- The document discusses the history and development of barbiturates, which were originally synthesized in the 19th century as hypnotic compounds. Barbiturates were widely prescribed as sedatives until being displaced by benzodiazepines in the 1960s due to issues with abuse and overdose. - Barbiturates are classified based on duration of action and examples are provided. Their pharmacological properties and mechanisms of action in the central nervous system, respiratory system, and elsewhere are described. Adverse effects, signs of toxicity, and treatment approaches for barbiturate poisoning are outlined.

1. BARBITURATE POISONING
DR.VIVEK BENJAMIN.MD

2. • Chemists and physicians have always been seeking chemical compounds that are characterized as
hypnotics, or sleeping compounds.
• The original “drugs” that met this requirement were alcohol, which was used for centuries.
• 19th century, with the beginning of discoveries in chemistry, doctors were prescribing compounds such
as paraldehyde, chloral hydrate and bromides.
• It is documented that in the 1830s, the wife of Abraham Lincoln, Mary Todd Lincoln was given chloral
hydrate for her sleep problems.
HISTORY

3. THE HISTORY OF THE DEVELOPMENT OF BARBITURATES IS AS
BIZARRE AS THE EFFECTS OF THE DRUG ITSELF
• Its founder was a German chemist, Adolph von Baeyer, the person who founded Bayer Chemicals Company,
which is still a major manufacturer of analgesics and well-known and criticized for many of its pesticides and
fertilizers.
• The barbiturates are derivatives of barbituric acid (2,4,6-trioxohexahydropyrimidine)
and were extensively used as sedativehypnotics
• Till the 1960s when the benzodiazepines arrived and quickly displaced them.

4. WHY NAMED BARBI-TURATE ?
• In 1864, Bayer was working on the synthesis of a drug using urea and malonic acid.
• This synthetic drug became known as barbituric acid, named after St. Barbara’s Day.
• In those days, chemists tested drugs by tasting their discovered compounds and seeing what effects they had
on themselves or their employees.
• In 1903 he and two other chemists in Germany altered the compound and created a psychoactive drug named
“barbiturate”.
• It induced sleep and was one of the first hypnotic drugs.
• Mr. Baeyer became famous and his established chemical research won him the Nobel Prize in chemistry in
1905.

5. TYPES
• 1. Long acting (duration of action 6–12 hrs)
•
a. Mephobarbitone.
b. Phenobarbitone.
• 2. Intermediate acting (duration of action 3–6 hrs)
a. Amobarbitone
b. Aprobarbitone
c. Butobarbitone.
3. Short acting (duration of action < 3 hrs)
a. Hexobarbitone
b. Pentobarbitone
c. Secobarbitone.
4. Ultra-short acting (duration of action <15–20
min)
a. Thiopentone
b. Methohexitone.

14. PHARMACOLOGICAL PROPERTIES
• CNS – Suppression post synaptic neurons of cortical and cerebellar pyramidal cell response & pre
synaptic suppression in spinal cord.
Mild sedation to general anaesthesia.
• Sleep
increase in total time of sleep
decrease in sleep latency, number of awakening,duration of REM and slow wave sleep.
• Tolerance
occurs within few days.
Sleep time decreased as much as 50% after 2 weeks.
Cross tolerance to all CNS depressants including ETHANOL

15. • PNS:
DECREASES autonomic ganglionic transmission and nicotinic excitation by choline esters = low BP.
• RESPIRATION:
DEPRESS Resp. drive and mechanism responsible for rhythmic character of respiration.
• CVS:
DECREASED BP and HR = decreased Renal & Cerebral Blood flow.
When used with epinephrine and Halothane = ventricular Arrhythmia.
• RENAL : Oliguric Renal Failure.
• GI:
DECREASES tone of musculature and amplitude of rhythmic contraction.

