Local Anesthetics

What is the MOA of local anesthetics?

blocks Na ion influx thru nerve cells

→

decreases signal transduction

→

nerve paralysis

Describe the makeup of the outer membrane of Na channels

• rich in Glu and Asp (neg anions)

  • helps attract Na+ from outside to inside cell

Describe the makeup of the inner membrane of Na channels

• rich in highly lipophilic AAs

  • helps Na+ move down the channel

What is the structure of a local anesthetic?

• basic nitrogen

• spacer

• aromatic lipophilic structure

What is the significance of the basic nitrogen in a local anesthetic?

• can be ionized @ physiological pH

  • becomes (+) to compete w/ Na+ at the membrane

  • will be attracted by negatively charged Glu + Asp

What is the significance of the spacer in a local anesthetic?

• connects basic N to aromatic lipophilic area

• FG in spacer determines DOA!!

What functional groups act as spacers in local anesthetics?

• esters

• amides (benzamide + aniline)

• ethers

• ketones

What is the significance of the aromatic lipophilic structure in a local anesthetic?

• slides into channel + interacts w/ lipophilic AAs inside channel

T/F: drugs with the same functional groups do NOT have cross sensitivity

FALSE

T/F: local anesthetic injections are contraindicated with coadministration with epinephrine.

FALSE

• often mixed w/ E as a vasconstrictor

What is the purpose of adding epinephrine to a local anesthetic injection?

• keeps drug local → decreases cardiotoxicity

• increases DOA

Cocaine

• ester spacer

• similar structure to atropine

• plasma esterase metabolism → PABA

Benzocaine

• ester spacer

• aniline group

  • no basic N (pKb = 9) → weak anesthetic

Why is benzocaine considered a weak anesthetic?

• No basic N

  • will NOT be ionized at plasma pH since pKb = 9

(basic N must be ionized to compete with Na)

Procaine

• ester spacer

• aniline

• DOA: 30 mins

  • coadministered w/ epinephrine bitarate → DOA: 90 mins

Proparacaine

• ester spacer

• ether on aniline

  • increased lipophilicity → increased DOA (90 mins) + tighter bind + high PPB

• ophthalmic use

Tetracaine

• ester spacer

• increased # of carbons

  • increased lipophilicity → longer DOA (2 hours)

  • high PPB

• HCl salt intrathecal injection

Dibucaine

• benzamide spacer

  • increased lipophilicity → very long t ½

  • chemically stable

• too cardiotoxic for injection

Lidocaine

• amide spacer

• aniline

• basic N is closer to aromatic ring → less stable/shorter DOA (60 mins)

Mepivicaine

• similar to lidocaine

• methyl on basic nitrogen

Bupivicaine

• more lipophilic than mepivicaine

  • DOA: 2-4 hrs

• aniline

• butyl group

Etidocaine

• increased # of carbons

  • increased lipophilicity

  • longer DOA than lidocaine

Prilocaine

• similar to mepivicaine

Pramoxine

• ether spacer

• very long lasting

• can be used topically

  • max 3 weeks or accumulation occurs

Dyclonine

• ketone spacer

• non-irritating

  • used as lozenges

• injection for infiltration anesthesia

Which local anesthetics have ester FGs?

a. mepivicaine

b. prilocaine

c. proparacaine

d. dibucaine

C

Which local anesthetics have amide FGs?

a. pramoxine

b. prilocaine

c. proparacaine

d. procaine

B