin ... 

In this prodrug form, the hydrophobic tert-butyl groups enabie the compound to cross the nonpolar membrane of the eye more readily. Once the drug reaches the other side of the membrane, it Is hydrolyzed to release the active drug (epinephrine). 

The prodrug approach 2 has been resorted to in some instances to improve the ocular/systemic absorption ratio, as in the case of dipivalylepinephrine (Dipivefrin, DPE), a lipophilic prodrug of epinephrine (EP), an antiglaucoma topical drug. The majority of topical EP, administered as a 2% solution, enters the systemic circulation, as a result of systemic absorption through the nasal mucosa, and has been reported many times to produce systemic a- and p-adrenergic symptoms. DPE has no apparent systemic effect, because the enzymatic release of EP occurs most efficiently in the cornea, which is better penetrated by the more lipophilic DPE. The rationale for the realization of prodrugs is illustrated in Fig. 8. 

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