• Work on neural transmission outside the CNS (at site of injury)
• ASA
• NSAIDs

• Work on neural transmission within the CNS (ie. at the thalamus, which relays pain to the brain)
• Acetaminophen
• Opioids

• Amtripyline
• Carbamazepines
• Caffeine

• produce a loss of sensation in a circumscribed area 
• local pain control without CNS depression
• act on any part of NS and on every type of nerve fiber
• block impulse conduction (AP) along axon
• Inhibit Na+ channels inside and outside the CNS (non-discriminating)

1. Amides (lidocaine, prilocaine...)
2. Esters (Tetracaine, Benzocaine)
3. Others (Cocaine)

1.) Skin - Benzocaine, lidocaine

2.) Rectum - Benzocaine, lidocaine

3.) Spinal, epidural, caudal, subarachnoid -

Teraceine, lidocaine, bupivacaine, mepivacaine, ropivacaine

Others: Chronic pain (nerve block); Corneal anesthesia; cough; Dental; Topical

Lidocaine & Prilocaine

enhanced penetration, longer duration of action

Medical uses: 

Catheter insertions, Injections, Genital mucosa,

Tattoo removal (laser)

Dental uses: (2.5% of each drug): Oral mucosa (provides 15-20 minutes)

Lidocaine (IV); Mexilitine (oral); Tocainamide (oral)

• investigated for a # of chronic pain conditions:  (diabetic neuropathy, peripheral nerve injury, reflex sympathetic dystrophy)
• Clinical use limited by systemic toxicity:
  • CNS: dizziness, lightheadedness, somnoence
  • Cardiac effects (can be used for arrhythmias b/c block Na channels)

Ex: those with epinephrine 

Should not be used in following locations:

Fingers

Toes 

Nose

Ear lobes

Penis

uses based on form

• Solution - injectables
• Topical - cream, gels, polymers
• Transdermal systems (heart issues)
• Liposomal formulation of bupivacaine (DepoBupivacaine)

• Reversible effect
• Effective - topically or when injected locally
• Non irritating to tissue
• Minimal systemic toxicity
• Rapid onset, sufficient duration
  • appropriate anesthetic window
• Potent
• Non allergenic

• inhibit excitation at the nerve ending or blockade of the conduction process in peripheral nerve tissues
• effects are reversible, no evidence of structural damage to nerve fibers or cells

• block depolarization (the first part of an action potential, when Na+ channels open allowing influx of Na+)
• thus prevent AP from occuring

1. Resting (closed) maintain high K+ an low level of Na+ within the cell
2. Activated (open)...AP (increase in Na+ permeability: depolarization)
3. Inactivated (blocked) Na+ channels are inactivated, they are close and refractory

1. Local must 1st cross the cell membrane
2. binds to intracellular cell membrane receptor sites of the nerve 
   1. blocks the channel, Na+ prevented form entering the nerve
   2. Therefore, interfere with Na conductance

• inhibit generation and conduction of APs
• do not significantly alter the resting membrane potential of the nerve. Impairs certain dynamic responses to nerve stimulation
• interfere with nerve Na+ conductance

Lidocaine

prilocaine

Bupivacaine

etidocaine

• All contain an aromatic group (lipophilic) and an amine group (hydrophilic) (on each end)
• These 2 groups are linked by:
  • Amide
  • Ester
  • others: ketone
• can cross the cell membrane b/c contains both lipophilic and hydrophilic groups

1. Lipid solubility (aromatic group) → Potency
2. Protein binding → Duration of action
3. pKa → Rate of onset

 lipid solubility and protein binding:

Tetracaine, Bupivacaine, >> Lidocaine, mepivacaine> Procaine

Cocaine → Vasoconstricts

All other local anesthetics → Vasodilate

vasodilation washes out anesthetic, so epinephrine is added to prevent this effect

(epi causes vasoconstriction)

• inflammation interferes with efficacy of LAs due to:
• a ↓ in tissue pH, which impairs the ability of LA to enter the nerve
• Vasodilation: ↑ blood flow can contribute to inability to achieve anesthetic [ ]s within axons
• Enhance nerve conduction: inflammation mediators directly activate nociceptors, ↑ing the response to additional stimuli

• only non-ionized can readily diffuse across lipid nerve sheaths and cell memb.
• onset of action directly related to rate of diffusion, which correlates with the amount of drug in non-ionized form
• Thus pKa is directly related to onset of action (because it defines the proportion of drug that can easily diffuse into cell)

when pH ↓, the % of non-ionized species ↓

Therefore, the efficacy of LA is ↓ b/c drug can not cross membrane

• Differential nerve block and critical length
• effect of nerve diameter
• peripheral nerve organization
• intensity and frequency of stimulation (use-dependent block): effect of firing frequency

1. Pain
2. Cold
3. Warmth
4. Touch
5. Deep pressure

* recovered in reverse order

• Pain fibers are the smallest sensory fibers
• deep pressure fibers are the thickest
• Therefore, pain fibers more susceptible to LAs and are inhibited by doses that have little effect on other sensory modalities

• Smaller diameter nerve fibers are more susceptible to LAs
  • The block is faster and takes longer to recover
• Smaller length fibers have smaller distances between nodes of Ranvier
  • LAs have to block 3+ nodes to block pain

