A guiding review! Nembutal as Pentobarbital, dosage and uses with side-effects

A short-acting barbiturate that is known as the brand name of Nembutal is pentobarbital. It is a medication used by physicians to manage and treat several medical conditions like insomnia, intracranial pressure control, seizures, and sometimes as a pre-anesthetic in the operation theatre. A water-soluble chemical with an estimated vapor pressure of 3×10^-10   mm Hg. Since pentobarbital does not contain any chromophores to absorb wavelengths of light greater than 290m so it is not susceptible to photolysis. It can be removed from the atmosphere by wet or dry deposition as a particulate. Pentobarbital is not susceptible to hydrolysis due to the absence of functional hydrolyzable groups. It possesses low bioconcentration in aquatic organisms.

Pentobarbital is a barbiturate with a direct action on the central nervous system. It has different uses at different doses, as at low doses it may be prescribed for insomnia as short-term sedatives and as a pre-anesthetic for surgery. It may be used as an anti-convulsant for emergency seizure control or medically induced comas at higher studies. Pentobarbital and phenobarbital, another barbiturate may be compared in the use of refractory status epilepticus, a serious form of seizure that is hard to manage. Although pentobarbital is superior to all others with faster brain penetration and a short half-life and thus considered the treatment of choice.

Mechanism of action:

The central nervous system has several receptors where the drugs bind for their agonistic or antagonistic action to produce either stimulating actions or inhibiting actions. The receptors are of different types as enzyme receptors, ion-gated channels, voltage-gated channels, and second messenger receptors. One of the second messenger receptors to which pentobarbital binds is the gamma-aminobutyric acid (GABA)-A receptors. GABA-A receptors are dominated by chloride channels, once the pentobarbital binds with the GABA receptors, the chloride channels are stimulated and a change is induced in the chloride transport receptor due to which the duration of chloride channel opening increases thus potentiating GABA effects. The receptors are either inhibited or stimulated by binding with the drugs depending upon their neurotransmitters that are released bearing either inhibitory or stimulatory neurotransmitters. GABA is an inhibitory receptor that causes central nervous system depression by prolonging the chloride channel opening time thus intensifying depressant effects on the central nervous system. Glutamate, a stimulatory neurotransmitter is inhibited by the pentobarbital. Glutamate is responsible for nerve depolarization in the voltage-activated calcium currents, so inhibiting glutamate intimates an additive effect on central nervous system depression.

Administering pentobarbital; how to give?

There are three routes of administration of pentobarbital, intravenous, intramuscular, or oral route. The intravenous route of administration is highly beneficial to be administered for direct and quick action as it overrules and bypasses the liver route avoiding the first-pass effect. An approximate dose of 50mg/ minute is administered by slow injection in the undiluted form. It must be administered with extreme precaution in this case to avoid tissue extravasation. Rapid intravenous injection of such a potent central nervous system acting drug can also cause hypotension (sudden low blood pressure), bronchospasm, and respiratory depression by sudden infusion so this route must be avoided until very necessary. Intramuscularly 5mL of pentobarbital is to be injected into a large muscle to avoid necrosis or tissue irritation. Oral administration of pentobarbital by mixing the drug with a flavored syrup for taste improvement may be a good choice for the pediatric population.

How to monitor pentobarbital administered?

Many parameters are to be determined while administering pentobarbital through either route of administration. These parameters may include electroencephalogram (EEG), complete blood count (CBC), serum drug levels, blood urea nitrogen (BUN) to creatinine ratio, liver function tests (LFTs), etc. The therapeutic window of the drug that is the difference between the therapeutic dose of the drug and its toxic dose is very narrow. Slight overdose can produce fatal results due to its action on the central nervous system including the brain and neurons.

