Anxiolytic and Hypnotic

هذه المشاركة بواسطة : د. ياسمين المغربي

Anxiolytic and Hypnotic Drugs

 

Anxiety is an unpleasant state of tension, or uneasiness, a fear that seems to arise from a sometimes unknown source.

Disorders involving anxiety are the most common mental disturbances.

 

The physical symptoms of severe anxiety:

are similar to those of fear (such as tachycardia, palpitations, sweating and trembling) and involve sympathetic activation.

 

The symptoms of severe, chronic anxiety may be treated with:

1.     antianxiety drugs (sometimes called anxiolytic or minor tranquilizers)

2.     and/or some form of behavioral or psychotherapy.

 

Because many of the antianxiety drugs also cause some sedation, the same drugs often function clinically as:

1.     both anxiolytic and hypnotic (sleep-inducing) agents.

2.     In addition, some have anticonvulsant activity.

 

N.B. Episodes of mild anxiety are common life experiences and do not warrant treatment.

 

Benzodiazepines

 

Benzodiazepines are the most widely used anxiolytic drugs.

They have largely replaced barbiturates and meprobamate in the treatment of anxiety, because the benzodiazepines are safer and more effective.

 

Mechanism of action

•      The targets for benzodiazepine actions are the aminobutyric acid (GABAA) receptors (GABA is the major inhibitory neurotransmitter in the CNS)

•      Binding of GABA to its receptor triggers an opening of a chloride channel, which leads to an increase in chloride conductance.

•      Benzodiazepines increase the frequency of channel openings produced by GABA.

•      Binding of a benzodiazepine to its receptor site will increase the affinity of GABA for the GABA-binding site (and vice versa) without actually changing the total number of sites.

 

Actions

1. Reduction of anxiety: At low doses, the benzodiazepines are anxiolytic.

They are thought to reduce anxiety by selectively enhancing GABAergic transmission in neurons, thereby 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. Their effects have been shown to be mediated by GABAA receptors.

 

3. Anterograde amnesia: The temporary impairment of memory with use of the benzodiazepines is also mediated by the GABAA receptors.

This also impairs a person’s ability to learn and form new memories.

 

4. Anticonvulsant: Several of the benzodiazepines have anticonvulsant activity and some are used to treat epilepsy (status epilepticus) and other seizure disorders.

This effect is partially, although not completely, mediated by GABAA receptors.

 

5. Muscle relaxant: At high doses, the benzodiazepines relax the spasticity of skeletal muscle, probably by increasing inhibition in the spinal cord, where the GABAA receptors are largely located.

Baclofen is a muscle relaxant that is believed to affect GABAb receptors at the level of the spinal cord.

 

Therapeutic uses

a-Anxiety disorders:

Benzodiazepines are effective for the treatment of the anxiety symptoms secondary to:

1.     panic disorder.

2.     generalized anxiety disorder.

3.     social anxiety disorder.

4.     performance anxiety.

5.     post traumatic stress disorder.

6.     obsessive-compulsive disorder.

7.     the extreme anxiety encountered with specific phobias, such as fear of flying.

8.     the anxiety that accompanies some forms of depression and schizophrenia.

Agents used:

The longer-acting agents, such as clonazepam, lorazepam and diazepam are often preferred in those patients with anxiety that may require treatment for prolonged periods of time.

 

b-Muscular disorders:

Diazepam is useful in the treatment of:

1.  skeletal muscle spasms, such as muscle strain.

2.  spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy.

 

c- premedication for anxiety-provoking procedures:

The shorter-acting agents are often employed as premedication for anxiety-provoking and unpleasant procedures, such as:

•      endoscopic and bronchoscopic procedures.

•      certain dental procedures.

•      angioplasty.

They also cause a form of conscious sedation, allowing the person to be receptive to instructions during these procedures.

Midazolam is an injectable-only benzodiazepine, also used for the induction of anesthesia.

 

d-Seizures:

•      Clonazepam is occasionally used in the treatment of certain types of epilepsy.

•      Diazepam and lorazepam are the drugs of choice in terminating grand mal epileptic seizures and status epilepticus.

 

e-Alcohol withdrawal:

Due to cross-tolerance, chlordiazepoxide, clorazepate, diazepam, and oxazepam are useful in the acute treatment of alcohol withdrawal and reducing the risk of withdrawal-related seizures.

