Dantrolene sodium, sold under the brand name Dantrium among others, is a postsynaptic muscle relaxant that lessens excitation-contraction coupling in muscle cells. It achieves this by inhibiting Ca²⁺ ions release from sarcoplasmic reticulum stores by antagonizing

ryanodine receptor Ryanodine receptors (RyR for short) form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissu ...

s. It is the primary drug used for the treatment and prevention of malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia or

drugs A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...

. It is also used in the management of neuroleptic malignant syndrome, muscle spasticity (e.g. after

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

s, in

paraplegia Paraplegia, or paraparesis, is an impairment in motor or sensory function of the lower extremities. The word comes from Ionic Greek () "half-stricken". It is usually caused by spinal cord injury or a congenital condition that affects the neural ...

, cerebral palsy, or patients with

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

), and poisoning by

2,4-dinitrophenol 2,4-Dinitrophenol (2,4-DNP or simply DNP) is an organic compound with the formula HOC6H3(NO2)2. It is a yellow, crystalline solid that has a sweet, musty odor. It sublimates, is volatile with steam, and is soluble in most organic solvents as well ...

or by the related compounds dinoseb and dinoterb. The most frequently occurring side effects include drowsiness, dizziness, weakness, general malaise, fatigue, and diarrhea. It is marketed by Par Pharmaceuticals LLC as Dantrium (in North America) and by Norgine BV as Dantrium, Dantamacrin, or Dantrolen (in Europe). A hospital is recommended to keep a minimum stock of 36 dantrolene vials totaling 720 mg, sufficient for a 70-kg person.

Adverse effects

Central nervous system side effects are quite frequently noted and encompass speech and visual disturbances, mental depression and confusion, hallucinations, headache, insomnia and exacerbation or precipitation of seizures, and increased nervousness. Infrequent cases of respiratory depression or a feeling of suffocation have been observed. Dantrolene often causes sedation severe enough to incapacitate the patient to drive or operate machinery. Gastrointestinal effects include bad taste, decreased appetite, nausea, vomiting, abdominal cramps, and diarrhea. Liver side effects may be seen either as asymptomatic elevation of liver enzymes and/or

bilirubin Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...

or, most severe, as fatal and nonfatal

liver inflammation Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain ...

. The risk of liver inflammation is associated with the duration of treatment and the daily dose. In patients treated for hyperthermia, no liver toxicity has been observed so far. Patients on chronic dantrolene therapy should routinely have LFTs monitored. Pleural effusion with inflammation of the fibrous sac around the heart (oral treatment only), rare cases of bone marrow damage, diffuse muscle pains, backache, dermatologic reactions, transient cardiovascular reactions, and crystals in the urine have additionally been seen. Muscle weakness may persist for several days following treatment.

Mutagenicity and carcinogenity

It is unclear whether dantrolene has carcinogenic effects.

Contraindications

Oral dantrolene cannot be used by: * people with a pre-existing liver disease * people with compromised lung function * people with severe cardiovascular impairment * people with a known hypersensitivity to dantrolene * pediatric patients under five years of age * people who need good muscular balance or strength to maintain an upright position, motoric function, or proper neuromuscular balance If the indication is a medical emergency, such as malignant hyperthermia, the only significant contraindication is hypersensitivity.

Pregnancy and breastfeeding

If needed in pregnancy, adequate human studies are lacking, therefore the drug should be given in pregnant women only if clearly indicated. It may cause hypotonia in the newborn if given closely before delivery. Dantrolene should not be given to breastfeeding mothers. If a treatment is necessary, breastfeeding should be terminated.

Interactions

Dantrolene may interact with the following drugs: Retrieved on December 31, 2008. *

Calcium channel blocker Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...

s of the

diltiazem Diltiazem, sold under the brand name Cardizem among others, is a calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used ...

