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Anxiotytic and hypnotics drugs
Anxiety is an unpleasant state of tension, apprehension, or uneasiness--a fear that seems to
arise from an unknown source. Disorders involving anxiety are the most common mental
disturbances. The symptoms of severe anxiety are similar to those of fear (such as,
tachycardia, sweating, trembling, palpitations) and involve sympathetic activation.
Episodes of mild anxiety are common life experiences and do not warrant treatment.
However, the symptoms of severe, chronic, debilitating anxiety may be treated with
antianxiety drugs (sometimes called anxiolytic or minor tranquilizers). Since all of the
antianxiety drugs also cause some sedation, the same drugs often function clinically as
both anxiolytic and hypnotic (sleep-inducing) agents
BENZODIAZEPINES
Benzodiazepines are the most widely used anxiolytic drugs. They have largely replaced
barbiturates and meprobamate in the treatment of anxiety, since the benzodiazepines are
more effective and safer.
Approximately 20 benzodiazepine derivatives are currently available (Alprazolam ,
Chlordiazepoxlde ,Clonazepam, Clorazepate ,Diazepam , Lorazepam, Quazepam ,
oxazepam, Midazolam, Estazolam , Flurazepam, Temazepam ,Triazolam).
Mode of action
The target for Benzodiazepines actions are the of γ-aminobutyric acid (GABA). Binding
of GABA to its receptor on the cell membrane triggers an opening of a chloride channel,
which leads to an increase in chloride conductance. The influx of chloride ions causes a
small hyperpolarization that moves the postsynaptic potential away from its firing
threshold and thus inhibits the formation of action potentials. Benzodiazepines bind to
specific, high affinity sites on the cell membrane, which are separate from but adjacent to
the receptor for GABA. The benzodiazepine receptors are found only in the central
nervous system (CNS), and their location parallels that of the GABA neurons. The binding
of benzodiazepines enhances the affinity of GABA receptors for this neurotransmitter,
resulting in a more frequent opening of adjacent chloride channels. This in turn results in
enhanced hyperpolarization and further inhibition of neuronal firing.
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Actions
The benzodiazepines have no antipsychotic activity, nor any analgesic action and do not
affect the autonomic nervous system. All of the benzodiazepines exhibit the following
actions to a greater or lesser extent:
1. Reduction of anxiety: At low doses, the benzodiazepines are anxiolytic. They are
thought to reduce anxiety by selectively inhibiting neuronal circuits in the limbic
system of the brain.
2. Sedative and hypnotic actions: All of the benzodiazepines used to treat anxiety have
some sedative properties. And some can produce hypnosis (artificially-produced
sleep). At higher doses
3. Anterograde amnesia: The temporary impairment of memory with use of
benzodiazepines is also mediated by GABA receptors . this is also impair person’s
ability to learn and form new memories.
4. Anticonvulsant: Several of the benzodiazepines have anticonvulsant activity and are
used to treat epilepsy and other seizure disorders.
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5. Muscle relaxant: At high doses The benzodiazepines relax the spasticity of skeletal
muscle, probably by increasing presynaptic inhibition in the spinal cord. Baclofen is
an muscle relaxant that is believed to effect GABA receptors at spinal cord level.
Therapeutic uses
The individual benzodiazepines show small differences in their relative anxiolytic,
anticonvulsant, and sedative properties. However, the duration of action varies widely
among this group, and pharmacokinetic considerations are often important in choice of
drug.
1. Anxiety disorders: The benzodiazepines are useful in treating the anxiety that
accompanies some forms of depression and schizophrenia. These drugs should not
be used to alleviate the normal stress of everyday life, but should be reserved for
continued severe anxiety, and then should only be used for short periods of time
because of addiction potential. The longer acting agents such as diazepam, are often
preferred in those patients with anxiety that may require treatment for prolonged
periods of time. The antianxiety effects of the benzodiazepines are less subject to
tolerance than the sedative and hypnotic effects. For panic disorders, alprazolam is
effective for short- and long-term treatment, although it may cause withdrawal
reactions in about 30% of sufferers.
2. Muscular disorders: Diazepam is useful in the treatment of skeletal muscle spasms
such as occur in muscle strain, and in treating spasticity from degenerative
disorders, such as multiple sclerosis and cerebral palsy.
3. Amnesia: the short acting agent are often employed as premedication for anxiety
provoking and unplaseant procedure such as bronchoscopic, endoscopic and some
dental procedure. They also cause a form of conscious sedation. Midazolam is an
injectable only benzodiazepine used for the induction of anaesthesia
4. Seizures: Clonazepam is useful in the chronic treatment of epilepsy, whereas
diazepam is the drug of choice in terminating grand mal epileptic seizures and status
epilepticus. Chlordiazepoxide, clorazepa, diazepam, and oxazepam are useful in the
acute treatment of alcohol withdrawal.
