Core pharmacology

Class Group

Amide Local Anaesthetic

Legacy Cicm Level

Level 1

Indications Uses

local anaesthetic

Chemical Pharmaceutics

amino amide which is member of the pipecoloxylidide
group of local anaesthetics

Presentation

- As a clear, colourless solution containing racemic ropivacaine hydrochloride monohydrate (s- and R-enantiomers) in concentrations of 0.2/0.75/1.0% equivalent to 2.0, 7.5, and 10 mg/ml, respectively,
of ropivacaine hydrochloride.

A pure s-ropivacaine preparation is also
available.

It is not available in combination with a vasoconstrictor, as this
does not alter its tissue uptake or the duration of action.

The pKa of ropivacaine is 8.1, and it is 15% unionized at pH 7.4. The heptane:buffer partition
coefficient is 2.9.

The preparation also contains sodium hydroxide equivalent to 3.7 mg of sodium per ml

Main Action

Local anaesthetic

Mechanism of action

Local anaesthetics diffuse in their uncharged base form
through neural sheaths and the axonal membrane to the internal surface
of cell membrane Na+ channels; here they combine with hydrogen ions
to form a cationic species which enters the internal opening of the Na+
channel and combines with a receptor. This produces blockade of the Na+
channel, thereby decreasing Na+ conductance and preventing depolarization of the cell membrane.

s-ropivacaine is more potent and less cardiotoxic than R-ropivacaine.

Physiological effects

CVS Ropivacaine is less cardiotoxic than bupivacaine; in toxic concentrations, the drug decreases the peripheral vascular resistance and myocardial
contractility, producing hypotension and possibly cardiovascular collapse.
Ropivacaine has a biphasic vascular effect, causing vasoconstriction at low,
but not at high, concentrations.
CNS The principal effect of ropivacaine is reversible neural blockade; this
leads to a characteristically biphasic effect in the CNs. Initially, excitation
(light-headedness, dizziness, visual and auditory disturbances, and seizure
activity) occurs due to inhibition of inhibitory interneurone pathways in the
cortex. With increasing doses, depression of both facilitatory and inhibitory
pathways occurs, leading to CNs depression (drowsiness, disorientation,
and coma). Local anaesthetic agents block neuromuscular transmission
when administered intraneurally; it is thought that a complex of neurotransmitter, receptor, and local anaesthetic is formed, which has negligible
conductance.
GU Ropivacaine does not compromise uteroplacental circulation.

Adverse Effects Toxicity

Allergic reactions to the amide-type local anaesthetic agents are extremely rare. The side effects are predominantly correlated with excessive plasma concentrations of the drug, as described above

Absorption

The absorption of local anaesthetic agents is related to:
1. the site of injection (intercostal > caudal > epidural > brachial plexus >
subcutaneous)
2. the dose—a linear relationship exists between the total dose and the
peak blood concentrations achieved and
3. the presence of vasoconstrictors which delay absorption.

Distribution

Demonstrates a biphasic absorption profile from the epidural space, with half-lives of 14 minutes and 4 hours in adults.

Protein binding

94%
predominantly to alpha-1 acid glycoprotein

Volume of distribution

52–66 L

Metabolism

Ropivacaine is metabolized in the liver by aromatic hydroxylation via cytochrome CYP1A2 to 3-hydroxy-ropivacaine, the major
metabolite, 4-hydroxy-ropivacaine, and 4-hydroxy-dealkylated-ropivacaine.
Co-administration of a CYP1A2 inhibitor (e.g. fluvoxamine, enoxacin) may
reduce plasma clearance of the drug by up to 77% in vitro. The isoenzyme
CYP3A4 is also involved in the metabolism of ropivacaine, as administration of a CYP3A4 inhibitor (e.g. fluconazole) reduces the plasma clearance
of the drug by 15% in vitro, although this is unlikely to cause a clinically
significant effect. Ropivacaine has an intermediate hepatic extraction ratio
of approximately 0.4. There is no evidence of in vivo racemization of
ropivacaine.

Excretion

86% of the dose is excreted in the urine, 1% unchanged; 37% of 3-hydroxy-ropivacaine is excreted in the
urine, predominantly conjugated.

Clearance

0.44–0.82 l/min

Half-life

terminal elimination
half-life is 59–173 minutes.
The elimination half-life is longer after epidural (4.2 hours) than after intravenous administration due to the biphasic absorption from the former, as described above.

Special Points

The onset and duration of conduction blockade are
related to the pKa, lipid solubility, and the extent of protein binding. A low
pKa and high lipid solubility are associated with a rapid onset time; a high
degree of protein binding is associated with a long duration of action. Local
anaesthetic agents significantly increase the duration of action of both
depolarizing and non-depolarizing relaxants.

Route And Dose

Ropivacaine may be administered
topically, by infiltration, or epidurally; the drug is not currently intended for
use in spinal anaesthesia.

The maximum recommended dose of ropivacaine
is 3 mg/kg.

sensory blockade is similar in time course to that produced by bupivacaine; motor blockade is slower in onset and shorter in duration than
that after an equivalent dose of bupivacaine.

Alkalinization of 0.75% ropivacaine significantly increases the duration of action of epidural blockade.