Sodium Oxybate - Uses, Mechanism of Action, Precautions, and Side Effects

Overview:

Sodium oxybate is a drug that is a central nervous system depressant used in the treatment of daytime sleepiness and cataplexy associated with narcolepsy.

How Does Sodium Oxybate Work?

The actions of Sodium oxybate are mediated by its active component, gamma-hydroxybutyrate (GHB). The exact mechanism of GHB in narcolepsy is unknown; it is thought that GHB has different modes of action. At low doses, GHB binds to high and low-affinity G-protein-coupled GHB receptors. The activation of gamma-hydroxybutyrate receptors leads to the release of glutamate, an excitatory neurotransmitter. At higher doses, gamma-hydroxybutyrate activates GABAB receptors at noradrenergic and dopaminergic neurons and thalamocortical neurons involved in sleep-wake regulation, attention, and vigilance. Gamma-hydroxybutyrate metabolizes to y-Aminobutyric acid or GABA, modulating GABAA and GABAC receptors.

Uses of Sodium Oxybate:

Sodium oxybate treats cataplexy or excessive daytime sleepiness (EDS) in seven years and older individuals with narcolepsy.

Dosage Restrictions:

1. Route of Administration- Oral.

2. Dosage Strengths- 0.5 g/mL

3. Dosage Forms- Sodium oxybate is a clear, slightly opalescent solution.

Special Considerations:

• Pregnancy - There is insufficient data on the risk associated with the intake of Sodium oxybate in pregnant women. The placental transfer of the drug is fast and has been found in newborns after intravenous administration of Sodium oxybate to mothers. The effects of Sodium oxybate on growth, development, and maturation are unknown.

• Lactation - Sodium oxybate is found to be excreted in human milk after its oral administration. More information should be provided on breastfed babies and milk production in nursing mothers.

• Pediatric - Sodium oxybate in pediatric patients leads to severe adverse reactions such as central sleep apnea and oxygen desaturation, suicidal tendency, and neuropsychiatric reactions such as acute psychosis, confusion, anxiety, and sleepwalking.

• Geriatric - Adverse reactions have been found to appear to a greater extent in elder individuals.

• Hepatic Impairment - The initial dosage of Sodium oxybate is reduced in individuals with liver impairment because of increased exposure to the drug.

Warnings and Contraindications:

• Sodium oxybate is contraindicated in individuals treated with hypnotic sedatives.

• Individuals who are addicted to alcohol.

• Sodium oxybate is contraindicated in individuals with succinic semialdehyde dehydrogenase deficiency, a rare metabolic disorder characterized by mental retardation, hypotonia, and ataxia.

Warnings and Precautions:

• Central Nervous System Depression - Sodium oxybate is a central nervous system (CNS) depressant. Adults treated with Sodium oxybate have been found to show signs of reduced alertness or consciousness and significant respiratory depression. Alcohol and sedative-hypnotics are contraindicated in patients on Sodium oxybate. The simultaneous use of Sodium oxybate with other CNS depressants, including opioid analgesics, sedating antiepileptic drugs, Benzodiazepines, antipsychotics, general anesthetics, muscle relaxants, or illicit CNS depressants, might increase the risk of hypotension, respiratory depression, syncope, profound sedation, and death.

• Misuse - Sodium oxybate, or gamma-hydroxybutyrate (GHB), is a schedule I controlled substance with no medicinal use and a high potential for misuse and abuse. Abuse of illegitimate gamma hydroxybutyrate, either alone or in combination with other central nervous depressants, is associated with adverse reactions of the CNS, such as seizure, respiratory depression, reduced level of consciousness, coma, and death. The fast action of sedation, along with the amnesia induced by Sodium oxybate, in combination with alcohol, is dangerous for the person taking them.

• Respiratory Depression and Sleep-Disordered Breathing- Sodium oxybate has been found to impair respiration in individuals with compromised respiratory function. Severe life-threatening respiratory depression has been found to occur in cases of overdosage. Kids with narcolepsy treated with Sodium oxybate have been found to undergo central sleep apnea and oxygen desaturation.

• Depression and Suicide - Individuals with narcolepsy are associated with suicides when treated with Sodium oxybate. Adverse reactions of depression are reported to have occurred in individuals treated with Sodium oxybate. Individuals with a previous history of a depressive illness or suicide attempts tend to aggravate the symptoms when treated with Sodium oxybate.

