1. Local Anesthetics Agents,Action,Misconceptions

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

3. 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.

4. 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.

5. - 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. - 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.

12. - 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.

13. 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.

14. - 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.

15. 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.

16. - 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.

17. 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.

18. 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.

19. 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.