Benzodiazepines, GABAergic drugs and the GABA-A receptor

Benzodiazepines are GABA agonists, binding indirectly to the GABA-A receptor but not the ligand binding site itself, and GABA binding to the ligand site is still neccessary for ion channel opening. Benzodiazepines bind to an allosteric site on the receptor know as the benzodiazepine binding site. When benzodiazepines are bound to the receptor in the presence of GABA, ion pore opening is enhanced, and therefore allowing greater conductance of Cl- ions through the pore.

The GABA-A receptor is a heteromer consisting of 5 protein subunits (pentamer) in a ring shape around a central pore. All GABA-A receptors contain α and β subunits, with most containing 2α and 2β subunits and 1γ subunit (α₂β₂γ). 6 different α _{subunits, 3}β and ₃γ subunits exist, so there are many possibilities. The GABA binding site is located between alpha and beta subunits, making two per receptor protein, and the benzodiazepine binding site exists between the alpha and gamma subunits, making one available in a common receptor protein. Note: Not all GABA-A receptors have a benzodiazepine site - some do not have gamma subunits, and α4 and α6 subunits are arginine not histine based meaning they cannot functionally bind with benzodiazepines. Binding sites with an α1 subunit  may higher affinity for more sedative benzodiazepines over binding sites with α2 or α3 subunits, which may be associated with drugs with a more anxiolytic effect.

Benzodiazepines - A Drug History

Benzodiazepines are a class of drugs with varying sedative, hypnotic, anxiolitic, anticonvulsant and muscle relaxant properties based on a core molecule containing a benzene and diazepine ring. The first benzodiazepine (chlordiazepoxide) was discovered in 1955 and the chlordiazepoxide and diazepam were released by Hoffmann LaRoche in the 60's with the brandnames Librium and Valium respectively. They changed the world of pharmacology and medical prescribing (along with meprobamate and methaqualone) by replacing barbiturates for most uses, and in time replacing methaqualone and its derivatives too with one major reason being the therapeutic index for clinical benzodiazepine use is far wider than many drugs with similar properties with death rarely occuring from overdose of a benzodiazepine if taken alone.

Benzodiazepines were considered relatively safe and problem-free at least compared to the drugs they replaced. They quickly became prescribed for a variety of uses. The Rolling Stones released a song called "Mothers Little Helper" in 1967 about Valium, with the lyrics:-  

"She goes running for the shelter

Of a mother's little helper

And it helps her on her way

Gets her through her busy day."

Valium became the biggest pharmaceutical seller in the US for the 1970's with 2.3bn tablets prescribed in 1978. The drugs were directly marketed to the public as well as to doctors. During the 70s, 1 in 5 European women and 1 in 10 European men would be prescribed a benzodiazepine at some point annually. As the 70s progressed reports of tolerance, dependence and withdrawal symptoms began to increase. In the 1980s media interest grew as evidence reguarding the use of benzodiazepines became more and more convincing. The largest ever British class-action lawsuit concerned drug manufacturers involving over 14,000 plaintiffs - an event that changed procedures for class action litigation in the UK.
Benzodiazepine prescribing was clamped down upon in most countries because of widespread use and misuse. Although all drugs of the class have misuse and abuse potential, some have gained notorioty. Flunitrazepam (Rohypnol) is synonomous for the 'Date Rape' drug even if its use as a date rape drug is rare in many countries. Temazepam has a long history of misuse in Europe, particularly Scotland and particularly when available in liquid filled capsules, the drug was injected. Sometimes benzodiazepines are still injected but because of low solubility necrosis may occur. Benzodiazepines in combination with opiates or alcohol are a the most common cause of accidental overdose and benzodiazepine-alcohol combinations are common in deliberate overdoses.
Modern day prescribing of benzodiazepines is very much different to the "cure for all ailments" attitude of the 60's and 70's - They are however of great clinical use for a variety of reasons such as:-

• Status epilepticus
• Short-term treatment of acute anxiety
• Short-term treatment of acute insomnia
• Alcohol and opiate withdrawal
• Pre/Post-operative sedation 

According to the British National Formulary:- 

“Benzodiazepines are indicated for the short-termrelief (2-4
weeks only) of anxiety that is severe, disabling or subjecting
the individual to unacceptable distress, occurring alone or in
association with insomnia or short-term psychosomatic,
organic or psychotic illness.”

Indeed, despite the risks in prescribing benzodiazepines the clinical benefits to patients may outway those risks:-

"…Benzodiazepines will usually be reserved for the
treatment of patients who have not responded to at least
two treatments (such as after non-response to both an
SSRI and a psychological treatment) but concerns about
potential problems in long term use should not prevent their
use in patients with persistent, severe, distressing, and
impairing anxiety symptoms (Nutt, 2005)."