Ester compounds, local anaesthetic

Procaine is a derivative of p-aminobenzoic acid, and is a one of the oldest used ester-type local anaesthetic agents [1], The compound was originally developed by Einhom [2,3], and later with and Uhlfelder [4]. This anti-arrhythmic drug itself has a short half-life, but is able to form salts with other drugs which causes an increase in the duration of action [5]. 

The nature of the configuration is the basis upon which local anaesthetics are classified. Ester local anaesthetics are characteristically unstable compounds that are broken down in the plasma by plasma cholinesterases. In contrast, the amide agents are very stable compounds that require extensive hepatic biotransformation. The more complex the linkage, the greater the tendency for toxicity. 

In further attempts to obtain useful drugs related to cocaine (30) with modified pharmacological activity, a series of tropane esters (31) has been synthesized in which the aromatic ring is attached directly to position 3. In most of the compounds synthesized a 5—60-fold increase in some biological parameters was observed, but a 10-fold reduction in local anaesthetic activity and a four-fold lowering of intravenous toxicity were also noted. 

A large number of new tropanyl esters and other related compounds have been prepared, with the purpose of contributing further structure-pharmacological activity relationships. Inter alia, para-substituted tropanyl benzoates (for studies of the substrate specificity of atropine esterase), benzazocines (narcotic antagonists) from 6-hydroxytropinone, 5-aryl-furan-2-carboxylic esters of pseudotropine (local anaesthetics), 2,4,5-trimethylpyrrole-3-carboxylic acid... 

Knowledge of the chemistry of local anaesthetics also helps in finding possible substitutes, e.g., the replacement of an ester by an amide agent which neither cross-reacts, nor is likely to cause allergy by itself. Many other compounds have local anaesthetic properties, and may be thought of as potential alternatives, e.g., certain phenothiazine antihistamines and propranolol (the jS-adrenoceptor blocker). 

The activation of ester prodmgs via the action of esterases is described above and in various other chapters, e.g. Chapter 5 and Chapter 22. Esterases are also employed to inactivate dmgs or to prepare them for phase II conjugation. For example, the local anaesthetic lidocaine is rapidly hydrolysed to p-aminobenzoic acid deactivating it (Fig. 8.35). The closely related antianythmic compound procainamide is not readily hydrolysed and its major deactivated metah-olite is desethyl procainamide (Fig. 8.35), although much of the dmg is excreted unchanged. Hydrolysis of esters occurs much more readily than the hydrolysis of amides... 

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