16. • LIVER:
Alters MICROSOMAL DRUG METABOLISING SYSTEM i.e,CYPs
increase DELTA ALA synthase exacerbates Acute intermittent porphyria.
• EXCRETION : RENAL AND HEPATIC

17. USUAL FATAL DOSE
■ Phenobarbitone: 6 to 10 grams.
■ Amobarbitone, pentobarbitone, secobarbitone: 2 to 3 grams.
■ Lethal blood level for short- and intermediate-acting barbiturates varies from 3 to 4 mg/100 ml,

18. Toxicokinetics
■ Most barbiturates which are used as sedative-hypnotics are administered orally. Intravenous route is usually reserved
for management of status epilepticus or induction/maintenance of general anaesthesia.
■ Following absorption, barbiturates are distributed widely. The long acting barbiturates have a plasma half-life of
about 80 hours.
■ Metabolism of most of these drugs occurs by oxidation in the liver resulting in the formation of alcohols, ketones,
phenols, or carboxylic acids which are excreted in the urine as such or in the form of glucuronic acid conjugates.
Metabolism of barbiturates is more rapid in children and is slower in the elderly.

19. Adverse Effects
■ Residual depression after the main effect of the drug has passed off.
■ Paradoxical excitement (especially in the elderly).
■ Hypersensitivity reaction—localised swelling of eyelid,cheek, or lip, erythematous or exfoliative dermatitis.
■ Synergistic action with ethanol and antihistamines.
■ Barbiturates are contraindicated in patients with acute intermittent
porphyria since they enhance porphyrin synthesis.

20. Clinical (Toxic) Features
1. Slurred speech, ataxia, lethargy, confusion, headache,nystagmus.
2. CNS depression, coma, shock.
3. Pupils are at first constricted, but later dilate because of hypoxia.
4. Hypothermia.
5. Cutaneous bullae (“barb burns”, barbiturate blisters): These are clear, erythematous or haemorrhagic blisters, and
occur in various areas of the body, most typically on the hands, buttocks, and between the ankles and knees, usually
over pressure points. These lesions have also been reported over non-pressure points, such as dorsal surfaces of fingers
and toes, and ocular conjunctiva.

21. 6. Death may occur from respiratory arrest or cardiovascular collapse. Delayed death may be due to acute renal
failure,pneumonia, pulmonary oedema, or cerebral oedema.
7. Chronic barbiturate (ab)use is associated with the development of tolerance which is responsible for decreasing the
therapeutic to toxic index. An addict may obtain therapeutic benefit only with 5 to 6 times the normal dose. Abrupt
withdrawal results in anorexia, tremor, insomnia, cramps,seizures, delirium, and orthostatic hypotension.

22. Diagnosis
1. Serial plasma levels may be useful in the management of phenobarbitone overdose.
Plasma levels exceeding 8 mg/dL (80 mcg/mL) (344 mcmol/L) are generally associated
with some degree of coma.
2. EEG: alpha coma* indicates poor prognosis.
{Alpha coma, an electroencephalogram (EEG) pattern, characterized by a diffuse or
widespread rhythmic activity in the alpha frequency band, is typically recorded in
patients with profound coma].

23. Treatment
1.Monitor CBC, serum electrolytes, glucose, blood urea nitrogen,creatinine, and urine myoglobin in patients with
significant intoxication.
2.The onset of toxic effects is usually within 2 hours, but peak toxicity may not occur for 18 or more hours.
Repeat serum phenobarbitone level at approximately 6 hours after the initial level.
3. Gastric lavage (preferably with a large-bore, double-lumen tube), can be done with benefit upto 12 to 24 hours
postingestion.
4. Multiple dose activated charcoal has been shown to greatly increase phenobarbitone elimination.

24. 5. Forced alkaline diuresis is said to be particularly useful in phenobarbitone poisoning .
no value in the treatment of short acting barbiturate intoxication.
6. ■ Haemodialysis or haemoperfusion:
Barbiturate elimination can be increased by haemodialysis or charcoal haemoperfusion.
Even though haemoperfusion can clear barbiturates two to four times more rapidly than dialysis, haemoperfusion will not
correct electrolyte imbalances, and has been associated with platelet consumption, hypothermia, hypotension, and
decreased serum calcium.
7. ■ Exchange transfusion may be beneficial in severe cases.
8.For hypotension: First administer 10 to 20 ml/kg of isotonic intravenous fluids and place in Trendelenburg position.
If the patient is unresponsive to isotonic fluid therapy administer a vasopressor. Dopamine or noradrenaline should be titrated
to desired response.

