Phenobarbital


Article Author:
Cassaundra Lewis


Article Editor:
Ninos Adams


Editors In Chief:
Niamh Condon
Terry Tressler


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
5/17/2019 4:08:15 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 60-year-old African American patient with a past medical history of hypertension, type 2 diabetes, bipolar disorder, epilepsy, deep vein thrombosis, and chronic atrial fibrillation is being treated with phenobarbital to control the seizures. The patient is seen in the emergency room after complaining of pain and stiffness in the right calf. The patient is complaining of right calf pain, which is described as 7/10, crampy, and non-radiating. Vital signs reveal blood pressure 130/85mmHg, temperature 98.7 F, pulse 70 beats per minute, and respirations 18 breaths/minute. The physical exam is positive for pain with dorsiflexion of right foot, swelling, erythema, and tenderness of right calf. Doppler ultrasound study showed a clot in the right calf. During the patient's hospital stay, INR was consistently 1.0, putting the patient at risk for future thrombosis. Which drug is impacted by phenobarbital's hepatic enzyme induction and would have to be increased or decreased in order to maintain therapeutic levels while on phenobarbital?



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A mother arrives at the emergency department with her 12-month-old female infant. The mother rushed over with the infant after she said her child's entire body started to violently and uncontrollably shake in her arms after waking up from a nap. Past medical history is absent of congenital diseases and child has currently not prescribed any medications. The mother denies any family history of epilepsy or brain tumors. Obstetric history includes uncomplicated vaginal birth at 39 weeks. As per developmental history, the infant can sit without assistance, pulls self up to stand, and says the word, mama. The mother said this has never happened to her child before. She had 3 more seizures all within the time span of 5 minutes on the way to the emergency room without a return to her normal self and continues to convulse. Vital signs include blood pressure 90/65mmHg, temperature 98.6 F, pulse rate 150 beats per minute, respiratory rate 25 breaths/minute. What is this patient's diagnosis and what is an appropriate dose of phenobarbital for a 12-month-old child with this diagnosis?



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A 30- year- old female patient with a past medical history significant for childhood diagnosed epilepsy comes to the emergency department with her husband after experiencing an abrupt seizure at home. In the ED, she has 3 more seizures in a 5 minute period where she is seen convulsing on the floor in her husband's arms. Between each seizure, the patient did not return to her normal baseline. Vitals reveals a blood pressure of 130/85mmHg, Pulse 90 beats per minute, Temperature 98.7 F, Respirations 30 breaths/minute. A thorough physical exam was challenging to perform due to an actively convulsing patient. The first-line drug was not available. What is the effect of the second-line drug whose mechanism of action involves lengthening the time chloride gates stay in an open state?



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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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A 36-year-old Caucasian male with a past medical history of epilepsy diagnosed 10 years ago, type 2 diabetes mellitus, and hyperlipidemia comes into his primary care physician's office with a hand complaint. Patient states for the past 6 months he has noticed his right hand progressively become more and more rigid. Vital signs include blood pressure 125/80 mmHg, temperature 98.6 F, pulse 70 beats per minute, and respirations 16 breaths/minute. He describes not being able to extend his right hand fully, and he feels as if there is a tight rubber band preventing this action. The patient denies any pain or past trauma to the area. On physical examination, the right digitus medius is in a partially flexed state bending toward the palm. The patient is unable to exhibit the full extension of the right third digit. The radial pulse is present and intact bilateral. The left hand has a complete range of motion. What of the following drugs is associated with such complaint?



