Sleep antihistamines

Roehrs T, Tietz E, Zorick F, Roth T. Daytime sleepiness and antihistamines. Sleep 1984 7 137-141. 

Diphenhydramine Antihistamine, sleep aid 1981 Benadryl Allergy, Sominex, Nytol... 

The principal OTC pharmaceutical products include cold remedies, vitamins and mineral preparations, antacids, analgesics, topical antibiotics, antiftingals and antiseptics, and laxatives. Others include suntan products, ophthalmic solutions, hemorrhoidal products, sleep aids, and dermatological products for treatment of acne, dandmff, insect parasites, bums, dry skin, warts, and foot care products (11). More recent prescription-to-OTC switches have included hydrocortisone, antihistamine and decongestant products, antiftingal agents, and, as of 1995, several histamine H2-receptor antagonists. 

The short-acting clomethia2ole [533-45-9] (1), sometimes used as therapy for sleep disorders ia older patients, shares with barbiturates a risk of overdose and dependence. Antihistamines, such as hydroxy2iae [68-88-2] (2), are also sometimes used as mild sedatives (see HiSTAMlNES AND HISTAMINE antagonists). Antidepressants and antipsychotics which have sedative effects are used to treat insomnia when the sleep disorder is a symptom of some underlyiag psychiatric disorder. 

Since there was some evidence that these compounds owe their action to interference with the action of histamine, this class has earned the soubriquet "antihistamines." This class of drugs is further characterized by a spectrum of side effects which occur to a greater or lesser degree in various members. These include antispasmodic action, sedative action, analgesia, and antiemetic effects. The side effects of some of these agents are sufficiently pronounced so that the compounds are prescribed for that effect proper. Antihistamines, for example, are used as the sedative-hypnotic component in some over-the-counter sleeping pills. 

Although histamine has mixed excitatory and inhibitory effects on central neurons, those antihistamines (Hi-receptor antagonists) that enter the brain produce sedation this indicates that the predominant overall effect of histamine is excitatory. The preferred explanation for this rests on evidence that histaminergic neurons in the posterior hypothalamus are active in waking and silent in deep SWS and REM sleep. 

Antihistamines such as diphenhydramine are known for their sedating properties and are frequently used over-the-counter medications (usual doses 25-50 mg) for difficulty sleeping. Diphenhydramine is approved by the FDA for the treatment of insomnia and can be effective at reducing sleep latency and increasing sleep time.43 However, diphenhydramine produces undesirable anticholinergic effects and carryover sedation that limit its use. As with TCAs and BZDRAs, diphenhydramine should be used with caution in the elderly. Valerian root is an herbal sleep remedy that has inconsistent effects on sleep but may reduce sleep latency and efficiency at commonly used doses of 400 to 900 mg valerian extract. Ramelteon, a new melatonin receptor agonist, is indicated for insomnia characterized by difficulty with sleep onset. The recommended dose is 8 mg at bedtime. Ramelteon is not a controlled substance and thus may be a viable option for patients with a history of substance abuse. 

The hypothesis of the role of HA in wakefulness stems from the observation that administration of the classical antihistamines (i.e. H3 receptor antagonists) induced sedation. These first-generation antihistamines, used to treat inflammatory reactions, could cross the blood-brain barrier and block the central Hi receptor (White Rumbold, 1988). The first study examining the effect of antihistamines on sleep-wakefulness in cats reported an increase in NREM sleep and a decrease in REM sleep (Jewett, 1968). Similar results were also obtained in dogs (Wauquier et ah, 1981) and humans (Risberg et ah, 1975 Bassano Caille, 1979 Nicholson et ah, 1985 Adam Oswald, 1986). Intraventricular application of HA in the anesthetized rat caused a dose-dependent decrease in the duration of narcosis, whereas intraventricular application of HA in conscious... 

Bassano, J. L. Caille, E. J. (1979). Effects of two antihistaminic compounds (mequitazine, dexchlorpheniramine) on sleep. Sleep distortion by antihistaminics. Waking Sleeping 3, 57-61. 

