Unit 5 - Local Anesthetics Flashcards
which LA does not undergo protein binding
chloroprocaine
what is conduction velocity
measure of how fast an axon transmits AP
what increases conduction velocity
myelination and a larger fiber diameter
insulates axons
myelin
what is saltatory conduction
the way an electrical impulse skips from node to node down the full length of an axon
what are nodes of ranvier
a gap in the myelin sheath of a nerve, between adjacent Schwann cells
myelination of A fibers
alpha & beta - heavy
gamma & delta - medium
function of A alpha nerve fibers
skeletal muscle motor
proprioception
function of A beta nerve fibers
touch, pressure
function of A gamma nerve fibers
skeletal muscle tone
function of A delta nerve fibers
fast pain, temperature, touch
function of B nerve fibers
preganglionic ANS fibers
function of C sympathetic nerve fibers
postganglionic ANS fibers
function of C dorsal root nerve fibers
slow pain, temperature, touch
peripheral nerve fiber block onset
- B fibers
- C fibers
- A gamma & delta
- A alpha & beta
block regression is in opposite order
what is Cm
minimum effective concentration
unit of measure that quantifies the concentration of LA required to bloc
what is Cm analogous to
ED50, MAC
are fibers easier or harder to block if Cm is increased
harder
(more resistant to blockade)
what reduces Cm
higher tissue Ph
high frequency of nerve stimulation
Cm is typically higher in nerves with diameter that is wider or more narrow?
wider
what is a differential blockade
- Provides analgesia at lower concentrations & spares motor function
- As concentration increases, it anesthetizes resistant nerve types (motor function, proprioception)
ex - epidural bupivacaine
MOA of LAs
- conjugate acid reversibly binds to alpha subunit of voltage-gated sodium channel
- Reduces Na+ conductance, blocks nerve conduction
LAs do NOT affect RMP or TP
what forms ion-conducting pore of Na+ channel in a nerve fiber
alpha subunit
3 possible states of Na+ channel
- resting
- active
- inactive
what determines the state of the Na+ channel
Voltage near the sodium channel determines the state of the channel
voltage of Na+ channel in resting state
-70 mV
when does the nerve fiber’s voltage-gated Na+ channel open
Channel opens when threshold potential is reached
Open channel allows Na+ to follow concentration gradient (outside to ins
what state of Na+ channel is repolarization
inactive state
Inactivation gate plugs channel until RMP is re-established
voltage of Na+ channel in inactive state
+35 to -70 mV
what converts Na+ channel from inactive to resting state
restoration of RMP
what is the guarded receptor hypothesis
LAs can only bind to Na+ channels in active (open) and inactive (closed refractory) states
The more frequently the nerve is depolarized and the voltage-gated Na+ c
3 things that influence RMP
1) Chemical force (concentration gradient)
2) Electrostatic counterforce
3) Na+/K+ ATPase (3 Na+ out for every 2 K+ in)
primary determinant of RMP
serum K
primary determinant of threshold potential
serum calcium
how does serum Ca2+ affect threshold potential
- ↓ Ca2+ = TP more negative (easier to depolarize)
- ↑ Ca2+ = TP more positive (harder to depolarize)
how does serum K affect RMP
- ↓ serum K+ = RMP more negative
- ↑ serum K+ = RMP more positive
what makes a cell depolarize
when Na+ or Ca2+ enters cell
what causes a cell to repolarize
K+ leaves or Cl- enters
what is hyperpolarization
movement of a cell’s membrane potential to more negative value beyond baseline RMP
More difficult to depolarize (RMP further from TP)
primary determinant of LA onset
LA’s pKa
primary determinant of LA potency
lipophilicity
primary determinant of LA duration of action
protein binding
how do LAs produce effects
via voltage-gated Na+ channels and excitable tissue
what is the Henderson-Hasselbach equation
pH = pKa + log ([base]/[conjugate acid])
3 possible things LA can do once in ECF
1) diffuse into nerve
2) diffuse into surrounding tissue and bind to other proteins
3) diffuse into systemic circulation
are LAs weak acids or weak bases
weak bases
pKa > 7.4
can predict that > 50% of the LA will exist as the ionized conjugate acid
what happens to LA after it’s injected near a nerve
rapidly dissociates into an uncharged base (LA) and an ionized conjugate acid (LA+)
how does uptake of LAs occur
Diffusion into bloodstream (removal of LA from tissue into blood)
how does blood flow affect LA duration
Highly vascular areas remove LA faster than sites with less blood flow
decreased LA duration and increased plasma concentration
what characteristic of LAs guards against precipitation
Solution has low pH
how do vasoconstrictors like epi affect LA admin
prolong LA duration (↓ rate of vascular uptake)
Most useful with LAs that exhibit significant intrinsic dilating activit
how does LA enter axoplasm
by diffusing through lipid-rich axolemma
what makes a greater fraction of inoized conjugate acid once inside the cell
ICF is slightly more acidic than ECF
what part of LA binds to alpha subunit inside voltage-gated Na+ channel
nonionized conjugate acid
what happens to ester LAs after entering bloodstream
metabolized by pseudocholinesterase in plasma
what happens to amide LAs after entering bloodstream
delivered to liver for metabolism by CYPP450 system
3 key components of LA molecule
benzene ring, intermediate side chain, tertiary amine
what molecular component of LA determines lipophilicity
benzene ring
what molecular component of LA determines metabolism & allergic potential
intermediate chain
what molecular component of LA determines hydrophilicity
tertiary amine
what molecular component of LA accepts proton
tertiary amine
what molecular component of LA makes molecule a weak base
tertiary amine
which LA class has the structure -COO-
esters
which LA class has the structure -NHCO-
amides
how to distinguish amides from esters by LA name
amides have 2 i’s in the name
metabolism of cocaine
pseudocholinesterase + liver
which LA class has a higher allergic potential
esters
do amides have cross sensitivity in the same class?
