- Raw materials
- Barbiturates
- Butalbital
Butalbital API Manufacturers & Suppliers
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Butalbital | CAS No: 77-26-9 | GMP-certified suppliers
A medication that manages tension-type headaches with muscle contraction symptoms when other non-opioid analgesics and treatments have proven inadequate.
Therapeutic categories
Anticholinergic AgentsAnticonvulsantsBarbituratesCentral Nervous System DepressantsCytochrome P-450 CYP3A InducersCytochrome P-450 CYP3A4 Inducers
Generic name
Butalbital
Molecule type
small molecule
CAS number
77-26-9
DrugBank ID
DB00241
Approval status
Approved drug, Illicit drug
ATC code
N05CB01
Primary indications
- Indicated for the management of the symptom complex of tension (or muscle contraction) headache, when other non-opioid analgesics and alternative treatments are inadequate, in various combinations with acetaminophen, aspirin, caffeine, and codeine
Product Snapshot
- Butalbital is available in oral and rectal formulations including syrup, coated tablets, capsules, and suppositories
- It is primarily used in combination therapies for the management of tension or muscle contraction headache symptoms
- The product is approved for use in the US and Canada markets
Clinical Overview
Butalbital (CAS Number 77-26-9) is a barbiturate derivative structurally characterized as 5-allyl-5-isobutylbarbituric acid. It belongs to the class of barbituric acid derivatives and functions as a short-to-intermediate acting central nervous system (CNS) depressant with muscle-relaxant and anxiolytic properties. Its pharmacological effects result from reversible depression of excitable tissues, particularly within the CNS, inducing sedation that may range up to general anesthesia depending on dosage.
Clinically, butalbital is primarily indicated for the management of tension-type headaches, especially those with a muscular contraction component. This indication is typically considered after non-opioid analgesics and other treatment modalities have proven inadequate. It is commonly formulated in combination with agents such as acetaminophen, aspirin, caffeine, and occasionally codeine. Notably, butalbital is not indicated for migraine treatment, and clinical trials supporting its efficacy in this context are lacking.
The mechanism of action of butalbital is mediated through enhancement of inhibitory neurotransmission via GABA-A receptors. As an allosteric modulator, butalbital potentiates the binding of gamma-aminobutyric acid (GABA) to these chloride ion channels, increasing chloride influx and postsynaptic neuronal inhibition. Additionally, it suppresses excitatory signaling through inhibition of AMPA receptor-mediated glutamate responses and depresses voltage-gated calcium currents. This broad CNS depressant action affects polysynaptic neuronal pathways, contributing to muscle relaxation and anxiolysis.
Key pharmacokinetic parameters include absorption, metabolism predominantly via hepatic cytochrome P-450 enzymes, particularly CYP3A4 induction, and excretion, though specific ADME data for butalbital may vary depending on formulation and co-administered agents.
Safety considerations with butalbital include its narrow therapeutic index and potential for CNS and respiratory depression, tolerance, dependence, abuse, and overdose-related fatalities. Use is associated with risks of paradoxical excitation, drug-induced headache, withdrawal phenomena, and additive sedative effects when combined with other CNS depressants. Owing to these factors, clinical use of butalbital-containing products requires careful patient monitoring and is generally reserved for cases where alternative treatments have failed.
From a procurement perspective, API quality must ensure compliance with established pharmacopeial standards for barbiturates, including stringent control of impurities and stability parameters. Suppliers should be evaluated for conformity with Good Manufacturing Practices (GMP) to mitigate risks related to potency variation and contamination. Attention to regulatory status and potential illicit diversion is advised due to butalbital’s controlled substance classification in many jurisdictions.
Clinically, butalbital is primarily indicated for the management of tension-type headaches, especially those with a muscular contraction component. This indication is typically considered after non-opioid analgesics and other treatment modalities have proven inadequate. It is commonly formulated in combination with agents such as acetaminophen, aspirin, caffeine, and occasionally codeine. Notably, butalbital is not indicated for migraine treatment, and clinical trials supporting its efficacy in this context are lacking.
The mechanism of action of butalbital is mediated through enhancement of inhibitory neurotransmission via GABA-A receptors. As an allosteric modulator, butalbital potentiates the binding of gamma-aminobutyric acid (GABA) to these chloride ion channels, increasing chloride influx and postsynaptic neuronal inhibition. Additionally, it suppresses excitatory signaling through inhibition of AMPA receptor-mediated glutamate responses and depresses voltage-gated calcium currents. This broad CNS depressant action affects polysynaptic neuronal pathways, contributing to muscle relaxation and anxiolysis.
Key pharmacokinetic parameters include absorption, metabolism predominantly via hepatic cytochrome P-450 enzymes, particularly CYP3A4 induction, and excretion, though specific ADME data for butalbital may vary depending on formulation and co-administered agents.
