Anxiolytic and hypnotic drugs (1)

Anxiolytic and hypnotic drugs:

• Anxiety is an unpleasant state of tension, apprehension, or uneasiness (a fear that seems to arise from a unknown source).
• The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation.
• Episodes of mild anxiety are common life experiences & do not warrant treatment.
• However, the symptoms of severe, chronic, debilitating anxiety may be treated with anti-anxiety drugs (anxiolytic or minor tranquilizers) and/or some form of behavioral therapy or psychotherapy.
• Many of the anti-anxiety drugs also cause some sedation, thus they often function clinically as both anxiolytic & hypnotic (sleep-inducing) agents.
• In addition, some have anticonvulsant activity.

Benzodiazepines (BZDs)
• The most widely used anxiolytic drugs.
• They have largely replaced barbiturates & meprobamate in the treatment of anxiety, because BZDs are safer & more effective.

Mechanism of action
• They targets the GABAA receptors (GABA is the major inhibitory neurotransmitter in the CNS).
• These receptors are primarily composed of ?, ? and ? subunit families of which a combination of five or more span the postsynaptic membrane.
• Depending on the types, number of subunits & brain region localization, the activation of the receptors results in different pharmacologic effects.
• BZDs modulate GABA effects by binding to a specific, high-affinity site located at the interface of the ???subunit & the ? 2 subunit.
Note: BZ1 and BZ2 receptors subtypes (they contain ? 1 subunit or ? 2 subunit, respectively) have been found in the CNS.
• Binding of a BZD to its receptor site will increase the affinity of GABA for the GABA-binding site & triggers an opening of a chloride channel, which leads to an increase in chloride conductance.
• BZDs increase the frequency of channel openings produced by GABA.
• The influx of chloride ions causes a small hyperpolarization that moves the postsynaptic potential away from its firing threshold & thus, inhibits the formation of action potentials.
• The clinical effects of the various BZDs correlate well with each drug’s binding affinity for the GABA receptor–chloride ion channel complex.

Actions
• BZDs have neither antipsychotic nor analgesic effects, and they do not affect the autonomic nervous system.
• All BZDs exhibit the following actions to a greater or lesser extent:

1. Reduction of anxiety:
• Mediated by the ? 2 subunit.
• At low doses, BZDs are anxiolytic by selective enhancement of GABAergic transmission in neurons, thereby inhibiting neuronal circuits in the limbic system of the brain.

2. Sedative & hypnotic actions:
• Mediated by the ? 1 subunit.
• All BZDs used to treat anxiety have some sedative properties & some can produce hypnosis at higher doses.



3. Anterograde amnesia:
• Mediated by the ? 1 subunit.
• Memory is temporary impaired with the use of BZDs, person’s ability to learn & form new memories is also impaired.

4. Anticonvulsant:
• Mediated (partially not completely) by the ? 1 subunit.
• Several BZDs have anticonvulsant activity & some are used to treat epilepsy (status epilepticus) & other seizure disorders.

5. Muscle relaxant:
• At high doses, BZDs relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord, where the ? 2-GABAA receptors are largely located.
• Baclofen is a muscle relaxant that is believed to affect GABA receptors at the level of the spinal cord.

Therapeutic uses
Notes:
• BZDs show small differences in their relative anxiolytic, anticonvulsant & sedative properties.
• Duration of action varies widely among BZDs, and pharmacokinetic considerations are often important in choosing one BZD over another.

1. Anxiety disorders:
• BZDs are effective for the treatment of the anxiety symptoms secondary to panic disorder, generalized anxiety disorder (GAD), social anxiety disorder, performance anxiety, posttraumatic stress disorder, obsessive-compulsive disorder, and the extreme anxiety sometimes encountered with specific phobias such as fear of flying.
• BZDs are also useful in treating the anxiety that accompanies some forms of depression & schizophrenia.
Notes:
• Because of their addiction potential, BZDs should be reserved for continued severe anxiety, and should only be used for short periods of time (BZDs should not be used to alleviate the normal stress of everyday life).
• Clonazepam , lorazepam & diazepam are longer-acting agents, that are preferred for treatment of anxiety for prolonged periods.
• BZDs anti-anxiety effects are less subject to tolerance (occurs after more than 1 to 2 weeks of usage) than the sedative & hypnotic effects.
• Cross-tolerance exists among BZDs group with ethanol.
• Tolerance is associated with a decrease in GABA-receptor density.
• Alprazolam is effective for panic disorders, although it may cause withdrawal reactions in about 30 % of sufferers.

