Local Anaesthetics Flashcards
Mechanism of Action of local anaesthetics
- stop axonal conduction by binding to the sodium channels at the axonal membrane, preventing sodium ion entry and bringing conduction to a halt.
- passage of train of action potentials causes LA molecules to cycle through open and inactivated states.
- LA molecules are non-selective so they will bind to the sodium channels of any neuron and inhibit its action potential.
Use-dependency of local anaesthetics
- depth of LA block increases with action potential frequency because:
- LA molecules have higher affinity to inactivated than closed channels.
LA molecules can gain access to channel more readily when its open.
How can we make LAs more selective?
Apply LAs to a localised spot to reduce the possibility/extent of systemic action.
What are the factors affecting LA action?
- lipid solubility (more hydrophobic drugs are more potent)
- size (smaller axons are more potent than larger ones)
- frequency of firing (high (sensory) > low (motor))
- position: circumferential > deep (large nerve trunk)
- myelination: myelinated > non-myelinated
- pH dependency (more LA molecules unionised at alkaline pH, increased LA activity).
Classification of LAs
- Characteristic chemistry: ester-type LAs have ester bonds. amide-type LAs have amide bonds.
- Representative agents: ester-type (procaine), amide-type (lidocaine)
- Incidence of allergic reactions: low (ester-type), very low (amide-type)
- Method of metabolism: plasma/tissue non-specific esterases (ester-type), hepatic enzymes (amide-type)
What are the pharmacokinetics of LA molecules?
Absorption: mostly local action (small extent systemic)
Distribution (2-compartment model)
- Phase I (alpha phase): exponential decline in [LA], rapid distribution in well-perfused organs (brain, heart, lungs, kidney)
- Phase II (beta phase): slower decline in [LA], almost linear. Distributes slower to less well-perfused organs (e.g. gut)
Metabolism: ester-type LA molecules get hydrolysed by esterases in blood. Amide-type LA molecules get hydrolysed by enzymes in liver.
Which LA molecules have a faster onset of action?
smaller, hydrophilic ones that have low ionisation at tissue pH
When do LA molecules induce toxicity?
- Route of administration: may result in systemic toxicity if LA molecules are administered intra-arterially or via IV.
- Dosing: excessively large doses of LA molecules can lead to systemic toxicity.
How to reduce the toxicity of LA molecules?
LA molecules can combine with epinephrine to prevent systemic distribution from site of action.
What are the symptoms of LA toxicity?
CNS - shivering, convulsions, visual and auditory, sleepiness, nystagmus, stoppage of vital signs –> death
CVS: cardiovascular contractility decreases, arteriolar dilation increases and hypotension occurs, resulting in cardiovascular collapse.
Which LA is the most cardiotoxic?
Bupivacaine
Side effects of cocaine
Blocks NA reuptake, leading to vasoconstriction and hypertension.
Side effects of o-toluidine
causes methaemoglobin –> blood cannot carry enough oxygen, skin will turn blueish
Ester LAs vs amide LAs: which one causes more allergic reactions and why?
Ester LAs: hydrolysed by PABA derivatives which induce allergy in the population.
What are the clinical applications of LA?
Topical (surface):
- skin
- eye
- dental
- gynaecology
- otorhinolaryngology
Injected:
- epidural anaesthetics (lidocaine, bupivacaine + fentanyl)
- dental anaesthetics (lidocaine, bupivacaine + epinephrine)
