Dantrolene
Encyclopedia
Dantrolene sodium is a muscle relaxant
that acts by abolishing excitation-contraction coupling
in muscle cells
, probably by action on the ryanodine receptor
. It is the only specific and effective treatment for malignant hyperthermia
, a rare, life-threatening disorder triggered by general anesthesia. It is also used in the management of neuroleptic malignant syndrome
, muscle spasticity
(e.g. after stroke
s, in paraplegia
, cerebral palsy
, or patients with multiple sclerosis
), 3,4-methylenedioxymethamphetamine ("ecstasy") intoxication, serotonin syndrome
, and 2,4-dinitrophenol
poisoning. It is marketed by JHP Pharmaceuticals LLC as Dantrium (in North America) and Dantrolen (Europe).
derivatives proposed as a new class of muscle relaxant. Dantrolene underwent extensive further development, and its action on skeletal muscle
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
. Harrison experimentally induced malignant hyperthermia with halothane
anesthesia in genetically susceptible pig
s, and obtained a 87.5% survival rate, where seven of his eight experiments survived after intravenous
administration of dantrolene; only one animal died during the course of the study. The efficacy of dantrolene in humans was later confirmed in a large, multicenter study published in 1982. Before dantrolene, the only available treatment for malignant hyperthermia was procaine
, which was associated with a 60% mortality rate in animal models.
If the indication is a medical emergency
such as malignant hyperthermia, the only significant contraindication is hypersensitivity.
Dantrolene should not be given to breastfeeding mothers. If a treatment is necessary, breastfeeding should be terminated.
side effect
s 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, anorexia, nausea, vomiting, abdominal cramps, and diarrhea.
Hepatic side effects may be seen either as asymptomatic elevation of liver enzymes and/or bilirubin or, most severe, as fatal and nonfatal hepatitis
. The risk of hepatitis is associated with the duration of treatment and the daily dose. In patients treated for hyperthermia, no liver toxicity has been observed so far.
Pleural effusion
with pericarditis (oral treatment only), rare cases of bone marrow
damage, diffuse myalgia
s, backache, dermatologic reactions, transient cardiovascular reactions, and crystalluria
have additionally been seen. Muscle weakness may persist for several days following treatment.
in skeletal muscle
by binding
to the ryanodine receptor
, and decreasing intracellular
calcium
concentration.
Chemically it is a hydantoin
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
of dantrolene, azumolene, is under development for similar indications. Azumolene has a bromine
residue instead of the nitro
group found in dantrolene, and is 30 times more water-soluble.
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
that acts by abolishing excitation-contraction coupling
Excitation-contraction coupling
Excitation-contraction coupling is a term coined in 1952 to describe the physiological process of converting an electrical stimulus to a mechanical response . This process is fundamental to muscle physiology, whereby the electrical stimulus is usually an action potential and the mechanical...
in muscle cells
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
, probably by action on the ryanodine receptor
Ryanodine receptor
Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...
. It is the only specific and effective treatment for malignant hyperthermia
Malignant hyperthermia
Malignant hyperthermia or malignant hyperpyrexia is a rare life-threatening condition that is usually triggered by exposure to certain drugs used for general anesthesia; specifically, the volatile anesthetic agents and the neuromuscular blocking agent, succinylcholine...
, a rare, life-threatening disorder triggered by general anesthesia. It is also used in the management of neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
, muscle spasticity
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
(e.g. after stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
s, in paraplegia
Paraplegia
Paraplegia is an impairment in motor or sensory function of the lower extremities. The word comes from Ionic Greek: παραπληγίη "half-striking". It is usually the result of spinal cord injury or a congenital condition such as spina bifida that affects the neural elements of the spinal canal...
, cerebral palsy
Cerebral palsy
Cerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....
, or patients with multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
), 3,4-methylenedioxymethamphetamine ("ecstasy") intoxication, serotonin syndrome
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
, and 2,4-dinitrophenol
2,4-Dinitrophenol
2,4-Dinitrophenol , C6H4N2O5, is a cellular metabolic poison. It uncouples oxidative phosphorylation by carrying protons across the mitochondrial membrane, leading to a rapid consumption of energy without generation of ATP....
poisoning. It is marketed by JHP Pharmaceuticals LLC as Dantrium (in North America) and Dantrolen (Europe).
History
Dantrolene was first described in the scientific literature in 1967, as one of several hydantoinHydantoin
Hydantoin, which is also known as glycolylurea, is a heterocyclic organic compound that can be thought of as a cyclic "double-condensation reaction" product of glycolic acid and urea...
derivatives proposed as a new class of muscle relaxant. Dantrolene underwent extensive further development, and its action on skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
was described in detail in 1973.
Dantrolene was widely used in the management of spasticity
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
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
British Journal of Anaesthesia
BJA: British Journal of Anaesthesia is a monthly peer-reviewed medical journal published by Oxford University Press on behalf of the Royal College of Anaesthetists, of which it is the official journal. It was established in 1923 and covers all aspects of anaesthesia. The current editor-in-chief is...
. Harrison experimentally induced malignant hyperthermia with halothane
Halothane
Halothane is an inhalational general anesthetic. Its IUPAC name is 2-bromo-2-chloro-1,1,1-trifluoroethane. It is the only inhalational anesthetic agent containing a bromine atom; there are several other halogenated anesthesia agents which lack the bromine atom and do contain the fluorine and...
anesthesia in genetically susceptible pig
Pig
A pig is any of the animals in the genus Sus, within the Suidae family of even-toed ungulates. Pigs include the domestic pig, its ancestor the wild boar, and several other wild relatives...
s, and obtained a 87.5% survival rate, where seven of his eight experiments survived after intravenous
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
administration of dantrolene; only one animal died during the course of the study. The efficacy of dantrolene in humans was later confirmed in a large, multicenter study published in 1982. Before dantrolene, the only available treatment for malignant hyperthermia was procaine
Procaine
Procaine is a local anesthetic drug of the amino ester group. It is used primarily to reduce the pain of intramuscular injection of penicillin, and it was also used in dentistry. Owing to the ubiquity of the trade name Novocain, in some regions procaine is referred to generically as novocaine...
