Barbiturate

Barbiturates - What are Barbiturates?

Barbiturates are an older version of currently used tranquillizers or sedatives that act by depressing the nervous system. These are one of the oldest sedatives that are in use.

They are prescribed to patients with sleep disorders and other mental illnesses to calm them down and put them to sleep.

Due to their side effects and increased risk of dependence and abuse and also the large number of fatal accidents that result due to their misuse they are largely replaced by safer agents called tranquillizers.

How they are available?

Barbiturates are rarely prescribed these days due to their safety concerns. They are prescribed for certain indications. Patients may take these drugs in the form of capsules with the powder form of the drug within them.

Effects of barbiturates

In small doses, barbiturates relieve insomnia or difficulty in sleeping. They relieve anxiety and tension.

There may be a hangover or residual sleepiness. Users may appear drunk and experience loss of balance and co-ordination.

Overdose

The normal therapeutic dose range is small and thus there is a high risk of overdose. Many persons may overdose barbiturates without being aware.

Overdose carries the risk of serious side effects and depression of the respiratory center that may cause death. Barbiturates also interact with alcohol and drugs of abuse like heroin in a life threatening manner.

Side effects

Over long term use there is a risk of severe side effects. Barbiturates are highly addictive and dependence may develop over long term use. Those who are long term users are also at risk of pneumonia and bronchitis.

With long term use there is risk of developing extreme mood swings, bouts of depression, impaired memory, judgement, coordination, altered sleep schedules and insomnia and intense weakness and fatigue.

Types of barbituate

Commonly used barbiturates include:-

  • Amylobarbitone
  • Methyl phenobarbitone
  • Pentobarbitone
  • Butobarbitone
  • Phenobarbitone
  • Quinalbarbitone

What are they used for?

Barbiturates are used for:-

  • Pentobarbitone or thiopentone is used in induction of general anesthesia
  • Phenobarbitone and Pentobarbitone is used in some cases of epilepsy
  • Sedation and hypnosis to calm the patient and induce sleep

Legal status of barbiturates

Barbiturates are a prescription-only medicine and a class B controlled drug (Schedules 2 and 3). This indicates that it is illegal to possess the drug without a prescription or to supply it to others.

Injectable barbiturates are class A drugs. For possession of barbiturates injections the maximum penalty is seven years imprisonment and/or unlimited fine.

For dealing in these injectable barbiturates there may be life sentence and/or unlimited fine.

For possession of barbiturates capsules the maximum penalty is five years imprisonment and/or unlimited fine. For dealing in these capsule barbiturates there may be 14 years imprisonment and/or unlimited fine.

Barbiturate History

Sleep disorders have been managed using several means throughout the history of mankind. It all began with alcohol and alkaloids of opium and other narcotic plants (hemp, belladonna, henbane, etc). It was in the late 19th and early 20th centuries that drugs such as paraldehyde, chloral hydrate, and bromides were developed for induction and maintenance of sleep.

In 1864 Adolf von Bayer developed malonylurea from which in the early 20th century came the barbiturates. These agents were first brought to the market in 1904 by Farbwerke Fr Bayer and Co.

Barbiturates are basically a closed-chain ureic compound, whose nucleus is malonylurea. Malonyurea is a combination of urea and malonic acid, an acid derivative taken from apples.

Barbiturates were synthesized in 1864 by Adolf von Baeyer. The process was then perfected by the French chemist Edouard Grimaux in 1879.

Origin of the term barbiturates

There are several speculations about the origin of the term barbiturates. Some suggest it was a name given by Baeyer in honor of his friend Barbara.

Yet others suggest that Baeyer celebrated his discovery of these compounds in a tavern near his home that was frequented by artillery officers. These officers were celebrating the day of their patron, St Barbara. The name could have come from there.

Another possibility of the name was that the name came from the “barbed” appearance of the molecule due to the appearance of the crystals of these ureic compounds.

Revolution in psychiatric and neurological disorders

The first agent of this class was diethyl-barbituric acid. This spelled a revolution in psychiatric and neurological disorders of the time.

It was successfully used in many patients with serious neuroses and psychoses. They were one of the first agents to be used in controlling seizures and in inducing sleep in insomniacs.

With time barbiturates started the era of intravenous anesthetic agents. Before thiopentone, general anesthesia meant induction using the gases like nitrous oxide.

Barbiturates in the 20th century

Over the initial years of the 20th century more than 2,500 barbiturates were synthesized. Of these 50 were eventually employed clinically. Their use spread wide before physicians became aware of their risk of dependence and abuse liability.

