PENTOBARBITAL SODIUM (Generic for NEMBUTAL SODIUM)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Extemporaneous Compounding-Oral
-Although details regarding stability are not available, the parenteral solution has been mixed in a 3:1 ratio with cherry syrup and given orally. In both of these studies, oral pentobarbital was better tolerated and as effective as the comparator (IV pentobarbital or chloral hydrate).



Injectable Administration
-IV administration is restricted to conditions in which other routes are not feasible (unconscious or noncooperative patients; conditions may include cerebral hemorrhage, status epilepticus, and delirium) or because prompt action is imperative.
-Parenteral solutions are very alkaline (pH = 9.5); avoid intra-arterial injection and extravasation.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Intermittent IV Injection
-Do not admix with any other medication or solution; administer undiluted.
-Slow IV injection is essential; do not exceed a rate of 50 mg/minute. Rapid IV injection may cause respiratory depression, apnea, laryngospasm, and hypotension.
-At least 1 minute is necessary to determine the full effect of intravenous pentobarbital.
-Monitor patients carefully during administration; monitor vital signs and take measures to maintain blood pressure, respiration, and cardiac function as needed. Equipment necessary for resuscitation and artificial ventilation should be readily available.

Continuous IV Infusion
-Administer the bolus over a minimum of 30 to 60 minutes. Increase administration time to reduce the risk of hypotension; larger doses may be given over 2 to 3 hours. Adjust infusion rate based on clinical response (e.g., seizure activity, intracranial pressure, cerebral perfusion pressure, blood pressure).
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 8 mg/mL or 50 mg/mL.
-Pentobarbital 0.6 mg/mL or 1.25 mg/mL in either 0.9% Sodium Chloride Injection or 5% Dextrose Injection was stable for 12 hours, and the use of a 0.45-micron filter did not affect the amount of pentobarbital that was delivered to a patient. In another compatibility study, pentobarbital concentrations less than 8 mg/mL in either 0.9% Sodium Chloride Injection or 5% Dextrose Injection were stable for 24 hours; precipitation was noted at higher pentobarbital concentrations.

Intramuscular Administration
-Inject deeply into a large muscle mass.
-Administer undiluted. While a maximum volume in pediatric patients has not been specified, FDA-approved labeling states that a volume of 5 mL at a single injection site not be exceeded in adults.

Pentobarbital is a CNS-depressant. It is used therapeutically as a sedative-hypnotic and in high doses to induce therapeutic coma in status epilepticus or traumatic brain injury. Reported CNS adverse effects and general CNS-depressant effects of pentobarbital include ataxia, confusion, drowsiness, dizziness, lethargy, headache, hallucinations, impaired cognition (abnormal thinking), vertigo, anxiety, weakness, and irritability. Hypnotic doses produce residual sedation, emotional lability, and motor skill impairment that can last for several hours. Children may experience more CNS reactions than other populations. Some children respond with paradoxical CNS stimulation (e.g., agitation, hyperactivity, nightmares, insomnia). Other CNS effects include hyperkinesis, nervousness, and psychiatric disturbances.

Apnea, respiratory depression, hypoventilation, bronchospasm, hypotension, sinus bradycardia, syncope, and vasodilation leading to circulatory collapse may occur with rapid intravenous (IV) administration of pentobarbital. IV doses should be given slowly at recommended infusion rates and the patient should be monitored frequently. Resuscitation equipment should be readily available during IV therapy. An injection site reaction, such as phlebitis or pain, is also possible during parenteral therapy with pentobarbital. Severe local reactions from inadvertent intra-arterial administration of pentobarbital have included pain, arterial spasm, and tissue necrosis (gangrene). Parenteral preparations are highly alkaline (pH = 9.5); extravasation should be avoided. To minimize the risk of tissue damage, intramuscular (IM) injections should not be given repeatedly at the same site. Subcutaneous administration is also not recommended as localized adverse effects, which range from slight erythema or irritation to serious reactions (tissue necrosis), may occur.

