Ropivacaine Other names: Ropivacaine hydrochloride

Ropivacaine is a long-acting amide-type local anaesthetic with both anaesthetic and analgesic effects. At high doses ropivacaine produces surgical anaesthesia, while at lower doses it produces sensory block with limited and non-progressive motor block.

The mechanism is a reversible reduction of the membrane permeability of the nerve fibre to sodium ions. Consequently the depolarisation velocity is decreased and the excitable threshold increased, resulting in a local blockade of nerve impulses.

The most characteristic property of ropivacaine is the long duration of action. Onset and duration of the local anaesthetic efficacy are dependant upon the administration site and dose, but are not influenced by the presence of a vasoconstrictor (e.g. epinephrine). For details concerning the onset and duration of action of ropivacaine.

Healthy volunteers exposed to intravenous infusions tolerated ropivacaine well at low doses and with expected CNS symptoms at the maximum tolerated dose. The clinical experience with ropivacaine indicates a good margin of safety when adequately used in recommended doses.

Absorption and distribution

Ropivacaine hydrochloride has a chiral centre and is available as the pure S-(-)-enantiomer. It is highly lipid-soluble. All metabolites have a local anaesthetic effect but of considerably lower potency and shorter duration than that of ropivacaine hydrochloride.

The plasma concentration of ropivacaine hydrochloride depends upon the dose, the route of administration and the vascularity of the injection site. Ropivacaine hydrochloride follows linear pharmacokinetics and the C_max is proportional to the dose.

Ropivacaine hydrochloride shows complete and biphasic absorption from the epidural space with half-lives of the two phases of the order of 14 min and 4 h in adults. The slow absorption is the rate-limiting factor in the elimination of ropivacaine hydrochloride, which explains why the apparent elimination half-life is longer after epidural than after intravenous administration. Ropivacaine hydrochloride shows a biphasic absorption from the caudal epidural space also in paediatric patients.

Ropivacaine hydrochloride has a mean total plasma clearance in the order of 440 ml/min, a renal clearance of 1 ml/min, a volume of distribution at steady state of 47 litres and a terminal half-life of 1.8 h after intravenous administration. Ropivacaine hydrochloride has an intermediate hepatic extraction ratio of about 0.4. It is mainly bound to α1-acid glycoprotein in plasma with an unbound fraction of about 6%.

An increase in total plasma concentrations during continuous epidural infusion has been observed, related to a postoperative increase of α1-acid glycoprotein.

Variations in unbound, i.e. pharmacologically active, concentration have been much less than in total plasma concentration.

Since ropivacaine hydrochloride has an intermediate to low hepatic extraction ratio, its rate of elimination should depend on the unbound plasma concentration. A postoperative increase in AAG will decrease the unbound fraction due to increased protein binding, which will decrease the total clearance and result in an increase in total plasma concentrations, as seen in the paediatric and adult studies. The unbound clearance of ropivacaine hydrochloride remains unchanged as illustrated by the stable unbound concentrations during postoperative infusion. It is the unbound plasma concentration that is related to systemic pharmacodynamic effects and toxicity.

Ropivacaine hydrochloride readily crosses the placenta and equilibrium in regard to unbound concentration will be rapidly reached. The degree of plasma protein binding in the foetus is less than in the mother, which results in lower total plasma concentrations in the foetus than in the mother.

Biotransformation and elimination

Ropivacaine hydrochloride is extensively metabolised, predominantly by aromatic hydroxylation. In total 86% of the dose is excreted in the urine after intravenous administration of which only about 1% relates to unchanged ropivacaine hydrochloride. The major metabolite is 3-hydroxy-ropivacaine, about 37% of which is excreted in the urine, mainly conjugated. Urinary excretion of 4-hydroxy-ropivacaine, the N-dealkylated metabolite (PPX) and the 4-hydroxy-dealkylated metabolite accounts for 1-3%. Conjugated and unconjugated 3-hydroxy-ropivacaine shows only barely detectable concentrations in plasma.

Regarding metabolites a similar pattern has been found in paediatric patients above one year compared to adults.

There is no evidence of in vivo racemisation of ropivacaine hydrochloride.

Paediatric population

The pharmacokinetics of ropivacaine hydrochloride was characterised in a pooled population PK analysis on data in 192 children between 0 and 12 years. Unbound ropivacaine hydrochloride and PPX clearance and ropivacaine hydrochloride unbound volume of distribution depend on both body weight and age up to the maturity of liver function, after which they depend largely on body weight. The maturation of unbound ropivacaine hydrochloride clearance appears to be complete by the age of 3 years, that of PPX by the age of 1 year and unbound ropivacaine hydrochloride volume of distribution by the age of 2 years. The PPX unbound volume of distribution only depends on body weight. As PPX has a longer half-life and a lower clearance, it may accumulate during epidural infusion.

Unbound ropivacaine hydrochloride clearance (Clu) for ages above 6 months has reached values within the range of those in adults. Total ropivacaine hydrochloride clearance (Cl) values displayed in the table are those not affected by the postoperative increase in AAG.

Estimates of pharmacokinetic parameters derived from the pooled paediatric population PK analysis:

^a Median bodyweight for respective age from WHO database.
^b Unbound ropivacaine hydrochloride clearance
^c Ropivacaine hydrochloride unbound volume of distribution
^d Total ropivacaine hydrochloride clearance
^e Ropivacaine hydrochloride terminal half life
^f PPX terminal half life

The simulated mean unbound maximal plasma concentration (Cu_max) after a single caudal block tended to be higher in neonates and the time to Cu_max (t_max) decreased with an increase in age. Simulated mean unbound plasma concentrations at the end of a 72 h continuous epidural infusion at recommended dose rates also showed higher levels in neonates as compared to those in infants and children.

Simulated mean and observed range of unbound Cu_max after a single caudal block:

^a Unbound maximal plasma concentration
^b Time to unbound maximal plasma concentration
^c Observed and dose-normalised unbound maximal plasma concentration

At 6 months, the breakpoint for change in the recommended dose rate for continuous epidural infusion, unbound ropivacaine hydrochloride clearance has reached 34% and unbound PPX 71% of its mature value. The systemic exposure is higher in neonates and also somewhat higher in infants between 1 to 6 months compared to older infants and children, which is related to the immaturity of their liver function. However, this is partly compensated for by the recommended 50% lower dose rate for continuous infusion in infants below 6 months.

Simulations on the sum of unbound plasma concentrations of ropivacaine hydrochloride and PPX, based on the PK parameters and their variance in the population analysis, indicate that for a single caudal block the recommended dose must be increased by a factor of 2.7 in the youngest group and a factor of 7.4 in the 1 to 10 year group in order for the upper prediction 90% confidence interval limit to touch the threshold for systemic toxicity. Corresponding factors for the continuous epidural infusion.

Based on conventional studies of safety pharmacology, single and repeated dose toxicity, reproduction toxicity, mutagenic potential and local toxicity, no hazards for humans were identified other than those which can be expected on the basis of the pharmacodynamic action of high doses of ropivacaine hydrochloride (e.g. CNS signs, including convulsions, and cardiotoxicity).