Safety considerations with butalbital include its narrow therapeutic index and potential for CNS and respiratory depression, tolerance, dependence, abuse, and overdose-related fatalities. Use is associated with risks of paradoxical excitation, drug-induced headache, withdrawal phenomena, and additive sedative effects when combined with other CNS depressants. Owing to these factors, clinical use of butalbital-containing products requires careful patient monitoring and is generally reserved for cases where alternative treatments have failed.
From a procurement perspective, API quality must ensure compliance with established pharmacopeial standards for barbiturates, including stringent control of impurities and stability parameters. Suppliers should be evaluated for conformity with Good Manufacturing Practices (GMP) to mitigate risks related to potency variation and contamination. Attention to regulatory status and potential illicit diversion is advised due to butalbital’s controlled substance classification in many jurisdictions.
Identification & chemistry
| Generic name | Butalbital |
|---|---|
| Molecule type | Small molecule |
| CAS | 77-26-9 |
| UNII | KHS0AZ4JVK |
| DrugBank ID | DB00241 |
Pharmacology
| Summary | Butalbital is a short to intermediate-acting barbiturate that acts as a central nervous system depressant by allosterically enhancing GABA-A receptor-mediated inhibitory neurotransmission, leading to decreased neuronal excitability. It also modulates glutamatergic signaling by inhibiting AMPA receptor-mediated excitatory responses. These pharmacodynamic effects contribute to its use in managing tension-type headaches through CNS sedation and muscle relaxation. |
|---|---|
| Mechanism of action | Butalbital is a CNS depressant that suppresses neuronal excitability, impulse conduction, and the release of neurotransmitters, similar to actions of other barbiturates. Barbiturates primarily mediate suppressive actions on polysynaptic neuronal responses by diminishing facilitation while enhancing inhibition. Inhibition occurs at GABAergic synapses that express GABA-A receptors, which are transmembrane chloride ion channels that bind an inhibitory neurotransmitter GABA, barbiturates, benzodiazepines, neurosteroids, and ethanol. Upon activation, GABA-A receptors allow Cl- influx and K+ efflux into the postjunctional terminal, resulting in inhibition of the postsynaptic neuron. It is suggested that barbiturates, including butalbital, enhances GABA binding to the GABA-A receptors by binding to the α+/β− interface in the intracellular domain (ICD) as an allosteric modulator. Additionally, barbiturates promote benzodiazepine binding to the receptor. Barbiturates potentiate GABA-induced increases in chloride conductance and depress voltage-activated calcium currents while prolonging the duration of GABA-induced chloride channel opening. Butalbital may also inhibit the excitatory effects mediated by AMPA receptors by reducing glutamate-induced depolarizations of the receptor. It is also proposed that barbiturates and opioids may potentiate the analgesic effects of each other when co-administered, although there are inconsistencies across preclinical data. |
| Pharmacodynamics | Butalbital is a short to intermediate-acting barbiturate that reversibly depresses the activity of excitable tissues, including the central nervous system in a nonselective manner. Barbiturates exhibit muscle-relaxing and anti-anxiety properties and they are capable of producing all levels of CNS mood alteration from excitation to mild sedation, hypnosis, and deep coma. The sedative dose of butalbital in nontolerant individuals is 5-100 mg and the hypnotic dose is 100-200 mg. Pain perception and reaction are relatively unimpaired until the moment of unconsciousness. In some cases, an unwanted paradoxical response of excitement may be observed instead of sedation with barbiturate treatment, which may be due to their depressant effects on inhibitory centers of the CNS. At sufficiently high therapeutic doses, barbiturates induce anesthesia; however, barbiturates are reported to lose their effectiveness for sleep induction and sleep maintenance after 2 weeks. Barbiturates are habit-forming; they can produce tolerance and both dependence and addiction, which is partly explained by decreased drug concentration at the site of action due to enhanced drug metabolism by induced enzymes, or to cellular adaptive changes. In addition, butalbital may lead to analgesic overuse headache. While butalbital is expected to mediate similar actions as other members of the barbiturate drug class, the effects of butalbital in isolation are not well understood. It is suggested that butalbital is added in combination products to antagonize the unwanted central stimulating effect of stimulatory ingredients such as caffeine. Butalbital may decrease blood pressure and heart rate when administered at sedative and hypnotic doses. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Gamma-aminobutyric acid receptor subunit alpha-2 | Humans | potentiator |
| Gamma-aminobutyric acid receptor subunit alpha-3 | Humans | potentiator |
| Gamma-aminobutyric acid receptor subunit alpha-4 | Humans | potentiator |
ADME / PK
| Absorption | Butalbital gets readily and rapidly absorbed from the gastrointestinal tract. The time to reach the peak plasma concentrations is reported to be approximately 2 hours. Typical blood concentrations of butalbital peaked at 2.1 mg/L and declined to 1.5 mg/L at 24 hr. Plasma concentrations of 10 to 20 μg/mL have been associated with toxicity; coma and fatalities have occurred with concentrations of 25 to 30 μg/mL. |