5. Sleep disorders: Not all of the benzodiazepines are useful as hypnotic agents,
although all have sedative or calming effects. The three most commonly prescribed
benzodiazepines for sleep disorders are long-acting flurazepam , intermediate acting
temazepam and short-acting triazolam.
A. Flurazepam: This long-acting benzodiazepine significantly reduces both sleepinduction time and the number of awakenings, and increases the duration of sleep.
Flurazepam has a long-acting effect and causes little rebound insomnia. With
continued use, the drug has been shown to maintain its effectiveness for up to 4
weeks.
B. Temazepam: This drug is useful in patients who experience frequent wakening.
However, the peak sedative effect occurs two to three hours after an oral dose, and
therefore it may be given several hours before bedtime.
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C. Triazolam: This benzodiazepine has a relatively short duration of action and is
therefore used to induce sleep in patients with recurring insomnia. Whereas
temazepam is useful for insomnia caused by the inability to stay asleep, triazolam is
effective in treating individuals who have difficulty in going to sleep. Tolerance
frequently develops within a few days, and withdrawal of the drug often results in
rebound insomnia, leading the patient to demand another prescription. Therefore,
this drug is best used intermittently rather than daily. In general, hypnotics should
be given for only a limited time, usually less than 2 to 4 weeks.
Pharmacokinetics
A. Absorption and distribution: The benzodiazepines are lipophilic and are rapidly and
completely absorbed after oral administration and are distributed throughout the
body.
B. Duration of actions: The half-lives of the benzodiazepines are very important
clinically, since the duration of action may deter- mine the therapeutic usefulness.
The benzodiazepines can be roughly divided into short (Oxazepam andTriazolam),
intermediate (Alprazolam, Estazolam, Lorazepam and Temazepam) and long-acting
groups (Chlordiazepoxide , Diazepam , Flurazepam and Quazepam). The longer
acting agents form active metabolites with long half-lives.
C. Fate: Most benzodiazepines, including chlordiazepoxide and diazepam, are
metabolized by the hepatic microsomal metabolizing system to compounds that are
also active. For these benzodiazepines, the apparent half-life of the drug represents
the combined actions of the parent drug and its metabolites. The benzodiazepines
are excreted in urine as glucuronides or oxidized metabolites.
Dependence
Psychological and physical dependence on benzodiazepines can develop if high doses of
the drug are given over a prolonged period. Abrupt discontinuation of the benzodiazepines
results in withdrawal symptoms, including confusion, anxiety, agitation, restlessness,
insomnia, and tension. Because of the long half-lives of some of the benzodiazepines,
withdrawal symptoms may not occur until a number of days after discontinuation of
therapy. Benzodiazepines with a short elimination half-life, such as triazolam, induce more
abrupt and severe withdrawal reactions than those seen with drugs that are slowly
eliminated, such as flurazepam .
Adverse effects
1. Drowsiness and confusion: These effects are the two most common side effects of
the benzodiazepines. Ataxia occurs at high doses and precludes activities that
require fine motor coordination, such as driving an automobile. Cognitive
impairment can occur with use of benzodiazepines.
2. Precautions: Use benzodiazepines cautiously in treating patients with liver disease.
They potentiate alcohol and other CNS depres- sants. Benzodiazepines are,
however, considerably less dangerous than other anxiolytic and hypnotic drugs. As
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a result, a drug overdose is seldom lethal, unless other central depressants, such as
alcohol, are taken concurrently.
BENZODIAZEPINE ANTAGONIST
Flumazenil is a GABA receptor antagonist that can rapidly reverse the effects of
benzodiazepines. The drug is available by IV administration only. Onset is rapid but
duration is short, with a half-life of about one hour. Frequent administration may be
necessary to maintain reversal of a long-acting benzodiazepine. Administration of
flumazenil may precipitate withdrawal in dependent patients or may cause seizures if a
benzodiazepine is used to control seizure activity. Dizziness, nausea, vomiting, and
agitation are the most common side effects.
OTHER ANXIOLYTIC AGENTS
1. Buspirone
Buspirone is useful in the treatment of generalized anxiety disorders and has an
efficacy comparable to the benzodiazepines. The actions of buspirone appear to be
mediated by serotonin (5-HT1A) receptors. The mode of action thus differs from
that of the benzodiazepines. Further, buspirone lacks anticonvulsant and musclerelaxant properties of the benzodiazepines and causes only minimal sedation. The
frequency of adverse effects is low, the most common effects being headaches,
dizziness, nervousness, and lightheadness. Sedation and psychomotor and cognitive
dysfunction are minimal, and dependence is unlikely. Buspirone has the
disadvantage of a slow onset of action.
