HUF 2-66 Local anesthetics

Question 1

Anaethesia vs. analgesia

Answer 1

• Analgesia = loss of pain sensation
• Anaesthesia = loss of pain AND touch ,pressure, temp sensations, AND autonomic, motor functions

Local anaesthesia: anaesthesia confined to a localised region of body

General anaesthesia: anaesthesia aimed at whole body primarily by depression of CNS

Question 2

Local anaesthetics

Answer 2

• Inhibit AP propagation by blockade of VGNC
• Physiochemical properties of LA
  => Diff. onset time, potency and duration
• Neuronal diameter, myelination
  => Sensitivity to LA
• Various routes of administration
• High circulating LA level
  => Adverse effects (local anaesthetic systemic toxicity - LAST)

Question 3

Naming and chemical structures of LAs

Answer 3

• “‘CAINE’
• Aromatic ring group: hydrophobicity
• Amine group: hydrophilicity (except benzocaine)

Question 4

LAH+ and LA: gaining access to VGNC channel

Answer 4

• Most LAs (except benzocaine, Pka 2.5) are weak bases
• Diff. proportions of uncharged LA and charged LAH+
• pKa 7.7-8.9 due to hydrophilic amine group
• Uncharged LA permeates cell membrane to reach VGCN (hydrophobic pathway)
• LA binding site near intracellular side of channel
• Uncharged LA becomes charged LAH+ to access binding site of VGNC directly
• Charged LAH+ more soluble in aqueous environment
  => Diffuse to binding site from inside of call (hydrophilic pathway)
• LAH+ binds more strongly than LA

Question 5

pKa and hydrophilicity of LA: onset, potency. duration of action

Answer 5

Before and during permeation into cell
- Smaller pKa
=> Greater LA:LAH+ ratio
=> Faster drug (LA) uptake via hydrophobic pathway
=> Faster onset
- Aromatic group modified
=> ↑ hydrophobicity (NOT prohibiting protonation to become LAH+)

After permeation into cell
- LA binding site (aqueous, hydrophilic VGNA channel pore contains aa residues that also favour hydrophobic interactions
=> ↑ Binding affinity, potency, duration of action

Question 6

Comparison of LAs

Answer 6

Lidocaine, Prilocaine, Bupivacaine, Levobupivacaine, Ropivacaine
Procaine, Benzocaine

• Benzocaine (pKa 3.5): water-insoluble; only exists in uncharged form
  => Binds LA binding site of VGNC weakly (low potency)

- Prepare injectable LA as HCl salt
=> ↑ LAH+ proportion
=> ↑ Water solubility (for storage)
- Time of injection
=> Alkalinisation with NaHCO3
=> ↑ LA proportion
=> ↑ Membrane permeation
=> Faster uptake and onset

(Lidocaine + HCl, then NaHCO3)

Question 7

LA binding to different states of VGNC

Answer 7

VGNC: Closed (stage 1, 2) → Activation (3) → Inactivation (4)

High affinity for LA at:

• Intermediate closed conformation (slight change in channel subunit conformation due to small depolarisation)
• Open conformation
• ***Inactivated conformation
• More activation-inactivation cycles
  => Channels are “used” more often
  => More blocked by LA
• Small AP firing rate
  => Low freq. of VGNC use
  => Small LA-blocking effect

Question 8

Diff. nerve blockade: anaesthesia (Aδ, C) first, motor (Aα, Aβ) blockade later

Answer 8

• Myelinated neurons: VGNC only in nodes of Ranvier
  => LA must reach channels to effect nerve blockade
• Critical length = length spanning at least 3 consecutive nodes of Ranvier
• Thicker neurons: longer myelin sheath
  => Nodes of Ranvier are spaced out over longer distance
  => Longer critical length
  => Same amount of LA must diffuse over a large area
  => Lower effective [LA] reaching VGNC
• Thinner neurons
  => LA more concentrated within smaller area
  => Easier and quicker channel blockade

Unmyelinated neurons: even thinner, BUT VGNC over entire neuron
=> LA needs to reach sufficient number of channels for nerve blockade
=> Critical length of C fibre ~ Aδ and B

Question 9

Types of local anaesthesia and common drugs used

Answer 9

Topical
- Skin or mucosal surface for short-term pain-relief
- Benzocaine, Lidocaine, Prilocaine
Infiltration
- Injected into skin, more efficient than topical LA
- Lidocaine, Procaine, Bupivacaine, Ropivacaine
Field block
- Anaesthesia achieved distal to injection site (less LA than infiltration)
- Lidocaine, Bupivacaine
Nerve block
- A injected near major peripheral n. => Larger area of anaesthesia
- Lidocaine, Bupivacaine, Ropivacaine
Intravenous regional
- Anaesthesia of limbs
- Lidocaine, Prilocaine
Epidural
- Injected into epidural space; childbirth; high plasma [LA]
- Lidocaine, Bupivacaine, Ropivacaine
Spinal
- Injected into subarachnoid space; less drug than epidural
- Lidocaine, Prilocaine, Bupivacaine, Ropivacaine

Question 10

PK of LA: points to note; LAST

Answer 10

Absorption
- Faster LA absorption when vessels dilated (topical LA_
=> ↑ Risk of LAST
- LA can be given with vasoconstrictors
=> ↓ Consumption rate

Distribution
- Amide LAs taken up by lungs in large amounts (protective)
- Repeated LA injection to small subarachnoid space
=> Neurotoxicity
- Muscle toxicity

Metabolism
- Ester LAs quickly hydrolysed by plasma cholinesterase
- Product (para-amino-benzoic acid - PABA) may cause skin and systemic hypersensitivity
- Amide LAs metabolised slower by P450 enzymes
- Prilocaine metabolised to otoluidine
=> Methaemoglobinaemia

Question 11

LAST and treatments

Answer 11

Toxicity in CNS
- First excitation: dizziness, restlessness, seizures, ms twitching
=> BZD, barbiturates, neuromuscular blockers
- Then depression: sedation, loss of consciousness, respiratory and cardiovascular failure
=> Respiratory and cardiovascular support

Toxicity in cardiovascular system
- ↓ BP, myocardial electrical conduction and contractility
=> Cardiac arrest
- Advanced cardiac life support
- Treated with intravenous lipid emulsion (ILE)
- Most effective against lipophilic LAs (“-IVACAINE)
- Lipid sink: extracts LAs from circulation
=> NOT deposited in cardiac and brain tissues

Question 12

CVS toxicity of “-IVAcaines”

Answer 12

Bupivacaine: cardiotoxicity; greater depression of cardiac activity

Safer LAs for heart: Levobupivacaine, Ropivacaine