Elephant specific information, if available, is in blue.

Chemistry – A hydantoin derivative which is dissimilar structurally and pharmacologically from other skeletal muscle relaxant drugs, dantrolene sodium is a weak acid with a pKa of 7.5. It occurs as an odorless, tasteless, orange, fine powder that is slightly soluble in water. It rapidly hydrolyzes in aqueous solutions to the free acid form which precipitates out of solution.

 

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 exhibits muscle relaxation activity by direct action on muscle. While the exact mechanism is not well understood, it probably acts on skeletal muscle by interfering with the release of calcium from the sarcoplasmic reticulum. It has no discernible effects on the respiratory or cardiovascular systems, but can drowsiness and dizziness. The reasons for these CNS effects are not known.

 

Uses/Indications – In humans, oral dantrolene is indicated primarily for the treatment associated with 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 of malignant 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 of equine post-anesthetic myositis (PAM) and equine exertional rhabdomyolysis. It has also been recommended to be used in the treatment of bites from Black Widow Spiders in small animals and in the treatment of porcine stress syndrome.

 

Pharmacokinetics – The bioavailability of dantrolene after oral administration in humans is only about 35% and after intragastric administration to horses, approximately 39%. The drug is fairly slowly absorbed, with peak levels occurring about 5 hours after oral administration (humans) and 1.5 hours in horses. The drug is substantially bound to plasma proteins (principally albumin), but many drugs may displace it from such (see Drug Interactions).

 

Dantrolene is rapidly eliminated from the horse (t1/2≈130 minutes). The elimination half-life in humans is approximately 8 hours. Dantrolene is metabolized in the liver and the metabolites are excreted 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 used with extreme caution in patients with preexisting liver disease. It should be used with caution in patients with severe cardiac dysfunction or pulmonary disease. The safe use of dantrolene during pregnancy has not been determined.

 

Adverse Effects/Warnings – The most significant adverse reaction with dantrolene therapy is hepatotoxicity. In humans, it is most commonly associated with high dose chronic therapy, but may also be seen after short high dose therapy. The incidence of this reaction is unknown in veterinary medicine, 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, and possibly hypotension.

 

Overdosage – There is no specific antidotal therapy to dantrolene overdoses, therefore remove the drug 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 not been demonstrated to alter the plasma protein binding of dantrolene.

 

Increased risks of hepatotoxicity from dantrolene have been seen in women >35 years of age who are also receiving estrogen therapy. The veterinary significance is unknown for this potential interaction. Increased sedation may be seen if tranquilizing agents are used concomitantly with dantrolene.

 

Doses –

Horses:

For treatment of acute rhabdomyolosis:

a)   15 – 25 mg/kg slow IV qid (Robinson 1987)

 

  For prevention of rhabdomyolysis:

a)   2 mg/kg PO once daily (Robinson 1987)

 

For prevention of post-anesthetic myositis (PAM):

a)   10 mg/kg PO (intragastric) 1.5 hours before surgery. This should give peak levels at the time surgery begins and maintain postulated therapeutic levels for an additional 2 hours. The intragastric preparation was made by dissolving/suspending the contents of oral capsules into 500 ml of normal saline. Should further doses be warranted, additional doses of 2.5 mg/kg PO (intragastric) q60 minutes can be given.

      Alternatively, IV doses of 1.9 mg/kg loading will give therapeutic levels but will only persist for about 20 minutes. An IV dose of 4 mg/kg will maintain therapeutic levels for about 2 hours but peak levels will be quite high. (Court et al. 1987)

 

Monitoring Parameters –

Depending on the reason for use:

1)   Baseline and periodic liver function tests (ALT, AST, Alk Phos, etc) if projecting to be used chronically or using high dosages

2)   Body temperature (malignant hyperthermia)

3)   Urine volume, frequency, continence

 

Client Information – This drug should only be used by professionals familiar with its use.

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times –

 

Veterinary-Approved Products: None

 

Human-Approved Products:

Dantrolene Sodium 25 mg, 50 mg, 100 mg capsules; Dantrium® (Procter & Gamble Pharm.) (Rx)

 

Dantrolene Sodium for Injection 20 mg per vial (with mannitol 3 g.); Dantrium® Intravenous (Procter & Gamble Pharm.) (Rx)

 

Note: Because of the expense, minimum order quantity, and non-returnable nature of the commercially available intravenous product, it is not well suited for veterinary use.