Voltage-gated sodium channels (Na+ channels).

Ropivacaine inhibits the pressure-induced increase in filtration coefficient (Kf) without affecting pulmonary artery pressure (Ppa), pulmonary capillary pressure (Ppc), and dispersion characteristics (ZC) [2]. Ropivacaine prevents PaO2, lung wet-to-dry ratio, and choroidal volume from maintaining at pseudo-waveform levels demonstrating pressure-induced pulmonary edema and associated hyperpermeability [2]. Ropivacaine blocks pressure-induced pulmonary edema in lung nitro compared with choroidal lung

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In a rat model of neuropathic pain induced by unilateral L5/L6 spinal nerve ligation, a single epidural administration of ropivacaine in mesylate injection form (200 µg free base) produced significant blockade of mechanical allodynia (52.0%) and heat hyperalgesia (70.9%) with a biological half-life of approximately 3 hours.
The equivalent dose of ropivacaine free-base in a sustained-release suspension (castor oil-based) prolonged the duration of anti-allodynia and anti-hyperalgesia, with biological half-lives of 5.2±1.4 hrs and 6.4±1.3 hrs, respectively.
Multiple daily epidural injections (200 µg/day for 3 days) of either formulation did not induce tolerance or potentiation to the anti-hypersensitivity effects.
Preemptive epidural administration of ropivacaine mesylate injection (200 µg, single dose 1 hour before surgery) delayed the development of neuropathic pain, extending the biological half-life from less than 4 hrs to approximately 1 day.
Preemptive administration of ropivacaine sustained-release suspension (200 µg, single dose) further delayed the biological half-life to approximately 2 days.
Multiple daily preemptive epidural injections (200 µg/day for 3 days) of the sustained-release suspension further prolonged the delay, with biological half-lives reaching 75.3±15.9 hrs for mechanical allodynia and 78.5±7.4 hrs for heat hyperalgesia. [2]

Animal/Disease Models: Adult SD (SD (Sprague-Dawley)) rat (300–400g) [1]
Doses: 1 μM
Route of Administration: Infusion (added to in the perfusate reservoir)
Experimental Results:diminished pressure dependence. The filter coefficient (Kf) increases.

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Adult male Wistar rats (240±20 g) were used. A polyethylene catheter (PE-10) was surgically implanted into the lumbar epidural space (L3-L4 level) under isoflurane anesthesia for drug administration.
Neuropathic pain was induced by unilateral ligation of the L5 and L6 spinal nerves under isoflurane anesthesia.
For drug treatment, ropivacaine mesylate injection was diluted with sterile normal saline. Ropivacaine sustained-release suspension (free-base in castor oil vehicle with benzyl alcohol and benzyl benzoate) was used as provided/diluted with its sterile oil vehicle.
Epidural injections were administered slowly (100 µL volume over 30 sec) followed by a 10 µL saline flush.
For efficacy studies in established neuropathy, rats received single or multiple daily epidural injections of 200 µg free ropivacaine (in either formulation) or vehicle. Pain behaviors (mechanical allodynia via electronic von Frey, heat hyperalgesia via plantar test) were assessed before and at multiple time points (e.g., 1.5, 2.5, 4, 8, 16 hrs) after injection.
For preemptive studies, single or multiple daily epidural injections were given 1 hour before spinal nerve ligation surgery, and pain behaviors were assessed post-surgery for several days. [2]

