Basic Pharmacology of LAs Flashcards
LAs are ___ molecules
amphipathic
T/F
LAs bind exclusively to Na channels and plasma proteins
False
primarily to Na channels
but also K, Ca, & G-protein-coupled receptors
🔷
What determines…
onset
potency
duration
onset = pka
potency = lipid solubility
duration = protein binding
⭐️
T/F
LAs suppress action potentials in excitable tissues by blocking ligand-gated Na+ channels.
False
voltage gated
LAs block pain impulse transmission by inhibiting action potentials in ___ fibers
nociceptive
Four groups of myelinated A fibers
Aa: skeletal muscle
Ab: tactile sensation
Ag: muscle spindles
Ad: nociception & cold
Unmylinated C
dull pain from skin and viscera
Myelinated B
autonomic preganglionic
slower
Where are voltage-gated Na channels found?
nerves
myocardium
Which fibers are affected by Surgical incision or trauma
free nerve endings of Ad
(skin, muscle, joints, bone and viscera)
Voltage-gated Na channel
structure
pore-forming alpha subunit
-one or two b subunits.
alpha subunit:
four domains (I-IV) each w/ six segments (S1-S6) that wrap round a bell-shaped central channel
channel is formed by:
S5 & S6 segments + short loops of amino acids linking them
inactivation gate:
loop connecting domains III & IV
S4 in each domain:
+ charged arginine or lysine amino acids
voltage-sensitive region of the Na+ channel.
voltage-sensitive region of the Na+ channel.
S4
Resting-state:
MP
generated by…
-70 mv
K+ out (along their gradient)
anions stay inside (mostly proteins)
inactivation gate location
between domains III and IV
S4 segment activity
resting state:
S4 in “down” position
makes it nonconductive
depolarization:
outward spiraling opens Na channel
exposes inactivation gate
🔷
The ionized form binds to ___ voltage-
gated Na+ channels in a reversible and concentration-dependent manner.
open
binding site for local anesthetics
domain IV, loop S6
only accessible when the channel is open
use-dependent or phasic block
binding of LA to open Na+ channels increases with the frequency of nerve depolarization
(MoA)
Dose dependent effects of LAs
increased LA [ ]:
↓ peak action potential
↑ firing threshold
↓ impulse conduction
↑ refractory period
↓ all nerve conduction
Why does Bupivicaine cause more cardiac effects than Lidocaine?
bupivacaine:
higher affinity & slower dissociation
↓
accumulates in diastole
↓
prolong conduction
↓
re-entry-induced arrhythmias
(para/sympathetic) fibers are most easily blocked & require lowest LA [ ].
sympathetic
Usually reaches higher dermatome
sympathetic block
LAs are ___ soluble salts of lipid-soluble ___
water
alkaloids
How can LA structure be changed to increase lipid solubility, potency & duration of action
increasing the length of carbon chains attached to either the aromatic ring, amide linkage, or the tertiary amine
Replacement of the tertiary amine by a piperidine ring
↑ lipid solubility and duration of action
butyl group in place of the amine on the benzene ring of procaine gives
tetracaine
addition of a propyl or butyl group to the amine end of mepivacaine results
in
ropivacaine or bupivacaine, respectively
Bupivacaine enantiomers
dextro-enantiomer: selectively blocks 🩷 Na channels
bad
so we started using 2 different Levo-enantiomers
levobupivacaine & ropivacaine
(less effect on 🩷 conduction & contractility)
pKa
pH at which the ionized and unionized forms are present in equal amounts
LAs are (acids/bases) so a higher pka means (more/less) inonization
bases
more
high protein binding to ___ have a longer duration of action and lower
bioavailability.
a1-acid glycoprotein
decreases protein binding & thus and increases the risk of toxicity (3)
Hypoxia, hypercarbia, and acidaemia
vasoactivity of local anaesthetics influences (2)
potency
duration
Levobupivacaine and ropivacaine
bimodal vasoactivity
vasodilate at clinical doses
vasoconstrict at subclinical doses
Routes of administration
topical (skin and airway)
subcutaneous
intravenous
perineural
epidural
intrathecal
peak plasma concentration after a
single dose
intrapleural > intercostal > lumbar epidural >brachial plexus > subcutaneous > sciatic > femoral.
M&M:
intravenous (or intraarterial) > tracheal > intercostal > paracervical > epidural > brachial plexus > sciatic > subcutaneous
Which are less protein bound?
esters or amides
esters
(lower protein binding = shorter duration)
Tissue distribution tends to be proportional to (3)
LA’s tissue/blood partition coefficient
tissue mass
tissue perfusion
We’re concerned about PABA with (ester/amide) LAs
ester
(ester/amide) LAs are more prone to accumulation with hepatic dysfunction or reduced hepatic blood flow
Amide
they are metabolized by the liver
and
have slower metab than esters
(esters = rapid hydrolysis by plasma esterases!)
undergoes metabolism in the lungs
Prilocaine
An allergy to an amide LA is most likely due to…
an additive such as the stabilizing
agent methylparaben
or
response to vasopressors mistakenly seen as allergy
has a high hepatic extraction ratio: clearance depends on hepatic blood flow & ~unaltered by changes in hepatic enzyme activity
Lidocaine
LA Adjuvants
adrenaline
clonidine
opioids
ketamine
dexamethasone
dexmedetomidine
midazolam
eutectic
mixing 2 compounds to produce a substance that has 1 set of physical characteristics
eutectic mixture of local anaesthetic (EMLA)
crystalline bases of 2.5% lidocaine and 2.5% prilocaine in an oil/water emulsion
↓ melting point than separately
can use higher [ ]
rate and degree of diffusion across the
placenta depends on
protein binding
pKa
maternal & fetal pH
Considerations for LAs in prolonged labour
acidosis in the fetus
↓
ion trapping
↓
accumulation in the fetus
(Amide/ester) LAs do not cross the placenta in significant amounts
Ester
d/t rapid hydrolysis
T/F
Local anesthetics cause both systemic AND local toxicity.
True
lower systemic toxicity among the amides
Ropivacaine and levobupivacaine
lower affinity for 🩷 channels
T/F
majority of perioperative nerve injuries are unrelated to regional anaesthesia
True
methaemoglobinaemia shifts the OxyHgb curve
left
↓ ability of Hgb to release oxygen to tissues
LAs that can cause methemoglobinemia
prilocaine
Benzocaine
lidocaine
Intra-articular local anaesthetics
risks
chondrotoxicity (esp w/ osteoarthritis)
LAs anti-inflammatory effects
MoA
↓ polymorphonuclear leukocyte adherence, migration & accumulation at site
alters macrophage and monocyte function
LAs anti-inflammatory effects
cons
~↑risk bacterial infxn
Possible antimetastatic properties
Surgery
↓ antitumour cell activity
↑ protumor activity
LA may ↓ cancer recurrence:
-attenuation this stress response
-direct anti-tumor effect
not proven
lidocaine for neuropathic pain
MoA
unexplained by only blockade of voltage gated Na channels
reduction of spontaneous pain, allodynia, & hyperalgesia
Catheter for continuous or repeated administration of local anesthetic
risks
leakage, migration, infection
Phentolamine mesylate
non-selective alpha-adrenergic antagonist
vasodilates
halve the reversal time of LA
T/F
All local anesthetics target the voltage-gated Na channel
True
T/F
Only certain LAs carry risk of toxicity.
False
All have toxicity risk
