LA.txt

• 1850s hypodermic needle, cocaine isolated
• 1884 Freud cocaine, cocaine in medicine, LA by Halsted & Hall
• 1905 Procaine (Einhorn)
• 1921 Cartridge syringe
• 1947 Aspirating syringe
• 1948 Lidocaine
• 1959 Disposable needle

• drugs that reversibly block gen & propagation of nerve impules
• depress conduction in all exciteable cells
• sensory/motor periph, ANS ganglia, CNS, NMJ, cardiac & smooth muscle

pain in brain.

rubbing can interrupt pain transmission

unpleasant sensory & emotional experience associated w/ actual or potential tissue damage or described in terms of such

• sensory: detection threshold, ID/loc, reproducible, intensity
• affective: escape threshold, reaction, variable, unpleasantness

• transduction: physical to electrical
• transmission: to CNS
• modulation: endogenous opiods
• perception: experience

potentially tissue damaging thermal or mechanical energy impinging upon specialized nerve endings (A-delta & C fibers)

• nociceptor-> dorsal root of spinal cord-> decussation to ascend via anterolateral system to thalamus and cortex vial spinothalmic and reticulothalmic tracts
• LA blocks nociceptors

• CN (V,VII, IX, X)
• C (1,2,3)
• Sympathetic nervous system

• main sensory: non-nociceptive
• spinal trigeminal nucleus: nociceptive info, nucleus cauadalis
• mesencephalic nucleus: proprioception
• rostral to caudal (center of face to outside therefore central face is harder to block with anesthesia than outside face)

• topical: skin & mucous membranes
• infiltration: direct injection
• regional nerve block: injected proximal to nerve supplying area
• spinal: injection to lumbar subarachnoid CSF
• epidural, peridural or extradural: inject to extradural space where nerve roots pass, less likely to rise to higher segment then intended
• IV: distal to point and interrupted by tourniquet
• Sympathetic blocks: reflex symp dystrophies or intractable pain such as carcinoma

spinal is in subarachnoid CSF which may rise to higher parts

• Stellate ganglion: CRPS upper arm, herpes zoster of H&N
• Celiac plexus: pancreatitis pain
• Lumbar sympathetic: CRPS lower legs: acute herpes zoster of legs

mixed population of nerve fibers w/different diameters and rates of conduction.

• axon: individual cell
• endoneurium: surrounds ind axon
• perineurium: bundles into fascicles
• epineurium: invests fascicles (vessels, fat cells)
• Core(deep) vs. Mantle(peripheral) fibers

• myelination: saltatory conduction
• diameter: directly (larger=faster)

• innervate skeletal muscle
• biggest, fastest

smallest, slowest nociceptor

A-delta and C

• A-alpha: skeletal (15um, 100m/sec)
• A-beta: touch/pressure (8um, 50 m/sec)
• A-gamma: muscle spindles (6um, 20 m/sec)
• A-delta: nocicpetors (3um, 15 m/sec) (sharp acute myelinated)
• B: symp preganglionic (3um, 7 m/sec)
• C: nociceptors (1um, 1 m/sec) (unmyelinated
• Symp post (unmyelinated)

• very selective Na+, regulated or gated by membrane potential
• closed(resting)->depolarize->open(ion-conducting)->inactive->repolarized to closed(recovery)
• Na+ influx makes intracelluar more positive

• Na+: impermeable, high extracellular (1:14)
• K+: selectively permeable, high intracellular (27:1 in:out)
• Cl-: 1:11 in:out
• gradient = -70mV (inside is negative)

• magnitude of decrese in negative transmembrane potential that is necessary to initiate an action potential(impulse)
• about 15mV
• ALL or none: anything less will not initiate

• m gate: activation, initial depolarization opens
• h gate: inactivation, rapid depolarization closes
• 4 alpha subunits, 1 beta holds alphas in membrane

• prevent closed->open
• binds to transmembrane segments IS6, IIIS6, and IVS6
• S4 segments unwind to open channel, LA prevents unwinding
• induce reversible/dose-dependent reduction in rate of rise and height of action potential
• causes an elevation of firing threshold and slowing of spread of conduction as conc of LA inc
• in myelinated nerves only at nodes of Ranvier

