Cisatracurium besylate

Muscle relaxants

Cisatracurium besylate is the benzene sulfonate salt form of atracurium. It is a kind of artificially synthetic non-depolarizing muscle relaxants with its role similar as tubocurarine. It has an onset time of 1 minute and duration time of 15 minutes. The treatment dose does not affect the heart, liver and kidney function. It also has no accumulation property. It also can induce the release of histamine when used at large doses. For muscle relaxation or breathing control required in surgery, compared with current clinical major muscle-relaxing anesthetic drugs, cisatracurium besylate is not metabolized through liver or kidney, and has cardiovascular stability; its effect of muscle relaxation is 3 times as strong as atracurium without any cardiovascular side effects. Cisatracurium besylate is mainly applied to general anesthesia, and can be widely used in intubation, treating liver and kidney dysfunction, used in cardiovascular surgery and elderly and pediatric patients. Compared with atracurium, this product has no dose-dependent adverse effects of histamine release; however, the disadvantage is that patients with liver and kidney dysfunction should administrate with caution. Since 1996 for the first time when this drug has entered into market in UK, foreign countries have gradually applied it to replace vecuronium and atracurium as the mainstream of clinical muscle relaxants.

Pharmacological effects

The mechanism of action of cisatracurium besylate is similar with that of tubocurarine chloride; but this product is a kind of non-depolarizing muscle relaxant drugs which is mainly used for blocking the transmission of nerve impulses, boost muscle relaxation and can release histamine; but it has a lower effect than tubocurarine alkaline; it is characterized by a rapid onset and a high muscle relaxant effect.

Pharmacokinetics

After its intravenous injection of the product into the body tissue, it rapidly play a pharmacological effect in the target, and can further pass through the placenta into the fetal circulation.

Clinical application

Clinically, it is generally used for maintaining muscle relaxing or facilitating the mechanical respiration; larger doses can be used for endotracheal intubation.

Cisatracurium Besilate

Cisatracurium besylate is one of the 10 kinds of isomers of atracurium, accounting for about 15% of the total mixture of ammonium atracurium. Like the case of the its parent compound, it also belongs to benzyl isoquinoline non-depolarizing muscle relaxants. Cisatracurium besylate has a ED95 of 0.05 mg/kg; the muscle relaxation potency of it is 3 to 5 times as high as that of atracurium. It has a low lipid-solubility, and is not directly subject to the hydrolysis of nonspecific esterase in plasma; 80% is inactivated by Hofmann degradation with no effect of histamine release as well as a low incidence of allergic reactions. Clinical data has shown that the rapid intravenous injection of 8 × ED95 amount of cis-atracurium to healthy patients undergoing elective surgery rapid intravenous injection causes no signs of histamine release. On contrary, only 2 × ED95 amount of atracurium is enough to induce a histamine release effect. It only has a slight influence on cardiovascular function, and it has only a few metabolites. The effect of the decomposition products of cis-atracurium, N-laudanosine is only about 1/3 to 1/10 of that of equal dose of atracurium dose. From this angle, long-term application will not result in convulsion caused by high plasma concentration. It can be used for endotracheal intubation and maintaining muscle relaxation during anesthesia, especially be suitable for patients suffering liver and kidney dysfunction who are undergoing anesthesia.

Dosage

It can be intravenously injection or dropping without local injection. The dose is decided by the weight as well as the surgery requirement of the patients. Adult conventional dose: before induction of anesthesia medication (such as propofol) for intubation, take 0.15 mg/kg of this product (about 10mg/10mL) for intravenous injection within 1~1.5 min and can achieve good intubation efficacy in 2 min; for maintaining the muscle relaxing during the surgery, injecting 0.03mg/kg per time for maintaining muscle relaxing for about 20min. Intravenous dropping: for maintaining muscle relaxing, first apply a dose of 0.18mg/(kg ? h) for administration until a steady state is reached, change to 1~2mg/(kg ? min) which can mostly achieve sustained muscle relaxation state.

Suitable solvents

0.9% sodium chloride injection liquid, 5% dextrose injection or sodium chloride (0.45%) combined with glucose (2.5%).

Rate of administration

Intravenous administration: When used for endotracheal intubation, inject within 1~1.5 min. Intravenous dropping: according to the situation of muscle relaxing and the dose controlling, when the steady state of muscle relaxation is reached, a rate of 0.1 mg/min is suitable for the average adult (60kg) for maintaining muscle relaxing.

Stability

For storage, it should be sealed, kept in dark and preserved at 2~8 °C; avoid freezing. Original injection exhibits pale yellow to yellow-green and clean. It can be stored at room temperature for 3 to 6 weeks. After unsealing and dilution for more than 24h, it is not suitable for re-applying.

