PHARM - Local Anesthesia Flashcards
briefly - how do local anesthesics relieve pain?
by reverisbly blocking nerve conduction
describe the structural components of local anesthetics (LA) & their importance
- lipophillic portion: directs the LA to the proper location
-
hydrophillic portion: blocks the Nav channels
- can be charged or uncharged
- hydrocarbon chain: joins lipophillic & hydrophillic components
what are the two variations of LA structures?
why is this relevant pharmacologically?
- esters: ester bond connects lipophillic part to hydrophobic chain
- amides: amide bond connects lipophillic part to hydrophobic chain
esters are degraded by circulating esterases, and thus have a shorter duration of action than amides. amides are more commonly used
which LAs are esters?
- procaine
- chloroprocaine
- tetracaine
- benzocaine
- cocaine
which LAs are amides?
- lidocaine
- mepivacaine
- bupivacaine
- ropivacaine
LA - MOA
-
LA are activated (open state) sodium channel blockers
- i.e, they only work on Na+ channels that are open, which - in a pain state - many are d/t noxious stimuli stimulating nerve terminals
- LA must be uncharged to enter channel (achieved by buffering)
- LA must be charged (once inside channel) to block Na+ entry
- Na+ blockage decreases rate of firing
- i.e, they only work on Na+ channels that are open, which - in a pain state - many are d/t noxious stimuli stimulating nerve terminals
the degree of blockage provided by LAs depends on…?
the frequency of nerve impulses (rate of firing)
high frequency = high blok
what happens when LAs become trapped in closed or inactivated channels?
the unblock from the anesthesia is slow
which physiochemical factors influence the onset of action of LAs?
- the pH of the environment (tissue) LA is injected
- the pH of the solution containing the LA
- the lipid solubility of the LA
- the protein content of the LA
how does tissue pH affect onset LA onset of action?
- lidocaine has a pkA of 7.4
- at physiological pH (7.8), it is mostly charged (cationic)
- after enough time, the body buffers lidocaine so that more molecules are neutral (non-ionized), & can thus enter Na channels.
- but this buffering capacity is affected by the pH of the surrounding tissue
- low pH [acidosis]
- lidocaine gets protonated (becoming charged)
- takes longer to buffer drug & produce neutral moleccules
- longer onset of action
- high pH [alkalosis]
- lidocaine gets deprotonated (becoming neutral)
- takes less time drug & produce neutral moleccules
- shorter onset of action
- low pH [acidosis]
how does acidosis affect LA onset of action?
what is an example of acidosis?
delays onset of action
infection / inflammation (releases H+)
how does alkalosis affect LA onset of action?
faster onset of action
lidocaine can be administered in which formulations?
why is this pharmacologically relevant
- 2% lidocaine solution - pH of 3.9
- 2% lidocaine + EPI solution - pH of 6.0
- soution + bicarbonate = higher pH
acidic LA solutions (that don’t have bicarb) contain drug in mostly in charged state, and will take longer to buffer = faster onset of action
more basic LA solutions (come with bicarb) contain drug mostly in a neutral state, and will take less time to buffer = faster onset of action
what are the disadvantages of low pH LAs?
- pain on injection (H+ stimulates ASIC channels)
- tissue injury (H+ is inflammatory)
- slow onset of analgesia (5-10 min)
- litte / no analgesia in low pH tissues (infections)
what are the advantages of buffered LAs (bicarbonate added)?
- reduced pain on injection
- reduced risk of tissue damage
- faster onset (1-2 minutes)
- the ability fo obtain analgesia in infected tissue
how does LA lipid solubility affect duration of action?
higher solubility = longer duration of action
which LA is the most lipophillic?
bupivacaine
how does the protein binding capacity of LAs affect the duration of action?
higher protein binding = longer duration of action
how does anesthesia spread anatomically?
why is this the case?
- anesthetizes proximal areas before distal areas
- b/c mantle (outer nerve) fibers are blocked before core (inner nerve) fibers
to which locations can LAs distribute?
- brain
- lungs
- fat
- placenta
LAs - metabolism
- amides - by liver microsomal enzymes
- esters - rapidly by plasma / liver esterases
esters metabolized faster, have a much shorter duration of action than amides
what is the role of epinephrine in EPI-containing LA formulations?
vasoconstricts the vasculature near the injection site, limiting flow to & from the site. this “traps” LA at the site, which
- prolongs its duration of action
- limits its systemic aborption & thus its systemic toxicity
what are the disadvantages of epinephrine in EPI-containg LA formulations?
