PHARM - Local Anesthesia

Question 1

briefly - how do local anesthesics relieve pain?

Answer 1

by reverisbly blocking nerve conduction

Question 2

describe the structural components of local anesthetics (LA) & their importance

Answer 2

• lipophillic portion: directs the LA to the proper location
• hydrophillic portion: blocks the Na_v channels
  
  • can be charged or uncharged
• hydrocarbon chain: joins lipophillic & hydrophillic components

Question 3

what are the two variations of LA structures?

why is this relevant pharmacologically?

Answer 3

• 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

Question 4

which LAs are esters?

Answer 4

• procaine
• chloroprocaine
• tetracaine
• benzocaine
• cocaine

Question 5

which LAs are amides?

Answer 5

• lidocaine
• mepivacaine
• bupivacaine
• ropivacaine

Question 6

LA - MOA

Answer 6

• 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

Question 7

the degree of blockage provided by LAs depends on…?

Answer 7

the frequency of nerve impulses (rate of firing)

high frequency = high blok

Question 8

what happens when LAs become trapped in closed or inactivated channels?

Answer 8

the unblock from the anesthesia is slow

Question 9

which physiochemical factors influence the onset of action of LAs?

Answer 9

• 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

Question 10

how does tissue pH affect onset LA onset of action?

Answer 10

• 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

Question 11

how does acidosis affect LA onset of action?

what is an example of acidosis?

Answer 11

delays onset of action

infection / inflammation (releases H+)

Question 12

how does alkalosis affect LA onset of action?

Answer 12

faster onset of action

Question 13

lidocaine can be administered in which formulations?

why is this pharmacologically relevant

Answer 13

• 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

Question 14

what are the disadvantages of low pH LAs?

Answer 14

• 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)

Question 15

what are the advantages of buffered LAs (bicarbonate added)?

Answer 15

• reduced pain on injection
• reduced risk of tissue damage
• faster onset (1-2 minutes)
• the ability fo obtain analgesia in infected tissue

Question 16

how does LA lipid solubility affect duration of action?

Answer 16

higher solubility = longer duration of action

Question 17

which LA is the most lipophillic?

Answer 17

bupivacaine

Question 18

how does the protein binding capacity of LAs affect the duration of action?

Answer 18

higher protein binding = longer duration of action

Question 19

how does anesthesia spread anatomically?

why is this the case?

Answer 19

• anesthetizes proximal areas before distal areas
• b/c mantle (outer nerve) fibers are blocked before core (inner nerve) fibers

Question 20

to which locations can LAs distribute?

Answer 20

• brain
• lungs
• fat
• placenta

Question 21

LAs - metabolism

Answer 21

• amides - by liver microsomal enzymes
• esters - rapidly by plasma / liver esterases

esters metabolized faster, have a much shorter duration of action than amides

Question 22

what is the role of epinephrine in EPI-containing LA formulations?

Answer 22

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

Question 23

what are the disadvantages of epinephrine in EPI-containg LA formulations?

Answer 23

• locally: ischemia d/t vasoconstriction, esp in areas with low collateral blood flow: digits, ears
• systemically: could increase BP, affect HR

Question 24

how are the actions of LAs terminated?

Answer 24

by eventual removal from the injection site by the circulatory system

this is why vasoconsriction from EPI containing formulation prolong DUA

Question 25

which LAs come in a formulation with EPI?

Answer 25

* both amides: * bupivicaine: epi * 1:200,000 * lidocaine: epi * 1:200,000 * 1:100,000 * 1:50,000 the 1 represents EPI, and the 2nd # represents the LA: the higher the second number, the less EPI the formulation contains

Question 26

how much EPI is "necessary" to optimize LA duration of action?

Answer 26

* 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

Question 27

LAs can lead to what _systemic AEs_?

Answer 27

* CNS: * **restlessness / tremors / seizures -\> _depression & coma_** * ​this is b/c _inhibitory interneurons_ are anesthetized first * **TNS (**transient neurological symptoms): * **​**pain * dystheisa * CV: * **​heart collapse d/t decreased** * contractie force * conduction velocity * ​excitability * **vasculature** * vasodilation * hypotension * allergies

Question 28

local anesthetics are C/I in a patient taking what other drugs?

Answer 28

methemoglobin causing drugs * nitroglycerine * phenytoin

Question 29

which LA is the most likely to cause TNS?

Answer 29

**lidocaine** (is the most neurotoxic) pain, dysthesia

Question 30

which LA is most likely to cause CV collapse? * how is this treated? why? * which drug can be used as an alternative?

Answer 30

**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**

Question 31

which LA is most likely to induce allergic reactions? why?

Answer 31

the ester LAs: procaine, cholorproctain, benzocaine this is because the are metaoblized to PABA, an allergen to certain patients

Question 32

how most LAs affect the vasculature? why is the exception?

Answer 32

vasodilate -\> hypotension exception is cocaine (which vasoconstricts)

Question 33

list the uses of each amide LA

Answer 33

* all: local infusion, nerve blocks, epidural * **mepivacaine, bupivacaine, ropivacaine** - spinal * **lidocaine** - topical, IV

Question 34

lidocaine * is the only amide LA that can has what anesthetic use? * cannot be used for? why?

Answer 34

* 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

Question 35

describe the onset and duration of each amide LA

Answer 35

* lidocaine: rapid osnet, intermediate duration * mepivacaine: rapid onset, long duration * bupivacaine: slow onset, long duration * ropivacaine: slow onset, long duration

Question 36

which amide can be effectively used as an alternative to bupivicaine? when might this be useful?

Answer 36

* ropivacaine - has the same onset, duration and uses as bupivacaine * can be used to avoid the _cardiotoxic affect_s of bupivacaine

Question 37

what are the clinical uses for neuromuscular blocking drugs (NMBs)?

Answer 37

**procedures that require muscle paralysis**

Question 38

the NMBs work primarily via which methods?

Answer 38

* 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

Question 39

succinylcholine * what kind of drug * clinical use * MOA * onset * AEs

Answer 39

* 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

Question 40

rocuroniom * what kind of drug * clinical use * MOA * AEs

Answer 40

* drug: is an NMB * clinical use: **tracheal intubation** * MOA: **non-depolarizating agent (AChR antagonist)** * onset: **1-2 minutes** * AEs**: none significant**

Question 41

how are neuromuscular blocks by _non-depolarizing_ NMBs reversed? why?

Answer 41

* **via AChE inhibitors** - **endophonium, neostigmine** * AChE inhibitors inc ACh concentrations, so ACh can _outcompete_ the competitive AChR antagonists **(i.e., rocuronium**)

Question 42

how are neuromuscular blocks by _depolarizing_ NMBs reversed? why?

Answer 42

**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)