Lec 17 Local Anesthetics Flashcards
What is clinical use for local anesthetics?
- produce analgesia in restricted region by inhibiting neurons that transmit nociception
- blockade not specific to nociceptors so get general loss of sensation
- ideally do not alter brain activity [unlike general anesthetics]
What is the general structure of local anesthetics?
aromatic group + linker + amino group
–> either ester or amide
What are routes of administration of local anesthetics?
- topical [surface]
- injection near a nerve
- regional block [iv injection into extremity, tourniquet to reduce systemic distribution
What is primary mech of action of local anesthetics ?
- block voltage-gated sodium channels
- bind site formed by 3 of the S6 helices that line pore
- little selectivity for subtypes of Na channel [contributes to adverse effects]
What is a field block?
- injection of local anesthetic near nerve
- anesthetizes region distal to injection
what is a local infiltration?
injection of local anesthetic at site to be excised
What is a nerve block?
injection near a peripheral nerve or nerve plexus
How is potency of local anesthesia correlated with lipid solubility? molecular size?
small molecular size + more lipid soluble = more potent
As a general rule are C nerve fibers carrying pain and temp or larger A fibers more easily blocked?
- smaller fibers blocked first
What are the 3 important structural features of local anesthetics?
- aromatic group [lipophilic]
- linker [either amide or ester]
- amino group [hydrophilic, ionizable]
How do you tell if a local anesthetic is an amide or an ester based on its name?
- all amIdes have an I before the “caine”
What form of local anesthetic can traverse cell membrane? what form has higher affinity for binding site in Na channel?
- nonionized form traverses cell membrane
- ionized form has higher affinity for binding site in Na channel
What is pKA of most weak bases?
7-9
What is pka?
pH at which half of drug is in ionized and half in nonionized
What is henderson hasselbach?
log (protonated)/(unprotonated) = pKa - pH
“protonated = more, goes on top”
Which one local anesthetic can only be found in ionized form?
benzocaine
How does reduced pH affect ability of local anesthetic to function? in what scenarios do you see this?
when low pH –> more of drug is in protonated form –> less avaible that can diffuse into nerve cell
- reduces effect of a given dose
- seen in inflamed tissues, infection
What are the two major routes by which local anesthetic accesses channel?
major: via intracelluar, drug in cytoplasm enters and blocks open channel
minor: membrane delimited, drug diffused from within lipid bilayer to channel pore
How does carbonation of local anesthetic solution affect its action?
- decreases intracellular pH –> increases prevalence of cationic active form inside the nerve = increase activity
What is use-dependent inhibition?
in order for local anesthetic to block channel via major cytoplasmic route, requires channel to be open
means that really active neurons [like those sensing pain] will be blocked faster
What is use-independent inhibition?
access to channel from lipid bilayer does not require it to be open
with long enough exposure to drug, even relatively inactive neurons become inhibited this way
Do fibers on inside or outside of nerve get blocked by local anasthetics first?
fibers on outside –> easier to get to
outside usually proximal, inside = distal, so proximal blocked before distal
How does hydrophobicity of the local anesthetic base corelated with potency?
- highly hydrophobic base accumulates in lipid bilayer –> create reservoir of drug molec that can be pronated at cyto surface to block open channel
- because more potent, lower concentration used so tend to block more slowly [ b/c lower conc gradient]
Which fiber types are most sensitive to local anesthetics?
most sensitive = C type fibers
- sensory = pain
- motor = sympathetic [a receptors, vasoconstrictors]
A-d also pretty sensitive = pain
large fibers relatively spared but will always have some effect
Why are smaller fibers more susceptible?
- AP decays if Na channels block
- smaller neuron = shorter space constant = more rapid decay
- same region of block will cause thin fibers to fail first [and not large fiber]
given constant region of block and equal diameter, are myelinated or unmyelinated fibers more susceptible?
myelinated are more susceptible
Are most local anastheticcs vasoconstrictors or vasodilators? 2 exceptions?
most are vasodilators [inhibit sympathetic fibers to vasculature]
2 exceptions: cocaine, prilocaine
Why do you often give a vasoconstrictor with local anasthetic? which one usually?
usually epinephrine
- administer b/c anesthetics are vasodilators, increase blood flow/permeability which causes drug to distribute away from the target tissue.
- giving vasoconstrictor increases duration of effect and reduces systemic adverse effects
Why shouldn’t you coadminister epinephrin for nerve block in fingers/toes?
