LOCAL ANESTHETICSBy

S. Bohlooli, PhDSchool of Medicine, Ardabil University of Medical Sciences

INTRODUCTION

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

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 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 Heavy 30–70 ++

  Gamma Muscle spindles 3–6 Heavy 15–30 ++

  Delta Pain, temperature 2–5 Heavy 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 None 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

Lidociaine Cardiovascular System

Bupivacaine Hematologic Effects

Prilocaine: metabolite o-toluidine Allergic Reactions

The ester-type local anesthetics: p-aminobenzoic acid derivatives