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3-24 Local Anesthetics
n/a
155
Pharmacology
Graduate
03/29/2010

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Term
pain transduction begins?
Definition
in the periphery (peripheral nerve)
Term
location of cell bodies for peripheral nerves involved in pain transduction?
Definition
dorsal root ganglion
Term
2 routes of pain signaling to the cortex?
Definition
1. direct - through the thalamus
2. indirect - extra synapse in the brain stem
Term
location of voltage gated Na channels?
Definition
present in excitable cells - neurons, myocytes, cardiac cells
Term
role of voltage gated Na channels?
Definition
essential for AP generation
Term
are voltage gated Na channels autonomous?
Definition
NO - need 'starter' channels

undergo rapid activation with plasma membrane depolarization
Term
a cell with autonomous voltage gated Na channel is considered what?
Definition
pacemaker cell - like SA node
Term
can other ions travel through voltage gated Na channels?
Definition
NO - they are highly selective for Na ions
Term
what things depend on voltage gated Na channels (4)?
Definition
1. sensation
2. emotion
3. thought
4. movement
Term
what blocks voltage gated Na channels?
Definition
Term
in response to a stimulus, upstroke of AP is a result of what?
Definition
Na influx
Term
once a cell reaches full depolarization (up to +80 mV), Na channels become ___?
Definition
inactivated
Term
what happens at the peak of an AP?
Definition
Na channels become inactivated
K channels open --> K efflux and repolarization
Term
what cardiac inherited disorders are due to voltage gated Na channels?
Definition
1. congenital long QT syndrome
2. ventricular fibrillation
3. sick sinus syndrome
4. atrial standstill
5. sudden infant death syndrome
Term
composition of each alpha subunit of voltage gated Na channel?
Definition
4 hexamers - each with 6 transmembrane segments (S1-6)
Term
location of voltage sensor in voltage gated Na channels?
Definition
S4 transmembrane segment of each hexamer of the alpha subunit
Term
which segment of the voltage gated Na channel controls its activity?
Definition
S4
Term
location of inactivation 'h-gate' in the voltage gated Na channels?
Definition
between hexamers III and IV
Term
function of inactivation h-gate in voltage gated Na channels?
Definition
portion of the receptor that closes the channel immediately following activation to effectively inactivate it
Term
location of binding site for local anesthetics in voltage gated Na channels?
Definition
in the carboxy terminus
between F1764 and Y1771
Term
what is the length of the binding site for local anesthetics on the voltage gated Na channels and why is this important?
Definition
11 amino acids

important because it is the length of most effect local anesthetics
Term
what skeletal muscle inherited disorders are due to voltage gated Na channels?
Definition
1. hyper/hypokalemic periodic paralysis
2. myasthenic syndrome
3. malignant hyperthermia susceptibility
Term
what brain inherited disorders are due to voltage gated Na channels?
Definition
1. epilepsy
2. febrile seizures
3. myoclonic seizures
Term
what peripheral nerve inherited disorder is due to voltage gated Na channels?
Definition
primary erythermalgia
Term
what is the most potent toxin on earth?
Definition
tetrodotoxin - from the puffer fish
Term
saxitonin comes from where?
Definition
snails
Term
how do tetrodotoxin and saxitonin work?
Definition
both act by occluding the pore of the Na channel
Term
where does the brevetoxin come from?
Definition
red tide
Term
what is the mechanism of action of local anesthetics?
Definition
use-dependent block - differ in what they block in terms of their use

always act on hexamer IV at transmembrane segment 6 of the alpha subunit of the voltage gated Na channel
Term
what are the 2 gates of the voltage gated Na channel?
Definition
1. M gate
2. H gate
Term
what is the state of the voltage gated Na channel in the resting state?
Definition
closed

M gate is closed; H gate is open
Term
what is the state of the voltage gated Na channel in the activated state?
Definition
open

M gate open; H gate open
Term
what is the state of the voltage gated Na channel in the inactivated state?
Definition
closed

M gate open; H gate closed
Term
what happens when you use voltage gated Na channels in the presence of local anesthetics?
Definition
the more you use the channels, the greater the percentage of blocked channels
Term
what is 'use-dependent' block of channels?

