Local Anaesthetics

Question 1

Local anaesthesia

Answer 1

Regional anaesthesia

The goal is to reversibly
block sensory perception
of pain, with the patient’s
consciousness maintained

Question 2

A good LA should be

Answer 2

Soluble in water and stable in

solution preparations

Question 3

Cocoa was derived from

Answer 3

Cocaine

Question 4

Due to cocaines structure, LA have 3 structural requirements:

Answer 4

1. Lipophillic group (aromatic
   ring)
2. intermediate bond (ester
   or amide linkage)
3. hydrophillic group (basic
   amine side chain; either
   tertiary or quaternary
   amino group).

Question 5

Common LAs

The ‘Caines’

Answer 5

Procaine,
Lidocaine
Bupivicaine, and
Tetracaine

Question 6

Procaine

Answer 6

Less toxic and not addictive like cocaine!

very long time of onset of anaesthetic,

wore off too quickly,

was not nearly as potent as cocaine.

causes vasodilation, so is quickly
absorbed away from injection site.

is an ester, and has a very high potential
to cause allergic reactions ~(1:100).

Question 7

Procaine treats

Answer 7

procaine is combined with penicillin and used in deep intramuscular
injection for slow absorption

Question 8

Esters (except cocaine) are inactivated by:

Answer 8

plasma esterases, and excreted via urine.

Cocaine is metabolized in liver

Question 9

Lidocaine

Answer 9

is an amide and hypoallergenic
as the amide linkage does not
sensitize patients.

anaesthetic effect occurs quickly,

causes vasodilation at the injection
site, so is quickly absorbed away

Question 10

Amide LAs are degraded by

Answer 10

CYP450s
in the liver, so hepatic disease
requires caution in use.

Question 11

How do we resolve the vasodilation issue with

procaine and lidocaine/lignocaine?

Answer 11

Cocaine blocks noradrenaline reuptake
transporters as well, which increases NA and
leads to vasoconstriction.

these LAs lack this NA effect, causing
vasodilation of the local blood vessels,
increasing the blood flow in the area and
absorption into circulation before it have
complete effect, increasing adverse effects.

Therefore, these synthetic anaesthetics are
always mixed with low concentrations of
adrenaline which causes vasoconstriction and
slows blood flow through the area, keeping
anaesthetic in position long enough to
produce long-lasting numbness (1-2 hours).

Question 12

All local anaesthetic agents are weak bases T/F

Answer 12

True

Question 13

At physiological pH (7.4) all local anaesthetics are

Answer 13

more ionised than un-ionised as all

pKa values are greater than 7.4.

Question 14

Ionised molecules of any size are

Answer 14

much less likely to cross the nerve sheath and

axonal phospholipid bilayer of the neuron unassisted by transport proteins.

Question 15

Un-ionised molecules may be

Answer 15

hydrophobic/lipophillic enough to enter/cross the

neuronal membrane without assistance.

Question 16

Commercial LA solutions are designed to have an

Answer 16

acidic pH, which maximises

water solubility and chemical stability – increasing shelf-life.

Question 17

Prior to injection, alkali (sodium bicarbonate) can be added to raise pH to that of
tissues (pH 7.4).

Answer 17

This increases the proportion of non-ionised drug present, and reduces pain felt by the patient

Question 18

Un-ionised drug will enter the neuron more readily than ionised drug. T/F

Answer 18

True

Question 19

Why shouldnt you inject a LA into inflammed tissue?

Answer 19

Infected tissue may also have an increased
blood supply and hence more anaesthetic
may be removed from the area before it can
affect the neurons.

Question 20

The target of LAs

Answer 20

Voltage-dependant sodium ion channels

Question 21

LAs have greater affinity for inactivated channels, and by binding to them, they
prevent channels from re-opening. Thus, there appears to be a “loss of ion
channels (and ion current)” during a train of pulses.

Answer 21

LAs have greater affinity for inactivated channels, and by binding to them, they
prevent channels from re-opening. Thus, there appears to be a “loss of ion
channels (and ion current)” during a train of pulses.

Question 22

90% of LA block occurs via the

Answer 22

Hydrophillic pathway

 only if the charged
form of the LA can enter
sodium ion channels from
the inside when they open,
as they bind to a site within
the pore region when
inactivated

Question 23

If a neuron is actively firing

action potentials,

Answer 23

these
sodium ion channels will
open frequently, allowing
greater access of the LA
molecule to the inner pore
region

Question 24

10% of LA block occurs via the

Answer 24

Hydrophobic pathway

The blocking site
within the sodium ion
channel is thought to
be reached directly
from the membrane
by the uncharged B,
and the molecule will
become charged
upon arriving in the
cytoplasm (BH+) (10%
of action)

Question 25

most LA block is from

the intracellular side…

Answer 25

True
Only if the charged form of the
LA can enter sodium ion
channels from the inside when
they open, as they bind to a site
within the pore region when
inactivated.

Question 26

If a neuron is actively firing

action potentials,g.

Answer 26

these sodium
ion channels will open
frequently, allowing greater
access of the LA molecule to
the inner pore region, hence
use-dependent bindin

Question 27

Amide LAs are degraded by

Answer 27

CYP450s in the liver

Question 28

Esters (except cocaine) are

inactivated by

Answer 28

plasma esterases

Question 29

LAs have greatest effect on

Answer 29

small diameter afferent neurons of the
peripheral nerves, making them useful in reducing pain
transmission.

Non-myelinated C fibres with low conduction velocities

Myelinated (Ad) fibres with rapid conduction velocities due to
saltatory conduction.

Question 30

The dorsal root senses

Answer 30

Pain

High sensitivity to block

Question 31

Delta senses

Answer 31

Pain and temperature

Moderate sensitivity to block

Question 32

Adverse effects of LAs

Answer 32

Temporary weakness or paralysis of the
affected area.

• This is often useful after
  surgery, and wears off with time.

In the CNS, high concentrations have a
biphasic effect.
–> temporary weakness or paralysis of the
affected area. This is often useful after
surgery, and wears off with time.
• In the CNS, high concentrations have a
biphasic effect.

Question 33

Should LAs affect the cardiovascular

system:

Answer 33

a reduction in myocardial
contractility and force of contraction can
occur due to block of cardiac Na+
channels reducing phase 0 of the cardiac
action potential. Decreased Na+
movement reduces Ca2+ mobility as well.

Question 34

Bupivicaine: an example of cardiotoxicity

Answer 34

A widely used amide local anesthetic, bupivicaine can be used
for prolonged anesthesia. Its long duration of action plus its tendency to provide more sensory than motor block make it
popular for providing prolonged analgesia during labor or the
postoperative period.

Bupivacaine dissociates much
more slowly than does lidocaine during diastole, so a
significant fraction of Na+ channels at physiological heart rates
remains blocked with bupivacaine, giving rise to adverse
effects

Question 35

Bupivacaine is more cardiotoxic (severe ventricular

arrhythmias and reduced heart function) than

Answer 35

equal doses of

lidocaine if it reaches sufficient systemic concentrations.