Term
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Definition
[image]
phenyl ring with an amino group
ester group directly attached to the phenyl ring
all are weak bases
2 have a pKa around 2: they don't have the tertiary amine; the pKa is for the aromatic amino group = will NOT be ionized
tertiary amine is a requirement for these drugs (except for benzocaine and butamben); classified here b/c they have an ester group
benzocaine and butamben have different mechanisms of action
butamben and benzocaine are NOT parenteral; if a salt is prepared from these, once it is in the blood stream it will precipitate; the pH of the solution of benzocaine would be ~2 (very acidic, cannot be used parenterally) |
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Term
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Definition
[image]
phenyl ring, amide, tertiary amino group
main difference is: no aromatic amino group, other substituents on the aromatic ring
articaine: aromatic system is a bioisostere; doesn't have a tertiary amine
prilocaine also has a secondary amine
solubility of these drugs: pKa is lower, similar solubility to the amino esters |
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Term
| examples of amino ethers and ketones |
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Definition
[image]
amino ether:
phenyl ring, ether functionality, tertiary amine
amino ketone:
tertiary amine, ketone, and phenyl ring |
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Term
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Definition
[image]
alcohols are very different
all are local anesthetics, not as potent as the other classes |
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Term
| chemical considerations of LAs |
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Definition
chemical stability:
amides > esters
amides are more stable than esters (chemically and metabolically)
the mechanism by which they are hydrolyzed are similar, but the amides are more stable
aqueous solubility:
increased lipid solubility = increased local anesthetic activity |
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Term
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Definition
interaction with phospholipids and Ca
action on voltage-sensitive channels
action on Na conductance
local anesthetics binding to Na channel |
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Term
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Definition
[image]
the binding site of LAs is inside the cytoplasm
2 ways for the LA to bind to the receptor:
1) only the neutral forms of the drug will go through the membrane; unionized form
2) ionized form goes through the channel; the ionized form is the one that will bind to the receptor in the binding site |
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Term
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Definition
[image]
lipophilic portion = aromatic ring
for esters: electron donating group in ortho or para position; this will INCREASE THE STABILITY OF THE ESTER; increased stability of the zwitterionic form, the greater the LA activity
[image]
for amides: ortho substituents protect from hydrolysis; increasing the steric hindrance will help to protect the amide
intermediate = ester, ketone, amide
optimal length is 1-3 C
branching: steric hindrance for amidases or esterases
pKa increases with increasing length
metabolic inactivation: amide < esters
hydrophilic portion:
tertiary alkylamine - good for salt formation
benzocaine doesn't have the tertiary amine, cannot be used parenterally, only topically, the other amino group of benzocaine is not ionizable |
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Term
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Definition
no differences in activity
differences in pharmacokinetics and toxicity
ropivacaine and levobupivacaine have lower cardiac toxicity |
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Term
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Definition
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Term
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Definition
therapeutically useful nicotinic antagonists are competitive
2 subclasses: neuromuscular blocking agents and ganglionic blocking agents
tubocurarine helped in understanding nicotinic receptors
curare (d-tubocurarine) = model for neuromuscular blocking agents
[image]
curare was thought to have just one quaternary ammonium group, but then it was noted that there are 2 quaternary ammoniums
BIS-QUATERNARY ammonium salts (10-12C)
for any nicotinic activity, this quaternary activity is important
the distance between quaternary ammonium groups (10-12 C) makes it fit perfectly into the receptor site
nicotinic reeptors: 2 anionic binding sites
new bis-quaternary ammonium agents produce DEPOLARIZATION of the postjunctional membrane
D-tubocurarine like agents DO NOT produce depolarization |
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Term
| ideal neuromuscular agent |
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Definition
| non-depolarizing, metabolically inactivated, and rapidly eliminated |
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Term
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Definition
decamethonium bromide
succinylcholine chloride
[image]
succinylcholine has rapid induction and short duration (2 ester groups will be hydrolyzed fast and eliminated quickly, this is good for these drugs)
important structural features between depolarizing and non-depolarizing: restriction and non-restriction of the groups linking the quaternary amines
depolarizing = freely moving
non-depolarizing = rigid forms |
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Term
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Definition
d-tubocurarine chloride
[image]
metocurine iodide
[image]
long duration and eliminated unchanged |
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Term
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Definition
[image]
non depolarizing agents
amino-steroids: malouetine
intermediate to long acting agents
[image]
most amino groups are part of a heterocyclic system
pancuronium: may increase HR and BP
hydrolysis to 3-OH (active), 17-OH, and 3m17 diOH
vecuronium: no cardiovascular effects
hydrolysis to 3-OH, 17-OH, and 3,17 diOH
pipecuronium: minimal cardiovascular effect
excreted primarily unchanged
rocuronium: rapid onset |
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Term
| tetrahydroisoquinoline based agents |
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Definition
atracurium besylate
[image]
short to intermediate acting agent
metabolism: non enzymatic - Hoffman elimination and ester hydrolysis
mivacurium chloride
[image]
mixture of equipotent stereoisomers (refers to the double bond)
short acting
rapidly hydrolyzed - not hoffmann elimination
doxacurium
[image]
mixture of 6 steroisomers
no hoffmann elimination, metabolism is mainly through hydrolysis |
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Term
metabolism of atracurium besylate
[image] |
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Definition
[image]
hofmann elimination = non enzymatic dealkylation at the amino group
ester hydrolysis |
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