2. Barbituric acid
Barbiturates were synthesized in 1864 by Adolf von Baeyer, though
the synthetic process was developed and perfected by the French
chemist Edouard Grimaux in 1879, making possible the subsequent
widespread development of barbiturate derivatives.
The first of the barbiturates to come onto the market was diethyl-
barbituric acid, also known as barbital, since then barbiturates were
used extensively as sedative-hypnotic drugs.
Except for a few specialized uses, they have been largely replaced
by the much safer benzodiazepines and non-benzodiazepine sedative
compounds.
Barbituric acid is 2,4,6-trioxohexahydropyrimidine, In general,
structural changes that increase lipid solubility decrease duration of
action, decrease latency to onset of activity, accelerate metabolic
degradation, and increase hypnotic potency.
Introduction
3. Classification
They often are divided into four major groups according to
their pharmacologic activity and clinical use:
o ultra–short-acting
o short-acting
o intermediate- acting
o long-acting
4.
5. Therapeutic uses
1. Anesthesia: The ultra–short-acting barbiturates, such as
thiopental.
2. Anticonvulsant: Phenobarbital is used in long-term
management of tonic–clonic seizures. Similarly, phenobarbital
may be used for the treatment of refractory status epilepticus.
3. Sedative/hypnotic:. When used as hypnotics, they suppress
REM sleep more than other stages, Butalbital is commonly used
in combination products (with acetaminophen and caffeine or
aspirin and caffeine) as a sedative to assist in the management of
tension-type or migraine headaches
Surgery Sleep Epilepsy
Short-acting Intermediate-acting Long-acting
6. Mechanism of action
Enhancement of inhibition occurs primarily at
synapses where neurotransmission is mediated by
GABA acting at GABA-A receptors.
Barbiturates bind to a distinct allosteric site on the
GABA-A receptor; binding leads to an increase in the
mean open time of the GABA-activated Cl- channel,
with no effect on frequency. At higher concentrations,
barbiturates directly activate channel opening, even
in the absence of GABA
7. Side effect
Profound sedation, mental dulling, memory impairment, mood
changes and respiratory depression. With chronic therapy, tolerance
can develop within weeks, The effects on CYP450 vary with the
duration of exposure to the barbiturate.
- Acute exposure: barbiturates interact with several CYPs and
inhibit the biotransformation of a number of other drugs and
endogenous substrates, such as steroids; other substrates may
reciprocally inhibit barbiturate biotransformations.
- Chronic administration markedly increases the protein and lipid
content of the hepatic smooth endoplasmic reticulum, as well as
the activities of glucuronyl transferase and CYPs 1A2, 2C9, 2C19,
and 3A4. leading to increases in the metabolism of a number of
drugs and endogenous substances.
8. Route of exposure
Typically, the route of exposure is oral through ingesting
tablets unintentionally or even intentionally in suicidal
attempts, other routes include intravenous and
intramuscular injections.
9. Toxic dose
The toxic dose of barbiturates varies widely and depends on the
drug, the route and rate of administration, and individual patient
tolerance. In general, toxicity is likely when the dose exceeds 5–
10 times the hypnotic dose.
Chronic users or abusers may have striking tolerance to
depressant effects.
A. The potentially fatal oral dose of the shorter-acting agents
such as pentobarbital is 2–3 g, compared with 6–10 g for
phenobarbital.
B. Several deaths were reported in young women undergoing
therapeutic abortion after they received rapid IV injections of as
little as 1–3 mg of methohexital per kilogram.
10. Diagnosis
o History of ingestion
o Skin bullae (sometimes and non-specific)
o Exclusion of other sedative-hypnotic agents, narcotics, alcohol
intoxication or overdose of TCAs, trazodone and antipsychotics,
o Carbon monoxide poisoning, head trauma, CNS infections, sepsis,
hypoglycemia, electrolyte abnormalities, and hypothermia may
present similarly to barbiturate overdose and must be excluded.
o Specific plasma levels concentrations greater than 60–80 mg/L are
usually associated with coma, and those greater than 150–200 mg/L
with severe hypotension. For short- and intermediate-acting
barbiturates, coma is likely when the serum concentration exceeds
20–30 mg/L.
o Other useful laboratory studies include electrolytes, glucose, BUN,
creatinine, arterial blood gases or pulse oximetry, and chest
radiography.
11. Mechanism of toxicity
All barbiturates cause generalized depression of neuronal
activity in the brain. Interaction with a barbiturate receptor
leads to enhanced gamma aminobutyric acid (GABA)–mediated
chloride currents and results in synaptic inhibition.
Hypotension that occurs with large doses is caused by
depression of central sympathetic tone as well as by direct
depression of cardiac contractility.
This also leads to depression in both the respiratory drive
and the mechanisms responsible for the rhythmic character of
respiration. The oxybarbiturates tend to decrease the tone of
the GI musculature and the amplitude of rhythmic
contractions.
12. Toxicokinetics
Vary by agent and group; depending on the lipid solubility and rate of
metabolic inactivations; the onset of action ranges from 20 to 60
minutes if taken orally, and 5 minutes if taken intravenously.
1. Ultra–short-acting barbiturates are highly lipid soluble and rapidly
penetrate the brain to induce anesthesia, then are quickly redistributed
to other tissues. For this reason, the duration of effect is much shorter
than the elimination half-life for these compounds.
2. Long-acting barbiturates like phenobarbital: phenobarbital is only
partially converted and can be found unchanged in the urine. It is a long-
acting, polar drug that is slowly absorbed and slowly redistributed,
contributing to its longer duration of action. they easily cross the
placenta and are excreted into breast milk, and abrupt cessation of
these barbiturates while taking a beta blocker could increase the effect
of the beta blocker or cause frank toxicity.
