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Lecture 64

:
Local Anesthetics

Richard D. Minshall, PhD
Tobias Piegeler, MD

Departments of Anesthesiology and Pharmacology

February 28
th
, 2012
Outline
A. Pharmacologic aspects:

Basic structural characteristics
Mechanism of nerve conduction
Mechanisms of local anesthetic action
Characteristics of local anesthetic action
Metabolism
Why are vasoconstrictors often added to the local anesthetic preparations?

B. Clinical Aspects:

Problem-based learning with clinical vignettes
Chemical structure
Procaine
Lidocaine
Bupivacaine
Tetracaine
H
2
N C
O
CH
2
CH
2
N
C
2
H
5
C
2
H
5
O
HN C
O
CH
2
CH
2
N
CH
3
CH
3
O
C
4
H
9
C
O
N
CH
3
CH
3
NH
C
4
H
9
C
O
CH
3
CH
3
NH CH
2
N
C
2
H
5
C
2
H
5
Lipophilic group Linker Hydrophilic group
Ester-linked
Amide-linked
Local anesthetics…

 are drugs used to prevent or relieve pain
in specific regions of the body without
loss of consciousness

 reversibly block pain sensation by
blocking nerve conduction

Definition
Neural transmission
Resting potential
Action potential
- - - - - - - ++++ + + + + + + + - - - - - -
Mechanism of action
Local anesthetics reversibly bind to the voltage-
gated Na
+
channel (VGSC)

 block Na
+
influx and thus
 block action potential and nerve conduction.
Local anesthetics
Propagation failure
VGSC(1)
I II III IV
Catterall WA, Neuron 2000; 26(1):13-25
LA
VGSC(2)
Pink:
Local anesthetic binding site
in the inner cavity of the pore
In Segment 6 of Domain IV
(IVS6-Helix)

Green:
Binding site for Tetrodrotoxin
Catterall WA, Neuron 2000; 26(1):13-25
- - - - - - - ++++ + + + +
Local anesthetics
+ + + - - - - - -
++++ + ++ ++ ++ + + + + + + + + + + + + + +
Propagation failure
Influence of fiber type
Local anesthetics more effectively block
small nerve fibers!
Different nerve fiber types
Use-dependent block
Nerves with higher firing frequency and
more positive membrane potential are more
sensitive to local anesthetic block!
Influence of pH
+
+
+
+
+
Low pH
High pH Normal pH
+
+
+
+
+
+
+
+
+
Reason for pH influence?
closed
BH
+
B + H
+
B
B BH
+
BH
+
open
inactivated
Na
+
extracellular
intracellular
H
+
+

Metabolism
1. Most ester-linked local anesthetics are quickly hydrolyzed
by plasma cholinesterase (exception: cocaine)

2. Amide-linked local anesthetics undergo oxidative
dealkylation/oxygenation by monooxygenases and
hydroxylation by carboxylesterase in the liver

3. Water-soluble metabolites are excreted in the urine.
Vasoconstrictor addition
1. Local anesthetics are removed from depot site mainly by
absorption into blood.
2. Addition of vasoconstrictor drugs (e.g. epinephrine)
reduces absorption of local anesthetics, thus prolonging
anesthetic effect and reducing systemic toxicity.

NOTE:
Do not use vasoconstrictors in areas with
(functional) end arteries
 possible development of necrosis
due to prolonged hypoperfusion!!!
What’s the problem?
Too much local anesthetic!
Corning JL:
Spinal anaesthesia and local
medication of the cord.
New York State Med J 42:483 (1885)
Bier A:
Versuche über Cocainisirung des Rückenmarkes.
Deutsche Zeitschrift für Chirurgie 1899;51:361.
History
Today
Examples of local anesthetic use:


Infiltration
Field block
Nerve block
Intravenous regional block
Spinal anesthesia
Epidural nerve block
Topical anesthesia
Case 1
67 y.o. male with a histologically proven malignancy in the right sidewall of
his bladder presenting for a TUR-B.

PMH:
COPD w/ 90 py (and counting...), FEV1 = 65% VC, HTN,
no known CAD or CVD
Meds:
Tiotropium bromide inhaler
ACE-I
Previous surgeries/anesthesias:
Cystoscopy 01/2012 under GA  PONV
Vitals:
HR 78/min, BP 135/78, RR 14/min, Pulse regular, SpO
2
91% at room air
Auscultation: S1, S2, no murmurs, rhythmic, lungs with discrete basal
expansion crackling rales on both sides

Proposed anesthesia?
Case 1
Spinal Anesthesia!

(Hyperbaric) Bupivacaine +/- opioid
Is that enough?
SPA: testing the effect
Try to establish the area where the
patient will recognize a cool pack as
a warm sensation or won’t recognize it at all!

