L8 Local Anesthetics Flashcards
For ion channels: inactivation vs deactivation
ion flow blocked by a gating mechanism vs closing of the channel
What is the MOA of LA?
Stop axonal conduction by blocking sodium channels in axonal membrane
- when applied locally in appropriate concentration
- prevent sodium ion entry
- slow down or bring conduction to a halt
Many LAs bind most strongly to the
inactivated and activated states
Passage of train of action potentials causes the sodium channel to
cycle through open and inactivated states
depth of LA nerve block increases with action potential frequency because LA molecules
- gain access to the channel more easily when channel is open
- have higher affinity for the inactivated than for the resting (closed) channels
Depth of LA nerve block increases with action potential frequency because LA molecules
- gain access to the channel more easily when channel is open
- have higher affinity for the inactivated than for the resting (closed) channels
Are LAs selective/non-selective modifiers of neuronal function?
non-selective ie. they will block action potentials in all neurons to which they have access
How to achieve selectivity for LAs?
by delivering LA to a limited area: topical dosage form or superficial injection
Factors affecting LA action (3)
lipid solubility, nerve types (size, frequency, position, myelination), pH dependency
Are more/less lipid soluble drugs more potent and act longer?
More
Examples of more hydrophobic LA
Tetracaine, etidocaine, bupivacaine
Examples of less hydrophobic LA
Lidocaine, procaine, mepivacaine
Does more potent or longer of duration equate to better efficacy?
Depending on applications!
Is size or myelination a more important factor affecting LA action?
size
- small myelinated axons > small non-myelinated axons > large myelinated axons
- nociceptive and sympathetic transmission is blocked first
LA molecules are
weak bases (pKa 8-9) - mainly (but not completely) ionized at physiological pH
LA binding site
inner end of the sodium channel
- must penetrate nerve sheath and axon membrane to reach
Does LA work better in acidic or alkaline pH?
Alkaline, low proportion of ionized molecules, increased LA activity
Examples of LA in the esters class
cocaine, procaine, pontocaine, benzocaine
short acting ester LA
procaine (Novocain)
long acting ester LA
pontocaine
Examples of LA in the amides class
lidocaine, mepivacaine, bupivacaine
long acting amide LA
bupivacaine (Marcaine)
medium acting amide LA
lidocaine, mepivacaine
Does ester- or amide-type LA have a lower incidence of allergic reactions?
Amide-type
Difference between method of metabolism of ester- vs amide-type LA
plasma/tissue non-specific esterases vs hepatic enzymes
Which type of LA can patients with chronic liver disease not use?
Amide-type, metabolised by hepatic enzymes
What is a toxicity arsing from large dose of LA?
Systemic toxicity
How can we minimise LA systemic toxicity?
Combine LA with epinephrine (vasoconstrictor, blood flow at area of application reduced, hence reduced rate of absorption into systemic circulation)
- prevent LA systemic distribution from the site of action
Most cardiotoxic LA
bupivacaine - use with caution in patients with heart disease
Cocaine toxicity
Blocks NA reuptake, increased NA in synapse and cause vasoconstriction + hypertension
What is the metabolite of prilocaine and what toxicity does it induce?
O-toluidine: causes methaemoglobin
How can we treat O-toluidine toxicity?
iv methyleneblue/ascorbic acid to convert methaemoglobin back to Hb
What are ester LAs hydrolysed into?
PABA derivatives
What kind of toxicity can PABA derivatives cause?
allergic rections in a small percentage of population
Which LA is most often used for ear, nose and throat procedures?
Cocaine: gives good penetration and vasoconstriction
- surface anaesthesia requires rapid penetration of the skin (mucosa) and limited tendency to diffuse away
Surface anaesthetics
lidocaine, tetracaine (amethocaine), dibucaine, benzocaine
