BARBITURATES

Since the synthesis of diethylbarbituric acid and

its introduction into medicine as a sedative and

hypnotic agent many other structural analogues

have been prepared and investigated. Fisher &

Von Mering introduced Diethyl Barbituric acid in

to medicine in 1904 under the name of Venoral

(vera means true) that proved to be an effective

hypnotic without serious side reactions.

The barbiturates were used as sleeping tablets

and sedatives that led to their widespread abuse

till 1960s when they were replaced by nonbarbiturate

hypnotics, such as the benzodiazepines.

Unfortunately, barbiturates are still available in the

market either alone or in combination with other

substances such as amphetamines.

Classification of Barbiturates

The classification of barbiturates into short, intermediate

and long acting is arbitrary and may be

misleading. The onset of action is about ¼–½ hour

but the duration varies up to 8 hours or so for

Phenobarbitone (Table 40.2).

Fatal period→1-2 days.

Pharmacological Action of Barbiturates

Pharmacological action of barbiturates of all types

is the same that is depression of central nervous

system. However, the structural variations result

Table 40.2: Classification of Barbiturates

Barbiturates Duration Fatal

of action dose

Long acting 8-16 hrs 3-4 gm

• Barbitone (venoral), white tab

• Barbitone sodium

(medinal), white tab

• Phenobarbitone (gardenal,

luminal), white tab

• Methyl Phenobarbitone

(prominal)

Intermediate acting 4-8 hrs 2-3 gm

• Allobarbitone

• Amylobarbitone

• Butobarbitone (Soneryl),

pink tab

• Pentobarbitone

(Nembutal), yellow tab

Short acting 3-6 hrs 1-2 gm

• Cyclobarbitone

(phanoderm), white tab

• Hexobarbitone
(evipan), white tab

• Quininalbarbitone

(seconal), red tab

Ultra short acting 1-few min. 1.5-2 gm

• Thiopentone (pentothal),

white powders or ampoules

• Metho- hexo- barbitone

(brevital)

in differences in rate of absorption and distribution.

By altering the dose, the degree of depression

can be altered. Phenobarbitone has a specific

depressant action on cerebral motor cortex that

makes it a valuable drug for epilepsy. In hypnotic

doses, it has no analgesic action and if prescribed

alone in painful conditions, there may be

excitement, restlessness, mental confusion and

delirium. Barbiturates act as synergists with

analgesics and potentiate the action of alcohol.

As barbiturates are cumulative drugs, they are

contraindicated in hepatic and renal disorders.

After the oral ingestion, the peak concentration in

blood and brain of

1. Medium and short acting barbiturates is after

→1-2hours

2. Long acting is after→4-8hrs after ingestion

3. Ultra short acting is after→30seconds to a few

minutes

CNS Depressants 621

They are rapidly absorbed from the gastrointestinal

tract including rectum and from the

subcutaneous tissues. They are concentrated in

the liver for a short time and evenly distributed in

the body fluids. Lipid solubility is the primary

determinant of binding. Ultra short acting is 80%

more bound to plasma proteins or stored in the

body fat from which they are subsequently cleared

and degraded in the liver. Long acting is only 5%

bound to plasma proteins and mainly cleared by

urinary excretion. Medium acting are bound more

than the long acting and they are detoxified in

liver and tissues and finally excreted quickly. Short

acting barbiturates are also excreted quickly.

Highly lipid soluble barbiturates such as

thiopental, methohexal undergo rapidly to the

vascular areas of brain and first to the gray matter.

Maximum uptake occurs within 30 seconds and

sleep may be induced within few minutes. Within

30 minutes, there is redistribution to the less

vascular areas of the brain and other tissues.

Other factors that affect the binding capacity are

the dose absorbed and the patient’s habit

Excretion of barbiturates: The Barbiturates are

removed from the body by two different

mechanisms: (i) Long acting Barbiturates are

mainly excreted by the kidneys. As much as 85%

of these compounds may be recovered from the

urine. Excretion is slow and takes place in several

days (ii) The liver mainly metabolizes short acting

Barbiturates. Other tissues may also participate

in this process. These compounds are not

recovered from the urine if taken in sedative doses.

Mode of action: Barbiturates are cellular,

histotoxic agents. They (i) Produce histotoxic or

tissue anoxia (ii) Partially inhibit the cytochrome

enzyme system (iii) Toxic action may occur

following a large single dose or repeated

medication in slow excreting Barbiturates.