Spinal segments correlate with dermatomes!
 T10 is sufficient for cystoscopy

NOTE:
1. Hypotension due to loss of
sympathetic tone (C fibers T5-L1!)
2. High spinal above T4
 block of the Nn. accelerantes
= sympathetic cardiac accelerators
Obturator nerve
Obturator nerve block
General technique for a block with a nerve stimulator:

1. Stimulation started at e.g. 2 mA for 0.1 ms at 1 Hz
2. Advance the needle at the correct location until desired muscle twitching is visible
3. Current is gradually decreased to 0.2 mA to confirm proximity to the nerve
4. After confirmation of needle position, LA is injected
Case 2
You are on call. It‘s 3 am in the morning. You receive a call from the OB
resident requesting your service for a 27 y.o. female, gravida 1, para 0 in
the labor room, otherwise healthy.
“She just needs a little pain relief“, the resident tells you...

When you enter the room, you find a profusely sweating young woman in
serious distress and pain, who is yelling at an exhausted young male, who
seems to be her husband, as well as at the mid-wife, who tries to calm her
down.

Now she starts screaming at you…

Procedure?
Case 2
Epidural Anesthesia!

Epidural Anesthesia(1)
Disinfection and
prepping
Skin and
subcutaneous
infiltration
Needle insertion
Epidural Anesthesia(2)
Needle advancement
with loss of resistance
technique
Catheter insertion
Then:
1. Test dose of LA with
epinephrine
 Tachycardia?

2. Start of LA:
 e.g. ropivacaine 0.1%
(„walking epidural“)
+/- low dose sufentanil
Case 2: Unforeseen…
The epidural works fine, the mother stopped yelling and swears to name
her baby after you for taking her pain away and you get back to bed.

4 am: The OB resident tells you now, that they have to do a non-emergent
C-section on your patient due to unforeseen positioning of the baby.


And now?
General anesthesia with a high risk of aspiration and airway problems?

Solution: Change the ropivacaine from 0.1% to 0.33% and give a bolus.
Check the effect (dermatomes!) and repeat and/or raise continuous infusion
until effective analgesia is reached.

Case 3
A 37 y.o. male with a fracture of the distal radius after an accident with his
bicycle is scheduled for ambulant surgical repair of the fracture.

PMH: healthy
Meds: None
Past surgeries: None
Vitals: excellent

You decide to cover the patients needs with a axillary plexus block plus a
musculocutaneous nerve block.

Oh no…
After an easy approach you inject the local anesthetic (bupivacaine),
remove the needle and are proud of yourself...

Seconds later the patient tells you, that his tongue and lips are getting
“a little numb“ and you notice that he gets more and more aggitated and
anxious.

Right after that, the patient suffers from a generalized seizure, looses
consciousness, and stops breathing.
Your patient is dying – unless YOU help him!
What would you do?
Let’s save a life!
Working hypothesis: Local Anesthetic Systemic Toxicity (LAST)

1. Get help!

2. Initial Focus:
a. Airway management: ventilate with 100% oxygen
b. Seizure suppression: benzodiazepines preferred;
AVOID propofol in patients with cv instability
(vasodilation  hypotension!)
Modified after ASRA Checklist for treatment of LAST, Reg Anesth Pain Med, 2012;37:16-18
You are able to establish a secure airway by intratracheal intubation after
induction of anesthesia with midazolam and fentanyl and succinylcholine as
the muscle relaxant.
Suddenly the ECG monitor makes some unfamiliar noises. It looks like this:
It gets worse…
Further treatment
1. Management of Cardiac Arrhythmias
a. BLS and ACLS (adjustment of medication and prolonged effort
might be necessary
b. AVOID vasopressin, Ca2+ channel blockers, beta-blockers and
LA (lidocaine is an antiarrhythmic drug class 1B!)

2. Lipid emulsion (20%) therapy
a. Bolus 1.5 ml/kg iv over 1 min
b. Continuous infusion 0.25 ml/kg/min
c. Bolus repetition in case of persisting cv collapse
Modified after ASRA Checklist for treatment of LAST, Reg Anesth Pain Med, 2012;37:16-18
Case closed
After 2 boluses and a total 20 minutes of resuscitation, you are finally able
to re-establish a sufficient circulation in your patient and
transfer him to the ICU.
He leaves the hospital 10 days later without any residual damage…
Systemic LA toxicity
Toxic effect
CV depression
Respiratory arrest
Coma
Convulsions – Unconsciousness
Muscular twitching
Visual disturbance
Light headedness - Numbness of tongue
Tachycardia
F
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Lipid solubility
Lidocaine 7.8 2.9 64 %

Mepivacaine 7.7 0.8 77 %

Bupivacaine
Levobupivacaine

Ropivacaine 8.1 14 94 %
pKa
8.1 27 95 %
Lipid
solubilty

Protein
binding


LipidRescue
Guy Weinberg, MD
Professor of Anesthesiology at UIC
How does it work?

We don’t exactly know!

Lipid emulsion probably works as a “scavenger”,
that is able to absorb the LA from the
cardiac sodium channel and keep it in the vessel!

More information: www.lipidrescue.org

The End
Questions?
For feedback, questions or a request for a research internship in the Minshall lab:

rminsh@uic.edu
piegeler@uic.edu

Thank you very much for your attention!