- locally: ischemia d/t vasoconstriction, esp in areas with low collateral blood flow: digits, ears
- systemically: could increase BP, affect HR
how are the actions of LAs terminated?
by eventual removal from the injection site by the circulatory system
this is why vasoconsriction from EPI containing formulation prolong DUA
which LAs come in a formulation with EPI?
- both amides:
- bupivicaine: epi
- 1:200,000
- lidocaine: epi
- 1:200,000
- 1:100,000
- 1:50,000
- bupivicaine: epi
the 1 represents EPI, and the 2nd # represents the LA: the higher the second number, the less EPI the formulation contains
how much EPI is “necessary” to optimize LA duration of action?
- 1:200,000
- available in both lidocaine & buprivacaine formulations
- gets duration of action to ~ 90 min
- beyond this, adding more EPI just inc risk of systemic AEs
LAs can lead to what systemic AEs?
- CNS:
-
restlessness / tremors / seizures -> depression & coma
- this is b/c inhibitory interneurons are anesthetized first
-
TNS (transient neurological symptoms):
- pain
- dystheisa
-
restlessness / tremors / seizures -> depression & coma
- CV:
-
heart collapse d/t decreased
- contractie force
- conduction velocity
- excitability
-
vasculature
- vasodilation
- hypotension
-
heart collapse d/t decreased
- allergies
local anesthetics are C/I in a patient taking what other drugs?
methemoglobin causing drugs
- nitroglycerine
- phenytoin
which LA is the most likely to cause TNS?
lidocaine (is the most neurotoxic)
pain, dysthesia
which LA is most likely to cause CV collapse?
- how is this treated? why?
- which drug can be used as an alternative?
bupivacaine
- tx = ACLS + IV infusion of intralipid
- ACLS often insufficient to tx bupivacaine-induced CV arrest
- intralipid = a supplement that can bind & the highly lipophillic bupivacaine, negating its affects
- ropivicane can be used an an alternative
which LA is most likely to induce allergic reactions?
why?
the ester LAs: procaine, cholorproctain, benzocaine
this is because the are metaoblized to PABA, an allergen to certain patients
how most LAs affect the vasculature?
why is the exception?
vasodilate -> hypotension
exception is cocaine (which vasoconstricts)
list the uses of each amide LA
- all: local infusion, nerve blocks, epidural
- mepivacaine, bupivacaine, ropivacaine - spinal
- lidocaine - topical, IV
lidocaine
- is the only amide LA that can has what anesthetic use?
- cannot be used for? why?
- only amide used for topical or IV anesthesia
- no longer used for spinal anesthesia - b/c it is neurotoxic and poses a high risk for TNS
describe the onset and duration of each amide LA
- lidocaine: rapid osnet, intermediate duration
- mepivacaine: rapid onset, long duration
- bupivacaine: slow onset, long duration
- ropivacaine: slow onset, long duration
which amide can be effectively used as an alternative to bupivicaine?
when might this be useful?
- ropivacaine - has the same onset, duration and uses as bupivacaine
- can be used to avoid the _cardiotoxic affect_s of bupivacaine
what are the clinical uses for neuromuscular blocking drugs (NMBs)?
procedures that require muscle paralysis
the NMBs work primarily via which methods?
- two major MOAs
- non-depolarization agents: competitive antagonists of AChR at NMJ
- depolarization agents: agonists of AChR that work in two phases
- phase I: continous AChR stimulation = strong depolarization
- phase II: desentitization of AChRs to any more AChR -> no AP
succinylcholine
- what kind of drug
- clinical use
- MOA
- onset
- AEs
- drug: is an NMB
- clinical use: tracheal intubation
- MOA: depolarization agent (AChR agonist)
- onset: 1-2 minutes
- AE
- malignant HTN
- cardiac dysarthmia - cardiac / sinus arrest
- fasciculations
- kyperkalemia
rocuroniom
- what kind of drug
- clinical use
- MOA
- AEs
- drug: is an NMB
- clinical use: tracheal intubation
- MOA: non-depolarizating agent (AChR antagonist)
- onset: 1-2 minutes
- AEs: none significant
how are neuromuscular blocks by non-depolarizing NMBs reversed?
why?
- via AChE inhibitors - endophonium, neostigmine
- AChE inhibitors inc ACh concentrations, so ACh can outcompete the competitive AChR antagonists (i.e., rocuronium)
how are neuromuscular blocks by depolarizing NMBs reversed?
why?
by waiting for recovery in 5-10 minutes
AChE inhibitors wont work: increased ACh at the synapse wont work on desensitized receptors (i.e., succinylcholine)
