Local Anesthetics

definition of local anesthetic

local anesthesia refers to loss of sensation in specific region of the body

Delivered directly to the target organ/tissue

Recovery is spontaneous, predictable, with no residual effects

local anesthetics MOA

Reversible inhibition of action potential conduction in sensory neurons

Anesthetic mechanism of action: block voltage-gated sodium channels

Where does the conduction of action potential occur in the neuron?

Blocking voltage gated sodium channels Along the axon

Review of action potential

1. Resting potential of -70 mV

2. Excitation (depolarization) reaches threshold; leads to sodium channel opening

3. Continued depolarization causes sodium channels inactivation as potassium channels begin to open

4. K+ and Na+ re-establish equilibrium conditions, channels return to resting state

Sodium Na channels exist in what states

Resting, open, inactive

Sodium has the inactivation gate

Potassium only has 2 states: Open or Closed

Local Anesthetic Molecule

Amine is hydrophilic (ex is it charged or uncharged?)

local anesthetics are the most active in the charged state

Local anesthetics are classified via ester or amide linkage

Lipophilic part is aromatic ring

what is the lipophilic part of the local anesthetic

Aromatic ring is lipophilic: required to cross the cell membrane

The charged form is most active at the receptor (channel binding) but the receptor site is intracytoplasmic

T/F local anesthetics need to be in the uncharged form to bind to the voltage gated Na channel

FALSE. They have to be charged!

The charged form is most active at the _______ but the receptor site is ______

The charged form is most active at the receptor (channel binding) but the receptor site is intracytoplasmic

Must be uncharged at physiologic pH to cross the barrier and then they become charged intracellularly to become charged and bind inside the cytoplasm

anesthetic drugs are given with CO2; why?

CO2 can cross the cell membrane; resulting an in acidifying environment (after crossing); the local anesthetic can now become protonated after crossing to become more charged

(CO2 increases intracellular space, cells accumulate the charged form of the drug)

-repeated use would acidify the extracellular space

Examples of amides

Long Duration:

• Bupivacaine

• Etidocaine

• Ropivacaine

Medium Duration:

• Lidocaine

• Mepivacaine

• Prilocaine

Long duration amides

Bupivacaine

Etidocaine

Ropivacaine

Medium duration amides

Medium Duration:

• Lidocaine

• Mepivacaine

• Prilocaine

Examples of Esters

Long Duration: Tetracaine

Medium Duration: Cocaine

Short Duration: Procaine

Surface Action: Benzocaine and cocaine

Absorption of local anesthetics

Administered via local injections

Absorption and distribution is not relevant for determining rate of onset (THESE ARE NOT SUPPOSED TO ENTER SYSTEMIC CIRCULATION)

Absorption into blood is dependent on:

• Drug-tissue binding

• Degree of vascularization of targeted tissue

what is absorption of local anesthetics dependent on?

Absorption into the blood is dependent on:

• Drug-tissue binding

• Degree of vascularization of target tissue

Dependent on physicochemical properties of the drug: anesthetics more lipid soluble have higher efficacy and longer duration of action

Protein binding can also increase duration of action because proteins do not get eliminated in the kidney

Distribution is not relevant because for onset because we WOULD NOT WANT THIS IS SYSTEMIC CIRCULATION

how can you prevent systemic absorption of a local anesthetic

Can be minimized by inducing vasoconstriction (aAR agonist)

• could give epinephrine to vasoconstrict to reduce risk of systemic circulation

Decreases blood flow and distribution of anesthetic away from injection site

What local anesthetic does not need to be coadministered with epinephrine?

COCAINE

is its own vasoconstrictor via sympathomimetic activity

Inhibit reuptake of NE and high binding affinity to NE transporter NET

Esters are hydrolyzed in the blood by

ester hydrolases made in the liver and found in systemic circulation

procaine>cocaine>tetracaine

(within minutes)

amides are hydrolyzed by

liver microsomal P450; NOT Blood

Degradation/Elimination is Much slower in pts with liver disease or reduced renal blood flow, high risk of toxicity

Prilocaine, lidocaine (1.5 hours) > mepivacaine > ropivacaine, bupivacaine (4 hrs)

how can subcellular location factor affect channel blockade

The target is located subcellular (inside the cell membrane); the drug has to cross the cell membrane and go to the cytoplasm

local anesthetics bind the receptor within the channel pore

how can channel state factor affect channel blockade

anesthetic affinity is higher for open channels

• preferentially blocks rapidly firing neurons (during depolarization)

how can fiber type factor affect channel blockade

pain-transmitting fibers are among the most sensitive

rapid firing, small

how can ions affect the channel blockade

• Extracellular calcium (+) partially reverses the effects of local anesthetics: promotes the low-affinity resting state of the channel (Not good; local anesthetics have the highest affinity for the open state, activated state)

• Extracellular potassium amplifies anesthetic function: promotes the inactive channel state (inactivated channels cannot be opened) (Good; promotes the inactivated state)

short acting local anesthetics

procain, chloroprocaine (ester)

intermediate local anesthetics

lidocaine, mepivacaine, prilocaine (amide)

long acting local anesthetics

tetracaine (ester), bupivacaine, levobupivacaine, etidocaine, ropivacaine

lipid-solubility correlates with

higher potency

drugs used for epidural administration in pregnancy

bupivacaine is NO LONGER USED

Ropivacaine and levobupivacaine are less toxic in pregnancy

clinical use of local anesthetics for neuropathic pain

lidocaine is used

neuropathic pain is caused by damage or injury to the nerves

adjuvant to tricyclic antidepressant/anticonvulsant combinations

The following anesthetics are all long-acting except

A. Tetracaine

B. Bupivacaine

C. Procaine

D. Etidocaine

E. None of the above

Procaine

Which one of these local is NOT an amide

A. Benzocaine

B. Bupivacaine

C. Mepivacaine

D. Lidocaine

E. Etidocaine

A. Benzocaine (this is an ester type)