Local Anaesthetics Flashcards
What are piezo receptors?
Piezo proteins constitute a family of excitatory ion channels directly gated by mechanical forces. These ion channels are involved in cell mechanotransduction — the conversion of mechanical forces into biological signals
Describe TRPV1 channels
Vannilinoids; non selective cation channels that respond to thermal stimuli
Sodium moves via conc gradient to depolarize the membrane potential
What are the sodium and potassium equilibriums respectively?
Sodium; 60 mV (depolarization)
Potassium; -80mV (hyperpolarization)
Describe the different phases of the action potential
Resting state (A); primary ion channel open is the potassium leak channel (constitutive channels)
Depolarizing phase (B); voltage activated sodium channels open, allows sodium influx. Initially K+ channels are closed, they activate more slowly
Repolarizing phase (C); Na+ become inactive, K+ opens allowing for K+ efflux
Undershoot (K); sodium channels not deactivated, K+ open. Membrane potential becomes hyperpolarized
Back to the resting state (A)
What is the threshold for an AP?
-50mV; IF the sodium channels are in the resting state
All or none
What is the difference between inactivation and deactivation?
Inactivation; channel otherwise in open state, but has become inactivated (h gate closes)
Deactivation; ion channel closes (M gate)
What do C fibres respond to?
Polymodal; temp, mechanical, inflammatory
Inflammatory mediators; bradykinin, serotonin, prostaglandin and histamine)
Why is there a difference in conduction between unmyelinated and myelinated axons?
In unmyelinated axons; the whole membrane is required to become depolarized for conduction of the action potential
Myelinated axons; Schwann cells allow for insulation, action potentials can undergo salutatory conduction whereby they jump from one node of Ranvier to the next
What mediated fast and slow pain?
Fast pain; A-delta (blocked by LA)
Slow/ second pain; C-fibres (blocked by NSAIDs and LAs)
What is the site of action of LA?
Voltage activated sodium channels
Which aspects of the voltage activated sodium channel acts as voltage sensors?
4th membrane spanning domain of 1,2,3 and 4th repeat
6 spanning transmembrane proteins
Voltage sensor on 4th domain (+ve charged amino acids that respond to membrane potential)
Re-entrant loop between 5 and 6 - lines the ion channel pore. Enables the ion channel to attract +ve Na+ ions
H-gate (inactivation part)
N and C terminal are intracellular
Are there different types of sodium channels?
Yes; SNC 1-11
TTX sensitive isoforms generally activate at more depolarized potentials compared to TTX resistant forms
There are 4 beta subunit genes (b1-4)
NaV 1.7, 1.8, 1.9 are nociceptive
NaV 1.3 are also involved with nociceptive transmission
What is the difference between how TTX and LA block these voltage activated Na+ channels
TTX extracellularly blocks the channel. Independent of inactivation
LA gains access to the channel through the intracellular environment or lipid bilayer and trans versing the channel. Use dependent block; the channel must be activated for LA to block. Highest affinity when it enters the inactivated state, stabilises the channel in the inactive state
What is the difference between an ester and an amide LA?
Lidocaine; amide
Cocaine; ester
All LA have an aromatic portion (benzene ring) - allows for lipid solubility and hydrophobicity
Intermediate chain; longer the chain, the more lipid soluble the LA
Amine portion; enables charge at appropriate pH
Amides; contain an amide link (nitrogen and hydrogen)
Ester link; carbon to oxygen link
What LAs are esters and amides
Ester; cocaine, procaine, tetracaine, benzocaine
Amides; lidocaine, mepivacaine, bupivacaine, etidocaine, prilocaine, ropivacaine
Why does it matter whether a LA is an ester or an amide?
Dictates the route through which the LA can become metabolised
Esters; Short duration (metabolized by plasma and liver pseudocholinesterase's) Allergies; most likely for esters - PABA metabolites produced by metabolism through pseudocholinesterase's
Amides;
Longer duration of action; metabolised in liver CYP3A4 p450 enzyme
When administered correctly, LA do not have behavioural effects . If enters systemic circulation; visual or taste symptoms (systemic toxicity). LA in CNS; block lots of ion channels causing seizures - treat with BZD
What does it mean to be amphipathic?
A molecule that is both hydrophilic and hydrophobic
Are LA amphipathic?
Yes
Contain an amine group (can be uncharged or charged)
Uncharged; basic
Charged; proton acceptor; cationic form. At physiological pH, the cationic form cannot enter the cell to block the sodium channel, limits the level of LA that can enter the cells