Phenobarbital


Article Author:
Cassaundra Lewis


Article Editor:
Ninos Adams


Editors In Chief:
Eric Flake


Managing Editors:
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Scott Dulebohn
Sobhan Daneshfar
William Gossman
Pritesh Sheth
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Richard Ciresi
Hajira Basit
Phillip Hynes


Updated:
10/27/2018 12:31:47 PM

Indications

Sedative-hypnotic agents include a class of drugs called barbiturates. Barbiturates, specifically phenobarbital, offer a wide array of clinical uses that commonly include anti-seizure management.[1] It is even recommended as an agent to treat status epilepticus.[2] A study performed in China comparing valproic acid to phenobarbital for the treatment of status epilepticus, showed intravenous phenobarbital to have better clinical outcomes in the study population compared to valproic acid.[3] Although proven effective for status epilepticus, phenobarbital has widely been replaced with other drugs that offer less harmful side effects.[4][2] Phenobarbital can also be used to relieve insomnia[5] and apprehensiveness, although addiction is a point of concern when phenobarbital is used for insomnia. This drug can also be used for benzodiazepine and alcohol withdrawal treatment,[6] due to its anti-seizure properties and sedative effect. The syndrome resulting from alcohol withdrawal has a better clinical outcome when treated with benzodiazepines according to significant evidence-based studies.[7][8] Long-acting agents such as phenobarbital are not the preferred option for surgical induction; short-acting barbiturates are commonly used for this purpose.[9] Phenobarbital's involvement in severe brain injury management is to reduce intracranial pressure by suppressing cerebral metabolism, but phenobarbital's adverse effect of hypotension negatively impacts the brain's supply of oxygen thus offsetting any clinical benefit.[10]

Mechanism of Action

Phenobarbital works by increasing the amount of time chloride channels are open which in turn depresses the central nervous system. This is done by acting on GABA-A receptor subunits. When phenobarbital binds to these receptors, the chloride ion gates open and stay open allowing a steady flow of these ions into neuronal cells.[1] This action hyperpolarizes the cell's membrane, thereby increasing the threshold for the action potential. This is the reasoning as to why this drug is effective in the treatment of seizures. As per the metabolism and clearance of the drug, phenobarbital is a water-soluble agent metabolized by the liver and expelled mainly through the kidneys.[1] It is important to remember clearance rates vary with patients and their specific presentations. For instance, terminally ill cancer patients on phenobarbital may need dose adjustments due to reduced clearance of this drug.[11] Cytochrome p450 is induced by phenobarbital, and so careful consideration must be made when given concurrently with other medications. For instance, an epileptic woman who takes oral contraceptive pills and phenobarbital must be fully aware of the possible interaction between the medications. Phenobarbital, an antiepileptic drug, is known to induce the liver's cytochrome p450 enzyme. Inducing this enzyme speeds up the metabolism of estrogens and progestins. Thus, a woman taking both anti-epileptic medication and oral contraceptive pills can have an unexpected pregnancy due to the decreased efficacy of her oral contraceptive pills[12]. This is why it is crucial to educate the patient about potential risks.

Administration

Phenobarbital is given through a variety of routes. These include[13]:

  • Intramuscular (IM)
  • Oral
  • Intravenous (IV)

When phenobarbital is given intravenously, it should be for emergency cases. Other routes of administration should be accessed first and checked for any indurations. Studies have shown that an induration at a site of infusion results in a decreased bioavailability of phenobarbital.[14] Another study has shown rectal administration of phenobarbital to be effective, with a relative bioavailability reaching 90%.[15]

Adverse Effects

Complications associated with phenobarbital use are coma, decreased effort to breathe, and low blood pressure.[1] The more common adverse effects include[16]:

  • Incoordination
  • Impaired balance
  • Drowsiness

These adverse effects, stemming from phenobarbital usage, impact the geriatric patients to a greater degree, and therefore, the use of newer antiepileptics (lamotrigine, levetiracetam) are preferred for seizure treatment in this population.[16]

This drug has been associated with Steven-Johnson syndrome, but this is a rare complication. The following have been associated with long-term use of Phenobarbital: irritability, loss of appetite, achiness in the bones, joints or muscles, depression, and liver damage, although liver damage is a rare complication.[1]

