Dantrolene - Indications, Contraindications, Warnings, and Precautions

Overview:

Dantrolene is an extensively advised medication that has the potential effect of checking the development of malignant hyperthermia, where the person experiences a sudden rocketing of body temperature. It is marketed under various brand names. In addition to hyperthermia, it is also proven to be effective for certain neurological issues. The Food and Drug Administration (FDA) authorized the usage of the injection form of Dantrolene for hyperthermia in the year 1979. It can be used in both adult and younger population groups.

Drug Group:

Dantrolene belongs to the skeletal muscle relaxant drug class. It works by bringing relaxation to the skeletal muscles. Thereby collapsing the heat production that accompanies muscle constructions.

Available Doses and Dosage Forms:

• Dosage Forms: Dantrolene is released into the market in two distinct dosage forms - injection and capsule. An injection form is preferred for dealing with hyperthermia that develops all of a sudden, in which the medicine is introduced into the vein. Injection form ensures prompt release of the drug molecules into the circulation.

• Available Doses: Capsule form of Dantrolene is available in 25 milligrams and 100 milligrams doses. However, the dosage for each patient is determined by the concerned doctor after taking into account the patient’s age and body weight.

For Patients:

What Is Hyperthermia?

Hyperthermia, as the name suggests, is a condition where the person experiences unexplainable inflation in the body temperature. Malignant hyperthermia often develops in response to certain medicines that are widely employed as anesthetic agents. In addition, the person also elicits muscle pain and a remarkable loss in muscle tone. The person notices trouble in carrying out exercises and day-to-day activities. Compromised muscle flexibility restricts the range of movement. At times, the urine acquires dark color due to the precipitation of a specific muscular protein (myoglobin).

Breathing rate, heart rate, and other metabolic processes in the body gear up during malignant hyperthermia. Metabolic activities in the body often utilize energy and thereby produce heat in the body (exothermic reactions). Enhanced body temperature impairs the functions of various vital organs and precipitates grave complications. The susceptibility to developing malignant hyperthermia is more or less connected with the genetic makeup of the person. Alteration in the genetic makeup predisposes the person to develop malignant hyperthermia, and hence it exhibits a familial influence. General anesthetic medicines (medicines that help one to lose consciousness and thereby make procedures pain-free for the patients) are known to trigger and precipitate malignant hyperthermia in vulnerable individuals. This condition entails immediate medical attention, and if left unattended and untreated, it can endanger one’s life.

How Does Dantrolene Work?

Dantrolene falls under the category of direct-acting skeletal muscle relaxants, which work by loosening and calming down the contractions of skeletal muscles. The contractions of the skeletal muscles are the result of a chain of processes. This cascade finally brings in the discharge of calcium ions, which is the triggering agent for muscle contractions. Dantrolene interferes with calcium ion liberation and thereby impedes muscle contractions. Muscle contraction is an energy-driven process that takes place by eating up calories. As a result of energy utilization, muscle contractions are accompanied by heat liberation and hence reflect a remarkable contribution to basal temperature level. Dantrolene thereby reduces the temperature in malignant hyperthermia, where the affected person experiences a pronounced rise in their body temperature.

What Is the Dosage of Dantrolene?

The dose of Dantrolene that a person should consume is determined by taking into account the patient’s body weight and the purpose for which the Dantrolene is being advised. In the case of malignant hyperthermia, which is detected when the patient is under general anesthesia, one milligram per kilogram (mg per kg) of body weight of Dantrolene is administered as an inceptive dose. The dose is then gradually modified to 2.5 mg per kg. However, in certain patients, the anticipated results cannot be reflected in that particular dose. In such cases, further dose titration is advised, provided the daily dose does not exceed the limit of ten milligrams per kilogram of body weight.

Once the patient elicits a proper response for the initial doses, the treatment regimen should be continued with one mg per kg at an interval of six hours. It should be continued for a day, even after the manifestations of hyperthermia settle, to check the reappearance of the symptoms.

It is also employed as a preventive medicine to check malignant hyperthermia in individuals who are likely to precipitate the condition upon exposure to general anesthesia. In such individuals, Dantrolene is recommended prior to the procedure at a dose of 2.5 mg per kg.

How Effective Is Dantrolene?

Dantrolene is proven to be highly effective in tackling malignant hyperthermia. It not only treats the condition but can also offer preventive coverage for susceptible patients. It checks the enhanced metabolic activities in the skeletal muscles and thereby controls hyperthermia. In addition to hyperthermia, it is also employed for atypical and abnormal muscle rigidity and stiffness.

What Are the Things to Inform the Doctor Before Taking the Drug?