Absorption, Distribution and Excretion
The pharmacokinetics of ropivacaine are highly dose-dependent, route of administration, and patient condition. Following epidural administration, ropivacaine is completely absorbed in a biphasic manner. Following intravenous administration, 86% of the administered dose is excreted in the urine, of which 1% is the unchanged drug. Following intravenous infusion, the steady-state volume of distribution of ropivacaine is 41 ± 7 L. Ropivacaine readily crosses the placenta. Following intravenous administration, the mean plasma clearance of ropivacaine is 387 ± 107 mL/min, the free plasma clearance is 7.2 ± 1.6 L/min, and the renal clearance is 1 mL/min. Metabolism/Metabolites Ropivacaine is extensively metabolized, primarily through CYP1A2-mediated aromatic hydroxylation to 3-hydroxyropivacaine. The main metabolites excreted in the urine are N-dealkylated metabolite (PPX) and 3-hydroxyropivacaine. Other identified metabolites include 4-hydroxyropivacaine, 3-hydroxy-N-dealkylated metabolite (3-OH-PPX), and 2-hydroxymethylropivacaine (identified but not quantified). Free PPX, 3-hydroxyropivacaine, and 4-hydroxyropivacaine exhibit lower pharmacological activity in animal models than ropivacaine itself. Known human metabolites of ropivacaine include PPX and 3-hydroxyropivacaine. Hepatic metabolism: Ropivacaine is extensively metabolized in the liver, primarily through cytochrome P4501A-mediated aromatic hydroxylation to 3-hydroxyropivacaine. Following a single intravenous injection, approximately 37% of the total dose is excreted in the urine as free and bound 3-hydroxyropivacaine. After intravenous administration, 86% of the total ropivacaine dose is excreted in the urine, of which only 1% is the unchanged drug.
Half-life: Approximately 4.2 hours.

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Biological half-life>
The mean terminal half-life of ropivacaine is 1.8 ± 0.7 hours after intravascular administration and 4.2 ± 1 hours after epidural administration.

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The elimination half-life (t1/2B) of epidural ropivacaine mesylate in rats is approximately 100 minutes.
Ropivacaine sustained-release suspension (free base in castor oil) has a significantly longer elimination half-life than mesylate injection due to its slow and sustained release from the lipid pool. The exact half-life value of this suspension was not provided in this study, but it is said to have a significantly longer half-life.
The intrathecal bioavailability of epidural ropivacaine is low, approximately 10%. [2]

Toxicity Summary
Local anesthetics such as ropivacaine can block the generation and conduction of nerve impulses. Their mechanism of action may be to increase the threshold of nerve electrical excitation, slow the propagation speed of nerve impulses, and reduce the rate of action potential rise. Specifically, they block sodium channels, reducing the probability of depolarization and subsequent action potentials. Generally, the progression of anesthesia is related to the diameter of the affected nerve fibers, the degree of myelination, and the conduction velocity. Ropivacaine has less toxicity to the central nervous system and cardiovascular system compared to bupivacaine. In this study, epidural injection of ropivacaine (60, 180, 600 µg) resulted in dose-dependent, immediate, and reversible hindlimb motor paralysis in rats. At the same dose, the duration of paralysis was longer with the sustained-release suspension than with the mesylate injection. No other systemic toxicity or death was reported with the epidural administration regimens used. [2]

[1]. Ropivacaine: a review of its use in regional anaesthesia and acute pain management. Drugs. 2005;65(18):2675-717.

[2]. Epidural sustained release ropivacaine prolongs anti-allodynia and anti-hyperalgesia in developing and established neuropathic pain. PLoS One. 2015 Jan 24;10(1):e0117321.

[3]. The inhibitory effects of bupivacaine, levobupivacaine, and ropivacaine on K2P (two-pore domain potassium) channel TREK-1. J Anesth.

[4]. Ropivacaine Inhibits Pressure-Induced Lung Endothelial Hyperpermeability in Models of Acute Hypertension. Life Sci. 2019 Apr 1;222:22-28.

