Local anesthetics

Question 1

General structure of local anesthetics

Answer 1

structure = tripartite structure with
1) lipophilic aromatic portion = allows local anesthetic to travel thru plasma membrane

2) intermediate alkyl chain = ester or amide moiety (determines side effects)
3) hydrophilic amine = becomes cation and bind Na channel

Question 2

amide anesthetics are signfiicantly bound by __

Answer 2

plasma protein a1-acid glycoprotein

Question 3

compare amide and ester local anesth
which has longer duration of action
which are primary hydrolyzed by esterase

which are metab by liver

Answer 3

amide = longer duration

ester = hydrolyzed by esterase

amide = metab by liver so don’t use in liver failure
more toxic

Question 4

role of pH in determining effectiveness of local anesth

why can they rapidly interconvert btwn positively charged and neutral

Answer 4

weak bases with pKa btwn 7.7 - 9.0 and partially ionized at pH 7.4

rapid protonation/deprot reaction at N of amino group

Question 5

at pH 7.4 drugs in charged or neutral

benefits of neutral vs charged

Answer 5

charged more

charged = binds to local anesth binding site

neutral = cross plasma membrane to reach site

Question 6

effect of tissue acidity on amount of neutral local anesth present

Answer 6

tissue acidity decr amt of neutral local anesth

requires applied dose to be incr

Question 7

binding site for local anesth

why can’t enter extracellular entrance

main route of local anesth

Answer 7

in region of water filled pore of Na channel

ion conduction path is too narrow for drug to reach binding site

main route = when channel open, Na ions rush

Question 8

alternative rout of local anesth

Answer 8

partition into plasma membrane and cross over to intracellular compartment due to membrane solubility

once enters, becomes protonated by H+ that pass thru narrow entrance and reach drug

Question 9

low potency
med potency
high potency

ex of local anesth
potency determiend by __

Answer 9

low = procaine
med = lidocaine
high = bupivacaine, etidocaine 

determined by lipid solubility

Question 10

onset of local anesth determined by

Answer 10

determined by pKa and lipid solubility

lower pKa and higher lipid solubility = more rapid onset

lower pKa incr fraction of local anesth molec in neutral membrane crossing form

Question 11

duration of action of local anesth related to

Answer 11

protein binding capacity

more bound to protein, longer duration
AMIDES BIND PROTEINS BETTER SO LAST LONGER

Question 12

methods of local anesth application
topical anesth
where can apply?
disadvantage

Answer 12

topical = skin, cornea, muc membrane of nose, mouth, throat

disadv = considerable abs into circulation

Question 13

methods of local anesth application

infiltration
benefit
downside

ex

Answer 13

injection of local anesth into tissue without considering nerve location

very superficial
need large doses

Lidocaine
procaine
bupivacaine

Question 14

methods of local anesth application
nerve block anesthesia
advantage

ex

Answer 14

inject high concentration near periph nerve or plexus

larger body regions can be anesth

lidocaine = 2-4 hr
bupivacaine = longer

Question 15

methods of local anesth application
IV regional anesth (Bier’s block)

downside

ex

Answer 15

blood squeezed out of limb using tight elastic bandage then inject local anesth

only good for 2 hrs

Lidocaine

Question 16

methods of local anesth application
spinal anesthesia

useful when?

ex

Answer 16

inject into CSF bathing lumbar cord and anesth large area without high plasma concentration

for surgical procedures of lower half

lidocaine (short)
bupivacaine (intermed)
tetracaine (longer)

esters can also be prolonged b/c no plasma esterase activity

Question 17

methods of local anesth application
epidural

downside

ex

Answer 17

injection outside dura cord at base of canal

use catheter so can repeat application but high plasma levels and potential toxicity

lidocaine = short
bupivacaine = long

Question 18

rationale for use of vasoconstrictor + local anesth

example?

what is only anesth you don’t need vasoconstrictor

Answer 18

vasoconstrictor prolong duration of blockade by decr blood flow in area of injection to decr systemic abs and prevent toxic

epinephrine usu

only anesth = cocaine

Question 19

side effects of local anesth

Answer 19

overdose =
1) convulsions via action on inhib interneuron (cross BBB)

2) interfere with autonomic nervous system (so use epi)
3) proarrhythmic (esp bupivicaine)
4) significant arteriolar dilation
5) fetal damage
6) inhib NT block nAChR
7) allergy

Question 20

2 most potent toxins
TTX and saxitoxin

affects what more?

cause of death?

Answer 20

both bind and block extracell entrance of VG Na+ channels

affects nerve and muscle more than heart so die from paralyzed resp muscles not heart
nano vs micromolar affinity

Question 21

Henderson-Hasselbalch for neutral/cationic

Answer 21

neutral/cationic = 10^(pH - pKa)

Question 22

how does infection affect pH

Answer 22

incr acidity, therefore more neutral so anesthetic effect decr, longer onset of action

Question 23

Define use-dependent block of LA

Answer 23

more NaV channels used, more they become blocked

Question 24

faster onset, more potent, longer lasting LAs have

Answer 24

lower pKa
higher lipid solubility
greater protein binding

Question 25

why are C fibers more sensitivite to block compared to Aalpha and Abet afibers

Answer 25

motor fibers = higher density so if block 50% of drug, then less effect compared to block 50% on C fibers with less Na channels

Question 26

EMLA cream consists of

Answer 26

lidocaine + prilocaine

penetrates skin up to 5 mm

Question 27

LAs lacking terminal amino group have

Answer 27

low solubility (benzocaine) so slow absorption and no CNS and no cardiac effects

Question 28

main culprit in local anesthetic hypersensitivity

Answer 28

PABA = metabolite of ester LAs