, ANAESTHETICS
All LAs are weak bases (Aspirin is weak acid). At
physiological pH are mostly ionized. To penetrate the
membrane uncharged form is required but to interact
with VGSC from intracellular space cationic form is
necessary. If bicarb added to the solution -> faster onset
of action in inflamed tissue with low pH. Las show
frequency-dependent and voltage-dependent block
meaning the higher the frequency of Aps (higher the pain)
-> the greater the eventual block + LA bound channels
recover much more slowly.
VGSC: alpha subunit has 4 domains each of them
composing of 6 transmembrane units.
S4 – voltage sensor
S5-S6 – form pore
S6 – LAs thought to bind here
Lidocaine is AMID-TYPE. Has longer T1/2 = 2h (With
Epinephrine = 3h) due to it’s metabolism in liver (CYP3A4
BDZs, Z-compounds, Haloperidol, Quetiapine, Citalopram,
Escitalopram, Sertraline) not in plasma/tissue. Also Ib
VGSC blocker. (Lowers the AP duration in Cardiac
myocyte). If use parenteral in areas like nose, ears,
fingers, penis do not co-use with adrenaline -> increased
chance of tissue necrosis.
Toxicity: Starts at 5ug/ml. Seizures at 8ug/ml.
,Benzocaine is ESTER-TYPE. Metabolised by plasma/tissue
esterases. Onset of action: 1 min. Duration: minutes.
Interactions: AChE inhibitors -> decreased benzocaine
metabolism
Allergies -> degraded by esterases to paraaminobenzoic
acid
Methemoglobinaemia: DON’T USE IN <2y.o.
Cocaine is ESTER-TYPE. Metabolised by plasma/tissue
esterases. Duration of action: 15 min – 1 h. TOPICAL USE
ONLY (spray/paste). S/Es: hyperthermia, euphoria,
vasoconstriction (headache), seizures.
Interactions: AChE inhibitors (Myasthenia gravis,
Alzheimers) - > increase duration of action.
MAOIs -> risk of hypertension
Other sympathomimetics
Elderly/children
High doses: seizures & bronchoconstriction.
LD50 = 500mg
LAs S/Es:
All to some degree VGSC blockade in cardiac
myocytes (as they all are VGSC Blockers!)-> slows
phase 0 -> prolongs QRS -> cardiac depression.
Spinal block: cauda equina syndrome ->
urinary&faecal incontinence. May be permanent
paralysis unless treated quickly
, Transient neurologic syndrome: increased pain in
buttocks&legs. No other tissue.
Care in individuals with atypical/mutant plasma
esterases.
With adrenaline: vasoconstriction (headache),
tachycardia -> CV events, tissue necrosis on ears,
nose, fingers, penis.
GENERAL ANAESTHETICS
MOA: Almost all enhance action of GABA at the GABAa
receptor. Except:
Xenon is competitive antagonist of glycin binding site
on NMDA receptor (glycine is facilitator, required for
glutamate action at NMDA receptor)
Ketamine non-competitive is NMDA (excitatory
glutamate receptor) receptor blocker
NO2 similar to Ketamine
They all reduce excitatory activity at CNS.
Sites of action:
Two-pore domain K+ channels modulate neuronal
excitability through mechanism of hyperpolarization.
Do not affected by IV GAs (e.g. Propofol). Only by
gaseous and volatile.
VGSN: inhibition give rise to reduced excitability.
Volatiles
Glycine receptors: Gate Cl- -> hyperpolarization
K ATP channels: ADP&ATP gated
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