Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Norgine Pharmaceuticals Limited, Norgine House, Widerwater Place, Moorhall Road, Harefield, Uxbridge, UB9 6NS, UK
Pharmacotherapeutic group: Muscle relaxants, directly acting agents
ATC code: M03CA01
The receptor molecule for dantrolene 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 vary 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 inhibits the binding of ryanodine to heavy sarcoplasmic reticulum vesicles from rabbit skeletal muscle. Under some conditions, dantrolene 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 does not bind to the same sites as calcium channel blocking drugs such as nitrendipine or calmodulin. There is no electrophysiological evidence that dantrolene interferes with the influx of calcium from outside the cell. This may be one reason why paralysis by dantrolene has never been reported in animals or man; the muscle cell has alternative sources of calcium which are not influenced by dantrolene.
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, from 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 the 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 the 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. anthopleurin-a.
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 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.
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-hydroxydantrolene.
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.
Whilst there is no clinical evidence of carcinogenicity in humans, this possibility cannot be absolutely excluded.
Dantrolene sodium has shown some evidence of tumourgenicity at high dose levels in Sprague-Dawley female rats, but these effects have not been seen in other studies in Fisher 344 rats or HaM/ICR mice.
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