Local Anesthetics Flashcards
What are local anesthetics?
- 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
How many nodes of ranvier in a myelinated axon does a local anesthetic need to inhibit to block impulses?
3 successive nodes
fasciculi
- bundles of axons
- covered with three layers of connective tissue
- LAs must diffuse through these to exert their effects
endoneurium
- 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
perineurium
- consists of layers of flattened cells that binds groups of fascicles together
- covers nerve root
epineurium
- surrounds the perineurium and is composed of connective tissue that holds fascicles together to form a peripheral nerve
- surrounds nerve bundle
RMP of axon
-70 to -90 mV
LA MOA
- 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
LA specific binding sites
- preferential binding to OPEN and INACTIVE Na+ channel states
- also blocks K+ channels, Ca2+ channels, and GPCRs to a lesser extent
frequency dependent blockade
- 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
differential blockade
- 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
type A alpha
- function is proprioception, motor
- diameter is 6-22 um
- heavy myelination
- last/longest to block onset
type A beta
- function is touch, pressure
- diameter is 6-22 um
- heavy myelination
- block onset intermediate
type A gamma
- function is muscle tone
- diameter is 3-6 um
- heavy myelination
- block onset intermediate
type A delta
- function is pain, cold temperature, touch
- diameter 1-5 um
- heavy myelination
- block onset intermediate
type B
- function preganglionic autonomic vasomotor
- diameter < 3um
- light myelination
- block onset early
type C sympathetic
- function is postganglionic vasomotor
- diameter 0.3-1.3 um
- no myelination
- block onset early
type C dorsal root
- function pain, warm and cold temperature, touch
- diameter 0.4-1.2 um
- no myelination
- block onset early
three characteristic segments of LAs
- 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
ester local anesthetics
- procaine
- chloroprocaine
- tetracaine
- cocaine
- benzocaine
amide local anesthetics
- lidocaine
- mepivacaine
- prilocaine
- bupivacaine
- ropivacaine
- articaine
why is the ester or amide linkage important
- 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
differences between ester and amide LAs
- 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
minimum effective concentration (Cm)
- 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
PK/PD of LA
- 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
Potency of LA
strong relationship between potency and lipid solubility; larger lipid-soluble LA are water insoluble and highly protein bound
what does lipid solubility of LA correlate with?
- protein binding
- increased potency
- longer DOA
- tendency for severe cardiac toxicity
- amides usually more lipid soluble/protein bound than esters
LA DOA
- 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
LA onset of action
- 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
Tetracaine pKa
8.5
Tetracaine % ionized at pH 7.4
93%
tetracaine % protein bound
94%
tetracaine onset
slow
tetracaine DOA
180-600 min
lidocaine pKa
7.9
lidocaine % ionized at pH 7.4
76%
lidocaine % protein bound
64%; more available free drug so shorter DOA
lidocaine onset
fast
lidocaine DOA
90-120 min
bupivacaine pKa
8.1
bupivacaine % ionized at pH 7.4
83%
bupivacaine % protein bound
95%; less free drug available; longer DOA
bupivacaine onset
slow
bupivacaine DOA
180-600 min
LAs vasomotor action
- LA cause relaxation of smooth muscle (lidocaine, ropivacaine, and cocaine are the exceptions)
- relaxation –> vasodilation that decreases DOA, increases plasma concentration, potential toxicity
LA absorption
- speed of absorption has toxicity implications
- total dose of LA determines plasma level, not volume or concentration
LA route of administration highest to lowest blood concentration
- IV
- tracheal
- caudal
- paracervical
- epidural
- brachial
- sciatic
- subcutaneous
common additives in LA
- epinephrine
- sodium bicarbonate
- clonidine
- dexmedetomidine
- opioids
- ketorolac
- dexamethasone
- hyaluronidase
epinephrine in LAs
- vasoconstrictor that reduces rate of vascular absorption of LAs
- leads to increased duration/potency of block
- decreases risk of systemic toxicity
- does not have equal effects for all LAs
- lidocaine, mepivacaine, and procaine (greater effect with local infiltration, peripheral block, and epidural)
- prilocaine and bupivacaine (lesser effect; prolonged with peripheral nerve block but not epidural)
sodium bicarbonate in LAs