 

f-Sleep disorders:

Not all benzodiazepines are useful as hypnotic agents, although all have sedative or calming effects.

They tend to decrease the latency to sleep onset and increase Stage II of non-rapid eye movement (REM) sleep.

 

Flurazepam: is a long-acting benzodiazepine.

1.  It reduces sleep-induction time.

2.  It reduces the number of awakenings.

3.  It increases the duration of sleep.

 

Temazepam:

  • This drug is useful in patients who experience frequent wakening (the inability to stay asleep).
  • The peak sedative effect occurs 1 to 3 hours after an oral dose; therefore, it should be given 1 to 2 hours before the desired bedtime.

 

Triazolam:

  • This benzodiazepine has a relatively short duration of action and, therefore, is 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 or higher dose. Therefore, this drug is best used intermittently rather than daily.

 

Dependence

•      Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given over a prolonged period.

•      Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including:

1.     Anxiety, restlessness, tension.

2.     Confusion, insomnia.

3.     Agitation, and rarely, seizures.

•      Because of the long half-lives of some benzodiazepines, withdrawal symptoms may occur slowly and last 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.

•      Anxiolytics should not be used to alleviate the normal stress of everyday life. They should be reserved for continued severe anxiety, and then should only be used for short periods of time because of their addiction potential.

•      The antianxiety effects of the benzodiazepines are less subject to tolerance than the sedative and hypnotic effects.

 

N.B. Tolerance that is, decreased responsiveness to repeated doses of the drug occurs when used for more than one to two weeks.

 

Adverse effects

•      Drowsiness and confusion: These effects are the two most common side effects of the benzodiazepines.

•      Triazolam, one of the most potent oral benzodiazepines with the most rapid elimination, often shows :

1.     a rapid development of tolerance.

2.     early morning insomnia

3.     daytime anxiety

4.      amnesia

5.     confusion.

 

Precautions:

1.  Benzodiazepines should be used cautiously in treating patients with liver disease.

2.  They should be avoided in patients with acute narrow-angle glaucoma.

3.  Alcohol and other CNS depressants enhance the sedative-hypnotic effects of the benzodiazepines. Benzodiazepines are, however, considerably less dangerous than the older anxiolytic and hypnotic drugs. As 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.

Pharmacokinetics:

  • Administration: The drug is available for intravenous administration only.
  • Onset of action: rapid
  • Duration: is short.
  • half-life: about 1 hour.

Side effects:

1.   nausea, vomiting.

2.   Dizziness

3.   agitation.

Precautions:

  • Frequent administration may be necessary to maintain reversal of a long-acting benzodiazepine.
  • Administration of flumazenil may precipitate withdrawal in dependent patients or cause seizures if a benzodiazepine is used to control seizure activity.
  • Seizures may also result if the patient ingests tricyclic antidepressants.

 

Agent Duration of action use
clonazepam Long acting agent  1.  Anxiety disorders2.  treatment of certain types of epilepsy
diazepam Long acting agent  1.                 Anxiety disorders2.                 Muscular disorders

3.                 Grand mal epileptic seizures and status epilepticus.

4.                 alcohol withdrawal

lorazepam Long acting agent  1.                 Anxiety disorders2.                 grand mal epileptic seizures and status epilepticus.
Midazolam Short acting agent 1.    premedication for anxiety-provoking and unpleasant procedures.2.    Causes conscious sedation.

3.    Induction of anesthesia.

chlordiazepoxide alcohol withdrawal
oxazepam alcohol withdrawal
clorazepate alcohol withdrawal
Triazolam Short acting agent For patients having difficulty in going to sleep.
Temazepam For patients who experience frequent wakening (the inability to stay asleep).
Flurazepam  long-acting 1.  It reduces sleep-induction time.2.  It reduces the number of awakenings.

3.  It increases the duration of sleep.

Flumazenil Benzodiazepine Antagonist:

 

Barbiturates

  • The barbiturates were formerly the mainstay of treatment to sedate the patient or to induce and maintain sleep.
  • Today, they have been largely replaced by the benzodiazepines, primarily because barbiturates:

1.     Induce tolerance.

2.     Physical dependence with very severe withdrawal symptoms.

3.     Induce drug-metabolizing enzymes.

4.     Cause coma in toxic doses.

  • Certain barbiturates, such as the very short-acting thiopental, are still used to induce anesthesia

 

Mechanism of action

1.  The sedative-hypnotic action of the barbiturates is due to their interaction with GABAA receptors, which enhances GABAergic transmission.

