Pharmacology-1 PHL 211 2nd Term 1st Lecture Local Anesthetics I By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

Mechanisms that establish the resting membrane potential & action potential

Action Potential Depolarization Repolarization

Local Anesthetics, Introduction Local anesthetics (LAs) are drugs used to prevent or relieve pain in specific regions of the body without loss of consciousness LAs reversibly block pain sensation by blocking nerve conduction along nerve axons and other excitable membranes Mechanism of action: LAs reversibly bind to voltage-gated Na+ channels, block Na+ influx, and thus block action potential and nerve conduction LAs bind to receptors near the intracellular end of the sodium channel and block the channel in a time- and voltage-dependent fashion The blockade of sodium channels by most LAs is both voltage- and time-dependent: Channels in the rested state, which predominate at more -ve membrane potentials, have a much lower affinity for LAs than activated (open state) and inactivated channels, which predominate at more +ve membrane potentials. Thus, the effect of a given drug concentration is more marked in rapidly firing axons than in resting fibers Between successive action potentials, a portion of the sodium channels will recover from the LA block. The recovery from drug-induced block is 10 to 1000 times slower than the recovery of channels from normal inactivation. As a result, the refractory period is lengthened and the nerve conducts fewer impulses When applied locally to nerve tissue, LAs can act on any part of the NS and on every type of nerve fiber, reversibly blocking the action potentials responsible for nerve conduction. Thus, a LA in contact with a nerve trunk can cause both sensory and motor paralysis in the area innervated

Local Anesthetics, Introduction, contd. LAs are usually administered by injection into dermis and soft tissues located in the area of nerves. Thus, absorption and distribution are not as important in controlling the onset of effect as in determining the rate of outcome of local analgesia, and the likelihood of CNS and cardiac toxicity LAs are weak bases and are usually made available clinically as salts to increase solubility and stability. In the body, they exist either as the uncharged base or as a cation Because the pKa of most LAs is in the range of 8.0-9.0, the larger percentage in body fluids at physiologic pH will be the charged, cationic form The uncharged form of LAs is more likely to penetrate the biologic membranes but the charged form is more active in blocking the Na+ channel Vasoconstrictor substances e.g., epinephrine reduce systemic absorption of LAs from the injection site by decreasing blood flow in these areas, thus, localized neuronal uptake is enhanced because of higher local tissue concentrations in the region of drug administration, and the systemic toxic effects are reduced Pregnancy appears to increase susceptibility to LA toxicity, with reductions in the median doses required for neural blockade and to induce toxicity

Local Anesthetics, Introduction, contd. Local effects: LAs can provide highly effective analgesia in well-defined regions of the body The most common routes of administration include: Topical application (e.g., nasal mucosa, wound margins) Injection in the vicinity of peripheral nerve endings (infiltration) and major nerve trunks (blocks) Injection into the epidural or subarachnoid spaces surrounding the spinal cord

Structure, Classification & Properties of LAs Ester-type LAs (procaine is a prototype of this class): These generally are well hydrolyzed by plasma esterases (e.g., butyrylcholinesterase), contributing to the relatively short duration of action of drugs in this group Most LAs consist of a hydrophobic (aromatic) moiety, a linker region, and a substituted amine (hydrophilic region) LAs are grouped by the nature of the linker region: Amide-type LAs (lidocaine is a prototype of this class): These generally are more resistant to clearance and have longer durations of action. They, in general, are degraded by the hepatic CYPs and extensively bound to plasma proteins There are exceptions, including benzocaine (poorly water soluble; used only topically) and the structures with a ketone, an amidine, and an ether linkage