Local anesthetics Flashcards
General structure of local anesthetics
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
amide anesthetics are signfiicantly bound by __
plasma protein a1-acid glycoprotein
compare amide and ester local anesth
which has longer duration of action
which are primary hydrolyzed by esterase
which are metab by liver
amide = longer duration
ester = hydrolyzed by esterase
amide = metab by liver so don’t use in liver failure
more toxic
role of pH in determining effectiveness of local anesth
why can they rapidly interconvert btwn positively charged and neutral
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
at pH 7.4 drugs in charged or neutral
benefits of neutral vs charged
charged more
charged = binds to local anesth binding site
neutral = cross plasma membrane to reach site
effect of tissue acidity on amount of neutral local anesth present
tissue acidity decr amt of neutral local anesth
requires applied dose to be incr
binding site for local anesth
why can’t enter extracellular entrance
main route of local anesth
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
alternative rout of local anesth
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
low potency
med potency
high potency
ex of local anesth
potency determiend by __
low = procaine med = lidocaine high = bupivacaine, etidocaine
determined by lipid solubility
onset of local anesth determined by
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
duration of action of local anesth related to
protein binding capacity
more bound to protein, longer duration
AMIDES BIND PROTEINS BETTER SO LAST LONGER
methods of local anesth application
topical anesth
where can apply?
disadvantage
topical = skin, cornea, muc membrane of nose, mouth, throat
disadv = considerable abs into circulation
methods of local anesth application
infiltration
benefit
downside
ex
injection of local anesth into tissue without considering nerve location
very superficial
need large doses
Lidocaine
procaine
bupivacaine
methods of local anesth application
nerve block anesthesia
advantage
ex
inject high concentration near periph nerve or plexus
larger body regions can be anesth
lidocaine = 2-4 hr bupivacaine = longer
methods of local anesth application
IV regional anesth (Bier’s block)
downside
ex
blood squeezed out of limb using tight elastic bandage then inject local anesth
only good for 2 hrs
Lidocaine
methods of local anesth application
spinal anesthesia
useful when?
ex
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
methods of local anesth application
epidural
downside
ex
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
rationale for use of vasoconstrictor + local anesth
example?
what is only anesth you don’t need vasoconstrictor
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
side effects of local anesth
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
2 most potent toxins
TTX and saxitoxin
affects what more?
cause of death?
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
Henderson-Hasselbalch for neutral/cationic
neutral/cationic = 10^(pH - pKa)
how does infection affect pH
incr acidity, therefore more neutral so anesthetic effect decr, longer onset of action
Define use-dependent block of LA
more NaV channels used, more they become blocked
faster onset, more potent, longer lasting LAs have
lower pKa
higher lipid solubility
greater protein binding
why are C fibers more sensitivite to block compared to Aalpha and Abet afibers
motor fibers = higher density so if block 50% of drug, then less effect compared to block 50% on C fibers with less Na channels
EMLA cream consists of
lidocaine + prilocaine
penetrates skin up to 5 mm
LAs lacking terminal amino group have
low solubility (benzocaine) so slow absorption and no CNS and no cardiac effects
main culprit in local anesthetic hypersensitivity
PABA = metabolite of ester LAs