Barbiturates potentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel openings.

The binding site is distinct from that of the benzodiazepines.

2.  In addition, barbiturates can block excitatory glutamate receptors.

3.  Anesthetic concentrations of pentobarbital also block high-frequency sodium channels. All of these molecular actions lead to decreased neuronal activity.

 

Classification

Barbiturates are classified according to their duration of action

  • For example, thiopental which acts within seconds and has a duration of action of about 30 minutes, is used in the intravenous induction of anesthesia.
  • By contrast, phenobarbital, which has a duration of action greater than a day, is useful in the treatment of seizures.
  • Pentobarbital, secobarbital, and amobarbital are short-acting barbiturates, which are effective as sedative and hypnotic (but not antianxiety) agents.

Actions

1-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.
  • Chronic use leads to tolerance.

 

2-Respiratory depression:

  • Barbiturates suppress the hypoxic and chemoreceptor response to CO2.
  • Overdosage is followed by respiratory depression and death.

 

3-Enzyme induction:

Barbiturates induce P450 microsomal enzymes in the liver. Therefore, chronic barbiturate administration diminishes the action of many drugs that are dependent on P450 metabolism to reduce their concentration.

 

Therapeutic uses

1. Anesthesia:

Selection of a barbiturate is strongly influenced by the desired duration of action.

The ultrashort-acting barbiturates, such as thiopental, are used intravenously to induce anesthesia.

 

2. Anticonvulsant:

Phenobarbital has specific anticonvulsant activity

Phenobarbital is used in long-term management of:

1.                 tonic-clonic seizures

2.                 status epilepticus

3.                 eclampsia.

4.                 Phenobarbital has been regarded as the drug of choice for treatment of young children with recurrent febrile seizures.

Side effect of Phenobarbital:

phenobarbital can depress cognitive performance in children, and the drug should be used cautiously.

 

3. Anxiolytic and hypnotic:

  • Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia.
  • When used as hypnotics, they suppress REM sleep more than other stages.
  • However, most have been replaced by the benzodiazepines.

 

Drug Duration of action Use
thiopental ultrashort-acting (acts within seconds)duration of action:30 minutes intravenous induction of anesthesia
phenobarbital duration of action greater than a day 1.                 tonic-clonic seizures2.                 status epilepticus

3.                 eclampsia.

4.                 The drug of choice for treatment of young children with recurrent febrile seizures.

Pentobarbital short-acting sedative and hypnotic (but not antianxiety)
secobarbital short-acting sedative and hypnotic (but not antianxiety)
amobarbital short-acting sedative and hypnotic (but not antianxiety)

 

Precautions and contraindications:

1.  Barbiturates induce the P450 system and, therefore, may decrease the duration of action of drugs that are metabolized by these hepatic enzymes.

2.  Barbiturates increase porphyrin synthesis, and are contraindicated in patients with acute intermittent porphyria.

 

Adverse effects

1. CNS: Barbiturates cause:

1.        Drowsiness.

2.        Impaired concentration.

3.        Mental and physical sluggishness.

The CNS depressant effects of barbiturates synergize with those of ethanol.

 

2. Drug hangover: Hypnotic doses of barbiturates produce:

1.A feeling of tiredness well after the patient wakes.

2.Impaired ability to function normally for many hours after waking.

3.Occasionally, nausea and dizziness occur.

 

3. Physical dependence:

Withdrawal is much more severe than that associated with opiates and can result in death.

Abrupt withdrawal from barbiturates may cause:

1.     Tremors, seizures.

2.     Anxiety, restlessness.

3.     Weakness

4.     Delirium.

5.     Nausea and vomiting.

6.     Cardiac arrest.

 

4. Poisoning:

Barbiturate poisoning from drug overdoses can cause:

1.  Severe depression of respiration

2.  central cardiovascular depression,

3.  That results in a shock-like condition with shallow, infrequent breathing.

4.  Barbiturate poisoning is a leading cause of death.

 

Treatment of poisoning:

1.  Artificial respiration

2.  Purging the stomach of its contents if the drug has been recently taken.

3.  Hemodialysis may be necessary if large quantities have been taken.

4.  Alkalinization of the urine often aids in the elimination of Phenobarbital.

Note: No specific barbiturate antagonist is available.