Hypersensitivity reactions, including angioedema, rash (unspecified), and exfoliative dermatitis have been reported in patients treated with pentobarbital. Anticonvulsant hypersensitivity syndrome, while not generally associated with pentobarbital because of its therapeutic use, can occur with barbiturate therapy. A hypersensitivity syndrome may present as various organ system problems, including blood, liver, renal, and skin disorders and usually occurs 2 weeks to 3 months after therapy initiation. Discontinuation of the drug may not be sufficient to reverse progression of a serious hypersensitivity reaction because of the slow metabolism and excretion of pentobarbital. Patients who have experienced such reactions due to barbiturate therapy should not be further exposed to the implicated drug. Hypersensitivity reactions may first appear as cutaneous reactions, that include scarlatiniform or morbilliform maculopapular rash and urticaria. Because skin eruptions may be indicators of serious sensitivity reactions, they should be investigated promptly, with consideration of drug discontinuation. Angioedema, bullous rash, exfoliative dermatitis, lupus-like symptoms, photosensitivity, purpura, serum sickness, Stevens-Johnson syndrome, or toxic epidermal necrolysis are relatively rare but serious adverse effects. Although uncommon, barbiturates have been reported to cause interstitial nephritis and liver damage including hepatitis and jaundice (with accompanying elevated hepatic enzymes). Blood dyscrasias (e.g., agranulocytosis, aplastic anemia, neutropenia, or thrombocytopenia) can also occur rarely during therapy. Periodic blood tests (CBC) may be considered with prolonged use of pentobarbital, but such tests are not considered mandatory. Symptoms such as unusual tiredness or weakness (asthenia), unusual bleeding or bruising (ecchymosis), and unexplained sore throat or fever should be investigated promptly.

Nausea, vomiting, and constipation have been reported during therapy with pentobarbital. Gastrointestinal effects are generally not severe.

Barbiturates are associated with vitamin D deficiency and decreased bone mineral density and may induce osteopenia or osteomalacia with long-term use. While such effects are generally associated with chronic phenobarbital use, bone development in pediatric patients is critical and those receiving prolonged pentobarbital infusions should be monitored. Unusual bone pain or tenderness should be investigated. Mild macrocytosis has been reported with barbiturate use in children; megaloblastic anemia has been reported rarely with chronic use. Barbiturates can exacerbate porphyria, causing a buildup of porphyrin precursors and enhancing porphyrin synthesis; pentobarbital is contraindicated for use in patients with a history of porphyria.

Ocular adverse reactions with barbiturates, like pentobarbital, occur most commonly after prolonged use or toxic doses. Miosis is seen most frequently, but mydriasis predominates during toxic states. Disturbances in ocular movement may be seen with weakness of the extraocular muscles and nystagmus. Ptosis has been reported after prolonged use.

Prolonged use of barbiturates, including pentobarbital, can result in tolerance, physiological dependence, and psychological dependence. Due to its limited use, pentobarbital dependence is more likely to occur in the setting of prolonged infusions in critically ill patients. Withdrawal symptoms usually occur within 8-12 hours of discontinuing the drug and may include mild symptoms such as anxiety, muscle twitching, tremor of hands, progressive weakness, dizziness, distortion of vision, insomnia, nausea/vomiting, and postural hypotension. Major manifestations of withdrawal include hallucinations, delirium, and seizures. After prolonged use of pentobarbital, the drug should be withdrawn gradually whenever possible. In addition, phenobarbital may be used as an alternative barbiturate to alleviate symptoms of withdrawal. Prolonged use of barbiturates during the third trimester may cause physical dependence and respiratory depression in the neonate. Neonatal withdrawal symptoms include hyperactivity, restlessness, disturbed sleep, tremor, and hyperreflexia. In this scenario, treatment of withdrawal may be achieved by administering phenobarbital and gradually tapering the dose downward.

Pentobarbital injection contains 40% propylene glycol. Case reports of propylene glycol toxicity in adult patients receiving high-dose pentobarbital infusions have described symptoms of lactic acidosis, hyperosmolality, hypotension, and acute renal failure (unspecified). In addition, excessive propylene glycol can cause tachypnea, sinus tachycardia, diaphoresis, cardiorespiratory arrest, and central nervous system toxicity (e.g., seizures, intraventricular hemorrhage). Neonates have a prolonged half-life of propylene glycol (16.9 hours) compared to adults (5 hours) and are therefore at greater risk for toxicity. If signs of propylene glycol toxicity are present, the drug should be discontinued and supportive measures taken.