Signs and Symptoms

The clinical staging of barbiturates has been

classified in to five stages by ‘Sunshine and

Hackett’: (i) Awake, competent and normally sedated

(ii) Sedated: (a) reflexes are positive (b) prefers

sleep (c) answers question when aroused (d) does

not cerebrate properly (iii) Comatose with positive

reflexes (iv) Comatose and areflexia (v) Comatose;

difficulty in respiration and circulation and death

is from respiratory failure.

Central nervous system: (i) Drowsiness (ii)

Transient period of confusion, excitement, delirium

and hallucinations (iii) Ataxia, vertigo and slurring

sleep (iv) Headache (v) Consciousness is depressed

in a variable degree; can be assessed by

rubbing the clenched fist on patient’s sternum.

The response of the pupil and peripheral nerve

reflexes are so erratic that it has a little help in

assessing. (Pupils are constricted than dilated in

terminal hypoxia) (vi) “Rising up” sign (vii) Babinski

sign is positive (viii) The degree of consciousness

can be expressed by the following classification

Grade I: Response to vocal commands

Grade II: Maximum response to minimal painful

stimuli

Grade III: Minimal pain to maximum stimuli

Grade IV: Total unresponsiveness to maximal

painful stimuli

Respiratory system: They directly depress the

medullary centers. The rate and depth of respiration

is reduced and towards the end Cheyne-

Stoke’s type of breathing and then death. If coma

continues then infection, pneumonia and

pulmonary oedema may develop

Cardiovascular system: Barbiturates exert direct

toxic effect on the myocardium and interfere with

the myogenic tone of peripheral arterioles (i) Fall

in cardiac output (ii) Permeability of arterioles is

increased leading to transudation and increase in

extracellular fluid volume (iii) Cyanosis and

hypotension (iv) Weak and rapid pulse (v) Cold

and clammy skin.

Pupils: Pupils are little contracted and reacting

to light; may be dilated and unequal in terminal

asphyxia.

Body temperature: Barbiturates interfere with the

control of body temperature; hypothermia is

produced requiring the use of symptomatic

measures. During recovery the patient may

622 Textbook of Forensic Medicine and Toxicology

become febrile.

Gastro-intestinal tract: Bowel sounds may be

absent during severe poisoning and this is a bad

sign. When bowel functions return further drug

absorption may take place leading to fluctuating

levels of consciousness. Incontinence of faeces

may occur

Renal symptoms: Renal functions may fail

especially with hypotension and hypothermia.

Incontinence of urine may occur and sugar and

albumin may be present in the urine.

Dermatological symptoms: The skin lesions

develop in 6% of the cases; are diagnostic and

very commonly present in poisoning with medium

acting barbiturates. Bullous lesions occur where

the skin surface rubs the other part of the skin

such as inner aspects of thigh and pressure

bearing areas like hands and feet. Initially there

are slightly raised areas of erythema and later on

bullous eruptions are formed. The blister contains

serous fluid, the rupture of which leaves a red raw

surface that may be mistaken for burns.It is

suggested that bullous formation is either due to

toxic effects of the drug or patient is unduly

sensitive to the drug itself.

Differential diagnosis of bullous eruptions

in Barbiturate poisoning

1. CO poisoning: The eruptions are present under

the pressure areas, sacrum, spine, inner

aspect of knee and ankle. They are produced

due to impairment of circulation.

2. Thermal heat: The blisters due to burns will

show the effect of heat and the hair will be

seinged

3. Pemphigus: Pemphigus blisters are non-tense,

larger and the bullous spreading test is positive

4. Methaqualone (Mandrax) overdosage: The

following symptoms are present; hypoproteinemia,

gastric bleeding and cardiac

arrhythmias.

5. Glutathimide, meprobamate and tricyclics

antidepressants overdosages

6. Prolonged contact with petrol and paraffin

Clinical Diagnosis of Barbiturate Poisoning

1. In an unconscious patient, one has to rule out

other causes of coma such as: (i) Acute

alcoholic poisoning (a) odour of alcohol is

present in the breathing (b) eyes are congested

and pupils dilated (ii) Carbolic acid poisoning

(a) the odour is characteristic (b) white patches

can be seen on lips and mouth (c) carboluria is

diagnostic (iii) Co poisoning (a) history of

exposure to the carbon monoxide gas is there

(b) intermittent convulsions (c) cherry red colour

of the skin (d) carboxyhaemoglobin is present

in the blood (iv) Epileptic coma (a) there is

history of fits (b) pupils are fixed and dilated:

(a) Froth at mouth (b) cyanosis (v) Diabetic

coma: (a) gradual onset (b) odour of acetone is

present (v) Sugar and acetone is present in the

urine (vi) Brain trauma: (a) history is

characteristic (b) injuries and bleeding from the

nose (c) pulse is rapid (d) paralysis may be

present.

