Amide compounds, local anaesthetic

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. 

Semisynthetic amides of retronamine (66), itself prepared from retronecine (65) in three steps, have been synthesized by coupling with the appropriate acid using AW -dicyclohexylcarbodi-imide. Several of the compounds prepared, notably the p hydroxy benzoyl-, cinnamoyl-, and benzoyl-retronamines, had marked hypotensive activity. The amides could not be crystallized and details of their characterization were not given. Atal and his co-workers have also prepared - a number of semisynthetic diesters of retronecine, heliotridine, and platynedne by esterification of the necine base with the appropriate acid chloride. Several of the compounds prepared had marked local anaesthetic activity. 

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). 

Capsaicin is the pungent principle derived from fruits of cayenne pepper—Capsicum annum, C. frutescens (Solanaceae). Capsaicin, a phenolic amide, is present in the fruit at a level of only 0.02%, yet its taste is detectable even in minute doses. The compound acts as a local anaesthetic and pain reliever through a complex mechanism (see Chapter 8). 

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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