• Psychiatric Adverse Reactions- Sodium oxybate in increased dosages has been found to cause confusion, anxiety, hallucinations, paranoia, psychosis, aggression, and agitation.

• Parasomnias - Parasomnias or sleepwalking is the confusing behavior occurring at night associated with wandering and has been found in individuals with narcolepsy treated with Sodium oxybate.

• Individuals Sensitive to High Sodium Intake- Sodium oxybate has a high salt content. Individuals sensitive to salt intakes, such as those with heart failure, hypertension, or renal impairment, should take the drug mindfully.

For Patients

What Is Narcolepsy?

Narcolepsy is a sleep disorder causing excessive drowsiness during the day and sudden sleep attacks. It is difficult for individuals with narcolepsy to stay awake for extended periods. It can be accompanied by a sudden loss of muscle tone or cataplexy triggered by a strong emotion. This is called type 1 narcolepsy. Narcolepsy occurring without cataplexy is known as type 2 narcolepsy. Narcolepsy is a chronic condition that cannot be cured completely. However, medications and lifestyle changes can help one manage the symptoms to an extent.

What Are the Symptoms of Narcolepsy?

The following are the symptoms of narcolepsy:

• Excessive sleepiness during the day.

• Sudden loss of muscle tone.

• Sleep paralysis.

• Changes in the rapid eye movement of sleep.

• Hallucinations.

Why Is Sodium Oxybate Prescribed for Narcolepsy?

Sodium oxybate is used to prevent cataplexy attacks (sudden episodes of muscle weakness) and excessive daytime sleepiness in adults and kids seven years and older who have narcolepsy - a sleep disorder causing extreme sleepiness, sudden urge to sleep any time of the day and cataplexy. Sodium oxybate belongs to a class of medications called central nervous system depressants and is used to treat narcolepsy and cataplexy by decreasing brain activity.

Facts One Should Know About Sodium Oxybate:

How Should One Take Sodium Oxybate?

• Sodium oxybate is available to be mixed with water and taken orally.

• It should be taken twice every night because the drug wears out after a short time, and the effects of a single dose do not last for the entire night. Therefore, the first dose is generally taken at bedtime, and the second one is taken two to four hours after the first dose.

• Sodium oxybate should be taken on an empty stomach, so the first dosage should be taken at least two hours after food.

• Take the bedtime doses of Sodium oxybate when one is ready to sleep for the night.

• Sodium oxybate is a fast-onset drug and starts to work within five to fifteen minutes.

• The second dosage of the drug should be taken after two hors and 30 minutes of the first dose.

• Excess drug intake might experience life-threatening symptoms, such as seizures, shallow breathing, loss of consciousness, and coma. One may also crave sodium oxybate and have the urge to take larger doses, even after getting unpleasant symptoms.

What Should One Discuss With the Doctor Before Beginning Sodium Oxybate?

• The doctor should be informed if one is allergic to Sodium oxybate or any of its ingredients.

• The doctor should be informed if one is taking any other medicines, vitamins, nutritional supplements, or herbal products. Mention without fail in case one is taking Divalproex.

• The doctor should be informed if one has had or has a succinic semialdehyde dehydrogenase deficiency. It is an inherited condition causing various neurological problems such as intellectual disability, developmental delays, etc.

• The doctor should be informed if one is on a low-salt diet for medical reasons.

• The doctor should be informed if one snore or has self-harming or killing thoughts.

• The doctor should be informed if one has ever had lung disease, difficulty breathing, sleep apnea (a sleep disorder causing stoppage of breathing for a short duration during sleep), seizures, depression, liver or kidney disease, heart failure, or high blood pressure.

• Inform the doctor if one is pregnant, has plans to become pregnant, or is breastfeeding.

• The doctor should be informed about the drug intake if one is having any surgery, including dental surgery.

• Sodium oxybate can make one sleepy for the next six hours, making one drowsy. Thus, one should not drive a car, operate machines, fly an airplane, or perform other dangerous activities for six hours after the drug intake.

Is Sodium Oxybate Safe?

Sodium oxybate is safe if taken as prescribed and taken with precaution.

Is Sodium Oxybate Effective?

Sodium oxybate may help to control the symptoms but will not cure the condition completely. Therefore, sodium oxybate should be taken even if one feels well.

What Side Effects Can One Expect With Sodium Oxybate?

The following are the side effects of Sodium oxybate:

• Dizziness.

• Bedwetting.

• Headache.

• Sweating.

• Nausea.

• Vomiting.