2. Clear history of ingestion of barbiturates

3. Findings of general anaesthesia with low

respiration and decreased respiratory function

4. Presence or absence of bowel sounds

5. Urine or first stomach wash is to be tested for

barbiturates

6. Blood levels by gas chromatography,

calorimetric methods and spectrophotometry

are: (a) For long acting—8-10mg% (b) For

medium acting—4-7mg% (c) For short acting—

2-4mg% (d) For ultra short acting—0.8-1mg%.

7. ECG findings show inverted and flattened ‘T’

wave and depressed ST segment

8. EEG Findings in Barbiturate poisoning

Mild intoxication: Normal activity is replaced

by fast activity in the range of 20-30Hz

appearing first in the frontal regions and

spreading to the parietal and occipital regions

as intoxication worsens.
More severe intoxication: The fast waves

become less regular and interspersed with 3-

4Hz slow activity.

Still more advanced cases : There are short

periods of suppression of all activity, separated

by bursts of slow (delta) waves of variable

CNS Depressants 623

frequency

Extreme overdoses: All electrical activity

ceases in extreme of overdosage of the drug.

This is one instance in which a flat EEG cannot

be equated with brain death and the effects are

fully reversible unless anoxic damage has

supervened.

Treatment

Mild cases need no treatment but should be kept

under observation. Before treatment in comatose

patients, other causes of coma should be

excluded. The treatment includes the general and

specific measures.

General measures:

First part: Clear the airway by tracheo-bronchial

suction, oxygen inhalation, physiotherapy of

thorax. X-ray of lungs shows evidence of collapse.

No prophylactic antibiotics to be given unless

infection is present

Second part: Gastric lavage and suction: (i) It is

more useful if it is done within 4hours of the

ingestion of the poison (ii) Done with warm water

mixed with potassium permanganate and

suspension of animal charcoal and tannic acid

(iii) First sample is to be obtained in plain water

(iv) Magnesium sulphate is used for purgation as

it minimizes absorption.

Third part: Regular charting of pulse and blood

pressure along: (i) With correction of dehydration

(ii) Nor adrenaline 2mg with 500ml of 5% glucose

(iii) Intravenous saline drip for correction of shock

and hypotension (iv) Patient should be kept warm.

Specific measures: (i) No specific antidote is

known (ii) In prolonged coma with retention of

carbon dioxide, mechanical respirator and

tracheostomy may be considered (iii) Treatment

of pulmonary oedema by relieving heart failure by

aminophylline, digoxin etc. may be considered.

500 ml of 10% Mannitol should be given I.V.

Fureosemide is used as diuretic (iv) Analeptics:

Analeptics stimulate the central nervous system

especially respiratory center so they are used in

the treatment of narcotic poisoning. Their use is

opposed in barbiturate poisoning due to the

following measures: (a) Are generally ineffective

in severe poisoning (b) Awakening effect is

transient and followed by greater depression (c)

Leads to cardiac arrhythmias and convulsions;

cerebral ischemia and depression and then

irreversible brain damage (d) Overall results without

their use show a much reduced mortality rate (e)

10 ml of 0.5% Bemigride (50 mg) and 1ml of 1.5%

Amiphenazole (15 mg) are added to the 5%

glucose saline drip for two hours at 5 minutes

interval or till consciousness returns whichever is

earlier or return of pharyngeal or laryngeal reflexes.

If vomiting and muscular twitching is seen the

treatment should be stopped (f) Some use

Coramine (Nikethemide) 5ml i.v at 15 minutes

interval and then 10ml at 30 minutes interval till

reflexes return. If muscle twitching are present

stop the treatment. (v) Picrotoxin can be given

2ml intravenously but if muscle twitching are

present or corneal reflexes return, stop the

treatment (xi) Dialysis and exchange transfusion

are at times life saving.

Autopsy Findings

(i) External findings are not characteristic; signs

of asphyxia are present and cyanosis of face and

nails is seen (ii) Traces of tablets and capsules of

barbiturates may be found in the mouth,

oesophagus and stomach (iii) Mucous membrane

of stomach is congested and eroded badly from

the alkaline attack of drugs like sodium amytal

which, being the sodium salt of a weak organic

acid, hydrolyses in the stomach. The fundus may

be thickened, granular and haemorrhagic. The

cardia and lower oesophagus may be eroded from

the reflux and if the victim regurgitates, then black,

altered blood may appear at the nose and mouth

(iv) Lungs are congested, oedematous and findings

suggestive of pneumonia may be present. The

congested lungs in acute barbiturate poisoning

are more intense than in any other condition. The

lungs are almost black and the whole venous

system is engorged with dark, deoxygenated blood

(v) Petechial haemorrhages are seen in the pleura,

pericardium and meninges (vi) Kidneys are

congested and degenerative changes of the

tubules are present (vii) Brain is oedematous,

softening of globus pallidus is seen and multiple

624 Textbook of Forensic Medicine and Toxicology

petechial haemorrhages are seen in the white

matter (ix) All other organs are congested (x)

Barbiturates blisters: These blisters are found

on the dependent parts of the skin surface, especially

buttocks, backs of thigh, calve and forearms

(xi) For chemical analysis of viscera, besides the

other organs brain is to be preserved as venoral is

retained in the brain.