2. Hydroxyzine
Hydroxyzine is an antihistamine with antiemetic activity. It has a low tendency for
habituation; thus it is useful for patients with anxiety, who have a history of drug
abuse. It is also often used for sedation prior to dental procedures or surgery.
3. Antidepressant
Many antidepressant have proven efficacy in managing the long term symptoms of
chronic anxiety disorder.
BARBITURATES
The barbiturates were formerly the mainstay of treatment used to sedate the patient or to
induce and maintain sleep. Today, they have been largely replaced by the
benzodiazepines, mainly because barbiturates induce tolerance, drug-metabolizing
enzymes, physical dependence, and very severe withdrawal symptoms. Foremost is their
ability to cause coma in toxic doses. Certain barbiturates, such as the very short-acting
thiopental, are still used to induce anesthesia.
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Mode of action
The sedative hypnotic effect of barbiturates is due to their interaction with GABAA
receptors, which enhances GABAergic transmission thought to interfere with sodium and
potassium transport across cell membranes.
Actions
Barbiturates are classified according to their duration of action to long acting
(Phenobarbital), short acting ( Pentobarbital, Secobarbital, Amobarbital ) and ultra short
(thiopental).
Depression of CNS: At low doses, the barbiturates produce sedation (calming effect,
reducing excitement). At higher doses, the drugs cause hypnosis, followed by anesthesia
(loss of feeling or sensation), and finally coma and death. Thus, any degree of depression
of the CNS is possible, depending on the dose. Barbiturates do not raise the pain threshold
and have no analgesic properties. They may even exacerbate pain.
Respiratory depression: Barbiturates suppress the hypoxic and chemoreceptor response
to CO2, and overdosage is followed by respiratory depression and death.
Enzyme induction: Barbiturates induce P-450 microsomal enzymes in the liver.
Therefore, chronic barbiturate administration diminishes the action of many drugs that are
dependent on P-450 metabolism to reduce their concentration.
Therapeutic uses
1. Anesthesia: Selection of a barbiturate is strongly influenced by the desired duration
of action. The ultra-short-acting barbiturates, such as thiopental, are used
intravenously to induce anesthesia.
2. Anticonvulsant: Phenobarbital is used in long-term management of tonic-clonic
seizures, status epilepticus, and eclampsia. Phenobarbital has been regarded as the
drug of choice for treatment of young children with recurrent febrile seizures.
However, phenobarbital can depress cognitive performance in children, and the
drug should be used cautiously.
3. Anxiety: Barbiturates have been used as mild sedatives to relieve anxiety, nervous
tension, and insomnia. Most have been replaced by the benzodiazepines.
Adverse effects
1. CNS: Barbiturates cause drowsiness, impaired concentration, and mental and
physical sluggishness.
2. Drug hangover: Hypnotic doses of barbiturates produce a feeling of tiredness well
after the patient awakes. This drug hangover leads to impaired ability to function
normally for many hours after waking. Occasionally, nausea and dizziness occur.
Addiction: Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness,
restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest. Withdrawal is
much more severe than that associated with opiates and can result in death.
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Other hypnotic agents
1. Zolpidem : Although the hypnotic zolpidem is not a benzodiazepine, it acts on a
subset of the benzodiazepine receptor family. Zolpidem has no anticonvulsant or
muscle relaxing properties. It shows no withdrawal effects, exhibits minimal
rebound insomnia and little or no tolerance occurs with prolonged use. Zolpidem is
rapidly absorbed from the gastrointestinal tract, and has a rapid onset of action and
short elimination half-life (about 3 hours). Adverse effects of zolpidem include
nightmares, agitation, headache, gastrointestinal upset, dizziness, and daytime
drowsiness.
2. Zaleplon: it is very similar to zolpidem
3. Eszopiclone: it is an oral nonbenzodiazeoine hypnotic and also used for treating
insomnia
4. Ramelteon: is selective agonist at the MT1 and MT2 subtypes of melatonin
receptor. Ramelteon is indicated for the treatment of insomnia in which falling
asleep is the primary compliant. The potential for abuse of remelteon is believed to
be minimal and no evidence of dependence or withdrawal effect has been observed.
Therefore the drug can be administered for long period.
5. Chloral hydrate: Chloral hydrate is a trichlorinated derivative of acetaldehyde that is
converted to trichloroethanol in the body. The drug is an effective sedative and
hypnotic that induces sleep in about 30 minutes and lasts about 6 hours.
6. Antihistamines: these drugs are usually ineffective for all but the milder form of
situational insomnia. Further,they have numerous undesirable side effects that make
them less useful than the benzodiazepines.
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