Local Anesthetics - ES

Local anesthetics

drugs applied locally to block transmission of nerve impulses

Goal of local anesthesia

produce loss of sensation in a limited area

nociceptor

neuron that senses pain

what different types of pain signaling receptors do we have on nociceptors?

heat, injury, acid

general MOA of local anesthetics

inhibit opening of voltage gated Na channels → stops AP from being propagated

which Na channel conformation has greatest affinity for local anesthetics

inactivated conformation/stabilized conformation (closed can’t be opened)

what do local anesthetics do in the inactivated conformation of Na channels?

increase absolute refractory period - slows down frequency of AP which reduces pain

LA have a higher effect on neurons that are firing ____

action potentials more frequently

where is local anesthetics site of action?

intracellular side of a Na channel → means it needs to get through a lipid bilayer

LA ionization

mostly charged at physiological pH

needs to be uncharged to get to site of action

needs to be charged to bind to active site

why do we use epinephrine with some local anesthetics?

to make them last longer → pressers, like epinephrine, constrict blood vessels, reducing blood flow to the area and holds the LA in that local place (longer duration of action)

ester type local anesthetics

procaine, tetracaine

amide type local anesthetics

lidocaine, eidocaine

a high partition coefficient means a _____ potency

higher

high lipophilicity and protein binding leads to a ____ duration of action

longer

diffusion of LAs favors ____ conditions

alkaline

why are LAs less effective in infected tissues?

infected tissues tend to have a lower pH, which causes the weak base LAs to be more ionized

what do we add to some formulations of LAs to speed up onset of action?

sodium bicarbonate - keeps it from being ionized so it can distribute

loss of LA effect is due to

diffusion away from site of action and distribution away from site of action by the blood

why do we give LAs with epinephrine or phenylephrine?

cause vasoconstriction which holds the drug in place

LAs with a high partition coefficient are ____ tissue bound

highly → longer duration of action

Metabolism of ester LAs

hydrolyzed by plasma esterase (in blood)

metabolism of amide LAs

liver enzymes (in liver)

which kind of LA is more likely to cause an allergic reaction in some patients?

esters - have a metabolite that can cause allergic reactions

we see systemic toxicity with LAs at

high doses

Characteristics of LA systemic toxicity

CNS (tremors, nervousness, seizures, coma, respiratory depression) and CV (dec excitability and contractility, vasodilation)

why are esters less toxic at high doses than amides?

because they are metabolized in the blood

can we reverse LA toxicity?

no, just use supportive measures

clinical uses: infiltration anesthesia

topical anesthesia, intradermal and subQ injections

Clinical uses: IV regional anesthesia

rarely used because of toxicity risk, use tourniquet-occlusion

clinical use: peripheral nerve blockade (single or multiple nerves)

injected near nerve bundle

clinical use: central neural blockade

epidural or spinal (intrathecal)

short acting LAs time

<60 minutes

short acting LAs examples

cocaine, procaine, chloroprocaine

intermediate acting LAs time

90-120 minutes

intermediate acting LA examples

lidocaine, mepivicaine, prilocaine

Long acting LAs time

>180 minutes

Long acting LAs examples

bupivicaine, etidocaine, tetracaine

examples of ester LAs

cocaine, procaine, chloroprocaine, tetracaine

examples of amide LAs

lidocaine, mepivicaine, prilocaine, bupivicaine, etidocaine

benzocaine

very lipophilic, very low systemic absorption, topical agent for open wounds

eutectic mixture of local anesthetics (EMLA)

mixture of lidocaine and prilocaine - applied to the skin and covered with dressing (produces anesthesia in 30-60 minutes and lasts 1-2 hours)

eutectic mixture

mixture of two substances which result in a lower melting point than that of each individual constituent