Dantrolene Sodium

Dantrolene Sodium is a medication that treats muscle stiffness, spasms, and spasticity. It belongs to a class of drugs known as muscle relaxants. Dantrolene is primarily used to manage conditions like muscle spasticity associated with neurological disorders, including cerebral palsy, multiple sclerosis, and spinal cord injuries. Additionally, it is used to prevent and treat malignant hyperthermia, a potentially life-threatening condition that can occur during certain types of anesthesia.

Dantrolene affects the release of calcium ions from the sarcoplasmic reticulum in muscle cells. This action helps to reduce muscle contraction and spasticity.

Dantrolene alleviates muscle spasticity and stiffness associated with various neurological conditions. It is a key medication used to prevent and treat malignant hyperthermia, a rare but severe reaction to certain medications used during surgery.

Dantrolene is typically administered orally in capsules or intravenously, depending on the treated condition.

In malignant hyperthermia, dantrolene is often used as part of emergency treatment to reduce elevated body temperature and prevent further complications rapidly.

Common side effects of dantrolene may include drowsiness, weakness, dizziness, and gastrointestinal symptoms. Serious side effects are rare but can include liver toxicity, and liver function should be monitored during treatment.

Regular monitoring, including liver function tests, is often conducted during dantrolene therapy, especially with long-term use.

Dantrolene may interact with other medications, and you must inform your healthcare provider about all the medications and supplements you are taking.

It’s essential to use dantrolene under a healthcare professional’s guidance, and the treatment dosage and duration will be determined based on the specific condition being treated. If you have questions or concerns about dantrolene sodium, it’s best to discuss them with your healthcare provider.

Pharmacokinetics

Dantrolene sodium is slowly and almost completely absorbed from the gastrointestinal tract after oral doses. It is metabolized in the liver mainly to the hydroxylated metabolite, which is nearly as potent as dantrolene sodium, and the acetamide metabolite, which has weak muscle relaxant activity. It is excreted in the urine, mainly as metabolites with a small amount of unchanged dantrolene; some is excreted in the bile. Dantrolene is bound extensively to plasma proteins. The elimination half-life of oral dantrolene is about 9 hours, although half-lives of up to 12 hours have been reported after intravenous use.

Uses and Administration

Dantrolene sodium is a muscle relaxant with a direct action on skeletal muscle. It uncouples muscular contraction from excitation, probably by interfering with calcium release from the sarcoplasmic reticulum.

When given orally, it has a vital role in the symptomatic relief of chronic, severe spasticity. It is also given, usually by intravenous injection, to treat malignant hyperthermia. For spasticity, the initial oral dose is 25 mg daily, increased gradually as necessary, at 7-day intervals, over about seven weeks to a maximum dose of 100 mg four times daily. If no response is achieved within 45 days, treatment should be stopped. In children, US licensed product information suggests a dose of 500 micrograms/kg once daily, increased gradually if necessary to 2 mg/kg three times daily; dosage four times daily may be necessary for some children, but a dose of 100 mg four times daily should not be exceeded.

In treating malignant hyperthermia, dantrolene sodium is given, with supportive measures, in an initial dose of 1 mg/kg by rapid intravenous injection, repeated, if necessary, to a total dose of 10 mg/kg. An average dose of 2.5 mg/kg is usually effective. If a relapse or recurrence occurs, dantrolene should be given again at the last effective dose. In the USA, doses of 1 to 2 mg/kg orally four times daily have been recommended for up to 3 days after the crisis to prevent recurrence, and similar doses have been given for 1 to 2 days before surgery in individuals thought to be at risk of developing the syndrome.

Prophylactic doses may also be given intravenously; 2.5 mg/kg has been recommended, infused over about 60 minutes, starting about 75 minutes before anticipated anesthesia, with further doses during anesthesia and surgery if signs of malignant hyperthermia develop.

Hyperthermia

Dantrolene treats hyperthermia associated with muscle rigidity and fulminant hypermetabolism of skeletal muscle, which occurs in neuroleptic malignant syndrome and malignant hyperthermia. There is also anecdotal evidence that dantrolene may produce beneficial effects for treating similar symptoms resulting from poisoning with various agents such as carbon monoxide, MAOIs, and ethylene amfetamine. However, after suggesting that it might also be used in cocaine intoxication, the manufacturers warned physicians that they should not regard dantrolene as an effective treatment for all types of hyperthermia and rigidity accompanying poisoning. Dantrolene has been tried as part of treatment for heat stroke but does not appear to affect outcome.

