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Lecture 64: Local Anesthetics Richard D. Minshall, PhD Tobias Piegeler, MD Departments of Anesthesiology and

Lecture 64:

Local Anesthetics

Richard D. Minshall, PhD Tobias Piegeler, MD

Departments of Anesthesiology and Pharmacology

February 28 th , 2012

Outline

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

often added to the local anesthetic preparations? B. Clinical Aspects: Problem-based learning with clinical vignettes
often added to the local anesthetic preparations? B. Clinical Aspects: Problem-based learning with clinical vignettes
often added to the local anesthetic preparations? B. Clinical Aspects: Problem-based learning with clinical vignettes

Chemical structure

Chemical structure

Procaine

Tetracaine

Bupivacaine

Lidocaine

H 2 N

HN

C

O

C 2 H 5 C O CH CH N 2 2 C 2 H 5
C 2 H 5
C
O
CH
CH
N
2
2
C 2 H 5
O
CH 3
C
O
CH 2
CH 2
N
CH
3
4 H 9
O
CH 3
NH
C
N
CH 3
O C
CH 3
4 H 9
C 2
H 5
NH
CH 2
N
C 2 H
5
CH 3

Ester-linked

Amide-linked

Lipophilic group

Linker

Hydrophilic groupC N CH 3 O C CH 3 4 H 9 C 2 H 5 NH

Definition

Definition

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

Neural transmission

Neural transmission
Neural transmission

Resting potential

Resting potential
Resting potential

Action potential

Action potential
Action potential

Mechanism of action

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

action potential and nerve conduction. Local anesthetics Propagation failure ++++ + + + + + +
action potential and nerve conduction. Local anesthetics Propagation failure ++++ + + + + + +

Propagation failure

potential and nerve conduction. Local anesthetics Propagation failure ++++ + + + + + + +
potential and nerve conduction. Local anesthetics Propagation failure ++++ + + + + + + +
potential and nerve conduction. Local anesthetics Propagation failure ++++ + + + + + + +
potential and nerve conduction. Local anesthetics Propagation failure ++++ + + + + + + +

++++ + + +

+

+

+

+

- -

-

- -

-

VGSC(1)

VGSC(1)

I

II

III

IV

LA
LA

VGSC(2)

VGSC(2)
VGSC(2) Pink: Local anesthetic binding site in the inner cavity of the pore In Segment 6

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

Influence of fiber type

Influence of fiber type

Local anesthetics

Propagation failure - - - - - - - ++++ + + + + +
Propagation failure
- -
- -
-
- -
++++
+ + +
+ +
+
+
- -
-
-
- -
++++ + ++ ++ ++ + + +
+
+
+
+
+
+
+
++
+
+

Local anesthetics more effectively block small nerve fibers!

Different nerve fiber types

Different nerve fiber types
Different nerve fiber types

Use-dependent block

Use-dependent block
Use-dependent block Nerves with higher firing frequency and more positive membrane potential are more sensitive to

Nerves with higher firing frequency and more positive membrane potential are more

sensitive to local anesthetic block!

Influence of pH

Influence of pH

Low pH

+ + + + + + +
+
+
+
+ +
+ +

High pH

Influence of pH Low pH + + + + + + + High pH Normal pH

Normal pH

+ + + + + + +
+
+
+
+
+
+
+

Reason for pH influence?

Reason for pH influence?
 

BH +

  BH + B + H +  
B
B

+ H +

 
  BH + B + H +   extracellular Na + intracellular B BH +  

extracellular

Na +

intracellular

B
B

BH +

 

H + +

B
B

BH +

closed

open

inactivated

Metabolism

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.

and hydroxylation by carboxylesterase in the liver 3. Water-soluble metabolites are excreted in the urine.

Vasoconstrictor addition

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!!!

in areas with (functional) end arteries  possible development of necrosis due to prolonged hypoperfusion!!!

What’s the problem?

What’s the problem?
What’s the problem? Too much local anesthetic!

Too much local anesthetic!

History

History
History Corning JL: Spinal anaesthesia and local medication of the cord. New York State Med J

Corning JL:

Spinal anaesthesia and local medication of the cord.

New York State Med J 42:483 (1885)

medication of the cord. New York State Med J 42:483 (1885) Bier A: Versuche über Cocainisirung

Bier A:

Versuche über Cocainisirung des Rückenmarkes. Deutsche Zeitschrift für Chirurgie 1899;51:361.