|---|---|
| Half-life | The plasma half-life is about 35 hours. In a study of 5 healthy volunteers receiving 100 mg butalbital in combination with aspirin and caffeine, the mean plasma elimination half-life of butalbital was 61 hours, with the range of 35 to 88 hours.[A177838, T598] |
| Protein binding | The _in vitro_ plasma protein binding of butalbital is 45% over the concentration range of 0.5-20 mcg/mL. This falls within the range of plasma protein binding (20%-45%) reported with other barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. |
| Metabolism | Butalbital is expected to undergo nearly complete hepatic metabolism. It primarily undergoes C5 oxidation to form 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid, which is the major metabolite. Butalbital may also undergo omega-hydroxylation to form 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric acid.[A177835, L10370, T598] |
| Route of elimination | Butalbital predominantly undergoes renal elimination with 59 to 88% of the total dose administered being excreted from the kidneys as unchanged parent drug or metabolites. Urinary excretion products included parent drug (about 3.6% of the dose), 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8%), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% is conjugated. Elimination is not complete within 24 hours, and the drug accumulates with frequent administration. |
| Volume of distribution | The volume of distribution of butalbital is reported to be approximately 0.8 L/kg. Butalbital is expected to distribute to most of the tissues in the body , including the mamillary glands and placenta. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells. |
| Clearance | There is limited data on the clearance of butalbital. |
Formulation & handling
- Butalbital is a small molecule suitable for oral and rectal administration, commonly formulated as tablets, capsules, syrup, or suppositories.
- The compound has moderate water solubility and a logP indicating balanced lipophilicity, facilitating formulation in both aqueous and lipid-based systems.
- Handling should minimize exposure to alcohol due to the risk of CNS depression, but no specific sensitivity to food intake has been noted.
Regulatory status
| Lifecycle | The API has patents expiring between 2024 and 2026 in the US and Canada, with several generic versions available, indicating a mature market with established competition. Ongoing regulatory approvals support continued product availability across both regions. |
|---|
| Markets | US, Canada |
|---|
Supply Chain
| Supply chain summary | The manufacturing landscape for Butalbital involves multiple packagers and pharmaceutical companies, indicating a diverse supply network primarily serving the US and Canadian markets. Several branded formulations, including combinations with acetaminophen and caffeine, are present in these regions. Given the presence of numerous manufacturers and multiple brand variations, it suggests that original patents have expired, enabling existing generic competition. |
|---|
Safety
| Toxicity | Reported oral TDLO (woman) is 400 mg/kg and subcutaneous LD50 in rat is 160 mg/kg.[MSDS] The lowest acute dose of butalbital alone associated with death in adults is 2.0 g. Symptoms of acute barbiturate poisoning include drowsiness, confusion, coma, respiratory depression, hypotension, and shock. Due to the CNS depressant effects, an overdose of barbiturates may lead to death. Barbiturates are also associated with withdrawal reactions, which may lead to death if severe. |
|---|
High Level Warnings:
- Handle with appropriate protective equipment to prevent exposure
- Toxicity data indicate risk of CNS depression at elevated doses
- Avoid inhalation, ingestion, and dermal contact due to associated acute toxicity and potential for severe adverse effects
Butalbital is a type of Barbiturates
Barbiturates are a category of pharmaceutical active pharmaceutical ingredients (APIs) that have sedative, hypnotic, and anticonvulsant properties. They belong to the class of drugs called depressants, which slow down the central nervous system (CNS) activity. Barbiturates have been widely used in the medical field for their ability to induce sleep, reduce anxiety, and control seizures.
The mechanism of action of barbiturates involves enhancing the effects of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. GABA inhibits the transmission of signals between nerve cells, leading to relaxation and sedation. Barbiturates bind to specific GABA receptors, increasing the inhibitory effects of GABA and resulting in a calming effect on the CNS.
In the past, barbiturates were commonly prescribed for insomnia, anxiety disorders, and epilepsy. However, their use has decreased significantly due to the emergence of safer and more effective alternatives with fewer side effects. Nonetheless, barbiturates are still utilized in certain medical situations, such as anesthesia induction, emergency seizure control, and in some cases of refractory epilepsy.
Despite their therapeutic benefits, barbiturates carry potential risks and side effects. They can cause drowsiness, impaired coordination, and dependence when used for extended periods. Overdose of barbiturates can be life-threatening, leading to respiratory depression and coma.
In conclusion, barbiturates are a class of API widely known for their sedative, hypnotic, and anticonvulsant properties. While their use has diminished over time, they remain important in specific medical contexts. Proper caution and medical supervision are crucial when using barbiturates to ensure safety and efficacy.
