Term
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Definition
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
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
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
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
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
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
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
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
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
metocurine iodide
long duration and eliminated unchanged |
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Term
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Definition
non depolarizing agents
amino-steroids: malouetine
intermediate to long acting agents
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
short to intermediate acting agent
metabolism: non enzymatic - Hoffman elimination and ester hydrolysis
mivacurium chloride
mixture of equipotent stereoisomers (refers to the double bond)
short acting
rapidly hydrolyzed - not hoffmann elimination
doxacurium
mixture of 6 steroisomers
no hoffmann elimination, metabolism is mainly through hydrolysis |
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Term
metabolism of atracurium besylate
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Definition
hofmann elimination = non enzymatic dealkylation at the amino group
ester hydrolysis |
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