Anxiolytic and Hypnotic Drugs I.pdf

Anxiolytic and Hypnotic Drugs I Professor Dr. Haidar Al-Muthaffar M.B.Ch.B., M.Sc., Ph.D.  Overview Disorders involving anxiety are among the most common mental disorders. Anxiety is an unpleasant state of tension, apprehension, or uneasiness...

Anxiolytic and Hypnotic Drugs I Professor Dr. Haidar Al-Muthaffar M.B.Ch.B., M.Sc., Ph.D.  Overview Disorders involving anxiety are among the most common mental disorders. Anxiety is an unpleasant state of tension, apprehension, or uneasiness (a fear that arises from either a known or an 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 and do not warrant treatment. However, severe, chronic, debilitating anxiety may be treated with antianxiety drugs (sometimes called anxiolytics) and/or some form of psychotherapy. Because many antianxiety drugs also cause some sedation, they may be used clinically as both anxiolytic and hypnotic (sleep-inducing) agents. Some antidepressants are also indicated for certain anxiety disorders Anxiolytic and hypnotic drugs  Benzodiazepines Benzodiazepines are widely used anxiolytic drugs. They have largely replaced barbiturates and meprobamate in the treatment of anxiety and insomnia, because benzodiazepines are generally considered to be safer and more effective. Though benzodiazepines are commonly used, they are not necessarily the best choice for anxiety or insomnia. Certain antidepressants with anxiolytic action, such as the selective serotonin reuptake inhibitors (SSRIs), are preferred in many cases, and nonbenzodiazepine hypnotics and antihistamines may be preferable for insomnia. Benzodiazepines have high therapeutic index  Mechanism of action The targets for benzodiazepine actions are the γ- aminobutyric acid receptors type A (GABAA). The GABAA receptors are composed of a combination of five subunits (α (2), β (2), and γ (1)) that span the postsynaptic membrane. For each subunit, many subtypes exist (for example, there are six subtypes of the α subunit). Binding of GABA to its receptor triggers an opening of the central ion channel, allowing influx of chloride ions through the pore. The influx of chloride ions causes hyperpolarization of the neuron and decreases neurotransmission by inhibiting the formation of action potentials. (IPSP)  Benzodiazepines modulate GABA effects by binding to a specific, high-affinity site (distinct from the GABA binding site) located at the interface of the α subunit and the γ subunit on the GABAA receptor. Benzodiazepines increase the frequency of channel openings produced by GABA. The clinical effects of individual benzodiazepines correlate well with the binding affinity of each drug for the GABA receptor–chloride ion channel complex  Pharmacological effects All benzodiazepines exhibit the following effects to some extent: Reduction of anxiety At low doses, the benzodiazepines are anxiolytic. They are thought to reduce anxiety by selectively enhancing GABAergic transmission in neurons having the α2 subunit in their GABAA receptors, thereby inhibiting neuronal circuits in the limbic system of the brain.  Sedative/hypnotic All benzodiazepines have sedative and calming properties, and some can produce hypnosis (artificially produced sleep) at higher doses. The hypnotic effects are mediated by the α1-GABAA receptors Anterograde amnesia Temporary impairment of memory with the use of the benzodiazepines is also mediated by the α1-GABAA receptors. The ability to learn and form new memories is also impaired.  Anticonvulsant This effect is partially mediated by α1-GABAA receptors. Muscle relaxant At high doses, the benzodiazepines relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord, where the α2-GABAA receptors are largely located. [Note: Baclofen is a muscle relaxant that is believed to affect GABAB receptors at the level of the spinal cord.]  Therapeutic uses The individual benzodiazepines show small differences in their relative anxiolytic, anticonvulsant, and sedative properties. However, pharmacokinetic considerations are often important in choosing one benzodiazepine over another.  Anxiety disorders Benzodiazepines are effective for the treatment of anxiety associated with panic disorder, generalized anxiety disorder (GAD), social anxiety disorder, performance anxiety, and extreme phobias, such as fear of flying. The benzodiazepines are also useful in treating anxiety related to depression and schizophrenia. These drugs should be reserved for severe anxiety and should not be used to manage the stress of everyday life. Because of their addictive potential, they should only be used for short periods of time.  