Dantrolene sodium

Dantrolene sodium L-(-) - y-Amino-a-hydroxybutyric acid Amikacin... 

Succinylcholine-induced hyperkalemia may lead to cardiac arrhythmia and arrest when plasma reaches 7 and 10 mM, respectively. The drug also may precipitate a fulminant attack of malignant hyperthermia in susceptible individuals (not to be confused with neuroleptic malignant hyperpyrexia, which involves dopamine and the CNS). Treatment in either case consists of cooling the body and administering oxygen and dantrolene sodium (discussed later). 

There is a very great demand for drugs for the relief of anxiety. This was formerly met by the use of alcohol, bromides or barbiturates, which carried the risk of abuse or dangerous toxicity. The first of the modern minor tranquilizers, introduced from 1946 onwards, were drugs described as skeletal muscle relaxants. These were mainly derivatives of polyhydric alcohols, but heterocyclic examples included metaxolone (161), which is related to the aryl ethers of glycerol, chlorzoxazone (162) and chlormezanone (163). Dantrolene sodium (164) is a muscle relaxant and CNS depressant. 

A pulse polarographic method to determine dantrolene sodium and its major metabolites in urine after ethyl acetate extraction has been reported [181]. The ethyl acetate is brought to a residue and the dantrolene plus the total extract-able metabolites are analyzed for reduction of the azomethine linkage at -0.86 V in a DMF-acetate buffer (pH 4.0). The nitro compounds are simultaneously determined in the same media as dantrolene equivalents from the reduction of the nitro group at -0.26 V (see Fig. 26.13). The difference between the two determinations represents the metabolites not containing the nitro group. Levels as low as 0.1 fig/mL can be determined for either functional group. 

Quaternary ammonium salts of dantrolene and clodanolene have been prepared, and the effect of the organic cation on the aqueous solubility has been reported (Ellis et al., 1980). It was reasoned that since the hydantoin moiety in each drug is weakly acidic, a strong base should be found for salt formation. The 13 different quaternary ammonium compounds were therefore used in the hydroxide salt form. The acid-base reaction proceeded rapidly, and the salt products were stable during recrystallization steps. Of the four salts for clodanolene, the aqueous solubilities ranged from 2- to 100-fold that of clodanolene sodium, on a mass basis. Of the 11 salts for dantrolene, the benzyl-trimethyl ammonium salt exhibited comparable solubility to that of dantrolene sodium. Among the other 10 salts were several examples that yielded enhanced solubilities of up to 1000-fold that of the sodium salt. Twelve of the Lfteen salts successfully demonstrated muscle relaxant activity when administered orally. 

The three agents traditionally used in the treatment of spasticity are baclofen, diazepam, and dantrolene sodium (see Table 13-3, Fig. 13-2). Two newer agents, gabapentin and tizanidine, are also available for treating spasticity in various conditions. All of these agents are addressed below. 

Dantrolene sodium (Dantrium] Adult 25 mg/d initially increase up to 100 mg 2, 3, or 4 times per day as needed maximum recommended dose is 400 mg/day. Children (older than 5 yr of age] initially, 0.5 mg/kg body weight BID increase total daily dosage by 0.5 mg/kg every 4-7 days as needed, and give total daily amount in 4 divided dosages maximum recommended dose is 400 mg/d. Exerts an effect directly on the muscle cell may cause generalized weakness in all skeletal musculature. 

The only muscle relaxant available that exerts its effect directly on the skeletal muscle cell is dantrolene sodium (Dantrium).40,102 This drug works by impairing the release of calcium from the sarcoplasmic reticulum within the muscle cell during excitation (Fig. 13 -3).56,89 In response to an action potential, the release of calcium from sarcoplasmic storage sites initiates myofilament cross-bridging and subsequent muscle contraction. By inhibiting this release, dantrolene attenuates muscle contraction and therefore enhances relaxation. 

FIGURE 13-3 Possible mechanism of action of dantrolene sodium (DantriurrQ. Dantrolene blocks channels in the sarcoplasmic reticulum, thus interfering with calcium release onto the contractile [actin, myosin] filaments. Muscle contraction is reduced because less calcium is available to initiate cross-bridge formation between actin and myosin filaments. 

Coons, D. J., Hillman, F. J., Marshall, R. W. (1982). Treatment of neuroleptic malignant syndrome with dantrolene sodium A case report. American Journal of Psychiatry, 139, 943-945. 

Kaplan RF, Feinglass NG, Webster W, Mudra S. Phenelzine overdose treated with dantrolene sodium. JAMA 1986 255(5) 642-4. 

Dantrolene sodium produces its effects by affecting the contractile response of the skeletal muscle at a site beyond the neuromuscular junction, probably by interfering with the release of calcium ions from the sarcoplasmic reticulum. 

Ultraviolet Spectrum. Dantrolene sodium aqueous alkali-314 nm (AJ=487 b). 

Infra-red Spectrum. Principal peaks at wavenumbers 1600,1225, 1510, 850, 1713,1108 (dantrolene sodium, KBrdisk). 

Dose. Initially 25 mg of dantrolene sodium daily, increased to a maximum of 400 mg daily. 

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