School of Pharmacy, University of Nizwa Local Anesthetics Course Coordinator Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa Lecture-32 April 28, 2012

Original in the Royal College of Surgeons of England, London. 18th Century Surgery Original in the Royal College of Surgeons of England, London.

William T.G. Morton’s Ether Inhaler October 17, 1846: First public demonstration of the use of ether in anesthesia at Massachusetts General Hospital

Classic Stages of Anesthesia Stage 1: Analgesia decreased awareness of pain Stage 2: Excitation delirium & excitation, enhanced reflexes Stage 3: Surgical Anesthesia unconscious, no pain reflexes, regular respiration, BP is maintained Stage 4: Medullary Depression respiratory & CV depression requiring ventilation and pharmacologic support

Mechanisms of Action Enhanced GABA effect on GABAA Receptors Inhaled anesthetics, Barbiturates Block nicotinic receptor subtypes (analgesia) Moderate to high concentrations of inhaled anesthetics Activate K channels Nitrous oxide, ketamine Inhibit NMDA (glutamate) receptors

Local Anesthetics Applied locally and block nerve conduction of sensory impulses from the periphery to the CNS Abolish sensation in a limited area of the body without producing unconsciousness Onset of action should be quick, and duration of action should be sufficient to allow time for the surgical procedure

Local Anesthetics: Mechanism of Action Inhibit the inward migration of Na+ Elevates the threshold for electrical excitation, reduces the rate of rise of the action potential, and slows the propagation of the impulse

Local Anesthetics: Clinical Pharmacology Useful route of administration Topical (nasal, mucosal) Infiltration (injection in the vicinity of peripheral nerve endings) Injection into the epidural spaces surrounding the spinal cord Intravenous regional anesthesia is used for short surgical procedure (<45 min)

Local Anesthetics Lidocaine Bupivacaine Prilocaine Cocaine Benzocaine

Lidocaine Pharmacological Actions: Absorption, Fate, and Excretion: Produces faster, longer lasting, and more extensive anesthesia than does an equal concentration of procaine Absorption, Fate, and Excretion: Absorbed rapidly after parenteral administration Metabolized in the liver by CYPs enzymes Excreted in the urine Toxicity: The side effects of high doses include drowsiness, tinnitus, and dizziness. As the dose increases, seizures, coma, and respiratory depression and arrest occur Clinical Uses: Wide range of clinical uses as a local anesthetic

Bupivacaine Pharmacological Actions: Toxicity: Widely used amide local anesthetic A potent agent capable of producing prolonged anesthesia Long duration of action Can be used to provide several days of effective analgesia Toxicity: Bupivacaine is more cardiotoxic than lidocaine Bupivacaine-induced cardiac toxicity can be very difficult to treat

Prilocaine An intermediate-acting amino amide local anesthetic Pharmacological profile similar to that of lidocaine It is unique among the local anesthetics in its propensity to cause methemoglobinemia

Cocaine Cocaine remains useful as topical use Toxicity prohibits its use as anesthesia Cocaine has a rapid onset of action (1 minute) and a duration of up to 2 hours Lower concentrations are used for the eye, while higher ones are used on the nasal and pharyngeal mucosa Bradycardia, tachycardia and hypertension are associated with cocaine Larger doses are directly depressant to the myocardium, and death results from cardiac failure Over dosage leads to convulsions followed by CNS depression

Benzocaine Used primarily for topical application to skin and mucous membranes Its low aqueous solubility allows it to stay at the site of application for long periods Its minimal rate of absorption after topical administration is associated with a low incidence of systemic toxicity