L6. Local Anesthetics

How do local anesthetics work ?

Block voltage-gated sodium channels

Chemical structure of local anesthetics

lipophilic ring

intermediate chain = ester or amide

hydrophilic group

Local (ester intermediate chain) anesthetics

Cocaine

Procaine

Chloroprocaine

Tetracaine

Benzocaine

Local (amide intermediate chain) anesthetics

Lidocaine

Mepivacaine

Bupivicane

Ropivicaine

Pramoxine

ether local anesthetic

used for hemorrhoids / anti itch creams

Phenacaine

ether local anesthetic in opthamology

What local anesthetic form penetrates biological membranes?

Non ionic form = uncharged

What form is the most active form at the binding site?

cationic form = positively charged

Where is the binding site for local anesthetics?

Intracellular side of sodium channels

Local anesthetics are typically weak ---

weak bases

What happens when locals anesthetic is injected into infected tissues?

anesthetic remains in ionized form

can't penetrate through membrane unless non-ionized

What happens to the effectivenes of the local anesthetic when it is given in infected tissues?

anesthetic is less effective

What are local anesthetics usually in to increase their solubility in water?

HCL salt in solution

Why are local anesthetics given with HCL salt in solution?

salt form is more stable

What do repeated injections during epidural anesthesia cause?

tachyphylaxis

True / False: Local anesthetics are unique in that absorption is not important for action, but it is important for side effects and toxicity

True

What is added into local anesthetics?

Vasoconstrictor

epinephrine or phenylephrine

What is the common does for epinephrine?

1 : 50,000

1 : 100,000

What happens when a vasoconstrictor is added to a local anesthetic?

decreases blood flow

reduces system absorption

prolongs effects

Cocaine itself causes ---

vasoconstriction

Metabolism of ester local anesthetics

hydrolyzed by butylcholinesterase

or metabolized to p amino benzoic acid

Which ester local anesthetics are metabolized to p amino benzoic acid?

Procaine

Chloroprocaine

Tetracaine

Bevicaine

Metabolism of amide local anesthetics

hydrolyzed by CP450

What decreases metabolism of amide local anesthetics and increases toxicity ?

liver disease

reduced hepatic blood flow

Excretion of local anesthetics

metabolites = water soluble and excreted by kidneys

What happens with acid urine and excretion of local anesthetics?

decreased excretion = favors charged form

Resting membrane potential is between --

-60 to - 90mV

K+ intracellular/extracellular concentration in neurons and cardiac muscles

intracellular > extracellular

Na / CL intracellular/extracellular concentration in neurons and cardiac muscles

Extracellular > intracellular

What maintains ionic gradients in neurons and cardiac cells?

Na/K ATPase

Where do local anesthetics bind?

within intracellular side of voltage gated sodium channels

Why do local anesthetics bind to intracellular side of voltage gated sodium channels?

to inhibit sodium gated channels from working

Local anesthetics block sodium gated ion channels in a --- and --- dependent fashion

time and voltage

General anesthetics effects are --- dependent

dose

What is the purpose of general anesthetics binding to intracellular voltage gated sodium channels?

increased threshold to generate action potential

What increases rate of interaction of general anesthetic?

The smaller and more lipophilic the molecule

Potency is correlated with ---

lipid solubility does

High lipid soluble anesthetics can more easily accumulate in lipid rich tissues which is why they are ---

potent

How does lipid solubility affect inhaled anesthetics?

less solubility = greater inhalation induction rate

greater solubility = lower inhalation induction rate

What general anesthetics are more lipid soluble and therefore have a longer duration of action?

Tetracaine

Bupivicaine

Ropivicaine

In a differential nerve block, nerve fibers are blocked according to

- fiber size

- myelination

- frequency/duration of depolarization

- location of fiber in the nerve bundle

Among fibers of the same diameter, what type of fibers are more sensitive to general anesthetics: myelinated or unmyelinated?

Myelinated = have lipids

What fibers are anesthetized in a nerve bundle first?

