Phenobarbital

Article Author:
Cassaundra Lewis
Article Editor:
Ninos Adams
Updated:
5/17/2019 4:08:15 PM
PubMed Link:
Phenobarbital

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]


References

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