Pentobarbital is contraindicated in patients with a history of barbiturate hypersensitivity. Injectable solutions may also contain propylene glycol and should be avoided in patients with a hypersensitivity to propylene glycol. Barbiturates are associated with the anticonvulsant hypersensitivity syndrome, which can cause severe and potentially fatal reactions that are preceded by skin eruptions. Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of adverse hematologic (i.e., agranulocytosis), hypersensitivity, or other adverse reactions to barbiturate or other anticonvulsants. Hypersensitivity reactions have been reported in patients who previously experienced hydantoin hypersensitivity (e.g., phenytoin) or carbamazepine hypersensitivity. Estimates of cross-sensitivity vary, but may range from 30% to 80%. Phenytoin, carbamazepine, and phenobarbital are all metabolized to hydroxylated aromatic compounds via the cytochrome P450 hepatic oxidative enzymes; arene oxide intermediates are formed during metabolism and are thought to be responsible for cross-sensitivity among these anticonvulsants in susceptible individuals. Some individuals may have a reduced ability to detoxify the intermediate toxic metabolites (e.g., arene oxides) of these anticonvulsants, which may be genetically mediated. However, studies of familial reactions have also shown that allergies to 1 anticonvulsant may not translate to allergies to others. There is no way to predict with certainty which patients will exhibit cross-sensitivity.

Avoid the use of pentobarbital in patients with acute or chronic pain, as paradoxical reactions (e.g., agitation and hyperactivity) may occur and mask important symptoms. Pediatric patients may be at particular risk for paradoxical reactions. It is important to note that use of pentobarbital as a sedative during the postoperative period and cancer chemotherapy is well established.

Intraarterial administration of pentobarbital should be avoided; severe localized reactions such as pain, spasm, or gangrene (tissue necrosis) may occur. Subcutaneous administration should also be avoided; the highly alkaline parenteral solution may cause localized injection reactions, ranging from slight irritation to tissue necrosis. Parenteral administration of barbiturates should be given cautiously to patients with hypertension, hypotension, cardiac disease, or other hemodynamically-unstable states (i.e., heart failure, shock). High dose intravenous (IV) pentobarbital has been used to induce coma, but may result in hypotension requiring vasopressor agents. Intravenous administration of pentobarbital sodium should generally be reserved for emergency settings; close supervision is necessary in a monitored unit. Do not exceed recommended IV infusion rates; too rapid IV administration may cause severe respiratory depression, apnea, laryngospasm, or vasodilation with hypotension.

Pentobarbital can cause dose-dependent respiratory depression and should be used with caution in patients with pulmonary disease or respiratory insufficiency including sleep apnea, chronic lung disease (CLD), or other obstructive pulmonary conditions. Avoid in patients with bronchopneumonia. Too rapid intravenous (IV) administration may cause severe respiratory depression, apnea, laryngospasm, or vasodilation with hypotension.

Pentobarbital should be used with caution in patients with a history of substance abuse because of the potential for psychological and/or physical dependence to the drug. Avoid abrupt discontinuation of pentobarbital after prolonged use to limit drug withdrawal. Sudden, abrupt discontinuation of pentobarbital in epileptic patients may precipitate acute seizures, status epilepticus, or other seizure disorders. When discontinuing therapy, a gradual dose reduction is recommended.

Pentobarbital may cause blurred vision, drowsiness, dizziness, or mental status changes, especially with initial use. Patients should use caution with activities requiring coordination and concentration (e.g., getting in and out of bed) until they are aware of the effects of the drug. Ethanol ingestion or concomitant use of other sedating drugs can magnify CNS depression and should be avoided. The lethal dose of a barbiturate is significantly less if alcohol is also ingested.

Pentobarbital is extensively metabolized in the liver. Those with hepatic disease may be at increased risk for developing drug toxicity and may require lower dosage and slower dosage titration. Because barbiturates are sedating and also may impair the ability of the liver to metabolize ammonia, barbiturates are best avoided in patients with hepatic encephalopathy.

Barbiturates should be used cautiously in patients with renal impairment. Although less than 1% of pentobarbital is excreted unchanged via the kidney, uremia can lead to increased CNS sensitivity and toxicity.

Pentobarbital, like other barbiturates, is contraindicated in patients with a history of manifest or latent porphyria. Pentobarbital can exacerbate this disease. Barbiturates can stimulate the activity of enzymes like ALA synthetase, causing a buildup of porphyrin precursors and enhancing porphyrin synthesis.

Use pentobarbital with caution in patients with low bone density. Barbiturates such as pentobarbital are associated with a loss of bone mineral density and there may be an increased risk of osteopenia/osteoporosis and osteomalacia with long-term barbiturate therapy.

