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Pharm Fabs C Amaechina

SEDATIVES AND HYPNOTICS

Sedatives are drugs that cause sedation, relieve anxiety and exert calming effects, with
minimal depression of the central nervous system. Sedatives tend to remove worries and
exert a temporal calmness and reassurance on troubled mind. On the other hand,
hypnotics are drugs that cause hypnosis and enhance the onset and maintenance of state
of sleep that by all standards, is similar to natural sleep and importantly, from which the
patient can easily be aroused. Hypnotics achieve their effect by significantly depressing
the central nervous system.
The sedative and hypnotic effect of a drug is usually dose dependent, and correlates with
the degree of central nervous system depression. What we are trying to say here is that
sedatives achieve a mild depression of the central nervous system with the patient still
exhibiting a high level of consciousness whereas hypnotic exhibit a pronounced
depression of the central nervous system with complete loss of consciousness.
The dividing line a sedative and hypnotic effect of a drug is the dose of that drug taken at
any point in time. At much lower clinical dose, the effect is invariably sedative, while at
much higher clinical dose, the effect tends towards hypnosis.
These classes of pharmacological agents have found immense application in other areas
of medicines. They are used to achieve amnesia before surgical procedures. They are
used in the treatment of alcohol and other sedatives/hypnotics withdrawal syndrome and
also as muscle relaxants.
Clinically, induction of sedation or hypnosis can be said to have begun in the early 1800s
first with alcohol and the opium. These were replaced with bromide salts and chloral
hydrate before the introduction of ethyl alcohol which was then described as the knock
out drop. The introduction of paraldehyde marked the beginning of deliberate search for
newer synthetic sedative-hypnotic drugs.
Consequently, the barbiturates were introduced into clinical use, first with Phenobarbital
as the prototype drug in 1930. By the mid-1900s, the benzodiazepines were introduced
into clinical practice, and since have become the sedative-hypnotics of choice.

BENZODIAZEPINES
The benzodiazepines are the most widely used sedatives and hypnotic agents clinically.
Beside their hypnotic and sedative effects, they have very potent muscle relaxation,
anxiolytic and anticonvulsant properties. On the peripheral level, they cause dilatation of
the coronary artery and are potent neuromuscular blockers at very high doses.
Γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain that
functional depresses neuronal firing. GABA binds to all its receptor subtypes (GABAA,
GABAB and GABAC receptors. The benzodiazepines bind to GABAA–receptor at an
allosteric site that is different from the site bound by GABA thereby enhancing the GABA
induced ionic current especially chloride ions. Consequence of the opening of Cl- channels,
benzodiazepines potentiate the inhibitory effect of GABA neurotransmitter.
Some of the common benzodiazepines in clinical use especially in Nigeria include:
Diazepam (Valium), Nitrazepam (Mogadon), Bromazepam (Lexotan), Lorazepam (Ativan)
and Flunitrazepam (Rohypnol).

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Pharmacology and application of Benzodiazepines

Sleep: Sleep disorders are as varied as there are many causes. Sleep disorder could be
organic, psychological, or situational. No matter the cause, sedatives like
benzodiazepines have become resolution tools of such problems. At this point, it is
important to emphasize here that when the presenting clinical situation is insomnia
benzodiazepines are exceptionally effective and are the drugs of choice. Most
benzodiazepines decrease sleep latency, especially when used for the first time. They
also decrease the number of awakenings and its duration before falling asleep again.
Effect of benzodiazepines to a very large extent is dose dependent. As the dose increases,
the effect progresses from sedation to hypnosis and to a complete state of stupor. All the
stages of normal sleep are affected by benzodiazepines. In decreasing the sleep latency,
they in effect decrease the duration REM and slow wave sleep. On the other hand, the
duration of the NREM is increased and the end results is an increase in the total sleep
time and induced sense of deep and refreshing sleep.
Respiration
Respiration is not adversely affected by therapeutic dose of benzodiazepines in normal
adults. However, at higher doses like for pre-anaesthsia, benzodiazepines would cause
respiratory depression and acidosis. Benzodiazepines must be used with caution in
children and adults with compromised hepatic function.
Cardiovascular system
Effects of benzodiazepines on the CVS in normal individuals are mild. However, they
would decrease blood pressure and increase heart rate at pre-anaesthetic and toxic
doses.
Gastrointestinal tract
Most benzodiazepines would decrease nocturnal acid secretion in acid-peptic ulcer
patients.
Pharmacokinetic
The distribution of the lipid-water coefficient of all benzodiazepines is high in the non-
ionized form. Despite this fact, lipophilicity varies greatly among members and this is
highly influenced by the polarity and electronegativity of the substituents. They are
completely and rapidly absorbed orally. Clonazepate and indeed all benzodiazepines are
however first decarboxylated in the gastric system to N-desmethyldiazepam which is
eventually absorbed. Desmethyldiazepam is biologically active and has a half life of about
60 hrs. The pharmacokinetic profile of the benzodiazepine to a very large extent
determines half life, and hence their duration of action. Benzodiazepines are variably
bound to plasma proteins and this range from about 70% for aprazolam to almost 99% for
diazepam.
Benzodiazepines are rapidly taken up into the brain and other highly perfused tissues, and
the concentration in the cerebrospinal fluid is equal to the amount of free unbound drug
in the plasma. All benzodiazepines cross the placenta, and are secreted into the breast
milk.
They are metabolized by the Cytochrome-P enzyme complex of the liver and therefore
are involved greatly in drug /drug interactions. Drugs like erythromycin, ketoconazole,
itraconazole, clarithromycin and ritonavir inhibit metabolism of benzodiazepines
significantly, and will prolong the plasma half life.