Contraindications

A person with underlying obstructive lung disease will have a higher risk of complications.[1] The respiratory drive depression associated with barbiturate toxicity compounded with an already compromised respiratory system can contribute to complications.[17] It was also found that drug interaction from combined oral theophylline medication and phenobarbital, negatively impacted theophylline blood levels compared to plain oral theophylline pills.[17] Phenobarbital has been shown to decrease levels of steroids and theophylline via the cytochrome p450 liver metabolism system.[17] Therefore, persons receiving combined oral treatment for their lung condition can experience issues regarding subtherapeutic blood levels of theophylline and or corticosteroids. 

It is imperative not to drink alcohol while taking barbiturates because there is a danger of severe respiratory depression when both are in one's system. When taken simultaneously, both drug's individual effects on GABA-A add to the other.[1] This can cause a life-threatening scenario.

When taking a prescription of a barbiturate such as phenobarbital, one may go into withdrawal if they were to stop taking it suddenly. Tapering of the drug must be implemented.

Monitoring

The range of phenobarbital deemed effective without causing issues to an individual is between 10 To 40 mcg/mL. Once blood levels increase above 40 mcg/mL, the patient is in a lethal range and at substantial risk.[1]

Toxicity

Barbiturate toxicity is noticeable at 1 gram via oral route, although this amount varies depending on the individual. Doses above 2 grams have caused deaths, but a deadly dose usually spans from 40 to 80 mcg/mL according to the following article.[1]

Toxicity from barbiturates varies, but common symptoms include the following[1]:

  • Cognitive impairment
  • Decreased heart rate
  • Incoordination
  • Nausea
  • Muscle weakness
  • Polydipsia
  • Below normal urine output
  • Decreased body temperature
  • Mydriasis

Deaths have resulted from marked respiratory depression, hypotension, and coma.[1]

Treatment of phenobarbital toxicity is supportive[18]; comprising maintenance of airway function (through endotracheal intubation and mechanical ventilation), correction of bradycardia and hypotension (with IV fluids and vasopressors, if necessary). After properly assessing and correcting the patient's airway, breathing, and circulation; it is imperative to remove the drug from the body. This can be done via gastric irrigation, forced alkaline diuresis or dialysis.[18] For now, an explicit treatment does not exist.[1]

Enhancing Healthcare Team Outcomes

Phenobarbital is a drug that poses an urgent situation for healthcare workers when a patient arrives after an attempted overdose. Although restrictions on the access to barbiturates have caused the number of overdoses to decline,[1] it is still crucial to assess and treat patients with a phenobarbital overdose expeditiously.

Phenobarbital is known for being highly addictive and in prior years, found to be a common agent of choice for suicide attempts.[19] Phenobarbital overdose is a healthcare emergency and requires teamwork from the entire healthcare spectrum to help the patient.  Begin by assessing patient vitals. The healthcare team must ensure respiratory effort is optimal. If it is compromised, precautions for respiratory support must be put in place (endotracheal intubation and/or mechanical ventilation). Next, a urine toxicology or blood toxicology must be done to confirm the suspected diagnosis. It is imperative to implement the management of cardiac and respiratory status quickly.[1][19] Alkalinizing the urine can help eliminate the drug, but if prior interventions fail to advance patients in a positive direction, hemodialysis or hemoperfusion can be used to enhance drug clearance.[1][18][20] Hemoperfusion was thought to be more effective in phenobarbital overdose due to increased protein binding; however, a case of severe phenobarbital intoxication treated with high-efficiency dialyzers and increased rates of blood flow, showed that hemodialysis is the better option for drug clearance in compromised patients. The patient experienced a positive clinical outcome after phenobarbital levels dropped rapidly.[18][21] While in recovery, the patient needs to be properly counseled about barbiturates and proper/improper use.[1] This educational opportunity, along with a psychiatric evaluation, is pertinent for the patient. Regarding the prevention of future overdoses, an interprofessional effort among patient's health care providers must be employed to ensure that the patient is not prescribed many pills at once. They can also evaluate whether the patient can be switched to an alternative medication. An evidence level III-cohort study showed that subjects who purposely overdosed on barbiturates had an increased risk of an adverse ICU course. If the healthcare team judiciously prescribes barbiturates, the patient is less likely to overdose and thus less likely to suffer an adverse hospital course according to this study.[22]


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Phenobarbital - Questions

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A patient is being treated with phenobarbital to control seizures. The optimal dose of which of the following drugs is altered significantly by hepatic enzyme induction by phenobarbital?