Malignant Hyperthermia

Malignant hyperthermia (malignant hyperpyrexia) is a rare but potentially fatal syndrome associated with general anesthesia, in which a sudden increase in calcium concentration in muscle cytoplasm initiates a series of metabolic disturbances. The disorder appears to be genetically determined and is more common in males. In susceptible individuals, a reaction may be induced by inhalation anesthetics (mainly halogenated hydrocarbons), suxamethonium, prolonged anesthesia, pre-operative exercise, muscle trauma, fever, or anxiety. However, many reactions occur in individuals who previously had uneventful general anesthesia.

Early signs and symptoms of the syndrome include tachycardia, unstable blood pressure, hypercapnia, rising temperature, and hyperventilation followed by metabolic acidosis and hyperkalemia. Muscle rigidity develops in many patients, and later, there may be evidence of muscle damage, including raised serum concentrations of creatine phosphokinase and other enzymes, myoglobinuria, and myoglobinuria. Hyperthermia develops relatively late. Other late complications may include renal failure, intravascular coagulopathy, and pulmonary edema.

Treatment should be started as soon as possible after symptoms appear, with dantrolene given by rapid intravenous injection until symptoms disappear. Supportive treatment must also include:

• immediate anesthesia withdrawal;
• giving oxygen;
• correcting acidosis with sodium bicarbonate;
• controlling hyperkalemia with insulin;
• cooling procedures.

The incidence of reactions in susceptible individuals can be reduced by avoiding triggering agents. Dantrolene has also been given prophylactically, but a high incidence of adverse effects has been reported, and such use is not generally recommended. Susceptibility to malignant hyperthermia can be detected by histological examination of muscle fibers obtained by biopsy and study of their response to caffeine and/or halothane in vitro. Although such testing remains the gold standard for determining susceptibility, genetic testing is also being developed as an alternative.

Dantrolene has been suggested for use as a secondary drug in the treatment of a related and potentially fatal syndrome that has developed in some children after induction of anesthesia with halothane and suxamethonium (see also Children, under Precautions of Suxamethonium).

Neuroleptic Malignant Syndrome

Dantrolene has been used, usually alone or with bromocriptine, in treating neuroleptic malignant syndrome. However, some workers have not found it helpful, and evidence from controlled trials is lacking. Doses reported for dantrolene have varied considerably. For those patients unable to swallow and when rapid control of symptoms is required, doses of 1 mg/kg or more have been given initially by intravenous injection. Up to 600 mg has been given daily by mouth in divided doses.

Tetanus

Dantrolene has effectively controlled muscle spasms in the treatment of tetanus. It has also been used as an adjunct to neuromuscular blockade; conflicting reports show its value in avoiding mechanical ventilation.

Adverse Effects

Adverse effects associated with dantrolene sodium tend to occur at the start of treatment but are often short-lived and can be controlled by adjusting the dose. Drowsiness, dizziness, fatigue, weakness, and general malaise are the most common adverse effects. Diarrhea may be severe enough to require withdrawal. If diarrhea recurs on restarting dantrolene, treatment should probably be stopped permanently.

Other adverse effects reported include nausea and vomiting, anorexia, constipation, abdominal cramps, gastrointestinal bleeding, tachycardia, unstable blood pressure, dyspnoea, rashes (often acneform), pruritus, chills and fever, headache, myalgia, nervousness, insomnia, confusion, visual disturbances, mental depression, dysphagia and speech disturbances, and seizures. Haematuria, crystalluria, urinary frequency and retention, and incontinence may occur. Rare but serious adverse effects include hepatotoxicity, which may be fatal, and pleural effusion with pericarditis. Serious adverse effects do not appear to be a problem with the short-term use of intravenous dantrolene sodium in treating malignant hyperthermia.

