PDA III Local Anesthetics

Local anesthetics

-Drugs applied locally to block transmission of nerve impulses

-Intent is to produce loss of sensation in a limited area

-Actions are reversible and recovery is complete

Local anesthetic formulation

-Topical

-Injection (dental)

-Epidural or intrathecal injection

Peripheral primary afferent nociceptor

-An axon with two nerve endings

-Periphery: on the skin

-Primary: first in the neural pathway

-Afferent: carrying info to a center (spinal cord)

-Nociceptor: neuron that senses pain

-Ion channels open in response to acid, injury, heat, etc.

-Voltage gated Na channels propagate APs from peripheral nerve ending to other axon terminal (dorsal horn of the spinal cord)

Local anesthetic MOA

-Peripheral-primary afferent nociceptor

-Inhibit voltage gated sodium channels

Na gated sodium channel review

-At rest: Na channels are in resting/closed can be opened conformation (top left)

-If voltage reaches threshold, intermediate closed conformation into open conformation (Na flows in for rising phase of AP)

-At +40 mV, Na channels are at inactivated conformation (refractory conformation/closed can't be opened): absolute refractory period

LA Na channel MOA

-LAs don't bind resting conformation (low affinity)

-LAs may bind intermediate closed conformation and open conformation

-LAs have highest affinity at the inactivated/closed can't be opened conformation

-Blocking the channel (gives slight effect)

-Stabilizes the channel in its inactivated form

LA chemistry

-May be charged or uncharged (protonated or deprotonated)

-Weak bases

-pKa 8-10

-At 7.4, LA will be more charged than uncharged

-LA has to go through the lipid bilayer to get to its side of action (small minority of drug gets to site of action)

-Uncharged amount that gets in will make an equilibrium toward its charged form

-Charged form is the form that binds at its binding site

Cocaine

-Acts as a LA when rubbed on the skin

-Blocks sodium channels

-Other cocaine molecules are blocking NE reuptake, NE constricts blood vessels (specific to cocaine)

-Constricted blood vessels disallow the drug to be taken to other parts of the body (holds the cocaine to allow for a longer duration of action

Cocaine chemistry

-Tertiary amine is hydrophilic

-Aromatic ring is homophobic

-Anesthetics may be ester or amide (note differences in structure)

LA S-A-R

-Tetracaine more potent than procaine

-PC: partition coefficient

-Higher PC allows higher potency, protein binding, and duration of action (drugs stick to fat and proteins in the local area and stays there longer)

-True for both ester and amides

LA onset

-Depends on rate of diffusion which depends on ability to penetrate tissue (lipophilicity)

-More un-ionized form = quicker onset

-LAs are amines (weak bases) with a pKa of 8-10, so diffusion would be favored by alkaline conditions

-Changes with infected tissue

Infected tissue

-Lower pH, favoring LA's charged form

-LAs are less effective in infected tissue

-Bicarbonate (HCO3) can be added to the preparation and will raise the concentration of the unionized form and shorten onset block

Bicarbonate

-HCO3 can be added to the preparation and will rais

LA loss of effect

-Due to diffusion away from site of action

-Due to distribution away from site of action by the blood

LA duration of action

-Epi or phenylephrine: alpha 1 agonists increase duration of action by constricting blood vessels

-LAs tend to either vasodilate or have no effect on blood vessels (except cocaine and prilocaine)

-LAs with high PC are highly tissue bound: longer DOA

LA metabolism

-Doesn't play a role in DOA

-May be important upon systemic absorption

-Different for esters and amides

Ester metabolism

-Hydrolyzed by plasma esterases

-Faster hydrolysis means less systemic toxicity

-Metabolite of procaine is PABA and can cause allergic reactions

Amide metabolism

-Metabolized by liver enzymes

-Extremely rare to be allergic to these drugs or their metabolites

-If there is a reaction, check the preservatives first

LA systemic toxicity

-CNS effects

-CV effects

-Absorption plays a role

LA role of absorption in systemic toxicity

-Absorption of the drug into systemic circulation leads to toxicities

-We can limit absorption with a vasoconstrictor

-Esters are less toxic than amides because they're metabolized faster; amides require passage through liver

-If the LA is highly protein bound, this can limit free conc in the plasma

CNS systemic toxicities

-Tremor

-Nervousness

-Seizures followed by coma and respiratory depression

CV systemic toxicities

-Decreased excitability and force of contraction

-Vasodilation

Systemic toxicity treatment

-No direct pharmacological antidote

-Supportive measures: maintain airway and ventilation and BP

-Antiseizure meds

LA clinical uses

-Infiltration anesthesia

-IV regional anesthesia

-Peripheral nerve blockade

-Central neural blockade

-Topical anesthesia

Infiltration anesthesia

-Intradermal and subq injections

-Topical anesthetics are a subtype of infiltration anesthesia

IV regional anesthesia

-Rarely used due to toxicity risk

-Into a vein in a limb

-Used with tourniquet-occluded limb

Peripheral nerve blockade

-Single or multiple nerves

-Injected near nerve bundle

Central neural blockade

-Epidural or spinal (intrathecal)

Ester LAs and their durations of action

-Cocaine

-Procaine

-Chloro-procaine

-All 3 are short acting

Amide LAs and their durations of action

-Lidocaine: intermediate acting

-Mepivicaine: intermediate

-Prilocaine: intermediate

-Bupivacaine: long acting

-Etidocaine: long

-Tetracaine: long

Short acting

<60 mins

Intermediate acting

90-120 minute

Long acting

>180 min

Benzocaine

-Lacks aliphatic amino group

-Water insoluble, hydrophobic, and lipophilic: very low systemic absorption

-Used topically on open sores and wounds

EMLA

-Eutectic mixture of LAs (lidocaine and prilocaine)

-Applied to skin and covered with a dressing

-Produces anesthesia in 30-60 mins and lasts 1-2 hours