Diazapam

Absorption

After oral administration, it is considered that diazepam is rapidly and completely absorbed from the gastrointestinal tract as >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours with a range of 0.25 to 2.5 hours .
Absorption is delayed and decreased when administered with a moderate fat meal . In the presence of food mean lag times are approximately 45 minutes as compared with 15 minutes when fasting . There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting . This results in an average decrease in Cmax of 20% in addition to a 27% decrease in AUC (range 15% to 50%) when administered with food .

Toxicity

The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation . In most cases only observation of vital functions is required .
Extreme overdosage may lead to coma, areflexia, cardio-respiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support) .
Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease . Severe effects in overdose also include rhabdomyolysis and hypothermia . Overdose of benzodiazepines in combination with other CNS depressants (including alcohol) may be fatal and should be closely monitored .
In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus . The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus . Patients should also be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug .
Special care must be taken when diazepam is used during labor and delivery, as high single doses may produce irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia, and moderate respiratory depression in the neonates . With newborn infants it must be remembered that the enzyme system involved in the breakdown of the drug is not yet fully developed (especially in premature infants) .
Diazepam passes into breast milk . Breastfeeding is therefore not recommended in patients receiving diazepam .
Safety and effectiveness in pediatric patients below the age of 6 months have not been established .
In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated) . Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects. Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function . Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function .
Decreases in clearance and protein binding, and increases in volume of distribution and half-life has been reported in patients with cirrhosis . In such patients, a 2- to 5- fold increase in mean half-life has been reported . Delayed elimination has also been reported for the active metabolite desmethyldiazepam . Benzodiazepines are commonly implicated in hepatic encephalopathy . Increases in half-life have also been reported in hepatic fibrosis and in both acute and chronic hepatitis .

Description

Diazepam—much better known by its major trade name Valium—is a popular tranquilizer. Its?synthesis was first reported?by L. H. Sternbach and E. Reeder at Hoffmann-La Roche in 1961. The same researchers were awarded a process patent in 1963 and composition-of-matter patents in 1964 and 1968 on diazepam and several similar compounds.
Hoffmann-La Roche launched Valium in 1963. For most years until its patents ran out in 1985, it was the highest-selling drug in the United States. After it became generic, its cost plummeted. In the United States, it now costs about 40￠ per dose, but it can be bought for the equivalent of a penny per dose in some countries.
Serious side effects from the normal use of diazepam are rare. Overdoses can result in symptoms as serious as coma, but are not usually fatal. But when overdoses are combined with alcohol or opiate intake, the fatality rate increases.

Description

Diazepam is a yellow crystalline powder.Molecular weight = 284.75; Freezing/Meltingpoint = 125-126℃. Insoluble in water.

Chemical properties

Light Yellow Crystalline Solid

Chemical properties

Diazepam is a yellow crystalline powder.

Originator

Valium,Roche,Italy,1962

The Uses of Diazapam

Anxiolitic; muscle relaxant (skeletal); anticonvulsant. Controlled substance (depressant)

The Uses of Diazapam

Anxiolytic; muscle relaxant (skeletal); anticonvulsant. Controlled substance (depressant).

The Uses of Diazapam

Diazepam is an anxiolytic; muscle relaxant (skeletal); anticonvulsant. Diazepam is a controlled substance (depressant).

Indications

In general, diazepam is useful in the symptomatic management of mild to moderate degrees of anxiety in conditions dominated by tension, excitation, agitation, fear, or aggressiveness such as may occur in psychoneurosis, anxiety reactions due to stress conditions, and anxiety states with somatic expression.
Moreover, in acute alcoholic withdrawal, diazepam may be useful in the symptomatic relief of acute agitation, tremor, and impending acute delirium tremens.
Furthermore, diazepam is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathologies, such as inflammation of the muscle and joints or secondary to trauma; spasticity caused by upper motor neuron disorders, such as cerebral palsy and paraplegia; athetosis and the rare "stiff man syndrome".
Particular label information from the United Kingdom also lists particular age-specific indications, including for adults: (1) The short-term relief (2-4 weeks) only, of anxiety which is severe, disabling, or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness, (2) cerebral palsy, (3) muscle spasm, (4) as an adjunct to certain types of epilepsy (eg. myoclonus), (5) symptomatic treatment of acute alcohol withdrawal, (6) as oral premedication for the nervous dental patient, and (7) for premedication before surgery.
In the same UK label information, diazepam is indicated in children for: (1) control of tension and irritability in cerebral spasticity in selected cases, (2) as an adjunct to the control of muscle spasm in tetanus, and for (3) oral premedication.
A diazepam nasal spray is indicated in patients 6 years and older to treat intermittent, stereotypic episodes of frequent seizure activity that are different than the patient's usual seizure pattern.

