Exam 3-Local Anesthetics MedChem Flashcards
(36 cards)
MOA LA
direct inhibition of VG Na channel
How do LA get to area of action
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
What determines their ability to get to binding site
pKa-what proportion will be in ionized state versus unionized.
If unionized form is present
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.
If ionized form present
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.
Duration of action determined by
lipophilicity
Onset of action determined by
pKa (% ionized). best is low pka (more rapid onset)
Henderson hasselbach
10^pH-pka or UP/P or UI/I
Ideal LA
reversible, rapid onset but good DOA
More lipophilicity means what for DOA
more protein binding. this would increase DOA
LA would be terminated in two ways
- distribution in systemic circulation 2. metabolism (at site or in liver)
To reduce toxicity
give with epi to keep in area, give accurate dosage, consider protein binding (55-95% protein bound-may delay metabolism)
LA pharmaceutics
HCL salt (more water soluble/ionized-good for injections) and tertiary amines. may cause irritation.
LA and ester hydrolysis
eliminates activity
Vapo-coolant: ethyl chloride and fluro ethyl
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
Alcohols and phenols:benzyl alcohol, chlorobutanol, eugenol and phenol
benzyl-topical/component of abreva. eugenol-gums, helps with pain.
Alkaloids: cocaine
vasocontrictor, only used on mucus membranes, many problems-unstable in solution/short half life, can’t be sterilized.
SAR-LA optimal pka
7.5-9.5 higher is too ionized lower is not ionized enough tertiary alkylamine the best
SAR-LA 3 parts
- lipophilic portion (aryl group/aromatic ring) 2. alkyl bridge with carbon (ester/ketone) 3. hydrophilic portion (tertiary amine)-important for binding
Increasing lipophilicity would do what
increase rate of onset and lower toxicity
What SAR would increase lipo/partition coefficient
increase alkyl substitution on aryl group. increase alkyl substitution on the amine (with heterocycle or long chain aliphatic). point is to make more unionized!
Benzoic acid derivatives: amnio esters like cocaine
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!
P-amino benzoic acid SARs
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.
Methemoglobinemia
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.)
