Exam 3-Local Anesthetics MedChem

Question 1

MOA LA

Answer 1

direct inhibition of VG Na channel

Question 2

How do LA get to area of action

Answer 2

need to be lipophilic, site of binding is deep within the channel. they also act like bases-like to take a proton to become ionized species

Question 3

What determines their ability to get to binding site

Answer 3

pKa-what proportion will be in ionized state versus unionized.

Question 4

If unionized form is present

Answer 4

it can enter and exit the lipophilic membrane through the membrane into the cytosol. it can take a proton from inside and bind to the site (more affinity for charged species. The newly ionized form gets stuck in membrane. Unionized forms can also laterally cross membrane through Na channel.

Question 5

If ionized form present

Answer 5

Effects onset of action, because we need the unionized form to work at Na channel. However if the channel is in an open state, it can pass through the hydrophilic Na channel to bind on the inside.

Question 6

Duration of action determined by

Answer 6

lipophilicity

Question 7

Onset of action determined by

Answer 7

pKa (% ionized). best is low pka (more rapid onset)

Question 8

Henderson hasselbach

Answer 8

10^pH-pka or UP/P or UI/I

Question 9

Ideal LA

Answer 9

reversible, rapid onset but good DOA

Question 10

More lipophilicity means what for DOA

Answer 10

more protein binding. this would increase DOA

Question 11

LA would be terminated in two ways

Answer 11

1. distribution in systemic circulation 2. metabolism (at site or in liver)

Question 12

To reduce toxicity

Answer 12

give with epi to keep in area, give accurate dosage, consider protein binding (55-95% protein bound-may delay metabolism)

Question 13

LA pharmaceutics

Answer 13

HCL salt (more water soluble/ionized-good for injections) and tertiary amines. may cause irritation.

Question 14

LA and ester hydrolysis

Answer 14

eliminates activity

Question 15

Vapo-coolant: ethyl chloride and fluro ethyl

Answer 15

have very low bp (52 degrees F). these are usually used as a spray, evaporates as endothermic process-leaves your skin very very cold/chills the site. frost bite SE

Question 16

Alcohols and phenols:benzyl alcohol, chlorobutanol, eugenol and phenol

Answer 16

benzyl-topical/component of abreva. eugenol-gums, helps with pain.

Question 17

Alkaloids: cocaine

Answer 17

vasocontrictor, only used on mucus membranes, many problems-unstable in solution/short half life, can’t be sterilized.

Question 18

SAR-LA optimal pka

Answer 18

7.5-9.5 higher is too ionized lower is not ionized enough tertiary alkylamine the best

Question 19

SAR-LA 3 parts

Answer 19

1. lipophilic portion (aryl group/aromatic ring) 2. alkyl bridge with carbon (ester/ketone) 3. hydrophilic portion (tertiary amine)-important for binding

Question 20

Increasing lipophilicity would do what

Answer 20

increase rate of onset and lower toxicity

Question 21

What SAR would increase lipo/partition coefficient

Answer 21

increase alkyl substitution on aryl group. increase alkyl substitution on the amine (with heterocycle or long chain aliphatic). point is to make more unionized!

Question 22

Benzoic acid derivatives: amnio esters like cocaine

Answer 22

added substituents because ester hydrolysis happens readily-early products no longer on market d/t this. Tried to sterically hinder with substituents N. Now p-amino benzoic acid!

Question 23

P-amino benzoic acid SARs

Answer 23

slowing down metabolism by slowing ester hydrolysis via resonance (new amine that can electron donate on the aromatic ring). Resonance only in para or ortho position. ED group ONLY, EW group would more readily hydrolyze.

Question 24

Methemoglobinemia

Answer 24

ferrous heme carries O2 and ferric iron does not. Metabolism of procaine create metabolite that interferes with this ferric pathway. (benzocaine, chloroprocaine, prilocaine and butamen.)

Question 25

Chloroprocaine

Answer 25

shortened DOA compared to procaine d/t a Cl ortho to the ester (this is an EW group)

Question 26

Benzocaine

Answer 26

still used but doesn’t contain an amine. just lipophilicity drives interaction with Na channel

Question 27

Aniline derivatives: prilocaine, mepivacaine, lidocaine, bupivicaine.

Answer 27

replace ester with amide. (1st isogramine). same SAR as other LA. methyl group on ortho-help prevent attack by amidases.

Question 28

Termination method for aniline derivatives

Answer 28

liver amidases (cyp450s can n-dealkylate and aromatic hydroxylate)

Question 29

Termination method for PABA

Answer 29

pseudocholinsterases

Question 30

Mepivacaine

Answer 30

n-dealkylated for metabolism. exparel is the extended form of bupivicaine-pain relief long time. cannot give to infants d/t pka. PKA-7.6

Question 31

Bupivicaine

Answer 31

R-more cardiotoxic and more CNS effects at motor neurons S isomer less SE.

Question 32

Ropivicaine

Answer 32

change in alkyl substituent. S isomer so less cardiac/CNS effects.

Question 33

Non-ester and non-amide: sucrets and bactine

Answer 33

more lipophilic sucrets-lozanges bactine-tucks and mouth wash

Question 34

Articaine

Answer 34

dentistry. ester on left side, forms negative charge after hydrolysis which decreases CNS SE.

Question 35

Answer 35

a-hydrophobic pathway (unionized)

b-hydrophilic pathway (ionized). takes longer, has to wait for open state to get in

Question 36

Answer 36

1. lipophilic portion, d/t aromatic ring
2. ester bridge
3. hydrophilic portion, d/t tertiary amine