Diazepam


Article Author:
Jaberpreet Dhaliwal


Article Editor:
Abdolreza Saadabadi


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Alexandra Caley
Sameh Boktor


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Updated:
1/30/2019 9:53:20 AM

Indications

Diazepam is an anxiolytic benzodiazepine, first patented and marketed in the United States in 1963. It is a fast-acting, long-lasting benzodiazepine commonly used in the treatment of anxiety disorders, as well as alcohol detoxification, acute recurrent seizures, severe muscle spasm, and spasticity associated with neurologic disorders. In the setting of acute alcohol withdrawal, diazepam is useful for symptomatic relief of agitation, tremor, alcoholic hallucinosis, and acute delirium tremens.[1]

When administered intravenously, diazepam has been shown to act within 1 to 3 minutes, while oral dosing onset ranges between 15 to 60 minutes. Diazepam is long-lasting with a duration of action of more than 12 hours.

Benzodiazepines have largely replaced barbiturates in the treatment of anxiety and sleep disorders because of their improved safety profile, fewer side effects, and the availability of the antagonist flumazenil to reverse oversedation and benzodiazepine intoxication. 

Diazepam is FDA approved for the management of anxiety disorders, short-term relief of anxiety symptoms, spasticity associated with upper motor neuron disorders, adjunct therapy for muscle spasms, preoperative anxiety relief, management of certain refractory epilepsy patients and adjunct in severe recurrent convulsive seizures, and an adjunct in status epilepticus. Off label (non-FDA approved) use for diazepam includes sedation in the ICU and short-term treatment of spasticity in children with cerebral palsy.[2]

Mechanism of Action

Benzodiazepines exert their effects by facilitating the activity of GABA at various sites. Specifically, benzodiazepines bind at an allosteric site at the interface between the alpha and gamma subunits on GABA-A receptor chloride ion channels. The allosteric binding of diazepam at the GABA-A receptor leads to an increase in the frequency at which the chloride channel opens, leading to an increased conductance of chloride ions. This shift in charge leads to a hyperpolarization of the neuronal membrane and reduced excitability of the neuron.[3]

Specifically, the allosteric binding within the limbic system leads to the anxiolytic effects seen with diazepam. Allosteric binding within the spinal cord and motor neurons is the primary mediator of the myorelaxant effects seen with diazepam. Mediation of the sedative, amnestic, and anticonvulsant effects of diazepam is through receptor binding within the cortex, thalamus, and cerebellum.[4]

Once in the body, diazepam is mainly broken down by the CYP2C19 and CYP3A4 enzymes to several active metabolites, mainly desmethyldiazepam. Other minor active metabolites include oxazepam and temazepam. The average half-life of oral diazepam and desmethyldiazepam are about 46 hours and 100 hours, respectively. Strong inhibition of the 2C19 enzyme by certain drugs (fluoxetine and chloramphenicol) and 3A4 enzymes by certain drugs (ketoconazole, protease inhibitors, erythromycin) may cause increased levels of diazepam, while inducers of 2C19 (rifampicin and prednisone) and 3A4 (carbamazepine, topiramate, phenytoin, St. John's wort, rifampin, or barbiturates) may cause lower levels. Metabolites of diazepam are conjugated with glucuronide and excreted almost entirely in the urine.[5][6][7]

Administration

Diazepam is available in multiple formulations, including oral tablets, intramuscular injections (IM), intravenous injection (IV), or rectal gel. Of note, oral tablets have a more reliable absorption and controlled release when compared to IM.

Treatment of acute ethanol withdrawal: Initial dosing should be 10mg IM or IV. If needed, a follow-up dose of 5 to 10mg is permissible 3 to 4 hours later. If using the oral tablet, dosing is 10mg every 6 to 8 hours within the first 24 hours, then 5mg every 6 to 8 hours thereafter as needed.

Treatment of anxiety: 2 to 10mg can be given orally 2 to 4 times daily. If given parentally, dosing can be 2 to 10mg and repeated in 3 to 4 hours, if needed.

Treatment of muscle spasm: 2 to 10mg can be given orally 3 to 4 times daily. If given parentally, an initial dose of 5-10mg can be followed by another 5-10mg dose in 3 to 4 hours, if necessary.

