Pharmacology 19b – Local Anaesthesia
Anil Chopra
1 Revise the properties of electrically excitable cells that underlie the generation of
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neuronal action potentials.
Note the general chemical structures of local anaesthetics (LAs) and the two main
classes into which they can be divided. Name one drug from each class.
Describe the principal cellular mechanism of action of LAs. How does this give
rise to the property of ‘use-dependency’ of these agents?
Identify the effects of LAs on i) AP generation and propagation and ii) resting
membrane potential. How and why do these effects differ in infected tissue
compared to healthy tissue?
Outline the six main routes of administration of LAs, including their clinical
usefulness. Why are vasoconstrictor substances often co-administered with LAs?
Describe the pharmacokinetic properties of i) lidocaine and ii) cocaine, indicating
how their respective routes of metabolism influence their plasma half lives.
List and compare the major unwanted effects of lidocaine and cocaine on i) the
CNS and ii) the CVS.
Generation of Action Potentials
The generation of an action potential
takes place in a number of steps:
i. Na+ channels open causing an influx
of Na+ ions and thus depolarisation.
ii. When the membrane potential gets to
around +40mV, the Na+ channels
close and the K+ channels open. This
causes a huge efflux of K+ ions
causing repolarisation of the cell.
iii. Na+ channels begin to open again
and K+ channels close.
iv. Na+ and K+ channels restored to their
normal state.
Fig. 1: Generation of a neuronal action potential
ii Na+ channels close
(inactivation)
K+ channels open, K+
leaves cell
0 mV
iii Na+ channels
restored to resting
state but K+
channels still open
Resting Na+
channels open
Na+ enters cells
i
Local Anaesthetics
The structure of local anaesthetics
consists of an aromatic region, an ester
or amide bond and an amide side
chain. (exception is benzocaine which
has no basic amine acid side chain)
Names
-70 mV
(m secs)
iv
Depolarization
Na+ and K+ channels
restored to resting state
therefore cell will respond
normally to further
depolarizing stimulus
Procaine, cocaine, Tetraqcaine, Cinchocaine, Lidocaine, Prilocaine, Bupvacaine,
Benzocaine.
Usage
 Surface Anaesthesia
o These are used at mucosal surfaces (mouth, bronchial tree)
o Comes in the form of a spray (powder)
o At high concentrations can cause systemic toxicity
 Infiltration anaesthesia
o Injected directly into tissues so it affects sensory nerve terminals.
o Used in minor surgery
o Adrenaline is co-injected. (NOT extremities)
 Intravenous Regional Anaesthesia
o Injected i.v. distal to a pressure cuff
o Used in limb surgery
o Systemic toxicity can be caused if the cuff is released prematurely.
 Nerve block anaesthesia
o Close to nerve trunks e.g. dental nerves
o Widely used – low doses – slow onset
o Co-injected with a vasoconstrictor.
 Spinal anaesthesia
o Injected into the sub-arachnoid space – spinal roots
o Used in abdominal, pelvic or lower limb surgery
o Causes a decrease in blood pressure resulting in a prolonged headache.
 Epidural Anaesthesia
o Injected into fatty tissue of epidural space – spinal roots
o Uses as for spinal anaesthesia and painless childbirth
o Slower onset – higher doses
Mode of Action
Local anaesthetics disrupt ion channel
function within the neurone cell membrane
preventing the transmission of the neuronal
action potential. This is thought to occur via
specific binding of the local anaesthetic
molecules (in their ionised form) to sodium
channels, holding them in an inactive state
so that no further depolarisation can occur.
Fig. 3:
Interaction of local anaesthetics
with sodium channels
BH+
B
B
B
B
BH+
Na+
H+
BH+
BH+
CHANNEL
OPEN
Hydrophobic
pathway
Hydrophilic pathway
(use-dependent)
Na+
H+
BH+
BH+
CHANNEL
CLOSED
B
Outside
Connective
tissue sheath
B
Inside
Membrane
There are 2 pathways by which this occurs:
Hydrophilic Pathway
- Main mode of action
- Non ionised local anaesthetics must gain access to the inside of the cell
neurone to become effective
- Inside the neurone the anaesthetic becomes ionised and binds to the inside of
voltage gated Na+ channels causing blockage
- It is use dependent i.e. the more active the neuron, the more local anaesthetic
binds (because the Na+ channels have to be open to bind)
Hydrophobic Pathway
- Secondary mode of action
- When the local anaesthetic passes through the membrane, some enters the Na
channel from the outside (when the Na+ channel is closed)
- This only accounts for around 10% of the local anaesthetic as they are
normally weak bases (so they ionise quickly)
Side Effects and Pharmacokinetics
Lidocaine:
- well absorbed
- 70% binds to plasma proteins
- Metabolised hepatically by N-alkylation
- ½ life of 2 hrs
- Can causes restlessness, confusion and tremor in CNS
- Can cause vasodilation, drop in blood pressure, and myocardial depression.
Cocaine
- well absorbed
- 90% binds to plasma proteins
- Metabolised in the liver and plasma by esterases
- ½ life of 1 hr.
- Can cause euphoria and excitation in CNS
- Can cause increase in heart rate and stroke volume, vasoconstriction and
increase in blood pressure