, which was associated with a 60% mortality rate in animal models.
Contraindications
Dantrolene cannot be used in people with:- preexisting liver disease
- compromised lung function
- severe cardiovascular impairment
- known hypersensitivity to dantrolene
- pediatric patients under 5 years of age
- whenever good muscular balance/strength is needed to maintain an upright position, motoric function, or proper neuromuscular balance
If the indication is a medical emergency
Medical emergency
A medical emergency is an injury or illness that is acute and poses an immediate risk to a person's life or long term health. These emergencies may require assistance from another person, who should ideally be suitably qualified to do so, although some of these emergencies can be dealt with by the...
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.
Adverse effects
Central nervous systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
side effect
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s 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, anorexia, nausea, vomiting, abdominal cramps, and diarrhea.
Hepatic side effects may be seen either as asymptomatic elevation of liver enzymes and/or bilirubin or, most severe, as fatal and nonfatal hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
. The risk of hepatitis is associated with the duration of treatment and the daily dose. In patients treated for hyperthermia, no liver toxicity has been observed so far.
Pleural effusion
Pleural effusion
Pleural effusion is excess fluid that accumulates between the two pleural layers, the fluid-filled space that surrounds the lungs. Excessive amounts of such fluid can impair breathing by limiting the expansion of the lungs during ventilation.-Pathophysiology:...
with pericarditis (oral treatment only), rare cases of bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
damage, diffuse myalgia
Myalgia
Myalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
s, backache, dermatologic reactions, transient cardiovascular reactions, and crystalluria
Crystalluria
Crystalluria refers to crystals found in the urine when performing a urine test. Crystalluria is considered as one of the side effects of sulphonamides.-Clinical significance:It can be an indication of urolithiasis.It can be associated with cysteinuria....
have additionally been seen. Muscle weakness may persist for several days following treatment.
Mutagenicity and carcinogenity
Dantrolene gave positive results in animal high dose studies (with and without enzymatic activation) regarding mutagenicity and carcinogenity. No evidence for human mutagenicity and carcinogenity has been found during the long years of clinical experience.Mechanism of action
Dantrolene depresses excitation-contraction couplingExcitation-contraction coupling
Excitation-contraction coupling is a term coined in 1952 to describe the physiological process of converting an electrical stimulus to a mechanical response . This process is fundamental to muscle physiology, whereby the electrical stimulus is usually an action potential and the mechanical...
in skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
by binding
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...
to the ryanodine receptor
Ryanodine receptor
Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...
, and decreasing intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
concentration.
Chemistry
Hydantoin
Hydantoin, which is also known as glycolylurea, is a heterocyclic organic compound that can be thought of as a cyclic "double-condensation reaction" product of glycolic acid and urea...
derivative, but does not exhibit antiepileptic activity like other hydantoin derivates such as phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
.
The poor water solubility
Solubility
Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on...
of dantrolene leads to certain difficulties in its use. A more water-soluble analog
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of dantrolene, azumolene, is under development for similar indications. Azumolene has a bromine
Bromine
Bromine ") is a chemical element with the symbol Br, an atomic number of 35, and an atomic mass of 79.904. It is in the halogen element group. The element was isolated independently by two chemists, Carl Jacob Löwig and Antoine Jerome Balard, in 1825–1826...
residue instead of the nitro
Nitro
-Chemistry:*Nitroglycerin, an explosive chemical compound*Nitromethane, the simplest organic nitro compound; also used to fuel high-performance internal-combustion engines*Nitrous oxide, "laughing gas", used in some dental procedures as an anaesthetic...
group found in dantrolene, and is 30 times more water-soluble.
Drug interactions
Dantrolene may interact with the following drugs:- Calcium channel blockerCalcium channel blockerA calcium channel blocker is a chemical that disrupts the movement of calcium through calcium channels.CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with...
s of the diltiazemDiltiazemDiltiazem is a non-dihydropyridine member of the class of drugs known as calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia....
/verapamilVerapamilVerapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine...
type: Intravenous treatment with dantrolene and concomitant calcium channel blocker treatment may lead to severe cardiovascular collapse, arrhythmias, myocardial depressions, and hyperkalemia. - Non-depolarizing neuromuscular blocking agentsNeuromuscular-blocking drugNeuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine synthesis or release or by acting postsynaptically at the...
, such as vecuroniumVecuroniumVecuronium is a muscle relaxant in the category of non-depolarizing blocking agents. Vecuronium bromide is indicated as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...
bromide: Neuromuscular blockade is potentiated. - CNS depressantDepressantA depressant, or central depressant, is a drug or endogenous compound that depresses the function or activity of a specific part of the brain...
s: Sedative action is potentiated. BenzodiazepineBenzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s may also cause additive muscle weakness. - Combined oral contraceptives and hormone replacement therapyHormone replacement therapy (menopause)Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
with estrogenEstrogenEstrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
s: May enhance liver toxicity of dantrolene, particularly in women over 35 years of age.
External links
- http://www.kompendium.ch/MonographieTxt.aspx?lang=de&MonType=fi Swiss Drug Compendium on oral Dantrolene (German)