Local Anesthetics and Ion Channel Drugs Flashcards
cocaine
- first local anastetic
- also has central effects on dopamine and norepinephrine
desirable characteristics of local anastetics
- Anestitize tissue loaclly
- Should not be irritating or produce permanent damage to tissue (a lot of things can anesthetize tissue but will -> damage)
- Should not be addicting
- Systemic toxicity should be low (reversible)
- Onset should be rapid and duration of action should be sufficiently long to perform diagnostic or surgical procedures (duration of action usually fairly short but is long enough for diagnostics)
can modulate duration of action of local anesthetic by
modulating blood flow to area
3 general characteristics of local anesthetics
- Amine group
- Aromatic Grou
- Ester or amide linkage
amine group
confers hydrophilic properties, effects LA use
aromatic group
confers hydrophobic properties
ester or amide linkage
- determines route of metabolic degradation (how broken down and released form body)
- determines potential allergic rxns
active form local anesthetic
add proton to nitrogen of amine which makes local anesthetic into its charged form, has to get into the cell in uncharged form
choloneserases
- cleave bond between C-O in ester (the single bond NOT the double bond)
- made in liver
ester or amide LA better in animal with liver problems
better to use ester than amide bc ester proken down by cholinesterase which is made in liver while amides are broken down in the liver; there is usually enough cholinesterase in serum to break down ester even in cases of liver problems
esters break down
- hydrolyzed in plasma by serum cholinesterases (made in liver)
- also can be degraded in the liver
- more likely to cause allergic rxn (low probability that it will happen but it can happen)
- use this over amide in liver problem patient
amides breakdown
- degraded in liver
- essentially free of allergic rxns
esters examples
- cocaine
- procaine (novocaine)
- tetracaine (pontocaine)
- benzocaine (anesthesia)
amide examples
- lidocaine (xilocaine)
- mepivicane (Carbocaine-V)
- bupivacaine (marcaine)
Absorption of local anesthetic depends upon
- site of injection
- degree of vasoconstiction
- presence of vasoconstrictor in solution (ex epinephrine)
- dose
what do local anesthetics generally block
block Na+ channels in sensory afferents can also block Na+ channels in vasculature
degree of vasodilation caused by agent itself
bc block Na+ channels in vasculature
effect of vasoconstrictor on absorption
- keeps LA local and decreases chance of systemic toxicity
- LAs can spread from injection site rapidly bc they cause vasodilation so generally LA combined with vasoconstrictor when put in tissue to keep it locally
- don’t do this in extremities bc dnt want vasoconstriction here
- LAs can be broken down fairly quickly
what are important in assessing the toxicity of local anesthetics
- rate of metabolism
- metabolic biproducts
effect on toxicity fo LA when vasoconstrictor injected with it
slowing absorption via vasoconstrictor allows degradation to keep up with absorption decreasing toxicity
esters mainly degraded by
serum cholinesterase
amides miany degraded by
liver
toxicity and other sites of action of local anesthetics
- tend not to be very toxic
- can interact with nicotinic acetylcholine receptors (which is not important clinically)
synaptic transmission and local anesthetics
- neuromuscular and ganglionic
- local anesthetics can inhibit acetylcholine receptor at non-competitive site
cardiovascular system and local anesthetics
- LAs relax vascular smooth muscle (except cocaine through autonomic mechanisms)
- LAs (mainly lidocaine and procainamide) can be used as anti-arrhythmic agents bc of use dependency; work better as tissue fires more rapidly so in heart with arrhythmia -> rapid firing in pt of heart LA can slow this down these= class 1 anti-arhthymias
- can cause vasodilation
- OD can -> cardiovascular collapse
Central Nervous System and local anesthetics
- fairly mild effects in CNS except Coke
- therapeutic dose produces no CNS effect
- OD can cause excitatory effects resulting in convulsions and respiratory depression
- Toxicity can be treated with general anesthetics or diazepam
why can OD -> convulsions and respiratory depression
- anesthetics blocking neurotransmission can -> convulsions bc in brain have balance between excitation and inhibition so here LA block GABA circuits preferentially if we have OD -> convulsions treat with diazepam or other drug affecting GABA receptors
Allergic reactions and local anesthetics
- allergic rxns
- asthmatic or anaphylactic rxns
- more likely with esters than amides
Mechanism of action for local anesthetics
- major effect on axonal conduction of action potential
- local anesthetics block Na+ components of action potential; Na+ channels blocked from cytoplasmic side of membrane
- Blockade by LA is use-dependent
Describe mechanism of action for LA
Tissue outside of axon membrane more acidic than Pka which drives hydrogen onto nitrogen so there are predominantly positively changed LAs outside axon membrane; LA has to get inside axon membrane uncharged then become positievely charged once in there to bind with Na+ channel and block it
LA and inflamed tissue
- if tissue is inflamed the PH drops -> effect of how much uncharged form is there (less uncharged form because more hydrogen driven onto LA outside axon membrane -> less able to get into axon membrane)
- this means decreased efficacy of LA can try to combat this using LA with low PKA which would be mepivicane
High inflammation means
low PH means lower efficacy of LA because low PH and more LA+ outside membrane so less LA that can cross membrane and get into tissue
why does LA block sensation but not lead to paralysis
because LA preferentially effects sensory fibers not motor fibers because of its differential effects on nerve fibers
use dependent
- faster action potentials firing the better the drug works (higher frequency of sodium channel opening increases the inhibition)
LAs typically depress
- small
- myelinated
- higher firing rate fibers (bc use dependency)
- fibers on exertion of nerve bundle before those on interior (= mantel effect)
** Sensory fibers fit these criteria as opposed to motor fibers which is why LAs depress sensory fibers over motor fibers)
sensory fibers vs motor fibers
- sensory fibers fire at higher rate and are therefore more sensitive to use dependecy
- sensory fibers tend to be smaller and unmyelinated (the lack of myelination doesn’t matter they still get LA depression if 2 things are same size then myelinated fiber gets LA depression)
- sensory fibers on exterior of nerve bundle
why do LA depress myelinated nerve fibers more than unmyelinated nerve fibers if 2 nerves same size?
- myelinated axon has Schwann cells w/ Na+ channels at nodes ranvier and conduction signal = saltaotry -> speed up conduction as opposed to non-myelinated fiber where Na+ channels are spread out across surface; in myelinated fiber can block more bc can knock out localized Na+ at nodes easier
Characteristics of cocaine
- prototype drug
- vasoconstrictor; CNS stimulant; blocks reuptake norepinephrine and serotonin
cocaine duration of action
medium
procaine
- procaine itself discontinued but procinamide = a derivative= still used as antiarhytmic
- 1st synthetic LA
procaine use
- was used for tissue infiltration and IV regional anesthesia
- can be complexed with other drugs to prolong action and decrease pain of injection
procaine duration of action
- short
tetracaine
- more potent than cocaine or procaine
- can be used in ophthalmology for tissue infiltration
tetracaine duration of action
long
benzocaine
- stays uncharged so can be used as topical anesthetic
- may use to prevent pain of injection of other LA injection
lidocaine
- most commonly used LA for infiltration, nerve block, and epidural anesthesia
- antiarrhythmic agent
lidocaine duration of aciton
medium
mepivicane
- lowest PKA can be better in inflamed tissues than others though not by much
- used in lameness diagnosis in horse
- local tissue irritation less than lidocaine in horse
mepivicane duration of action
medium
bupivicane
- more potent than lidocaine
- used for epidural nerve blocks
bupivcane duration of action
long
