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| | Benzodiazepines Basic information |
| | Benzodiazepines Chemical Properties |
| | Benzodiazepines Usage And Synthesis |
| Chemical Properties | The basic chemical structure of the benzodiazepines
consists of a benzene ring coupled to a seven-member
heterocyclic structure containing two nitrogens (diazepine)
at positions 1 and 4. Of the 2,000
benzodiazepines that have been synthesized, approximately
15 clinically useful compounds are on the market
in the United States. | | Definition | Benzodiazepines are a group of medicines which are sometimes used to treat anxiety. | | Biological Functions | Benzodiazepines also possess muscle relaxant activity.
Their pharmacology is discussed in Chapter 30.
Diazepam (Valium) has been used for control of flexor
and extensor spasms, spinal spasticity, and multiple sclerosis.
The muscle relaxant effect of the benzodiazepines
may be mediated by an action on the primary afferents
in the spinal cord, resulting in an increased level of
presynaptic inhibition of muscle tone. Polysynaptic reflexes
are inhibited.The most troublesome side effect is
drowsiness, which is dose dependent. Tolerance to both
the therapeutic effects and the side effects develops. | | Biological Functions | The benzodiazepines constitute the most commonly used
group of anxiolytics and sedative–hypnotics. Since the
first member of this group, chlordiazepoxide, was introduced,
many congeners have been marketed. Most of
these drugs possess anxiolytic, sedative–hypnotic, and
anticonvulsant properties. Thus, the clinical indications
for specific benzodiazepines are not absolute. and their
uses overlaps considerably. | | General Description | For details of the chemistry and SARs of the BZDs, see thediscussion of anxiolytic sedative–hypnotic drugs. Amongthe current clinically useful drugs, the structural features associatedwith anticonvulsant activity are identical with thoseassociated with anxiolytic sedative–hypnotic activity. | | Mechanism of action | The benzodiazepines bind with high affinity to specific
macromolecules within the central nervous system.
These benzodiazepine-binding sites (receptors) are
closely associated with the receptors for γ-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter
in the mammalian brain. Benzodiazepines potentiate
GABAergic neurotransmission in essentially all
areas of the central nervous system. This enhancement
is thought to occur indirectly at the postsynaptic
GABAA receptor complex.
The functional significance of this drug–receptor interaction
is that the receptor complex regulates the entrance
of chloride into the postsynaptic cells. The increase
in chloride conductance mediated by GABA is
intensified by the benzodiazepines. This facilitation of
GABA-induced chloride conductance results in greater
hyperpolarization of these cells and therefore leads to
diminished synaptic transmission.
Another chemical class of sedative–hypnotic drugs,
the barbiturates, also binds to receptors associated with
the GABA–chloride ionophore, but these drugs appear
to prolong rather than intensify GABA’s effects. Fig.
24.4 shows the presumed drug receptor–GABA–
chloride ionophore relationship.
In addition to the clinically useful benzodiazepines,
which act as agonists at the benzodiazepine receptor, at
least two other types of ligands also interact with this
binding site. These are the benzodiazepine receptor
antagonists and the inverse agonists. For example,
flumazenil (Romazicon) is a receptor antagonist that selectively
blocks the effects of other benzodiazepines at
their binding sites; it has clinical application in the treatment treatment
of benzodiazepine overdose and in the reversal of
benzodiazepine-induced sedation. The inverse agonists
are compounds that interact with benzodiazepine receptors
and decrease, rather than increase, GABAmediated
changes. They also can antagonize the effects
of benzodiazepine agonists and when administered
alone, can be anxiogenic and proconvulsant. | | Pharmacology | The benzodiazepines, when given by slow IV infusion to
induce anesthesia, have minimal influences on the cardiovascular
and respiratory systems. Thus, they may be
logical substitutes for barbiturates in poor-risk patients
who cannot tolerate cardiovascular depression. In other
respects, they appear pharmacologically similar to the
barbiturates. IV administration causes unconsciousness
without analgesia; skeletal muscle relaxation is inadequate
for intubation or short surgical procedures.
