Local Anesthetics By S.Bohlooli, PhD

Schematic diagram of a primary afferent neuron mediating pain

Definition Local anesthetics are drugs that reversibly depress nerve conduction. "Caine" local anesthetics act more selectively than other agents.

Physical Properties (structure) Ester: Amide: Example(procaine): Exception: Benzocaine, which lacks a substituted amino group R —COO—R —N R —NHCO—R —N 1 2 R R R R 3 4 H N——COO—(CH ) —N 222 C H R — Lipophilic aromatic residue. R — Aliphatic intermediate connector. R, R — Alkyl groups, occasionally H. Constitute with N the hydrophilic terminus

Esters

Amides

(Acid-base considerations) Most local anesthetics are weak bases, pK a Usually prepared as a salt (e.g., with HCl) to increase stability, water solubility. When injected, 5%-40% is converted to the nonionized free base.

R-NH + R-N + H + acid base

O COCHHN 2 C CH 22 H H 2 N 5 C 52 HC 52 HC 52  O COCHHN 2 CH 22 NH + H + Nonionized baseCationic acid Base Acid Log = pH – pK a (Henderson-Hasselbalch equation) Base Acid 0.03 = For procaine (pK = 8.9) at tissue pH (7.4) a Base Acid Lipoid barriers(nerve sheath) Extracellular fluid AxoplasmBase Acid * Nerve membrane Alveolar mucosa [1.0] [2.5] [1.0] [3.1]

Mechanism of Action Axonal membrane Local anesthetics interfere with propagation of the action potential by blocking the increase in sodium permeability during depolarization.

Functional and structural features of the Na+ channel

Movement of S4 Segments ClosedOpen

Mechanism of Action Mixed nerve – Local anesthetics provide pain relief by blocking nociceptive fibers. Other fibers are affected as well. Sensitivity to local anesthetics depends on: Fiber diameter Fiber type Degree of myelination. – Sensory modalities are affected in the following order: pain, cold, warmth, touch, and pressure.

Table Susceptibility to Block of Types of Nerve Fibers CONDUCTION BIOPHYSICAL CLASSIFICATI ON ANATOMIC LOCATIONMYEL IN DIAMETER, uM CONDUC TION VELOCIT Y M·SEC -1 FUNCTIONCLINICAL SENSITIVIT TO BLOCK A fibers A αAfferent to and efferent from muscles and joints Yes Motor and proprioception + A β ++ A γEfferent to muscle spindles Yes Muscle tone++ A δSensory roots and afferent peripheral nerves Yes Pain, temperature, touch +++ B fibersPreganglionic sympatheticYes<33-15Vasomotor, visceromotor, sudomotor, pilomotor ++++ C fibers SympatheticPostganglionic sympathetic No Vasomotor, visceromotor, sudomotor, pilomotor ++++ Dorsal rootSensory roots and afferent peripheral nerves No Pain, temperature, touch ++++ SOURCE: Adapted from Carpenter and Mackey, 1992, with permission.

Pharmacokinetics Absorption – Local anesthetics are absorbed when ingested. Some local anesthetics may be absorbed in toxic amounts after topical use. Absorption after an injection depends on drug solubility in lipid and in water, tissue vascularity and local anesthetic and vasoconstrictor effects on local circulation.

Pharmacokinetics (2) Metabolism and excretion – Esters are hydrolyzed by plasma and liver esterases. Longer-acting esters are often metabolized more slowly. Patients with altered pseudo-cholinesterase activity may be highly sensitive to these drugs.

– Amides are metabolized in the liver. Patients with severe hepatic damage or advanced congestive heart failure may be unusually sensitive to these drugs. Some amides are partially excreted unchanged in the urine.

Local anesthetic metabolism NHC CH 3 O N R 1 R 2 R 3 Hydroxylation and conjugation N-dealkylation (and cyclization) R 4 Hydrolysis Amide Ester

Adverse Effects Side effects – CNS toxicity —Entry of local anesthetics into the brain depression of CNS pathways. The clinical picture may include stimulation (e.g., excitement, disorientation, increased heart rate and respiration, tremors, and frank convulsions) if inhibitory neurons are affected initially.

– CNS depression may cause: Hypotension, Respiratory depression, Unconsciousness Death. Treatment includes supportive measures. Excitement and convulsions may be controlled with 5 mg dosess of diazepam or 2 mg doses of midazolam. Respiratory depression requires oxygen and possibly rescue breathing.

Adverse Effects (2) – Cardiovascular derangement —High plasma titers may depress the cardiovascular system directly. Blood pressure may fall because of arteriolar dilation, myocardial depression, and/or cardiac conduction disruption. Treatment includes patient positioning, IV fluids, and vasopressors. Cardiac asystole will require CPR.

Prevention of systemic toxicity— Limit the amount of drug employed. Use proper injection techniques.

Adverse Effects (3) Allergy – Allergic reactions are rare, especially with amide local anesthetics. Urticarial rashes are most common, but more serious responses also occur. Mild skin reactions are treated with antihistamines; more serious sequela require epinephrine.

Adverse Effects (4) Syncope – The most common side effect of dental injections. Must be treated promptly since it may be dangerous in its own right and has to be differentiated from anaphylactic shock.

Adverse Effects (5) Local toxic reactions – Selective destruction of skeletal muscle fibers. Epithelial damage from topical preparations. Local necrosis from vasoconstrictor actions.