It was in 1912 that the first cases of dependence on barbiturates were reported from Germany. After initial reports, more physicians reported delirium and withdrawal symptoms on abrupt discontinuation or dose reduction of barbiturates.

It was in 1950 that researchers published a paper that finally established that physical dependence on barbiturates is a possibility that can be induced in the laboratory as well in experimental conditions.

What was surprising was that despite use of barbiturates for over five decades, it was only in the 1950’s that barbiturates were accepted as drugs that could cause dependence.

It took another two decades for the physicians to be aware that these agents could cause dependence and abuse and should be prescribed only sparingly in select cases.

Today 5 or 6 derivates of barbiturates are still being used as inducers of general anesthesia and serious forms of insomnia and in some types of epilepsy.

Barbiturate Abuse

Barbiturates were first used in 1903. They are derivatives of the chemical molecule barbituric acid. There are over 2000 derivatives of barbituric acid that have been used in medicine.

Dependence and abuse liability

It was in 1912 that the first cases of dependence on barbiturates were reported from Germany. Dependence or physical dependence is defined as a condition when long term use of a drug results in the phenomenon of tolerance and discontinuation or dose reduction of the drug leads to onset of negative symptoms called withdrawal symptoms. Tolerance means that increasingly high doses of the drug are needed to achieve the same efficacy.

After initial reports, more followed on the same lines. These reported delirium and withdrawal symptoms on abrupt discontinuation or dose reduction of barbiturates.

It was in 1950 that researchers published a paper that finally established that physical dependence on barbiturates is a possibility that can be induced in the laboratory as well in experimental conditions.

What was surprising was that despite use of barbiturates for over five decades, it was only in the 1950’s that barbiturates were accepted as drugs that could cause dependence.

It took another two decades for the physicians to be aware that these agents could cause dependence and abuse and should be prescribed only sparingly in select cases.

Drug abuse

Drug abuse has been defined by the World Health Organization (WHO, I969) as the “persistent or sporadic excessive use of a drug inconsistent with or unrelated to acceptable medical practice”.

Both dependence and abuse are closely related and are parts of the same spectrum of conditions with abuse being at the lower end of the spectrum and dependence being at the higher end.

Abuse of barbiturates may vary between occasional use of a barbiturate hypnotic at night to intermittent use during the day leading to intoxication.

Severe cases include intravenous use of the agent and finally physical dependence and addiction.

Barbiturate abuse

Regular consumption of 450 mg of a barbiturate that is traditionally used for sedation or sleep induction for a period of eight weeks is likely to lead to a psychological and/or physical dependence. There are around 60 different barbiturate compounds that are in use:-

  • The ones that have a short duration of action have a low abuse potential and their use in limited to the hospitals in general anesthesia.
  • The ones that have a longer duration of action include phenobarbitone and are used as anti-seizure drugs. Dependence of these agents are also rare but not impossible.
  • Barbiturates that are rapidly acting and useful for sleep induction are the ones that lead to a high or a mood change and intoxication. These have the highest abuse potential and may cause dependence. Common agents abused include amylobarbitone, quinalbarbitone, pentobarbitone etc.

Unlike the social profiles of other drug abusers barbiturate abuse is seen among socially stable, middle-aged persons who may be stably employed or housewives. These persons however do not abuse injectable barbiturates.

Barbiturate Mechanism

Barbiturates may have been abandoned as sedatives and tranquillizers due to their high abuse and dependence potential and risk of side effects, but they continue to hold an important place in neurology practice today.

There are several uses of these agents and at present there are two major uses – as an agent that induces general anesthesia and as an agent that may control seizures.

Mechanism of action

The primary mechanism of action of barbiturates is inhibition of the central nervous system. It causes central nervous system depression. This is brought about by stimulating the inhibitory neurotransmitter system in the brain called the [gamma]-aminobutyric acid (GABA) system.

The GABA channel is a Chloride channel that has five cells at its gate. When barbiturates bind to the GABA channel they lead to prolonged opening of the channel letting in Chloride ions into the cells in the brain. This leads to increased negative charge and alters the voltage in the brain cells.

This change in voltage makes the brain cells resistant to nerve impulses and thus depresses them.

Barbiturates used in anesthesia including Thiopentone sodium (also known as pentothal) also act by decreasing Calcium flow between the membranes.

Barbiturates for controlling seizures and maintaining sleep

Barbiturates that are used in controlling seizures include phenobarbitone. These are found to be effective in partial, complex partial and secondarily generalised seizures.

There are other first line and more effective agents useful for these conditions, but phenobarbitone remains one of the effective agents that may be used when all others fail.

