Antianxiety and Antiinsomnia Agents

Chapter 48


Antianxiety and Antiinsomnia Agents






INDICATIONS




• Anxiety


• Insomnia—short-term therapy


• Benzodiazepines: See Table 48-1.



TABLE 48-1


Indications and Unlabeled Uses of Benzodiazepines






































































Drug Indication Unlabeled Use Clinical Pearls About Drug Use
diazepam (Valium) Anxiety, generalized; alcohol withdrawal, muscle spasm, tonic-clonic seizures, status epilepticus, preanesthesia Panic disorder, IBS, insomnia, tension headache, RLS Preferred agent for Ménière’s disease; effective adjunct to baclofen for muscle spasms in MS
alprazolam (Xanax) Anxiety, generalized; panic disorder, agoraphobia Social phobia, PMS, agoraphobia, insomnia Most drug–drug interactions of class
chlordiazepoxide (Librium) Anxiety, acute alcohol withdrawal IBS, tension headache Historically used for alcohol withdrawal
clonazepam (Klonopin) Seizures, absence, akinetic, myoclonic, panic disorder Periodic leg movements, parkinsonian dysarthria, manic episodes in bipolar disorder, multifocal tic disorders; adjunct in treatment of schizophrenia, neuralgias, OCD Preferred agent for neurologic-psychiatric disorders; ineffective for tonic-clonic seizures
clorazepate (Tranxene) Anxiety, generalized; alcohol withdrawal, partial seizures    
estazolam (ProSom) Insomnia    
flurazepam (Dalmane) Insomnia   High incidence of residual daytime effects, especially sedation. Not recommended in the elderly.
lorazepam (Ativan) Anxiety, generalized; preanesthesia Status epilepticus, chemotherapy-induced nausea and vomiting, alcohol withdrawal, psychogenic catatonia, chronic insomnia, IBS, tension headache, muscle spasm, tremors, action Preferred parenteral drug for status epilepticus
oxazepam (Serax) Anxiety, generalized IBS, alcohol withdrawal Preferred agent in Europe and Canada. Generally preferred over diazepam for alcohol withdrawal.
quazepam (Doral) Insomnia   Not recommended in the elderly
temazepam (Restoril) Insomnia   Preferred agent for sleep; should be given 30-60 min before sleep due to onset of action.
triazolam (Halcion) Insomnia   Anterograde amnesia reported more frequently than other benzodiazepines. Shown to have significant effects on arterial blood gases and control of breathing in severe COPD.


image


RLS, restless leg syndrome.


• buspirone: Generalized anxiety disorder; off-label: opiate addiction, panic attack


• zolpidem: Insomnia; off-label: Parkinson’s disease


• eszopiclone, zaleplon, ramelteon: Insomnia only


• doxepin: Depression and/or anxiety, insomnia




Unlabeled Uses


The use of these drugs in the treatment of anxiety and insomnia is discussed in this chapter. Antidepressants have become a major category of drug treatment for anxiety. Their use in the treatment of anxiety is discussed in this chapter. See Chapter 46 for a detailed discussion of these medications.


In the past, barbiturates and medications similar to barbiturates were used to treat patients with anxiety and insomnia. Newer medications seem somewhat safer with minimal drug interactions and low side effect profiles that decrease the need for barbiturates. However, they should no longer be used for these purposes because of tolerance, addiction, and seizures upon withdrawal. These agents are discussed in Chapter 45.


Benzodiazepines still are commonly used, but their use for anxiety and insomnia should be strictly limited because of the potential for adverse effects and abuse. They remain an important class of medications and are discussed in detail in this chapter.


Three newer drug classes have improved safety profiles: Buspirone is used for anxiety, and the GABA-PZ agonists (zolpidem, zaleplon, and eszopiclone) and the melatonin receptor agonist ramelteon are used for insomnia.



Therapeutic Overview


Anatomy and Physiology


Fear is a normal and useful emotion when an individual is confronted with perceived danger. The sympathetic adrenergic nervous system releases epinephrine and norepinephrine, while the parasympathetic nervous system is inhibited. Serotonin and gamma-aminobutyric acid (GABA) also may be released at various levels of the neuraxis and in neurons of the brain. Stimulation of the endocrine system may result in the simultaneous release of β-endorphins that work with epinephrine and norepinephrine to produce physiologic changes such as mydriasis; pallor; increased respiratory, cardiac, and basal metabolic rates; increased blood sugar; decreased bladder, bowel, and genital functioning; and increased blood flow to the muscles. Heredity and early life experiences are thought to play a role in the development of anxiety. A 1992 analysis of 1033 female twins found that heritability was approximately 30%. This sharply contrasts with major depression, which is considered to have 70% heritability. Adverse childhood events—for example, witnessing a traumatic event—are associated with the onset but not the persistence of anxiety beyond childhood.