Sleep and sedative effects of the atypical antipsychotics could be related to different mechanisms antagonism of 5-HT2 receptors, antihistaminic and antimus-carinic effects, and probably an a-1 noradrenergic effect. The difference in the effect on sleep between risperidone and haloperidol may be due to their differential actions on serotoninergic receptors (Trampus and Ongini 1990 Trampus et al. 1993). 

Antihistamines are frequently used, but few clinical studies support their efficacy. A sedating antihistamine (e.g., hydroxyzine, diphenhydramine) can offer an advantage by facilitating sleep because pruritus is often worse at night. 

Antihistamines. After alcohol, antihistamines are the most commonly self-administered sleep medications. Foremost among these is diphenhydramine (Benadryl), which is also available as a component in a variety of over-the-counter nighttime medications including Tylenol PM and Excedrin PM. Prescription antihistamines like hydroxyzine (Vistaril, Atarax) are also occasionally used to treat insomnia. Finally, it is the antihistamine effect of some antidepressants and anti-psychotics that contribute to their utility as sedative-hypnotics. 

Antihistamines help to initiate sleep and, depending on their half-life, may produce little hangover. They are not addictive and therefore may be preferred for patients with a history of substance abuse. Diphenhydramine is usually an effective hypnotic at 25-50 mg at bedtime. The same dose tends to be effective for hydroxyzine. 

These include trazodone and a derivative of its metabolite nefazodone, both of which are strongly sedative, an effect which has been attributed to their potent alpha-1 receptor antagonism rather than to any antihistaminic effects. A main advantage of these drugs in the treatment of depression is that they appear to improve the sleep profile of the depressed patient. Their antidepressant activity is associated with their weak 5-HT reuptake inhibition and also a weak alpha-2 antagonism. However, unlike most of the second-generation antidepressants, neither drug is effective in the treatment of severely depressed patients. Furthermore, there is some evidence that trazodone can cause arrythmias, and priapism, in elderly patients. 

Antihistamines are popular as nonprescription (over-the-counter) sleep remedies (e.g., diphenhydramine, doxylamine, p. 114), in which case their sedative side effect is used as the principal effect. 

Quazepam (Doral) [C IV] [Sedative/Hypnotic/ Benzodiazepine] Uses Insomnia Action Benzodiazepine Dose 7.5-15 mg PO hs PRN i in elderly hqjatic failure Caution [X, /-] NA glaucoma Contra PRG, sleep apnea Disp Tabs SE Sedation, hangovCT, somnolence, resp depression Interactions T Effects W/ azole antifungals, cimetidine, digoxin, disulfiram, INH, levodopa, macrolides, neuroleptics, phenytoin, quinolones, SSRIs, verapamil, grapefruit juice, EtOH effects W/carbamazepine, rifampin, rifabutin, tobacco EMS Use caution w/ other benzodiazepines, antihistamines, opioids and verapamil, can T CNS depression concurrent EtOH and grapefruit juice use T CNS depression OD May cause profound CNS depression, confusion, bradycardia, hypotension, and altered reflexes flumazenil can be used as antidote activated charcoal may be effective... 

Histamine Hi receptor antagonists which enter the brain (diphenhydramine, promethazine and others) have sedative actions and polysomnographic recordings have shown that they suppress REM sleep and modestly increase SWS. A rebound in REM sleep sometimes occurs on discontinuation. Stimulation of central Hi and H2 receptors markedly potentiates signals produced by excitatory amino acids and it has been suggested that histamine acts as a waking amine (Schwartz et al., 1986). The effects of centrally acting antihistamines on sleep may be due to inhibition of these effects. 

Several Hi histamine antagonists (e.g., diphenhydramine, promethazine, and hydroxyzine) have been used as sedative-hypnotics, since they produce some degree of sedation. While this sedation is usually considered a side effect of their antihistaminic activity, in some cases the sedation is sufficient to allow the drugs to be used in the treatment of anxiety and sleep disturbances. For these drugs, the anxiolytic properties are thought to be a direct consequence of their ability to produce sedation. 