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49-year-old African American male with a past medical history of hypertension and hyperlipidemia comes in for an employment physical. He said he feels great but suddenly starts to drool and click his tongue; no longer interacting with the provider. This episode lasted for ten minutes. When the patient returned to his baseline, he was unaware of what happened but says his wife notices this happens to him approximately 4 times a month randomly for the past couple months. She told him they last about 3-4 minutes. He never went to a provider because he thought these episodes would eventually go away. The patient currently takes amlodipine and lovastatin. The family history is positive for hypertension in the mother and father and negative for epilepsy. Social history includes banker, married with 1 child, sexually active with wife. Denies alcohol, tobacco, or illicit drug use. Vitals: Blood pressure 135/90, Heart Rate 80, Temperature 98.5 F, and Respirations 16. Physical exam: Cardio S1 S2 no murmurs, Lungs vesicular bilateral, Abdominal exam non tender and negative for organomegaly. Triceps, Brachioradialis, patellar, and achilles reflex intact bilateral. Upper and lower extremity motor and sensory intact bilateral. Pupils equal, round, reactive to light and accommodation. Tympanic membrane pearly gray, moist mucus membranes in oral cavity. No cervical lymphadenopathy. Thyroid not palpable. Which medication can be used to treat the patient and will most likely increase beta activity on electroencephalogram?



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A 30-year-old Hispanic mother with a past medical history of type 2 diabetes and asthma, comes to the pediatric emergency room with her 4-day old male infant with the complaint that her baby looks yellow and is inconsolable. The mother noticed this change in her baby's appearance this afternoon. Obstetric history includes: the patient is the mother's only child, premature labor, and delivery at 35 weeks, uncomplicated vaginal birth, Hep B, and vitamin K were administered at birth. The patient is breastfed for 15 minutes every 2 hours daily. The mother denies the patient having any fever, chills, diarrhea, or vomiting. Upon inspection, the patient is observed crying and has a yellow hue all over the body. Vital signs: Blood pressure 83/53mmHg, pulse 130 beats per minute, temperature 97.9 F, Respirations 45 breaths/minute. Abdominal exam negative for protuberance or tenderness. Lung sounds were vesicular and resonant upon percussion bilateral. Cardio exam exhibited S1, S2, and no murmurs. Eye exam showed faint yellowing of sclera bilateral. Labs showed the patient having a bilirubin level of 22 mg per dL. Reticulocyte count and hemoglobin were 1% and 12.5 g/dL, respectively. Congenital, endocrine, and metabolic disease have all been ruled out. Which of the following medications can help in this infant's condition?



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A 40-year-old female with a past medical history of being HIV positive is rushed to the emergency department. Her boyfriend said that her entire body started to shake uncontrollably in the passenger seat of their car on the way to a restaurant. He also added that the patient had 3 of these episodes in a 5-minute time frame, without ever returning to her normal self. The boyfriend was not sure if this event has ever happened to his girlfriend before. Vitals include blood pressure 140/90 mmHg, temperature 98.7 F, heart rate 75 beats per minute, Respiration 20 breaths/minute. The emergency room physician administered a benzodiazepine, but the patient continues to seize. What drug can be used for long term therapy of this patient's condition?



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What is a Phenobarbital?



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Which of the following describes phenobarbital?



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A 16-year-old Hispanic male with a past medical history of status epilepticus and asthma is rushed to Emergency Room with suspected drug overdose after girlfriend came home and found a suicide note and an empty bottle of his prescription pills next to the unconscious body. When asked about any change in behavior leading up to the suicide attempt, the girlfriend said in the past couple of weeks she noticed his speech was slurred, he would stumble frequently, lose balance on level terrain, and complained about feeling sleepy. Vitals: Blood pressure 109/65, Heart Rate 45, Temperature 98.6 F, Respiration 6 breaths/minute. Physical exam: No needle track marks or visible wounds on the body. Cardio S1 S2 no murmurs, lung exam exhibited shallow breaths bilateral, and the abdominal exam was nonsignificant. The pupils are of normal size and reactive to light. Intubation was initiated and the patient started on intravenous fluids. Based on the girlfriend's interview and the patient's physical exam, which suspected drug of abuse could be found unchanged in the patient's urine?



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A 22-year-old female on oral contraceptive pills (OCP) for the past three years had an antiepileptic drug added to her prescribed medications three months ago. Today she visits the clinic complaining of early morning nausea and vomiting for the past month. She denies headache, chills, cough, fever, diarrhea, weight loss, and abdominal pain. Vital signs include blood pressure 130/80 mmHg, temperature 97.8F, pulse 70 beats per minute, respirations 14 breaths/minute. The physical examination is negative for abdominal tenderness, lung sounds are vesicular bilateral, and cardiac exam shows S1, S2 no murmurs. Also, the patient's pregnancy test returned positive even she admits of regular use of the oral contraceptive pills. The provider suspects this result was due to her new medication. How did the antiepileptic drug most likely exert its effect within the patient to increase the risk of pregnancy?



