4. Bupivacaine, Ropivacaine, Lidocaine and Prilocaine & Adjuncts Flashcards
Definitions:
four are local anaesthetics which produce a reversible block of
neuronal transmission, and which are synthetic derivatives of cocaine.
They each possess the same three essential functional units,
namely a hydrophilic chain joined
by an amide linkage to a lipophilic aromatic moiety
Structures
: The parent compound of ropivacaine and bupivacaine is
MEpivacaine, which has a single MEthyl group attached to the tertiary amine.
BUpivacaine is identical apart from a BUtyl (C4H9) side chain.
The structure of ROPivacaine differs only in its shorter pPROyl (C3H7) substituent
on the piperidine nitrogen atom.
Prilocaine has a different structure in the lipophilic moiety with a single methyl group on the aromatic ring (unlike the 2,6-xylidine ring in the other amides)
: Chloroprocaine > Lidocaine/Prilocaine > Bupivacaine/ Ropivacaine.)
latency of local anaesthetics is related to their pKa
Potency
Potency: this is determined primarily by lipid solubility, which is increased by the
substitution of longer side chains. Bupivacaine’s longer butyl (C4H9) side chain
increases at least threefold its lipid solubility in comparison with ropivicaine with
its shorter propyl (C3H7) substituent
Protein binding:
this is also affected by structural differences in the molecule.
The affinity of local anaesthetics for the sodium channel
is related to the length of the aliphatic chains.
Duration: bupivacaine 175’ > ropivacaine 150’ > lidocaine/prilocaine 100’.)
Toxicity:
The cardiovascular and CNS toxicity of bupivacaine, however, is a
function of the R (+) enantiomer.
The S (−) enantiomer has less affinity for, and
dissociates faster from, myocardial sodium channels.
This is now available as levobupivacaine (Chirocaine), and would appear
to be no more dangerous than ropivacaine.
(Toxicity: bupivacaine >
levobupivacaine > ropivacaine > lidocaine > prilocaine.)
methaemoglobinaemia
Prilocaine is both less lipid-soluble and more weakly
protein-bound than lidocaine, yet plasma concentrations are lower even when the
same dose is given by the same route,
and it is some 40% less toxic
toluidine ring is more rapidly metabolized to ortho (o)-toluidine
ortho-toluidine metabolite causes methaemoglobinaemia by
oxidizing the ferrous iron in haemoglobin to the ferric state
methaemoglobin crosses the placenta, this
further compromises oxygen delivery to the fetus, and so prilocaine is generally avoided in pregnancy.
Sensory–motor dissociation
capacity of a local anaesthetic to block sensory nerves preferentially while sparing motor nerves
continuous epidurals for labour and for surgical analgesia.
It is well known that this group of local anaesthetics demonstrates
preferential sensory block; the purported superiority of ropivacaine is illusory
and is based on the fact that it is simply a less potent drug
Frequency dependence:
which helps to explain true sensory– motor dissociation
Drug entry into the sodium channels occurs when the channel is
open during the period of membrane depolarization
pain and sensory fibres conduct at high frequency, whereas motor
impulses are at a lower frequency.
sodium channels are open
more times per second
Lidocaine, prilocaine, bupivacaine and ropivacaine all produce
a more rapid and denser block in these sensory nerves of higher frequency
Metabolism
: amide local anaesthetics bind mainly to α1-acid glycoprotein (highaffinity,
low-capacity binding site), and to albumin (low-affinity, high-capacity).
They undergo aromatic hydroxylation, amide hydrolysis and N-dealkylation (phase 1
reactions) in the liver. There is some suggestion of extrahepatic pulmonary metabolism
(uptake and sequestration is greatest with prilocaine).
Spinal opioids
Both onset and duration of action are related to the lipid solubility of the drug.
Duration:
Morphine has low lipid solubility, = 18 hours
whereas that of fentanyl is high, = 2–4 hours
Lipophilicity
lipophilic drugs cross rapidly into the cord, while hydrophilic
agents remain partly within the CSF,
in which they may be carried rostrally to act on higher centres.
delayed respiratory depression
may be caused
morphine than with other drugs, and is
better monitored by sedation scoring than respiratory rate
complications of spinal opioids include nausea, vomiting, urinary
retention and pruritus
A logical alternative treatment,
which can be useful for pruritus, is intravenous nalbuphine
Opioid receptors:
the specific receptors that are located in the dorsal horn of the spinal cord
They are
most densely concentrated in the substantia gelatinosa,
which comprises lamina II
and part of lamina III of the laminae of Rexed
75% of the receptors are
pre-synaptic, and they mediate inhibition of the release of nociceptive transmitters
such as substance P
Vasoconstrictors:
evidence that the addition of
vasoconstrictors does not have a consistent action; the addition of adrenaline prolongs
the action of intrathecal amethocaine, for example, but has little effect when
added to bupivacaine or lignocaine.
α2-agonists:
Pre-synaptic
activation inhibits noradrenaline release from the nerve terminal and thereby influences
descending pathways
Clonidine doubles the duration of action of intrathecal bupivacaine, prolonging
both sensory and motor block
hypotension, dry mouth
and sedation.
Dexmedetomidine is both more potent
and more α2-selective.
