Structure-activity Relationship. The smaller and more lipophilic the local anesthetic, the faster the rate of interaction with the sodium...
Structure-activity Relationship.
The smaller and more lipophilic the local anesthetic, the faster the rate of interaction with the sodium channel receptor. Potency is also positively correlated with lipid solubility as long as the agent retains sufficient water solubility to diffuse to the site of action on the neuronal membrane. Lidocaine, procaine, and mepivacaine are more water-soluble than tetracaine, bupivacaine, and ropivacaine. The latter agents are more potent and have longer durations of local anesthetic action. These long-acting local anesthetics also bind more extensively to proteins and can be displaced from these binding sites by other protein-bound drugs. In the case of optically active agents (eg, bupivacaine), the S(+)isomer can usually be shown to be moderately more potent than the R(-) isomer.
Cocaine is an ester of benzoic acid and the complex alcohol 2-carbomethoxy, 3-hydroxy-tropane . Because of its toxicity and addictive properties , a search for synthetic substitutes for cocaine began in 1892 with the work of Einhorn and colleagues, resulting in the synthesis of procaine, which became the prototype for local anesthetics for nearly half a century. The most widely used agents today are procaine, lidocaine, bupivacaine, and tetracaine.
The typical local anesthetics contain hydrophilic and hydrophobic moieties that are separated by an intermediate ester or amide linkage . A broad range of compounds containing these minimal structural features can satisfy the requirements for action as local anesthetics. The hydrophilic group usually is a tertiary amine but also may be a secondary amine; the hydrophobic moiety must be aromatic. The nature of the linking group determines some of the pharmacological properties of these agents. For example, local anesthetics with an ester link are hydrolyzed readily by plasma esterases.
The structure-activity relationship and the physicochemical properties of local anesthetics have been reviewed by Courtney and Strichartz (1987). Hydrophobicity increases both the potency and the duration of action of the local anesthetics. This arises because association of the drug at hydrophobic sites enhances the partitioning of the drug to its sites of action and decreases the rate of metabolism by plasma esterases and hepatic enzymes. In addition, the receptor site for these drugs on Na+ channels is thought to be hydrophobic (see below), so that receptor affinity for anesthetic agents is greater for more hydrophobic drugs. Hydrophobicity also increases toxicity, so that the therapeutic index is decreased for more hydrophobic drugs.
Molecular size influences the rate of dissociation of local anesthetics from their receptor sites. Smaller drug molecules can escape from the receptor site more rapidly. This characteristic is important in rapidly firing cells, in which local anesthetics bind during action potentials and dissociate during the period of membrane repolarization. Rapid binding of local anesthetics during action potentials causes the frequency- and voltage-dependence of their action
The smaller and more lipophilic the local anesthetic, the faster the rate of interaction with the sodium channel receptor. Potency is also positively correlated with lipid solubility as long as the agent retains sufficient water solubility to diffuse to the site of action on the neuronal membrane. Lidocaine, procaine, and mepivacaine are more water-soluble than tetracaine, bupivacaine, and ropivacaine. The latter agents are more potent and have longer durations of local anesthetic action. These long-acting local anesthetics also bind more extensively to proteins and can be displaced from these binding sites by other protein-bound drugs. In the case of optically active agents (eg, bupivacaine), the S(+)isomer can usually be shown to be moderately more potent than the R(-) isomer.
Cocaine is an ester of benzoic acid and the complex alcohol 2-carbomethoxy, 3-hydroxy-tropane . Because of its toxicity and addictive properties , a search for synthetic substitutes for cocaine began in 1892 with the work of Einhorn and colleagues, resulting in the synthesis of procaine, which became the prototype for local anesthetics for nearly half a century. The most widely used agents today are procaine, lidocaine, bupivacaine, and tetracaine.
The typical local anesthetics contain hydrophilic and hydrophobic moieties that are separated by an intermediate ester or amide linkage . A broad range of compounds containing these minimal structural features can satisfy the requirements for action as local anesthetics. The hydrophilic group usually is a tertiary amine but also may be a secondary amine; the hydrophobic moiety must be aromatic. The nature of the linking group determines some of the pharmacological properties of these agents. For example, local anesthetics with an ester link are hydrolyzed readily by plasma esterases.
The structure-activity relationship and the physicochemical properties of local anesthetics have been reviewed by Courtney and Strichartz (1987). Hydrophobicity increases both the potency and the duration of action of the local anesthetics. This arises because association of the drug at hydrophobic sites enhances the partitioning of the drug to its sites of action and decreases the rate of metabolism by plasma esterases and hepatic enzymes. In addition, the receptor site for these drugs on Na+ channels is thought to be hydrophobic (see below), so that receptor affinity for anesthetic agents is greater for more hydrophobic drugs. Hydrophobicity also increases toxicity, so that the therapeutic index is decreased for more hydrophobic drugs.
Molecular size influences the rate of dissociation of local anesthetics from their receptor sites. Smaller drug molecules can escape from the receptor site more rapidly. This characteristic is important in rapidly firing cells, in which local anesthetics bind during action potentials and dissociate during the period of membrane repolarization. Rapid binding of local anesthetics during action potentials causes the frequency- and voltage-dependence of their action
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