Nembutal (Pentobarbital Sodium) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

Data from one retrospective study of 235 children in which the types of barbiturates are not identified suggested an association between exposure to barbiturates prenatally and an increased incidence of brain tumor. (Gold, E., et al., “Increased Risk of Brain Tumors in Children Exposed to Barbiturates,” Journal of National Cancer Institute, 61:1031-1034, 1978).

OVERDOSAGE

The toxic dose of barbiturates varies considerably. In general, an oral dose of 1 gram of most barbiturates produces serious poisoning in an adult. Death commonly occurs after 2 to 10 grams of ingested barbiturate. Barbiturate intoxication may be confused with alcoholism, bromide intoxication, and with various neurological disorders.

Acute overdosage with barbiturates is manifested by CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may show paralytic dilation), oliguria, tachycardia, hypotension, lowered body temperature, and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur.

In extreme overdose, all electrical activity in the brain may cease, in which case a “flat” EEG normally equated with clinical death cannot be accepted. This effect is fully reversible unless hypoxic damage occurs. Consideration should be given to the possibility of barbiturate intoxication even in situations that appear to involve trauma.

Complications such as pneumonia, pulmonary edema, cardiac arrhythmias, congestive heart failure, and renal failure may occur. Uremia may increase CNS sensitivity to barbiturates. Differential diagnosis should include hypoglycemia, head trauma, cerebrovascular accidents, convulsive states, and diabetic coma. Blood levels from acute overdosage for some barbiturates are listed in Table 1.

Table 1.— Concentration of Barbiturate in the Blood Versus Degree of CNS Depression

		Blood barbiturate level in ppm (μg/mL)
Barbiturate	Onset/duration	Degree of depression in nontolerant persons*
		1	2	3	4	5
*Categories of degree of depression in nontolerant persons:
Under the influence and appreciably impaired for purposes of driving a motor vehicle or performing tasks requiring alertness and unimpaired judgment and reaction time. Sedated, therapeutic range, calm, relaxed, and easily aroused. Comatose, difficult to arouse, significant depression of respiration. Compatible with death in aged or ill persons or in presence of obstructed airway, other toxic agents, or exposure to cold. Usual lethal level, the upper end of the range includes those who received some supportive treatment.
Pentobarbital	Fast/short	≤2	0.5 to 3	10 to 15	12 to 25	15 to 40
Secobarbital	Fast/short	≤2	0.5 to 5	10 to 15	15 to 25	15 to 40
Amobarbital	Intermediate/Intermediate	≤3	2 to 10	30 to 40	30 to 60	40 to 80
Butabarbital	Intermediate/Intermediate	≤5	3 to 25	40 to 60	50 to 80	60 to 100
Phenobarbital	Slow/long	≤10	5 to 40	50 to 80	70 to 120	100 to 200

Treatment of overdosage is mainly supportive and consists of the following:

1. Maintenance of an adequate airway, with assisted respiration and oxygen administration as necessary.
2. Monitoring of vital signs and fluid balance.
3. Fluid therapy and other standard treatment for shock, if needed.
4. If renal function is normal, forced diuresis may aid in the elimination of the barbiturate. Alkalinization of the urine increases renal excretion of some barbiturates, especially phenobarbital, also aprobarbital and mephobarbital (which is metabolized to phenobarbital).
5. Although not recommended as a routine procedure, hemodialysis may be used in severe barbiturate intoxications or if the patient is anuric or in shock.
6. Patient should be rolled from side to side every 30 minutes.
7. Antibiotics should be given if pneumonia is suspected.
8. Appropriate nursing care to prevent hypostatic pneumonia, decubiti, aspiration, and other complications of patients with altered states of consciousness.

CONTRAINDICATIONS

Barbiturates are contraindicated in patients with known barbiturate sensitivity. Barbiturates are also contraindicated in patients with a history of manifest or latent porphyria.

DRUG ABUSE AND DEPENDENCE

Pentobarbital sodium injection is subject to control by the Federal Controlled Substances Act under DEA schedule II.

Barbiturates may be habit forming. Tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high doses of barbiturates. Daily administration in excess of 400 milligrams (mg) of pentobarbital or secobarbital for approximately 90 days is likely to produce some degree of physical dependence. A dosage of from 600 to 800 mg taken for at least 35 days is sufficient to produce withdrawal seizures. The average daily dose for the barbiturate addict is usually about 1.5 grams. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than two-fold. As this occurs, the margin between an intoxicating dosage and fatal dosage becomes smaller.

Symptoms of acute intoxication with barbiturates include unsteady gait, slurred speech, and sustained nystagmus. Mental signs of chronic intoxication include confusion, poor judgment, irritability, insomnia, and somatic complaints.

Symptoms of barbiturate dependence are similar to those of chronic alcoholism. If an individual appears to be intoxicated with alcohol to a degree that is radically disproportionate to the amount of alcohol in his or her blood the use of barbiturates should be suspected. The lethal dose of a barbiturate is far less if alcohol is also ingested.

The symptoms of barbiturate withdrawal can be severe and may cause death. Minor withdrawal symptoms may appear 8 to 12 hours after the last dose of a barbiturate. These symptoms usually appear in the following order: anxiety, muscle twitching, tremor of hands and fingers, progressive weakness, dizziness, distortion in visual perception, nausea, vomiting, insomnia, and orthostatic hypotension. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Individuals susceptible to barbiturate abuse and dependence include alcoholics and opiate abusers, as well as other sedative-hypnotic and amphetamine abusers.

Drug dependence to barbiturates arises from repeated administration of a barbiturate or agent with barbiturate-like effect on a continuous basis, generally in amounts exceeding therapeutic dose levels. The characteristics of drug dependence to barbiturates include: (a) a strong desire or need to continue taking the drug; (b) a tendency to increase the dose; (c) a psychic dependence on the effects of the drug related to subjective and individual appreciation of those effects; and (d) a physical dependence on the effects of the drug requiring its presence for maintenance of homeostasis and resulting in a definite, characteristic, and self-limited abstinence syndrome when the drug is withdrawn.

Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. In all cases withdrawal takes an extended period of time. One method involves substituting a 30 mg dose of phenobarbital for each 100 to 200 mg dose of barbiturate that the patient has been taking. The total daily amount of phenobarbital is then administered in 3 to 4 divided doses, not to exceed 600 mg daily. Should signs of withdrawal occur on the first day of treatment, a loading dose of 100 to 200 mg of phenobarbital may be administered IM in addition to the oral dose. After stabilization on phenobarbital, the total daily dose is decreased by 30 mg a day as long as withdrawal is proceeding smoothly. A modification of this regimen involves initiating treatment at the patient’s regular dosage level and decreasing the daily dosage by 10 percent if tolerated by the patient.

Infants physically dependent on barbiturates may be given phenobarbital 3 to 10 mg/kg/day. After withdrawal symptoms (hyperactivity, disturbed sleep, tremors, hyperreflexia) are relieved, the dosage of phenobarbital should be gradually decreased and completely withdrawn over a 2-week period.