Effects on the Liver

Dantrolene has caused hepatotoxicity with raised liver enzyme values, jaundice, and hepatitis; fatalities have been reported. Not all patients experienced symptoms such as anorexia, nausea, or abdominal discomfort before the onset of the disease, and the severity of hepatic injury was unrelated to clinical presentation. In the first report, the 14 fatalities occurred with doses over 200 mg daily; a later review found the mean dose associated with 27 fatalities to be 582 mg daily, while reports of non-fatal liver toxicity (95 cases) were associated with a mean dose of 263 mg daily.

The onset of hepatic injury was usually between 1 and 6 months after starting treatment, and fatalities were not reported in the first two months. Only rarely did injury develop before 45 days of treatment. Females appeared to be at greater risk of severe liver injury, and the severity of the reaction appeared to be age-related, with most fatalities occurring in patients over 30. The liver injury was usually hepatocellular and might include ascending cholangitis; there was little evidence of hypersensitivity.

Effects on the Lungs

Pulmonary edema associated with heart failure and pleural effusions with eosinophilia have been reported rarely in patients receiving dantrolene. These reactions generally resolve on drug withdrawal, but resolution may take several months; corticosteroid therapy may benefit dantrolene-related eosinophilic pleural effusion.

Lymphomas

A fatal lymphocytic lymphoma was associated with prolonged dantrolene therapy (600 mg daily) for progressive spastic paraplegia.

Precautions

It is recommended that dantrolene sodium should not be given to patients with active liver disease. Liver function tests should be performed in all patients before and during treatment; if abnormal values are found, treatment should generally be stopped. The risk of liver injury may be increased in patients over 30 years of age, in females (especially those taking estrogens), in those with a history of liver disease, and with doses above 400 mg daily. Dantrolene sodium should be used cautiously in patients with cardiac or pulmonary disorders. It should not be given to patients who use their spasticity to maintain posture or function or to patients with acute muscle spasms.

Dantrolene sodium may cause drowsiness; patients affected should not drive or operate machinery.

Interactions

The CNS effects of dantrolene sodium may be enhanced by alcohol or other CNS depressants. Use with other potentially hepatotoxic drugs, such as estrogens, may increase the risk of liver damage and should be avoided.

Calcium-channel Blockers

Severe hyperkalemia and myocardial depression occurred with intravenous dantrolene to prevent malignant hyperthermia in patients taking verapamil for angina. The peak serum-potassium concentration was 7.1 mmol/liter 2.5 hours after the dantrolene infusion. Nifedipine was substituted for verapamil in a subsequent operation, and only a slight increase in serum potassium occurred after dantrolene. This combination of ventricular fibrillation and cardiovascular collapse associated with hyperkalemia has been seen in animal studies, and the manufacturers recommend that calcium channel blockers and intravenous dantrolene should not be used together.

Drug Nomenclature

INNs in main languages (French, Latin, Russian, and Spanish):

Synonyms: Dantroleno sódico; F-368 (dantrolene); F-440

BAN: Dantrolene Sodium [BANM]

USAN: Dantrolene Sodium

INN: Dantrolene Sodium [rINNM (en)]

INN: Dantroleno sódico [rINNM (es)]

INN: Dantrolène Sodique [rINNM (fr)]

INN: Natrii Dantrolenum [rINNM (la)]

INN: Натрий Дантролен [rINNM (ru)]

Chemical name: The hemi heptahydrate of the sodium salt of 1-[5-(4-nitrophenyl)furfurylideneamino]imidazolidine-2,4-dione

Molecular formula: C14H9N4NaO5,31/2H2O =399.3

CAS: 7261-97-4 (dantrolene); 14663-23-1 (anhydrous dantrolene sodium); 24868-20-0 (dantrolene sodium, hemiheptahydrate)

ATC code: M03CA01

Read code: y031p [Musculoskeletal Use]; y03KP [Anaesthesia]

Pharmacopoeias. In Britain, Japan, and the US.

British Pharmacopoeia 2008 (Dantrolene Sodium). A yellowish-orange to orange crystalline powder. Very slightly soluble in water, slightly soluble in alcohol, practically insoluble in acetone, sparingly soluble in methyl alcohol.

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Dantrolene Sodium). A delicate orange to orange-brown powder. Sparingly soluble in acetone, dimethylformamide, and glycerol. Store in airtight containers. Protect from light.