NS: 75 Local Anesthetics

What is a local anesthetic?

an agent that interrupts pain impulses in a specific region of the body without a loss of patient consciousnessthe process is completely reversibleno residual effect on nerve fibers

What was the first anesthetic?

Cocaineisolated from Coca leaves by Albert Niemann in Germany in the 1860sused by Karl Kollar for clinical opthalmology anesthesia in 1884

What was the first local synthetic anesthetic?

Procaine-made in 1907

What is the target of all local anesthetics?

Sodium Voltage Gated Channels (NOT PUMPS!)

What are the 3 distinct stages of a voltage-gated sodium channel?

CLOSEDACTIVATEDINACTIVATED

What are the speeds between the three stages of voltage-gated Na+ channels?

C-O is fastO-I is fastI-C is a little slower

How long does a current exist in an action potential?

A few miliseconds or less

How many segments and domains are there per voltage gated sodium channel?

4 domains6 segments/domain

What is the voltage sensing segment on voltage-gated sodium channels?

Segment 4

Where does the pore lie in voltage-gated sodium channels?

between 5 and 6 segment

When can a LA reach the anesthetic binding site?

When the receptor is in an activated stateor if the drug is sufficiently lipophilic enough, it can reach when the channel is in the inactivated state

What is the percentage of non-ionized LA in vitro?

10%Remember 7.5=8.5*log(base/charged) --> base/charged=10-1Also remember Le Chatlier's Principle when discussing this

What form of the drug actually holds the Na+ channel in the inactive state?

the ionized

LAs with a lower pK or higher pK will have a more rapid onset of action? why?

lower pK --> aka LAs that are more uncharged will have a more rapid diffusion to the cytoplasmic side of the Na+ channel

What are the 5 mechanisms of action of LAs? What is NOT a mechanism of action of LA?

Reduce height of APReduce rate of rise of APSlow axonal conductionUltimately prevent propagation of APIncrease activation thresholdDO NOT alter the resting membrane potential

Functional Consequence of Na+ Channel Blockade by LAsNervesVascular Smooth MuscleHeartCNS

Nerves: decrease or abolition of conductionVascular Smooth Muscle: vasodilationHeart: decreased excitability (reduced pacemaker activity, prolongation of effective refractory period)CNS: increased excitability, followed by generalized depression

What are the four characteristics of LAs?

Blockade of sensory transmission to brain from a localized areaBlockade of voltage-gated Na+ channelsUse-dependent blockAdminister to site of action

What is the basic structure of an LA and what is the importance of each?

Aromatic Ring: LipophilicityConnecting Chain: ?Amino Terminus: Amine can become charged

What are the 2 classifications of LAs? What is the basis of the classification?

Benzoic Acid Derivatives: Ester connecting chainAniline Derivatives: Amide connecting chain

What determines potency and rate of onset of LAs?

Lipid Solubility (obviously) the more lipophilic a LA is, the more potent the LA isLAs are weak bases pKas of 7.5-9.0

Why are LAs less effective in infected tissues?

several reasons, the most important being that pH is lower/more acidic causing a decrease in lipophilicity of the drug as a whole

What LAs are esters?

cocaineprocainetetracainechloroprocaine

Which type of LA is more likely to produce an allergic affect and what is the cause of this effect?

ESTERScaused by the metabolism via pseudocholinesterase into paraaminobenzoic acid, which CAN cause allergic reactions

What LAs are amides?

lidocainemepivicaineprilocainebupivacaineetidocaine

Where are amides metabolized?

in the liver

What LAs are applied topically?

Benzocainelidocainetetracaine

What LAs are administered via infiltration?

lidocaineprocainebupivacaine

What drugs are administered via nerve block?

lidocainemepivacaine

What LAs are administered via spinal?

bupivacainetetracaine

What LA is commonly given as an epidural?

Bupivacaine

What LAs are given via caudal administration?

Lidocainebupivacaine

What are some toxicities of LAs?

CNS sedationrestlessnessnystagmustinnitusvertigoconvulsionscardiovascular-cardiac blockarrhythmiasvasodilationallergic reactions

What is common effect of LAs on vascular smooth muscle? How do we counter act this effect?

vasodilatationby using a vasoconstrictor which can cause prolongation of anesthetic action, decreased risk of toxicity, and decrease in bleeding from surgical manipulations

What is a conventional vasoconstrictor used with LAs?

Adrenaline (used in variuos concentrations expressed in grams/mL, ex. 1g:100,000mL)

What adrenergic receptor(s) do these vasoconstrictors work on and hence what is the effect produced when administered?EpinephrineNorephinephrineLevonordefrin

Epinephrine: a, B1, B2 increase HR, increase BPNorephinephrine: a, B1 increase BPLevonordefrin: a increase BP

What is the order of sensory function block of LAs?

paincold warmthtouchdeep pressuremotor

What factors influence a neuron's susceptibility to blockage by LAs?

relative sizemyelination

What does AP duration have to do with LA susceptibility?

the longer the AP, the more probability that Na+ channels are open, meaning more LA activity.....so PAIN is longest (3ms), therefore greatest action on pain

Is myocardium more or less susceptable to LAs? Why?

more susceptible because of extended duration in AP