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
Other clinical uses of LA
Anti-arrhythmic properties: If associate and dissociate before next HB, useful for treat arrhythmias (lidocaine)
Block Na+ channels in heart
Tetrodotoxin (TTX)
Not LA
More specific and potent blocker Na+ channels
Enter extracellularly
Not easy cross nerve sheath/ perineuronal tissues surrounding bundles of neurons
Metabolism
Esters: Procaine, tetracaine
Rapidly metabolised in blood by plasma cholinesterases/ liver esterase’s
Amides: lidocaine, bupivacaine
Widely distribute by circulation, only metabolise by liver enzymes, longer half-life/ duration
Factors influencing absorption
Dose, site of injection, drug-tissue binding, presence of vasoconstriction agents (loss LA from site of local application into circulation, prolong effect and reduce circulation of LA if vasoconstricting agent given)
Toxic action/ side effects
Result escape XS LA into systemic circulation
Toxicity more likely w/ impaired liver function (reduced break down of LA)
CNS toxicity
Light headed, leading to convulsions, respiratory depression, coma
Brain - block inhibitory neurons = excitatory symptoms (trembling, tingle round mouth, fits, coma)
Cardiovascular toxicity
myocardial depression - reduce HR, SV
Vasodilation
Reduce BP
Administration
Surface application (nose, mouth, cornea, brachial tree, urinary tract)
Direct injection into tissue for minor/ oral surgery (w/ vasoconstrictor e.g. adrenaline/felypressin)
*Can’t predict from injection how much reach spec. location
Injection close to nerve trunk - brachial plexus, intercostal/dental nerves (increase rate of systemic absorption)
Regional anaesthesia for limb surgery
Spinal anaesthesia - act on spinal roots and spinal cord
Epidural anaesthesia - act on spinal roots
Intravenous regional anaesthesia
Drug inject intravenously
Distal to pressure cuff on limb
Used prilocaine in past - lowest risk of cardiac toxicity, short acting
Now - nerve block
Spinal anaesthesia
Inject into subarachnoid space
Below outer membranes covering spinal chord
Between 2nd and 5th lumbar vertebrae
Major surgery (e.g. Caesarean section)
Epidural anaesthesia
Inject into epidural space
Outside dura matter
Direct action on nerve roots + spinal cord following diffusion across dura
Use in obstetrics
Sequence of blockade
Pain - general sensory - motor
Sequential block of different types of nerve fibre as exposed to LA
Small diameter axons more sensitive than large
Myelinated more sensitive than non
Nociceptor-specific anaesthesia
Current LA - block pain + tactile input + motor signals
Prefer - pain selective block
Target small unmyelinated C-fibres, selectively express TRPV1 channel, activated by capsaicin (in chilli)
Pharmacodynamics
What a drug does to the body
Pharmacokinetics
What the body does to a drug (metabolism)
Use-dependent block
LA drug bind Bettie to inactivated channel
Must first activate (neuron fired) to become inactivated
More neuron fired = more inactive channels = more binding LA