- common in epidural anesthesia
- adding bicarb raises pH of LA solution resulting in more drug in nonionized state
- may result in less pain on injection
- major limitation = precipitation
LA distribution
- absorption or injection of LA into systemic circulation –> rapid redistribution
- distribution of esters and amides are similar
- decrease in plasma concentration to highly perfused tissue (brain, heart, lungs receive most initially; can be a concern due to toxicity)
- secondary distribution to rest of body - muscle receives most
ester LA metabolism
- plasma esterases catalyze their hydrolysis
- procaine and chloroprocaine have plasma half life less than 1 min
- atypical plasma cholinesterase can increase risk of toxicity
amide LA metabolism
- metabolism of amide LA occurs in liver via CYP450 enzyme
- severe hepatic disease can prolong metabolism
LA excretion
- renal dysfunction affects clearance far less than hepatic failure
- hepatic failure – affect protein binding to both AAG and albumin
Pregnancy LA considerations
- mechanical changes in pregnancy - reduction in epidural space; you could cause compression of the space if you give to much and then cause movement of LA up and down epidural space
- hormonal changes - progesterone levels may affect sensitivity to LA
LAST
- local anesthetic systemic toxicity
- serious but rare event during regional anesthesia
- most commonly occurs with inadvertent IV injection
- shorter acting drugs thought to be less cardiotoxic (esters, bc metabolized much quicker)
MOA of LAST
- IV injection of LA
- initial blocking of inhibitory neurons thought to cause seizures
- blocking of cardiac ion channels results in bradycardia
- ventricular fibrillation = most serious complication
LAST clinical presentation
- rapid onset usually within a minute
- FIRST - agitation, tinnitus, circumoral numbness, blurred vision, metallic taste
- THEN - muscle twitching, unconsciousness, seizures
- VERY high levels - cardiac and respiratory arrest
LAST incidence
0.4 per 10,000 cases
LAST most common in
- epidural
- axillary
- interscalene
prevention strategies for LAST
- test dose
- incremental injection with aspiration
- use of pharmacologic markers
- ultrasound
LAST treatment
- prompt recognition and diagnosis!!
- airway management = priority
- seizure suppression - benzos, succs
- prevent hypoxia and acidosis
- lipid emulsion therapy
- vasopressors - EPI; NO vasopressin
- ACLS/cardiopulmonary bypass/ECMO if severe
LAST lipid emulsion therapy MOA
- capture LA in blood - lipid sink
- increase fatty acid uptake by mitochondria
- interference of Na+ channel binding
- promotion of calcium entry
- accelerated shunting
lidocaine max doses
- 4 mg/kg
- 7 mg/kg with epi
mepivacaine max doses
- 4 mg/kg
- 7mg/kg with epi
bupivacaine max dose
-3 mg/kg
ropivacaine max dose
-3 mg/kg
tetracaine max dose
-3 mg/kg
LA SE/considerations
- allergic reactions
- methemoglobinemia
- cauda equina syndrome (CES)
- transient neurologic syndrome (TNS)
LA allergic reactions
- more common in ester LA
- esters metabolized to derivatives of para aminobenzoic acid (PABA)
- cross reactivity to other esters but not amides
- amide related allergies more commonly associate with preservatives
methemoglobinemia
- high concentration of methemoglobin in the blood
- ferris form of hemoglobin (Fe2+) converted to ferric hemoglobin (Fe3+)
- presents as decreasing oxygen saturation not responsive to therapy
- benzocaine-induced methemoglobinemia (rise in cases since 2006; many involve infants less than 2 yo)
- prilocaine can cause also because metabolite is o-toluidine; dose should not exceed 2.5 mg/kg; avoid in children, pregnant women, pt taking oxidizing drugs
- treatment methylene blue 1-2 mg/kg over 3-10 min
- high level of methemoglobinemia may require transfusion or dialysis
cauda equina syndrome (CES)
- manifests as bowel and bladder dysfunction with lower extremity weakness and sensory impairment related to cord ischemia
- risk factors - supernormal doses of LA
- maldistribution of LA within intrathecal space
transient neurologic symptoms (TNS)
- associated with intrathecal lidocaine
- presentation - burning, aching, cramp like pain in low back and radiating down thighs for up to 5 days post-op
- risk factors - lithotomy and outpatient surgery
Lidocaine facts
- discovered in 1943 by Nils Löfgren in Sweden
- on WHO list of essential meds
- weak base
Lidocaine PK/PD
- pKa slightly above physiologic pH (7.9)
- protein binding 70-90%
- DOA 90-120 min
- max dose 4 mg/kg or 7 mg/kg with epi
what lidocaine concentration would you use for labor epidural test dose?
