Dantrolene

Dantrolene is a ryanodine receptor antagonist used intravenously as the specific treatment for malignant hyperthermia, and orally for chronic spasticity. Rapid intravenous access, immediate availability in theatres, and early use change survival in malignant hyperthermia. Oral dantrolene carries a boxed-warning-level risk of hepatotoxicity.

Mechanism. Blocks the ryanodine receptor on the sarcoplasmic reticulum of skeletal muscle, reducing calcium release and uncoupling excitation from contraction.

Pharmacokinetics. Oral bioavailability is about 70%. Half-life is 8 to 9 hours orally and about 12 hours intravenously. It is metabolised in the liver to active and inactive metabolites.

Emergency use. Malignant hyperthermia (hypermetabolic crisis with rising carbon dioxide, muscle rigidity, tachycardia, acidosis and temperature):

• Dantrolene intravenous 2.5 mg/kg as a rapid bolus, and repeat 1 mg/kg to 2.5 mg/kg boluses until signs settle. Usual cumulative dose up to 10 mg/kg. If there is no response after 10 mg/kg, reconsider the diagnosis.

• After the crisis: 1 mg/kg intravenously or orally every 4 to 6 hours for 24 to 48 hours (up to 3 days) to prevent recurrence.

• Supportive care is essential: stop volatile anaesthetics and succinylcholine, give 100% oxygen with high flow and hyperventilation, active cooling, treat hyperkalaemia and arrhythmias, and call for help.

Alternative use. Chronic spasticity of upper motor neurone origin:

• Adults, oral dantrolene: 25 mg once daily for 7 days, then 25 mg three times daily, increased by 25 mg steps each week to a maximum of 100 mg four times daily. Usual 75 to 400 mg daily. Stop if there is no benefit within about 6 weeks.

• Children: 0.5 mg/kg once daily for 7 days, then 0.5 mg/kg three times daily, increased weekly. Maximum 3 mg/kg four times daily, and not over 400 mg daily.

Kidney, liver, weight and age.

• Kidney: no adjustment.

• Liver: oral dantrolene is contraindicated in active liver disease; intravenous dantrolene is used for malignant hyperthermia regardless.

• Older adults: use caution with oral dosing.

Contraindications. Oral: active liver disease, and spasticity needed to maintain posture or walking. Intravenous: no absolute contraindication in malignant hyperthermia.

Serious adverse effects. Hepatotoxicity (oral, sometimes fatal), muscle weakness including respiratory weakness, pleural effusion and pericarditis (oral), cardiovascular collapse with calcium channel blockers, and tissue necrosis with extravasation.

Common adverse effects. Drowsiness, dizziness, weakness, fatigue, diarrhoea and photosensitivity.

Interactions. Calcium channel blockers (verapamil, diltiazem) given intravenously with dantrolene can cause hyperkalaemia and cardiovascular collapse. Oestrogens raise hepatotoxicity risk. Dantrolene potentiates non-depolarising muscle relaxants such as vecuronium. Alcohol and sedatives add drowsiness.

Common prescribing errors. Delay in giving dantrolene in suspected malignant hyperthermia. Giving a first dose too low. Missing liver tests on oral therapy. Mixing with saline or glucose.

Special groups.

• Pregnancy: avoid oral use; use intravenously for malignant hyperthermia if needed.

• Breastfeeding: interrupt breastfeeding after intravenous doses for the period set by the label (about 48 to 60 hours).

• Regional: dantrolene should be stocked wherever volatile anaesthetics or succinylcholine are used, and stock expiry should be checked.

Formulations. Capsules 25, 50 and 100 mg. Intravenous vials 20 mg and, in some markets, 250 mg as a concentrated suspension.

Preparation. Reconstitute each 20 mg vial with 60 mL of sterile water for injection and shake until clear. Do not use saline or glucose, and do not dilute. The 250 mg product is reconstituted with 5 mL of sterile water. The solution is highly alkaline, so use a large vein and avoid extravasation.

Monitoring.

• Malignant hyperthermia: temperature, end-tidal carbon dioxide, potassium, creatine kinase, blood gases, urine output and myoglobinuria.

• Oral therapy: liver function at baseline, then every 1 to 2 weeks for the first months, and stop for raised enzymes or no benefit by 45 days.

Stopping. Stop oral treatment gradually. Intravenous therapy ends after the post-crisis course.

Referral and escalation. Admit to critical care for malignant hyperthermia, and refer the patient and family for testing and a safety plan.