Unit 5 - Local Anesthetics Flashcards
1
Q
which LA does not undergo protein binding
A
chloroprocaine
2
Q
what is conduction velocity
A
measure of how fast an axon transmits AP
3
Q
what increases conduction velocity
A
myelination and a larger fiber diameter
4
Q
insulates axons
A
myelin
5
Q
what is saltatory conduction
A
the way an electrical impulse skips from node to node down the full length of an axon
6
Q
what are nodes of ranvier
A
a gap in the myelin sheath of a nerve, between adjacent Schwann cells
7
Q
myelination of A fibers
A
alpha & beta - heavy
gamma & delta - medium
8
Q
function of A alpha nerve fibers
A
skeletal muscle motor
proprioception
9
Q
function of A beta nerve fibers
A
touch, pressure
10
Q
function of A gamma nerve fibers
A
skeletal muscle tone
11
Q
function of A delta nerve fibers
A
fast pain, temperature, touch
12
Q
function of B nerve fibers
A
preganglionic ANS fibers
13
Q
function of C sympathetic nerve fibers
A
postganglionic ANS fibers
14
Q
function of C dorsal root nerve fibers
A
slow pain, temperature, touch
15
Q
peripheral nerve fiber block onset
A
- B fibers
- C fibers
- A gamma & delta
- A alpha & beta
block regression is in opposite order
16
Q
what is Cm
A
minimum effective concentration
unit of measure that quantifies the concentration of LA required to bloc
17
Q
what is Cm analogous to
A
ED50, MAC
18
Q
are fibers easier or harder to block if Cm is increased
A
harder
(more resistant to blockade)
19
Q
what reduces Cm
A
higher tissue Ph
high frequency of nerve stimulation
20
Q
Cm is typically higher in nerves with diameter that is wider or more narrow?
A
wider
21
Q
what is a differential blockade
A
- Provides analgesia at lower concentrations & spares motor function
- As concentration increases, it anesthetizes resistant nerve types (motor function, proprioception)
ex - epidural bupivacaine
22
Q
MOA of LAs
A
- 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
23
Q
what forms ion-conducting pore of Na+ channel in a nerve fiber
A
alpha subunit
24
Q
3 possible states of Na+ channel
A
- resting
- active
- inactive
25
what determines the state of the Na+ channel
Voltage near the sodium channel determines the state of the channel
26
voltage of Na+ channel in resting state
-70 mV
27
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
28
what state of Na+ channel is repolarization
inactive state
| Inactivation gate plugs channel until RMP is re-established
29
voltage of Na+ channel in inactive state
+35 to -70 mV
30
what converts Na+ channel from inactive to resting state
restoration of RMP
31
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
32
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)
33
primary determinant of RMP
serum K
34
primary determinant of threshold potential
serum calcium
35
how does serum Ca2+ affect threshold potential
* ↓ Ca2+ = TP more negative (easier to depolarize)
* ↑ Ca2+ = TP more positive (harder to depolarize)
36
how does serum K affect RMP
* ↓ serum K+ = RMP more negative
* ↑ serum K+ = RMP more positive
37
what makes a cell depolarize
when Na+ or Ca2+ enters cell
38
what causes a cell to repolarize
K+ leaves or Cl- enters
39
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)
40
primary determinant of LA onset
LA's pKa
41
primary determinant of LA potency
lipophilicity
42
primary determinant of LA duration of action
protein binding
43
how do LAs produce effects
via voltage-gated Na+ channels and excitable tissue
44
what is the Henderson-Hasselbach equation
pH = pKa + log ([base]/[conjugate acid])
45
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
46
are LAs weak acids or weak bases
weak bases
| pKa > 7.4
## Footnote
can predict that > 50% of the LA will exist as the ionized conjugate acid
47
what happens to LA after it's injected near a nerve
rapidly dissociates into an uncharged base (LA) and an ionized conjugate acid (LA+)
48
how does uptake of LAs occur
Diffusion into bloodstream (removal of LA from tissue into blood)
49
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
50
what characteristic of LAs guards against precipitation
Solution has low pH
51
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
52
how does LA enter axoplasm
by diffusing through lipid-rich axolemma
53
what makes a greater fraction of inoized conjugate acid once inside the cell
ICF is slightly more acidic than ECF
54
what part of LA binds to alpha subunit inside voltage-gated Na+ channel
nonionized conjugate acid
55
what happens to ester LAs after entering bloodstream
metabolized by pseudocholinesterase in plasma
56
what happens to amide LAs after entering bloodstream
delivered to liver for metabolism by CYPP450 system
57
3 key components of LA molecule
benzene ring, intermediate side chain, tertiary amine
58
what molecular component of LA determines lipophilicity
benzene ring
59
what molecular component of LA determines metabolism & allergic potential
intermediate chain
60
what molecular component of LA determines hydrophilicity
tertiary amine
61
what molecular component of LA accepts proton
tertiary amine
62
what molecular component of LA makes molecule a weak base
tertiary amine
63
which LA class has the structure -COO-
esters
64
which LA class has the structure -NHCO-
amides
65
how to distinguish amides from esters by LA name
amides have 2 i's in the name
66
metabolism of cocaine
pseudocholinesterase + liver
67
which LA class has a higher allergic potential
esters
68
do amides have cross sensitivity in the same class?
