Lecture 1: Local Anesthetics Flashcards
In the Resting State (-70 mV) which gates are open/closed?
Result?
H gate is open, M gate is closed
No Na entry
In the Activated State (-50 mV) which gates are open/closed? Result?
M gate opens –> BOTH H & M gates are open
Na entry –> depol
In the Inactivated State which gates are open/closed?
Result?
H gate closes –> H gate is closed, M gate is open
No Na entry
What are the 4 differences b/t C and A-delta pain fibers?
- A-delta are myelinated/faster
C fibers are not myelinated - A-delta responsible for 1st pain response
C-fibers do the 2nd response (slower, less intense) - A-delta rel glutamate
C fibers rel substance P - A-delta synapse onto Neospinothalmic neurons
C fibers synapse onto Paleospinothalamic neurons
What is the source of TTX (tetrodotoxin)?
MOA of TTX?
Bacteria in puffer fish synthesize TTX
TTX binds to the outer pore of the Na channel –> blocks it by steric hinderance in ALL STATES
How does TTX differ from Local anesthetics (2 ways)?
- TTX DOES NOT exhibit use dependent blockade,
LAs DO exhibit use dependent blockade - TTX blocks Na channels from outside (block all states)
LAs block Na channel intracellularly (cant block Na channel in Resting State)
When local anesthetics have increased lipophilicity what is the result?
What about the structure of LAs leads increased lipophilicity?
Earlier onset of action and increased potency
increased lipophilicity:
- longer length of hydrocarbon chain & interconnecting chain
- greater # and length of hydrocarbons connected to the ring
How do the ester and amide classes of LAs differ from each other?
Ester
- single I in name
- shorter duration of action (min)
- Metabolized by plasma & liver pseduocholinesterases
- Allergies more likely
Amides
- Two I’s in name
- longer duration of action
- Metabolized in liver by P450 enzymes
How do infected tissues affect local anesthetics?
infected tissues = lower pH –> LA is more charged –> decr ability to cross mem –> decr potency and longer onset of action
What are the four factors of fibers that affect LA ability to block them?
- Size: small fibers blocked more readily
- Myelinated blocked more readily
- More firing frequency –> blocked more readily
- More exterior fibers –> blocked more readily
When does the probability of systemic toxicity increase w/LAs?
What tissues have the most and least vasculature?
When administered to tissues w/denser vasculature
Most = Intercostal nerves Least = Sciatic nerves
(nemonic = “ICE is BS”)
High systemic absorption of LAs leads to convulsions, why? How to Tx?
Convulsions d/t blockade of GABA-A rec –> decr inhibitory transmission
Tx: BZ (diazepam/valium)
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?
Cocaine
- causes the opposite b/c it blocks catecholamine re-uptake –> acculm of NE
What are the three prototype short acting ester LAs?
- Benzocaine
- Procaine
- Cocaine
What are the two prototype long acting amide LAs?
- Lidocaine
2. Ropivacaine
What state can LA not block?
Resting state
What are the 3 adverse rxns of LAs?
- Allergic rxns (worse w/esters)
- Anxiety, confusion, tremors, convulsions
- CV collapse
(true for all except #1 not true for lidocaine, ropivacaine)
What type of procedures is cocaine used for?
Nose and throat procedures
Why is Ropivacaine only synthesized in the S-isomer?
It has a low affinity for cardiac Na channels –> lower cardiac toxicity than other LAs
What are the 3 LA adjuncts?
- Epinephrine
- Clonidine
- Diazepam
What is the main S/E assoc w/Epinephrine? Why?
Localized tissue necrosis
caused by vasoconstrictive action
What does admin of Epinephrine w/LAs result in?
- decr likelihood of systemic toxicity
2. incr LA action by 50%
How does clonidine decrease pain transmission when admin w/LAs? What other drug acts similar to clonidine?
It activates alpha 2 adrenegic rec –> decr rel of substance P and glutamate
Morphine
When is clonidine admin w/LAs?
For spinal and epidural administration