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A 47-year-old Asian male with a past medical history significant for chronic phenobarbital abuse, insomnia, and hypertension comes into the provider's clinic complaining of an issue he has been experiencing for the past couple weeks. He is taking hydrochlorothiazide and multivitamins. Medical history includes an appendectomy, and family history is significant for hypertension and gout on his maternal side. The patient is a divorced car salesman with 2 kids, eats mostly fast food and smokes 1 pack of cigarettes daily for the past 3 years. He denies alcohol use but admits to taking an old phenobarbital prescription for his insomnia. Upon exploring further, he reveals taking unprescribed phenobarbital for the past 10 years to help him sleep after the divorce. When asked what he likes to do for fun, the patient said he no longer finds joy in his hobbies. Vitals include blood pressure 125/80 mmHg, temperature 98.8 F, pulse 55 beats per minute, Respirations 12 breaths/minute. The physical exam shows a slightly overweight and balding male in no acute distress. Cardiac S1 S2 are regular without any murmurs. Lung sounds are vesicular and resonant bilaterally, and the abdominal exam shows healed laparoscopic scars from a past appendectomy and non-tender palpation. Which is the physical exam finding most likely be observed in a patient chronically abusing phenobarbital?



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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 African American female patient with a past medical history of epilepsy, type 2 diabetes, bipolar disorder, and hyperlipidemia all diagnosed 6 months ago, comes into the office complaining of severe abdominal pain, nausea, constipation, brown urine, feeling anxious, and tingling in her lower extremities. She experienced this myriad of complaints intermittently within the past 6 months. She mentions that the symptoms arise when she is feeling sick or stressed out, and today, she reports feeling sick. The patient denies any vomiting, diarrhea, hematochezia, change in stool color, or back pain. Medications include phenobarbital, metformin, lovastatin, lithium, and a multivitamin. Her mother and grandmother had these same constellations of symptoms that started in their thirties as well. The patient works as a retail sales assistant, denies alcohol, smoking, illicit drug use, and is currently single with no children. Vital signs include blood pressure 150/90 mmHg, heart rate 106 beats per minute, Respirations 18 breaths/minute, temperature 100.1F. The physical exam presents with non-tender abdominal palpation and no organomegaly; lungs sound vesicular bilateral, a cardiac exam revealed S1, S2 no murmurs. Throat exam revealed an erythematous oropharynx, no exudates, and tender cervical lymphadenopathy. Labs are ordered, and a spot urine test detects 8 mg/L porphobilinogen. Based on the patient's diagnosis, which medication should be discontinued due to the induction of Aminolevulinic acid synthetase?



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A 28-year-old Hispanic woman with a past medical history significant for genital herpes, treated syphilis, epilepsy, and drug abuse for the past 2 years is going into labor at 36 weeks. In the months before and during her pregnancy, she has complained about a loss of balance and drowsiness. Vitals of the mother includes Blood Pressure 100/75 mmHg, Temperature 98.6 F, Heart Rate 54 beats per minute, Respirations 9 breaths/minute. The Obstetrician suspects her abnormal vitals are a consequence of her drug abuse. Physical exam shows normal pupil size that exhibits direct and consensual response bilateral, cardio exam S1 S2 no murmurs, lung exam significant for shallow breaths bilateral, deep tendon reflexes intact bilateral. The genital exam reveals no active herpetic lesions on labia minora/majora or in the vaginal canal. The healed chancre scar from her past syphilis episode( treated 7 years ago with intramuscular penicillin G injection), was barely visible on left lower labia minora. Fetal heart rate monitor shows the baseline fetal heart rate at 110 beats/minute, variable decelerations, and moderate fetal heart rate variability. Based on the mother's history and physical exam, what features would most likely be exhibited with the newborn if delivered vaginally?



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Phenobarbital - References

References

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