• mechanical
• chemical (acids)
• thermal (extreme temp.)

1. activation of sodium channels
2. if reach threshold, more sodium channels open
3. eventually, acitivate calcium channels activate and calcium into cell

• C fibers
  • unmyelinated (slower)
  • mediate aching pain
  • main NT: substance P (also back propagate, mediate recruitment of more histamine, and getting more vasodilation)
• A delta fibers
  • myelinated (faster)
  • mediate sharp stinging pain'
  • main NT: glutamate

• fast pain: local anesthetics
• slow pain: local anesthetics, NSAIDS
  • NSAIDS prevent exacerbation of pain response (decrease cyclooxgenase, so decrease PG's)

• extracellular blocking of voltage gated sodium channels

1. when voltage gated sodium channels active, it will come into the cell
2. when it comes in, it will bind to the intracellular side and block sodium entry
   • called use dependent blockade
     • as you continually depolarize neuron, you see continual decrease in sodium currents

• aromatic portion
• intermediate chain (usually ester or amide)
• amine group (where ionization occurs)

Increasing the number of carbons or length of each of these groups will increase lipophilicity, leading to quickening of onset of action and increased potency.

• amides (amide link in intermediate chain)
  • lidocain
  • mepivacaine
  • bupivacaine
  • etidocaine
  • prilocaine
  • ropivacaine
• ester (ester link in intermediate chain)
  • cocaine
  • procain
  • tetracaine
  • benzocaine

• short DOA (more prone to hydrolysis)- metabolized by plasma and liver pseudocholinesterases
  • more likely to have allergies, because metabolism releases PABA and its derivatives
  • toxicity when dose overwhelms capacity of pseudocholinesterases

• longer DOA
• metabolized in the liver by microsomal P450 enzymes

• weak bases- exist in body as uncharged or as cations
  • usually has pKa of 7.7-9.1
    • means that most of the LA at physiological pH will be in cationic form (about 10 charged:1 uncharged)
    • physiological pH = 7 and pKa = 8
    • via Henderson Haselback, we know that 8-7=1, which is the log[cationic form/uncharged form]

• we know that the uncharged form is more lipid soluble and therefore better at penetrating membranes
• infected tissue tends to have low extracellular pH
  • this means we have more charged form, and less uncharged form
  • this leads to poor access, and a LA that is not as effective

• fiber diameter- the smaller the diameter, the better the block (due to poor passive conduction) (ex: C fibers)
• myelination- myelinated nerves blocked before unmyelinated nerves. (ex: A fibers)
• firing frequency- the more rapid the firing, the more chance of being blocked (ties into myelination) (ex: A fibers)
• fiber position in the nerve bundle- those deep in bundle harder to access

• C fibers the best (due to small diameter)
• A delta fibers second best (due to myelination and faster firing frequency)
• A gamma and beta fibers third best (myelination, faster firing freq. but larger diameter)
• A alpha (myelinated, fastest firing freq., but the largest diameter)

• injection into area to be blocked
  • topical
  • infiltration
  • Bier block
  • peripheral nerve block
  • epidural anesthesia
  • spinal anesthesia

• mechanism- application directly to the surface of area to be anesthetized
• examples
  • benzocaine
  • cocaine
• location- temporary relief for minor procedures at:
  • eye
  • ear nose
  • throat
  • dental conditions

• mechanism- inject into skin, subQ tissue, mucus membranes in area to be anesthetized
• examples
  • Procaine
  • Lidocaine

• mechanism
  1. ensure venous outflow is impeded by a tourniquets
  2. inject local anesthetics directly into vasculature
  3. obtain regional anesthesia
• example- lidocaine

• mechanism
  • regional anesthesia
  • inject LA into or around nerves in the area to be anesthetized
  • block single nerve or plexus
• example
  • Lidocaine
  • Ropivacaine

• mechanism- inject into epidural space
• examples
  • Procaine
  • Lidocaine

• mechanism- intrathecal administration
• examples
  • procaine
  • lidocaine

• probability of toxicity increases when anesthetics administered to tissues with dense vasculature (order of descending vasculature)
  • intercostal
  • caudal
  • epidural
  • brachial plexus
  • sciatic nerve
• toxicity occurs when local anesthetics are absorbed into the vasculature and reach high enough concentrations to in heart or brain (disrupts cardiac and CNS function)

• low systemic absorption: disruption of sensory perception
• high systemic absorption
  • brain
    • anxiety
    • confusion
    • tremors
    • convulsions
  • CV system (except cocaine: HTN, tachycardia, arrhythmia)
    • depressed myocardial contractility
    • bradycardia
    • hypotension

• role- reduces the likelihood of systemic toxicity
• mechanism of action
  • stimulate alpha 1 and vasoconstrict, leading to increased DOA
  • stimulate alpha 2 on C fibers, leading to reduction in substance P release, reducing pain transmission (can also use clonidine for this)

• convulsions
  • block GABA_A leading to reduced inhibitory neurotransmission
  • tx- IV benzodiazepines (ex: diazepam)
• blindness
• aphasia
• hemiparesis
• respiratory depression
• coma
• cardiac arrest

• pain (due to pH of solution)
• ecchymosis (discoloration of skin due to ruptured bv's)
• hematoma
• abscess
• nerve laceration
• tissue necrosis (associated with vasoconstrictor)

cocaine- indications, mechanism of action, unique disadvantage

• indication- topically (mucous membrane) in eye surgery
• mechanism- vasoconstrictor
• disadvantage- high abuse potential

• PK
  • slow onset
  • slow duration of action
  • relatively low systemic toxicity
• indications
  • infiltration
  • nerve block
  • epidural
  • spinal

• chemistry- xylidine derivative
• rapid onset
• intermediate DOA
• adverse effect- arrhythmia at high doses
• administered in all six possible forms

Also classified as a 1B antiarrhythmic drug.

• advantage- low cardiotoxicity
  • S isomer only, and this isomer form of LA contributes to reduced cardiotoxicity (normally, R form can block cadiac sodium channels)
  • vaoconstriction caused by it reduce spread of drug as well
• PK
  • the highest potency
  • slow onset of action
  • intermediate/long DOA
  • administered as:
    • infiltration
    • nerve block
    • epidural
    • spinal