• smaller distance for blockage of smaller fibers
• differential sensitivity of nerve fibers therefore smaller are more susceptible to blockacde than larger ones

• LA action increased by repeated firing which allows more access and affinity for binding site (when channel is open)
• aka freqency-dependent, use-dependent, phasic block

• dull/sharp pain, temperature
• less susceptible: touch, pressure, proprioception

• 1. Lipophilic: aromatic
• 2. Intermediate chaing: amide or ester linkage
• 3. Hydrophilic: tertiary amine group

• amide(xylidine)
• 7.9 pKa

• amide(xylidine)
• 7.6 pKa

• amide(xylidine)
• 8.1 pKa

• amide(toluidine)
• 7.9 pKa
• vasodilator

• amide(thiophene)
• 7.8 pKa

• procaine 8.9 pKa
• chloroprocaine 9.0 pKa
• tetracaine 8.2 pKa
• cocaine
• benzocaine
• cyclonine

• concentration/volume
• lipid solubility
• diffusion: proximitiy
• nerve morphology
• pH of tissue
• pKa of drug

• pKa-pH=log [ionized/un-ionized]
• ex: lidocaine pKa = 7.9
• 7.9-7.4 = log [ion/un-ion]
• 10^0.5 = ion / un-ion = 3/1
• Closer pKa to body pH = faster onset time

tissue pH of infected tissue is lower-> more acidic therefore the ration of ion/un-ion is higher and will have a slower onset time and less efficacy.

• concentration
• lipid solubility
• protein binding
• MOST IMPORTANT: DIFFUSION (hence vasoconstrictor)

lipid solubility: ability to move intraneuronally

• liver
• Lidocaine: N-dealkylated to monoethyl-glycine-xylidide(MEGX) (80% potency->sedation)
• Prilocaine: biotransformed in plasma and kidney->orhtotoludidine->methemoglobinemia
• Articaine: amide w/ester, ester hydrolysis more rapid
• Bupivacain is N-dealkylated

blocks conversion of Fe2+ to Fe3+ causing methoglobinemia

• plasma cholinesterase (pseudocholinesterase
• concern if atypical plasma cholinesterase (deficiency)

• not really unless severe liver dysfunction or pseudocholinesterase deficiency.
• total amount more important

• other LA (additive): stay below max
• opioid and phenothiazine: increases cerebral blood flow -> predisposed to toxicity, stay well below max

• inc depth of anesthesia
• inc duration (if LA doesn't vasodilate like prilocaine)
• decrease peak blood levels of LA (dec systemic toxicity)
• hemostasis: minimize bleeding (bware of CV effects)

• NE: both H, no B2
• E: (NH-CH3), all
• Levonordefrin: alpha-methyl-NE, decreased a1, B2

• a1-post ganglionic
• a2-bare extra-synaptic in periphery, (some presynaptic inhibition too)

• inc dysrhytmias
• inc HR, CO!!
• dec periph resistance -> MBP stable
• ventricular arrhythmias
• chest pain
• ST-segment depression->myocardial ischemia

• inc dysrhythmia, CO, PR, MBP
• no change in HR

• inc dysrhymia,
• inc! PR, MBP
• dec HR
• no change in CO

• CV:
• vasoconstriction (capacitance veins) a1
• increased contractility and HR b1
• vasodilation (skeletal muscle) b2
• Respiratory: Bronchodilation (b2)
• Metabolic:
• decrease plasma K+ (a2)
• increased lipolysis (b2)
• elevated plasma glucose (b2)

• rapid onset, short duration (5-10 IV, 10-20 Intraoral)
• exogenous epi metabolized by COMT

• a1: vasoconstriction, inc BP
• b1: HR & force, inc HR
• b2: skeletal vasodilation, dec BP

• Non selective Beta-blockers (hypertension & reflex bradycardia)
• NE-reuptake inhibitors: tricyclic, SNRI, SNE-reuptake inhibitors, cocaine & amphetamines
• COMT inhibitors