no
esters do
do amides have cross sensitivity in the same class?
no
esters do
component of esters assocated with allergic reactions
PABA
some multi-dose vials contain methylparaben
primary & secondary variables that determine onset of action
primary: pKa
secondary: dose, concentration
primary & secondary variables that determine potency
primary: lipid solubility
secondary: intrinsic vasodilating effect
primary & secondary variables that determine duration of action
primary: protein binding
secondary: lipid solubility, intrinsic vasodilating effect, addition of vasoconstrictors
how does pKa affect LA onset
if pKa of LA is closer to blood pH, a larger fraction of molecules are lipid soluble (uncharged base) - more molecules diffuse across axolemma = faster onset
pKa further away from blood pH = fewer molecules to penetrate cell membr
why does chloroprocaine have a rapid onset even with a high pKa
- Not very potent, large dose required
- giving more molecules creates a mass effect
which has a faster onset - 0.75% or 0.25% bupivacaine
0.75% (more molecules given)
LA structural component that increases lipid solubility
alkyl group substitution on amide group and benzene ring
how is LA removed from site of action
absorption into systemic circulation
what kind of response do nearly all LAs have on vascular smooth muscle
biphasic response
lower concentration = vasoconstriction (inhibit NO)
higher concentration
how does a greater degree of intrinsic vasodilation affect vascular uptake
results in faster rate of vascular uptake, prevents some of the dose from accessing the nerve
ex. lidocaine
how does a greater degree of intrinsic vasodilation affect vascular uptake
results in faster rate of vascular uptake, prevents some of the dose from accessing the nerve
ex. lidocaine
how does protein binding affect LA duration
- Molecules that bind to plasma proteins serve as a tissue reservoir
- extends duration
how does protein binding affect LA duration
- Molecules that bind to plasma proteins serve as a tissue reservoir
- extends duration
how does a strong acid or base behave in water
will completely dissociate
how does a weak acid or base behave in water
- a fraction will ionize, remaining fraction non-ionized
- Ionization depends on pH of solution & pKa of drug
LAs are weak bases that are ionized at physiologic pH
relationship between pKa and degree of ionization
As pKa gets further from physiologic pH, degree of ionization ↑
relationship between LA pKa and onset
The closer the pKa is to pH of blood, the faster the onset (exception: chloroprocaine)
which has higher pKa - esters or amides
All esters have higher pKa than amides
only available LA with pKa well below physiologic pH
Benzocaine
pKa = 3.5
uses of benzocaine
topical anesthesia of mucus membranes during endoscopy, TEE, bronchoscopy
significant risk with benzocaine
methemoglobinemia
Factors that influence vascular uptake & Cp
- site of injection
- tissue blood flow
- physiochemical properties of LA
- metabolism
- addition of vasoconstrictor
fastest to slowest sites for LA uptake
IV > tracheal > interpleural > intercostal > caudal > epidural > brachial plexus > femoral > sciatic > sub-q
what determines final LA plasma concentration
Total dose of LA (not concentration or speed of injection)
what protein do most LAs bind to
alpha-1 acid glycoprotein
how does adding a vasoconstrictor like epi affect LA duration
↓ systemic absorption by up to 1/3 and prolong duration
Effect greatest with LAs that have significant intrinsic dilating activi
liposomal bupivacaine
Exparel
key benefits of Exparel
duration of action up to several days, ↓ opioid consumption
how does Exparel work
As lipid membranes in suspension erode and reorganize over time, bupivacaine is released
max dose of Exparel
266 mg
how should Exparel be administered if a larger volume is needed to extend coverage
20 mL (266 mg) expanded with up to 300 mL NS or LR
Exparel contraindication
paracervical block in OB population
Not recommended for epidural or intrathecal anesthesia, intraarticular a
when should Exparel be used cautiously
hepatic and/or renal dysfunction
can other LAs be admin with Exparel?
