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Other names | Chandonium iodide; HS-310 |
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Routes of administration | IV |
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Bioavailability | 100% (IV)[ citation needed ] |
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Formula | C26H46I2N2 |
Molar mass | 640.477 g·mol−1 |
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Candocuronium iodide (INN, formerly chandonium, HS-310) [1] is an aminosteroid neuromuscular-blocking drug. It was clinically evaluated in India for use within anesthesia for endotracheal intubation and for providing skeletal muscle relaxation during surgery or mechanical ventilation. Its development was discontinued due to cardiovascular effects, primarily tachycardia that was about the same as the clinically established pancuronium bromide. [2] [3] [4] [5] Candocuronium demonstrated a short duration in the body, but a rapid onset of action. It had little to no ganglion blocking activity, with a greater potency than pancuronium. [1]
As with other neuromuscular-blocking agents, candocuronium is a preferential competitive antagonist of nicotinic acetylcholine receptors. [6] The agent was developed by the laboratory of Harkishan Singh, Panjab University, Chandigarh, India, as part of the search for a non-depolarizing replacement for the most popular clinical depolarizing agent, suxamethonium (succinylcholine).[ citation needed ]
The mono- and bis-quaternary azasteroid series of compounds to which candocuronium belongs are based on the same principle that led to aminosteroids such as pancuronium, vecuronium and rocuronium: use of the steroid skeleton to provide a somewhat rigid distance between the two quaternary ammonium centers, with appendages incorporating fragments of choline or acetylcholine. The discovery program initiated by Singh [7] initially led to the synthesis of the bis-quaternary non-depolarizing agent HS-342 (4,17a-dimethyl-4,17a-diaza-D-homo-5α-androstane dimethiodide) that was equipotent with tubocurarine and with one-third its duration of action, but not suitable for further clinical evaluation. [8] [9] Modifications of the chemical structure of HS-342 led to the synthesis of two related derivatives, HS-347 and HS-310 (subsequently named chandonium, then candocuronium). [1] [7] HS-347 was equipotent with tubocurarine but exhibited considerable ganglion blocking activity, and therefore the drug proceeded to clinical trials. [10] [11] [12] [13]
Candocuronium did not provide the desired profile that was required to fulfill its purpose (to be used as an neuromuscular-blocking anesthetic) and a further extension of research was undertaken to overcome its limitations in that regard. Further research provided derivatives of the candocuronium design, HS-692, HS-693, HS-704 and HS-705, [14] whose onset and duration were indistinguishable from candocuronium, but all demonstrated profound vagolytic effects and much weaker potencies than candocuronium. [11] To improve on potency, further research was conducted on derivatives of the candocuronium nucleus, leading to the identification of yet another potentially useful compound, HS-626. [15] Upon further preclinical evaluation, [16] HS-626 demonstrated a slightly more desirable neuromuscular-blocking profile than that of candocuronium, but its overall improvement was insufficient to warrant advancement to clinical testing.
The discovery of candocuronium led to numerous related neuromuscular-blocking agents with short durations of action but also having undesirable cardiovascular effects. The Marshall group then explored other modifications at the 3- and 16-positions of the androstane nucleus, [17] [18] and yielded an agent that can go through expanded evaluation to clinical testing.
Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.
Pancuronium is an aminosteroid muscle relaxant with various medical uses. It is used in euthanasia and is used in some states as the second of three drugs administered during lethal injections in the United States.
A muscle relaxant is a drug that 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. Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have no central nervous system (CNS) activity. They are often used during surgical procedures and in intensive care and emergency medicine to cause temporary paralysis. Spasmolytics, also known as "centrally acting" muscle relaxant, are used to alleviate musculoskeletal pain and spasms and to reduce spasticity in a variety of neurological conditions. While both neuromuscular blockers and spasmolytics are often grouped together as muscle relaxant, the term is commonly used to refer to spasmolytics only.
Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage. It is also used in anaesthesia to end the effects of non-depolarising neuromuscular blocking medication. It is given by injection either into a vein, muscle, or under the skin. After injection effects are generally greatest within 30 minutes and last up to 4 hours.
