Dantrolene

Article Author:
Dominic Ratto
Article Editor:
Robert Joyner
Updated:
12/13/2018 11:05:52 AM
PubMed Link:
Dantrolene

Indications

Dantrolene sodium (sold under a variety of trade names) is a postsynaptic muscle relaxant with multiple indications in the fields of anesthesiology and neurology.   Among the many indications for the use of dantrolene, its primary indication, and FDA approved usage in both children and adults, is for the treatment of malignant hyperthermia: the very rare, but life-threatening disorder triggered by general anesthesia.  Malignant hyperthermia is a reaction to the volatile halogenated anesthetics, or depolarizing muscle relaxants, causing sustained muscle contraction, hyperthermia, rhabdomyolysis, and hypercarbia; potentially leading to intraoperative patient demise.  These symptoms develop as a response to the anesthetic agents acting on defective ryanodine receptors (calcium channels in muscle cell sarcoplasmic reticulum).  Given the mechanism of action, dantrolene acts as an antagonist to these receptors, therefore halting and preventing the further progression of the symptoms of malignant hyperthermia.   Even though the incidence of susceptibility to malignant hyperthermia is estimated to be 1:50,000-100,000,[1] it is required, according to the Malignant Hyperthermia Association of the United States, that any facility that administers malignant hyperthermia triggering agents (Isoflurane, desflurane, sevoflurane, and succinylcholine) should stock dantrolene in their facilities at all times.  Other FDA approved uses for dantrolene include muscle spasticity disorders as seen with upper motor neuron disorders including stroke, spinal cord injury, cerebral palsy, and multiple sclerosis. It is the only FDA approved oral peripherally acting antispasmodic medication for these disorders.Dantrolene is also used for the treatment of neuroleptic malignant syndrome (given its similarity in presentation and symptoms to malignant hyperthermia) as well as for the overdose of 2,4-dinitrophenol (A banned "fat burner" medication that interrupts ATP synthesis and causes hyperthermia).  However, these are considered off-label uses.Recently, dantrolene has been studied in the treatment of vasospasm following aneurysmal subarachnoid hemorrhage. Single dose administration of intravenous dantrolene was found to decrease arterial vasospasm although this remains an off-label use.[2] Interestingly, research on Alzheimer's disease has shown that increased intracellular calcium release modulates amyloid genetic processing in the brain, thereby promoting memory loss.  Ryanodine receptors have been identified as a possible culprit of this phenomenon.  Given this information, Dantrolene may serve as a potential future treatment for Alzheimer's disease, although further studies are required to test this hypothesis before it can be recommended for this use.[3]

Mechanism of Action

Unlike the classic paralytic medications that function by blocking postsynaptic acetylcholine receptors, dantrolene acts intracellularly in skeletal muscle to lessen the excitation-contraction coupling interaction between actin and myosin within the individual sarcomere.  This function takes place by antagonizing ryanodine receptors within the sarcoplasmic reticulum, which leads to the inhibition of the release of Calcium ions vital to the contraction process.[4]  The precise mechanism of action remains controversial - direct action on the calcium release channel RyR1 versus indirect via other molecular components of the sarcoplasmic reticulum are both proposed mechanisms.[5][6]By decreasing the amount of calcium within each sarcomere, calcium cannot bind to the troponin on actin filaments.  This prevents the uncovering of the myosin binding site on the actin, preventing the actin and myosin cross-bridging from occurring; thus decreasing the contractibility and energy expenditure of the muscle cells.

Administration

Dantrolene is available as an intravenous injection and an oral capsule.  The choice of the method of administration is dependent on the intended use of the medication.Treatment of malignant hyperthermia: When symptoms of malignant hyperthermia are identified, 2.5mg/kg dantrolene via intravenous push should be administered immediately. If the signs and symptoms of malignant hyperthermia persist, additional intravenous boluses of 1-2.5mg/kg are indicated, to a maximum cumulative dose of 10mg/kg.  Following the successful treatment of the initial reaction, 1mg/kg of IV dantrolene should be provided every 6 hours for 24 hours since the last observed symptom of malignant hyperthermia to prevent recurrence.[7]  At any point during the treatment of malignant hyperthermia, contacting the Malignant Hyperthermia Association of the United States (MHAUS) at 1-800-MH-HYPER (1-800-644-9737) is appropriate for dantrolene doing recommendations and ongoing treatment.[8]

Prophylaxis of malignant hyperthermia: 2.5 mg/kg intravenously over a period of one minute approximately 75 minutes before surgery. Repeat doses can be given during anesthesia and surgery in prolonged cases. Although this is an approved indication for the use of dantrolene, it is an unnecessary use if patients avoid triggering agents when they are susceptible to malignant hyperthermia.  

Pediatric patients: The recommended weight-based dose is the same as for both adults and children.Chronic Muscle spasticity: Oral dantrolene started at 25mg daily for seven days is the initial dosing and should be titrated to the maximum individual effect.  Doses are typically increased by 25mg at a time and should be monitored for seven days prior to further advancement.  The maximum dose of 400mg/day.