/ verapamil type: Intravenous treatment with dantrolene and concomitant calcium channel blocker treatment may lead to severe cardiovascular collapse, abnormal heart rhythms, myocardial depressions, and high blood potassium. * Nondepolarizing neuromuscular blocking agents, such as

vecuronium Vecuronium bromide, sold under the brand name Norcuron among others, is a medication used as part of general anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. It is also used to help with endotracheal int ...

bromide: Neuromuscular blockade is potentiated. * CNS depressants: Sedative action is potentiated.

Benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

s may also cause additive muscle weakness. * Combined oral contraceptives and hormone replacement therapy with estrogens may enhance liver toxicity of dantrolene, particularly in women over 35 years of age.

Pharmacology

Dantrolene depresses excitation-contraction coupling in

skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...

by acting as a

receptor antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rece ...

to the

, and decreasing free intracellular calcium concentration.

Chemistry

Chemically it is a

hydantoin Hydantoin, or glycolylurea, is a heterocyclic organic compound with the formula CH2C(O)NHC(O)NH. It is a colorless solid that arises from the reaction of glycolic acid and urea. It is an oxidized derivative of imidazolidine. In a more general sen ...

derivative, but does not exhibit antiepileptic activity like other hydantoin derivates such as phenytoin. The poor water solubility of dantrolene leads to certain difficulties in its use. A more water-soluble

analog Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use analo ...

of dantrolene,

azumolene Azumolene is an experimental drug which is a derivative of dantrolene. In animal studies, azumolene showed similar efficacy to dantrolene at controlling symptoms of malignant hyperthermia Malignant hyperthermia (MH) is a type of severe reaction ...

, is under development for similar indications. Azumolene has a bromine residue instead of the

nitro Nitro may refer to: Chemistry *Nitrogen, a chemical element and a gas except at very low temperatures, with which many compounds are formed: **Nitro compound, an organic compound containing one or more nitro functional groups, -NO2 **Nitroalkene, ...

group found in dantrolene, and is 30 times more water-soluble.

Synthesis

The original patent synthesis started with ''para''-nitroaniline which undergoes diazotization followed by a copper(II) chloride catalyzed arylation with

furfural Furfural is an organic compound with the formula C4H3OCHO. It is a colorless liquid, although commercial samples are often brown. It has an aldehyde group attached to the 2-position of furan. It is a product of the dehydration of sugars, as occurs ...

(essentially a modified

Meerwein arylation The Meerwein arylation is an organic reaction involving the addition of an aryl diazonium salt (ArN2X) to an electron-poor alkene usually supported by a metal salt. The reaction product is an alkylated arene compound. The reaction is named afte ...

). This then reacts with 1-aminohydantoin to form the final product. Dantrolene synthesis

History

Dantrolene was first described in the scientific literature in 1967, as one of several

derivatives proposed as a new class of muscle relaxant. Dantrolene underwent extensive further development, and its action on

was described in detail in 1973. Dantrolene was widely used in the management of spasticity before its efficacy in treating malignant hyperthermia was discovered by South African anesthesiologist Gaisford Harrison and reported in a landmark 1975 article published in the ''

British Journal of Anaesthesia The ''British Journal of Anaesthesia'' is a monthly peer-reviewed medical journal published by Elsevier on behalf of the Royal College of Anaesthetists (and its Faculty of Pain Medicine), the College of Anaesthesiologists of Ireland, and the Hong ...

''. A reprint of the article, which became a "Citation Classic", is available in Harrison experimentally induced malignant hyperthermia with

halothane Halothane, sold under the brand name Fluothane among others, is a general anaesthetic. It can be used to induce or maintain anaesthesia. One of its benefits is that it does not increase the production of saliva, which can be particularly useful i ...

anesthesia in genetically susceptible pigs, and obtained an 87.5% survival rate, where seven of his eight experiments survived after

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

administration of dantrolene. The efficacy of dantrolene in humans was later confirmed in a large, multicenter study published in 1982, and confirmed epidemiologically in 1993. Before dantrolene, the only available treatment for malignant hyperthermia was procaine, which was associated with a 60% mortality rate in animal models.

References

External links

* * {{Portal bar , Medicine Chemical substances for emergency medicine Furans Hydantoins Muscle relaxants Nitrobenzenes