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Q2)
Introduction
“Benzodiazepines – wonder drug or worst nightmare?”
Benzodiazepines can be used to treat a range of neurological diseases and disorders and is
particularly useful in the treatment anxiety. Because of their wide range of therapeutic
benefits, benzodiazepines may be described as a wonder drug, however, these drugs can
produce significant adverse effects and should be highly regulated.
Clinical uses of Benzodiazepines
Benzodiazepines have several advantageous clinical uses. There many examples of
benzodiazepines and each of which, differ largely in their duration of effect. Ultrashort
duration benzodiazepines may be used for the treatment of insomnia. Examples of ultrashort
duration benzodiazepines include midazolam and zolpidem, which both function as hypnotics
(or sleeping pills). Benzodiazepines are the most commonly used and effective drug type
used to treat anxiety, and they are particularly useful for treatment of acute anxiety states.
Anxiety is defined as a specific emotional state which consists of unpleasant, consciously
perceived feelings of nervousness, tension and apprehension with associated activation or
arousal of the autonomic nervous system. Benzodiazepines are also commonly used in
behavioural emergencies as well as certain medical, surgical, and dental procedures.
Benzodiazepines may also be used as an anti-epileptic treatment; however, benzodiazepines
are only ever used in extreme cases of epilepsy because of their associated adverse effects.
For example, Benzodiazepines are used to treat status epilepticus, an extreme epileptic
condition in which a seizure may be continuously lasting for over 30 minutes.
Benzodiazepine’s Mechanism of Action
Benzodiazepines act by enhancing GABAergic transmission at the GABAA receptor, a ligand
gated ion channel which binds the main inhibitory neurotransmitter in the brain, gamma-
aminobutyric acid (GABA). This receptor is permeable to Cl- and thus, activation of the
receptor opens the channel and hyperpolarises the neuron and reduces its excitability. The
GABAA receptor has a pentameric structure comprising 5 different subunits (α, β and γ). In
vivo, each receptor comprises 2α, 2β and 1γ subunit, which are organised into a circular
structure with the sequence α-β-α-β-γ surrounding the pore. There 6 different types of α
subunit (α1-α6) whereas, there is only 3 of each type of β (β1-β3) and γ (γ1-γ3) subunit. The
pentameric structure also comprises 5 major binding sites including a Benzodiazepine
binding site. Benzodiazepines bind to the receptor at their specific binding site and increase
the affinity of GABA for the receptor and thus enhancing the action of GABA at the GABA A
receptor. Note that both barbiturates and Neurosteroids have the same effect to different
extents. Depending on which subunit the benzodiazepine binds appears to mediate different
effects of the drug. For example, if benzodiazepines bind the α1 subunit they have anti-
convulsant, sedative, amnesic and addictive effects, whereas if they bind the α3 or α5 subunit,
they produce muscle relaxation effects. For benzodiazepines to have anxiolytic effects, they
must bind the α2 subunit which also produces muscle relaxation effects. This leads to many
adverse effects associated with benzodiazepine treatment; however, it also suggests that α2
selective drugs may be developed which have anxiolytic effects without sedative, amnesic
and addictive effects.
Pharmacological effects
Benzodiazepines have a wide range of pharmacological effects making them a very effective
drug treatment, however severe adverse effects may develop as a consequence. Primary
examples of beneficial therapeutic effects of benzodiazepines include:
1) Sedation and the induction of sleep: Benzodiazepines reduce the time it takes an
individual to fall asleep and they also increase the total amount of time slept.
Benzodiazepines are useful for transient causes of sleep disturbance including jet lag and
for use as hypnotics however, they are only recommended for short durations as tolerance
and/or dependence can occur, as well as rebound insomnia. Benzodiazepines may also be
used as a premedication prior to surgery, due to its sedative and amnesic properties upon
binding to the α1 GABAA subunit.
2) Reduction of muscle tone: Increased muscle tone is a common feature of anxiety states
and can cause additional symptoms, such as headaches. Benzodiazepines may be used to
reduce increased muscle tone via central action on GABAA receptors located mostly on
the spinal cord. They may also be used to relax muscle spasms as binding the α2 subunit
produces muscle relaxation effects. Although this is mostly seen as a beneficial
pharmacological effect of benzodiazepines, in cases of abuse or following I.V.
administration in anaesthesia, an obstruction of the airways may occur, causing severe
and potentially fatal consequences.
3) Anticonvulsant effects: One mechanism by which anti-convulsants act, is by enhancing
the action of the inhibitory neurotransmitter, GABA. GABAergic transmission may be
enhanced by increasing the affinity of GABA for the GABAA receptor which can be
achieved by the binding of benzodiazepines. Benzodiazepines are occasionally used in the
treatment of epilepsy including the treatment of life-threatening epilepticus (unbroken
series of seizures). All benzodiazepines have been shown to have anticonvulsant activity
in experimental animals however, only certain benzodiazepines have been found to
produce anti-convulsant effects in humans and some have even caused worsened epileptic
effects. Since epileptic treatment must be continuous, benzodiazepines can be a
dangerous form of treatment due to their addictive properties and the likelihood of a
patient to develop tolerance and dependence. In general (non-extreme) cases of epilepsy,
drugs such as Phenytoin, Carbamazepine, Valproate, and Ethosuximide are preferentially
used in treatment as they have far fewer unwanted effects.
4) Anterograde amnesia effects: Benzodiazepines may be used to prevent the formation of
memories in events experienced while under their influence (e.g. flunitrazepam). This
effect is essentially unique to benzodiazepines in relation to other CNS depressants.
 Amnesiac effects of benzodiazepines are likely due to the binding of the drug to the α5
subunit of the GABAA receptor.
5) Reduction of Anxiety and Aggression: Benzodiazepines have proven useful for acute
anxiety states and are the main drug type used in treating anxiety. Paradoxically,
benzodiazepines have been found to potentially generate an increase in aggression in
some patients. This is especially seen with the use of the ultrashort acting triazolam.
Unwanted Effects
At normal clinical doses, benzodiazepines can produce a number of adverse side effects,
including drowsiness, confusion, amnesia, impaired coordination, and enhanced effects of
other CNS depressants such as alcohol. Impaired coordination affects normal manual skills
which is a common problem the morning after use of ultrashort duration benzodiazepines
used as hypnotics, e.g. midazolam. Tolerance to benzodiazepines may develop and results in
an increased dose required to produce the same effects. Physical dependence is also a
concerning adverse effect associated with prolonged use of benzodiazepines. These drugs
induce a physical withdrawal syndrome even after a short-term use. For example, triazolam is
a short-acting benzodiazepine which has been taken off the market as it induced physical
withdrawal symptoms in some patients within a few hours, even after a single dose. A
benzodiazepine overdose is relatively less dangerous than other anxiolytic/hypnotic drugs,
but it may cause prolonged sleep without serious respiratory or cardiovascular depression.
Although benzodiazepine overdose may be “relatively less dangerous”, in combination with
other CNS depressants (e.g. alcohol), they can lead to life-threatening respiratory depression.

It is clear that benzodiazepines have numerous therapeutic benefits, however their use must
be heavily regulated due to their potentially severe unwanted effects.

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Reference(s)
 Rang & Dale’s Pharmacology, 7th Ed.