which channels have this?
Definition
the more the channel is used, the greater the block (ie. the lower the peak current with each new pulse)

unique to voltage gated Na channels
Term
what is the guarded receptor theory of use dependent block of voltage gated Na channels by local anesthetics?
Definition
local anesthetic has to get intracellular to affect the VG Na channel

a conformational change in the VG Na channel leads to change in drug accessibility to receptor

affinity does not change
Term
what is the modulated receptor theory of use dependent block of voltage gated Na channels by local anesthetics?
Definition
increase use (change in channel state as cycle through) leads to change in receptor affinity for the drug
Term
the guarded receptor theory of use dependent block of voltage gated Na channels by local anesthetics is based on a change in the ____?
Definition
drug accessibility to the receptor
Term
the modulated receptor theory of use dependent block of voltage gated Na channels by local anesthetics is based on a change in the ____?
Definition
receptor affinity for the drug
Term
where along the nerve are voltage gated Na channels located?
Definition
nodes of ranvier
Term
location of action of local anesthetics in a nerve?
Definition
node of ranvier

location of voltage gated Na channels
Term
why is the node of ranvier the location of action for local anesthetics?
Definition
there is no myelin but there are voltage gated Na channels
Term
where alone a nerve is the greatest concentration of voltage gated Na channels?
Definition
nodes of ranvier
Term
how many nodes of ranvier must be blocked for local anesthetics to work?
Definition
3 successive nodes
Term
what are the 2 main types of pain fibers?
Definition
A-delta and C-dorsal root
Term
A-delta fibers carry what modalities (3)?
Definition
pain
cold temp
touch
Term
where do A-delta fibers make their synapse?
Definition
Rexed's lamina I of the dorsal horn
Term
C-dorsal root fibers carry what modalities (4)?
Definition
1. pain
2. temp
3. mechanoreception
4. reflex responses
Term
where do C-dorsal root fibers make their synapse?
Definition
substantia gelatinosa of the dorsal horn
Term
nerve blockade requires what?
Definition
a minimal length of fiber exposed to adequate anesthetic concentration
Term
what has be be blocked to induce sufficient anesthesia of a sensory fiber?
Definition
3 adjacent nodes of ranvier
Term
which fibers have the greatest internodal distance?
Definition
thick fibers
Term
why are B fibers blocked first with local anesthetics?
Definition
they are the thinnest
Term
how does fiber blockade proceed with local anesthetics?
Definition
from the thinnest (B) fibers to the thickest (A) fibers
Term
the ____ the fiber, the greater the distance between nodes of ranvier
Definition
thicker
Term
what are the thinnest pain fibers?
Definition
B fibers
Term
B fibers are associated with?

local anesthesia at B fibers leads to what?
Definition
autonomic preganglionic fibers

*vasoldilation with associated decrease in BP
Term
what side effect can be seen with local anesthetics before pain blocking and why?
Definition
*hypotension from blocking B fibers first and causing vasodilation
Term
in what order are the pain fibers blocked by local anesthetics?
Definition
B > C > A-delta > A-gamma > A-beta > A-alpha
Term
what is the last modality lost with local anesthetics use and what fiber type is it due to?
Definition
motor function

due to A-alpha fibers
Term
which has a greater diameter: C or A-delta fibers?
Definition
A-delta fibers

slow pain (C) is lost prior to losing fast pain (A-delta) with local anesthetics
Term
what channels contribute to repolarization phase of AP?
Definition
voltage gated K channels
Term
where are voltage gated K channels located?
Definition
DRG and dorsal horn neurons
Term
what are 2 drugs that can also bind to voltage gated K channels?
Definition
bupivacaine and lidocaine

bind with lower affinity than to Na channels
Term
where are voltage gated K channels located in the body and why is this important?
Definition
myocardium (heart)

sensitivity to bupivacaine and lidocaine - explains cardiotoxicity of these local anesthetics
Term
why can bupivacaine and lidocaine be cardiotoxic?
Definition
*due to their secondary effect on voltage gated K channels in the myocardium
Term
are local anesthetics specific to only voltage gated Na channels?
Definition
NO

voltage gated Ca and K channels are also sensitive
Term
what 2 drugs can increase the effects of bupivacaine?
Definition
nifedipine and nicardipine (L-type voltage gated Ca channel blockers)
Term
what characteristic of local anesthetics makes them short acting and why?
Definition
having an ester link - makes them susceptible to de-esterification by plasma pseudocholinesterase
Term
what are 2 local anesthetics with ester links in them?
Definition
procaine
tetracaine HCl
Term
why are lidocaine an bupivacaine long acting local anesthetics?
Definition
they have an amide link (instead of ester) and are hydrolyzed in hepatocytes by mixed function oxidase
Term
what are 2 local anesthetics with amide linkages in their structures that render them longer acting?
Definition
lidocaine
bupivacaine
Term
ester local anesthetics (4)
Definition
1. procaine
2. tetracaine
3. benzocaine
4. cocaine
Term
potency of procaine
Definition
1
Term
procaine properties?
Definition
low toxicity
short acting
no topical effect
vasodilation
Term
procaine can interact with what other drugs?
Definition
antibacterial drugs - sulfonamides
Term
how does procaine interact with sulfonamides?
Definition
*produces PABA as a metabolite which inhibits sulfonamides
Term
can tetracaine be given in a spinal block?
Definition
YES
Term
what has to be given with tetracaine in a spinal block and why?
Definition
10% dextrose

