midterm - 2 Flashcards
If admin of LA and it gets systemc effects and depressing the CNS it actually is considered a _
anything depressing the CNS is considered a GENERAL ANESTHETIC
the first general analgesic
cocaine
pH-pKa -5 -4 -3 -2 -1 0 1 2 3 4 5
about how much A- (base form, nonionized form)
about how much A-(base form) -5 = 0.001% -4=0.01% -3=0.1% -2= 1% -1=10% 0=50% 1=90% 2=99% 3=99.9% 4=99.99% 5=99.999%
if pKa is around 7 - we have both forms in solution
the pH-pKa is important because it is essential that LA crosses the neuronal membrane
_ form crosses the membranes
_ form once inside that blocks axonal conduction
basic form (uncharged) to cross membranes
acidic form once inside to block
so we need both forms and they have to be in equilibrium
Local anesthetics are _ class. At physiological pH(7.4) they are in equilibrium so that both the basic form and the acid form are represented Basic form crosses membrane Acidic form blocks Na+ channels
Amides
general structure of LA
aromatic group
ester or amide linkage
amine group(primary, secondary,tertiar)
quaternary none of these bc permanent postive charge and can’t cross membrane
generally secondary and tertiary amines are used
general structure of LA
the _ group renders the LA lipophilic
aromatic group
ring structure
esters vs amides
_ linkage will by hydrolyzed by pseudocholinesterase and have very short 1/2 life
_ linkage will be METABOLIZED by P450 enzymes in the live, longer half life in plasma
esters - pseudo and short 1/2
amides - liver P450 - longer 1/2 life
_ will have an “i” in their name somewhere prior to “caine”
_ will not
amides - I 0 lidocaine
esters - no i prior to caine - procaine
why are we worried about esters in LA
esters are generally more allergenic
not particularly worried about short 1/2 life
1-6 sensations blocks (nerves fiber types) relative sensitivity to LA
- pain - unmyelinated c fibers
- cold
- warmth
- touch
- deep pressure
- motor
recovery in reverse order
Unmyelinated pain C - most sensitive to local, stay block the longest
Motor nerves - hardest to block, easiest and fastest to come back
LA bind to the _ form of the sodium channel, they produce a more rapid nerve block on axons with a _ firing rate
bind to the OPEN form of Na channel
more rapid nerve block on axons with a more rapid firing
Peripheral nerves consist of bundles of nerve fibers encased by _
epineurium
perineurium
endoneurium
Connective tissue
fxns served by B and C fibers are more readily disrupted by LA than the _ fxns of _ fibers
motor fxns of A fibers
A delta - sharp pain
activity at several nodes of Ranvier must be blocked to achieve total nerve block
requires longer diffusion distance and larger diameter
_ LA (amide) would be favored for epidural anesthesia during childbirth (maintain uterine muscle contractility)
bupivacaine
why is inflamed tissue more difficult to anesthetize
products released by cells in inflamed tissue lower pH. making it more difficult to get sufficient levels inside the axon
lowered pH - more anesthetic in protonated state (HA)
there are structural differences of LA
balance between _ and _
LA must be sufficiently _ to diffuse to its site of action
Once at site, the more _ LA have a longer duration (increased protein binding, decreased clearance by blood)
hydrophilic to diffuse to the site of action
lipophilic has longer duration
the pKa of the LA can’t stray too far from the physiological pH, why
most LA are prepared as water soluable HCL salt(pH 6-7)
if epi is added, pH lowered to 4-5 to stabilize the epi
the buffering capacity at injection site should neutralize this
some might add NaHCO3 prior to injection of LA contained epi to increase the concentration of free base, this runs the risk of precipitating the LA out
toxicology of LA
readily pass from the periphery to the _ nervous system
CNS
CNS neurons are very sensitive to LA(concentrations in blood that do not affect peripheral activity can affect CNS fxn)
two systems affected by LA toxicity
CNS - more easily (lower LA BS threshold)
cardiovascular - direct effects on heart = block Na and at really high Ca channels, depress pacemaker activity, excitability, conduction
effects on ANS - inhibition of sympathetic response - depress contractility, produce HYPOtension
in general CNS more of a concern
ester LA allergic rxns
_ the intermediate of provaine is what causes allergy
p-aminobenzoic acid
effects of addition of vasoconstrictor
200ug limit per session
40ug for CV patient
increase success rate and intensity
toxicity reduced
less blood loss
normally no problems but if excess dosage or IV injection possible and can lead to cardiovascular side effects
alpha 1 2
beta 1 2
pharmacokinetics
Distribution
5-95% bind to _(depends on hydrophobicity of the LA)
unbound drugs free to diffuse to various tissues, including CNS and placenta
bind to plasma proteins - probably around 90% of it
alpha1 glycoprotein albumin binds drug and takes it to the liver for catabolism
esters metabolized by a combo of pseudocholinesterase in the plasma and tissue(liver)
the t1/2 for procaine hydrolysis is _
less than 1 min
less than 2% of drug leaves the kidneys unhydrolyzed
dealkylation of amines in the liver CYP3a4 and CYP1a2
_ limting the t1/2 1.5-3.5hrs
exception - amides inactivated more rapidily
hepatic blood flow limiting the half life
prilocaine - 2* amine, dealkylation not required, extrahepatic) little faster
articaine - inactivated by blood esterase - Has an ester group
Won’t get into CNS because
Hydrolyzed by esterases
Tx of serious adverse events:
_-benzodiapine, barbiturate(thiopental), succinylcholine(treats symptoms only)
convulsions
TX of allergic responses to LA
dermatologial -
anaphylactic shock
derm - antihistamines
anaphylactic shock - inject with epinephrine