Treatment of preoperative anxiety: Dosing is 10mg IM prior to surgery

For sedation in the ICU: Loading dose of 5 to 10mg for initial administration, followed by a maintenance dose of 0.03 to 0.10mg/kg every 0.5 to 6 hours (Barr 2013)

Treatment of seizures: 2 to 10mg orally dosed 2 to 4 times daily as adjunctive maintenance therapy. For intermittent management of seizures, rectal gel 0.2mg/kg is an option. It may be repeated in 4 to 12 hours if needed. Do not exceed five uses per month or more than one dose every 5 days.

Treatment of status epilepticus: 0.15 to 0.20mg/kg IV per dose,  and may be repeated once if needed. Do not exceed 10mg per single dose. Rectal administration of 0.2 to 0.5mg/kg administered one time. Do not exceed 20mg per dose.

Skeletal muscle relaxant: 2 to 10mg dosed 3 to 4 times daily as adjunct therapy

Adverse Effects

Like most benzodiazepines, the adverse reactions of diazepam include CNS and respiratory depression, dependence, and benzodiazepine withdrawal syndrome.

Serious adverse effects of diazepam include:

  • Respiratory depression
  • Seizures
  • Suicidality
  • Dependency and abuse
  • Withdrawal symptoms
  • Cardiovascular collapse
  • Bradycardia
  • Hypotension
  • Syncope
  • Paradoxical CNS stimulation

Common adverse effects of diazepam include:

  • Sedation
  • Fatigue
  • Confusion
  • Anterograde amnesia
  • Depression
  • Ataxia
  • Irritability
  • Disinhibition
  • Local injection site reaction
  • Headache
  • Tremor
  • Dystonia
  • Urinary retention
  • Incontinence
  • Nausea
  • Constipation
  • Diplopia
  • Libido changes
  • Rash
  • Menstrual irregularities
  • ALT and/or AST elevation

Contraindications

Contraindications to diazepam include patients with a known hypersensitivity to diazepam and, due to a lack of sufficient clinical evidence, diazepam is also contraindicated in patients under 6 months of age. Other contraindications to diazepam include patients with severe respiratory insufficiency, myasthenia gravis,  sleep apnea syndrome, and severe hepatic insufficiency. It is permissible in patients with open-angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow-angle glaucoma.

Use in Special Populations:

Pregnant Patients

Diazepam classifies as FDA pregnancy category D, which means that there is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk. The use of diazepam and other benzodiazepines in pregnancy correlates with an increased risk of congenital malformations, premature birth, low birth weight, and other neurodevelopmental abnormalities. However, additional studies are needed to confirm.

Diazepam has been shown to readily cross the placental barrier, and use during pregnancy may result in neonatal withdrawal soon after birth. Symptoms of neonatal withdrawal include high-pitched cry, hypertonia, tremor, irritability, feeding difficulties, sleep/wake disturbances, gastrointestinal and autonomic disturbances, respiratory problems, and failure to thrive. The onset of withdrawal in a neonate whose mother has taken diazepam during the pregnancy could be anywhere from the first days of life to the first few weeks. Diazepam use during the last trimester of pregnancy can result in “floppy infant syndrome,” characterized by hypotonia, hypothermia, lethargy, respiratory distress, and suckling difficulties.[8][9]

Breastfeeding women

Diazepam and its metabolites have been shown to be excreted in breast milk and may produce effects in the nursing infant. Some studies have shown the relative infant dose (RID) of diazepam to be approximately 9%. Relative infant dose (RID) is the dose received via breast milk relative to the mother’s dose. A relative dose below 10% is within an acceptable range regarded as reasonably safe in the short term. However, due to diazepam’s long half-life, metabolites may accumulate in a breastfed infant. Therefore, an infant breastfed by a mother receiving diazepam should undergo monitoring for drowsiness, decreased feeding, lethargy, and failure to thrive. Discontinue breastfeeding in cases with high doses of diazepam, or when repeated administration will be necessary.[10]

Elderly

One should exercise caution when prescribing diazepam to the elderly population. Elderly patients tend to have decreased renal function and clearing capability; therefore this population is at an increased risk for accumulation of diazepam and its major metabolites. It is recommended to limit dosage to the smallest effective amount.