Background

A benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnesic properties and a long duration of action. Its actions are mediated by enhancement of gamma-aminobutyric acid activity. It is used in the treatment of severe anxiety disorders, as a hypnotic in the short-term management of insomnia, as a sedative and premedicant, as an anticonvulsant, and in the management of alcohol withdrawal syndrome. (From Martindale, The Extra Pharmacopoeia, 30th ed, p589)
Given diazepam's storied history as a commonly used and effective medication for a variety of indications, contemporary advancements in the formulation and administration of the agent include the development and US FDA approval of an auto-injectable formulation for the rapid treatment of uncontrolled seizures in 2015-2016 . Combining diazepam, a proven effective therapy for acute repetitive seizures, with an auto-injector designed for subcutaneous administration that is quickly and easily administered offers the potential for complete, consistent drug absorption and rapid onset of effect . This current development is subsequently an important addition to the rescue therapy tool chest for patients with epilepsy .

Definition

ChEBI: Diazepam is a 1,4-benzodiazepinone that is 1,3-dihydro-2H-1,4-benzodiazepin-2-one substituted by a chloro group at position 7, a methyl group at position 1 and a phenyl group at position 5. It has a role as a xenobiotic, an environmental contaminant, an anxiolytic drug, an anticonvulsant and a sedative. It is a 1,4-benzodiazepinone and an organochlorine compound.

Manufacturing Process

Into a stirred, cooled (10°-15°C) solution of 26.2 grams (0.1 mol) of 2-amino5-chlorobenzophenone β-oxime in 150 ml of dioxane were introduced in small portions 12.4 grams (0.11 mol) of chloracetyl chloride and an equivalent amount of 3 N sodium hydroxide. The chloracetyl chloride and sodium hydroxide were introduced alternately at such a rate so as to keep the temperature below 15°C and the mixture neutral or slightly alkaline. The reaction was completed after 30 minutes. The mixture was slightly acidified with hydrochloric acid, diluted with water and extracted with ether. The ether extract was dried and concentrated in vacuum. Upon the addition of ether to the oily residue, the product, 2-chloroacetamido-5-chlorobenzophenone βoxime, crystallized in colorless prisms melting at 161°-162°C.
20 ml of 1 N sodium hydroxide were added to a solution of 6.4 grams (20 mmol) of 2chloroacetamido-5-chlorobenzophenone β-oxime. After 15 hours the mixture was diluted with ice cold 1 N sodium hydroxide and extracted with ether. The ether extract was discarded. The alkaline solution was acidified with hydrochloric acid and extracted with methylene chloride. The methylene chloride solution was concentrated to a small volume and then diluted with petroleum ether to obtain 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide.
To a stirred suspension of 10 grams (35 mmol) of 7-chloro-5-phenyl-3H-1,4- benzodiazepin-2(1H)-one 4-oxide in approximately 150 ml of methanol was added in portions an excess of a solution of diazomethane in ether. After about one hour, almost complete solution had occurred and the reaction mixture was filtered. The filtrate was concentrated in vacuum to a small volume and diluted with ether and petroleum ether. The reaction product, 7- chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide, crystallized in colorless prisms. The product was filtered off and recrystallized from acetone, MP 188°-189°C.
A mixture of 3 grams (0.01 mol) of 7-chloro-1-methyl-5-phenyl-3H-1,4- benzodiazepin-2(1H)-one 4-oxide, 30 ml of chloroform and 1 ml of phosphorus trichloride was refluxed for one hour. The reaction mixture was then poured on ice and stirred with an excess of 40% sodium hydroxide solution. The chloroform was then separated, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride and crystallized by the addition of petroleum ether. The product, 7- chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one, was recrystallized from a mixture of acetone and petroleum ether forming colorless plates melting at 125°-126°C.
The manufacturing procedure above is from US Patent 3,136,815. Purification of diazepam is discussed in US Patent 3,102,116.

brand name

Diastat (Valeant); Dizac (Pharmacia & Upjohn); Q-Pam (Quantum Pharmics); Valium (Roche).

Therapeutic Function

Tranquilizer

Synthesis Reference(s)

Journal of Heterocyclic Chemistry, 5, p. 731, 1968 DOI: 10.1002/jhet.5570050528

General Description

Off-white to yellow crystalline powder. Practically odorless. Tasteless at first with a bitter aftertaste.

General Description

Diazepam is given orally (Valium) or rectally (Diastat) as anadjunctive treatment in patients with generalized tonic–clonicstatus epilepticus (i.e., an acute and potentially fatal seizure)or in patients with refractory epilepsy in combination withother AEDs.For details on diazepam (Valium), see its discussionunder anxiolytics and sedative–hypnotic agents.

General Description

Diazepam, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one .Like chlordiazepoxide, repeated administration of diazepamleads to accumulation of an active nordazepam,which can be detected in the blood for more than 1 weekafter discontinuation of the drug. This drug is a long actingfor the same reason. Diazepam is metabolized to nordazepamby CYP2C19 and CYP3A4. Cimetidine, by inhibitingCYP3A4, decreases the metabolism and clearanceof diazepam. Thus, drugs that affect the activityof CYP2C19 or CYP3A4 may alter diazepam kinetics.Because diazepam clearance is decreased in the elderlyand in patients with hepatic insufficiency, a dosage reductionmay be warranted. It is widely used for several anxietystates and has an additional wide range of uses (e.g., asan anticonvulsant, a premedication in anesthesiology, andin various spastic disorders).