co-administration of other LAs can disrupt liposomal suspension & cause immediate release
If used, lidocaine must be infiltrated at surgical site min. 20 min prior to Exparel injection
when can bupivacaine be given after exparel admin
must be 96+ hours after exparel
what determines systemic levels of LA
- drug
- dose
- site of injection
- technique
max dose of levobupivacaine
2 mg/kg
max total = 150 mg
max dose of bupivacaine
2.5 mg/kg
max total = 175 mg
max dose of bupicavaine + epi
3 mg/kg
max total = 200 mg
max dose of ropivacaine
3 mg/kg
max total = 200 mg
max dose of lidocaine
3.5 mg/kg
max total = 300 mg
max dose of lidocaine + epi
7 mg/kg
max total = 400 mg
max dose of mepivacaine
7 mg/kg
max total = 500 mg
max dose of prilocaine
9 mg/kg
max total < 70 kg = 500 mg
max total > 70 kg = 600 mg
max dose of procaine
7 mg/kg
max total = 350-400 mg
max dose of chloroprocaine
11 mg/kg
max total = 800 mg
max dose of chloroprocaine + epi
14 mg/kg
max total = 1,000 mg
what determines plasma concentration of LA
net balance of vascular uptake relative to redistribution & metabolism
how to reduce risk of LAST
use test dose and incremental dosing with period aspiration
Most common cause of toxic LA plasma concentration
inadvertent intravascular injection
most frequent 1st symptom of LAST
seizure
exception: cardiac arrest may be first with bupivacaine
when are LAs more assoc. with LAST
peripheral nerve blocks (not epidural)
CV effects of lidocaine at plasma concentration > 25 mcg/mL
CV collapse
effects of lidocaine at plasma concentration 15-25 mcg/mL
coma
respiratory arrest
effects of lidocaine at plasma concentration 10-15 mcg/mL
- seizures
- LOC
CNS effects of lidocaine at plasma concentration 5-10 mcg/mL
- tinnitus
- skeletal muscle twitching
- lip/tongue numbness
- restlessness
- vertigo
- blurred vision
CV effects of lidocaine at plasma concentration 5-10 mcg/mL
- hypotension
- myocardial depression
plasma concentration of lidocaine assoc. with analgesia
1-5 mcg/mL
3 things that increase risk of CNS toxicity with LA use
- hypercarbia
- hyperkalemia
- metabolic acidosis
why does hypercarbia contribute to increased risk of LAST
- ↑ CBF
- ↑ drug delivery to brain
- ↓ protein binding
- ↑ free fraction
why does hyperkalemia contribute to increased risk of LAST
↑ RMP = neurons are more likely to depolarize
why does metabolic acidosis contribute to increased risk of LAST
↓ convulsion threshold, favors ion trapping inside brain
3 things that decrease risk of CNS toxicity with LAs
- hypocarbia
- hypokalemia
- CNS depressants
how does hypocarbia protect against CNS toxicity with LAs
↓ CBF, ↓ drug delivery to brain
how does hypokalemia protect against CNS toxicity with LAs
↓ RMP = requires larger stimulus to depolarize nerve
how do LAs disrupt hemodynamics
altering cardiac AP, myocardial performance, and vascular resistance
how do LAs cause myocardial depression
by impairing intracellular Ca2+ regulation
what 2 features determine extent of cardiotoxicity with LAs
1) affinity for voltage-gated Na+ channel in active and inactive states
2) rate of dissociation from receptor during diastole
why is cardiac morbidity with bupivacaine is higher & cardiac resuscitation is so difficult
- Bupivacaine has a greater affinity for Na+ channel & slower rate of dissociation vs. lidocaine
- bupivacaine remains at the receptor for longer
LAs with greatest to least difficulty of CV resuscitation
bupivacaine > levobupivacaine > ropivacaine > lidocaine
4 factors that increase risk of bupivacaine toxicity
- pregnancy
- beta blockers
- CCBs
- digoxin
Primary risk of cocaine toxicity
excessive SNS stimulation
meds to avoid with cocaine toxicity
- MAOIs
- TCAs
- sympathomimetics
- beta blockers
Cocaine dose range
1.5 – 3 mg/kg (max 150-200 mg depending on text)
best med to use to decrease BP in cocaine toxicity
Vasodilator like nitroglycerin
Labetalol or another mixed alpha agonist is a reasonable choice
treatment of LAST
- 100% FiO2
- treat sz with benzos
