23. Local Anaesthetics Flashcards
How are local anaesthetics classified?
what are they composed of
All local anaesthetics are
composed of an
aromatic group
linked to an
amine group via
an intermediate link chain.
It is the nature of this link that classifies
local anaesthetics as either esters or amides.
Amide local anaesthetics:
> The amides all contain an
‘i’ in the drug name
followed by ‘caine’,
e.g. lignocaine, bupivacaine, levobupivacaine, ropivacaine, prilocaine and etidocaine.
> They are extensively bound
to α1-acid glycoprotein
and albumin in the plasma.
Binding decreases with a
reduction in pH,
so that hypoxia and
acidosis can lead to toxicity.
> They undergo hepatic metabolism
by hepatic amidases.
Therefore, metabolism is affected
in conditions resulting in
reduced hepatic blood flow.
> Local anaesthetic preparations may
contain the preservative
sodium metabisulphite
or
methyl parahydroxybenzoate.
These preparations should not be used for subarachnoid injection,
as they have been
associated with arachnoiditis.
> They are stable in solution and
have a shelf-life of approximately two years.
Ester local anaesthetics:
examples
brokendown
differ from amide…
> Examples of esters include
cocaine, amethocaine and procaine.
(A way to remember: CAPE: Cocaine, Amethocaine, Procaine = Esters)
> Undergo hydrolysis by
pseudocholinesterases found
principally in plasma.
> Compared to amides,
esters are unstable in solution,
and the incidence
of hypersensitivity reactions is
greater with esters,
often due to the breakdown product
p-aminobenzoic acid (PABA).
How do local anaesthetics exert their effects?
> Local anaesthetics act by
blocking sodium channels.
> They are weak bases with a pKa > 7.4.
This means that they are ionised
at physiological pH (7.4).
> Open sodium channel block –
In the un-ionised form the local
anaesthetics are lipid soluble,
which allows transfer of the drug
across the neuronal membrane
into the axoplasm (pH 7.1),
where the drug subsequently
becomes ionised,
blocking the sodium channels in the
neuronal membrane from ‘inside’.
This stabilises the membrane and
prevents the generation
of further action potentials.
Local anaesthetics bind more avidly to sodium channels that are inactivated or open, and so they are more likely to affect nerves that have a rapid firing rate.
Pain and sensation nerves fire at a higher frequency than motor and so they are blocked preferentially, though all excitable membranes can be affected.
This is called ‘state-dependent blockade’.
> Closed sodium channel block
(membrane expansion theory) –
The un-ionised local anaesthetic
dissolves in the neuronal membrane
resulting in swelling of the
neuronal membrane and
consequent physical inactivation of
neuronal sodium channels
preventing depolarisation of the neuron.
What factors govern the potency of a local anaesthetic?
> The more lipid soluble the drug, the greater its potency, e.g. bupivacaine is seven times more lipid soluble than lignocaine and therefore more potent.
What factors govern the duration of action?
> The more protein bound the drug,
the longer its duration of action,
e.g. bupivacaine is 95% protein bound
and has a longer duration of action
than lignocaine,
which is 65% protein bound.
> Addition of vasoconstrictors, such as adrenaline, also prolongs the duration of action by reducing washout of the drug into the bloodstream.
What factors govern the speed of onset?
how can speed be improved
> Speed of onset of action is
closely related to the
pKa and the resulting
degree of ionisation.
> Local anaesthetics with a lower pKa (close to pH 7.4) will have a higher un-ionised fraction than those with a higher pKa.
This means that a greater proportion
of the administered dose will
be available to cross the neuronal membrane,
and so the drug will take effect more quickly.
At physiological pH (7.4),
bupivacaine (pKa 8.1) is 15% un-ionised.
Lignocaine (pKa 7.9) is 25% un-ionised
and therefore has a faster onset
of action.
> Clinically, bicarbonate may be added to some epidural solutions to raise the pH of the solution and therefore cause the local anaesthetic to be more un-ionised, resulting in faster onset of block.
> Infected tissue and abscesses
are associated with a reduced local pH.
This results in a higher fraction
of the local anaesthetic becoming ionised,
reducing its efficacy.
Reducing efficacy further is the increased local
blood flow to the infected area, causing local anaesthetic washout.
How does the rate of systemic vascular absorption of local anaesthetic agents vary?
The site of injection is important especially in
terms of toxicity as the rate of
systemic vascular absorption
of local anaesthetic varies:
> Intercostal space > Caudal > Epidural > Brachial Plexus > Femoral > Subcutaneous
What are the salient features
of the commonly used local
anaesthetics?
Lignocaine:
Lignocaine:
> Amide
> Fast onset (pKa 7.9)
> Medium duration of action (70% protein bound)
> Moderate vasodilatation
> Max dose 3 mg/kg or 7 mg/kg with adrenaline
Bupivacaine:
> Amide
> Racemic mixture of R and S enantiomers
> Long duration of action (95% protein bound)
> Max dose 2 mg/kg
> Extremely cardiotoxic in overdose
Levobupivacaine
> Amide
> S enantiomer of bupivacaine
> Long duration of action (95% protein bound)
> Less cardiotoxic in overdose than bupivacaine
> Max dose 2 mg/kg
Ropivacaine
> Amide
> Long duration of action (94% protein bound)
> More selective sensory
neuronal blockade, less motor block
> Less cardiotoxic than
both bupivacaine and levobupivacaine
> Max dose 3.5 mg/kg
Prilocaine
> Amide
> Fast onset (pKa 7.8).
> Medium duration of action
(56% protein bound)
> Contained in EMLA
(5% Eutectic Mixture of Local Anaesthetic –
2.5% lignocaine and 2.5% prilocaine)
> Methaemoglobinaemia
can occur at high doses
(due to breakdown product O-toluidine)
> Less toxic than lignocaine
> Used in intravenous regional anaesthesia
(Bier’s block)
> Maximum dose 6 mg/kg (9 mg/kg with felypressin)
Cocaine
> Ester
> Short duration of action
> Profound vasoconstriction –
constituent of Moffat’s solution (topical)
> Blocks neuronal re-uptake 1 and stimulates CNS
> Side effects include hypertension, hallucinations, seizures and coronary
ischaemia
> Max dose 3 mg/kg