- supplied by end-arteries
- may cause ischemia or necrosis
How are ester-type local anesthetics metabolized? effect of this?
- enter blood stream
- metabolized by plasma esterases to PABA or derivative
Are esters or amides more likely to have local rxn?
esters can get local allergic rxn because metabolized locally to PABA that triggers hypersensitivity
Are esters or amides more likely to have systemic effects?
- amides
- because local anesthetic effect terminated by systemic distrubution-
How are amide-type local anesthetics metabolized?
- by the liver, in part by cyt P450 enzymes
- excreted in metabolized + unchanged form by kidney
In what situations is rate of amide anesthetic metabolism decreased?
- patients with liver disease
- ## co-administration of drugs that interfere with cyt P450 enzymes
What are CNS side effects of local anesthetics?
- at low levels –> sedation
- at high levels –> seizure, loss of consciousness, may reflect blockade of inhibitory neurons
with increased dose: drowsiness –> sensory disturbance –> dizziness –> twitching –> seizures –> coma
What are cardiac effects of local anesthetics?
- generally occur at higher dose than CNS symptoms
- conduction cells most sensitive –> arrhythmia, AV block, ventricular arrest
- mediated by block of cardiac Na channels, or at very high dose can be due to direct inhibition Ca channels
- bradycardia, hypotension
cocaine
- ester or amide?
- What is onsent/duration/metabolism?
- clinical use?
- mech?
- side effects?
- ester
- onset/duration/metabolism: hepatic metabolism if systemically distributed
- use: topical use on mucous membranes
- mech: induces vasoconstriction, inhibits MO re-uptake [including NE]
- ## effects: euphoria, CNS stim, tachycardia, restlessness, tremors, seizures
procaine
- ester or amide
- onset/ duration/ met /potency/ etc
- clinical use
- ester
- onset/duration/met: rapidly hydrolyzed [short duration], low potency, slow onset, not effective topically
- use: infiltration anesthesia
tetracaine
- ester or amide
- onset/ duration
- clinical use
- ester
- onset etc: very slow onset, long acting
- use: spinal block, topical
benzocaine
- ester or amide
- properties
- ester
unique struct –> lacks ionizable group, poor aqueous solubility
use: surface anesthesia
what is longest acting –> shortest acting between procaine, tetracaine, cocaine
tetracaine > cocaine > procaine
What is prototypical amide?
lidocaine, most commonly used local anesthetic
lidocaine
- ester or amide
- onset
- duration
- clinical use
- amide
- rapid onset
- intermediate duration 1-2 hrs
- use: systemically to treat cardiac arrhythmias
What does it mean that lidocaine metabolism is flow-limited?
- clearance is sensitive to changes in hepatic blood flow
- extra caution in pts with liver disease
prilocaine
- ester or amide
- onset
- duration
- clinical use
- ester
- weak vasodilator so generally don’t need Epinephrine
- rapid systemic elimination [hepatic + renal]
- large Vd
- use: spinal anesthesia
What is an adverse affect seen with prilocaine use?
methemoglobinemia from its toluidine metabolites
- Fe3 [ferric] heme rather than normal Fe2 [ferrous]
Where do drugs with large Vd end up?
in lipid/fat cells
bupivacaine
- ester or amide
- onset
- duration
- clinical use
- side effects
- amide
- slow onset, long duration
- use: blocks sensory over motor, use in labor
- sustained-release liposomal formulation [24 hr] for post op pain management
- cardiotoxicity [arrhythmia
Which amide local anesthetic has greatest cardiotoxicity? why?
bupivacaine
- serious ventricular arrhythmias, myocardial depression
What is ropivacaine?
- R- enantiomer of bupivicaine
- less cardiotoxic
What measures to minimize likelihood of systemic effects of lidocaine or other local anesthetic?
- give NE or other vasoconstrictor
Would pt with local anesthetic induced CNS symptoms also experience direct cardio effects?
- maybe –> CNS effects come first, need higher dose to get cardio effect than CNS effect
What chemical characteristic of lidocaine increases likelihood of systemic effects?
- its an amide so metabolized in the liver rather than locally in the plasma so it has to go through systemic circulation first
would drug named mepivacaine likely share same chemical characteristics as lidocaine?
yes, i before the “caine” means its an amide just like lidocaine