to increase specific gravity of the drug so it can't travel back to the brain and block respiration
Term
potency of tetracaine?
Definition
16

more potent and toxic than procaine
Term
pharmacokinetics of tetracaine?
Definition
5 min onset and 2-3 hour duration
Term
benzocaine use?
Definition
topical only
Term
which ester local anesthetics are for topical use only?
Definition
benzocaine
cocaine
Term
cocaine use?
Definition
topical; for the eye

toxic
Term
what is the only local anesthetic that produces vasoconstriction?
Definition
*cocaine
Term
cocaine action
Definition
inhibits reuptake of catecholamines
enhances actions of noradrenaline
Term
what is unique about cocaine compared to other local anesthetics?
Definition
*it is the only one that produces vasoconstriction
Term
amide local anesthetics (5)
Definition
1. lidocaine
2. mepivacaine
3. bupivacaine
4. ropivacaine
5. prilocaine
Term
lidocaine properties?
Definition
rapid onset
medium acting
low toxicity
potency = 4
Term
mepivacaine properties?
Definition
medium acting
potency = 2
Term
bupivacaine use?
Definition
*epidural for labor
Term
what local anesthetic is used in an epidural for labor?
Definition
*bupivacaine
Term
bupivacaine properties?
Definition
low toxicity
long acting
potency = 16
Term
ropivacaine use?
Definition
surgical, post-surgical, and obstetric regional use

effective in orthopedic surgery
Term
ropivacaine properties?
Definition
less toxic
long acting
potency = 16
Term
what local anesthetic is effective in orthopedic surgery?
Definition
ropivacaine
Term
prilocaine use
Definition
topical dermal use as Eutectic Mixture of Local Anesthetic (EMLA) Cream for 2-3 hours effect

used under occlusive dressing
Term
what amide local anesthetic is for topical use?
Definition
prilocaine
Term
what 2 amide local anesthetics are good for surgery and why?
Definition
bupivacaine and ropivacaine

they are long acting and potent
Term
location of action of topical local anesthetics?
Definition
nerve endings closest to the skin
Term
administration for local anesthetics involved in infiltration, nerve block, epidural, or spinal blocks?
Definition
injection
Term
infiltration mode of local anesthetic administration?
Definition
tissue are is injected; no specific nerve is targeted
Term
nerve block mode of local anesthetic administration?
Definition
targeting a specific area

usually only done in the lower body to avoid important structures that could paralyze respiration
Term
epidural mode of local anesthetic administration?
Definition
DRG is injected

anesthetic will stay in DRG and not travel. enables lower doses because its effectively localized
Term
spinal block mode of local anesthetic administration?
Definition
injection of anesthetic into the CSF in the spinal cord

can travel throughout the CSF
Term
when will topical anesthetics not be effective?
Definition
if the skin is intact
Term
where are topical anesthetics used?
Definition
surface of wounds, burns, intact mucous membranes, nose, mouth, bronchi, cornea, urinary tract, dental paste, condoms

not effective on intact skin
Term
what drug is given topically for Herpes zoster blisters?
Definition
lidocaine
Term
what is EMLA?
Definition
lidocaine + prilocaine
Term
what is EMLA used for?
Definition
venepuncture
Term
when do you have to worry about systemic toxicity with topical anesthetics?
Definition
in high concentrations and large areas of application
Term
when is infiltration mode of administration of local anesthetics used?
Definition
injected in tissue around incision for minor operations
Term
what drugs are used for infiltration?
Definition
lidocaine, procaine, bupivacaine
Term
is procaine long or short acting?
Definition
short
Term
what is a good labor and delivery anesthetic?
Definition
bupivacaine

long acting
Term
what is often given with drugs administered by infiltration and why?
Definition
epi

to counter (vasoconstrict) the vasodilatory effects of the local anesthetics
Term
where should epi not be used in addition to local anesthetics administered by infiltration and why?
Definition
fingers, toes, ears, nose, or penis (end-organs)

can get necrosis and gangrene from occlusion of blood supply
Term
when do you have to worry about systemic toxicity with infiltration anesthetics?
Definition
in high concentrations and large areas of application
Term
IV regional anesthetics must be injected where?
Definition
distal to pressure cuff to arrest blood flow so the anesthetic can't travel upstream