• Diarrhea.

• Stomach pain.

• Uncontrollable shaking of a body part.

• Numbness, tingling, pricking, burning sensation of the skin.

• Difficulty in moving while sleeping or upon waking up.

• Back pain.

• Weakness.

• Swelling of the arms, hands, feet, ankles, or lower legs.

Other serious side effects include the following:

• Agitation.

• Aggression.

• Anxiety.

• Sleepwalking.

• Nightmare.

• Depression.

• Confusion or memory problems.

• Weight or appetite problems.

• Harming or suicidal thoughts.

• Hallucinations.

• Breathing problems, snoring, sleep apnea.

• Excessive drowsiness.

Can One Stop Taking Sodium Oxybate Without Your Doctor's Approval?

Please do not stop taking the drug without the doctor's consent, as suddenly stopping it might cause withdrawal symptoms such as difficulty falling asleep or staying asleep, restlessness, anxiety, abnormal thinking, loss of contact with reality, sleepiness, upset stomach, uncontrollable shaking of a body part, sweating, muscle cramps, and fast heartbeat.

Are There Any Dietary Restrictions to Consider When Taking Sodium Oxybate?

One should continue taking the regular diet unless advised by the doctor otherwise.

How Should One Store Sodium Oxybate?

The drug should be stored in a tightly closed container and out of the kid's reach. In addition, it should be stored at room temperature, away from excess heat and moisture.

How Should One Dispose of Sodium Oxybate?

Pour any leftover medication down the sink if it is more than 24 hours old. Put a cross on the bottle label with a marker before disposing of the empty bottle in the trash.

What To Do in Case of Overdose?

In case of an overdose, the doctor should be immediately informed.

The symptoms of overdose include the following:

• Sweating.

• Headache.

• Blurred vision.

• Confusion.

• Problems with coordination.

• Agitation.

• Vomiting.

• Loss of consciousness.

• Coma.

• Shallow breathing.

• The inability of bladder control.

• The failure to control the bowel.

• Muscle jerks.

• Seizure.

• Slow heartbeat.

• Low body temperature.

• Muscle weakness.

For Doctors

Indications:

Sodium oxybate is a drug that acts as a central nervous system depressant and is indicated for treating cataplexy or excessive daytime sleepiness (EDS) in individuals above seven years of age with narcolepsy.

What Is the Pharmacology of Sodium Oxybate?

Description

Chemically, Sodium oxybate is known as Sodium 4-hydroxybutyrate. The formula is C4H7NaO3, and the molecular weight is 126.09 g/mole. It is a white or off-white, crystalline powder soluble in aqueous solutions. Each mL of the drug contains 0.5 g of Sodium oxybate dissolved in purified water, neutralized to pH 7.5 with malic acid.

Components:

1. Active Ingredients- Sodium oxybate.

2. Inactive Ingredients- Purified water and Malic acid.

Clinical Pharmacology:

Mechanism of Action

Sodium oxybate relaxes the central nervous system. However, the mode of action of Sodium oxybate in treating narcolepsy is not understood.

Sodium oxybate is the sodium salt of the metabolite, gamma-hydroxybutyrate, the metabolite, and an endogenous compound of the neurotransmitter GABA. The therapeutic effects of Sodium oxybate on the symptoms of narcolepsy, like cataplexy and extreme daytime sleepiness, are carried out through the actions of GABAB at the noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.

Pharmacodynamics:

Sodium oxybate is a drug that acts as a central nervous system depressant that decreases the excessive daytime sleepiness and cataplexy in individuals with narcolepsy by modifying the sleep architecture and reducing fragmented night-time sleep. The mechanism by which Sodium oxybate acts is unknown; however, it is thought to act by promoting the delta sleep wave and consolidating night-time sleep. Sodium oxybate administered before sleep increases sleep patterns three and four sleep and increases sleep latency while reducing the frequency of sleep onset REM periods (SOREMPs).

Pharmacokinetics:

• Mean Cmax- 78 and 142 microgram/ml.

• Median Tmax- 0.5 to 1.25 hours.

Pharmacokinetic Changes- The pharmacokinetics of Sodium oxybate is non-linear.

A. Distribution

Sodium oxybate is a hydrophilic compound with a volume of distribution 190 to 384 ml/kg. Sodium oxybate concentrations range from 3 to 300 microgram/ml, and less than 1 % is bound to plasma proteins.