Disease Process


Anxiety


Anxiety is characterized by excessive unease and apprehension, usually in association with an event that may have an unknown outcome. It is a normal reaction and a positive motivating factor in many situations. Anxiety becomes a problem when it interferes with everyday personal, social, and/or occupational functions, or when it develops into panic attacks or compulsive behavior. This ultimately can lead to symptoms and psychologic distress that are incapacitating.


In the primary care setting, anxiety often is a symptom of an underlying disorder, such as a medical or a psychologic problem (Box 48-1). The practitioner must obtain a comprehensive history and perform a complete physical examination of the patient to assess the possible causes and effects of the anxiety. Symptoms of anxiety vary with the subtype of anxiety experienced. The physical symptoms of anxiety are listed in Box 48-2.



BOX 48-1   Conditions That Can Cause Symptoms of Anxiety


Medical Conditions











BOX 48-2   Physical Symptoms of Anxiety


Respiratory










Elements of the history that are particularly important in evaluating anxiety include the following:




Generalized Anxiety Disorder


Generalized anxiety disorder (GAD) is defined as excessive anxiety and worry about life circumstances that are difficult to control. It was responsible for 12.3 million office visits to primary care providers in 1998. Twice as many women as men suffer from GAD. As many as 50% of patients with major depression will meet diagnostic criteria for GAD, and one study found this to be true in 62% of patients.


The anxiety associated with GAD is unrealistic, generalized, and persistent. It is present on more days than not for longer than 6 months. The patient often complains of somatic symptoms such as restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and sleep problems. Patients generally lack the insight to connect their symptoms with their reported worries and present life stresses. A self-assessment tool called the GAD-7 has been shown to be a reliable screening tool for GAD.



Panic Disorder


A panic attack is an unexpected severe, acute exacerbation of psychic and somatic symptoms of anxiety accompanied by intense fear or discomfort that is not triggered by a particular situation and that the individual cannot “sit out.” It starts abruptly and reaches a peak within 10 minutes, with at least four of the following symptoms: palpitations, tachycardia, sweating, shaking or trembling, shortness of breath, choking, chest pain or discomfort, nausea or abdominal distress, dizziness or faintness, feeling unreal or detached from oneself, fear of going crazy, fear of dying, paresthesias, and chills or hot flashes. Typical presentations include cardiovascular symptoms (40%), neurologic symptoms (40%), or GI symptoms (30%).


A panic attack becomes a panic disorder when the patient worries about having another attack and about what will happen if that should occur. Also, changes in behavior are seen with multiple attacks and result in frequent medical or emergency room visits. Because panic attacks consist of a wide array of symptoms, two thirds of patients are prompted to seek a medical rather than a mental health provider. And, in most cases, patients are unsatisfied with the lack of definitive diagnosis. This results in an enormous utilization of health care resources; one study reported that 70% (40/57) of patients saw an average of 10 physicians before receiving a diagnosis of panic disorder.



Phobic Disorders


This is the most common mental health disorder in the United States. A patient who has a phobia displays a persistent and irrational fear of a clearly definable situation, object, or activity. Exposure to the feared stimulus results in intense anxiety and avoidance that interfere with the patient’s life. Three main groups of phobic disorders have been identified:



Specific phobias can be normal in children, and many persist in a mild form in adults. Incapacity depends on the frequency with which the situation is encountered and the amount of interference with function that results.



Obsessive-Compulsive Disorder


Obsessive-compulsive disorder (OCD) is a situational preoccupation with thoughts or acts that occur despite the patient’s efforts at resistance. Obsessions are persistent thoughts, ideas, or images that intrude into conscious awareness. Compulsions are urges or impulses for repetitive intentional behaviors that are performed in a stereotyped manner in an attempt to reduce anxiety. The patient realizes that these are senseless and intrusive but is unable to stop. Insight and resistance may not be present in children who have OCD. It occurs in approximately 3% of the population in the United States. Onset in children and adults occurs around the ages of 10 and 21, respectively, and it develops earlier in males than in females. The impact on a patient’s quality of life can be devastating; one study noted that 13% of patients attempted suicide.



