Local anaesthetics Flashcards
Chemistry
Analogues of cocaine
Hydrophobic group (aromatic) and ionisable group (e.g. amine)
Linked by ester/amide bond
Weak base (exist as B and BH+)
Permanently charged LA
QX-314 and QX-222
Useful for experiments - mechanism of action of local anaesthetics
Analogues of lidocaine
Widely used LA
Procaine, lidocaine, bupivacaine, amethocaine, tetracaine
Procaine
Potency = 1 Duration = short
Tetracaine
Potency = 16 Duration = long
Lidocaine
Potency = 4
Duration = med
Amine
pKa = 7.9
Bupivacaine
Potency = 16
Duration = long
Epidural
Amethocaine
Cream when take blood
Eye drop after cataract surgery
Mechanism of action
Block initiation and propagation of action potentials - block voltage gated Na+ channels Binding site in channel pore Threshold potential not reached Lose sensation Bind reversibly
Physiological pain circuits
Harmful stimuli sensed by specialised nerve fibres:
Unmyelinated C, thinly myelinated Aδ (both narrow)
Physiochemical properties convert to electrical by transient receptor potential (TRP) + purinergic channels
Electrical activity amplify by Na+ channels = action potentials
pH
LA = Weak base (exist as B and BH+)
Ratio between ionised and non-ionised drug in tissue depends on pH and pKa of drug
Henderson-Hasselbalch equation (pH)
pKa-pH = log[BH+]/[B]
Equilibrium (pH)
Want most drug outside cell = unionised - travel through membrane
Want most drug in cell = ionised - block channel
Achieve w/ diff. pH in and out
Factors influencing the activity of LA
pKa, pH, lipid solubility, intermediate chaine, protein binding
Factors influencing the activity of LA: pKa
pKa: ph when no. ionised drug = no. unionised (equilibrium)
More unionised present for given pH = faster onset action
Factors influencing the activity of LA: pH
Lower pH = lower potency
In acidic conditions - more ionised, less LA can cross lipid bilayer and block V-G Na+ channel
Worse reduction of pain in infected tissues (e.g. abscesses) - highly acidic, all LA ionised, not cross membrane
Factors influencing the activity of LA: Lipid solubility
More lipid soluble = higher potency = faster onset action = longer duration
More drug cross lipid bilayer of neuronal membrane, create store of drug in axoplasm
Factors influencing the activity of LA: Intermediate chain
Longer = higher potency
E.g. bipuvacaine has longer chain than lidocaine, more potent
Factors influencing the activity of LA: protein binding
Higher degree of protein binding = longer duration
Model for LA block
QX-314 and QX-222 = permanently charged
Not cross membrane
Only block when introduce to cytosol
Bind cumulatively w/ depolarising pulse = use-dependent block
Not unbind at rest = open channel block
Block is voltage dependent - negative holding pulse can remove block
LA pathways to access blocking site
Access blocking site in Na+ channel pore
Hydrophilic or hydrophobic
Hydrophilic pathway
Clinically useful LA = highly lipophilic (cross membranes)
LA solutions = acidic (from HCl salts), increase drug solubility, mostly charged form
Inject - buffering system in tissue increase pH of solution, establish equilibrium, increase uncharged form, can cross cell membrane
LA interconvert to BH+ in cytosol - block channel from intracellular side
Block and recovery - need open channels
Hydrophobic pathway
Experiment:
Hydrophilic analogue of lidocaine (GEA-968) - low lipid solubility
Show diff. route for drug access
Uncharged (B) gain direct access to channel through membrane
Hydrophobic LA - bind/unbind/leak out when channel closed
Low extracellular pH - slow leakage LA, extracellular H+ access LA in pore at rest
Leak from closed channels depend on lipid solubility of LA
Crystal structure of V-G Na+ channel - show side portals give hydrophobic access to central cavity
Other channels blocked by LA
LA = +ve charge - enter many cation channels, block cation currents
Nicotinic acetylcholine receptor
Ryanodine receptor
K+ channels