Pentobarbital injection contains 40% propylene glycol and 10% alcohol. Pediatric patients, in particular premature neonates and term neonates may be more sensitive to these compounds. Excessive propylene glycol can cause lactic acidosis, hyperosmolality, tachypnea, tachycardia, diaphoresis, cardiorespiratory arrest, renal failure, and central nervous system toxicity (e.g., seizures, intraventricular hemorrhage). Monitor all patients requiring high doses or continuous infusions of pentobarbital for signs of propylene glycol toxicity; use pentobarbital with caution in neonates. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in neonates, infants, and children younger than 3 years, including fetal exposure during the third trimester, may have negative effects on brain development. Consider the benefits of appropriate anesthesia in young children against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required during the first 3 years of life. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development. All neonates with a history of in utero exposure to pentobarbital should be monitored carefully. Consistent in utero exposure during the third trimester can cause physical dependence and respiratory depression in the neonate. Acute symptoms of withdrawal and seizures may occur any time during the first 14 days of life.

Description: Pentobarbital is a short-acting parenteral barbiturate that produces sedation, hypnosis, and anticonvulsant activity in a dose-dependent manner. Compared to phenobarbital, pentobarbital has faster brain penetration and a shorter half-life, although accumulation may occur with prolonged administration. Pentobarbital's greatest role in critically-ill children is in the treatment of refractory status epilepticus or increased intracranial pressure (ICP). Traumatic brain injury guidelines recommend high-dose barbiturate therapy in hemodynamically stable patients with refractory ICP despite maximal medical and surgical management. Pentobarbital is also used as an alternative agent for sedation maintenance in children refractory to standard therapy (i.e., benzodiazepines, opioids), though there is limited published experience for this use. Historically, oral pentobarbital (not currently marketed in the US) was prescribed for the short-term treatment of insomnia, however this indication is no longer generally accepted due to adverse effects and lack of efficacy. In addition, barbiturates as sedatives have in general been replaced by benzodiazepines. Compared to benzodiazepines, barbiturates lack specificity of effect in the central nervous system, have a lower therapeutic index, higher frequency of tolerance, narrower margin of safety, and significant adverse events. Pentobarbital is often associated with respiratory depression, myocardial depression, hypotension, and low cardiac output; children may be more prone to these adverse effects. In addition, the parenteral solution has a basic pH (9.5) and is formulated with propylene glycol and alcohol; these characteristics can cause injection site reactions and create the potential for toxicity, particularly in neonates. Pentobarbital is FDA-approved for use in pediatric patients with no defined age range and has been used in patients as young as neonates.

-Pentobarbital dosage should be individualized based on the patient's age, weight, and condition. There is no average dose. The drug should be administered slowly in fractional doses to minimize the possibility of respiratory depression and overdose.
-IV administration is restricted to conditions in which other routes are not feasible (unconscious or noncooperative patients; conditions may include cerebral hemorrhage, persistent seizures, and delirium) or because prompt action is imperative.
-Monitor patients carefully during intravenous administration. Cardiac function (e.g., blood pressure, heart rate), and respiratory function should be maintained. Equipment for respiratory and ventilatory support should be available.
-Neonates and infants younger than 6 months may have delayed metabolism and elimination; start with lower initial doses and monitor closely for respiratory and cardiovascular depression.

