Naropin Mechanism of Action

Pharmacotherapeutic group: (ATC Code): N01B B09.
Pharmacology: Pharmacodynamics: 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 nonprogressive motor block.
Onset and duration of the local anaesthetic effect of Naropin depend on the dose and site of administration, while presence of 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 administration, depending on the extent of the concomitant sympathetic block.
Pharmacokinetics: Ropivacaine has a chiral centre and is pure S-(-)-enantiomer. It has a pK_a of 8.1 and a distribution ratio of 141 (25°C n-octanol/phosphate buffer pH 7.4). The metabolites has a pharmacological activity that is less than that of ropivacaine.
The plasma concentration of ropivacaine depends on the dose, route of administration and vascularity of the injection site. Ropivacaine follows linear pharmacokinetics and the maximum plasma concentration is proportional to the dose.
Ropivacaine 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. 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 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 of distribution at steady-state of 47 l and a terminal half-life of 1.8 h after i.v. 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 and 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.
Ropivacaine is extensively metabolised in the liver, predominantly by aromatic hydroxylation to 3-hydroxy-ropivacaine mediated by cytochrome P4501A2, and N-dealkylation to PPX mediated by CYP3A4. After single intravenous 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.
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 central nervous system (CNS)-toxic unbound plasma concentration 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 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.
There is no evidence of in vivo racemization of ropivacaine.