Local Anesthetics Flashcards
1
Q
What are local anesthetics?
A
- drugs that reversibly block conduction of electrical impulses along nerve fibers
- MAJOR component of clinical anesthesia and is increasing used to treat chronic and acute pain
2
Q
How many nodes of ranvier in a myelinated axon does a local anesthetic need to inhibit to block impulses?
A
3 successive nodes
3
Q
fasciculi
A
- bundles of axons
- covered with three layers of connective tissue
- LAs must diffuse through these to exert their effects
4
Q
endoneurium
A
- thin, delicate collagen that embeds the axon in the fascicule
- around each little fascicle
- don’t want to inject LA here because can increase the pressure and compress causing a nerve injury
5
Q
perineurium
A
- consists of layers of flattened cells that binds groups of fascicles together
- covers nerve root
6
Q
epineurium
A
- surrounds the perineurium and is composed of connective tissue that holds fascicles together to form a peripheral nerve
- surrounds nerve bundle
7
Q
RMP of axon
A
-70 to -90 mV
8
Q
LA MOA
A
- bind to specific sites on Na+ channel
- block transmission of nerve impulses
- LA do not alter the RMP or threshold potential
- diffusion of unionized based across the nerve sheath and membrane
- re-equilibrium between the base and cationic forms in the axoplasm
- binding of the cation to a receptor inside the sodium channel inside the cell resulting in its blockade and inhibition of Na+ conduction
9
Q
LA specific binding sites
A
- preferential binding to OPEN and INACTIVE Na+ channel states
- also blocks K+ channels, Ca2+ channels, and GPCRs to a lesser extent
10
Q
frequency dependent blockade
A
- resting nerve is less sensitive to LA than one repeatedly stimulated –> AKA use dependent or phasic block
- quicker block potentially if person is actively using nerve
11
Q
differential blockade
A
- nerves have different sensitivity when exposed to LA
- smaller diameter and lack of myelin enhance sensitivity
- larger nerves conduct impulses faster and are harder to block
- in general it goes preganglionic –> loss of sensation –> loss of motor movement
12
Q
type A alpha
A
- function is proprioception, motor
- diameter is 6-22 um
- heavy myelination
- last/longest to block onset
13
Q
type A beta
A
- function is touch, pressure
- diameter is 6-22 um
- heavy myelination
- block onset intermediate
14
Q
type A gamma
A
- function is muscle tone
- diameter is 3-6 um
- heavy myelination
- block onset intermediate
15
Q
type A delta
A
- function is pain, cold temperature, touch
- diameter 1-5 um
- heavy myelination
- block onset intermediate
16
Q
type B
A
- function preganglionic autonomic vasomotor
- diameter < 3um
- light myelination
- block onset early
17
Q
type C sympathetic
A
- function is postganglionic vasomotor
- diameter 0.3-1.3 um
- no myelination
- block onset early
18
Q
type C dorsal root
A
- function pain, warm and cold temperature, touch
- diameter 0.4-1.2 um
- no myelination
- block onset early
19
Q
three characteristic segments of LAs
A
- unsaturated aromatic (benzene) ring system (the lipophilic portion)
- tertiary amine (hydrophilic portion)
- either an ester or an amide linkage binds the aromatic ring to the carbon group
20
Q
ester local anesthetics
A
- procaine
- chloroprocaine
- tetracaine
- cocaine
- benzocaine
21
Q
amide local anesthetics
A
- lidocaine
- mepivacaine
- prilocaine
- bupivacaine
- ropivacaine
- articaine
22
Q
why is the ester or amide linkage important
A
- clinically relevant because of its implications for metabolism, duration, and allergic potential
- changes in chemical structure affect drug potency, speed of onset, duration of action, and differential block potential
23
Q
differences between ester and amide LAs
A
- ester catalyzed by plasma and tissue cholinesterases by hydrolysis while amides metabolized in liver by CYP1A2 and CYP3A4
- esters have a higher potential for allergy (bc breakdown into PABA) while allergy to amides is very rare
- ester drugs tend to be shorter acting due to ready metabolism; amides are longer acting because they are more lipophilic and protein bound
24
Q
minimum effective concentration (Cm)
A
- minimum concentration of LA necessary to produce conduction blockade of a nerve impulse (analogous with MAC)
- Cm of motor approximately twice that of sensory fibers
- less LA needed for intrathecal vs epidural
25
Q
PK/PD of LA
A
- agents meant to remain localized in area of injection
- higher the concentration injection, the faster the onset
- systemic absorption –> termination of drug
- absorption also influences drug termination and toxicity
- the slower the LA is absorbed, the less likely toxicity
- metabolism and elimination readily keep up
26
Q
Potency of LA
A
strong relationship between potency and lipid solubility; larger lipid-soluble LA are water insoluble and highly protein bound
27
Q
what does lipid solubility of LA correlate with?
A
- protein binding
- increased potency
- longer DOA
- tendency for severe cardiac toxicity
- amides usually more lipid soluble/protein bound than esters
28
Q
LA DOA
A
- relationship between protein binding and lipid solubility; drug tends to remain in vicinity of Na+ channel
- LA = weak bases and bind to alpha1 acid glycoprotein (also albumin but to a lesser extent)
- injection site also plays a major role in DOA
29
Q
LA onset of action
A
- how readily LA diffuses across axolemma (axon cell membrane) depends on chemical structure
- LA = weak bases
- basic drugs become MORE ionized when placed in a solution with a pH < pKa
- drugs with a pKa closer to physiologic pH have a faster onset
- **EXCEPTION = chloroprocaine
30
Q
Tetracaine pKa
A
8.5
31
Q
Tetracaine % ionized at pH 7.4
A
93%
32
Q
tetracaine % protein bound
A
94%
33
Q
tetracaine onset
A
slow
34
Q
tetracaine DOA
A
180-600 min
35
Q
lidocaine pKa
A
7.9
36
Q
lidocaine % ionized at pH 7.4
A
76%
37
Q
lidocaine % protein bound
A
64%; more available free drug so shorter DOA
38
Q
lidocaine onset
A
fast
39
Q
lidocaine DOA
A
90-120 min
40
Q
bupivacaine pKa
A
8.1
