Introduction to Benzodiazepines Pharmacology

Benzodiazepines are among the most widely prescribed classes of medicines. They are used in the treatment of a wide variety of conditions – from anxiety to seizures – not least because of their mechanism of action. Today, we review the essential and relevant facts that underpin benzodiazepines pharmacology.

The first benzodiazepine, chlordiazepoxide, was discovered in 1955 by Leo Sternbach of the Swiss pharmaceutical giant, Hoffmann-La Roche. Marketed as Librium, it had notable sedative, anticonvulsant and muscle relaxant properties.

Eight years later another medicine, called diazepam, was introduced to the world. It was through the introduction of benzodiazepines that barbiturates were to go into terminal decline.

Fourteen years later, in 1977, benzodiazepines became the most widely prescribed class of medicines in the world.

Even today, they play an instrumental role in the treatment of a wide variety of medical conditions.

Pharmacology of Benzodiazepines

Before we review the mechanisms that underpin benzodiazepines pharmacology, let’s first review the many indications that they are used to treat:

  • First-line treatment of seizures and status epilepticus
  • Short-term treatment of both anxiety and insomnia
  • First-line treatment of alcohol withdrawal reactions
  • Sedatives for interventional surgeries

Benzodiazepines are compounds whose chemical structure is a fusion between a benzene ring and a diazepine ring. Through this fundamental structure they exert their anxiolytic, anticonvulsant, sedative, hypnotic and muscle relaxant properties at their target receptor.

Most benzodiazepines can be identified through their suffix -pam. The exceptions to this rule contain ‘-aze-’ within their drug names.

Examples of benzodiazepines include:

  • Diazepam
  • Lorazepam
  • Oxazepam
  • Temazepam
  • Nitrazepam
  • Midazolam
  • Chlordiazepoxide
  • Clorazepate

With these medicines in mind, let’s take a closer look at benzodiazepines pharmacology; the mechanism of action through which they exert their therapeutic effects.

Mechanism of action

The mechanism of action of benzodiazepines is simple.

Their target is the GABAA receptor; a chloride channel that opens in response to the binding of GABA, an inhibitor neurotransmitter, to the receptor.

Once the channel opens, chloride floods into the cell – meaning the cell is less receptive to the effects of depolarisation.

That’s where benzodiazepines come in. Benzodiazepines encourage the binding of GABA to the GABAA receptor, enhancing its inhibitory effects throughout the brain.

With less depolarisation, action potentials begin to dry up. An inhibitory, depressant, effect takes hold. It is this depressant effect that manifests in the many therapeutic roles that benzodiazepines offer the clinician.

In real terms, less depolarisation means:

  • Reduced anxiety
  • Increased sedation
  • Increased sleepiness
  • Anticonvulsive effects

Neurons in the brain become accustomed to the effects of benzodiazepines, leading to tolerance. As a result, when patients need to be withdrawn from the medicines, they should be withdrawn over a prolonged and defined period. This reduces the incidence of withdrawal effects.

Benzodiazepine Pharmacokinetics

Not all benzodiazepines have the same activity. They are divided into:

  • Short-acting
  • Intermediate-acting
  • Long-acting

Short and intermediate-acting drugs are generally more suitable for treating insomnia. Long-acting drugs are preferable for conditions such as anxiety.

SHORT-ACTING

The “ATOM” drugs:

  • Alprazolam
  • Triazolam
  • Oxazepam
  • Midazolam

INTERMEDIATE-ACTING

The “FuN TLC” drugs:

  • Flunitrazepam
  • Nitrazepam
  • Temazepam
  • Lorazepam
  • Clonazepam

LONG-ACTING

Easier to recall as they contain two rogue-named drugs that don’t end in “-pam”, as well as diazepam – the most well-known benzodiazepine.

  • Diazepam
  • Flurazepam
  • Clorazepate
  • Chlordiazepoxide

Long-acting compounds have a greater risk of accumulating in the elderly and in patients with reduced liver function. However, long-acting compounds are associated with reduced rebound effects and withdrawal effects.

Side effects

Benzodiazepines are associated with the following side effects:

  • Drowsiness
  • Sedation
  • Decreased alertness
  • Lack of coordination / concentration
  • Decreased libido

Long-term use of benzodiazepines is associated with behavioral disturbances – agitation, stress, depression and anxiety.

These are sometimes referred to as “paradoxical effects”.

Clinical considerations

When we talk about the clinical factors of benzodiazepines, we need to think about:

  • That the elderly are more likely to experience side effects, including falls, and so should be administered a reduced dose.
  • That withdrawal and rebound effects are less likely to occur with long-acting benzodiazepines compared to short-acting drugs.
  • That benzodiazepines should be avoided in patients with significant respiratory impairment or neuromuscular disease, such as myasthenia gravis.
  • That benzodiazepines should be avoided in patients with liver failure due to the risk of hepatic encephalopathy. However, if their use is necessary, drugs – such as lorazepam, which relies less on the liver for metabolism – may be used.
  • That side effects of benzodiazepines are increased in the presence of alcohol and opioids.
  • That drugs which inhibit CYP 450 enzymes – such as fluconazole, macrolides, diltiazem, amiodarone and protease inhibitors etc. – increase the risk of side effects with benzodiazepines.

In terms of drug choice and indications:

  • That IV diazepam or lorazepam are commonly used as first-line agents in the treatment of status epilepticus.
  • Nitrazepam and flunitrazepam are predominantly used in the short-term treatment of insomnia.
  • Midazolam is the one of the best choices for sedation for interventional procedures.
  • Chlordiazepoxide is often used as one of the first drug treatment options for alcohol withdrawal.

Benzodiazepines pharmacology is vast and complex. We have only touched upon many of the key factors you should consider. They remain a vital, instrumental drug class in the clinician’s toolkit. For more information and quiz questions on benzodiazepines, join our member’s zone today.