(S)-Ropivacaine is a piperidine carboxamide amide-type local anesthetic (rapivacaine), composed of (S)-N-propylpiperidinecarboxylic acid and 2,6-dimethylaniline forming an amide bond. It is a local anesthetic. It belongs to the piperidine carboxamide class and is also a member of the ropivacaine class. Ropivacaine is an aminoamide local anesthetic, marketed by AstraZeneca under the brand name Naropin. It exists as a racemic mixture of S- and R-enantiomers, but commercially available products only offer the purified S-enantiomer. Ropivacaine is an amide-type local anesthetic. The physiological effect of ropivacaine is achieved through local anesthesia. Ropivacaine is only present in individuals who have used or ingested the drug. It is a local anesthetic belonging to the aminoamide class. The name ropivacaine refers to both the racemic mixture and the commercially available S-enantiomer. Ropivacaine hydrochloride is commonly marketed by AstraZeneca under the brand name Naropin. Ropivacaine and other local anesthetics exert their effects by blocking the generation and conduction of nerve impulses. Their mechanisms likely involve increasing the electrical excitation threshold of the nerve, slowing the propagation speed of nerve impulses, and reducing the rate of rise of action potentials. Specifically, they block sodium channels, reducing the probability of depolarization and subsequent action potentials. Generally, the progression of anesthesia is related to the diameter, degree of myelination, and conduction velocity of the affected nerve fibers. Ropivacaine is an aniline drug used as a long-acting local anesthetic. It has different blocking effects on sensory and motor neurons. Drug Indications Ropivacaine is indicated for use in adult patients for induction of regional or local anesthesia for surgery or acute pain management. Mechanism of Action Ropivacaine and other local anesthetics block the generation and conduction of nerve impulses by increasing the electrical excitation threshold of the nerve, slowing the propagation speed of nerve impulses, and reducing the rate of rise of action potentials. Specifically, they block sodium channels, reducing the probability of depolarization and subsequent action potentials. Generally, the progression of anesthesia is related to the diameter, degree of myelination, and conduction velocity of the affected nerve fibers. Pharmacodynamics Unlike most other local anesthetics, the presence of adrenaline does not affect the onset time, duration of action, or systemic absorption of ropivacaine. Ropivacaine is a long-acting amide-type local anesthetic with a chemical structure similar to bupivacaine and mepivacaine. It is widely used for regional anesthesia and epidural analgesia. Compared to bupivacaine, ropivacaine exhibits better sensorimotor differential blocking (effective analgesia at doses below those causing motor blockade) and better toxicity characteristics. Its mechanism of action involves blocking voltage-gated sodium channels, thereby inhibiting the generation and conduction of neuronal action potentials. This method is particularly effective in inhibiting ectopic discharges in damaged nerves, which are one of the causes of neuropathic pain. The sustained-release formulation uses a castor oil-based suspension to delay systemic absorption and prolong the duration of action of the drug in the epidural space. This study suggests that epidural ropivacaine, especially in sustained-release formulations, has the potential to treat neuropathic pain and provide preventative analgesia without inducing tolerance. [2]

C17H26N2O

274.4

274.204

84057-95-4

Ropivacaine hydrochloride monohydrate;132112-35-7;Ropivacaine hydrochloride;98717-15-8;Ropivacaine-d7 hydrochloride;1217667-10-1;Ropivacaine mesylate;854056-07-8;Ropivacaine-d7;684647-62-9;(Rac)-Ropivacaine-d7;1392208-04-6

175805

White to off-white solid powder

1.0±0.1 g/cm3

410.2±45.0 °C at 760 mmHg

144 - 146ºC

201.9±28.7 °C

0.0±1.0 mmHg at 25°C

1.552

3.11

1

2

4

20

308

1

CCCN1CCCC[C@H]1C(=O)NC2=C(C=CC=C2C)C

ZKMNUMMKYBVTFN-HNNXBMFYSA-N

InChI=1S/C17H26N2O/c1-4-11-19-12-6-5-10-15(19)17(20)18-16-13(2)8-7-9-14(16)3/h7-9,15H,4-6,10-12H2,1-3H3,(H,18,20)/t15-/m0/s1

(2S)-N-(2,6-dimethylphenyl)-1-propylpiperidine-2-carboxamide

Ropivacaine Noropine Narop Ropivacainum LEA 103 Ropivacaina

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~12.5 mg/mL (~45.55 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (9.11 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (9.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)