8/30 Local Anesthetics - Kiss Flashcards
local anesthetic
definition
drug that reversibly blocks impulse conduction along nerve axons and other excitable membranes that utilize voltage-gated Na channels as primary means of AP generation
binding to other receptors (Ca, K, adenylate cyclase, NMDA) is potentially important but currently poorly understood
characteristics of the “perfect local anesthetic”
- non-irritating
- transient effect
- low systemic toxicity
- quick onset
- action able to span duration of surgery
structure-activity relationship
1. aromatic ring : lipophilic group
2. intermediate chain : ester vs amide
- account for diffs in metabolism and allergenicity
3. ionizable group (usually tertiary amine)
local anesthetics are…weak acids/weak bases?
which one
implications
weak BASES (pKa usually 7.6-9)
- the more acidic the pH, the more base in BH+ form
- the more basic the pH, the more base in B (neutral) form
only neutral can diffuse to site of action BUT the charged form is the active form
mechanism of action of local
-
block Na channels in excitable membranes without changing resting potential
- reduce aggregate inward sodium current
modulated receptor hypothesis
LAs have higher affinity for receptors in activated and inactivated states (versus resting state)
- binding is a function of the conformation state of the channel
implication: fibers that fire at raster rate → more susceptible to effects of LAs - repeated depol leads to more effective anesthetic binding
- aka “Frequency Dependent Block”
key properties of LAs
- lipophilicity : more lipophilic → more potent, longer duration of action (and slower onset of action)
- pKa : higher pKa → slower onset of action
-
protein binding : more protein binding → longer duration of action
* high potency, hydrophobic drugs tend to be highly bound to serum and tissue proteins → longer duration of action
clinical uses of LAs
- topical use (benzocaine, cocaine)
- infiltration
- regional anesthesia/analgesia
- peripheral blocks
- plexus anesthesia (single injection or continuous infusion)
- individ nerve blocks
- IV regional (Bier block)
- neuraxial blocks
- spinal (low vol, usually single injection)
- epidural/caudal (high vol - single injection or continuous infusion)
differential blockade
different nerve fiber types (A, B, C) vary in their sensitivity to LAs
- likely results of combination of geographic arrangement of nerve fibers and intrinsic sensitivity of nerve fiber types
in vivo studies are more clinically relevant and consistent than in vitro studies
in clinical practice, incremental increases in local anesthetic conc result in progressive interuption of
- autonomic pain fibers [most sensitive]
- sensory fibers
- motor fibers [least sensitive]
neuraxial blockade
vs
peripheral blockade
why?
neuraxial blockade order:
- autonomic/pain
- sensory
- motor
peripheral blockade
- motor block
- proximal sensory loss
- distal sensory loss
why? peripheral motor fibers are more peripheral, while sensory are more central; proximal sensory fibers are further outside, distal sensory fibers are further inside
PK of local anesthetics
absorption
role of vasoconstrictors
absorption, distribution, elimination varies from classical paradigm
absorption
- site-dependent
- ICE-BS : intercostal, caudal, epidural, brachial plexus, sciatic nerve blocks
role of vasoconstrictors: epi, phenylephrine
- decreases absorption (irrespective of site of inj) → can prolong effect of shorter acting drugs
- also used as a test dose to make sure you’re not accidentally injecting intravascularly! (if you are, HR will rise within 2 min)
PK of local anesthetics
elimination
esters: plasma pseudocholinesterase → derivatives: PABA
- pl pseudocholinesterase enzyme def may lead to protentiation of action
- usually have a short duration of action
amides: liver, cytochrome P450, water soluble metabolites, urinary excretion
- low flow states to liver (via portal HTN, CHF, etc) decreases delivery of LAs to liver → decreased amide LA metabolism, increased lifetime and serum conc
adverse effects of LAs
- system toxicity
- local (neural tissue) toxicity
- allergic rxns
- methemoglobin formation
system toxicity
results from effects of LA on excitable membranes and tissues (other than target nerves)
- range of effects proportional to serum LA concentration
manifests first as CNS tox → cardio tox
- CNS tox : tinnitus, preioral numbness, blurred vision, metallic taste, change in mental status, convulsions
- cardiotox : mostly with bupivicaine (ropivacaine less tox, more safe)
- depression of excitability + doncution (ventricular + prolonged QRS) as well as arteriolar dilation (Ca channel effect)
- systemic acidosis or hypercarbia, incre sensitivity to LA tox
- pregnancy : incr sensitivity to LA tox
- rescue via IV lipid emulsion
local toxicity
neural tissue injury
- high concentrations of LA for extended periods can lead to nerve tissue destruction via membrane damage, cytoskel disruption, etc
- NOT due to blockade of Na channel
- leads to motor and sensory loss
- can lead to paralysis, paresis
