Local Anesthetics

Question 1

What are the properties of electrical excitability?

Answer 1

To generate propagated action potentials
- Communicates in the nervous system
- Initiates mechanical activity in cardiac and striated muscle
- Voltage-gated sodium channels
~ Opens transiently when membrane is depolarized (sodium flows in from extracellular to intracellular)
~ vs ligand-gated (channel will open when a ligand/neurotransmitter binds to receptor)
~ Inactivation of ion channel means ion flow is blocked by a gating mechanism rather than closing the channel itself
~ Deactivation of ion channel means block by closing of the channel + gating mechanism

Question 2

What is the MOA of LA?

Answer 2

1) Stops axonal conduction by blocking sodium channels in axonal membrane
- Only if applied locally in appropriate concentration
- Prevention of sodium entry brings conduction to a halt

• In high pH (8-9), dissociated from proton, ie non-protonated
  ~ Only time sodium can pass through the channels -> becomes protonated again intracellularly -> activated -> can block channels
• In low pH, surplus of H+
  ~ Binds to base -> does not pass through membrane
• Most LAs bind most strongly to the inactivated and activated states

2) Passage of train of action potentials causes sodium channels to cycle through open and inactivated states
- Depth of LA nerve block increases with action potential frequency
~ LA molecules gain access to the channel more readily
~ LA molecules have higher affinity for the inactivated than for the closed channels

3) LAs are non-selective modifiers of neuronal function
- Will block action potentials in all neurons to which they have access
- Selectivity for LAs can be achieved by only delivering to a limited area

Question 3

What are the factors affecting LA action?

Answer 3

1) Lipid-solubility
- More lipid-soluble / hydrophobic = more potent, act longer
~ TETRACAIBE, ETIDOCAINE, BUPIVACAINE
- Less hydrophobic = shorter duration of action
~ LIDOCAINE, PROCAINE, MEPIVACAINE

2) Size
- Acts on smaller nerves > bigger nerves

3) Frequency of firing
- High (in sensory nerves)
- Low (in motor nerves)
~ Would cause paralysis so LA action not wanted

4) Position
- Circumferential/nearer to surface > deep

5) Myelination
- Myelinated > non-myelinated

6) pH dependency
- LA molecules are weak bases
~ Ionized at physiological pH
~ Lower pH in more inflamed tissues, so try to give LA before tissues get more inflamed
- Potency is strongly pH-dependent
~ Alkaline pH (^ LA activity)
~ In an alkaline (higher pH) environment, more of the local anesthetic exists in the unionized form. The unionized form can readily cross the lipid-rich nerve cell membrane and reach the intracellular site of action. This increases the amount of anesthetic inside the cell, where it can convert to the ionized form and block sodium channels effectively.
- Helps LA to penetrate the nerve sheat and axon membrane to reach the inner end of the sodium channel/LA binding site

tf:
(Highest potency) Small myelinated axons > Small non-myelinated axons > Large non-myelinated axons

Nociceptive/pain and sympathetic transmission is blocked first

Question 4

What is the classification of LAs?

Answer 4

1) Esters
- COCAINE, PROCAINE``/NOVOCAINE, TETRACAINE (most potent)
- C=OO double bond
- Gets metabolised by esterases throughout the body
~ tf liver not really needed
- Low risk of allergic rxns but still higher than amines

2) Amides
- LIGNOCAINE``, MEPIVACAINE, BUPIVACAINE, ETIDOCAINE (most potent)
- NHC=O
- Requires metabolism by liver, including CYP450
~ Not suitable for px with liver problems

Question 5

What are the pharmacokinetics of LA?

Answer 5

1) Absorption
- Mainly local action

2) Distribution (systemic)
- Phase 1/alpha
~ Steep exponential decline in LA
~ Rapid distribution in blood and highly perfused organs

• Phase 2/beta
  ~ Slower decline in LA
  ~ Distribution to less perfused tissue

3) Onset
- Anaesthetics that penetrate the axon most rapidly have the fastest onset
- Small size, high lipid solubility, low ionization at tissue pH have faster onset

4) Metabolism
- Ester-type by esterases in blood
- Amide-type by enzymes in liver

Question 6

How does toxicity occur in LA?

Answer 6

• Immediate s//s if injected into systemic IV
• Late s/s if local injection
• Can combine with epinephrine during toxicity
  ~ Prevents LA systemic distribution from leaving the site of action
• Epinephrine reduces vessel diameter at area of topical application
  ~ Dec blood flow so dec rate of absorption into systemic circulation
• Bupivacaine
  ~ More cardiotoxic than most other LAs
• Cocaine
  ~ Blocks sodium uptake -> ^ sodium causes vasoconstriction and HTN
• O-toluidine
  ~ Causes methaemoglobin (Hb is dysfunctional)
  ~ IV methylene blue/ascorbic acid is the antidote
• Ester LAs are hydrolysed to PABA derivatives
  ~ Can cause allergic rxns to some people

Question 7

What are some s/s of LA toxicity?

Answer 7

CNS:
- Sleepiness
- Visual and auditory
- Restlessness
- Nystagmus
- Shivering
- Convulsions
- Stoppage of vital functions

CVS:
- Cardiac contraction decreases
- Arteriolar dilation
- Hypotension
- Cardiovascular collapse

Question 8

What are the clinical applications of LAs?

Answer 8

• Topical
  ~ On skin for minor burns/inflammation/wounds
  ~ To remove foreign objects from the eye
  ~ On gums before injection
  ~ Insertion of endoscope
  ~ Episiotomy cuts
• Injected
  ~ Epidural (LIDOCAINE, BUPIVACAINE), can combine with opioid fentanyl to reduce LA dose
  ~ Dental anaesthesia (same drugs ^^), may combine w epinephrine to control bleeding
  ~ Infiltration (to tissues for minor surgery)