Naropin Mechanism of Action

Pharmacotherapeutic group: Local anaesthetics. ATC Code: N01B B09.
Pharmacology: Pharmacodynamics: Mechanism of Action: Ropivacaine is a long acting, amide-type local anaesthetic with both anaesthetic and analgesic effects. At high doses it produces surgical anaesthesia, while at lower doses, it produces sensory block (analgesia) with limited and non-progressive motor block.
Onset and duration of the local anaesthetic effect of Naropin depend on the dose and site of administration, while presence of a vasoconstrictor (e.g. adrenaline) has little, if any influence.
Ropivacaine, like other local anaesthetics, causes reversible blockade of impulse propagation along nerve fibres by preventing the inward movement of sodium ions through the cell membrane of the nerve fibres.
Local anaesthetics may have similar effects on other excitable membranes e.g. in the brain and myocardium. If excessive amounts of drug reach the systemic circulation, symptoms and signs of toxicity may appear, emanating from the central nervous and cardiovascular systems.
Cardiac effects measured in vivo in animal studies showed that ropivacaine has a lower cardiac toxicity than bupivacaine.
Pregnant ewes showed no greater sensitivity to systemic toxic effects of ropivacaine than non-pregnant ewes.
Healthy volunteers exposed to intravenous infusions of CNS toxic doses showed significantly less cardiac effects after ropivacaine than after bupivacaine.
Indirect cardiovascular effects (hypotension, bradycardia) may occur after epidural block, depending on the extent of concomitant sympathetic block, but is less pronounced in children.
Pharmacokinetics: Ropivacaine has a chiral centre and is the pure S-(-)-enantiomer.
Ropivacaine has a pKa of 8.1 and the distribution ratio of 141 (25°C n-octanol/phosphate-buffer with pH 7.4). The metabolites have a pharmacological activity that is less than that of ropivacaine.
Absorption: The plasma concentration of ropivacaine depends on the dose, the route of administration and the vascularity of the injection site. Ropivacaine follows linear pharmacokinetics and the maximum plasma concentration is proportional to the dose.
Ropivacaine shows complete and bi-phasic absorption from the epidural space, with half-lives for the two phases in the order of 14 minutes and 4 hours. The slow absorption is the rate-limiting factor in the elimination of ropivacaine, which explains why the apparent elimination half-life is longer after epidural than after intravenous administration. Ropivacaine shows a biphasic absorption from the caudal epidural space also in children.
Distribution: Ropivacaine has a mean total plasma clearance of the order of 440 mL/min, an unbound plasma clearance of 8 L/min, a renal clearance of 1 mL/min a volume distribution at steady state of 47 L and a terminal half-life of 1.8 h after iv administration. Ropivacaine 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 and interscalene 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.
Ropivacaine readily crosses the placenta with equilibrium in regard to unbound concentration is 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.
Metabolism: Ropivacaine is extensively metabolised in the liver, predominantly by aromatic hydroxylation to 3-hydroxy-ropivacaine (mediated by CYP1A2) and N-dealkylation to PPX (mediated by CYP3A4). After single iv administration approximately 37% of the total dose is excreted in the urine as both free and conjugated 3-hydroxy-ropivacaine, the major metabolite. Low concentrations of 3-hydroxy-ropivacaine have been found in the plasma. Urinary excretion of the PPX and other metabolites account for less than 3% of the dose.
Elimination: During epidural infusion, both PPX and 3-hydroxy-ropivacaine are the major metabolites excreted in the urine. Total PPX concentration in the plasma was about half of that of total ropivacaine, however, mean unbound concentrations of PPX was about 7 to 9 times higher than that of unbound ropivacaine following continuous epidural infusion up to 72 hours. The threshold for CNS-toxic unbound plasma concentrations of PPX in rats is about twelve times higher than that of unbound ropivacaine.
Impaired renal function has little or no influence on ropivacaine pharmacokinetics. The renal clearance of PPX is significantly correlated with creatinine clearance. A lack of correlation between total exposure, expressed as AUC, with creatinine clearance indicates that the total clearance of PPX includes a non-renal elimination in addition to renal excretion. Some patients with impaired renal function may show an increased exposure to PPX resulting from a low non-renal clearance.
Due to the reduced CNS toxicity of PPX as compared to ropivacaine the clinical consequences are considered negligible in short-term treatment.
Paediatric Patients: The pharmacokinetics of ropivacaine was characterized in a pooled population PK analysis on data in 192 children between 0 and 12 years of age from six studies. Unbound ropivacaine and PPX clearance and ropivacaine 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 clearance appears to be complete by the age of 3 years, that of PPX by the age of 1 year and unbound ropivacaine volume of distribution by the age of 2 years. The PPX unbound volume of distribution only depends on body weight.
Unbound ropivacaine clearance increases from 2.4 and 3.6 L/h/kg in the newborn and the 1-month neonate to about 8-16 L/h/kg for ages above 6 months, values within the range of those in adults. Total ropivacaine clearance values per kg body weight increase from about 0.10 and 0.15 L/h/kg in the newborn and the 1-month neonate to about 0.3-0.6 L/h/kg beyond the age of 6 months. Unbound ropivacaine volume of distribution per kg body weight increases from 22 and 26 L/kg in the newborn and the 1-month neonate to 42-66 L/kg above 6 months.
Total ropivacaine volume of distribution per kg body weight increases from 0.9 and 1.0 L/kg for newborn and the 1-month neonate to 1.7-2.6 L/kg beyond the age of 6 months. The terminal half-life of ropivacaine is longer, 6 to 5 h in the newborn and the 1-month neonate compared to about 3 h in older children. The terminal half-life of PPX is also longer, rom 43 and 26 h in the newborn and the 1-month old neonate to about 15 h in older children.
At 6 months, the breakpoint for change in the recommended dose rate for continuous epidural infusion, unbound ropivacaine 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 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 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 are 1.8 and 3.8 respectively.
Toxicology: Pre-Clinical Safety Data: 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 (e.g. CNS signs, including convulsions, and cardiotoxicity).