glutethimide

Action and Spectrum

Actions and Spectrum: 

glutethimide is a sedative-hypnotic medication primarily used to treat insomnia and promote sleep.  

Action:  

glutethimide depletes the central nervous system, leading to sedation and sleepiness. It has a depressant effect on the brain and spinal cord, which can help induce sleep and reduce anxiety. It achieves this by enhancing the effects of gamma-aminobutyric acid, inhibitory neurotransmitter in the brain. GABA’s role is to reduce the activity of neurons, thereby producing a calming effect. 

Spectrum:  

glutethimide’s primary use was as a sedative-hypnotic agent, specifically for the treatment of insomnia. It was intended to help people fall asleep and stay asleep through the night. The sedative properties of glutethimide made it effective for its intended purpose but also contributed to its misuse and adverse side effects. 

Drug Interaction

Adverse Reaction

Frequency not defined 

Toxic psychosis 

Blood dyscrasias 

Hiccups, blurred vision 

Gastric irritation 

Paradoxic excitement 

Vertigo 

Cyanosis 

Sudden apnea  

Exfoliative dermatitis 

Diminished intestinal motility 

Hypersensitivity reactions 

Headache 

Black Box Warning

Black Box Warning: 

None 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

• Hypersensitivity: glutethimide should not be used in individuals with known hypersensitivity or allergy to the medication. 
• Respiratory Depression: glutethimide is a central nervous system depressant, and its use can lead to respiratory depression, especially when combined with other depressant substances like alcohol or opioids. It should be avoided in individuals with respiratory issues. 
• Dependence and Addiction: glutethimide has a high potential for abuse, dependence, and addiction. Individuals with a prior history of the substance abuse or addiction should not be prescribed this medication. 
• Pregnancy and Lactation: glutethimide can harm fetal development and lead to withdrawal symptoms in newborns. It is contraindicated during pregnancy and should not be used by breastfeeding mothers. 
• Liver and Kidney Impairment: glutethimide is metabolized in the liver and excreted through the kidneys. Individuals with impaired liver/kidney function may experience altered metabolism and elimination of the drug, potentially leading to increased side effects or toxicity. 
• Elderly Patients: Elderly individuals may be more sensitive to the sedative and other effects of glutethimide, which can enhance the risk of falls, confusion, and other adverse events. 
• Concurrent Use with Other CNS Depressants: glutethimide should not be used concurrently with other central nervous system (CNS) depressant medications, such as opioids, benzodiazepines, or alcohol, as this can increase the risk of severe respiratory depression and other adverse effects. 
• Seizure Disorders: glutethimide may lower the seizure threshold and enhance the risk of seizures, particularly in individuals with a history of seizure disorders. 

Caution 

• Dependence and Abuse Potential: glutethimide has a high potential for abuse and dependence. It can lead to the physical and psychological dependence, and individuals may develop tolerance, meaning they need higher doses over time to achieve the same effects. This can increase the risk of addiction and withdrawal symptoms. 
• Withdrawal Symptoms: Abruptly stopping glutethimide after prolonged use can lead to withdrawal symptoms, including anxiety, restlessness, insomnia, nausea, vomiting, muscle aches, and more severe symptoms in some cases. Withdrawal from glutethimide should be managed under medical supervision. 
• Respiratory Depression: glutethimide is a central nervous system depressant that can slow down breathing. Taking high doses or combining glutethimide with other depressants like alcohol or opioids can lead to severe respiratory depression, which can be life-threatening. 
• CNS Depression: glutethimide can cause significant central nervous system (CNS) depression, leading to drowsiness, dizziness, impaired coordination, and decreased cognitive function. It can increase the risk of falls and accidents, especially in elderly individuals. 
• Interactions with Other Medications: glutethimide can interact with other medications, potentially leading to harmful effects. It should not be combined with other CNS depressants, and its use should be carefully monitored with other medications that affect liver metabolism or kidney function. 
• Elderly and Debilitated Patients: glutethimide’s sedative effects may be more pronounced in elderly or debilitated patients, increasing the risk of side effects like falls and confusion. 
• Psychiatric Conditions: glutethimide can worsen certain psychiatric conditions, such as depression or anxiety disorders. It may also lead to paradoxical reactions, where the medication has the opposite effect of what is intended. 
• Pregnancy and Lactation: glutethimide is contraindicated during pregnancy and breastfeeding due to the risk of harm to the fetus or newborn. 