Medicolegal Aspects

(i) Commonly used for suicide more by young male

than female, next only to organophosphorus

compounds. It is freely prescribed and easily

available (ii) Therapeutic uses: It is used for sleeplessness,

anxiety states, epilepsy, strychnine,

picrotoxin and cocaine poisoning (iii) Rarely used

for homicidal purposes (iv) Repeated small doses

cause addiction that leads to withdrawal symptoms,

used for the relief of worries and anxiety of

modern life (v) Automatism: The accidental or

suicidal overdose may lead to the poisoning

In ordinary doses, it induces natural sleep but

occasionally instead of sleep, there is mental

confusion. It is likely to happen in those cases

where insomnia is due to pain and an analgesic

is not taken for its relief. In these cases, the use

of barbiturates may lead to mental confusion. As

a result, to induce pain patient takes more of the

drug automatically for getting that he has already

taken a dose known as barbiturate automatism.

In some cases, the patient continues to take the

drug that leads to overdose that is fatal.

However, some workers have a different concept;

they feel that confusion and forgetfulness cannot

account for overwhelming overdose that is found

in these cases. It is possible that there are cases

of intentional suicide or alcoholics where confusion

is more likely and the action of barbiturates is

potentiated by alcohol. It is now over 40 years

since ‘automatism’ was offered as a socially

acceptable explanation of self-administered

overdoses of barbiturates. The idea was often

accepted without any real evidence that repeated

therapeutic doses were taken by a patient who

did not remember taking the drug and in some

studies by Dorpat concluded

Barbiturates

Barbiturates are sleep-inducing drugs. Their use as sleeping tab-

lets and general soporific sedative agents led to widespread abuse,

so that at one time they were easily the most common agents

of drug addiction. The development of nonbarbiturate hypnot-

ics such as benzodiazepines helped to remove the need for the

older and more lethal compounds. Unfortunately, barbiturates

Table 39.1

Differentiating Features of Body Packer and Body

Stuffer

Features

Body packer

Body stuffer

History

Specifically hired to

smuggle drugs

User or seller on

verge of arrest

swallows the evidence

Packing

Carefully packed

in plastic or latex

packages

Not so, usually due

to non-availability of

time

Co-ingestants Usually not present

Usually present

Toxicity

Rarely occurs (due to

bursting of packages)

Relatively common

Radiography

Usually helpful in

detection

Not always helpful

Treatment

Observation: rarely

surgical removal.

Emergency

intervention as needed

Aggressive treatment

often required

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Textbook of Forensic Medicine and Toxicology

508

are still available and either alone or in combination with other

substances can be the source of intoxication. Depending upon

the duration of action, barbiturates may be divided into four

groups:

Long-acting

(onset of action about 2 hours and duration

6–12 hours): barbital, mephobarbitone, phenobarbitone, and

primidone.
Intermediate-acting

(onset of action half to 1 hour and dura-

tion 3–6 hours): amobarbitone, aprobarbitone, butobarbitone.

Short-acting

(duration of action

<

3 hours): hexobarbi-

tone, pentobarbitone, secobarbitone.

Ultrashort-acting

(onset of action immediate and dura-

tion

<

15–20 minutes): thiopentone, methohexitone.

ABSORPTION, DISTRIBUTION AND ELIMINATION

They are rapidly absorbed from the gastrointestinal tract including

the rectum. They are concentrated in the liver for a short time

and then distributed into the body tissues and fluids. They are

partly destroyed in the liver and excreted in the urine. The excre-

tion is slow and may remain up to a week. With alcohol, there is

an additive action. With chlorpromazine, there is potentiation

that may be very dangerous. All sedatives, tranquilisers, anticon-

vulsants, hypnotics and analgesics are synergists of barbiturates.