B. Metabolism

The elimination pathway produces carbon dioxide and water through the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation. The primary path leads to a cytosolic NADP+-linked enzyme, gamma-hydroxybutyrate dehydrogenase, which catalyzes Sodium oxybate to succinic semialdehyde, which is biotransformed to succinic acid by succinic semialdehyde dehydrogenase. Succinic acid is metabolized to carbon dioxide and water after entering the Krebs cycle.

C. Excretion

The drug is primarily excreted through the lungs via carbon dioxide.

Recovery of Sodium Oxybate

• Urine - Less than five percent of unchanged Sodium oxybate is found in urine within six to eight hours after dosing.

• Feces - Excretion in the feces is negligible.

D. Elimination

The half-life is 30 minutes to one hour. The clearance is by biotransformation to carbon dioxide, which is eliminated by expiration.

Special Considerations:

• Pediatric - Sodium oxybate in pediatric patients leads to severe adverse reactions such as central sleep apnea and oxygen desaturation, suicidal tendency, and neuropsychiatric reactions such as acute psychosis, confusion, anxiety, and sleepwalking. In addition, body weight is one factor affecting the drug's pharmacokinetics.

• Geriatric - Adverse reactions have been found to appear to a greater extent in elder individuals.

• Hepatic Impairment- The initial dosage of Sodium oxybate is reduced in individuals with liver impairment because of increased exposure to the drug.

• Renal Impairment - No study on individuals with renal impairment has been conducted.

• Gender - No gender differences have been found in the pharmacokinetics of Sodium oxybate.

Drug Interactions:

• 1,2-Benzodiazepine - 1,2-Benzodiazepine might increase the central nervous system depressant activities of Sodium oxybate.

• Alprazolam - Alprazolam might increase the central nervous system depressant activities of Sodium oxybate.

• Bupivacaine - Bupivacaine, when combined with Sodium oxybate, the risk or severity of the adverse effects can be increased.

What Have Clinical Trials Shown With Regard to Sodium Oxybate?

Sodium oxybate was clinically studied in three placebo-controlled clinical trials (N1, N3, and N4, in sections 14.1 and 14.2) in six hundred eleven patients with narcolepsy. Seven hundred eighty-one narcoleptic people were treated with Sodium oxybate in uncontrolled and controlled clinical trials.

Results:

• Adverse Reactions Causing Discontinuation of the Treatment - The most common adverse reaction is nausea. Most adverse reactions leading to discontinuation began within the first few weeks of treatment.

• Common Adverse Reactions in Controlled Clinical Trials - The most common adverse reactions in individuals treated with Sodium oxybate were nausea, dizziness, vomiting, enuresis, and tremor.

• Adverse Reactions With an Incidence of 2 % Or Greater - The adverse reactions occurring at a frequency of 2 % or more were nausea, vomiting, abdominal pain, dry mouth, peripheral edema, cataplexy, muscle spasm, tiredness, etc.

Patient Counseling Information:

Administration Instructions

• The drug should be taken orally.

• Take the first dose of Sodium oxybate should be taken 2 hours after food.

• Prepare both doses of Sodium oxybate before bedtime. Before ingestion, each dose of Sodium oxybate should be diluted with approximately 1/4 cup of water in the empty pharmacy containers.

• The individuals should take both doses of Sodium oxybate in bed and lie down immediately as Sodium oxybate might cause sudden sleepiness. Individuals often fall asleep within five minutes of taking Sodium oxybate, though the time taken varies from person to person. Individuals should remain in bed after taking the first and second doses and not take the second dose till two hours 30 minutes to four hours after the first dose.

• Individuals might set the alarm to awaken for the second dose.

• If the second dosage is missed, that dose should be skipped, and Sodium oxybate should not be retaken until the next night. Both doses should be taken at different times.

Complications or Side Effects

Sodium oxybate includes the following side effects:

• Headache.

• Nausea.

• Dizziness.

• Pharyngitis.

• Infection.

• Vomiting.

• Drowsiness.

• Enuresis.

• Diarrhea.

• Disturbance in attention.

• Sleepwalking.

• Upper abdominal pain.

• Peripheral edema.

• Disorientation.

• Sleep paralysis.

• Pain in extremities.

• Irritability.

• Paresthesia.

• Cataplexy.

• Anxiety.

• Dry mouth.

• Muscle spasms.

In Kids:

• Enuresis.

• Nausea.

• Headache.

• Vomiting.

• Decrease in weight.

• Reduced appetite.

• Dizziness.