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A patient is being treated with phenobarbital to control seizures. Hepatic enzyme induction by phenobarbital can alter significantly the optimal dose of which of the following medications?



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What is an appropriate dose of phenobarbital for a 12-month-old child with status epilepticus?



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What is the mechanism of action of phenobarbital?



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Which one of the following medications is a potent liver enzyme inducer?



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Which of the following medications is a known enzyme inducer?



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Which of the following antiseizure medications has side effects of cognitive impairment, poor memory, and with chronic use, Dupuytren contractures?



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Select the medication that is most likely to increase beta activity on electroencephalogram.



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What percent of phenobarbital is excreted by the kidneys?



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Which of the following is a common adverse effect of phenobarbital?



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Which of the following medications can help in increasing the rate of neonatal liver bilirubin conjugation?



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Although newer and more effective drugs are available, phenobarbital is still considered an appropriate long-term therapy for which of the following conditions?



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What is a Phenobarbital?



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A patient is taking phenobarbital for seizures and sodium bicarbonate for gastritis. Which of the following could happen?



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Which of the following describes phenobarbital?



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A 23-year-old male is applying for a position at a local hospital. He has a history of seizures and has recently been hospitalized for status epilepticus. Which barbiturate could be found unchanged in the urine?



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A young woman on oral contraceptive pills (OCP) for the past three years had another drug added to her medications three months ago. Today she finds out that she is pregnant, even after strict adherence to her OCP regime. The provider suspects it was due to her new medication. What is the most likely drug that was recently added?



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A 47-year-old male with a past medical history significant for chronic phenobarbital abuse comes into the provider complaining of an issue. Which answer below is the most likely complaint?



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A 52-year-old patient with an extensive past medical history that includes epilepsy, diabetes mellitus type 1, chronic obstructive pulmonary disease, hypertension, and hyperlipidemia comes in asking for her seizure medication to be switched to phenobarbital because she has heard such great things about the drug for seizures. Which component of her past medical history could risk complications with phenobarbital?



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A 30-year-old patient with past medical history of epilepsy comes in complaining of abdominal pain, nausea, constipation, anxiety, dysuria, and paresthesia in her lower extremity. She experienced these myriads of symptoms twice before in the recent past. Her mother had these same episodes that started in her thirties as well. What antiepileptic medication is contraindicated in this patient?



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A newborn is found to have a facial cleft and patent ductus arteriosus and is exhibiting signs of drug withdrawal. Which of the following could have caused this presentation?



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Phenobarbital - References

References

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Ichikura K,Okumura Y,Takeuchi T, Associations of Adverse Clinical Course and Ingested Substances among Patients with Deliberate Drug Poisoning: A Cohort Study from an Intensive Care Unit in Japan. PloS one. 2016     [PubMed]
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Palmer BF, Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2000 Sep     [PubMed]
Sayer WJ, Hazards of barbiturates in the treatment of asthma, bronchitis, and obstructive pulmonary disease. The Western journal of medicine. 1975 Jun     [PubMed]
Roberts I,Sydenham E, Barbiturates for acute traumatic brain injury. The Cochrane database of systematic reviews. 2012 Dec 12     [PubMed]
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Oks M,Cleven KL,Healy L,Wei M,Narasimhan M,Mayo PH,Kohn N,Koenig S, The Safety and Utility of Phenobarbital Use for the Treatment of Severe Alcohol Withdrawal Syndrome in the Medical Intensive Care Unit. Journal of intensive care medicine. 2018 Jan 1     [PubMed]
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Lindberg MC,Cunningham A,Lindberg NH, Acute phenobarbital intoxication. Southern medical journal. 1992 Aug     [PubMed]

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