Consequently, when these characteristics of anesthetic
management are desired, benzodiazepines must be
coadministered with appropriate analgesic drugs and
neuromuscular blocking agents.
The popularity of the benzodiazepines as an anesthetic
supplement in cardiac surgery is related to their
amnesic potential.They can ensure unawareness during
the initial period, when the anesthetics are being diluted
in the fluid of the bypass circuit. Lorazepam is often
chosen for this purpose because it is longer acting and
more potent than either midazolam or diazepam.
Benzodiazepine administration may cause amnesia
even when used in doses that do not produce unconsciousness.
Antegrade amnesia may occur with the
doses that are used to relieve preoperative anxiety. | | Pharmacology | Although it is widely claimed that the benzodiazepine
drugs have a specific calming or anxiolytic effect, their
most prominent and easily quantifiable action is central
nervous system depression. In very low therapeutic
doses, this depression manifests as relief of anxiety that
is often accompanied by a feeling of sluggishness or
drowsiness. As the dose is increased, the degree of depression
is intensified such that muscle relaxation, hypnosis and a more intense central nervous system depression
occur. This depression is related to the ability
of these drugs to facilitate the inhibitory actions of
GABA.
A significant advantage of the benzodiazepines over
other central nervous system depressants (e.g., the barbiturates)
is that they possess a much greater separation
between the dose that produces sleep and the dose that
produces death. This increased margin of safety has
been one of the major reasons benzodiazepines have
largely replaced the barbiturates and other types of sedative–
hypnotics in the treatment of anxiety and insomnia.
In addition, benzodiazepine administration is associated
with few side effects. | | Clinical Use | Anxiety
Anxiety disorders are among the most common forms
of psychiatric illness. Anxiety often accompanies other
psychiatric disease and such medical illnesses as angina
pectoris, gastrointestinal disorders, and hypertension.Anxiety that results from fear caused by an acute illness
or a stressful event, such as a divorce or the loss of a
loved one, is usually self-limiting and can be of relatively
short duration. Other disorders that have anxiety
as a component are not necessarily associated with a life
event, and may persist for considerable periods, even
throughout the individual’s life.
Both acute and chronic anxiety can be treated with
benzodiazepines, although it is anticipated that for most
anxiety disorders counseling will also play an important
role. Benzodiazepines employed in the treatment of
anxiety should be used in the lowest effective dose for
the shortest duration so that they will provide maximum
benefit to the patient while minimizing the potential
for adverse reactions. For most types of anxiety,
none of the benzodiazepines is therapeutically superior
to any other. Choice of a particular agent is usually
made on the basis of pharmacokinetic considerations.
A benzodiazepine with a long half-life
should be considered if the anxiety is intense and sustained.
A drug with a short half-life may have advantages
when the anxiety is provoked by clearly defined
circumstances and is likely to be of short duration.
Insomnia
All of the benzodiazepines will produce sedative–
hypnotic effects of sufficient magnitude to induce sleep,
provided that the dose is high enough. However, the aim
in the treatment of sleep disorders is to induce sleep
that is as close as possible to natural sleep so that the
patient falls asleep quickly, sleeps through the night,
and has sleep of sufficient quality to awake refreshed.
Extensive sleep studies have been conducted with a
variety of sedative–hypnotic drugs, and all of these
drugs appear to alter the normal distribution of rapid
eye movement (REM) and non-REM sleep. Most of the
older sedative–hypnotic agents markedly depress REM
sleep. In contrast, when the benzodiazepines are used in
appropriate doses, they depress REM sleep to a much
smaller extent. As with treatment of anxiety, the choice of a particular benzodiazepine to treat a sleep disturbance
is again generally based on pharmacokinetic criteria.