In adults, the toxicity level of the dose of pentobarbital may be achieved by almost only one gram, and death may be caused by two to ten grams. Intended therapeutic desire may determine the therapeutic value that might be effective for the purpose. For instance, 1 to 5 mcg/mL is prescribed to create sedation. Almost 30 to 40mcg/mL is prescribed for intracranial pressure therapy and 20 to 50 mcg/mL for therapeutic coma. Steady-state concentration may be achieved in adults in approximately three to six days.

Drug act laws have considered and referred to pentobarbital as a high-risk-habit-forming drug. If used for a long term in high doses on daily basis, e.g. more than 400 mg daily for more than 90 days may create a threshold for developing a dependence phase. The dependence phase (physical and mental), tolerance, and psychological effects are a few of the warnings against the long-term use of pentobarbital. Time duration and dose are the inter-related parameters to estimate the long-term effects of the drug on patients as exceeding the dose from 400 to 600 or 800 mg and reducing the duration from 90 days to 35 days may correlate with withdrawal seizures.

Uses of pentobarbital administered:

Pentobarbital may have several uses and advantages in humans as well as animals which makes it an important class of drug. These may include:

Uses for Humans:

General indications for uses in humans are:

• Sedative and hypnotic: Pentobarbital may be used as a sedative or hypnotic for short-term sleep management or long-term sleep management. It may act by acting on the sleep-activating neurotransmitters, inhibiting the stimulating neurotransmitters, and potentiating the sleep-initiating neurotransmitters.
• Pre-anesthetic medication: Pentobarbital may be used as a pre-medication in anesthetic procedures whereby it may potentiate dopamine and other inhibitory neurotransmitters thereby reducing the flow of neurotransmitters and thus potentiating sleep or unconsciousness before administering proper anesthesia.
• Anti-epileptic and anti-seizure: Epileptic conditions may prevail as idiopathic or secondary to some underlying neurological issues. Seizures representing the stages of epilepsy may either be simple, partial, or complex-generalized seizures anticipating its effects as a less severe manifestation of petit-mal seizure, infantile seizure, or a more serious impact as status epilepticus that imparts emergency. In such emergency cases of convulsive episodes, pentobarbital is approved by FDA, as in convulsions associated with cholera, eclampsia (state of high blood pressure creating fits especially during gestation), tetanus (may have created suddenly from grass, etc.), status epilepticus (long duration of fits and seizures creating stretched lying body for long), toxic reactions to strychnine ( a neurotoxin that may cause spastic muscle contractions by inhibiting glycine or acetylcholine) or local anesthetics (Lidocaine, etc. creating numbness in a localized area).
• Reduce intracranial pressure: Cranium is the part of the central nervous system referred to as the brain. An increase in the intracranial pressure caused by nonfatal submersion or traumatic/non-traumatic injury may be treated by pentobarbital.

Uses for Animals:

General indications for uses in animals are:

• Anesthetic: Pentobarbital by intra-peritoneal route of administration is given to small laboratory animals as mouse and rats as an anesthetic during experimental procedures.
• Anti-convulsant: Pentobarbital may be given to relieve convulsive seizures especially if caused by strychnine.

Off-label Uses:

Indications for some off-label uses of pentobarbital are:

• Against intracranial pressure: Pentobarbital may be used off-label for control of intracranial pressure in patients with cerebral ischemia (when oxygen level reaching the brain is reduced to a great extent), severe brain injuries, and in those receiving treatment for Reye syndrome.
• A punishment drug: Pentobarbital may be used as an off-label drug for capital punishment in certain states or prisons but still it’s under controversy.
• Anesthesia and euthanasia: Pentobarbital may be used by veterinarians for euthanasia and anesthesia in animals.

Adverse Effects of Pentobarbital:

The main adverse effects of pentobarbital use are related to the central nervous system. The adverse effects may include:

Confusion: The patient may feel confused due to overdosage and be unable to decide anything for him or her.

 Drowsiness: The patient may remain drowsy or dizzy for a long time and be prohibited from driving, teaching, or attending anything important to avoid any risk.