Outer fibers

Local anesthetics can cause --- to cardiac cell membranes at high concentrations

arrhythmias

--- and --- block sodium channels at the extracellular surface, inhibiting the entrain of sodium into the cell

Tetrodotoxin and siaxotoxin

True /False: Batrachotoxin, aconitine and some scorpion venoms bind to receptors within the sodium channeling cause prolonged activation

true

What can bind to intracellular sodium voltage gated channels and cause prolonged activation?

Batrachotoxin

Aconitine

Scorpion venoms

What is the function of local anesthetics?

temporary anesthesia to localized area of the body

How are local anesthetics administer?

Topical

Opthamological

IV

---- is poorly water soluble and is used only topically. It is applied to wounds and ulcerated surfaces

Benzocaine

What is used for anesthesia of cornea and conjuctiva?

Proparacaine and tetracaine = ester local anesthetics

What is used for anesthesia of mucous membranes of the nose, mouth, throat, tracheo-bronchialtree, esophagus, genitourinary tract procedures and for cosmetic surgery.

Tetracaine and lidocaine

Lidocaine combined with --- is most widely used

epinephrine

Local anesthetics

- drug interactions

alcohol

opioids

CNS depressants

antidepressants

antipsychotics

antihistamines

Drug interactions with amide local anesthetics

Beta blockers reduce hepatic blood flow

Cemitidine decreases liver metabolism of amides

Drug interactions with ester local anesthetics?

acetylcholinesterase inhibit esters

esters inhibits sulfonamides

Choice of local anesthetic is based on --

duration of action

Short acting local anesthetics

Procaine

Chloroprocaine

Intermediate acting local anesthetics

lidocaine, mepivacaine, prilocaine

Long acting local anesthetics

Tetracaine

Bupivicaine

Ropivicaine

What local anesthetic should not be used in labor?

Bupivicaine

True / False: local anesthetics are safe in pregnancy and in children

true

What kind of surgical procedures is local anesthetic used in?

Spinal anesthesia

Infiltration block of sympathetic fibers

How are local anesthetics used in reference to cardiovascular status?

anti-arrythmics = cardiac depression

Local Anesthetics

- adverse effects

Tinnitus

Visual disturbances

Restlessness

Parasthesia

Convulsions

CNS depression

decreased cardiac contraction rate / strength

hypotension (arteriolar dilation)

For patients with convulsions pre-medicate with ---

benzodiazepines (IV diazepam)

If seizures occurs give --- or ---

IV benzodiazepines = diazepam

Barbiturates = thiopental

What can happen to the cardiovascular system with large doses of local anesthetics?

cardiovascular collapse = arteriolar dilation

What local anesthetic is not suited for cardiac patients?

mepivicaine and bupivicaine

What local anesthetic has a better safety profile for cardiac patients?

Lidocaine

How do ester local anesthetics elicit an allergic reaction?

metabolized to p amino benzoic acid = can create an allergic reaction

Prilocaine at doses higher than 10mg/kg can lead to the accumulation of a metabolite called

o-tuluidine

O-tuluidine converts --- to ---

hemoglobin to methomeglobin

--- cannot bind and transport oxygen effectively leading to hypoxia because iron is in a --- oxidation state

methomeglobin; Fe+3

True / False: at high doses all local anesthetics are toxic

true

What happens to sensory and motor effects following spinal anesthesia with large doses of lidocaine or chloroprocaine?

prolonged sensory and motor defects

What are the results of cocaine use?

CNS stimulation

Euphoria

Cocaine blocks the re-uptake of ---

norepinephrine, epinephrine, serotonin, dopamine

What is the result of high systemic dose of cocaine

CNS excitation = blocks norepinephrine, epinephrine, dopamine, and serotonin re-uptake

What is the result of low anesthetic dose of cocaine?

CNS depression = blocks voltage gated sodium channels

The route of --- and the --- is critical in determining whether the effect of cocaine is CNS excitation of CNS depression

delivery and dosage