Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Norgine Pharmaceuticals Limited, Norgine House, Widewater Place, Moorhall Road, Harefield, Uxbridge, UB9 6NS, UK
Pharmacotherapeutic group: Muscle relaxants, directly acting agents
ATC code: M03CA01
The receptor molecule for dantrolene sodium has not been identified. Radiolabelled dantrolene sodium binds to specific components of the striated muscle cell, namely the t-tubules and the sarcoplasmic reticulum; however the kinetics of binding varies between these two organelles. The binding of ryanodine is thought to compete with the binding of calcium in these organelles; further evidence for the specificity of binding is that dantrolene sodium inhibits the binding of the insecticide ryanodine to heavy sarcoplasmic reticulum vesicles from rabbit skeletal muscle. Under some conditions, dantrolene sodium will lower intra-sarcoplasmic calcium concentrations in the resting state. This may be more important in diseased muscle (e.g. in malignant hyperthermia in humans and swine stress syndrome) than in muscle with normal function.
Dantrolene sodium does not bind to the same sites as calcium channel blocking drugs such as nitrendipine or calmodulin. There is no electrophysiological evidence that dantrolene sodium interferes with the influx of calcium from outside the cell. This may be one reason why paralysis by dantrolene sodium has never been reported in animals or man; the muscle cell has alternative sources of calcium which are not influenced by dantrolene sodium.
Whatever the molecular mechanism, the cardinal property of dantrolene sodium is that it lowers intracellular calcium concentration in skeletal muscle. Calcium concentrations may be lower in both the quiescent state, and as a result of a reduction in the release of calcium form the sarcoplasmic reticulum in response to a standard stimulus. This effect has been observed in striated muscle fibres from several species, and is not seen in myocardium. Fast fibres may be more sensitive than slow fibres to the action of dantrolene sodium.
Diverse other properties of dantrolene sodium have been observed in-vitro, and in animal studies. Dantrolene sodium may inhibit the release of calcium from the smooth endoplasmic reticulum of smooth muscle, but the significance of this observation is questionable; for example, dantrolene sodium has no effect on isolated human urinary bladder smooth muscle. Calcium dependent, pre-synaptic neurotransmitter release may also be inhibited by dantrolene sodium. Again, the clinical significance of this has not been demonstrated.
Elevation of intracellular, free calcium ion concentration is an obligatory step in excitation-contraction coupling of skeletal muscle. Dantrolene sodium, therefore, acts as a muscle relaxant by a peripheral mechanism which is quite different, and easily distinguishable from neuromuscular junction blocking drugs. In contrast with compounds that relax skeletal muscle by acting principally on the central nervous system, dantrolene sodium acts directly on skeletal muscle cells. In rabbit atria, dantrolene sodium has no effect alone, but it may antagonise inotropic agents which act by increasing intramyocardial cell calcium e.g. the experimental drug anthopleurin-A.
Dantrolene sodium is easily and almost completely absorbed from the gastrointestinal tract. After dosing on an empty stomach, plasma dantrolene sodium levels peak within three hours in most subjects.
Dantrolene sodium is a highly lipophobic drug. In addition it lacks hydrophilicity. Dantrolene sodium binds to human serum albumin (HSA) with a molar ratio of 0.95 to 1.68 in-vitro. The association constant in-vitro is higher (2.3 to 5.4 × 10 -5 per mol). In-vitro dantrolene sodium can be displaced from HSA by warfarin, clofibrate and tolbutamide but these interactions have not been confirmed in humans (re. manufacturer’s database). Single intravenous dose studies suggest that the primary volume of distribution is about 15 litres. Single oral doses achieve peak plasma concentration of about a quarter of that for a similarly sized intravenous dose.
The biological half life in plasma in most human subjects is between 5 and 9 hours, although half lives as long as 12.1 ± 1.9 hours have been reported after a single intravenous dose. Inactivation is by hepatic metabolism in the first instance. There are two alternative pathways. Most of the drug is hydroxylated to 5-hydroxy-dantrolene. The minor pathway involves nitro-reduction to amino-dantrolene which is then acetylated (compound F-490). The 5-hydroxy metabolite is a muscle relaxant with nearly the same potency as the parent molecule, and may have a longer half life than the parent compound. Compound F-490 is much less potent and is probably inactive at the concentrations achieved in clinical samples. Metabolites are subsequently excreted in the urine in the ratio of 79 5-hydroxy-dantrolene: 17 compound F-490: 4 unaltered dantrolene (salt or free acid). The proportion of drug excreted in the faeces depends upon dose size.
Dantrolene sodium showed some evidence of tumourgenicity at high dose levels in Sprague-Dawley female rats. However, these effects were not seen in other studies in Fischer 344 rats or HaM/ICR mice. There is no clinical evidence of carcinogenicity in humans; however, this possibility cannot be absolutely excluded.
Sprague-Dawley female rats fed dantrolene sodium for 18 months at dosage levels of 15, 30 and 60 mg/kg/day showed an increased incidence of benign and malignant mammary tumours compared with concurrent controls. At the highest dose level, there was an increase in the incidence of benign hepatic lymphatic neoplasms. In a 30-month study at the same dose levels also in Sprague-Dawley rats, dantrolene sodium produced a decrease in the time of onset of mammary neoplasms. Female rats at the highest dose level showed an increased incidence of hepatic lymphangiomas and hepatic angiosarcomas.
The only drug-related effect seen in a 30-month study in Fischer-344 rats was a dose-related reduction in the time of onset of mammary and testicular tumours. A 24-month study in HaM/ICR mice revealed no evidence of carcinogenic activity.
The significance of carcinogenicity data relative to use of dantrolene sodium in humans is unknown.
Dantrolene sodium has produced positive results in the Ames S.Typhimurium bacterial mutagenesis assay in the presence and absence of a liver activating system.
Dantrolene sodium administered to male and female rats at dose levels up to 45 mg/kg/day showed no adverse effects on fertility or general reproductive performance.
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