Local Anesthetics By S. Bohlooli, PhD School of Medicine, Ardabil University of Medical Sciences

Introduction Schematic diagram of a primary afferent neuron mediating pain, its synapse with a secondary afferent in the spinal cord, and the targets for local pain control. The primary afferent neuron cell body is not shown. At least three nociceptors are recognized: acid, injury, and heat receptors. The nerve ending also bears opioid receptors, which can inhibit action potential generation. The axon bears sodium channels and potassium channels (not shown), which are essential for action potential propagation. Synaptic transmission involves release of substance P, a neuropeptide (NP) and glutamate and activation of their receptors on the secondary neuron. Alpha2 adrenoceptors and opioid receptors modulate the transmission process.

History Cocaine, the first local anesthetic introduced into medical practice, was isolated by Niemann in 1860 Procaine was synthesized by Einhorn in 1905 Lidocaine, which is still a widely used local anesthetic, was synthesized in 1943 by Löfgren.

Basic Pharmacology of Local Anesthetics

Chemistry: Structure Ester Cocaine Procaine (Novocain) Tetracaine (Pontocaine) Benzocaine

Chemistry: Structure Amides Lidocaine (Xylocaine) Mepivacaine Bupivacaine; Levobupivacaine Ropivacaine (Naropin)

Chemistry Local anesthetics are weak bases the pKa of most local anesthetics is in the range of 8.0–9.0 Cationic form is the most active form The uncharged form is important for rapid penetration of biologic membranes

Pharmacokinetics Local anesthetics are usually administered by injection into dermis and soft tissues around nerves Absorption and distribution are not as important

Absorption Systemic absorption of injected local anesthetic depends on: Dosage Site of injection Drug-tissue binding Local tissue blood flow Use of vasoconstrictors (eg, epinephrine) Physicochemical properties of the drug

Distribution, Metabolism and Excretion The amide local anesthetics are widely distributed after intravenous bolus administration The local anesthetics are converted in the liver (amide type) or in plasma (ester type) to more water-soluble metabolites Decreased hepatic elimination of local anesthetics would be anticipated in patients with reduced hepatic blood flow or hepatic diseases

Pharmacodynamics: Mechanism of Action Functional and structural features of the Na+ channel that determine local anesthetic interactions. A: Cartoon of the sodium channel in an axonal membrane in the resting (m gates closed, h gate open), activated (m gates open, h gate open), and inactivated states (m gates open, h gate closed). Recovery from the inactivated, refractory state requires closure of the m gates and opening of the h gate. Local anesthetics bind to a receptor (R) within the channel and access it via the membrane phase or from the cytoplasm. B: Molecular arrangement of the six membrane-spanning peptides, four of which combine to form the channel around a central pore. The S4 segments (marked with "+" signs) are thought to constitute the voltage-sensing m gates of the channel. The linker peptide connecting the III and IV hexamers acts as the inactivation h gate. Ions travel through an open channel along a pore defined at its narrowest dimension by partial membrane penetration of the four extracellular loops of protein connecting S5 and S6 in each domain. Local anesthetic binding occurs on S6 segments and at other regions of the channel. C: Three-dimensional drawing showing the configuration of the four hexamers around the central pore in the membrane.

Pharmacodynamics The function of sodium channels can be disrupted in several ways: batrachotoxin, aconitine, veratridine bind to receptors within the channel and prevent inactivation tetrodotoxin (TTX) and saxitoxin block sodium channels by binding to channel receptors near the extracellular surface Spinal neurons can be differentiated on the basis of tetrodotoxin effect into: TTX-sensitive TTX-resistant neurons

Pharmacodynamics With increasing concentrations of a local anesthetic The threshold for excitation increases Impulse conduction slows The rate of rise of the action potential declines The action potential amplitude decreases The ability to generate an action potential is completely abolished These effects result from binding of the local anesthetic to more and more sodium channels Effect of repetitive activity on the block of sodium current produced by a local anesthetic in a myelinated axon. A series of 25 pulses was applied, and the resulting sodium currents (downward deflections) are superimposed. Note that the current produced by the pulses rapidly decreased from the first to the 25th pulse. A long rest period after the train resulted in recovery from block, but the block could be reinstated by a subsequent train. nA, nanoamperes. (Modified and reproduced, with permission, from Courtney KR: Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther 1975;195:225.)

Effect of Extra cellurar Ions Increase in extracellular calcium partially antagonizes the action of local anesthetics Owing to the calcium-induced increase in the surface potential on the membrane. Increases in extracellular potassium enhancing the effect of local anesthetics.: Depolarize the membrane potential and favor the inactivated state.

Relative Size and Susceptibility of Different Types of Nerve Fibers to Local Anesthetics Fiber Type Function Diameter (m) Myelination Conduction Velocity (m/s) Sensitivity to Block Type A      Alpha Proprioception, motor 12–20 Heavy 70–120 +   Beta Touch, pressure 5–12 30–70 ++   Gamma Muscle spindles 3–6 15–30   Delta Pain, temperature 2–5 5–25 +++ Type B  Preganglionic autonomic < 3 Light 3–15 ++++ Type C    Dorsal root Pain 0.4–1.2 None 0.5–2.3   Sympathetic Postganglionic 0.3–1.3 0.7–2.3

Nerve fibers differ significantly in their susceptibility Effect of Fiber Diameter Effect of Firing Frequency Effect of Fiber Position in the Nerve Bundle Effects on Other Excitable Membranes

Clinical Pharmacology of Local Anesthetics

Clinical Pharmacology Can provide highly effective analgesia in well- defined regions of the body The usual routes of administration Topical application Injection in the vicinity of peripheral nerve endings (perineural infiltration) Injection in the vicinity of major nerve trunks (blocks) Injection into the epidural or subarachnoid spaces surrounding the spinal cord Intravenous regional anesthesia (Bier block)

Schematic diagram of the typical sites of injection of local anesthetics in and around the spinal canal

The choice of local anesthetic The choice of local anesthetic is usually based on the duration of action required Short-acting: Procaine and chloroprocaine Intermediate duration : lidocaine, mepivacaine, and prilocaine long-acting : tetracaine, bupivacaine, levobupivacaine, and ropivacaine

Some tips The onset of local anesthesia can be accelerated by the addition of sodium bicarbonate Repeated injections of local anesthetics can result in loss of effectiveness Pregnancy appears to increase susceptibility to local anesthetic toxicity

Toxicity Central Nervous System Neurotoxicity Cardiovascular System Lidociaine Cardiovascular System Bupivacaine Hematologic Effects Prilocaine: metabolite o-toluidine Allergic Reactions The ester-type local anesthetics: p-aminobenzoic acid derivatives