Cisatracurium
Encyclopedia
Cisatracurium is a neuromuscular-blocking drug
Neuromuscular-blocking drug
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine synthesis or release or by acting postsynaptically at the...

 or skeletal muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...

 in the category of non-depolarizing neuromuscular-blocking drugs
Neuromuscular-blocking drugs
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine synthesis or release or by acting postsynaptically at the...

, used adjunctively in anesthesia
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...

 to facilitate endotracheal intubation
Intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...

 and to provide skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...

 relaxation during surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...

 or mechanical ventilation
Mechanical ventilation
In medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...

. It is a bisbenzyltetrahydroisoquinolinium agent with an intermediate duration of action. Cisatracurium is one of the ten isomers of the parent molecule, atracurium
Atracurium
Atracurium besylate is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical...

. Moreover, cisatracurium represents approximately 15% of the atracurium mixture.

History

The generic name cisatracurium was conceived by scientists at Burroughs Wellcome Co. (now part of GlaxoSmithKline) by combining the name "atracurium" with "cis" [hence cisatracurium] because the molecule is the cis-cis isomer comprising the ten isomers of the parent, atracurium
Atracurium
Atracurium besylate is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical...

. Atracurium itself was invented at Strathclyde University and licensed to Burroughs Wellcome Co., Research Triangle Park, NC, for further development and subsequent marketing as Tracrium. As the secondary pharmacology of atracurium was being developed, it became clear that the primary clinical disadvantage of atracurium was likely to be its propensity to elicit histamine release. To address this issue, a program was initiated to investigate the individual isomer constituents of atracurium to identify and isolate the isomer(s) associated with the undesirable histamine effects as well as identify the isomer that might possibly retain the desirable properties without the histamine release. Thus, in 1989, D A Hill and G L Turner, PhD (both chemists at Wellcome, Dartford, UK) first synthesized cisatracurium as an individual molecule in its own right. The pharmacological research of these individual isomers was then developed further primarily by R. Brandt Maehr and William B. Wastila, PhD (both of whom were pharmacologists within the Division of Pharmacology at Burroughs Wellcome Co.) in collaboration with John J. Savarese MD (who at the time was an anesthesiologist in the Dept. of Anesthesia, Harvard Medical School
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....

 at the Massachusetts General Hospital
Massachusetts General Hospital
Massachusetts General Hospital is a teaching hospital and biomedical research facility in the West End neighborhood of Boston, Massachusetts...

, Boston
Boston
Boston is the capital of and largest city in Massachusetts, and is one of the oldest cities in the United States. The largest city in New England, Boston is regarded as the unofficial "Capital of New England" for its economic and cultural impact on the entire New England region. The city proper had...

, MA). Thereafter, the entire clinical development of cisatracurium
Cisatracurium
Cisatracurium is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...

 was completed in a record short period from 1992 to 1994: the team of scientists was led by J. Neal Weakly PhD, Martha M. Abou-Donia PhD, and Steve Quessy PhD, in the Division of Clinical Neurosciences at Burroughs Wellcome Co., Research Triangle Park
Research Triangle Park
The Research Triangle Park is a research park in the United States. It is located near Durham, Raleigh, and Chapel Hill, in the Research Triangle region of North Carolina...

, NC. By the time of its approval for human use, in 1995, by the US Food and Drug Administration, Burroughs Wellcome Co. had merged with Glaxo Inc., and cisatracurium was approved to be marketed as Nimbex by GlaxoWellcome Inc. The trade name "Nimbex" was derived from inserting an "i" to the original proposal "Nmbex," which stood for excellent Neuromuscular blocker.

Owing to the intense marketing rivalry, during the 1980s and 1990s, between the two major competitors at the time in this area of anesthesia (i.e., Organon Inc. and Burroughs Wellcome, Co.), it was not surprising then that the knives of scrutiny and skepticism were already being sharpened against cisatracurium in the court of peer-reviewed publications even before the voluminous documentation necessary for impartial review and approval of the drug had barely been dispatched to the desks at the US Food and Drug Administration.

Preclinical Pharmacology

In vitro studies using human plasma indicated that cisatracurium spontaneously degrades at physiological pH via Hofmann elimination to yield laudanosine and the quaternary monoacrylate. Subsequent ester hydrolysis of the monoacrylate generates the monoquaternary alcohol, although the rate-liminting step is Hofmann elimination
Hofmann elimination
Hofmann elimination is a process where an amine is reacted to create a tertiary amine and an alkene by treatment with excess methyl iodide followed by treatment with silver oxide, water, and heat.After the first step, a quaternary ammonium iodide salt is created...

. In rat plasma, cisatracurium is also metabolized by non-specific carboxylesterases (a rate-limiting step) to the monoquaternary alcohol and the monoquaternary acid.

Clinical pharmacology

As is evident with the parent molecule, atracurium, cisatracurium is also susceptible to degradation by Hofmann elimination and ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

 hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...

 as components of the in vivo metabolic processes. See the atracurium
Atracurium
Atracurium besylate is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical...

 page for information on Hofmann elimination in vivo versus the Hofmann degradation chemical reaction.

Because Hofmann elimination is a temperature- and plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 pH-dependent process, cisatracurium's rate of degradation in vivo is highly influenced by body pH and temperature just as it is with the parent molecule, atracurium: thus, an increase in body pH favors the elimination process, whereas a decrease in temperature slows down the process.

One of the metabolites of cistracurium via Hofmann elimination is laudanosine - see the atracurium
Atracurium
Atracurium besylate is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical...

 page for further discussion of the issue regarding this metabolite and its undesirable CNS effects. 80% of cisatracurium is metabolized eventually to laudanosine
Laudanosine
Laudanosine or N-methyltetrahydropapaverine is a recognized metabolite of atracurium and cisatracurium. Laudanosine decreases the seizure threshold, and thus it can induce seizures if present at sufficient threshold concentrations; however such concentrations are unlikely to be produced consequent...

 and 20% is metabolized hepatically or excreted renally. 10-15% of the dose is excreted unchanged in the urine.

Since Hofmann elimination is an organ-independent chemodegradative mechanism, there is little or no risk to the use of cisatracurium in patients with liver or renal disease when compared with other neuromuscular-blocking agents.

Histamine release - hypotension, reflex tachycardia and cutaneous flush

Unlike the parent, atracurium, cisatracurium affords a much better pharmacological profile with respect to eliciting histamine release.

Bronchospasm - Pulmonary compliance

To date, cisatracurium has not been reported to elicit bronochospasm at doses that are clinically prescribed.

Laudanosine - Epileptic foci

Cisatracurium undergoes Hofmann elimination as a primary route of chemodegradation: consequently one of the metabolites from this process is laudanosine
Laudanosine
Laudanosine or N-methyltetrahydropapaverine is a recognized metabolite of atracurium and cisatracurium. Laudanosine decreases the seizure threshold, and thus it can induce seizures if present at sufficient threshold concentrations; however such concentrations are unlikely to be produced consequent...

, a tertiary amino alkaloid reported to be a modest CNS stimulant with epileptogenic activity and cardiovascular effects such a hypotension and bradycardia.. As a tertiary amine, Laudanosine is unionised and readily crosses the blood-brain barrier. Presently, there is little evidence that laudanosine accumulation and related toxicity will likely ever be seen with the doses of cisatracurium that are administered in clinical practice especially given that the plasma concentrations of laudanosine generated are lower with cisatracurium than those seen with atracurium.
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