Paradoxical reactions of CNS hyperactivity have also been reported with the use of benzodiazepines in the elderly, manifesting as hyperactivity, aggressive behavior, irritability, anxiety, and hallucinations. Should this occur, discontinuation is the recommendation.[11][12]

Monitoring

It is important to monitor respiratory and cardiovascular status, blood pressure, heart rate, and for symptoms of anxiety in patients taking diazepam.  With long-term use, monitor liver enzymes, CBC, and for signs of propylene glycol toxicity, including serum creatinine, BUN, serum lactate, and osmolality gap. With critically ill patients, monitor the depth of sedation.[13]

Toxicity

Diazepam Overdose

The toxic-to-therapeutic ratio of benzodiazepines is very high, making them relatively safe medications. However, the potential of overdose from diverted diazepam always exists when combined with opioids, alcohol, or other centrally acting agents. Overdose in adults frequently involves co-ingestion of other CNS depressants, which act synergistically to increase toxicity. In the case of single-agent diazepam overdose, symptoms manifest as CNS depression and are very rarely fatal. In mild cases, lethargy, drowsiness, and confusion are common symptoms. In cases of severe overdose, symptoms manifest as ataxia, diminished reflexes, hypotonia, hypotension, respiratory depression, coma (rarely), and death (very rarely).[8]

Treatment of benzodiazepine overdose involves protection of the airway, fluid resuscitation, and the use of flumazenil if indicated. Flumazenil works via competitive antagonism at the benzodiazepine receptor and can rapidly reverse coma. However, in patients with benzodiazepine tolerance, the use of flumazenil can precipitate acute withdrawal symptoms, autonomic instability, and seizures. 

Potential for Diazepam Abuse and Dependence

Diazepam is a Schedule IV controlled substance with the potential for abuse. Development of dependence and tolerance can occur in those who are addiction-prone, on long-term treatment, or in those patients taking high doses. Thus, these individuals should be under careful supervision. Once an individual develops dependence, the risk of developing withdrawal symptoms increases. Signs of benzodiazepine withdrawal include tremor, rebound anxiety, perceptual disturbances, dysphoria, psychosis, agitation, irritability, restlessness, sweating, headache, confusion, myalgias, abdominal pain, and vomiting. In cases of long-term use and abrupt cessation, there is potential for hallucinations and epileptic seizures to occur.[14]

Propylene Glycol Toxicity

Propylene glycol toxicity is a rare toxidrome associated with the parenteral use of diazepam. Propylene glycol is a common diluent used in the suspension of IV diazepam. Large doses or long-term infusions of IV diazepam can cause accumulation of propylene glycol and subsequent anion gap metabolic acidosis. Signs of the propylene glycol poisoning include the development of serum hyperosmolality, hemolysis, cardiac dysrhythmias, hypotension, lactic acidosis, seizure, acute kidney injury, and multisystem organ failure.[15]

Enhancing Healthcare Team Outcomes

Diazepam is a fast-acting potent anxiolytic popular in use due to its broad therapeutic index, low toxicity, and improved safety profile. Nonetheless, diazepam is still a drug with high potential for use disorder associated with severe adverse/toxic effects. Managing patients on benzodiazepines requires an interdisciplinary team approach consisting of physicians, nurses, and pharmacists. Further, prescribing physicians should be responsible for making use of state and federal controlled substance databases to monitor for possible use disorder, diversion, and improper drug use.


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Diazepam - Questions

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Diazepam fits into which FDA pregnancy category of the drug labeling system?



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A practitioner decides to prescribe diazepam to a patient that has just been diagnosed with general anxiety disorder. Which of the following represents a typical initial prescription for diazepam?



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Which route should NOT be used to premedicate with diazepam before a procedure?



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Which of the following medications can be used to stop acute convulsions?



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Which of the following is the longest acting benzodiazepine?