For procedural sedation:
Intramuscular dosage:
Infants, Children, and Adolescents: 2 to 6 mg/kg/dose (Max: 100 mg/dose) IM; may give an additional 1 to 3 mg/kg/dose if adequate sedation is not achieved within 1 hour of administration.
Intravenous dosage*:
Neonates: Although neonatal-specific data are limited, 1 to 3 mg/kg/dose IV every 1 to 5 minutes as needed has been reported; Max cumulative dose: 2 to 6 mg/kg.
Infants, Children, and Adolescents: 1 to 3 mg/kg/dose (Max: 100 mg/dose) IV every 1 to 5 minutes as needed; Max cumulative dose: 6 mg/kg or 200 mg, whichever is less. Supplementary doses of 1 to 3 mg/kg may be required to maintain adequate sedation for imaging procedures. Patients receiving barbiturates for medical therapy may receive as much as 9 mg/kg total dose.
Oral dosage:
NOTE: Oral capsules are no longer commercially available in the US. Although details regarding stability are not available, the parenteral solution has been mixed in a 3:1 ratio with cherry syrup and given orally. In these studies, oral pentobarbital was better tolerated and as effective as the comparator (IV pentobarbital or chloral hydrate).
Infants: 4 mg/kg/dose PO once; may give additional doses of 2 to 4 mg/kg/dose every 30 minutes as needed for adequate sedation. Max cumulative dose: 6 to 8 mg/kg. FDA-approved labeling recommends 2 to 6 mg/kg/24 hours and dependent on age, weight, and degree of desired sedation.
Children 1 to 3 years: 3 to 6 mg/kg/dose (Max: 100 mg/dose) PO once. Max cumulative dose: 6 mg/kg or 200 mg, whichever is less. FDA-approved labeling recommends 2 to 6 mg/kg/24 hours and dependent on age, weight, and degree of desired sedation.
Children and Adolescents 4 to 17 years: 1.5 to 4 mg/kg/dose (Max: 100 mg/dose) PO once. Max cumulative dose: 6 mg/kg or 200 mg, whichever is less. FDA-approved labeling recommends 2 to 6 mg/kg/24 hours and dependent on age, weight, and degree of desired sedation.

For the treatment of refractory status epilepticus:
Intravenous dosage:
Neonates: 5 to 15 mg/kg/dose IV as a single dose, then by 1 mg/kg/hour continuous IV infusion, initially. Titrate by 0.5 to 1 mg/kg/hour every 12 hours for breakthrough status epilepticus; may also consider additional 5 to 10 mg/kg/dose IV as a single dose if needed. Usual dose: 0.5 to 5 mg/kg/hour. Maintain EEG burst suppression for 12 to 48 hours before tapering the infusion. Guidelines recommend continuous IV infusion of pentobarbital for refractory status epilepticus.
Infants, Children, and Adolescents: 5 to 15 mg/kg/dose IV as a single dose, then 1 mg/kg/hour continuous IV infusion, initially. Titrate by 0.5 to 1 mg/kg/hour every 12 hours for breakthrough status epilepticus; may also consider additional 5 to 10 mg/kg/dose IV as a single dose if needed. Usual dose: 0.5 to 5 mg/kg/hour. Maintain EEG burst suppression for 12 to 48 hours before tapering the infusion. Guidelines recommend continuous IV infusion of pentobarbital for refractory status epilepticus.

For the reduction of increased intracranial pressure (ICP)* in patients with traumatic brain injury (i.e., head trauma)*:
Intermittent Intravenous dosage:
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 4 to 6 hours has been suggested; titrate as needed to treat elevated ICP. Mechanical ventilation required. Some experts suggest this lower dose may be effective and avoid hypotensive effects; data suggests complete burst suppression on EEG may not be necessary for pentobarbital's protective effects. Of note, traumatic brain injury guidelines recommend high-dose barbiturate therapy in hemodynamically stable patients with refractory ICP despite maximal medical and surgical management.
Continuous Intravenous Infusion dosage:
Children and Adolescents: 10 mg/kg IV load over 30 minutes, then 5 mg/kg/dose IV every 3 hours for 3 doses, then a continuous infusion of 1 mg/kg/hour IV. Titrate infusion to clinical response; dosage range = 1 to 2 mg/kg/hour. Mechanical ventilation required. The goal is an induced coma state characterized by absent brainstem reflexes and suppression of the EEG. Monitor ICP, mean arterial pressure, cerebral perfusion pressure, and EEG burst suppression. Taper pentobarbital after 24 hours of controlled ICP. Traumatic brain injury guidelines recommend high-dose barbiturate therapy in hemodynamically stable patients with refractory ICP despite maximal medical and surgical management.

For sedation maintenance* and to alleviate agitation* and anxiety* in patients refractory to standard therapy who are mechanically-ventilated:
Continuous Intravenous Infusion dosage:
Infants, Children, and Adolescents: 1 to 2 mg/kg IV load, then 1 to 2 mg/kg/hour continuous IV infusion. May administer bolus doses equivalent to the hourly rate of infusion every 2 hours as needed; if 4 to 6 boluses or more are needed in a 24-hour period, increase infusion rate by 1 mg/kg/hour. Titrate to adequate sedation; reported range: 1 to 6 mg/kg/hour (median range 2 mg/kg/hour). Monitor blood pressure. Gradually taper infusion or convert to an oral barbiturate (e.g., phenobarbital) after prolonged therapy to avoid symptoms of withdrawal. Pentobarbital therapy is an alternative option for sedation in those who fail standard therapy; significant complications including hypotension, oversedation, neurologic sequelae, and drug reaction limit its use.