- lipid emulsion therapy
why might you give NMB for LAST
to stop muscle contraction (seizures)
minimize O2 consumption, hypoxemia, acidosis
why should propofol be avoided in treatment of LAST
augments myocardial depression
ACLS modifications for LAST
- If epi is used, give < 1 mcg/kg doses
- For ventricular arrythmias: avoid lidocaine and procainamide, use amiodarone
dosing of lipid emulsion therapy for LAST
> 70 kg:
* 100 ml bolus over 2-3 min
* 250 ml over 15-20 min
< 70 kg:
* Bolus 20% 1.5 mL/kg (LBW) over 1 minute
* infusion = 0.25 mL/kg/min
* Can repeat bolus up to 2 more times and increase infusion to max 0.5 mL/kg/min
* Continue infusion 10 min after HD stability
max recommended dose of lipid emulsion therapy for LAST
10 mL/kg in first 30 min
theoretical complication of lipid emulsion therapy for LAST
pancreatitis
meds to avoid in treatment of LAST
- code-dose epi
- lidocaine
- procainamide
- beta blockers
- CCBs
treatment of LAST if unresponsive to modified ACLS and lipid emulsion
CPB
proposed MOA of lipid emulsion therapy for LAST
- lipid sink: sequesters LA
- metabolic effect: enhanced myocardial fatty acid metabolism
- inotropic effect: increased Ca influx
- membrane effect: impairs LA binding to Na+ channels
most common cause of death from liposuction
pulmonary embolism
what is Tumescent anesthesia
- Dilute solution of sodium chloride, lidocaine, epi, & bicarb injected into adipose tissue
- firms adipose tissue & increases ease of removal
function of epi & lidocaine in tumescent anesthesia
- Lidocaine prevents discomfort
- epi minimizes vascular uptake of LA & tumescent solution
current American Academy of Dermatology recommendation for max lidocaine in tumescent anesthesia
55 mg/kg
metabolism of lidocaine in Tumescent anesthesia
- metabolized by CP3A4 & 1A2
- completely eliminated from body at 36 hours
peak Cp of lidocaine in tumescent anesthesia
12 hours
when is GA recommended over MAC if tumescent anesthesia used
if > 2-3 L injected (due to risk of fluid shifts)
complications of tumescent anesthesia
Fluid overload & pulmonary edema may occur as a result of intravascular volume expansion
subunits of Hgb molecule
- 2 alpha
- 2 beta
how is methemoglobin produce
when the iron moiety in heme is oxidized from ferrous state (Fe+2) to ferric state (Fe+3)
2 ways methemoglobin decreases CaO2
1) methemoglobin can’t bind oxygen molecules
2) shifts oxyhemoglobin
why does methemoglobin result in physiologic anemia
Oxyhgb shift ↑ HgbA’s affinity for O2, which makes it harder to release O2 to tissues
why does methemoglobinemia cause pulse ox errors
- Methemoglobin absorbs 660 nm and 940 nm infrared wavelengths equally
- tends to push SpO2 towards 85%
why is a co-oximeter required to diagnose methemoglobinemia
Uncouples normal relationship between SpO2 & SaO2
LAs assoc. with methemoglobinemia
- benzocaine
- cetacaine
- prilocaine
- EMLA
presentation of methemoglobinemia with 0-20% HgbMet
usually well tolerated
presentation of methemoglobinemia with 20-50% HgbMet
- tachypnea
- tachycardia
- AMS
- slate-gray pseudocyanosis
presentation of methemoglobinemia with 50-70% HgbMet
dysrhythmias, coma
% HgbMet not compatible with life
> 70%
s/s that is highly suggestive of methemoglobinemia
Cyanosis in the presence of a normal PaO2
1st line treatment of methemoglobinemia
methylene blue
Helps accelerate reduction of methemoglobin
methylene blue dosing
- 1-2 mg/kg over 5 min
- Max dose 7-8 mg/kg
- May require redosing (rebound can occur up to 12 hours after methylene blue admin)
how does methylene blue treat methemoglobinemia
Metabolized by methemoglobin reductase to form leucomethylene blue – electron donor, reduces methemoglobin back to hemoglobin
treatment of methemoglobinemia in a patient with G6PD deficiency
- exchange transfusion
- don’t possess methemoglobin reductase – methylene blue can precipitate hemolytic crisis
population at higher risk for developing methemoglobinemia & why
neonates
Fetal hemoglobin is relatively methemoglobin reductase deficient (suscep