Posttraumatic Stress Disorder


Patients with posttraumatic stress disorder (PTSD) have recurrent anxiety precipitated by exposure to or memory of some past traumatic situation. They may have recurrent dreams or suddenly may act or feel as if the event is recurring. The patient will have increased arousal and hypervigilance, leading to flashbacks and severe anxiety with an enhanced startle reaction (positive symptoms of PTSD). As a means of compensating for this intense arousal, patients may be withdrawn in an attempt to avoid reminders of the trauma. The result is a sense of numbness and emotional blunting (negative symptoms of PTSD). These patients have experienced a catastrophic event that would be clearly distressing to anyone. Onset follows the trauma after a latency period of a few weeks to months, but not longer than 6 months, and the condition lasts for at least 1 month. In a study of 368 primary care clinic patients, nearly two thirds were witnesses to or were the victims of a traumatic event; 12% of these individuals were given a diagnosis of PTSD. More than four times as many women as men develop PTSD. Traumatic events reported in women include molestation and physical assault.



Insomnia


As many as 30% of adults report problems with sleep; these are seen more commonly in women. Sleep disorders are a symptom and not a diagnostic entity; thus, a comprehensive review of the patient’s history and a thorough physical examination is required to rule out all possible causes of the sleep disturbance. Research suggests that people who routinely experience problems going to sleep have an increased risk of myocardial infarction and may have a higher risk of mortality during sleep from all causes.


Sleep disorders are categorized into the following four groups to facilitate diagnosis and management:



Insomnia may be associated with depression, manic disorders, alcohol or other drug abuse, heavy smoking, caffeine use, an adverse effect of many drugs, and specific medical conditions. Medications that may contribute to insomnia include the psychotropic drugs and CNS stimulants such as OTC cold medicines and theophylline. Medical conditions associated with insomnia include delirium, respiratory distress, pain, and hyperthyroidism. Certain sleep disorders such as sleep apnea are made worse by insomnia medications. The only sleep disorder discussed in this chapter is insomnia because it is the one disorder that these medications are used to treat. Insomnia generally is classified as short term, 7 to 10 days, and long term.


The appropriate and effective treatment of insomnia is under widespread debate. Some data suggest that sedative hypnotics do not provide as much relief from insomnia as promised. A common definition of insomnia is that the patient takes 30 minutes or more to fall asleep and the patient gets less than 6½ hours of sleep. Even when the drugs work better than placebos—and they don’t always—data submitted to the FDA show that people still don’t fall asleep in less than 30 minutes, and they still don’t sleep much longer than 6 hours—and they may have grogginess or other side effects as well. These products are also intended for short-term use, although many patients take them for years. For those patients who demand other, more effective medications for insomnia, antipsychotics that produce heavy sedation have been used. There is growing unrest among many clinicians about the long-term use of these powerful drugs in patients who have no mental problems and for whom they are not intended.


The practitioner must rule out all possible causes of a sleep disorder and must determine the type of disorder that is present before prescribing any type of medication. The patient should be encouraged to practice good sleep hygiene principles, such as avoiding stimulating food and drink before retiring, having nighttime rituals that are relaxing, and not using the bed for reading, work, or other non–sleep-associated activities. Clinicians must also reevaluate the practice of renewing prescriptions intended for short-term use for long periods of time.



Mechanism of Action


Benzodiazepines


Benzodiazepines act by potentiating the action of GABA, an amino acid and an inhibitory neurotransmitter, which results in increased neuronal inhibition and CNS depression. Benzodiazepines bind to specific benzodiazepine receptor sites (e.g., BZ1, BZ2). BZ1 is involved in sleep; BZ2 is involved in memory, motor, sensory, and cognitive functions. The BZ receptor is a ligand-gated C1– channel, and GABA activation of the receptor results in inward flow of C1–, which causes increased neuronal inhibition and CNS depression. BZ1 to BZ6 refers to distinct receptor subtypes and not simply to binding sites on the same receptor molecule.


Inhibition of benzodiazepine receptors in the spinal cord causes muscle relaxation; in the brainstem, it acts as an anticonvulsant; in the cerebellum, it causes ataxia; and in the limbic and cortical area, it affects emotional behavior. Anxiolytic effects are distinct from the nonspecific consequences of CNS depression (e.g., sedation, motor impairment). Benzodiazepines act as a sedative hypnotic by acting on the limbic system and the subcortical CNS. They shorten REM sleep and stage 4 sleep but increase total sleep time. These medications have high abuse potential because they are so widely available.


Clonazepam, diazepam, and clorazepate suppress neural discharges in the patient during seizures. Seizure activity is inhibited by depressing nerve transmission in the motor cortex and suppressing the spike-and-wave discharge in absence seizures. Clonazepam has high potency and increased efficacy against absence seizures. Buspirone lacks the BZ effect.


The onset and duration of benzodiazepines are variable. Triazolam and midazolam are considered short acting; alprazolam, lorazepam, oxazepam, and temazepam are considered intermediate acting; and diazepam, chlordiazepoxide, flurazepam, and clonazepam are considered long-acting drugs.


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Jul 22, 2016 | Posted by in PHARMACY | Comments Off on Antianxiety and Antiinsomnia Agents

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