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. It is even recommended as an agent to treat status epilepticus. A study in China compared valproic acid to phenobarbital for the treatment of status epilepticus. Results showed intravenous phenobarbital to have better clinical outcomes in the study population compared to valproic acid. Although proven effective for status epilepticus, phenobarbital has mostly been replaced with other drugs that offer less harmful side effects. Phenobarbital can also be used to relieve insomnia and apprehensiveness, although addiction is a point of concern when using phenobarbital for insomnia. This drug is also useful for benzodiazepine and alcohol withdrawal treatment 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. Long-acting agents such as phenobarbital are not the preferred option for surgical induction; short-acting barbiturates are commonly used for this purpose. The involvement of phenobarbital 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.
Phenobarbital's mechanism of action increases the amount of time chloride channels are open, which in turn depresses the central nervous system. This action occurs 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. This action hyperpolarizes the cell's membrane, thereby increasing the threshold for the action potential. This increase in action potential is the reason 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. 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. Phenobarbital induces cytochrome p450, and so careful consideration is necessary when given concurrently with other medications. For instance, a woman with epilepsy who takes oral contraceptive pills and phenobarbital at the same time 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. The induction of this enzyme speeds up the metabolism of estrogens and progestins. Thus, a woman taking both antiepileptic medication and oral contraceptive pills can have an unexpected pregnancy due to the decreased efficacy of her oral contraceptive pills. This scenario is why it is crucial to educate the patient about potential risks.
Phenobarbital administration is via a variety of routes. These include:
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. Another study demonstrated the rectal administration of phenobarbital to be effective, with a relative bioavailability reaching 90%.
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 preferable as seizure treatment in this population.
This drug has some correlations with Steven-Johnson syndrome, but this is a rare complication. The following adverse events also correlate 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.
Patients with underlying obstructive lung disease will have an increased risk of complications. The depression of respiratory drive associated with barbiturate toxicity compounded with an already compromised respiratory system can contribute to complications. Research has also found that the drug interaction from combined oral theophylline medication and phenobarbital, exerted a negative impact on theophylline blood levels compared to plain oral theophylline pills. Phenobarbital has shown a capacity to decrease levels of steroids and theophylline via the cytochrome p450 liver metabolism system. Therefore, patients receiving combined oral therapy for their lung condition may experience issues with subtherapeutic blood levels of corticosteroids and/or theophylline.
It is imperative not to use alcohol while taking barbiturates because of the danger of severe respiratory depression when both drugs are in the patient's system. When taken simultaneously, both drugs' individual effects on GABA-A are additive, potneitally resulting in a life-threatening scenario.
When taking barbiturates such as phenobarbital, one may go into withdrawal if they were to stop taking it suddenly. Tapering off the drug is necessary.
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.
Barbiturate toxicity is noticeable at 1 gram via the 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.
Toxicity from barbiturates varies, but common symptoms include the following:
Deaths have resulted from marked respiratory depression, hypotension, and coma.
Treatment of phenobarbital toxicity is supportive, 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 evaluating and correcting the patient's airway, breathing, and circulation, it is imperative to remove the drug from the body; this can occur via gastric irrigation, forced alkaline diuresis, or dialysis. For now, a specific treatment does not exist.
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, 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. 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, urine toxicology or blood toxicology is necessary to confirm the suspected diagnosis. It is imperative to implement the management of cardiac and respiratory status quickly. 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. 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. While in recovery, the patient requires proper counsel about barbiturates and proper/improper use. 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 is necessary to ensure that the patient is not prescribed many pills at once. They can also evaluate whether the patient can switch 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.