what is EMLA cream made of
50/50 combination of 2.5% lidocaine and 2.5% prilocaine
what characteristic of EMLA cream facilitates its absorption
Melting point is lower than either of its constituents
effects of EMLA cream
Produces analgesia within 1 hour, max effect in 2-3 hours
increases risk of toxicity with EMLA cream
eczema, psoriasis, skin wounds d/t altered pharmacokinetics
can be applied simultaneously with EMLA cream to hasten absorption
nitroglycerin
metabolite of prilocaine
o-toludine
max dose of EMLA cream:
- 0-3 months or < 5 kg
- 3-12 months and > 5 kg
- 1-6 years and > 10 kg
- 7-12 years and > 20 kg
- 0-3 months or < 5 kg: 1 g
- 3-12 months and > 5 kg: 2 g
- 1-6 years and > 10 kg: 10 g
- 7-12 years and > 20 kg: 20 g
max application area of EMLA cream:
- 0-3 months or < 5 kg
- 3-12 months and > 5 kg
- 1-6 years and > 10 kg
- 7-12 years and > 20 kg
- 0-3 months or < 5 kg: 10 cm2
- 3-12 months and > 5 kg: 20 cm2
- 1-6 years and > 10 kg: 100 cm2
- 7-12 years and > 20 kg: 200 cm2
additives that prolong LA duration
- epi
- decadron
- dextran
additives that supplement LA analgesia
- clonidine
- epi
- opioids (neuraxial only)
additive that shortens LA onset
sodium bicarbonate
additive that improves LA diffusion through tissues
hyaluronidase
LA that decreases effectiveness of epidural opioids
chloroprocaine
how does epi prolong block duration & enhance block quality
- decreases systemic LA uptake
- better matching of uptake and metabolism
- decreased LA in plasma
epi is best at prolonging which LAs
intermediate duration
ex. extends duration of lidocaine > bupivacaine
how does dexamethasone extend LA duration
glucocorticoid activity - acts on steroid receptor, affects systemic uptake
Can increase duration of brachial plexus block by up to 50%
how does dextran affect LA
prolongs block duration by ↓ systemic uptake
how does clonidine affect LA
alpha agonism = analgesia
how does sodium bicarb affect LA
- Alkalinization ↑ number of lipid soluble molecules = speeds onset of action
- Can also increase quality of block and ↓ pain on injection
Mix 1 mL of 8.4% of bicarb with 10 mL LA solution
how does sodium bicarb affect LA
- Alkalinization ↑ number of lipid soluble molecules = speeds onset of action
- Can also increase quality of block and ↓ pain on injection
Mix 1 mL of 8.4% of bicarb with 10 mL LA solution
how does hyaluronidase affect LA
Hydrolyzes hyaluronic acid
facilitates diffusion of substances in tissues
what is an AP an how does it depolarize a nerve
- AP = temporary change in transmembrane potential followed by return to transmembrane potential
- Na+ or Ca2+ must enter cell for neuron to depolarize
- once threshold potential occurs, cell depolarizes and propagates AP
what is an AP an how does it depolarize a nerve
- AP = temporary change in transmembrane potential followed by return to transmembrane potential
- Na+ or Ca2+ must enter cell for neuron to depolarize
- once threshold potential occurs, cell depolarizes and propagates AP
what happens when a nerve repolarizes
removal of positive charges from inside the cell
accomplished by removing potassium
RMP and threshold potential of peripheral nerves
RMP = - 70 mV
TP = - 55 mV
after peripheral nerve repolarization, how is RMP maintained until the nerve is depolarized again
Na/K-ATPase
why is epi avoided in the treatment of LAST
decreases efficacy of lipid emulsion therapy
possible adverse effect of giving a beta blocker in cocaine overdose
heart failure
allows unopposed alpha 1 stimulation
high SVR and reduced inotropy set t
possible adverse effect of giving a beta blocker in cocaine overdose
heart failure
allows unopposed alpha 1 stimulation
high SVR and reduced inotropy set t
which nerve fibers do not experience saltatory conduction
C fibers
no myelination
which nerve fibers do not experience saltatory conduction
C fibers
no myelination
which LA is assoc. with neurotoxicity and therefore not used in spinal anesthesia
chloroprocaine