Antihistamines such as diphenhydramine, a mainstay of OTC sleep preparations, are also used widely by parents for their children at doses of 1 mg/kg. Most of the reports of the use of clonidine for sleep disorders are clinical and anecdotal case reports of use in children with ADFFD (Wilens et ah, 1994 Prince et ah, 1996). There are some safety concerns about using clonidine once a day at bedtime, especially in patients who take a daytime stimulant. Melatonin was studied using a double-blind, placebo-controlled, crossover design (Jan et ah, 1994) on a mixed group of 15 children with sleep disturbances, with some improvement reported. However, caution is warranted in using this agent because melatonin is unregulated, and there are concerns about the purity and safety of some commercially available preparations (Werry and Aman, 1999). 

The same molecules used to treat allergies and cold symptoms have many other uses. Antihistamines are particularly effective as antiemetics in suppressing nausea associated with gastrointestinal illnesses. They can also be used to treat the symptoms of motion sickness or even vestibular disturbances (vertigo). Because of their ability to induce sedation, antihistamines are widely used in over-the-counter sleep aids. 

Majority of antihistaminic drugs produce variable degree of CNS depression i.e. sedation, drowsiness and sleep. Drugs like diphenhydramine, promethazine are potent sedatives and is often accompanied by inability to concentrate. 

Sleep aids Diphenhydramine, 25-50 mg at bedtime Nytol, Simply Sleep, Sominex, various generic Diphenhydramine and doxylamine are antihistamines with well-documented CNS depressant effects. Because insomnia may be indicative of a serious underlying condition requiring medical attention, patients should consult a physician if insomnia persists continuously for longer than 2 weeks. 

Sometimes secondary effects can be used therapeutically. Antihistamines, for example, have as their primary effect the alleviation of an immune response. Secondarily, they cause drowsiness and reduce nausea associated with motion. Over-the-counter sleep aides and antinausea preparations contain antihistamines such as dimenhydrinate... 

Drugs that alter sleep produce their effects on the brain by altering the actions of neurotransmitters and consequently how neurons communicate with each other. However, different drugs can alter the actions of neurotransmitters in different ways. Stimulants such as amphetamine cause neurons to release excess amounts of neurotransmitters like dopamine and serotonin. Other drugs, such as the prescription sleeping pills Halcion or Ambien or antihistamines, can interact directly with the neurons receptors to either enhance or block the effects of the neurotransmitters. In later chapters, we will discuss how drugs that help you sleep or stay awake alter the chemistry of the brain. 

So how is insomnia treated Most commonly, people self-medicate their insomnia with over-the-counter medications such as Tylenol PM , Sominex , Unisom , or other drugs such as antihistamines (discussed in Chapter 3). Other people try natural remedies such as melatonin (see Chapter 4). When such medications don t work, people often ask their doctor for a prescription sleep aid, which is usually a type of medication called a benzodiazepine such as Halcion or a related type of drug such as Ambien or Sonata (see Chapter 6 for more on these types of drugs). 

The most popular OTC sleep aids are those that contain antihistamines such as diphenhydramine or doxylamine (Table 3.1). As noted in Chapter 1, nerve cells in the brain communicate with each other by secreting chemicals called neurotransmitters. One such neurotransmitter that regulates sleep is histamine. When histamine is released by a nerve cell, it diffuses over to the target nerve cell and binds to specialized proteins called receptors located on the outer surface of the nerve cell. These receptors are specially designed to bind only histamine, and when they do, the target nerve cell will become either activated or deactivated. In the brain, histamine serves the function of keeping us awake, and when drugs such as antihistamines are taken, they block the ability of histamine receptors to bind histamine. 

Table 3.1 Common OTC Sleep Aids Containing Antihistamines...

Not everyone reacts to antihistamine-containing sleep aids the same way. Some people, particularly those of Asian descent, are less sensitive to the sedative effects of these medications. Others can have reactions that are opposite to the intended effect of inducing sleepiness—some people feel nervous, jittery, anxious, restless, or agitated after taking antihistamines. This is particularly true in elderly persons and young children. Others can experience a morning hangover effect, characterized by sleepiness, headache, dry mouth, constipation, and blurred vision. 

Take OTC sleep aids containing antihistamines if you are already taking an antihistamine for allergy or cold symptoms. This can increase your risk of antihistamine overdose. 

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