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A decision is made to administer a benzodiazepine to relieve muscle spasms in a patient with multiple sclerosis. Which of the following benzodiazepines is FDA approved to treat muscle spasms?



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Which of the following is true of Diastat?



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What drug schedule class is diazepam?



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What disease process is not treated with diazepam?



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A 46-year-old male is being treated for moderate alcohol withdrawal with diazepam. The patient provides you with a list of medications and herbal supplements. What will prompt you to increase his therapeutic dose?



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A 16-year-old male presents to the ER with the complaint of sudden onset chest tightness, palpitations, and a choking sensation. He has never experienced this before and has a non-contributory family history. The feeling started all of a sudden when he was eating from a restaurant near his home and believes that the food contained something that might have caused the problem. His parents inform that he recently gave his exams and is stressed about the result. On physical examination, his pulse is 100, BP 120/80, RR 18, temp A/F. He is given a medication that helps relieve his symptoms. Which of the following is the mechanism of action of this drug?



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Diazepam - References

References

Calcaterra NE,Barrow JC, Classics in chemical neuroscience: diazepam (valium). ACS chemical neuroscience. 2014 Apr 16;     [PubMed]
Friedman H,Greenblatt DJ,Peters GR,Metzler CM,Charlton MD,Harmatz JS,Antal EJ,Sanborn EC,Francom SF, Pharmacokinetics and pharmacodynamics of oral diazepam: effect of dose, plasma concentration, and time. Clinical pharmacology and therapeutics. 1992 Aug;     [PubMed]
Sakai N,Ishizuka M, Impact of rat P450 genetic polymorphism on diazepam metabolism. Expert opinion on drug metabolism     [PubMed]
American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society. 2015 Nov;     [PubMed]
Brandt R, Passage of diazepam and desmethyldiazepam into breast milk. Arzneimittel-Forschung. 1976;     [PubMed]
Li Y,Ning J,Wang Y,Wang C,Sun C,Huo X,Yu Z,Feng L,Zhang B,Tian X,Ma X, Drug interaction study of flavonoids toward CYP3A4 and their quantitative structure activity relationship (QSAR) analysis for predicting potential effects. Toxicology letters. 2018 Sep 15;     [PubMed]
Nutt DJ,Malizia AL, New insights into the role of the GABA(A)-benzodiazepine receptor in psychiatric disorder. The British journal of psychiatry : the journal of mental science. 2001 Nov;     [PubMed]
Mandelli M,Tognoni G,Garattini S, Clinical pharmacokinetics of diazepam. Clinical pharmacokinetics. 1978 Jan-Feb;     [PubMed]
Vozeh S, [Pharmacokinetic of benzodiazepines in old age]. Schweizerische medizinische Wochenschrift. 1981 Nov 21;     [PubMed]
Weintraub SJ, Diazepam in the Treatment of Moderate to Severe Alcohol Withdrawal. CNS drugs. 2017 Feb;     [PubMed]
Bellantuono C,Tofani S,Di Sciascio G,Santone G, Benzodiazepine exposure in pregnancy and risk of major malformations: a critical overview. General hospital psychiatry. 2013 Jan-Feb;     [PubMed]
Brett J,Murnion B, Management of benzodiazepine misuse and dependence. Australian prescriber. 2015 Oct;     [PubMed]
Dallmann A,Ince I,Coboeken K,Eissing T,Hempel G, A Physiologically Based Pharmacokinetic Model for Pregnant Women to Predict the Pharmacokinetics of Drugs Metabolized Via Several Enzymatic Pathways. Clinical pharmacokinetics. 2018 Jun;     [PubMed]
Ku LC,Hornik CP,Beechinor RJ,Chamberlain JM,Guptill JT,Harper B,Capparelli EV,Martz K,Anand R,Cohen-Wolkowiez M,Gonzalez D, Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus. CPT: pharmacometrics     [PubMed]
Jahn A,Bodreau C,Farthing K,Elbarbry F, Assessing Propylene Glycol Toxicity in Alcohol Withdrawal Patients Receiving Intravenous Benzodiazepines: A One-Compartment Pharmacokinetic Model. European journal of drug metabolism and pharmacokinetics. 2018 Aug;     [PubMed]

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