• Before the inception of the treatment with Dantrolene, the patients should convey prior encounters of exaggerated reactivity towards the drug or reaction towards any of its components. Undesired and unexpected reactions to any of the related drugs should also be discussed with the concerned doctor to exclude the risk of allergic reactions.

• The patients should disclose all the information concerning their disease and health status to the doctor. A thorough understanding of the patient's medical condition is necessary to assess the safety of Dantrolene.

• In addition to the medical history, the doctors should also be updated with details of all the medications that have been taken by the patient. It includes dietary supplements and other over-the-counter medicines that might not look relevant for the condition. However, such drugs can have a direct impact on the effectiveness and processing of either the medicine or both.

• The pregnancy and breastfeeding status of the patient should be promptly brought to the doctor's attention. Such patients should be assessed separately to check associated harm to the child upon administration of Dantrolene.

• Dantrolene is reported to precipitate lethargy and sleepiness. Hence, patients should be made aware of it beforehand and are advised to stay away from activities involving proper attention and motor skills.

How Is Dantrolene Administered?

The mode of administration of Dantrolene for malignant hyperthermia is via the intravenous route, where the drug molecules are directly introduced and discharged into the veins so the drug molecules are available for action in the bloodstream. However, when it is employed for dealing with muscle rigidity, oral intake is preferred, and hence it is also marketed in capsule form.

What Are the Side Effects of Dantrolene?

Side effects of Dantrolene differ with the route of administration. Dantrolene, when introduced directly into the vein, can bring in loss of muscle strength and failing muscles. The respiratory process, which is aided by a group of muscles, will also get affected by Dantrolene. It precipitates trouble in breathing and compromised intake of breathing air due to weakness in the muscles that are involved in the process of breathing. Instances of pulmonary edema (fluid gathering in the lung space) and thrombophlebitis (vein clogged by a blood clot) are also reported following Dantrolene's introduction into the bloodstream. The patient often experiences exhausted feelings, weakness, and fatigue while undergoing therapy using Dantrolene. Dantrolene intake via mouth carries the potential risk of developing toxicity issues in the liver. Specific clinical trial reports suggest that Dantrolene impairs the functions of the liver. Other less frequently observed side effects include collapsed blood cell counts, gastric issues, compromised vision, and skin issues.

Missed Dose:

The scope for missing a dose of Dantrolene for malignant hyperthermia patients is remarkably low as it is administered by healthcare professionals in the form of an injection. However, when given for other conditions, especially in the capsule form, it requires patient cooperation to ensure prompt intake of the medicine. At times, the patient may unintentionally miss taking the medicine on time and become aware later. In such cases, the patients can take the medicine right away, provided there is sufficient time for the next dose. Otherwise, the missed dose can be simply disregarded, and the patient can go ahead with the next dose to check the intake of the double doses of the medicine.

Overdose:

There is no specific medicine that is available for dealing with the overdose of Dantrolene. Overdose may precipitate in the form of exaggerated side effects like failing muscles, collapse, and compromised breathing. Gastric lavage (flushing out the stomach content) seems to be fruitful for dealing with sudden overdose issues precipitated by the capsule form of Dantrolene. Mechanical support should be provided to assist with compromised breathing, and the patient should be looked for development of other complications.

Storage:

Dantrolene injection medicine is available as powder and liquid, which need to be mixed to form an injection solution. Care should be employed to keep the vials away from getting exposed to sunlight, and once the powder and liquid mix are formed, it remains safe and effective for only six hours. Till then, it should be kept under the temperature range of 20 to 25 degree Celsius. However, immediately prepared injection solutions are reported to be the best for administration into the vein.

For Doctors:

Indications:

• Malignant hyperthermia (treatment).

• Malignant hyperthermia (prophylaxis).

• Chronic muscle spasticity.

• Neuroleptic malignant syndrome (off-label use).

• 2, 4 - dinitrophenol overdose (off-label use).

Dose:

1. Malignant Hyperthermia: One mg per kg is the recommended starting dose for a patient eliciting active symptoms of malignant hyperthermia. In the next step, the dose can be altered to 2.5 mg per kg. In the event of persisting symptoms, a further bolus dose of Dantrolene is injected. However, the aggregate dose should be within ten mg per kg. When Dantrolene is advised for prophylaxis, the recommended dose is 2.5 mg per kg and should be given an hour before undergoing the procedure. A capsule form of Dantrolene can also be used for prophylaxis, and the daily dosage should range between four to eight mg per kg of body weight. The stipulated daily dose should be orally given in the form of three or four small doses rather than a single high dose for two consecutive days before surgery.

2. Chronic Muscle Spasticity: The daily drug dose begins at 25 mg, which is then maintained for a week time period so that appreciable results are achieved. It is followed by tripling the daily dose for the upcoming week. For the third week, the dose is further raised to 50 mg three times a day. However, the daily dose should be restricted to 100 mg four times. The dosage increment is made only after assessing the patient’s response toward the drug in the lower doses.

