Pharmacology of Benzodiazepines

Benzodiazepines: Depression nowadays is very common, but it is mostly seen in young peoples. A person goes through different phases of life, some of them are happy moments and some are intensely unbearable. People might feel difficulty in facing them and they unfortunately develop depression as a result of continues failure in life.Disorders involving anxiety are among the most common mental disorders. Anxiety is an unpleasant state of tension, apprehension, or uneasiness (a fear that arises from either a known or an unknown source). The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations).

ANXIOLYTIC AND HYPNOTIC AGENTS
Episodes of mild anxiety are common life experiences and do not warrant treatment. However,severe, chronic anxiety may be treated with anti anxiety drugs (anxiolytics). Because many antianxiety drugs also cause some sedation, they may be used clinically as both anxiolytic and hypnotic (sleep- inducing) agents.

BENZODIAZEPINES
 Benzodiazepines are widely used anxiolytic drugs.
 They have largely replaced barbiturates in the treatment of anxiety and insomnia, because
benzodiazepines are generally considered to be safer and more effective.
 Benzodiazepines are commonly used, they are not necessarily the best choice for anxiety or insomnia.
CLASSIFICATION OF BENZODIAZEPINES
 Alprazolam
 Triazolam
 Diazepam
 Flurazepam
 Lorazepam
 Clorazepate

Key: ATDFLC
MECHANISM OF ACTION
The targets for benzodiazepine actions are the γ-aminobutyric acid (GABAA) receptors.
Gaba Receptors
 GABA is the major inhibitory neurotransmitter in the central nervous system, they reduce or inhibit the activity of the neurons or nerve cells.
 GABA plays an important role in behavior, body’s response to stress and controls fear and anxiety when neurons become over excited.
 GABA is a pentameric transmembrane ion channel gated structure.

 There are two classes of GABA receptors GABAA and GABAB
 GABAA in which a receptor is a part of ligand-gated ion channel which is a group of transmembrane ion channel proteins which allow ions such as sodium, potassium,calcium is allowed to pass through the membrane in response to the binding of a ligand(drug)
 GABAB are g-protein coupled receptors that open or close ion channels via intermediate(G-proteins) These receptors are composed of a combination of five α1, α2, β1, β2 and γ subunits.
WHAT HAPPENS WHEN THERE IS A PANIC ATTACK OF DEPRESSION?

1- During anxiety, Chloride channels are closed and there is no Cl- influx.
2- The channels for Cl- influx remain close until GABA binds to its receptor.
3- GABA neurotransmitter attaches at GABA receptor.
4- Chloride channel opens and Cl- influx increases.
5- If Benzodiazepine is give, it attaches to GABA receptor along with GABA neurotransmitter in result to which Cl- influx further increases causing “hyper-polarization” (inhibit action potential)

Short summary
GABA (neurotransmitter) attaches to GABA (receptor) = Cl- influx increases GABA(neurotransmitter) + Benzodiazepines attaches on GABA (receptor) = Cl- influx further increases(hyperpolarization)
MAJOR PHARMACOLOGICAL AND THERAPEUTIC ACTIONS OF

ANXIOLYTICS:

1. Reduction of anxiety
At low doses, the benzodiazepines are anxiolytic. They are thought to reduce
 E.g. Generalized anxiety disorder (GAD)
 social anxiety disorder
 posttraumatic stress disorder
 obsessive–compulsive disorder
 extreme anxiety associated with phobias, such as fear of flying.
The longer-acting agents, such as diazepam are often preferred in those patients with anxiety that may require prolonged treatment.
2. Amnesia (temporary loss of memory):
The shorter-acting agents are often employed as pre- medication for anxiety-provoking and unpleasant procedures, such as endoscopy, dental procedures, and angioplasty.
They cause a form of conscious sedation, allowing the person to be receptive to instructions during the surgical procedures Midazolam is used to facilitate Amnesia while causing sedation prior to anesthesia.

3. Seizures
Diazepam, lorazepam, and oxazepam are useful in the acute treatment of alcohol withdrawal and reduce the risk of withdrawal-related seizures.
4. Muscle relaxant
At high doses, the benzodiazepines relax the spasticity of skeletal muscle
Diazepam is useful in the treatment of skeletal muscle spasms.
5. Sleep disorders
A few of the benzodiazepines are useful as hypnotic agents.
Examples may include Triazolam used for insomnia.

RISKS OF HIGHER DOSES
Dependence:
Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given for a prolonged period. It Comprises of
 Physical dependence: The removal of drug evokes unpleasant symptoms usually opposite of drug effect.
 Physiological dependence: A drug user feels compelled to use the drug and suffer anxiety when separated from the drug

CLASSIFICATION OF BENZODIAZEPINE
(REGARDING DURATION OF ACTION)
1 Long acting (1-3 days)
Increase duration of Sleep
Examples: Clorazepate, Chlordiazepoxide, Diazepam, Flurazepam, Quazepam
2 Intermediate Acting (10-20 hours)
Peak sedative effect in 1-3 hours
1-2 hours before going to sleep
Examples: Alprazolam, Lorazepam, Temazepam
3 Short Acting (3-8 hours)
Examples: Oxazepam, Triazolam

BENZODIAZEPINE ANTAGONIST
Patients who have been taking Benzodiazepines from a long time develop toxicity. We may also do Gastric lavage, use activated charcoal, induce emesis, may do alkalization of urine and even
dialysis.Flumazenil is a GABA receptor antagonist that can rapidly reverse the effects of benzodiazepines
 Intra- venous (IV) administration only
 Onset is rapid
 Duration is short
 Half-life of about 1 hour
 Frequent administration may be necessary

By Mahum Zulqarnain Pharm-D University Of Central Punjab