Today

Today

Examples of local anesthetic use:

Infiltration Topical anesthesia

Spinal anesthesia

Epidural nerve block Nerve block Field block Intravenous regional block

Infiltration Topical anesthesia Spinal anesthesia Epidural nerve block Nerve block Field block Intravenous regional block

Case 1

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

no known CAD or CVD Meds:

Tiotropium bromide inhaler

ACE-I

),

FEV1 = 65% VC, HTN,

Tiotropium bromide inhaler ACE-I ), FEV1 = 65% VC, HTN, Previous surgeries/anesthesias: Cystoscopy 01/2012 under GA

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

Case 1

Spinal Anesthesia!

Case 1 Spinal Anesthesia! (Hyperbaric) Bupivacaine +/- opioid
Case 1 Spinal Anesthesia! (Hyperbaric) Bupivacaine +/- opioid

(Hyperbaric) Bupivacaine +/- opioid

SPA: testing the effect

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!

pack as a warm sensation or won’t recognize it at all! Spinal segments correlate with dermatomes!

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

Is that enough?

Obturator nerve

Obturator nerve
Obturator nerve

Obturator nerve block

Obturator nerve block
Obturator nerve block General technique for a block with a nerve stimulator: 1. Stimulation started at
Obturator nerve block General technique for a block with a nerve stimulator: 1. Stimulation started at

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

Case 2

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.

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

Case 2

Epidural Anesthesia!

Case 2 Epidural Anesthesia!

Epidural Anesthesia(1)

Epidural Anesthesia(1)
Epidural Anesthesia(1) Disinfection and prepping Skin and subcutaneous infiltration Needle insertion

Disinfection and

prepping

Epidural Anesthesia(1) Disinfection and prepping Skin and subcutaneous infiltration Needle insertion

Skin and

subcutaneous

infiltration

Epidural Anesthesia(1) Disinfection and prepping Skin and subcutaneous infiltration Needle insertion

Needle insertion

Epidural Anesthesia(2)

Epidural Anesthesia(2)
Epidural Anesthesia(2) Needle advancement with loss of resistance technique Catheter insertion Then: 1. Test dose of

Needle advancement with loss of resistance technique

Needle advancement with loss of resistance technique Catheter insertion Then: 1. Test dose of LA with

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…

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.

a bolus. Check the effect (dermatomes!) and repeat and/or raise continuous infusion until effective analgesia is

Case 3

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.

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

Oh no…

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?

seizure , looses consciousness, and stops breathing . Your patient is dying – unless YOU help
seizure , looses consciousness, and stops breathing . Your patient is dying – unless YOU help

Let’s save a life!

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!)

with cv instability (vasodilation  hypotension!) Modified after ASRA Checklist for treatment of LAST, Reg
with cv instability (vasodilation  hypotension!) Modified after ASRA Checklist for treatment of LAST, Reg

Modified after ASRA Checklist for treatment of LAST, Reg Anesth Pain Med, 2012;37:16-18

It gets worse…

It gets worse…

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:

and succinylcholine as the muscle relaxant. Suddenly the ECG monitor makes some unfamiliar noises. It looks

Further treatment

Further treatment

1. Management of Cardiac Arrhythmias

a.

BLS and ACLS (adjustment of medication and prolonged effort

might be necessary

AVOID vasopressin, Ca2+ channel blockers, beta-blockers and LA (lidocaine is an antiarrhythmic drug class 1B!)

b.

and LA ( lidocaine is an antiarrhythmic drug class 1B!) b. 2. Lipid emulsion (20%) therapy

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

c. Bolus repetition in case of persisting cv collapse Modified after ASRA Checklist for treatment of

Modified after ASRA Checklist for treatment of LAST, Reg Anesth Pain Med, 2012;37:16-18

Case closed

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…

in your patient and transfer him to the ICU. He leaves the hospital 10 days later

Systemic LA toxicity

Systemic LA toxicity
Toxic effect CV depression Respiratory arrest Coma Convulsions – Unconsciousness Muscular twitching Visual
Toxic effect
CV depression
Respiratory arrest
Coma
Convulsions – Unconsciousness
Muscular twitching
Visual disturbance
Light headedness - Numbness of tongue
Tachycardia
Free LA concentration in plasma

Lipid solubility

Lipid solubility

Lidocaine

Mepivacaine

Bupivacaine

Levobupivacaine

Ropivacaine

Mepivacaine Bupivacaine Levobupivacaine Ropivacaine pKa Lipid solubilty Protein binding 7.8 2.9 64 %

pKa

Lipid

solubilty

Protein

binding

7.8

2.9

64 %

7.7

0.8

77 %

8.1

27

95 %

8.1

14

94 %

LipidRescue

LipidRescue
LipidRescue How does it work? We don’t exactly know! Lipid emulsion probably works as a “scavenger”,

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

Guy Weinberg, MD Professor of Anesthesiology at UIC

The End

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!