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Local Anaesthetics
Physiology and Pharmacology
| Question | Answer |
|---|---|
| What is the effect of inflammation on sensory neurons | When there is inflammation around a sensory neuron, it becomes easier to fire The inflammation causes the neuron to be depolarised closer to threshold, making it easier to trigger an action potential |
| What is cocaethylene | An active metabolite of cocaine formed in the liver when ethanol is also present Has a plasma half life of 3-5 times the half life of cocaine Associated with seizure, liver damage and compromised immune function |
| Cocaine | The first local anaesthetic Made from purification of coca leaves Switched between a charged and neutral state to remove different molecules also in the leaves |
| Mode of action of cocaine | Inhibits dopamine transporter - increases dopamine concentration in the synapse Changes gene expression Has other effects e.g. cardiovascular - causes arrhythmias |
| Cocaine derivatives - Disjunctive Approach | Starting form a polycyclic structure, a chemist proceeds to progressively simplify the molecule The final molecule may have very little resemblance to the original E.g. Procaine from cocaine |
| Experiencing pain | Sensory neuron cell bodes are in the dorsal root ganglia Axons spread to both the central nervous system and the skin Pain sensing fibres are C fibres To block the perception of pain we prevent signals reaching the CNS |
| Susceptibility of nerve fibres to local anaesthetics | We aim to target C fibres, which have the highest susceptibility to local anaesthetics (slowest transmission fibres) However, all sensory nerves are affected to some degree by local anaesthetics |
| General structure of local anaesthetics | Contain an aromatic group An ester/amide bond A tertiary or secondary amino group |
| Effect of pKa on time to onset of action | pKa = pH at which 50% of drug is ionised Only nonionised form crosses into the nerve Decrease in pH shifts equilibrium towards ionised form, delaying onset of action Presence of inflammation with retard the action of LAs |
| Effect of lipid solubility on potency | With higher solubility one can use a lower concentration and reduce potential for toxicity 90% of the nerve cell membrane is composed of lipid |
| Procaine | 1 potency Short duration |
| Tetracaine | 16 potency long duration |
| Lidocaine | 4 potency Medium duration 95% protein binding |
| Bupivacaine | 16 potency Long duration 65% protein binding |
| Metabolism of local anaesthetics | Esters are rapidly metabolised in the blood by plasma cholinesterase or liver esterase (non-specific esterase also in solution) Amides are widely distributed via the circulation and metabolised exclusively in the liver. Longer half life |
| How do local anaesthetics block Na+ channels | The ionised form only enters the channel from the cytosolic side and blocks Na+ current The non-ionised form can gain access to the same site within the channel through the membrane (hydrophobic pathway) More AP - More LA enters channels = better block |
| QX-314 and QX-222 | Permanently charged Cannot pass through the membrane and can only cause block of Na+ current when they are introduced into the cytosol Important experimental tools for understanding action of LAs |
| Nociceptor specific anaesthesia | Charged LAs can block ion channels when mixed with capsaicin Capsaicin activated TRPV1 channels which can accommodate permeation of QX-314 which cannot cross the membrane This allows local anaesthetic action of QX-314 only n nerves expressing TRPV1 |
| Use of Lignocaine | Combinations of lignocaine, capsaicin and QX-314 can block sensory nerves expressing TRPV1 in a way that outlasts blockage of motor nerves |
| Use dependence of Na+ channel block by lignocaine | The more stimulus of the nerve the better the blockade Local anaesthetics can only enter open Na+ channels So the more the neuron is fired, the more Na+ channel will be open and the more LA that will enter |
| Access of LA to channels via the membrane | Na+ channel have holes in the side known as side portals This allows neutral local anaesthetics into the channel via the membrane through the hydrophobic pathway |
| Effect of Local anaesthetics on K+ channels | LAs can also block K+ channels This still blocks the action potential so has the same effect E.g. Benzocaine |
| Use of vasoconstrictors with LA | LA may produce some degree of vasodilation and may be rapidly absorbed after local injection LAs are normally mixed with adrenaline Addition of a vasoconstrictor has several effects |
| Benefits of adding a vasoconstrictor to LAs | Decreases peak plasma concentration, decreasing systemic toxicity and reducing rate of absorption Increases duration and quality of anaesthesia Reduces minimum concentration needed for nerve block Decrease blood loss in a surgical procedure |
| How does adrenaline cause local vasoconstriction | Binds to alpha 1 receptors - converts PIP2 to IP3 and GAG which triggers Ca release. This binds to calmodium leading to smooth muscle contraction Binds to alpha 2B receptors which activates PKA and leads to relaxation |
| Effects of tetrodotoxin | A specific and potent blocker of Na channels Not all channels are susceptible Works extracellularly, so does not easily cross nerve sheath and perineuronal tissues that surround bundles of neurons Can use lower concentrations |
| Examples of Na+ channel toxins | Tetrodotoxin ATX-II alpha-scorpion toxins Beta scorpion toxins Batrachotoxin Hanatoxin Pompilidotoxins |
| Local anaesthetics and arrhythmias | Local anaesthetics exhibit antiarrhythmic properties According to Vaughan William's classes of antiarrhythmic agents, local anaesthetics are Class 1 Class 1 drugs block Na+ channels - use dependant blockers |
| Class 1A antiarrhythmics | Block Na+ channels in cardiac cells, which slows the rate of channel recovery from inactivation prolonging the AP and recovery period Used for a wide range of arrhythmias including supraventricular and atrial fibrillation E.g. Quinidine, Procainamide |
| Class 1B antiarrhythmics | Block Na+ channels with faster kinetics than 1A. Minimal effect on AP and refractory period Used mainly for ventricular arrhythmias in the context of acute myocardial infarction E.g. Lidocaine and Mexiletine |
| Class 1C antiarrhythmics | Block sodium channels but have the slowest kinetics. Have large effect on conduction velocity and slow down impulse propagation Used for ventricular arrhythmias in ventricular tachycardia Not used in patients with structural heart disease Flecainide |
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