no
| esters do
69
do amides have cross sensitivity in the same class?
no
| esters do
70
component of esters assocated with allergic reactions
**PABA**
some multi-dose vials contain **methylparaben**
71
primary & secondary variables that determine onset of action
**primary**: pKa
**secondary**: dose, concentration
72
primary & secondary variables that determine potency
**primary**: lipid solubility
**secondary**: intrinsic vasodilating effect
73
primary & secondary variables that determine duration of action
**primary**: protein binding
**secondary**: lipid solubility, intrinsic vasodilating effect, addition of vasoconstrictors
74
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
75
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
76
which has a faster onset - 0.75% or 0.25% bupivacaine
0.75% (more molecules given)
77
LA structural component that increases lipid solubility
alkyl group substitution on amide group and benzene ring
78
how is LA removed from site of action
absorption into systemic circulation
79
what kind of response do nearly all LAs have on vascular smooth muscle
biphasic response
| lower concentration = vasoconstriction (inhibit NO)
higher concentration
80
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
80
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
81
how does protein binding affect LA duration
* Molecules that bind to plasma proteins serve as a tissue reservoir
* extends duration
82
how does protein binding affect LA duration
* Molecules that bind to plasma proteins serve as a tissue reservoir
* extends duration
83
how does a strong acid or base behave in water
will completely dissociate
84
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
85
relationship between pKa and degree of ionization
As pKa gets further from physiologic pH, degree of ionization ↑
86
relationship between LA pKa and onset
The closer the pKa is to pH of blood, the faster the onset (exception: chloroprocaine)
87
which has higher pKa - esters or amides
All esters have higher pKa than amides
88
only available LA with pKa well below physiologic pH
Benzocaine
| pKa = 3.5
89
uses of benzocaine
topical anesthesia of mucus membranes during endoscopy, TEE, bronchoscopy
90
significant risk with benzocaine
methemoglobinemia
91
Factors that influence vascular uptake & Cp
* site of injection
* tissue blood flow
* physiochemical properties of LA
* metabolism
* addition of vasoconstrictor
92
fastest to slowest sites for LA uptake
IV > tracheal > interpleural > intercostal > caudal > epidural > brachial plexus > femoral > sciatic > sub-q
93
what determines final LA plasma concentration
Total dose of LA (not concentration or speed of injection)
94
what protein do most LAs bind to
alpha-1 acid glycoprotein
95
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
96
liposomal bupivacaine
Exparel
97
key benefits of Exparel
duration of action up to several days, ↓ opioid consumption
98
how does Exparel work
As lipid membranes in suspension erode and reorganize over time, bupivacaine is released
99
max dose of Exparel
266 mg
100
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
101
Exparel contraindication
paracervical block in OB population
| Not recommended for epidural or intrathecal anesthesia, intraarticular a
102
when should Exparel be used cautiously
hepatic and/or renal dysfunction
103
can other LAs be admin with Exparel?