For the treatment of insomnia:
Intramuscular dosage:
Infants, Children, and Adolescents: 2 to 6 mg/kg/dose (Max: 100 mg) IM at bedtime. Guidelines no longer recommend barbiturates for the treatment of insomnia.

Therapeutic Drug Monitoring:
-The serum concentration at which toxicity occurs varies; results should be interpreted in light of the clinical situation. In general, serum concentrations >= 10 mcg/ml are considered toxic.
-For treatment of status epilepticus or increased intracranial pressure (ICP), the goal is an induced coma state characterized by absent brainstem reflexes and EEG suppression.
-Pentobarbital serum concentrations associated with EEG suppression are generally in the range of 20-50 mcg/ml. Pentobarbital should be dosed based on clinical response.

Maximum Dosage Limits:
-Neonates
Specific maximum dosage information not available; individualize dosage based on clinical parameters and serum pentobarbital concentrations. For sedation, doses above 6 mg/kg/dose IV are not usually necessary.
-Infants
Specific maximum dosage information not available; individualize dosage based on clinical parameters and serum pentobarbital concentrations. For sedation, doses above 6 mg/kg/dose IM/IV and 8 mg/kg/dose PO (Max: 100 mg/dose and 200 mg cumulative) are not usually necessary.
-Children
Specific maximum dosage information not available; individualize dosage based on clinical parameters and serum pentobarbital concentrations. For sedation, doses above 6 mg/kg/dose IM/IV/PO (Max: 100 mg/dose and 200 mg cumulative) are not usually necessary.
-Adolescents
Specific maximum dosage information not available; individualize dosage based on clinical parameters and serum pentobarbital concentrations. For sedation, doses above 6 mg/kg/dose IM/IV/PO (Max: 100 mg/dose and 200 mg cumulative) are not usually necessary.

Patients with Hepatic Impairment Dosing
Use with caution at reduced doses in hepatic impairment; specific guidelines for dosage adjustments are not available. Avoid use in patients with hepatic encephalopathy.

Patients with Renal Impairment Dosing
The manufacturer recommends reduced dosage in renal impairment due to increased barbiturate sensitivity; specific guidelines for dosage adjustments are not available.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: In general, barbiturates are non-selective central nervous system (CNS) depressants with sedative-hypnotic actions. All barbiturates confer anticonvulsant activity in anesthetic doses, however, only certain barbiturates (e.g., phenobarbital) are effective in subhypnotic doses. Pentobarbital, like other barbiturates, may cause CNS depression in various degrees ranging from mild sedation to general anesthesia or coma. With sufficient intoxication (i.e., overdose), all barbiturates may induce peripheral and central depression of respiratory drive, a fall in blood pressure, cardiovascular compromise, and other effects.

Anticonvulsant actions
Pentobarbital inhibits the spread of seizure activity in the cortex, thalamus, and limbic systems, and increases the threshold for electrical stimulation of the motor cortex. There is a decrease in both pre- and postsynaptic excitability. The inhibition of seizure activity occurs primarily at synapses where GABA and GABA-A receptors mediate neurotransmission. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes; GABA-A is the primary receptor subtype in the CNS. Barbiturates augment GABA responses by promoting the binding of GABA to the receptor and increasing the length of time that chloride channels are open. Pentobarbital, unlike phenobarbital, appears to have direct GABA-mimetic properties, causing neuronal hyperpolarization by increasing chloride conductance even in the absence of GABA. Pentobarbital is a more potent enhancer of GABA responses and a more potent inhibitor of calcium currents than phenobarbital. Pentobarbital is also less selective in blocking abnormal paroxysmal discharges than phenobarbital. The differences in pharmacology probably explain why phenobarbital displays anticonvulsant activity with minimal sedation versus pentobarbital, which produces marked sedation and CNS depression at anticonvulsant dosages.