13. Clinical manifestations (1)
Significant ingestion of barbiturates is life threatening and
typically presents as a depressed level of consciousness ranging
from lethargy to deep coma. Patients may also have respiratory
depression, which is responsible for most deaths that occur.
With the short- and intermediate-acting barbiturates,
symptoms usually begin within 1 hour of ingestion, and peak
effects are seen within 4 to 6 hours. Patients with chronic lung
disease are more susceptible to respiratory depression, even at
therapeutic doses.
Other clinical findings in overdose include hypothermia,
sluggish papillary light reflex, nystagmus, and diminished bowel
sounds. Bullous skin lesions, occasionally referred to as “coma
blisters,” may appear on shoulders, hands, buttocks, and knees.
About 40% of patients who present with severe toxicity develop
aspiration pneumonia.
14. Clinical manifestations (2)
Cardiovascular collapse may be manifested by bradycardia or
tachycardia, hypotension, and shock. Drug-induced dilatation of
capacitance vessels (venous circulation) with consequent
pooling of blood and reduction in effective vascular volume can
lead to shock. Other complications include rhabdomyolysis and
acute tubular necrosis secondary to shock and a mixed
respiratory and metabolic acidosis.
Ethanol and barbiturates have synergistic effects, and there is
increased toxicity even when lesser amounts are ingested.
Chronic use of barbiturates leads to tolerance and physical
dependence as well as withdrawal symptoms when the drug is
discontinued. Tolerance can develop with prolonged use and
abuse, the withdrawal state is similar to ethanol withdrawal.
15. Management (1)
Treatment of barbiturate toxicity remains supportive as
there is no specific antidote for overdose. Patients with
depressed respirations and altered mental status require
airway management and intubation to support breathing and
protect the airway. Blood pressure should be supported
initially with intravenous crystalloid, administering 500- to
1,000 mL boluses, and with close monitoring of response.
The core temperature should be checked and rewarming
instituted if needed.
For serious phenobarbital overdose, multiple-dose
activated charcoal (MDAC) leads to more rapid recovery and
a significant reduction in elimination half-life. The usual dose
is 1 g/kg initially in sorbitol, followed in 2 to 4 hours by 0.5
g/kg in aqueous solution without sorbitol and alternating for
24 hours.
16. Management (2)
Since barbiturates are weak acids with pKas ranging from
7.2 to 8.5. Increasing the urine pH increases the fraction of
ionized drug in the urine and thus decreases the amount of
unionized drug available for passive tubular reabsorption.
Urine alkalinization can increase the renal clearance of
phenobarbital up to 10-fold and can shorten the half-life by
one-half to two-thirds.
Hemodialysis may be used in life-threatening barbiturate
overdose. Both charcoal hemoperfusion and high-flux
hemodialysis enhance the elimination of all barbiturates,
Sustained low efficiency dialysis might be taken under
consideration as an extracorporeal treatment modality in
severe phenobarbital poisoning with hemodynamic instability
where conventional hemodialysis may be difficult to initiate.
17. Example ( case )
A 30-year-old female who was a known case of chronic depression aggravated by
postpartum status (history of child-birth 6 months back) and on venlafaxine therapy was
found unconscious, 4 h after a suspected overdosage of 54 g of phenobarbital (90 tablets of
60 mg each), Being healthcare personnel, she had access to phenobarbital tablets.
In the emergency department, she was intubated and ventilated. Toxicology screen came
back positive for barbiturate, and she was shifted to the Intensive Care Unit (ICU). In the ICU,
she was further resuscitated with fluids. She developed severe hypoxia due to large
aspiration of gastric contents, possibly during transport. It was opted for initial treatment in
the form of forced alkaline diuresis with sodium bicarbonate, ventilator support and gastric
decontamination with activated charcoal every six hourly for 48 h.
The first measured phenobarbital level (about 20 h from time of ingestion) was 198
mcg/ml. After 2 days of therapy, the phenobarbital level came down only to 153.8 mcg/ml.
18. Example ( case )
A trial of 4 h sustained low-efficiency dialysis (SLED) with dialysate-flow rate 300
ml/min was opted, blood-flow rate 150 ml/min and no fluid removal, since she was
hypotensive and requiring noradrenaline support.
Following the first dialysis her phenobarbital level dropped from 153.8 mcg/ml to 92.5
mcg/ml, hemodynamics improved and vasopressors were tapered off. Following the next
dialysis, the drug level further dropped to 40.7 mcg/ml, patient started having
spontaneous eye opening and became restless for which mild sedative in the form of
dexmedetomidine in a low dose had to be started. Phenobarbital level continued to fall
subsequently and in the next day with a drug level of 27.8 mcg/ml, the patient was
extubated. Within the following 6 h, she started communicating verbally and started
taking oral feeds. A full psychiatric assessment was carried out and she was started on
appropriate medication. She was shifted out of the ICU the next day and went on to
make a full recovery.
19. References
- Poisoning and drug overdose 7th edition, Edited by: Kent R. Oslon, Lange
Mcgraw Hill education, 2018.
- Lippincott’s manual of toxicology, Lippincott Williams and Wilkins, 2012.
- Goodman and Gilman’s the pharmacological Basis of therapeutics, 13th
edition, Laurence L. Brunton Mc Graw Hill education.
- Basic and clinical pharmacology, Bertram G. Katzung, 13th edition, Mc
Graw Hill, 2018.
- Successful use of sustained low efficiency dialysis in a case of severe
phenobarbital poisoning, Sayandeep Jana, Chandrashish Chakravarty,
Abhijit Taraphder, and Suresh Ramasubban Indian J Crit Care Med,
v.18(8); 2014 Aug.