lidocaine 1.5% with epi 1:200,000
clinical uses for lidocaine
- antiarrhythmic
- topical
- induction (blunt SNS)
- nebulized
- multimodal pain management
- regional anesthesia
ACLS algorithm and lidocaine
- depresses myocardial automaticity
- class 1B anitarrhythmic
ACLS VT/VF lidocaine dose
1-1.5 mg/kg IV or IO
0.5-0.75 mg/kg (refractory)
3 mg/kg (total)
maintenance infusion 1-4 mg/min (30-50 mcg/kg/min)
Topical lidocaine
- EMLA = eutetic mixture of local anesthetics; 1:1 lidocaine prilocaine mixture
- contraindications - mucous membranes, broken skin, infants <1 month, history of methemoglobinemia
lidocaine for induction
- 1-1.5 mg/kg, 1-3 min prior to laryngoscopy
- to decrease pain of propofol
- attenuate CV response to intubation
- attenuate increase in ICP in patients with decreased compliance
- study shows 2 mg/kg completely attenuates cough given 1-5 min prior to intubation
pain of propofol and lidocaine
- pain = phenol
- 1 mL of 2% lidocaine reduced pain on injection from 70% to 30%
- most significant interventions to reduce pain –> AC vein, veno occlusion, small dose of opioids
- 20 mg lidocaine in 10 mL with venous occlusion for 60 seconds
topical lidocaine
-decreasing emergence phenomenon - coughing, sore throat, dysphonia
LTA
- laryngotracheal topical anesthesia
- administered at induction has little effect o prevention of coughing during extubation; best to admin closer to the time of extubation; admin 30 prior to extubation = significant decrease
best way to prevent emergence phenomenon
- ETT alkalized lidocaine, shown to prevent EP more than any other technique
- approximately 60 min required to achieve desired effect
- adding bicarb increases non-ionized fraction of drug
- low dose alkalized lidocaine (40 mg) shown more effective
ETT alkalized lidocaine technique
- should use a manometer each time they fill the ETT
- achieve correct pressure using air first
- remove and record amount of air required
- add 2 mL lidocaine
- add 1-2 mL of bicarb
- add saline to match cuff volume
- need at least 60 min for lidocaine to diffuse/leak out of cuff
airway block
- nebulized lidocaine
- 4% lidocaine applied directly to oropharynx
transtracheal block
-4% lidocaine injected through the cricothyroid membrane
lidocaine in multimodal pain management
- often part of ERAS protocols
- used to supplement general anesthesia
- 1.5 mg/kg bolus dose
- 2 mg/kg/hr infusion
- goal = give a lot less narcotic
lidocaine inufsion
- MOA of IV lidocaine relatively unknown - may involve sodium channels, block priming of polymorphonuclear granulocytes
- not beneficial for all surgeries
- shown to reduce post-op pain and speed up return of bowel function in open and laparoscopic procedures
- decreases pain and improves functional outcomes in prostatectomy, thoracic, and spine cases
- accumulation = concern, but ERAS usually way under toxicity
- monitor patients at risk
bier block
- IV regional anesthesia
- short procedures
- 25-50 mL of 0.5% lidocaine
- onset time 5-10 min
- tourniquet pain at 20 min
lidocaine plasma concentration 1-5 mcg/mL
analgesia
lidocaine plasma concentration 5-10 mcg/mL
- circumoral numbness
- tinnitis
- skeletal muscle twitching
- systemic hypotension
- myocardial depression
lidocaine plasma concentration 10-15 mcg/mL
- seizure
- unconsciousness
lidocaine plasma concentration 15-25 mcg/mL
- apnea
- coma
lidocaine plasma concentration >25 mcg/mL
cardiovascular collapse
Exparel
- new generation LA
- injected directly into surgical site
- shown to provide reduced opioid requirements for up to 72 hours (up to 28% reduction in opioids)
- bupivacaine + liposomal agent DepoFoam
- multivesicular liposomes composed of honeycomb-like structure of numerous aqueous chambers
- lipid membrane separate each chamber
- each chamber encapsulates bupivacaine
- dose based on surgical site and volume required to cover area
- part of multimodal treatment regimen to provide non-opioid pain control
liposomal LAs administration
- single-dose infiltration only
- admin with a 25G or larger bore needle
- not to exceed 266 mg (20mL 1.3% of undiluted drug)
- inject slowly via infiltration into surgical site with frequent aspiration to minimize the risk of IV injection
- do not administer product if discolored
liposomal LAs anesthetic considerations
- do not mix with non-bupivacaine LAs
- use cautiously in patients with hepatic disease
liposomal LAs contraindications
OB paracervical block
Exparel NOT used for
- patients < 18 years
- epidural or intrathecal anesthesia
- peripheral nerve block
liposomal LAs adverse effects
- > 10% N/V
- <10% dizziness, tachycardia, HA, somnolence, bradycardia, hypoesthesia, lethargy