Side effects

As one kind of the combined anesthesia drugs; it had ever caused a kind of rarely but seriously allergic reaction. Common adverse reactions include visible rash, flushing, hypotension, bradycardia, and bronchospasm.

Taboo and caution

People who are allergic to this product or atracurium should be prohibited for applying. Patients of renal insufficiency, electrolyte imbalance, low body temperature, neuromuscular disease, cancer, and cachexia should apply with caution.

Drug Interactions

1. when combined with a variety of anesthetics, ganglion blockers (such as six methylamine), potent diuretics, antiarrhythmic drugs, and other polypeptide antibiotics tetracycline, the muscle relaxation effect can be extended or strengthened. 2. Drug which can interfere with potassium, magnesium, lithium salt balance, and potassium releasing hormones can change the muscle relaxing effect of this product. 3. the application of succinylcholine can cause that the drug’s effect can’t be antagonized by neostigmine.

Description

Cisatracurium besylate is a new intermediate-duration non-depolarizing muscle relaxant launched in the U.S.A. for intubation and maintenance of muscle relaxation during surgery and intensive care. Cisatracurium besylate is the single 1 R cis-1'R cis isomer of the commercial preparation of atracurium, a mixture of 10 isomers. It is 3 to 5 times more potent than the mixture with similar onset and duration of action. The single isomer was also reported to have reduced propensity to release histamine and have a stable cardiovascular profile. Similar to structurally related mivacurium, cisatracurium has distinct advantages of rapid degradation, enzymatic metabolism that is independent of liver or kidney resulting in short duration of action and fast, complete recovery.

Chemical Properties

White Solid

Originator

Glaxo Wellcome (United Kingdom)

Uses

Cisatracurium Besylate is a nondepolarizing neuromuscular blocking agent, antagonizing the action of acetylcholine by inhibiting neuromuscular transmission.

Definition

ChEBI: The (1R,1'R,2R,2'R)-diastereoisomer of atracurium besylate. Commercial preparations of atracurium are mixtures of 10 stereoisomers, of which cisatracurium generally constitutes about 15%. isatracurium besylate is about 3 times more potent than the mixture of atracurium isomers as a neuromuscular blocking agent, and is used as a muscle relaxant for endotracheal intubation, to aid controlled ventilation, and in general anaesthesia.

Manufacturing Process

Acryloyl chloride (0.2 mole) in dry benzene (60 ml) was added over 0.5 hour to pentane-1,5-diol (0.1 mole), triehylamine (0.2 mole) and pyrogallol (0.1 g) in dry benzene (100 ml). Further dry benzene (100 ml) was added followed by triehylamine (10 ml), and the mixture stirred at 50°C for 0.5 hour. The triehylamine hydrochloride was filtered off and the solvent removed in vacuo to leave yellow oil which was distilled in the presence of a trace of pmethoxyphenol, excluding light, to give 1,5-pentamethylene diacrylate (12.9g, 61%, b.p. 90-95°C/0.01 mm Hg). A solution of tetrahydropapaverine (4.43 g) and 1,5-pentamethylene diacrylate (1.30 g) in dry benzene (15 ml) was stirred under reflux for 48 hours, excluding light. The solvent was removed in vacuo and the residual pale red oil dissolved in chloroform (10 ml). Addition of ether (ca. 400 ml), followed by saturated ethereal oxalic acid solution (ca. 500 ml) gave a flocculent white precipitate, which was filtered off, washed with ether and dried. Crystallization (twice) from ethanol gave N,N'-4,10-dioxa-3,11- dioxodecylene-1,13-bis-tetrahydropapaverine dioxalate as a white powder (3.5 g, 51%, m.p. 117-121°C). The free base N,N'-4,10-dioxa-3,11-dioxodecylene-1,13-bistetrahydropapaverine was obtained by basifying an aqueous solution of the dioxalate with sodium bicarbonate solution, followed by extraction with toluene and evaporation of the solvent, to give a colorless viscous oil. Scrupulously dried base in spectroscopically pure acetonitrile was treated with benzenesulfonic acid at room temperature for 22 hours. The filtered reaction mixture was added dropwise to dry ether (ca. 450 ml). The flocculent white precipitate was filtered off, washed with dry ether, and dried in vacuo over P2O5 at 50°C to yield N,N'-4,10-dioxa-3,11-dioxodecylene-1,13-bistetrahydropapaverine dimesylate, a white powder with m.p. 104-112°C.

Brand name

Nimbex (Abbott).

Therapeutic Function

Neuromuscular blocker