While longer-acting compounds may ensure that a
patient will sleep through the night, they also may cause
cumulative effects resulting in daytime sluggishness or
drug hangover. Shorter-acting compounds avoid the
hangover problem, but their use may be associated with
early awakening and an increase in daytime anxiety. | | Clinical Use | Several benzodiazepines are used in the management of
epileptic seizures, although only a few are approved for
the treatment of seizure disorders in the United States.
Since the benzodiazepines share many properties, they
will be discussed as a class; individual members will be
mentioned for specific indications.
The primary action of the benzodiazepines as anticonvulsants
is to enhance inhibition through their interaction
with the GABAA receptor at the benzodiazepine
binding site. However, there appears to be an additional
action of benzodiazepines: blocking voltage-dependent
sodium channels. This effect is not seen at usual doses
but is likely a factor in their use in the treatment of status
epilepticus.
Benzodiazepines are well absorbed, and the oral
route is preferred in most situations. In the treatment of
status epilepticus, the preferred route is usually intravenous.
Benzodiazepines are extensively metabolized
by the microsomal drug-metabolizing system; frequently
an active compound is broken down to another
agent that is also active pharmacologically. This is the
reason for the long duration of action of several benzodiazepines.
The benzodiazepines have many clinical indications
and are discussed in Chapters 25, 30, 35, and 40. As
AEDs, they have their major usefulness in the treatment
of absence, myoclonic, and atonic seizures and in
the emergency treatment of status epilepticus.
Drowsiness occurs readily and unfortunately is usually
a problem at therapeutic doses. The other limiting
side effect of the benzodiazepines is the rapid development
of tolerance to their anticonvulsant effects.
Although all of the benzodiazepines are similar, certain
ones are employed more for the treatment of
seizure disorders. Clonazepam was the first benzodiazepine
approved in the United States specifically for
the treatment of convulsive disorders. Clonazepam is a
very long acting compound with potent anticonvulsant
activity. Unfortunately, sedation and tolerance tend to
limit its usefulness. Drooling and hypersalivation may
be troublesome in children and in infants. | | Side effects | Most adverse effects associated with use of the benzodiazepines
are related to their ability to produce central
nervous system depression.These include drowsiness, excessive
sedation, impaired motor coordination, confusion,
and memory loss.These effects are most troublesome during
the initial week or two of treatment. Subsequently, the
patient becomes tolerant and these effects produce less
difficulty. Although for most individuals these symptoms
are mild, patients should be cautioned against engaging in
potentially dangerous tasks such as operating machinery
or driving a car during the initial treatment period.
Less common adverse effects include blurred vision,
hallucinations, and paradoxical reactions consisting of
excitement, stimulation, and hyperactivity.Also, a variety
of gastrointestinal complaints occur, and blood
dyscrasias have been reported, but these are rare.
Benzodiazepine administration during pregnancy, delivery,
or lactation has the potential to have adverse effects
on the fetus or newborn.
As with other central nervous system depressants,
the effects of benzodiazepines are additive with those
of ethanol. Patients should be warned that ethanolcontaining
beverages may produce a more profound depression
when taken simultaneously with a benzodiazepine.
One of the major reasons for the popularity of the
benzodiazepines is their relative safety. Overdoses with
the benzodiazepines occur commonly, but fatal toxic occurrences
are rare. Fatal intoxications are more likely in
children, in individuals with respiratory difficulties, and
in individuals who have consumed another central nervous
system depressant, such as alcohol. After an overdose,
the patient begins a deep sleep that may last for 24
to 48 hours, depending on the dose. However, even with
large overdoses, the patient can usually still be aroused. | | Side effects | Midazolam (Versed), diazepam (Valium), and lorazepam
(Ativan) are benzodiazepine derivatives that
are useful in anesthesia. Midazolam is the most popular
of these agents for the induction of anesthesia. Its popularity
is related to its aqueous solubility and to its short
duration of action, which permits a prompt return of
psychomotor competence. Unlike midazolam, lorazepam
and diazepam are not water soluble and must
be formulated in propylene glycol; the latter is irritating
to the vasculature on parenteral administration.