|||Suddock JT,Cain MD, Barbiturate Toxicity null. 2018 Jan [PubMed PMID: 29763050]|
|||Falco-Walter JJ,Bleck T, Treatment of Established Status Epilepticus. Journal of clinical medicine. 2016 Apr 25 [PubMed PMID: 27120626]|
|||Su Y,Liu G,Tian F,Ren G,Jiang M,Chun B,Zhang Y,Zhang Y,Ye H,Gao D,Chen W, Phenobarbital Versus Valproate for Generalized Convulsive Status Epilepticus in Adults: A Prospective Randomized Controlled Trial in China. CNS drugs. 2016 Dec [PubMed PMID: 27878767]|
|||Hocker S,Clark S,Britton J, Parenteral phenobarbital in status epilepticus revisited: Mayo Clinic experience. Epilepsia. 2018 Aug 29 [PubMed PMID: 30159873]|
|||Sachdeva A,Choudhary M,Chandra M, Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond. Journal of clinical and diagnostic research : JCDR. 2015 Sep [PubMed PMID: 26500991]|
|||Hammond DA,Rowe JM,Wong A,Wiley TL,Lee KC,Kane-Gill SL, Patient Outcomes Associated With Phenobarbital Use With or Without Benzodiazepines for Alcohol Withdrawal Syndrome: A Systematic Review. Hospital pharmacy. 2017 Oct [PubMed PMID: 29276297]|
|||Dumps C,Halbeck E,Bolkenius D, [Drugs for intravenous induction of anesthesia: barbiturates]. Der Anaesthesist. 2018 May 9 [PubMed PMID: 29744526]|
|||Roberts I,Sydenham E, Barbiturates for acute traumatic brain injury. The Cochrane database of systematic reviews. 2012 Dec 12 [PubMed PMID: 23235573]|
|||Nakayama H,Echizen H,Ogawa R,Orii T,Kato T, Reduced Clearance of Phenobarbital in Advanced Cancer Patients near the End of Life. European journal of drug metabolism and pharmacokinetics. 2018 Jul 19 [PubMed PMID: 30027304]|
|||Sabers A, Pharmacokinetic interactions between contraceptives and antiepileptic drugs. Seizure. 2008 Mar [PubMed PMID: 18206393]|
|||Wilensky AJ,Friel PN,Levy RH,Comfort CP,Kaluzny SP, Kinetics of phenobarbital in normal subjects and epileptic patients. European journal of clinical pharmacology. 1982 [PubMed PMID: 7128675]|
|||Nakayama H,Echizen H,Ogawa R,Akabane A,Kato T,Orii T, Induration at Injection or Infusion Site May Reduce Bioavailability of Parenteral Phenobarbital Administration. Therapeutic drug monitoring. 2017 Jun [PubMed PMID: 28328763]|
|||Graves NM,Holmes GB,Kriel RL,Jones-Saete C,Ong B,Ehresman DJ, Relative bioavailability of rectally administered phenobarbital sodium parenteral solution. DICP : the annals of pharmacotherapy. 1989 Jul-Aug [PubMed PMID: 2763578]|
|||Anderson GD,Hakimian S, Pharmacokinetic Factors to Consider in the Selection of Antiseizure Drugs for Older Patients with Epilepsy. Drugs [PubMed PMID: 30003428]|
|||Sayer WJ, Hazards of barbiturates in the treatment of asthma, bronchitis, and obstructive pulmonary disease. The Western journal of medicine. 1975 Jun [PubMed PMID: 1136437]|
|||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 PMID: 10977799]|
|||Lindberg MC,Cunningham A,Lindberg NH, Acute phenobarbital intoxication. Southern medical journal. 1992 Aug [PubMed PMID: 1502622]|
|||Roberts DM,Buckley NA, Enhanced elimination in acute barbiturate poisoning - a systematic review. Clinical toxicology (Philadelphia, Pa.). 2011 Jan [PubMed PMID: 21288146]|
|||Ruhe M,Grautoff S,Kähler J,Pohle T, [Suicide attempt by means of phenobarbital overdose. Effective treatment with continuous veno-venous hemodialysis]. Medizinische Klinik, Intensivmedizin und Notfallmedizin. 2016 Mar [PubMed PMID: 26070921]|
|||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 PMID: 27560966]|