Air & Water Reactions

Hydrolysis occurs in aqueous solutions with a maximum stability around pH 5. . Insoluble in water.

Fire Hazard

Flash point data for Diazapam are not available; however, Diazapam is probably combustible.

Biological Activity

Ligand at the GABA A receptor benzodiazepine modulatory site. Anxiolytic, anticonvulsant and sedative/hypnotic agent.

Pharmacokinetics

Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle- relaxant, anticonvulsant and amnestic effects . Most of these effects are thought to result from facilitation of the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system .

Pharmacokinetics

The second group of antispastic drugs to be developed were the benzodiazepines, typified by diazepam. Diazepam exerts its skeletal muscle relaxant effect by binding as an agonist at the benzodiazepine receptor of the GABAA receptor complex, which enhances GABA potency to increase chloride conductance. The muscle relaxant properties of classical benzodiazepines, such as diazepam, appear to be mediated mainly by the GABAA α2 and α3 subunits. The result is neuronal hyperpolarization, probably at both supraspinal and spinal sites for spasmolytic activity. Its actions are sufficient to relieve spasticity in patients with lesions affecting the spinal cord and in some patients with cerebral palsy.

Clinical Use

Benzodiazepine:
Perioperative sedation (IV)
Anxiolytic
Muscle relaxant
Status epilepticus

Side Effects

Few high-quality clinical trials have evaluated diazepam as a muscle relaxant, but these few suggest that diazepam is no more efficacious than, for example, carisoprodol, cyclobenzaprine, or tizanidine (i.e., efficacy is marginal). Moreover, diazepam produces drowsiness and fatigue in most patients at doses required to significantly reduce muscle tone.

Safety Profile

Poison by ingestion, parenteral, subcutaneous, intravenous, and intraperitoneal routes. Moderately toxic by skin contact. Questionable carcinogen with experimental tumorigenic data. Human systemic effects: dermatitis, effect on inflammation or mediation of inflammation, change in cardiac rate, somnolence, respiratory depression, and other respiratory changes, visual field changes, diplopia (double vision), change in motor activity, muscle contraction or spasticity, ataxia (loss of muscle coordination), an antipsychotic and general anesthetic. Human reproductive effects by ingestion and intravenous routes causing developmental abnormalities of the fetal cardiovascular (circulatory) system and postnatal effects. Experimental teratogenic and reproductive effects. Human mutation data reported. An allergen. A drug for the treatment of anxiety. When heated to decomposition it emits very toxic fumes of Cl and NOx.

Potential Exposure

Those involved in the manufacture,packaging, or consumption of this widely used tranquilizingdrug.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: metabolism enhanced by rifampicin; metabolism inhibited by isoniazid.
Antifungals: concentration increased by fluconazole and voriconazole - risk of prolonged sedation.
Antipsychotics: increased sedative effects; increased risk of hypotension, bradycardia and respiratory depression with parenteral diazepam and IM olanzapine; risk of serious adverse effects in combination with clozapine
Antivirals: concentration possibly increased by ritonavir.
Sodium oxybate: enhanced effects of sodium oxybate - avoid.

First aid

If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. If thisDiazepam 877chemical contacts the skin, remove contaminated clothingand wash immediately with soap and water

Metabolism

Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam . N-desmethyldiazepam and temazepam are both further metabolized to oxazepam . Temazepam and oxazepam are further largely eliminated by way of conjugation to glucuronic acid via glucuronidation .
Furthermore, oxidation of diazepam is mediated by cytochrome P450 isozymes; formation of desmethyl-diazepam mainly by CYP2C19 and CYP3A and 3-hydroxy-diazepam (temazepam) and oxazepam by CYP3A. Because CYP2C19 is polymorphic, extensive metabolizers (EMs), and poor metabolizers (PMs) of diazepam can be distinguished . PMs of diazepam showed significantly lower clearance (12 vs 26 mL/min) and longer elimination half-life (88 vs 41 h) of diazepam than EMs after a single oral dose . Also, PMs had lower clearance, higher AUC and longer elimination half-life of desmethyl-diazepam .

Metabolism

Diazepam is rapidly and completely absorbed after oral administration. Maximum peak blood concentration occurs in 2 hours, and elimination is slow, with a half-life of approximately 20 to 50 hours. As with chlordiazepoxide, the major metabolic product of diazepam is N-desmethyldiazepam, which is pharmacologically active and undergoes even slower metabolism than its parent compound. Repeated administration of diazepam or chlordiazepoxide leads to accumulation of N-desmethyldiazepam, which can be detected in the blood for more than 1 week after discontinuation of the drug. Hydroxylation of N-desmethyldiazepam at the 3-position gives the active metabolite oxazepam.

storage

Store at RT

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.