Benzodiazepines are useful as orally administered
premedications. They are also used intravenously in
doses that produce conscious sedation rather than hypnosis.
Sedated patients tolerate unpleasant procedures
(e.g., wound repair, bronchoscopy, angiography) while
maintaining cardiorespiratory function and the ability
to respond to tactile stimulation or verbal commands.
Midazolam has a shorter half-life (t1/2β = 1.3–2.2
hours) than either diazepam (t1/2β = 30 hours) or lorazepam
and is not converted in the liver to active
metabolites, as is diazepam. Thus, use of midazolam results
in a more rapid return to psychomotor competence.
Doses may need to be lowered by at least 30% in
older patients and in those premedicated with opioids
or other sedative drugs. | | Drug interactions | When used with other sedative–hypnotics or alcohol,
the benzodiazepines will produce additive central nervous
system depression.
Many benzodiazepines are metabolized by the cytochrome
P450 (CYP) enzyme designated CYP3A4.
CYP3A4 is inhibited by grapefruit juice and by drugs
such as ketoconazole, itraconazole, nefazodone, erythromycin,
and ritonavir. Coadministration of these substances
along with a benzodiazepine may result in intensification
and prolongation of the benzodiazepine
effect. Conversely, rifampin, carbamazepine, and phenytoin
can induce the CYP3A4 enzyme, and therefore
their coadministration can reduce the therapeutic effect
of the benzodiazepines. | | Metabolism | Benzodiazepines are usually given orally and are well
absorbed by this route. Since the benzodiazepines are
weak bases, they are less ionized in the relatively alkaline
environment of the small intestine, and therefore,
most of their absorption takes place at this site. For
emergency treatment of seizures or when used in anesthesia,
the benzodiazepines also can be given parenterally.
Diazepam and lorazepam are available for intravenous
administration.
The distribution of the benzodiazepines from blood
to tissues and back again is a dynamic process with considerable
influence on the onset and duration of the
therapeutic effects produced by these compounds.
Those having greater lipid solubility tend to enter the
central nervous system more rapidly and thus tend to
produce their effects more quickly. Several of the benzodiazepines
have therapeutic effects that are much
shorter in duration than would be predicted based on
their rates of metabolism and excretion; redistribution
away from the central nervous system is of primary importance
in terminating their therapeutic effects.
Although tissue redistribution of benzodiazepines
may be an important means of terminating the actions of
selected members of this class of drugs, many benzodiazepines
do undergo extensive biotransformation.
Metabolism takes place both by dealkylation
and conjugation reactions. In many instances,
dealkylation can result in the formation of pharmacologically
active compounds. Indeed, most clinically available
benzodiazepines are converted in the liver to one or
more active metabolites. In several cases the active
metabolites have a much longer half-life than the parent
compound. In one case, acid hydrolysis in the stomach
converts an inactive compound (clorazepate) to an active
drug (nordazepam).The water-soluble metabolites of the
benzodiazepines are excreted primarily in the urine.
Since most of the benzodiazepines do undergo biotransformation,
it is possible that changes in liver function
may alter the duration of the therapeutic effect
produced by these drugs. Despite the fact that few clinical
studies have demonstrated serious toxicities associated
with benzodiazepine administration in individuals
with compromised liver function, prudence in the use of these compounds in the elderly and in individuals with
liver disease seems advisable.
One of the great disadvantages associated with
many of the sedative and hypnotic drugs (e.g., barbiturates,
propanediol carbamates), which have now largely
been replaced by the benzodiazepines, is the fact that
those drugs are very effective inducers of hepatic drugmetabolizing
enzymes. Since the benzodiazepines are
only weak inducers of hepatic microsomal enzymes,
they cause relatively few clinically significant drug interactions
related to metabolism of other drugs. |
| | Benzodiazepines Preparation Products And Raw materials |
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