25. ■ Supportive measures: supplemental oxygen, intubation, assisted ventilation,
IV fluids.
■ Withdrawal may be treated by reinstitution of phenobarbitone, and a
programme of gradual reduction over three weeks. A tapering schedule of 10
percent every 3 days has been used successfully.
■ The incidence of poisoning with barbiturates has declined dramatically in
recent years as a direct result of decline
in their use as sedative-hypnotics.
This type of (suicidal) poisoning was rampant in the 1960s when these drugs
were widely prescribed and
consequently abused.
One of the most famous cases during this period concerned immortal
Hollywood actress Marilyn Monroe who at the end of her short, tempestuous
career became hopelessly addicted to alcohol and barbiturates.In 1962, at the
age of 36, Marilyn Monroe was found dead at home following an overdose of
barbiturates.

26. ■ Intravenous thiopentone has been used as truth serum. This controversial practice
is closely related to the legitimate psychiatric practice of narcoanalysis used to diagnose certain mental ailments
by placing the patient in a reclining position and administering amylobarbitone or some other short-acting
barbiturate intravenously until lateral nystagmus is induced or drowsiness is noted, when the interview is begun
and sustained in a gentle fashion with periodic maintenance doses of the drug. This is sometimes referred to as
the “Amytal interview”,
Amytal being a popular trade name for amylobarbitone in Some Western countries.
“TRUTH SERUM”

27. Case Report
An 18-year old girl was admitted in the medicine department in an unconscious state with no response to deep painful stimuli
(Grade III coma).
History as elicited from her attendants was suggestive of oral intake of phenobarbitone tablets a night before, after which the
patient was not arousable in the morning.
There was no history of convulsions, vomiting, urinary incontinence or tongue bite. Within few hours of admission,
patient became febrile and tachypnoeic with pulse rate 130 min-1, blood
pressure 120/70 mmHg and arterial oxygen saturation 93%.
Pupils were of normal size and reaction. Plantar and deep tendon reflexes were absent.
A diagnosis of barbiturate poisoning was made and patient was shifted to ICU. Shortly after admission, she had tonic clonic
convulsions which subsided after few seconds spontaneously. She became increasingly tachypnoeic and oxygen saturation
started falling. Blood gas analysis done showed hypocarbia with metabolic acidosis. She was intubated nasally and ventilated by
Evita-2 (Drager) ventilator on intermittent positive pressure ventilation mode with tidal volume 400 ml, FiO2-80% and frequency
– 14/min.

28. Continuous temperature monitoring was done and care was taken to avoid hypothermia.
Antibiotics, phenytoin, ranitidine, low dose dopamine and bronchodilator were started. In
addition, ten tablets of activated charcoal 500mg (5g) with egg albumin were given four hourly
through Ryle’s tube.
Forced alkalinediuresis was started. One litre of lactated Ringer solution was rushed and
injection sodabicarbonate 50cc was given intravenously six hourly. Aim was to keep urinary pH
between 8-8.5. Her serum potassium was 2.5.eq lt-1 and SGOT and SGPT were 118 IU and 99IU
respectively.
Serum proteins were 6g%. Urine was positive for ketone bodiesand serum barbiturate assay was
positive. As her consciousness level did not improve, haemodialysis was planned. Haemodialysis
was done using Sresenius Haemodialyser. Within hours, the patient’s condition improved and
she stared responding to verbal commands. Her vitals were stable. She was extubated once
regular spontaneous respiration was restored.
Oxygen therapy with ventimask (FiO2 – 60%) was instituted. Gradually, the patient was weaned
to FiO2 of 28%. SGOT and SGPT were still elevated (222 IU and 240 IU respectively). Repeat
serum assay now revealed no residual barbiturate.
She was discharged home a week later