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 amide

s, based on the chemical link between th e aromatic moiety and hydrocarbon chai

n.

Electrophysiology , Na channel , and LA action.

- Local anesthesia results when LAs bind Na channels in nerves , inhibiting th

e Na permeability that underlies action potential.

- Na channels can exist in at least 3 conformations : resting , open , and inact

ivated .

- LAs will bind to many different sites ; t hus, 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 chan

nels , including tetrodotoxin and other to xins , 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 permeat

e 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 prote

- in bound. - It is more logical to state that LA duratio

n 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 an

d 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 clon

-idine, opioids, neostigmine, hyalu ronidase, and NaHCO3. - -LAs more potently block action poten tial at basic pH , where there are increas

e amount of LA in the uncharged form,tha

n at more acid pH.

- Some clinical studies show that the ad dition of sodium bicarbonate to LAs spe

eds the onset of nerve blocks. - The potency of LAs increase in vitro an

-d in vivo with cooling in some circum stances, but not in others. - Spread of epidural or spinal anesthesi

a increase during pregnancy. - Pregnancy appears to increase the sus

ceptibility of nerves to LAs.

LA Concentrations, Protein Bindin g, Metabolism, and Phamacokineti

cs. - Peak LA concentrations vary by the site of injection. - After plexus, epidural, or intercostal block

s, the latter consistenly produced the greate st 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 se

izure at lower blood concentration and lower doses than less potent LAs - Both elevated pCO2 and acidosis decre

ase 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 rel

ated agents. - The bupivacaine R[+] isomer binds car

diac Na channels more avidly than - the S [ ] isomer , forming the basis for th

-e 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 muc h 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 regardli

ng whether lidocaine produces persisting sacral deficit and whether it may be associated with an excessive incidence o

f transient radicular irritation after SPB.

Treatment of LA Toxicity. - - Essential treatment of LA induced seizu

re should include maintaining the airway a

nd providing oxygen. - Seizures may be terminated with IV thiopental , BZP, or a paralytic dose of succinyl choline followed by tracheal int

ubation. - Hypotension may be treated by IV fluid and vasopressors.