Lecture 1: Local Anesthetics

Question 1

In the Resting State (-70 mV) which gates are open/closed?

Result?

Answer 1

H gate is open, M gate is closed

No Na entry

Question 2

In the Activated State (-50 mV) which gates are open/closed? Result?

Answer 2

M gate opens –> BOTH H & M gates are open

Na entry –> depol

Question 3

In the Inactivated State which gates are open/closed?

Result?

Answer 3

H gate closes –> H gate is closed, M gate is open

No Na entry

Question 4

What are the 4 differences b/t C and A-delta pain fibers?

Answer 4

1. A-delta are myelinated/faster
   C fibers are not myelinated
2. A-delta responsible for 1st pain response
   C-fibers do the 2nd response (slower, less intense)
3. A-delta rel glutamate
   C fibers rel substance P
4. A-delta synapse onto Neospinothalmic neurons
   C fibers synapse onto Paleospinothalamic neurons

Question 5

What is the source of TTX (tetrodotoxin)?

MOA of TTX?

Answer 5

Bacteria in puffer fish synthesize TTX

TTX binds to the outer pore of the Na channel –> blocks it by steric hinderance in ALL STATES

Question 6

How does TTX differ from Local anesthetics (2 ways)?

Answer 6

1. TTX DOES NOT exhibit use dependent blockade,
   LAs DO exhibit use dependent blockade
2. TTX blocks Na channels from outside (block all states)
   LAs block Na channel intracellularly (cant block Na channel in Resting State)

Question 7

When local anesthetics have increased lipophilicity what is the result?

What about the structure of LAs leads increased lipophilicity?

Answer 7

Earlier onset of action and increased potency

increased lipophilicity:

1. longer length of hydrocarbon chain & interconnecting chain
2. greater # and length of hydrocarbons connected to the ring

Question 8

How do the ester and amide classes of LAs differ from each other?

Answer 8

Ester

1. single I in name
2. shorter duration of action (min)
3. Metabolized by plasma & liver pseduocholinesterases
4. Allergies more likely

Amides

1. Two I’s in name
2. longer duration of action
3. Metabolized in liver by P450 enzymes

Question 9

How do infected tissues affect local anesthetics?

Answer 9

infected tissues = lower pH –> LA is more charged –> decr ability to cross mem –> decr potency and longer onset of action

Question 10

What are the four factors of fibers that affect LA ability to block them?

Answer 10

1. Size: small fibers blocked more readily
2. Myelinated blocked more readily
3. More firing frequency –> blocked more readily
4. More exterior fibers –> blocked more readily

Question 11

When does the probability of systemic toxicity increase w/LAs?

What tissues have the most and least vasculature?

Answer 11

When administered to tissues w/denser vasculature

Most = Intercostal nerves 
Least = Sciatic nerves 

(nemonic = “ICE is BS”)

Question 12

High systemic absorption of LAs leads to convulsions, why? How to Tx?

Answer 12

Convulsions d/t blockade of GABA-A rec –> decr inhibitory transmission

Tx: BZ (diazepam/valium)

Question 13

Which LAs is the exception in that high systemic absorption in the CV system does not lead to decr myocardial contractility, bradycardia, vasodilation and HoTN? Why?

Answer 13

Cocaine

- causes the opposite b/c it blocks catecholamine re-uptake –> acculm of NE

Question 14

What are the three prototype short acting ester LAs?

Answer 14

1. Benzocaine
2. Procaine
3. Cocaine

Question 15

What are the two prototype long acting amide LAs?

Answer 15

1. Lidocaine

2. Ropivacaine

Question 16

What state can LA not block?

Answer 16

Resting state

Question 17

What are the 3 adverse rxns of LAs?

Answer 17

1. Allergic rxns (worse w/esters)
2. Anxiety, confusion, tremors, convulsions
3. CV collapse

(true for all except #1 not true for lidocaine, ropivacaine)

Question 18

What type of procedures is cocaine used for?

Answer 18

Nose and throat procedures

Question 19

Why is Ropivacaine only synthesized in the S-isomer?

Answer 19

It has a low affinity for cardiac Na channels –> lower cardiac toxicity than other LAs

Question 20

What are the 3 LA adjuncts?

Answer 20

1. Epinephrine
2. Clonidine
3. Diazepam

Question 21

What is the main S/E assoc w/Epinephrine? Why?

Answer 21

Localized tissue necrosis

caused by vasoconstrictive action

Question 22

What does admin of Epinephrine w/LAs result in?

Answer 22

1. decr likelihood of systemic toxicity

2. incr LA action by 50%

Question 23

How does clonidine decrease pain transmission when admin w/LAs? What other drug acts similar to clonidine?

Answer 23

It activates alpha 2 adrenegic rec –> decr rel of substance P and glutamate

Morphine

Question 24

When is clonidine admin w/LAs?

Answer 24

For spinal and epidural administration

Question 25

MOA for Diazepam? What is Diazepam used to Tx?

Answer 25

Activates GABA-A rec in CNS

Tx convulsions (d/t systemic absorption of LAs in CNS)

Question 26

How do NSAIDs decrease pain by affecting a-delta and c fibers?

Answer 26

NSAIDs inhibit COX 2 –> blocks production of PGs –> decr sensitization of C & a-delta fibers –> decr pain

Question 27

What is a use dependent blockade?

Answer 27

More use –> less Na current entering b/c more channels are activated and blocked –> less depol w/ each use

Question 28

Which LA causes vasodilation and is therefore used in combination w/Epi to combat its vasoconstrictive effects?

Answer 28

Lidocaine

also used as anti-arrhythmic