Local anesthetic structure features

The observation that very significant parts of the cocaine molecule could be deleted from synthetic analogs without loss of biologic activity led to the search for the minimal structural feature consistent with activity. This exercise, sometimes referred to as molecular dissection, not only led to great simpli-fi cation of the structure of local anesthetics but resulted fi-tially in the preparation of active molecules that bear only the remotest structural relation to the prototype, cocaine. 

Structural and theoretical chemistry studies of phenytoin and carbamazepine suggest that they bind to the Na+ channel via a pharmacophore that consists of an aromatic ring and an amide linkage. This pharmacophore consists of two of the three structural features found in local anesthetics. The ionizable group, which is characteristic of local anesthetics, precludes the ability to diffuse across the blood-brain barrier. 

Local anesthetics have similar structural features, including an aromatic ring, an intermediate chain, and an amine group. Ask your dentist which ones he or she uses for your treatment. 

Local anesthetics are drugs that produce reversible conduction blockage of nerve impulses. Autonomic system blockade followed by sensory anesthesia and skeletal muscle paralysis occur when local anesthetic concentration is increased. The effects of local anesthetics are completely reversible, with no evidence of structural damage to the nerve fibers. Another prominent clinical feature of local anesthesia is that loss of sensation occurs without loss of consciousness. This property makes local anesthetics highly useful for many office procedures and for eye surgery. This chapter considers the pharmacologic properties of anesthetics cmrently used for ophthalmic procedures. 

It is an important feature of the local anesthetics in clinical use that their structures include tertiary amine groups that coexi.st in equilibrium with the conjugate acid at physiological pH ... 

The first totally synthetic substitute was eucaine. It was synthesized by Harries in 1918 and retains many of the essential skeletal features of the cocaine molecule. The development of this new anesthetic partly confirmed the portion of the cocaine structure essential for local anesthetic action. The advantage of eucaine over cocaine is that it does not produce mydriasis and is not habit forming. Unfortunately, it is highly toxic. 

Over the years, hundreds of new local anesthetics have been synthesized and tested. For one reason or another, most have not come into general use. The search for the perfect local anesthetic is still under way. All the drugs found to be active have certain structural features in common. At one end of the molecule is an aromatic ring. At the other is a secondary or tertiary amine. These two essential features are separated by a central chain of atoms usually one to four units long. The aromatic part is usually an ester of an aromatic acid. The ester group is important to the bodily detoxification of these compounds. The first step in deactivating them is a hydrolysis of this ester linkage, a process that occurs in the bloodstream. 

After determining cocaine s structure, chemists could ask, "How is the structure of cocaine related to its anesthetic effects Can the anesthetic effects be separated from the habituation effect " If these questions could be answered, it might be possible to prepare synthetic drugs with the structural features essential for the anesthetic activity but without those giving rise to the undesirable effects. Chem -ists focused on three structural features of cocaine its benzoic ester, its basic nitrogen atom, and something of its carbon skeleton. This search resulted in 1905 in the synthesis of procaine, which almost immediately replaced cocaine in dentistry and surgery. Lidocaine was introduced in 1948 and today is one of the most widely used local anesthetics. More recently, other members of the "caine" family of local anesthetics have been introduced (e.g., etidocaine). All of these local anesthetics are administered as their water-soluble hydrochloride salts. 

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