2. Muscular disorders:
• Diazepam is used for treatment of skeletal muscle spasms, such as occur in muscle strain & in treating spasticity from degenerative disorders, such as multiple sclerosis & cerebral palsy.

3. Amnesia:
• The shorter-acting agents are often employed as premedication for anxiety-provoking & unpleasant procedures, such as endoscopic, bronchoscopic & certain dental procedures as well as angioplasty.
• They also cause a form of conscious sedation, allowing the person to be receptive to instructions during these procedures.
• The BZD midazolam is also used for the induction of anesthesia.



4. Seizures:
• Clonazepam is occasionally used in the treatment of certain types of epilepsy, whereas diazepam & lorazepam are the drugs of choice in terminating grand mal epileptic seizures & status epilepticus.
• Due to cross-tolerance, chlordiazepoxide, clorazepate, diazepam & oxazepam are useful in the acute treatment of alcohol withdrawal & reducing the risk of withdrawal-related seizures.

5. Sleep disorders:
• All BZDs have sedative or calming effects, although not all are useful as hypnotic agents.
• BZDs decrease the latency to sleep onset & increase Stage II of nonrapid eye movement (REM) sleep.
• Both REM sleep & slow-wave sleep are decreased.
• In the treatment of insomnia, it is important to balance the sedative effect needed at bedtime with the residual sedation (“hangover”) upon awakening.
• Commonly prescribed BZDs for sleep disorders are flurazepam, temazepam & triazolam.

a. Flurazepam:
• Long-acting BZDs, reduces both sleep-induction time & number of awakenings & increases the duration of sleep.
• Causes little rebound insomnia.
• With continued use, its effectiveness is maintained for up to 4 weeks.
• Flurazepam & its active metabolites have long half-life (85 hours), which may cause daytime sedation & accumulation of the drug.

b. Temazepam:
• Intermediate-acting BZD, useful in patients who experience frequent wakening.
• Should be taken 1 - 2 hours before the desired bedtime (peak sedative effect occurs after 1 - 3 hours).

c. Triazolam:
• Short -acting BZD 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 develops within a few days, & withdrawal of the drug results in rebound insomnia.
• Therefore, this drug is best used intermittently rather than daily.
Note: In general, hypnotics should be given for only a limited time (less than 2 - 4 weeks).

Pharmacokinetics
1. Absorption and distribution
• BZDs are lipophilic, rapidly & completely absorbed after oral administration.

2. Durations of action:
• BZDs half-lives are very important clinically, because the duration of action may determine the therapeutic usefulness.
• BZDs can be roughly divided into short, intermediate & long-acting groups.
• Longer-acting agents form active metabolites with long half-lives. However, with some BZDs, the clinical durations of action do not always correlate with actual half-lives

3. Fate:
• For most BZDs, including chlordiazepoxide & diazepam, the apparent half-lives represents the combined actions of the parent drug & its metabolites.
• The drugs’ effects are terminated not only by excretion but also by redistribution.
• All BZDs cross the placental barrier & may depress the CNS of the newborn if given before birth.
• Nursing infants may also become exposed to the drugs in breast milk.

E. Dependence
• Psychological & physical dependence on BZDs can develop if high doses of the drugs are given over a prolonged period.
• Abrupt discontinuation of BZDs results in withdrawal symptoms (confusion, anxiety, agitation, restlessness, insomnia, tension and rarely seizures).
• Withdrawal symptoms may occur slowly & last a number of days after discontinuation of BZDs with long half-lives.
• BZDs with a short elimination half-life, such as triazolam, induce more abrupt & severe withdrawal reactions than those seen with drugs that are slowly eliminated such as flurazepam.

Adverse effects
• Drowsiness & confusion are most common.
• Ataxia occurs at high doses & precludes activities that require fine motor coordination, such as driving an automobile.
• Cognitive impairment.
• Triazolam, one of the most potent oral BZDs with rapid elimination, often shows a rapid development of tolerance, early morning insomnia & daytime anxiety as well as amnesia & confusion.

Precautions: BZDs
• Should be used cautiously in patients with liver disease.
• Should be avoided in patients with acute narrow-angle glaucoma.
• sedative-hypnotic effects are enhanced by alcohol & other CNS depressants.
• Are less dangerous than the older anxiolytic & hypnotic drugs, thus, 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 BZDs.
• It is available for IV administration only.
• Has rapid onset, but short duration, with a half life of about 1 hour.
• Frequent administration may be necessary to maintain reversal of a long-acting BZD.
• Administration of flumazenil may precipitate withdrawal in dependent patients or cause seizures if a BZD is used to control seizure activity.
• Seizures may also result if the patient ingests TCAs.
• Most common side effects are dizziness, nausea, vomiting & agitation.