Tubocurarine is a toxic benzylisoquinoline alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxation during surgery or mechanical ventilation. Safer alternatives, such as cisatracurium and rocuronium, have largely replaced it as an adjunct for clinical anesthesia and it is now rarely used.
Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.
Rocuronium bromide is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia to facilitate tracheal intubation by providing skeletal muscle relaxation, most commonly required for surgery or mechanical ventilation. It is used for standard endotracheal intubation, as well as for rapid sequence induction (RSI).
Atracurium besilate, also known as atracurium besylate, is a medication used in addition to other medications to provide skeletal muscle relaxation during surgery or mechanical ventilation. It can also be used to help with endotracheal intubation but suxamethonium (succinylcholine) is generally preferred if this needs to be done quickly. It is given by injection into a vein. Effects are greatest at about 4 minutes and last for up to an hour.
Mivacurium chloride is a short-duration non-depolarizing 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.
Aminosteroids are a group of steroids with a similar structure based on an amino-substituted steroid nucleus. They are neuromuscular blocking agents, acting as competitive antagonists of the nicotinic acetylcholine receptor (nAChR), and block the signaling of acetylcholine in the nervous system. These drugs include candocuronium iodide, dacuronium bromide, dihydrochandonium, dipyrandium, malouetine, pancuronium bromide, pipecuronium bromide, rapacuronium bromide, rocuronium bromide, stercuronium iodide, and vecuronium bromide.
Sugammadex, sold under the brand name Bridion, is a medication for the reversal of neuromuscular blockade induced by rocuronium and vecuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA). It is marketed by Merck.
Doxacurium chloride is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. Unlike a number of other related skeletal muscle relaxants, it is rarely used adjunctively to facilitate endotracheal intubation.
Alcuronium chloride is a neuromuscular blocking (NMB) agent, alternatively referred to as a skeletal muscle relaxant. It is a semi-synthetic substance prepared from C-toxiferine I, a bis-quaternary alkaloid obtained from Strychnos toxifera. C-toxiferine I itself has been tested for its pharmacological action and noted to be a very long acting neuromuscular blocking agent For a formal definition of the durations of actions associated with NMB agents, see page for gantacurium. The replacement of both the N-methyl groups with N-allyl moieties yielded N,N-diallyl-bis-nortoxiferine, now recognized as alcuronium.
Pipecuronium (Arduan) is a bisquaternary aminosteroid muscle relaxant which blocks nicotinic acetylcholine receptors at the neuromuscular junction. It is also an antagonist of M2 and M3 muscarinic receptors and is the most potent neuromuscular blocking agent of the aminosteroid class.
Selective relaxant binding agents (SRBAs) are a new class of drugs that selectively encapsulates and binds neuromuscular blocking agents (NMBAs). The first drug introduction of an SRBA is sugammadex. SRBAs exert a chelating action that effectively terminates an NMBA ability to bind to nicotinic receptors.
The muscle-type nicotinic receptor is a type of nicotinic acetylcholine receptor consisting of the subunit combination (α1)2β1δε (adult receptor) or (α1)2β1δγ (fetal receptor). These receptors are found in neuromuscular junctions, where activation leads to an excitatory postsynaptic potential (EPSP), mainly by increased Na+ and K+ permeability.
Gantacurium chloride is a new experimental neuromuscular blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in surgical anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Gantacurium is no longer in clinical development.
Malouetine is an aminosteroid neuromuscular blocking agent and antinicotinic alkaloid isolated from Malouetia spp.
Harkishan Singh was Professor Emeritus at the Panjab University. He was a well recognized pharmaceutical academic, medicinal chemistry researcher and science historian. He had more than half a century experience in his respective fields to his credit. He worked at the Banaras Hindu University, University of Saugar, and the Panjab University in India, and abroad at the University of Maryland, University of Mississippi and the University of London.
Cholinergic blocking drugs are a group of drugs that block the action of acetylcholine (ACh), a neurotransmitter, in synapses of the cholinergic nervous system. They block acetylcholine from binding to cholinergic receptors, namely the nicotinic and muscarinic receptors.