Hypnotic effects
The sedative-hypnotic effects of pentobarbital are related to its inhibition of ascending conduction in the reticular formation, which controls CNS arousal. This inhibition depresses the sensory cortex, decreases motor activity, alters cerebral function, and produces drowsiness, sedation, and hypnosis. It has also been suggested the sedative-hypnotic effects of barbiturates may be due to their ability to mimic the inhibitory synaptic action of GABA. In the presence of pain, the ability of the barbiturates to produce sedation may be reduced. During chronic administration, tolerance to sedative-hypnotic effects occurs quickly within a few days' time and the effects may be significantly reduced within 2 weeks of use. The development of tolerance indicates that barbiturates should only be considered for short term relief for acute sedation.

Other actions
Unlike most other barbiturates, high doses of pentobarbital protect the brain from ischemia and intracranial pressure (ICP), possibly by exerting an anesthetic action in the brain. Though the exact mechanism is unclear, it has been suggested barbiturates lower ICP by reducing cerebral blood flow and cerebral metabolic rate of oxygen, therefore decreasing metabolic demand and altering cerebrovascular tone.

Tolerance, abuse, and dependence
Tolerance to barbiturates often confers tolerance to all CNS-depressant drugs (e.g., ethanol, others). As with other CNS-depressant drugs, selected individuals may abuse or become physically and psychologically dependent on barbiturates. Some patients may experience euphoria or paradoxic excitement with use. Tolerance generally develops to the effects on mood, sleep, and sedation but not to anticonvulsant or lethal effects.

Pharmacokinetics: Pentobarbital is administered orally, parenterally, and rectally. Pentobarbital is a weak acid that is rapidly distributed to all tissues and fluids with high concentrations in the brain, liver, and kidneys. The drug distributes throughout the body, with about 35% to 45% of a dose bound to plasma proteins in the blood. In adults, the volume of distribution of the central compartment (Vdc) is approximately 0.45 L/kg and the volume of distribution (Vd) at steady state is approximately 1 L/kg. Due to the small Vdc, initial concentrations following IV bolus administration or rapid infusions are relatively high, which can result in significant hypotension or cardiac arrhythmias. Metabolism takes place in the liver via oxidation and glucuronidation. Microsomal enzymes involved in the metabolism of other drugs may be induced by pentobarbital, but there is no clear evidence that it accelerates its own metabolism. Plasma clearance appears to be variable among subjects and may increase during prolonged therapy; mean clearance during high dose continuous infusion was 0.72 mL/kg/minute, as demonstrated in adult brain injury patients. Mean plasma half-life is approximately 22 hours in adults; range of 15 to 50 hours have been reported. Half-life appears to be dose-dependent. Excretion occurs through the urine, mainly as glucuronide conjugates of metabolites, with negligible amounts excreted as unchanged drug.


-Route-Specific Pharmacokinetics
Oral Route
Oral pentobarbital is approximately 95% bioavailable. The onset of action of pentobarbital is 15 to 60 minutes after oral administration. Duration of sedative effect is 30 minutes to 4 hours. Food may reduce the rate but not the extent of pentobarbital absorbed, delaying the onset of action.

Intravenous Route
The onset of action of pentobarbital is almost immediate, within 1 to 5 minutes after intravenous administration. Duration of sedative effect is 15 to 45 minutes.

Intramuscular Route
The onset of action of pentobarbital is 10 to 15 minutes after intramuscular administration. Duration of sedative effect is 1 to 2 hours.

Other Route(s)
Rectal Route
The onset of action of pentobarbital is 15 to 60 minutes after rectal administration. Duration of sedative effect is 1 to 4 hours.


-Special Populations
Pediatrics
Neonates, Infants, Children, and Adolescents
Pharmacokinetic data in children is limited. In a study of hypothermic brain-injured children (ages 5 months to 15 years), pentobarbital Vd was 0.8 L/kg after high-dose continuous infusion. Hypothermic effects on drug disposition most likely contributed to the reduction of both distribution and clearance from normothermic adult values, as hypothermia is known to reduce cardiac output and affect regional blood flow. Neonates, infants, and children receiving intermittent doses of pentobarbital after open-heart surgery had a Vd of 0.45 L/kg in the central compartment and 0.98 L/kg in the peripheral compartment, making total Vd 1.4 L/kg. Mean plasma clearance was 2 mL/kg/minute. The typical infant in the trial had 2-ventricle physiology, a median weight of 6.9 kg, mean age of 5.2 months, and a median bypass grafting time of 1 hour. Data suggested maturation-related increases in clearance until 12 months of age, independent of weight. Bypass grafting time may affect both distribution and clearance in cardiac patients. The elimination half-life in pediatric patients is 25.5 +/- 16 hours.