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BARBITURATES – AN ABUSE

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About Author:
Pooja Dhiman
Lecturer
Chitkara University, Solan [H.P]
Pooja.dhiman@chitkarauniversity.edu.in

The WHO defines drug abuse as “persistent or sporadic excessive drug use inconsistent with or unrelated to acceptable medical practice.” Barbiturates are the drugs which act on the central nervous system and produce depression.

Barbituric acid, the basic structure of all barbiturates. In the course of 20th century, more than 2500 barbiturates were synthesized, 50 of which were eventually employed clinically. These drugs can be broadly classified as “hypnotics and sedatives”. The pharmacological effects of barbiturates scale from mild sedation to anesthesia. These drugs are prescribed to treat insomnia, anxiety, tension and also help in palliating epileptic seizures and hence barbiturates are also termed as “downers”. They are also effective as analgesic, however these effects are somewhat weak, preventing barbiturates from being used as anesthetic in surgery, in the absence of other analgesics. They have addiction potential, both physical and psychological. Barbiturates have now been replaced by benzodiazepines in routine medical practice-for example, in the treatment of anxiety and insomnia-mainly because benzodiazepines are significantly less dangerous in overdose. However barbiturates are still used in general anaesthesia for epilepsy, and assisted suicide. Barbiturates in most of the cases used either as free acids or as salts of sodium, calcium, potassium, magnesium, lithium, etc. Codein and Dionine based salts of barbituric acid have been developed.

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Classification of barbiturates:

  • Long acting barbuiturates-this group of barbiturates act for longer duration, some of them are Phenobarbitone, Mephobarbitone.
  • Short acting  barbiturates-Thse group of drugs act for short duration of action,some them are Butobarbitone, Serobarbitone, Pentobarbitone.
  • Ultra short acting barbiturates-These group of drugs act for very shorter duration of time, some are Thiopentane, Methohexitone, Hexobaarbitone.

Mechanism of action:
The principle amechanism of action of barbiturates is believed to be their affinity for the GABAA receptor (Act on GABA: BDZ receptor Cl- channel complex).GABA is the principle inhibitory neurotransmitter in the mammalian central nervous system (CNS). Barbiturates bind to the GABAA receptor at the beta subunit, which are binding sites distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABA-ergic effect, barbiturates also block the AMPA receptor, a subtype of glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABAA receptors and inhibit excitatory AMPA receptors can explain the CNS-depressant effects of these agents. At higher concentration, they inhibit the Ca2+-dependent release of neurotransmitters. Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the potency of GABA). The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in overdose.

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Further, barbiturates are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABAA receptor channel is only one of several representatives. This superfamily of ion channels includes the neuronal nAChR channel, the 5HT3R channel, the GlyR channel and others. However, while GABAA receptor currents are increased by barbiturates (and other general anaesthetics), ligand-gated ion channels that are predominantly permeable for cationic ions are blocked by these compounds. For example, neuronal nAChR channels are blocked by clinically relevant anaesthetic concentrations of both thiopental and pentobarbital.[16] Such findings implicate (non-GABA-ergic) ligand-gated ion channels, e.g. the neuronal nAChR channel, in mediating some of the (side) effects of barbiturates.

Uses:
This medication is used for seizure disorders. It is also used as a short-term sleep aid (for insomnia), and for tension relief (e.g., before a medical procedure) Barbiturates such as phenobarbital were long used as anxiolytics and hypnotics. Today, benzodiazepines have largely supplanted them for these purposes, because benzodiazepines have less potential for lethal overdoses.

Side-effects:
This medication causes drowsiness and dizziness. Other side effects may include stomach upset, headache, weakness, grogginess or dreaming. If these effects persist or worsen, inform your doctor. Notify your doctor if you develop: chest pain, rapid heart rate, nosebleeds, confusion, hallucinations. In the unlikely event you have an allergic reaction to this drug, seek immediate medical attention. Symptoms of an allergic reaction include: rash, itching, swelling, dizziness, trouble breathing. If you notice other effects not listed above, contact your doctor or pharmacist.

Precautions:
Tell to doctor about medical history, especially about: liver problems, blood disorders (porphyria), asthma, any allergies. Avoid alcohol while taking this as it can lead to extreme drowsiness. Use caution performing tasks requiring alertness such as driving or using machinery. Elderly persons are usually more sensitive to the effects of this medication. Use cautiously. This drug is not recommended for use during pregnancy. Consult your doctor before using this drug. This drug is excreted into breast milk though its effects on the nursing infant are unknown. Consult your doctor before you breast-feed.