effective until cuff is de-pressurized
Term
IV regional anesthesia use?
Definition
limb surgeries - amputations, etc
Term
what drugs are used for IV regional anesthesia?
Definition
lidocaine
prilocaine
Term
when are IV regional anesthetics useful outside of normal circumstances?
Definition
in a field hospital or place lacking more specific anesthetics
Term
IV regional anesthesia adverse effects?
Definition
systemic toxicity when cuff released before 20 mins
Term
a regional nerve block is injected where?
Definition
near peripheral nerves - accuracy of injection is important
Term
regional nerve block use?
Definition
surgical and dental analgesia
pudendal block for episiotomy during childbirth
Term
what type of administration would be used for a pudendal block for episiotomy?
Definition
regional nerve block
Term
what are the adverse effects of a regional nerve block?
Definition
slower onset of anesthesia
needs accuracy of injection
Term
spinal administration of local anesthetics is injected where?
Definition
into CSF - in subarachnoid space to act on spinal cord and spinal roots
Term
when is spinal administration used?
Definition
surgery of the abdomen, pelvis, leg, and in OB
Term
what drugs can be given by spinal administration?
Definition
lidocaine
tetracaine
Term
adverse effects of spinal administration of local anesthetics?
Definition
1. bradycardia, hypotension - due to sympathetic block
2. resp depression - due to phrenic nerve or resp center block
3. urinary retention - due to pelvic parasympathetic block
Term
how do you minimize cranial spread of local anesthetics administered spinally?
Definition
elevate head
use 10% dextrose to increase specific gravity so its heavier than CSF
Term
why do you add 10% dextrose to local anesthetics given by spinal injection?
Definition
to increase the specific gravity and make them heavier than CSF so they don't travel to the brain and cause resp depression or hypotension

also elevate their head
Term
epidurals are injected where?
Definition
into peridural space to act on nerve roots and spinal roots
Term
epidural administration of local anesthetics use?
Definition
surgery of abdomen, pelvis, leg, in OB ('painless' childbirth)
Term
what local anesthetics can be given by epidural injection?
Definition
lidocaine
*bupivacaine
Term
what drug is given by epidural injection for use in childbirth?
Definition
*bupivacaine
Term
adverse effects of epidural injections of local anesthetics?
Definition
similar to spinal but less likely because cranial spread is limited - drug stays in DRG

urinary retention - pelvic parasympathetic block
Term
what is the advantage of giving a drug by epidural rather than spinal injection?
Definition
can give a lower dose epidural because it stays in the DRG
Term
what are the adverse effects (3) common to all local anesthetics?
Definition
1. resp arrest, coma, death
2. decreased myocardial excitability, conduction rate, and contraction force
3. profound hypotension due to vasodilation
Term
what leads to toxicity of local anesthetics?
Definition
overdose
Term
what are the 2 main types of toxicity seen with OD of local anesthetics?
Definition
cariotoxicity
neurotoxicity
Term
what toxicity occurs at a lower dose?
Definition
neurotoxicity (lower than cardiac toxicity)
Term
what determines the relative of toxicity of local anesthetics and what does it mean?
Definition
CC:CNS ratio

the number tells the dose difference at which you will get CNS vs. cardiac toxicity

a CC:CNS of 7 = if at 3 mg/kg, get seizures, then at 21 mg/kg, get cardiac arrest
Term
what is the progression of neurotoxicity in a patient?
Definition
1. change in thought process
2. perioral paresthesia
3. whole body flushing feeling
4. tinnitus
5. generalized seizures
Term
what is the first clinical sign of neurotoxicity with local anesthetics?
Definition
start with a change in thought processes

culminates in generalized seizures
Term
what are the 2 phases of neurotoxicity with local anesthetics?
Definition
excitation phase - numbness, tinnitus, nystagmus, dizziness, excitability, restlessness, tremor, convulsions

depression phase - coma, resp and cardiac arrest
Term
what is the first sign of local anesthetic neurotoxicity?
Definition
*logorrhea or total silence
Term
what is logorrhea?
Definition
excessive talkativeness, especially when the words are uncontrolled or incoherent
Term
what is the OR rule of local anesthesia?
Definition
*keep the patient talking while the anesthetic is administered
Term
what happens in cardiotoxicity of local anesthetics?
Definition
1. peripheral vasodilation --> hypotension
2. inhibition of Ca channels --> decreased myocardial contractility
3. increase in refractory period, firing threshold, and conduction time lead to: bradycardia with long PR interval, wide QRS complex, increased QT, dysrhythmias (blocks, re-entry, ventricular ectopics)
Term
what are the heme side effects of local anesthetics?
Definition
*methemoglobinemia
Term
what local anesthetics can have methemoglobinemia as a side effect?
Definition
prilocaine
lidocaine
benzocaine
Term
how do local anesthetics lead to methemoglobinemia?
Definition
prilocaine is metabolized to O-toluidine in the liver --> this metabolite is a potent oxidizer of Hb to metHB
Term
symptoms of methemoglobinemia?
Definition
*1. cyanosis
2. cutanous discoloration - gray
3. tachypnea
4. dyspnea
5. exercise intolerance
6. fatigue
7. dizziness and syncope
8. weakness
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