Pregnancy / Lactation

Pregnancy consideration:  

US FDA pregnancy category: C 

Lactation:   

Excreted into human milk: Yes. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

glutethimide is a sedative-hypnotic medication with depressant effects on the central nervous system (CNS). It exerts its pharmacological action by enhancing the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) activity in the brain, leading to sedation, muscle relaxation, and sleep induction. glutethimide’s sedative effects are attributed to its ability to potentiate GABAergic transmission, ultimately resulting in a calming and hypnotic effect. 

Pharmacodynamics: 

Mechanism of action: The exact mechanism of action of glutethimide, a sedative-hypnotic medication that was historically used to treat insomnia, is not fully understood, but it is believed to primarily involve its interaction with the gamma-aminobutyric acid (GABA) system in the central nervous system.  

Enhancement of GABA Activity: glutethimide is thought to enhance the inhibitory effects of GABA, the primary inhibitory neurotransmitter in the brain. GABA works by reducing the activity of neurons and dampening the overall excitability of the central nervous system. glutethimide is believed to enhance the effects of GABA at GABA-A receptors, which are ion channels in the cell membranes of neurons. When GABA binds to these receptors, it influx chloride ions into the neurons, resulting in the hyperpolarization and reduced neuronal activity. This contributes to sedation, relaxation, and anxiolytic effects. 

Sedative and Hypnotic Effects: By potentiating GABAergic transmission, glutethimide produces a calming and sedative effect, which can help individuals fall asleep and also stay asleep. The increased inhibitory tone in the brain leads to reduced arousal and increased relaxation. 

Additional Neurochemical Effects: glutethimide may also affect other neurotransmitter systems in the brain, together with serotonin and dopamine pathways, which could contribute to its sedative and mood-altering effects. 

Pharmacokinetics: 

Absorption 

glutethimide is well-absorbed from the gastrointestinal tract after oral administration. It reaches peak plasma concentrations within a few hours. 

Distribution 

glutethimide distributes throughout the body, including the central nervous system, due to its lipophilic nature. It can cross the blood-brain barrier, contributing to its sedative effects. 

Metabolism 

glutethimide undergoes extensive metabolism in the liver. It is primarily metabolized through hepatic microsomal enzymes, particularly the cytochrome P450 system. The primary metabolite of glutethimide is norglutethimide, which contributes to the medication’s pharmacological effects. There can be significant interindividual variability in metabolism. 

Elimination and Excretion 

The metabolites of glutethimide, including norglutethimide, are excreted primarily in the urine. A small portion may also be excreted in feces. The elimination half-life of glutethimide and its metabolites varies among individuals and can range from several hours to about a day. 

Adminstartion

Administration: 

glutethimide was typically administered orally in tablet or capsule form. 

Dosage Form: glutethimide was typically available in tablet form.  

Dosage and Administration: The dosing of glutethimide varied based on the individual’s condition and response to the medication. It was typically prescribed to be taken orally, usually before bedtime, to help induce sleep. The dosage would depend on factors such as insomnia severity and the patient’s age and overall health. 

Prescription: glutethimide was a prescription medication, and it should only have been taken under the supervision and guidance of a qualified healthcare professional. 

Avoid Alcohol and Other Depressants: Patients were advised to avoid alcohol and other central nervous system (C.N.S) depressants while taking glutethimide due to the risk of increased sedation and respiratory depression. 

Short-Term Use: glutethimide was generally prescribed for short-term use to avoid the risk of dependence, tolerance, and withdrawal. 

Tapering and Discontinuation: If glutethimide was used for some time, it was essential to gradually taper off the drug under the supervision of the healthcare provider to avoid withdrawal symptoms. 

Monitoring: Patients taking glutethimide were typically monitored for its effects and potential adverse reactions. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: glutethimide  

Why do we use glutethimide? 

glutethimide is a sedative-hypnotic medication historically used to treat insomnia and promote sleep.  

• Insomnia: glutethimide was primarily prescribed to help individuals with insomnia fall asleep through the night. It has sedative properties that can induce a calming effect and promote sleep.