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Adverse effect
Side effects resulting from peak plasma concentration of benzodiazepines are light
headedness, lassitude, increased reaction time, impaired motor coordination and mental
functions confusion and anterograde amnesia.

*THE NON-BENZODIAZEPINES (The Z-Compounds)

Benzodiazepine receptor agonists
These are hypnotic and sedative drugs that have novel chemical structure that is not in
any way similar to the benzodiazepines structure, but bind to preferentially to
benzodiazepine allosteric sites as GABA receptor agonists. They are used mainly to treat
insomnia. Examples of these drugs are: Zolpidem, Zaleplon, Esizoplicone etc.
Zaleplon is a pyrazolopyrimidine class of drug that preferentially binds to benzodiazepine
receptor site on the GABAA-receptor. It is effective in relieving delayed sleep onset in
insomnia, and has sustained efficacy as a hypnotic agent without rebound insomnia on
discontinuation of use. Zaleplon is rapidly absorbed after oral administration, reaching
peak plasma concentration in 1hour. This drug is about 60% bound to plasma protein, and
has a half-life of 1hour. Zaleplon is metabolized in the liver by aldehyde oxidase enzyme.
The oxidative metabolites are however converted to glucuronides, and excreted in the
urine. It is administered in doses of 5, 10 and 20mg. zaleplon is recommended for sleep at
bed time when the patient has difficulty falling asleep. This drug is more well tolerated
than zolpidem, as the side effects experienced by patients is not too different from that of
placebo. This however has been attributed to it short half.
Zolpidem: Zolpidem is an imidazopyrimidine sedative/hypnotic drug that act by
stimulating benzodiazepine receptors. Its effects are by all standards similar to the
effects produced by the benzodiazepines, except that it demonstrates a very weak
anticonvulsant activity in laboratory animals. Zolpidem does not significantly affect sleep
stages in normal human beings, but it effectively shortens sleep latency and prolongs
total sleep time in patients with insomnia. With a highly reduced case of rebound insomnia,
zolpidem-induced improvement and prolongation of total sleep time in insomnia has been
found to persist for as long as six months after the discontinuation of treatment.
At therapeutic doses of 5, 10 and 20mg, zolpidem produces residual daytime sedation
and amnesia especially in the elderly while other side effects are reduced.
Zolpidem is absorbed completely after oral administration. It undergoes first pass
metabolism, which reduce the bioavailability to 70% or even lower in the presence of food.
The half life of the drug can be increased in patients with liver cirrhosis and in the elderly.
Zolpidem is eliminated completely as in active metabolites.
Alternative sedative and hypnotic drugs
Certain drugs have found immense use as sedatives and hypnotic, although this effects
may not be their primary pharmacological actions and clinical usefulness. For such drugs,
advantage is usually taken of their central nervous system depression side effects. They
permeate the blood brain barrier, cause dose dependent depression of the CNS and
induce drowsiness and sedation. They are briefly discussed below.

1. Histamine (H-1)- receptor antagonists

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The first-generation H-1 receptor antagonists depress the CNS significantly in a dose
dependent manner to induce drowsiness as side effects. This is often taken advantage of
to manage sleep disorder and they are now formulated as sleep aid often with an
analgesic. The have the advantage of not cause addiction and dependence and do not
induce rebound insomnia like the benzodiazepines.
Others include:
Paraldehyde: This is a polymer of acetaldehyde that has very strong aromatic odour and
disagreeable taste. Paraldehyde is irritating to the throat and stomach when
administered orally, and it is not administered parenterally because of injurious effect to
tissues. When administered rectally, it must be diluted with olive oil.
Paraldehyde is rapidly absorbed and widely distributed after oral administration. Sleep
onset is 10 to 15minutes after administration of hypnotic dose. About 70 -80% of the
administered dose is metabolized by the liver through polymerization of acetaldehyde,
and finally through oxidation reaction to acetic acid. This is converted to carbon dioxide
and water.

Look up Chloral Hydrate, Meprobamate and Flumazenil, a benzodiazepine receptor

antagonist.