DANTROLENE SODIUM
Chemistry - A hydantoin derivative which is dissimilar structurally and pharmacologically fromother skeletal muscle relaxant drugs, dantrolene sodium is a weak acid with a pKa of 7.5. It occursas an odorless, tasteless, orange, fine powder that is slightly soluble in water. It rapidly hydrolyzesin aqueous solutions to the free acid form which precipitates out of solution.
CNS effects are not known.
Dantrolene is rapidly eliminated from the horse (t1/2ยป130 minutes). The elimination half-life inhumans is approximately 8 hours. Dantrolene is metabolized in the liver and the metabolites areexcreted in the urine. Only about 1% of the parent drug is excreted unchanged in the urine and bile.
Contraindications/Precautions - Because dantrolene can cause hepatotoxicity, it should be usedwith extreme caution in patients with preexisting liver disease. It should be used with caution inpatients with severe cardiac dysfunction or pulmonary disease. The safe use of dantrolene duringpregnancy has not been determined.
More common, but less significant are the CNS associated signs of sedation, dizziness, headache, etc. and GI effects (nausea, vomiting, constipation). Also seen are increased urinary frequency, andpossibly hypotension.
Overdosage - There is no specific antidotal therapy to dantrolene overdoses, therefore remove thedrug from the gut if possible and treat supportively.
Increased risks of hepatotoxicity from dantrolene have been seen in women >35 years of age whoare also receiving estrogen therapy. The veterinary significance is unknown for this potentialinteraction.
Increased sedation may be seen if tranquilizing agents are used concomitantly with dantrolene.
Storage, Stability, Compatibility
Dantrolene capsules should be stored in well-closed containers at room temperature. Dantrolene powder for injection should be stored at temperatures less than 30°C and protected from prolonged exposure to light. After reconstitution, the powder for injection should be used within 6 hours when stored at room temperature and should be protected from direct light. It is not compatible with either normal saline or D5W injection.Pharmacology - DANTROLENE SODIUM
Dantrolene exhibits muscle relaxation activity by direct action on muscle. Whilethe exact mechanism is not well understood, it probably acts on skeletal muscle by interfering withthe release of calcium from the sarcoplasmic reticulum. It has no discernible effects on therespiratory or cardiovascular systems, but can drowsiness and dizziness. The reasons for theseCNS effects are not known.
Uses, Indications
In humans, oral dantrolene is indicated primarily for the treatment associatedwith upper motor neuron disorders (e.g., multiple sclerosis, cerebral palsy, spinal cord injuries, etc.). In veterinary medicine, its proposed indications include the prevention and treatment ofmalignant hyperthermia syndrome in various species, the treatment of functional urethral obstruction due to increased external urethral tone in dogs and cats, the prevention and treatment ofequine post-anesthetic myositis (PAM) and equine exertional rhabdomyolysis. It has also beenrecommended to be used in the treatment of bites from Black Widow Spiders in small animals andin the treatment of porcine stress syndrome.Pharmacokinetics - DANTROLENE SODIUM
The bioavailability of dantrolene after oral administration in humans is onlyabout 35% and after intragastric administration to horses, approximately 39%. The drug is fairlyslowly absorbed, with peak levels occurring about 5 hours after oral administration (humans) and1.5 hours in horses. The drug is substantially bound to plasma proteins (principally albumin), butmany drugs may displace it from such (see Drug Interactions).Dantrolene is rapidly eliminated from the horse (t1/2ยป130 minutes). The elimination half-life inhumans is approximately 8 hours. Dantrolene is metabolized in the liver and the metabolites areexcreted in the urine. Only about 1% of the parent drug is excreted unchanged in the urine and bile.
Contraindications/Precautions - Because dantrolene can cause hepatotoxicity, it should be usedwith extreme caution in patients with preexisting liver disease. It should be used with caution inpatients with severe cardiac dysfunction or pulmonary disease. The safe use of dantrolene duringpregnancy has not been determined.
Adverse Effects, Warnings
The most significant adverse reaction with dantrolene therapy ishepatotoxicity. In humans, it is most commonly associated with high dose chronic therapy, but mayalso be seen after short high dose therapy. The incidence of this reaction is unknown in veterinarymedicine, but must be monitored for.More common, but less significant are the CNS associated signs of sedation, dizziness, headache, etc. and GI effects (nausea, vomiting, constipation). Also seen are increased urinary frequency, andpossibly hypotension.
Overdosage - There is no specific antidotal therapy to dantrolene overdoses, therefore remove thedrug from the gut if possible and treat supportively.
Drug Interactions
Dantrolene may be displaced from plasma proteins by warfarin with increased effects or adverse reactions resulting. Diazepam, phenytoin or phenylbutazone have notbeen demonstrated to alter the plasma protein binding of dantrolene.Increased risks of hepatotoxicity from dantrolene have been seen in women >35 years of age whoare also receiving estrogen therapy. The veterinary significance is unknown for this potentialinteraction.
Increased sedation may be seen if tranquilizing agents are used concomitantly with dantrolene.