co-administration of other LAs can disrupt liposomal suspension & cause immediate release
## Footnote
If used, lidocaine must be infiltrated at surgical site min. 20 min prior to Exparel injection
104
when can bupivacaine be given after exparel admin
must be 96+ hours after exparel
105
what determines systemic levels of LA
* drug
* dose
* site of injection
* technique
106
max dose of levobupivacaine
2 mg/kg
max total = 150 mg
107
max dose of bupivacaine
2.5 mg/kg
max total = 175 mg
108
max dose of bupicavaine + epi
3 mg/kg
max total = 200 mg
109
max dose of ropivacaine
3 mg/kg
max total = 200 mg
110
max dose of lidocaine
3.5 mg/kg
max total = 300 mg
111
max dose of lidocaine + epi
7 mg/kg
max total = 400 mg
112
max dose of mepivacaine
7 mg/kg
max total = 500 mg
113
max dose of prilocaine
9 mg/kg
max total < 70 kg = 500 mg
max total > 70 kg = 600 mg
114
max dose of procaine
7 mg/kg
max total = 350-400 mg
115
max dose of chloroprocaine
11 mg/kg
max total = 800 mg
116
max dose of chloroprocaine + epi
14 mg/kg
max total = 1,000 mg
117
what determines plasma concentration of LA
net balance of vascular uptake relative to redistribution & metabolism
118
how to reduce risk of LAST
use test dose and incremental dosing with period aspiration
119
Most common cause of toxic LA plasma concentration
inadvertent intravascular injection
120
most frequent 1st symptom of LAST
seizure
| exception: cardiac arrest may be first with bupivacaine
121
when are LAs more assoc. with LAST
peripheral nerve blocks (not epidural)
122
CV effects of lidocaine at plasma concentration > 25 mcg/mL
CV collapse
123
effects of lidocaine at plasma concentration 15-25 mcg/mL
coma
respiratory arrest
124
effects of lidocaine at plasma concentration 10-15 mcg/mL
* seizures
* LOC
125
CNS effects of lidocaine at plasma concentration 5-10 mcg/mL
* tinnitus
* skeletal muscle twitching
* lip/tongue numbness
* restlessness
* vertigo
* blurred vision
126
CV effects of lidocaine at plasma concentration 5-10 mcg/mL
* hypotension
* myocardial depression
127
plasma concentration of lidocaine assoc. with analgesia
1-5 mcg/mL
128
3 things that increase risk of CNS toxicity with LA use
* hypercarbia
* hyperkalemia
* metabolic acidosis
129
why does hypercarbia contribute to increased risk of LAST
* ↑ CBF
* ↑ drug delivery to brain
* ↓ protein binding
* ↑ free fraction
130
why does hyperkalemia contribute to increased risk of LAST
↑ RMP = neurons are more likely to depolarize
131
why does metabolic acidosis contribute to increased risk of LAST
↓ convulsion threshold, favors ion trapping inside brain
132
3 things that decrease risk of CNS toxicity with LAs
* hypocarbia
* hypokalemia
* CNS depressants
133
how does hypocarbia protect against CNS toxicity with LAs
↓ CBF, ↓ drug delivery to brain
134
how does hypokalemia protect against CNS toxicity with LAs
↓ RMP = requires larger stimulus to depolarize nerve
135
how do LAs disrupt hemodynamics
altering cardiac AP, myocardial performance, and vascular resistance
136
how do LAs cause myocardial depression
by impairing intracellular Ca2+ regulation
137
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
138
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
139
LAs with greatest to least difficulty of CV resuscitation
bupivacaine > levobupivacaine > ropivacaine > lidocaine
140
4 factors that increase risk of bupivacaine toxicity
* pregnancy
* beta blockers
* CCBs
* digoxin
141
Primary risk of cocaine toxicity
excessive SNS stimulation
142
meds to avoid with cocaine toxicity
* MAOIs
* TCAs
* sympathomimetics
* beta blockers
143
Cocaine dose range
1.5 – 3 mg/kg (max 150-200 mg depending on text)
144
best med to use to decrease BP in cocaine toxicity
Vasodilator like nitroglycerin
| Labetalol or another mixed alpha agonist is a reasonable choice
145
treatment of LAST
* 100% FiO2
* treat sz with benzos
* lipid emulsion therapy
146
why might you give NMB for LAST
to stop muscle contraction (seizures)
| minimize O2 consumption, hypoxemia, acidosis
147
why should propofol be avoided in treatment of LAST
augments myocardial depression
148
ACLS modifications for LAST
* If epi is used, give < 1 mcg/kg doses
* For ventricular arrythmias: avoid lidocaine and procainamide, use **amiodarone**
149
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
150
max recommended dose of lipid emulsion therapy for LAST
10 mL/kg in first 30 min
151
theoretical complication of lipid emulsion therapy for LAST
pancreatitis
152
meds to avoid in treatment of LAST
* code-dose epi
* lidocaine
* procainamide
* beta blockers
* CCBs
153
treatment of LAST if unresponsive to modified ACLS and lipid emulsion
CPB
154
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
155
most common cause of death from liposuction
pulmonary embolism
156
what is Tumescent anesthesia
* Dilute solution of sodium chloride, lidocaine, epi, & bicarb injected into adipose tissue
* firms adipose tissue & increases ease of removal
157
function of epi & lidocaine in tumescent anesthesia
* Lidocaine prevents discomfort
* epi minimizes vascular uptake of LA & tumescent solution
158