Barbiturate Names

Generic Name

Street Name

Amobarbital

Downers, blue heavens, blue velvet, blue devils

Pentobarbital

Nembies, yellow jackets, abbots, Mexican yellows

Phenobarbital

Purple hearts, goof balls

Secobarbital

Reds, red birds, red devils, lilly, F-40s, pinks, pink ladies, seggy

Tuinal

Rainbows, reds and blues, tooies, double trouble, gorilla pills, F-66s

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Tolerance and dependence:
With regular use tolerance to the effects of barbiturates develops. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect. Barbiturate use can lead to both psychological and physical dependence and the drugs have a high abuse liability. Psychological addiction to barbiturates can develop quickly. The GABAA receptor, one of barbiturates' main sites of action, is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates, as well as the euphoric "high" that results from their abuse. especially clozapine, olanzapine or low potency phenothiazines eg chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required.

Overdose:
An overdose results when a person takes a larger-than-prescribed dose of a drug. Symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgment, drowsiness or coma, shallow breathing, staggering, and in severe cases coma and death. The lethal dosage of barbiturates varies greatly with tolerance and from one individual to another. Even in inpatient settings, however, the development of tolerance is still a problem, as dangerous and unpleasant withdrawal symptoms can result when the drug is stopped after dependence has developed.

generic structure of a barbiturate, including numbering scheme.

Barbiturates

Short Name

R1

R2

IUPAC Name

Allobarbital

CH2CHCH2

CH2CHCH2

5,5-diallylbarbiturate

Amobarbital

CH2CH3

CH2CH2CH(CH3)2

5-ethyl-5-isopentyl-barbiturate

Aprobarbital

CH2CHCH2

CH(CH3)2

5-allyl-5-isopropyl-barbiturate

Alphenal

CH2CHCH2

C6H5

5-allyl-5-phenyl-barbiturate

Barbital

CH2CH3

CH2CH3

5,5-diethylbarbiturate

Brallobarbital

CH2CHCH2

CH2CBrCH2

5-allyl-5-(2-bromo-allyl)-barbiturate

Phenobarbital

CH2CH3

C6H5

5-ethyl-5-phenylbarbiturate

How is barbiturate abuse diagnosed?
The diagnosis of barbiturate abuse is based on the history of the use of barbiturates by the affected individuals. Additional information about the abuse can be gathered from friends and family members of the affected individuals. Enquiry about the signs and symptoms of abuse is also performed. The pattern of drug use and the dosage commonly consumed can give an idea about the barbiturate abuse. Blood tests and urine tests may be used to detect the presence or levels of these drugs in the body.

How is barbiturate abuse treated?
There are many pharmacological and non-pharmacological modes of treatment that can help the abuser get rid of the above mentioned symptoms. However, the aim of therapy is to stop or control barbiturate abuse. Providing education to the abuser and his caregivers is the major concern of treatment, this also helps in preventing further complications. For the safety of abuser and as a preventionary measure, the physician may ask the abuser not to drive or operate machineries. Initial treatment may require the abuser to be admitted in the hospital to prevent any adverse event when the barbiturate use is stopped completely.

Barbiturate abuse treatment may include any of the following measures:

Detoxification: Detoxification procedure is done to flush out the toxic residues of barbiturates present in the patient’s body. During detoxification, medicines are given to help prevent withdrawal symptoms when the person stops taking barbiturates. The affected persons are also educated about the harms of barbiturate abuse and counseled for stress relief and coping with the problems in hand. You may also be advised to avoid places, people or things that remind about barbiturate use.

Medical treatment: 
The medical treatment in barbiturate abuse is largely symptomatic.

The healthcare provider may give certain medicines to relieve symptoms. These may include medicines to treat anxiety or sleeping problems. The physician may also suggest certain medicines to help control barbiturate abuse and other related problems. The dosage and frequency of the barbiturates may be altered to prevent you from becoming dependent upon these medications.

References:
1. Schears RM. Barbiturates. In: Tintinalli JE, Kelen GD, Stapczynski JS, Ma OJ, Cline DM, eds. Emergency Medicine: A Comprehensive Study Guide . 6th ed. New York, NY: McGraw-Hill; 2004:chap 163.
2. Public Health Service, US Department of Health, Education, and Welfare: Barbiturates as Addicting Drugs, Washington, DC: Publication No. 545, US Government Printing Office.
3. Fraser, H.F., et al:  Chronic Barbiturate Intoxication , Arch Intern Med (Chicago) 194:34-41 ( (July) ) 1954;. Isbell, H.:  Treatment of Barbiturate Addiction , Postgrad Med 9:3 ( (March) ) 1951;.
4 Essig, C.F.:  Failure of Diphenylhydantoin in Preventing Barbiturate Withdrawal Convulsions in Dog , Neurology (Minneap) 12:481-484 ( (July) ) 1962;.
5 Essig, C.F.:  Addictive and Possible Toxic Properties of Glutethimide , Amer J Psychiat 119:10 ( (April) ) 1963;.
6. Essig, C.F.; and Ainslie, J.D.:  Addiction to Meprobamate (Equanil and Miltown) , JAMA 164:1382 ( (July 20) ) 1957;.
7. Essig, C.F.:  Withdrawal Convulsions in Dogs Following Chronic Meprobamate Intoxication , Arch Neurol (Chicago) 80:414-417 ( (Oct) ) 1958;.

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