It is important to note that multiple formulations exist for IV Dantrolene.  The classic preparation is supplied as a lyophilized powder in 20mg vials that must be reconstituted in approximately 60ml of sterile water prior to administration. These vials also contain 3gm of mannitol each.  Given the known difficulty in mixing the solution, it is essential to call for additional help to assist with the medication preparation as the provider continues to monitor and provide resuscitative measures. A new formulation is supplied in 250mg vials and only requires 5ml of sterile water for reconstitution.  Because of the hyper-concentration of this form of dantrolene, blood concentrations rise to a much faster rate, presumably leading to a more rapid onset and effect.

Adverse Effects

The intravenous administration of dantrolene in healthy volunteers has resulted in skeletal muscle weakness,[9] dyspnea, respiratory muscle weakness, and decrease inspiratory capacity.  These are expected symptoms given the mechanism of action of the medication.Oral dantrolene carries a black box warning for the potential for hepatotoxicity including overt hepatitis.  Hepatic function should be evaluated prior to the administration of the oral capsule form and should be monitored throughout the course of treatment.  The medication should be stopped immediately if liver function becomes impaired.[10]

Dantrolene is classified as FDA pregnancy category C.

Contraindications

No contraindications exist to the use of IV dantrolene for the treatment of malignant hyperthermia.  Oral dantrolene is contraindicated in patients who have underlying liver disease including cirrhosis, non-alcoholic steatohepatitis, and hepatitis B or C infections.

Monitoring

Monitoring therapeutic levels of IV dantrolene is unnecessary. When treating a patient, endpoints of therapy are when the symptoms of malignant hyperthermia (hypercarbia, hyperthermia, tachycardia, rigidity, etc.) have subsided.  When using the lyophilized form of dantrolene, large volumes of sterile water are administered with the medication.  Although mannitol is included with the dantrolene, monitoring fluid status and output is paramount to the ongoing care a resuscitation of these patients.

For those taking the oral capsule for muscle spasticity,  liver function tests should be monitored, and dantrolene discontinued if signs and symptoms of liver injury are noted. These include elevated LFTs, jaundice, right upper quadrant pain, etc.  These symptoms typically resolve upon the discontinuation of dantrolene.  If dantrolene is to be reinstated, per recommendations the patient should be hospitalized, and the drug initiated in very small doses with gradual increases.[11]

Toxicity

No reversal drug or antidote exists for IV or oral dantrolene.  For hepatotoxicity induced by oral dantrolene, discontinue the medication and initiate symptomatic therapy.

Enhancing Healthcare Team Outcomes

Use of dantrolene for malignant hyperthermia:  Dantrolene is the only known treatment for malignant hyperthermia and should be administered as soon as possible following the identification of the symptoms of the disease process. (III)[12]Availability of dantrolene for malignant hyperthermia: Facilities that stock and can potentially administer any potentially triggering agent, to include succinylcholine without volatile agents, should have dantrolene immediately available (i.e., the capability for dantrolene administration within 10 minutes of the first sign of MH) if a patient in that facility develops MH. Large medical facilities with multiple operating rooms should have some form of malignant hyperthermia cart (V-Expert opinion, MHAUS).Training:  All personnel who administer anesthesia or frequently work in the operating room should undergo training in the identification of malignant hyperthermia and the appropriate administration and dosing of dantrolene. (V-Expert opinion, MHAUS)Performing RCTs for malignant hyperthermia on humans would be unethical, given the known response and treatment with dantrolene, as well as the known mortality if left untreated. Finally, it is important to understand that substantial evidence indicating the efficacy of dantrolene for malignant hyperthermia is lacking.


References

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[2] Sabouri M,Momeni M,Khorvash F,Rezvani M,Tabesh H, The Effect of a Single dose Dantrolene in Patients with Vasospasm Following Aneurysmal Subarachnoid Hemorrhage. Advanced biomedical research. 2017     [PubMed PMID: 28808649]
[3] Liang L,Wei H, Dantrolene, a treatment for Alzheimer disease? Alzheimer disease and associated disorders. 2015 Jan-Mar     [PubMed PMID: 25551862]
[4] Zucchi R,Ronca-Testoni S, The sarcoplasmic reticulum Ca2 channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states. Pharmacological reviews. 1997 Mar     [PubMed PMID: 9085308]
[5] Ellis KO,Castellion AW,Honkomp LJ,Wessels FL,Carpenter JE,Halliday RP, Dantrolene, a direct acting skeletal muscle relaxant. Journal of pharmaceutical sciences. 1973 Jun     [PubMed PMID: 4712630]
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[8] Riazi S,Kraeva N,Hopkins PM, Updated guide for the management of malignant hyperthermia. Canadian journal of anaesthesia = Journal canadien d'anesthesie. 2018 Jun     [PubMed PMID: 29600483]
[9] Ward A,Chaffman MO,Sorkin EM, Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity. Drugs. 1986 Aug     [PubMed PMID: 3527659]
[10] Amano T,Fukami T,Ogiso T,Hirose D,Jones JP,Taniguchi T,Nakajima M, Identification of enzymes responsible for dantrolene metabolism in the human liver: A clue to uncover the cause of liver injury. Biochemical pharmacology. 2018 May     [PubMed PMID: 29522712]
[11] Chan CH, Dantrolene sodium and hepatic injury. Neurology. 1990 Sep     [PubMed PMID: 2392230]
[12] Harrison GG,Chapman DC, Dantrolene sodium in the treatment of malignant hypertension. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde. 1982 Oct 2     [PubMed PMID: 7123413]