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Pharmacologic Treatment of Insomnia BY AHMAD YOUNES PROFESSOR OF THORACIC MEDICINE Mansoura faculty of medicine. Gamma-aminobutyric acid (GABA). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS).

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  1. Pharmacologic Treatment of Insomnia BYAHMAD YOUNESPROFESSOR OF THORACIC MEDICINE Mansoura faculty of medicine

  2. Gamma-aminobutyric acid (GABA) • Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). • The two major GABA receptor subtypes are GABA-A and GABA-B. • The GABA-A receptor is associated with a chloride(Cl–) channel ionophore located in cell membranes. • Ionophores are molecular complexes located in cellular lipid membranes that allow transport or passage of compounds across the membrane.

  3. GABA–benzodiazepine–chloride ionophore complex (GBC) • The GABA-A receptor is the binding site for several drugs other than GABA , including agonists (muscimol, gaboxadol) and antagonists (bicuculline). • The GABA-A receptor complex also contains a receptor for benzodiazepines (BZs) and related compounds, hence the complex is usually referred to as the GABA–benzodiazepine–chloride ionophore complex (GBC). • When GABA binds the GABA-A receptor on the complex, this allows passage of chloride ions through the membrane, resulting in hyperpolarization and reduced neuronal activity.

  4. GABA–benzodiazepine–chloride ionophore complex (GBC) • When BZs and certain nonbenzodiazepine medications bind the BZ receptor on the GBC, the configuration of the GABA receptor changes to enhance the ability of GABA binding to the GABA-A receptor to open the associated chloride channel (increased frequency).The medications are, therefore, sometimes called GABA-A receptor modulators. • Medications (including nonbenzodiazepines) that bind the BZ receptor and enhance the ability for GABA to open the chloride channel are called benzodiazepine receptor agonists (BZRAs). • Although BZRAs do not actually bind the GABA receptor (actually bind a BZ receptor on GBC complex),they are often referred to as GABA-A receptor agonists.

  5. GABA–benzodiazepine–chloride ionophore complex (GBC). • The GBC is composed of five protein subunits surrounding the chloride channel . • The subunits composing the GBC have different structure and are denoted as alpha, beta, gamma, epsilon, and rho units.The receptor complex is usually composed of two alpha, two beta, and one gamma-subunit. • The alpha, beta, and gamma-subunits have isoforms (e.g., alpha-1, alpha-2, alpha-3,etc.). The GABA-A binding site is located between the alpha and beta subunits and the BZ receptor site is located between the alpha and gamma-subunits .

  6. Left, A schematic representation of the gammaaminobutyric acid A (GABAA)–benzo-diazepine–chloride ionophore complex with five subunits arranged around the chloride pore. Right, A view from overhead shows the location of the GABAA receptors at the junction of the alpha-1 and beta-2 subunits and the benzo-diazepine receptor at junction of alpha-1 and gamma-2 subunits.

  7. GABA–benzodiazepine–chloride ionophore complex (GBC). • The most common GBC receptor configuration is denoted as alpha1, beta2, gamma 3 (understood to mean two alpha-1, two beta-2, and one gamma-2 subunits), also known as a BZ type 1 receptor. • The GBC also has receptors for barbiturates, certain inhaled anesthetics, and alcohol. • The GBCs composed of alpha-1 subunits mediate sedation (hypnotic effect), amnesia, and anticonvulsant effects. Those associated with alpha-2 and alpha-3 subunitsmediate anxiolytic and myorelaxant effects. • BZs tend to have high affinity for all these subtypes.

  8. “Z” hypnotics • The new nonbenzodiazepine BZRAs (zolpidem, zaleplon, eszopiclone),also known as the “Z” hypnotics, have preferential binding to GBCs containing certain subunits. • Zolpidem (ZODIUM)and zaleplon (SIESTA, sleep aid)selectively bind GBCs containing alpha-1 subunits and are often called selective BZRAs. These non-BZ BZRAs have less anxiolytic and myorelaxant activity compared with BZs. • Eszopiclone(night calm) is another non-BZ BZRA with receptor binding more like traditional BZs but has many of the same effects on sleep as the other Z hypnotics. • Eszopiclonedoes bind alpha-1 subunits with higher affinity than alpha-3 but also binds alpha-2 subunit receptors with only slightly lower affinity than alpha-1 subunits. • The major property to consider in choice of a BZRA is the duration of action.

  9. “Z” hypnotics • zolpidem and zaleplon have minimal anxiolytic or muscle relaxant activity. If a patient’s insomnia has a component on anxiety, these medications may be less effective. • Eszopiclone appears to have more affinity for GBCs with alpha-2 units than zolpidem and zaleplon and, therefore, possibly more anxiolytic effects. • Zolpidem, zaleplon, and eszopiclone has less tolerance,respiratory depression, and rebound insomnia compared to BZs.

  10. Benzodiazepine Receptor Agonists

  11. BZRA Effects on Sleep • A decrease in sleep latency is common to all medications. • Those with an intermediate or longer duration of action also may increase total sleep time (TST) and decrease wakefulness after sleep onset (WASO). • BZRAs may increase sleep spindle activity and the amplitude of higher EEG frequencies. • The BZs reduce stage N3 sleep via a reduction in slow wave amplitude with either no reduction or a mild reduction in REM

  12. Effects of Benzodiazepine Receptor Agonists on Sleep

  13. BZRA Effects on Sleep • Nonbenzodiazepine BZRAs (Z hypnotics) cause no or minimal decrease in the amount of stage N3 because they do not substantially reduce the amplitude of slow waves. • All three Z drugs are associated with less rebound insomnia or evidence of tolerance(decreased effect at the same dose) compared with the BZ BZRAs. • Zaleplon has a very short duration of action and may have less residual sedative effects especially after midnight dosing than longer acting Z drugs. Zaleplon may also be used for midnight awakening.

  14. BZRA Effects on Sleep • Zolpidem has a longer half-life compared with zaleplon but shorter compared with eszopiclone • Zolpidemmay not increase TST in some patients, and for this reason, zolpidem CR continuous / extended release) was developed . This is a two layered tablet, with one layer for rapid release and the other for slower release. • The half-life of zolpidem CR is that same as zolpidem, but there is a greater concentration of the medication 4 hours after drug administration

  15. BZRA Effects on Sleep • Zolpidem CR, eszopiclone, and temazepam have an intermediate duration of action and may be more effective for treating sleep-maintenance insomnia compared with medications with a shorter duration of action. • The only hypnotic approved for treating midnight awakening by the U.S. Food and Drug Administration (FDA) is Intermezzo (a buffered sublingual zolpidem preparation). • Temazepam is useful for treating sleep maintenance insomnia in patients in whom medications with a shorter duration of action are not effective. It has a delayed onset of action in some patients and may not be as effective as other medications for sleep-onset insomnia.

  16. BZRA Effects on Sleep • Some patients have a combination of anxiety and insomnia that may respond to Benzodiazepines that have NOT been approved by the FDA as hypnotics better than other hypnotics FDA approved for insomnia treatment.

  17. Side Effects of BZRAs • Eszopiclone is associated with an unpleasant (often metallic) taste in 25% of patients. • BZRAs may also be associated with nausea in some patients. They are not recommended for use in nursing or pregnant women. • BZRAs have been associated with sleep behaviors, including sleepwalking and eating , driving, and sexual behavior during sleep. • