Local Anesthetics Agents,Action,Misconceptions

Lecture Objectives Review the mechanism of action, pharmacodynamics, phamacokinetics, toxicity, and common misconceptions about local anesthetics.

General considerations - All local anesthetics [ LA ] contain an aromatic ring at one end of the molecule and an amine at the other, separated by hydrocarbon chain. - LAs segregate into esters and amides, based on the chemical link between the aromatic moiety and hydrocarbon chain.

Electrophysiology, Na channel, and LA action. - Local anesthesia results when LAs bind Na channels in nerves, inhibiting the Na permeability that underlies action potential. - Na channels can exist in at least 3 conformations : resting, open, and inactivated.

- LAs will bind to many different sites ; thus, the molecular mechanism by which LAs produce spinal or epidural analgesia may include LA binding to targets other than Na channels. - Other chemicals also bind and Na channels, including tetrodotoxin and other toxins, calcium channel blockers, a 2 adrenergic agonists, volatile general anesthetics, and meperidine.

LA Pharmacodynamics - Potency, duration of action, speed of onset,and tendency for differential block. LA potency - The larger,more lipophilic LAs permeate nerve membranes more readily and bind Na channels with greater affinity.

LA Duration : regulated by protein binding? - It is a misconception that the duration of regional anesthesia directly relates to LA protein binding. - More lipid soluble LAs are less relatively water- insoluble and, therefore, highly protein - bound. - It is more logical to state that LA duration of action relates to LA lipid solubility.

LA Speed of Onset : Controlled by pKa ? - At any pH, percentage of LA molecule present in the uncharged form is largely responsible for membrane permeability decrease with increasing pKa. - One should consider the two LAs of fastest onset in the clinic : eticocaine and chloroprocaine.

Differential Sensory Nerve Block - All LAs will block myelinated or unmye- linated fibers of smaller diameter at lower concentration than are required to block larger fibers of the same type. - Bupivacaine and ropivacaine are relatively selective for sensory fibers ; adequate sensory analgesia, with little or no motor block.

Other Factor Influencing LA Activity. - A variety of factor influence the quality of regional anesthesia, including LA dose, site of administration, additives, temp., and pregnancy. - In general, the fastest onset and shortest duration of anesthesia occurs with spinal or subcutaneous injections ; a slower onset and longer duration are obtain with plexus blocks.

- Epinephrine is frequently added to LA solution in a 1 :200,000 dilution. - Other popular LA additives include clonidine, opioids, neostigmine, hyalu- ronidase, and NaHCO 3. - LAs more potently block action poten- tial at basic pH, where there are increase amount of LA in the uncharged form,than at more acid pH.

- Some clinical studies show that the addition of sodium bicarbonate to LAs speeds the onset of nerve blocks. - The potency of LAs increase in vitro and in vivo with cooling in some circum- stances, but not in others. - Spread of epidural or spinal anesthesia increase during pregnancy. - Pregnancy appears to increase the susceptibility of nerves to LAs.

LA Concentrations, Protein Binding, Metabolism, and Phamacokinetics. - Peak LA concentrations vary by the site of injection. - After plexus, epidural, or intercostal blocks, the latter consistenly produced the greatest peak LA concentrations. - The least potent, shortest-acting LAs are less protein-bound than the more potent, longer-persisting agents.

- For esters metabolism, the primary step is ester hydrolysis, catalyzed by plasma pseudocholinesterase. - For amides metabolism, undergo nearly exclusive metabolism by the liver. - Ester metabolism can, theoretically, be slowed by cholinesterase deficiency or long-term cholineserase inhibition - Amide clearance is highly dependent on hep.blood flow, hep.extraction and enz. function.

Toxic Side Effects of LAs CNS Side Effects. - More potent LA consistently produce seizure at lower blood concentration and lower doses than less potent LAs - Both elevated pCO 2 and acidosis decrease the LA convulsive dose. CV Toxicity. - Occur when blood concentration is at least 3 times that producing seizure.

- There are reports of simultaneous CNS and CV toxicity with bupivacaine and related agents. - The bupivacaine R[+] isomer binds cardiac Na channels more avidly than the S [-] isomer, forming the basis for the development of ropivacaine and levo- bupivacaine.

Allergic Reaction to LAs. - Uncommon. - True anaphylaxis has been documented with esters, particularly those which are metabolized directly to PABA. - Anaphylaxis to amide anesthetic is much less common.

Neurotoxic Effect of LAs. - 2-chloroprocaine occasionally produce cauda equina syndrome when large doses were accidentally injected into spinal fluid. - Presently, there is controversy regardling whether lidocaine produces persisting sacral deficit and whether it may be associated with an excessive incidence of transient radicular irritation after SPB.

Treatment of LA Toxicity. - Essential treatment of LA-induced seizure should include maintaining the airway and providing oxygen. - Seizures may be terminated with IV thiopental, BZP, or a paralytic dose of succinyl choline followed by tracheal intubation. - Hypotension may be treated by IV fluid and vasopressors.