Ester Drugs as Intravenous and Topical Agents

Lability can be used to advantage to create drugs that are designed for topical or intravenous infusion administration. For topical administration compounds may benefit from rapid systemic clearance to overcome possible side-effects. Thus the compound is stable at its topical site of action (skin, eye etc.) but rapidly degraded by the esterases present in blood, liver and kidneys to its inactive metabolites. This approach renders the compound selective.

The aim of intravenous infusion is often to achieve a steady state plasma concentration as rapidly as possible and to ensure that the concentration of the drug declines as rapidly as possible once the infusion is stopped. This gives the clinician complete control and the opportunity to react quickly to the patient's needs. Figure 7.19 shows how existing drugs such as the anaesthetic/analgesic sulfentanil, the p-blocker propranolol and the ACE inhibitor captopril, have been used as the starting point for the design of short-acting infusion agents. Essential to this design is the

Fig. 7.19 Design of rapidly cleared ester analogues of sulfentanil propranolol and captopril. The compounds remifentanil, esmolol and FPL 66564 are all cleared to inactive metabolites.

7.5 Pro-drugs to Aid Membrane Transfer 89

need for the acid metabolites produced from ester hydrolysis to be devoid of activity. In the case of remifentanil two sites of hydrolysis were incorporated into the molecule to provide sufficient metabolic lability [12, 13].

Topical agents can also be produced by the "soft-drug" approach. Bodor [14] has produced "soft" analogues of methatropine and methscopolamine. These are potent anticholinergics with a short duration of mydriatic action. Moreover the compounds show no systemic side-effects. They thus have a highly selective local action with a much decreased potential for systemic side-effects. Again the design of these drugs depends on knowing that the acidic metabolites produced are inactive.

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