Local Anesthetics

MOA: Local anesthetics bind to a receptor near the intracellular edge of the pore of the Na+ channel and block the channel in a time- and voltage-dependent fashion. Sodium permeability is reduced. Blockage of the nerve impulse propagation can occur without a significant change in the RMP. Because activated (open) and inactivated (depolarized) Na+ channels have higher affinity for local anesthetics than resting (repolarized) channels, a given concentration of local anesthetic tends to have greater effects on rapidly firing axons and those with longer AP. Slightly depolarized neurons are more susceptible to local anesthetics than hyperpolarized neurons. Increases in extracellular calcium antagonize local anesthetic action, while elevated extracellular potassium enhances efficacy. Anesthetics stabilize the inactivated state.

Effect of pH: Local anesthetics are weak bases (pKa 8-9). It is the uncharged form that penetrates the lipid membrane of the axon, but it is the charged form that binds inside the channel to produce anesthetic action. In the body, most anesthetics are charged. Thus, the rate of conversion from the charged to the uncharged form and the lipid solubility of the uncharged form are limiting factors with respect to penetration of the drug.

Structure-activity relationship: Potency is correlated with lipid solubility.

Differential sensitivity to nerve block: The smaller B and C fibers are generally affected before A fibers. Type A delta fibers are blocked before type A beta fibers. Pains fibers are blocked early, other sensations are affected next, and motor function is the last to disappear. Recovery occurs in the reverse order with motor function first and pain sensation last. This effect is due to the smaller diameter of pain fibers and relatively longer AP duration. With infiltration of a large nerve, sensation would be lost first over proximal areas and then distally as the drug penetrates the nerve.

Chemical structures: Most local anesthetics contain three groups – lipophilc group, intermediate chai (ester or amide linkage), ionizable (hydrophilic) group. Ester-linked local anesthetics are more likely to produce hypersentivity reactions than the amide-linked compounds.

Pharmacokinetics:

When blocking large nerves for regional anesthesia, the order of maximal blood levels is

intercostals>caudal>epidural>brachial plexus>sciatic nerve.

The presence of a vasoconstrictor retards absorption by decreasing blood flow to and away from the injection area (greatest prolongation seen with procaine and lidocaine). The toxic effects of the drug are reduced in the presence of vasoconstrictors because the blood concentration may be decreased.

Cocaine produces vasoconstriction, while the others all show some vasodilation. Amide-linked anesthetics are widely distributed and taken up by most tissues. Ester-linked agents are metabolized very rapidly by plasma butyrylcholinesterase and secondarily by liver esterases.

Cholinesterase inhibitors may increase the possibility of toxicity. Amides are normally cleared by hepatic microsomal metabolism. Patients with impaired liver function or reduced hepatic blood flow will be more susceptible to amide toxicity. Propanolol may prolong the half-life of lidocaine.

Esters – Short half-lives, hypersensitivity reactions, injectable, NOT SURFACE

• Procaine – Prototype; short-acting; poorly absorbed from mucous membranes; requires injection; used for infiltration and nerve block; hydrolysis produces PABA, which may interefere with sulfonamides NOT TOPICAL.

• Cocaine – Surface anesthesia of the respiratory tract, NOT EYE; significant CNS stimulant action; blocks catecholamine uptake; toxicity produces pyrexia.

• Chloroprocaine – Least toxic; short-acting; contraindicated IV due to thrombosis; NOT TOPICAL; motor and sensory deficits.

• Tetracaine – Long-acting; topical or spinal anesthesia

• Benzocaine – Topical (creams and ointments); use on denuded areas due to poor absorption.

Amides – Longer-lasting than esters, efficiently absorbed from mucous membranes, all routes except eyes.

• Lidocaine – Intermediate-acting; more prompt, more intense, longer-lasting than procaine; less likely to produce hypersensitivity; all routes except eyes.

• Prilocaine – Intermediate-acting; rapid hepatic metabolism; use during labor and delivery may result in methemoglobinemia.

• Bupivacaine – Long-acting; injectable; not effective on surface; more cardiotoxic than others.

Toxicology: Reactions due to rapid absorption of drug into the vascular system. Convulsions are best treated with IV diazepam. CNS: Global excitation due to depression of inhibitory pathways. CV: Decrease electrical excitability, conduction velocity, and force of contraction of myocardium,. Most also cause arteriolar vasodilation. Sufficienct amounts can cause severe hypotension, CV collapse and death from cardiac arrest and depression of pacemaker tissue or sudden onset of ventricular fibrillation. Allergic reactions: Reactions to esters due to liberation of PABA. Blood: Prilocaine can cause methemoglobinemia.

Therapeutic application: Infiltration anesthesia is injection of the drug into tissue without taking into consideration the course of cutaneous nerves. Epidural anesthesia requires a relatively large amount of agent. Spinal anesthesia usually results in altered CV function and headache due to loss of CSF.

Category: Pharmacology Notes