Local Anaesthetics

Question 1

How do Local anaesthetics affect ion channels?

Briefly describe RMP and what occurs on depolarisation

What is the chemical structure of a local anaesthetic?

Which bonds present in its structure are easily hydrolysed?

Answer 1

• Block Na+ channels
• • Rest - High K+ in cell, Low K+ out cell due to Na/K Pump - membrane selectively permeable to K+ so cell is at equilibrium
  • Depolarisation - Reaching threshold voltage for Na channels cause them to open and Na+ influx to occur, causing a quick upstroke of APs
• • Weak base - Proton acceptor at pH 7.2 = ionised, Membrane impermeable
  • Proton donor in alkaline conditions = non-ionised, Membrane permeable
• Ester Bonds

Question 2

What are the effects of PH on LA activity?

In what state are most channels blocked by the ionised LA?

What is the process of Ion Trapping?

Answer 2

• Action of LA increased in alkaline PH in a NON-IONISED form; Ionised LA is more effective at blocking Na channels
• Inactivated state
• • Outside of cell is Alkaline, so LA is non-ionised; able to move across the ‘fatty’ myelin sheath and axon membrane
  • Once inside cell, LA becomes ionised due to the acidic conditions - blocks Na channels and can’t move out cell anymore

Question 3

How do LAs work to suppress pain?

Why are LAs given locally instead of systemically?

What are Use-dependence drugs?

What are the 2 types of pain fibres present? Describe them

How does the effect of a LA change over time?

Answer 3

• • Blocks Na channels and the generation/conduction of APs from inside cell
  • Pain stimulus reaches threshold but there’s a lack of VGNaC opening = no depolarisation = no information sent to CNS = NO PAIN
• Block any VGNaC irrespective of tissue type; given locally to reduce systemic effects
• Only work in high activity; less side effects, low activity neurons unaffected
• Aδ and C nociceptive fibres; Small, Unmyelinated - better targets for LA
• Pain sensation is lost at first; With time, LA’s block all axonal conduction, causing Local Paralysis

Question 4

Potential adverse effects:
How can LAs affect the CNS? Symptoms?

How can LAs affect the CVS? Symptoms?

Answer 4

• If in brain, there’s initial stimulation (Tremor, Agitation, Convulsions), and Respiratory Depression
• • LA block Cardiac VGNaC = ↓Ca influx and Force of contraction = ↓CO
  • Inhibition of sympathetic activity on blood vessels = Vasodilation
  *Both of these with cause a ↓BP = Affect blood flow to vital organs

Question 5

What are the 4 different routes of administration of LA?

Why are LA administered with Adrenaline?

What side-effect can this cause?

Answer 5

• • Surface anaesthetic - applied to mucosal surfaces (e.g. Bronchi, Nose), but LA’s don’t cross skin very well
  • Local nerve block - injected close to sensory nerve
  • Spinal anaesthetic - injected into subarachnoid space between 2nd and 5th Lumbar vertebrae into CSF
  • Epidural - injected into epidural space to block nerve roots e.g. childbirth
• • Adrenaline produces vasoconstriction by acting on α1-receptors; constriction keeps LA localised to injection site, inhibits LA absorption into blood to reduce chance of systemic toxicity
  • Adrenaline prolongs LA action and prevents bleeding
• Can cause Local Hypoxia and its absorption could lead to an Arrhythmia