Dosing Considerations:

The dosage regimen for pediatric patients is the same as that of adult patients and is calculated based on the child’s body weight.

What Are the Pharmacological Aspects of Dantrolene?

• Mechanism: Being a direct-acting muscle relaxant, Dantrolene interferes with the myosin and actin interaction. It hampers the calcium ion liberation that is crucial for triggering the contraction. It is the calcium ion that exposes the hidden myosin attaching point, which is present on the actin filament. Both the protein filaments can successfully establish cross-bridging only if the binding site is revealed. Energy is burned to produce this cross-bridging, which is coupled with heat liberation. The contractility of the skeletal muscles gets remarkably impaired by Dantrolene, which precipitates muscle weakness. In malignant hyperthermia, there will be an appreciable increase in the metabolic processes in the body involving various muscular activities. Dantrolene checks muscle contraction and helps to bring down the raised temperature.

• Pharmacodynamics: Dantrolene, when introduced directly into the circulation, can precipitate weakness in the muscles. It helps to tackle the boosted calcium ions liberation evoked by certain general anesthetic medications. Peaking of calcium ions in the myoplasmic reticulum enhances catabolism and energy utilization, which in turn reflects hyperthermia. Dantrolene helps in keeping track of the calcium ion concentration in the myoplasmic reticulum, thus hampering the progression of hyperthermia.

• Pharmacokinetics: The utmost concentration of Dantrolene is established within minutes following the intravenous introduction of the medicine. However, the bioavailability upon oral intake is estimated to be around 70 percent. Drug distribution occurs primarily with the help of plasma proteins. Albumin is the plasma protein of choice for Dantrolene to bind with. Liver enzymes break down the Dantrolene drug molecule into simpler metabolites. Acetylamino metabolite and 5-hydroxy dantrolene are the chief metabolites that are formed by processing Dantrolene. Urine is the major route for the removal of Dantrolene and its metabolites from the body. At the same time, a smaller proportion is eliminated via bile.

Toxicity:

Dantrolene is known to precipitate hepatotoxicity in susceptible individuals. Animal studies with a higher dose of Dantrolene have reported carcinogenic changes. However, there is no relevant data available reflecting carcinogenic changes in humans upon exposure to Dantrolene.

Clinical Studies:

Clinical studies with Dantrolene have been conducted to assess the dose-response relation. The dosage of Dantrolene should be restricted in aged populations as there is a potential risk for hepatotoxicity.

What Are the Contraindications of Dantrolene?

There is no specific contraindication for intravenous Dantrolene. However, oral intake of Dantrolene is contraindicated in patients with:

• Liver cirrhosis.

• Non-alcoholic steatohepatitis.

• Hepatitis B.

• Hepatitis C.

Warnings and Precautions:

• Dantrolene usage risks impairing liver functions; hence its administration in patients with compromised liver functions needs to be restricted and monitored promptly.

• In addition, individuals with lung conditions like obstructive pulmonary disease and cardiac issues like myocardial diseases require special attention while advising Dantrolene. Therefore necessary precautions and proper monitoring should be employed for such patients before prescribing Dantrolene.

• Patients should be informed about the possibility of complex liver disorders that can be precipitated upon therapy using Dantrolene. The functional status of the liver needs to be assessed prior to starting the therapy to ensure safety and lessen the risk of liver damage. Pre-existing irregularities in the liver function can be a driving force for precipitating complications in the liver.

• While using Dantrolene for malignant hyperthermia, it should be coupled with other supportive therapeutic interventions. Even if Dantrolene is given for prophylaxis, make sure that the general anesthetic regimen does not encompass the use of hyperthermia-evoking agents.

What Are the Drug Interactions of Dantrolene?

Special emphasis should be given when Dantrolene is administered with other drugs like tranquilizers and sedatives. It can induce severe drowsiness and fatigue in the patients. Likewise, reports suggest an increased prevalence of hepatotoxicity when estrogen therapy and Dantrolene therapy are given simultaneously. Interaction of Dantrolene with calcium channel blockers can trigger the development of cardiovascular complications like ventricular fibrillation.

Specific Considerations:

• Dantrolene During Pregnancy: The effects of Dantrolene on the developing child in the womb and maternal health are less known. Hence the usage of Dantrolene is highly restricted in pregnancy and is preferred if the maternal health conditions demand it.

• Dantrolene During Breastfeeding: Studies have identified the presence of Dantrolene in the breast milk of women who are undergoing therapy using Dantrolene. In order to check Dantrolene from getting into the child’s body through the breast milk, patients are clearly instructed not to breastfeed while undergoing therapy.