Barbiturates are also used for inducing and maintaining sleep. Due to the narrow therapeutic dose range that leads to an increased risk of over dosage these agents are not routinely prescribed in sleep disorders. Another use of these agents is in the evaluation of patients with medically intractable seizure disorders for possible surgical therapy.

Uses of barbiturates

  • Sedation – these agents have largely been replaced by more modern and safer agents like benzodiazepines in this area.
  • Sleep induction or hypnosis – in short term insomnia, barbiturates may be effective. This is because they tend to lose their effectiveness in sleep induction and maintenance after 2 weeks of use.
  • Before surgery as a preanesthetic agent – sedation is given prior to surgery to allay anxiety and to ease the process of induction of general anesthesia. This is also an area where benzodiazepines have replaced barbiturates.
  • Induction of general anesthesia – Thiopentone or pentothal is routinely used as an injectable induction agent in general anesthesia.
  • Treatment of seizures - treatment of partial and generalized tonic-clonic and cortical focal seizures could still utilize barbiturates including mephobarbital, Phenobarbital.
  • Acute convulsions – acute onset convulsions including  status epilepticus, eclapmsia during pregnancy, meningitis, tetanus and toxic reactions to strychnine or local anesthetics, convulsions during cholera etc. are indications for use of barbiturates.

Onset and duration of action

  • Long-Acting Barbiturates – these are generally used in seizures. The action starts slow (30-60 minutes) and lasts longer (10-16 hrs).
  • Intermediate-Acting Barbiturates – these are generally used in inducing and maintaining sleep. The action starts slow (45-60 minutes) and lasts for an intermediate duration (6-8 hrs).
  • Short-Acting Barbiturates – these are also used as sedatives. Relatively rapid onset (10-15 minutes) and relatively short duration of action is seen (3-4 hrs).
  • Ultra-Short-Acting Barbiturates – these are used in induction of anesthesia. These have an immediate onset of action that lasts for a very short duration.

Barbiturate Risks

Barbiturates once enjoyed vast popularity as sedatives and sleep inducing agents. Over time their side effects led to more caution and at present these agents are seldom prescribed for insomnia and sleep disorders. Some of the risks associated with barbiturates use include:-

Drowsiness

Barbiturates are primarily sedatives and they induce sleep. Since this is their primary pharmacological effect, some amount of excessive drowsiness is commonly seen especially in case of overdose.

This sleepiness may persist over the next day as well. This may manifest as a hangover sleepiness that makes driving and operating heavy machinery on the next day morning a hazard. There is impaired psychomotor function and increased pain perception that may persist over the next day.

Dependence and tolerance to barbiturates

Over long term use dependence develops to barbiturates. This means that patients are unable to sleep without taking barbiturates.

Tolerance is an associated phenomenon. This means over long term use sleep is difficult without increasing the dose. Finally the highest dose range of the drugs fails to produce sleep but may lead to other side effects.

Depression of respiration

Barbiturates have a narrow therapeutic range. This means these agents lead to side effects when they cross the normal dose range. Since this range is a narrow one there is a risk of over dose.

Barbiturates in high doses cause depression of the respiratory centre of the brain leading to decreased drive for respiration. In severe cases of over dosage there is a complete suppression of respiration leading to respiratory failure.

Peripheral Nervous System depression

The peripheral nervous system is also depressed with over dosage of barbiturates. There is a decreased excitation of neuronal receptors that is enhanced by several other concomitant agents and drugs.

Cardiovascular depression

There is decreased cardiac contractility and cardiac output. This means the heart pumps blood with less power of contraction. There is also a decrease in blood flow to the brain.

Action on enzymes of the liver

There are several enzymes present in the liver that function in metabolizing various drugs. Barbiturates enhance the action of these enzymes. This is called enzyme induction.

Enzyme induction leads to increased metabolism of certain medications concomitantly taken along with barbiturates. This means the duration of action of these drugs is markedly reduced when taken alongside barbiturates.

Some of the drugs whose metabolism and effectiveness is affected by barbiturate use include anti-seizure drugs like phenytoin and carbamazepine, antibiotics like rifampicin etc.

Action on the renal function

There is decreased flow rate (glomerular flow rate) into the kidneys and decreased blood flow to the kidneys due to use of barbiturates. This results in lowered blood pressure and decreased urine volume

Barbiturate risks in older patients and pregnant women

The risk of side effects of barbiturates is higher in older patients and among pregnant women. This is because with age the ability to excrete and eliminate the drugs from the system decreases.

Elderly over the age of 65 are at higher risk of experiencing adverse effects of barbiturates and also are at risk of drug dependence and accidental overdose.

If taken during pregnancy these agents pass through the mother’s blood into the fetus via the placenta. The baby may be born with congenital abnormalities.