current American Academy of Dermatology recommendation for max lidocaine in tumescent anesthesia
55 mg/kg
159
metabolism of lidocaine in Tumescent anesthesia
* metabolized by CP3A4 & 1A2
* completely eliminated from body at 36 hours
160
peak Cp of lidocaine in tumescent anesthesia
12 hours
161
when is GA recommended over MAC if tumescent anesthesia used
if > 2-3 L injected (due to risk of fluid shifts)
162
complications of tumescent anesthesia
Fluid overload & pulmonary edema may occur as a result of intravascular volume expansion
163
subunits of Hgb molecule
* 2 alpha
* 2 beta
164
how is methemoglobin produce
when the iron moiety in heme is oxidized from ferrous state (Fe+2) to ferric state (Fe+3)
165
2 ways methemoglobin decreases CaO2
1) methemoglobin can’t bind oxygen molecules
2) shifts oxyhemoglobin
166
why does methemoglobin result in physiologic anemia
Oxyhgb shift ↑ HgbA’s affinity for O2, which makes it harder to release O2 to tissues
167
why does methemoglobinemia cause pulse ox errors
* Methemoglobin absorbs 660 nm and 940 nm infrared wavelengths equally
* tends to push SpO2 towards 85%
168
why is a co-oximeter required to diagnose methemoglobinemia
Uncouples normal relationship between SpO2 & SaO2
169
LAs assoc. with methemoglobinemia
* benzocaine
* cetacaine
* prilocaine
* EMLA
170
presentation of methemoglobinemia with 0-20% HgbMet
usually well tolerated
171
presentation of methemoglobinemia with 20-50% HgbMet
* tachypnea
* tachycardia
* AMS
* slate-gray pseudocyanosis
172
presentation of methemoglobinemia with 50-70% HgbMet
dysrhythmias, coma
173
% HgbMet not compatible with life
> 70%
174
s/s that is highly suggestive of methemoglobinemia
Cyanosis in the presence of a normal PaO2
175
1st line treatment of methemoglobinemia
methylene blue
| Helps accelerate reduction of methemoglobin
176
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)
177
how does methylene blue treat methemoglobinemia
Metabolized by methemoglobin reductase to form leucomethylene blue -- electron donor, reduces methemoglobin back to hemoglobin
178
treatment of methemoglobinemia in a patient with G6PD deficiency
* exchange transfusion
* don’t possess methemoglobin reductase -- methylene blue can precipitate hemolytic crisis
179
population at higher risk for developing methemoglobinemia & why
neonates
| Fetal hemoglobin is relatively methemoglobin reductase deficient (suscep
180
what is EMLA cream made of
50/50 combination of 2.5% lidocaine and 2.5% prilocaine
181
what characteristic of EMLA cream facilitates its absorption
Melting point is lower than either of its constituents
182
effects of EMLA cream
Produces analgesia within 1 hour, max effect in 2-3 hours
183
increases risk of toxicity with EMLA cream
eczema, psoriasis, skin wounds d/t altered pharmacokinetics
184
can be applied simultaneously with EMLA cream to hasten absorption
nitroglycerin
185
metabolite of prilocaine
o-toludine
186
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
187
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
188
additives that prolong LA duration
* epi
* decadron
* dextran
189
additives that supplement LA analgesia
* clonidine
* epi
* opioids (neuraxial only)
190
additive that shortens LA onset
sodium bicarbonate
191
additive that improves LA diffusion through tissues
hyaluronidase
192
LA that decreases effectiveness of epidural opioids
chloroprocaine
193
how does epi prolong block duration & enhance block quality
* decreases systemic LA uptake
* better matching of uptake and metabolism
* decreased LA in plasma
194
epi is best at prolonging which LAs
intermediate duration
| ex. extends duration of lidocaine > bupivacaine
195
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%
196
how does dextran affect LA
prolongs block duration by ↓ systemic uptake
197
how does clonidine affect LA
alpha agonism = analgesia
198
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
## Footnote
Mix 1 mL of 8.4% of bicarb with 10 mL LA solution
199
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
## Footnote
Mix 1 mL of 8.4% of bicarb with 10 mL LA solution
200
how does hyaluronidase affect LA
Hydrolyzes hyaluronic acid
facilitates diffusion of substances in tissues
201
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
202
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
203
what happens when a nerve repolarizes
removal of positive charges from inside the cell
| accomplished by removing potassium
204
RMP and threshold potential of peripheral nerves
RMP = - 70 mV
TP = - 55 mV
205
after peripheral nerve repolarization, how is RMP maintained until the nerve is depolarized again
Na/K-ATPase
206
why is epi avoided in the treatment of LAST
decreases efficacy of lipid emulsion therapy
207
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
208
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
209
which nerve fibers do not experience saltatory conduction
C fibers
| no myelination
209
which nerve fibers do not experience saltatory conduction
C fibers
| no myelination
210
which LA is assoc. with neurotoxicity and therefore not used in spinal anesthesia
chloroprocaine