Once initiated the AP impulse moves along axon from one node of Ranvier to another

• LAs must block at least 3 nodes to block pain
• inter-nodal distance is directly related to the nerve fiber diameter

• location of various axons in a nerve trunk effects the rate and depth of LA
• Nerve sheath prevents spread of anesthetic solution by bulk flow, drug must rely on diffusion to reach axons within the nerve
• diffusion takes time. Net result = outer (mantle) fibers blocked before inner (core) fibers

• Noxious stimuli have rapid bursts of impulses
  • as nerve activity ↑ more Na channels open
  • results in greater sensitivity to LA action 
• dental LA preferentially inhibit high frequency trains of impulses over single APs
• effectiveness of LA is ↑ by rubbing to open Na+ channels

• Injections:
  • co-administration of vasoconstrictor
  • vascular supply at injected site effects abs (vascular space)
• Topical
  • Wide variations
  • Degree of keratin effects abs.
  • Formulation: ointments have less systemic abs. Gel aqueous spray have greater systemic abs

Strong vasodilators:

Bupivacaine, Etidocaine

Weak vasodilators:

Mepivacine, Prilocaine

• Once in blood, LAs are reversibly bound to plasma proteins
  • mainly a₁-acid glycoprotein (lesser extent albumin and RBCs)
• Unbound drug distributed to all body tissues
• Crosses BBB and Placenta, enters circulation of fetus
• distributed 1º to vessel rich organs (liver, spleen, lungs, kidney (central compartment), brain
• at same time distributed to less perfused organs (muscle, fat, CT)
•  

• By Pseudocholinesterases in blood
  • found in plasma, tissues, liver
  • hydrolysis results in loss of activity (hydrolytic products undergo further biotransformations)
  • PABA is major metabolite
  • 95% changed & 5% unchanged, both excreted via kidney

PABA

(para-aminobenzoid acid)

• major metabolite of ester LAs
• Patients allergic to LAs are allergic to PABA (metabolite) and the parent compound
• cross sensitivity with sulfa drugs and celecoxib 

• genetically linked (1 in 2800 persons)
• ↓ capacity to hydrolyze ester anesthetics and other ester drugs (i.e. succinylcholine)
• results in prolonged blood levels of agent and ↑ potential for toxicity
• a relative contraindication to use of any ester anesthetics agent

• Hepatic Metabolism (90% changed, 10% unchanged)
• Depends on:
  • Liver blood flow and function
  • complex biotransformation in liver, by several CYP450 isoenzymes
  • prilocaine and articaine, have extrahepatic biotransformation

1º in liver by CYP450 isoenzymes

1. N-dealkylation of 3º amides
2. Hydrolysis of 2º amides
3. Conjugation, hydroxylation, dealkylation

• significant liver dysfunction (cirrhosis)
• Heart failures (CHF, hypotension)
• drugs that ↓ hepatic blood flow (β-adrenergic blockers, H₂ antihistamines)

Benzocaine (an ester)

• non-medical ingredients: (cause of allergic rxns)
  • Methylparabens, MHB, Menthol & phenol (not recommended for children < 2 years old), Lanolin
• can cause Methaemoglobinaemia 

• Oxidized hemoglobin, cannot bind/carry O₂
• normally<1% in blood, can be ↑ by meds that act as oxidants
• patients turn blue due to ↓ O₂ carrying capacity
• can be caused by use of topical or injectable LAs
  • caution in infants and young children
  • do not use in infants < 4 months

• congenital or idiopathic methemoglobinemia
• most likely due to prilocaine allergy, but can also be due to lidocaine allergy

• Depend on plasma [ ] 
  • > 5 ug/ml affects CNS and CVS
  • less than this associated with mild sedation, and anticonvulsant activity
• Most true overdoses occur mainly with:
  • young children
  • elderly patients
  • b/c of body weight

• Psychogenic
  • ↑ HR or BP
    
  • mimicking of allergic rxn (urticaria, edema and bronchospasm)
• Toxic effects: due to repeated injections or a single inadvertent intravascular admin
• Methemoglobinemia

• Ester: Benzocaine 
• Amides: Prilocaine, Articaine 
  • < 8mg/kg will not cause
  • any dose is contraindicated in congenital or acquired methemoglobinemia

• antidote for Methemoglobinemia
• 1-2 mg/kg IV over 3-5 minutes
• repeated at 1 mg/kg every 30 minutes as necessary to control symptoms (don't exceed 7 mg/kg)
• not effective in pts with G6PD deficiency or with hemoglobin M disease

• drugs that lower hepatic blood blow 
  • β blockers
  • H₂ antihistamines

Anticholinesterases: prevent breakdown of esters, therefore, duration of ester LA is ↑ in blood 

be aware of in myasthenia gravis (MG) patients

• Esters:
  • extremely common
  • cross sensitivity between all esters
  • cross sensitivity with PABA (sulfa), and chemicals found in hair dye
• Amides:
  • Extremely rare
  • little or not cross sensitivity between amides

CONTRPVERSIAL

• no documented cases
• amides are both safe and acceptable