FATAL DOSE

Long-acting, 4–7 gm; intermediate-acting, 2–3 gm; short- and

ultrashort-acting, 1.5–2 gm. (Plasma levels of 3.5 mg/dl for short-

acting and 10 mg/dl for long-acting barbiturates are indicative of

serious toxicity. It may be mentioned that most of the quantitative

assays just measure barbiturate moiety and do not differentiate

between the various barbiturates. Deterioration of symptoms

may sometimes occur due to delayed absorption caused by the

formation of concretions of the drug in the gut. Much lower

levels may be found in fatal poisonings by short-acting barbitu-

rates as the death may occur more quickly from the usual mode

of action, a central depression of the respiratory centres).

SYMPTOMS AND SIGNS

Impairment of consciousness, respiratory depression, hypo-

tension and hypothermia are typical of barbiturate poisoning

and, in common with all forms of hypnotic overdose, are

potentiated by alcohol and benzodiazepines. Hypotonia and

hyporeflexia are the rule and the planter responses are either

flexor or absent. Hypotension is due not only to depression of

medullary centres but also to peripheral venous pooling and

myocardial depression. Most deaths result from respiratory

complications. However, death may occur from respiratory

failure or ventricular fibrillation in early stages.

TREATMENT

Respiration has to be safeguarded by keeping the airways

clean and if need be, by using endotracheal tube.

There is no specific antidote. Analeptics stimulate central ner-

vous system, especially the respiratory centre: (

) amphet-

amine sulphate 20 mg IV may be tried, (

ii

) cardiazol 5 ml IV

initially and the dose may be increased depending upon the

circumstances, (

iii

) 15 mg of amiphenazole in saline and

50 mg bemegride are added to the drip as indications arise.

Analeptic therapy should be avoided unless a clear and

compelling need is warranted.

If the patient is not in coma, stomach wash should be

carried out.

In long-acting barbiturate poisoning, purgatives may be

given for elimination from the intestine.

Forced alkaline diuresis is most useful in poisoning by bar-

biturates, which are not protein bound like phenobarbitone,

allobarbitone and barbitone. Forced diuresis is brought

about by mannitol (100–200 ml of 25% solution) followed

by an infusion of half litre of 5% solution during the next

3 hours. It can be continued alternative with 5% dextrose

for the next 24 hours so as to maintain a urine volume of

10–20 litres in that period.

Haemodialysis is advised for severely poisoned patients

(blood levels

>

10 mg/dl for phenobarbital and

>

5 mg/dl

for short-acting barbiturates).

In patients with prolonged coma, miniheparinisation, elas-

tic stockings, etc., are useful in preventing deep vein throm-

bosis and thromboembolism.

POSTMORTEM APPEARANCES

They are not characteristic, but are mainly those of asphyxia.

Cyanosis is usually present. Postmortem staining may be promi-

nent. In a few cases, there may be skin blisters, the so-called

bar-

biturate blisters

. They are commonly found at the sites where

pressure has been exerted between the skin surfaces, such as but-

tocks, backs of thighs, calves and forearms. They are the result of
cutaneous oedema and may be found in any deep coma where

there has been immobility and lack of venous return from mus-

cle movement. Some of the blisters may burst leaving a red, raw

surface which later dries to a brown parchment-like area.

Inter-

nally,

some white particles of ingested barbiturate may be seen in

the stomach. Gastric mucosa may be eroded. The cardiac end and

lower oesophagus may be eroded from regurgitation. The lungs

are congested, oedematous and may show petechial haemorrhages

on the pleura. The organs in acute barbiturate poisoning are quite

intensely congested and may be almost black, and the whole

venous system may be engorged with dark, deoxygenated blood.

Kidneys may show tubular degeneration. Brain is congested, oede-

matous with punctate haemorrhages.

In delayed deaths,

there

may be necrosis of globus pallidus and corpus callosum, focal

areas of necrosis in the cerebrum and cerebellum. Putrefaction

causes decrease in blood barbiturate levels. Barbiturates, alcohol

and CO produce irreversible brain damage and yet the patient

may survive for a sufficiently long period so that they are com-

pletely metabolised or excreted before death occurs.

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509

Non-narcotic

Drug Abuse

Chapter 39

Section 2

Forensic Toxicology

MEDICOLEGAL ASPECTS

Poisoning is mostly suicidal. Due to large size of fatal dose and

prolonged unconsciousness, they are rarely used for homicide.

Accidental poisoning may occur due to overdose (particularly

due to automatism or due to mixed therapy with other additive or

synergistic drug). The so-called

barbiturate automatism

may

occur when the patient after taking dose of barbiturate confuses

and thinks he has not taken the drug. That way he repeats the

dose and ultimately consumes a toxic dose in total. Intravenous

thiopentone has been used as

truth serum

to extract confessions

during interrogation by inducing a state of drowsy disorientation

in the course of which the person may reveal the truth.