The longer-acting agents, such as clonazepam, lorazepam, and diazepam, are often preferred in patients with anxiety that require prolonged treatment. The antianxiety effects of the benzodiazepines are less subject to tolerance than the sedative and hypnotic effects. Tolerance is decreased responsiveness to repeated doses of the drug that occurs when used for more than 1 to 2 weeks. For panic disorders, alprazolam is effective for short- and long-term treatment, although it may cause withdrawal reactions in approximately 30% of patients.  Sleep disorders Benzodiazepine hypnotics decrease the latency to sleep onset and increase stage II of non–rapid eye movement (REM) sleep while both REM sleep and 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. Short-acting triazolam is effective in treating individuals who have problems falling asleep (increased sleep latency). The risk of withdrawal and rebound insomnia is higher with triazolam than with other agents.  Intermediate-acting temazepam is useful for patients who experience frequent awakenings and have difficulty staying asleep. Temazepam should be administered 1 to 2 hours before the desired bedtime. Long-acting flurazepam is rarely used, due to its extended half-life, which may result in excessive daytime sedation (“hangover”) and accumulation of the drug, especially in the elderly. Estazolam and quazepam are considered intermediate- and long-acting agents, respectively. In general, hypnotics should be used for only a limited time, usually 1 to 3 weeks.  Amnesia The shorter-acting agents are often employed as premedication for anxiety-provoking and unpleasant procedures, such as endoscopy, dental procedures, and angioplasty. They cause a form of conscious sedation, allowing the patient to be receptive to instructions during these procedures. Midazolam is a benzodiazepine used to facilitate anterograde amnesia while providing sedation prior to anesthesia.  Seizures Clonazepam is occasionally used as an adjunctive therapy for certain types of seizures, whereas lorazepam and diazepam are the drugs of choice in terminating status epilepticus. Chlordiazepoxide, clorazepate, diazepam, lorazepam, and oxazepam are useful in the acute treatment of alcohol withdrawal and reduce the risk of withdrawal-related seizures. Muscular disorders Diazepam is useful in the treatment of skeletal muscle spasms and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy.  Pharmacokinetics Absorption and distribution The benzodiazepines are lipophilic. They are rapidly and completely absorbed after oral administration, distribute throughout the body, and penetrate into the CNS.  Duration of action The half-lives of the benzodiazepines are important clinically, because the duration of action may determine the therapeutic usefulness. The benzodiazepines can be roughly divided into short-, intermediate-, and long-acting groups. The longer-acting agents form active metabolites with long half-lives.  Fate Most benzodiazepines, including chlordiazepoxide and diazepam, are metabolized by the hepatic microsomal 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 the urine as glucuronides or oxidized metabolites. All benzodiazepines cross the placenta and may depress the CNS of the newborn if given before birth. they are not recommended for use during pregnancy. Nursing infants may also be exposed to the drugs in breast milk.  Dependence Psychological and physical dependence can develop if high doses of benzodiazepines are given for a prolonged period. All benzodiazepines are controlled substances. Abrupt discontinuation of these agents results in withdrawal symptoms, including confusion, anxiety, agitation, restlessness, insomnia, tension, and (rarely) seizures. 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 Drowsiness and confusion are the most common adverse effects of the benzodiazepines. Ataxia occurs at high doses and precludes activities that require fine motor coordination, such as driving an automobile. Cognitive impairment (decreased recall and retention of new knowledge) can occur with use of benzodiazepines. Benzodiazepines should be used cautiously in patients with liver disease.  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 or opioids, are taken concurrently.  Benzodiazepine Antagonist Flumazenil is a GABA receptor antagonist that rapidly reverses the effects of benzodiazepines. The drug is available for (IV) administration only. Onset is rapid, but the duration is short, with a halflife of about 1 hour. 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 has a mixed ingestion with tricyclic antidepressants or antipsychotics. Dizziness, nausea, vomiting, and agitation are the most common adverse effects. Thank you