 Respiratory depression: One may suffer from shortness of breath and suffering from dyspnea.

Agitation: the patient may feel agitated, in rage, and behaving abruptly.

Bradycardia: Heart rate may slow down due to continuous use of pentobarbital.

Cardiovascular collapse: Cardiovascular collapse may happen due to extreme slowing down and low blood pressure

Syncope: Sudden fainting of the patient may occur due to low blood pressure and a low amount of oxygen reaching the brain.

Contraindications of Pentobarbital:

Pentobarbital is contraindicated in people with a previous history of hypersensitivity reactions to any barbiturate class or any other drug use. Patients with a history of depressed respiratory functions or porphyria must avoid pentobarbital. It must be used with caution in people with hepatic impairment, renal dysfunction, or in the elderly. Related to gestation, it is strictly prohibited and contraindicated during pregnancy and breastfeeding.

Pentobarbital is classified as a category D drug for use in pregnancy since it has shown fatal fetal damages since it can cross the placental barrier easily to be distributed in the fetal tissue with the highest concentration in the brain, placenta, and liver. In the cases where mothers were addicted to barbiturates during pregnancy, the infants of such mothers should be closely monitored for hyperirritability and seizures.

Toxicity of Pentobarbital:

Pentobarbital toxicity may occur due to abrupt withdrawal of high dose intake or low dose for a long time etc. Neurological manifestations including speech alteration and gait abnormalities are the symptoms of acute intoxication while in chronic cases, the symptoms may include agitation, confusion, and insomnia, and generalized myalgia. Withdrawal symptoms may vary and lessen with time as minor withdrawal may be seen within eight to twelve hours while major within sixteen hours lasting for more than one hundred and sixty-eight days.

Management of Pentobarbital Withdrawal:

Pentobarbital dependence may be treated by close monitoring and gradual withdrawal of the drug by small dosage decreases over many weeks. Since there is no antidote so supportive and palliative care is the basic line of action for the management of pentobarbital withdrawal. Overdose can sometimes lead to a non-compromised situation as airway compromise, cardiovascular collapse, coma, and death. Hemodynamic support with vasopressors, body temperature maintenance with warmers especially in ICU (intensive care unit) are the peak strategies to be followed. Alkaline diuresis or activated charcoal may be added but with a low benefit ratio.

Hepatic impairment or renal impairment are two of the important perspectives that must be taken into account while managing pentobarbital withdrawal. Although there is no proper dose adjustment for such patients still kidney functions and liver functions must be monitored while using higher doses of Nembutal or for prolonged use.

Interactions of Pentobarbital:

Pentobarbital requires close monitoring and checking while being prescribed for any of the above-mentioned uses to maintain its adequate therapeutic level. Pentobarbital has a chemical formula that has some interactions with several major classes of drugs due to which either its dose may get enhanced or decreased to a greater extent altering the therapeutic level desired for the cause. Barbiturates induce hepatic microsomal enzymes which thereby increase the rate of metabolism of other drugs metabolized by these hepatic enzymes, especially anti-coagulant drug as warfarin.

So special dose adjustment is unavoidable while taking such drugs together whereby drug-drug interaction is a great concern. Some hormones as estrogen, progesterone, estradiol, etc., and few drugs as corticosteroids, phenytoin, valproic acid, alcohol, monoamine oxidase inhibitors, etc. must be given with great caution and may be monitored for dose adjustments while prescribing along with pentobarbital.

Pentobarbital known as Nembutal is a barbiturate that needs proper prescription by the physician and it is not available as an over-the-counter drug. It may cause serious health hazards by any misuse of overdosage, withdrawal strategy, and drug-drug interactions due to its direct effect on the central nervous system. Although in some severe cases, it may be given with caution by adjusting the dose according to the situation with special care. It is used more often for euthanasia and anesthesia of laboratory animals intra-peritoneal.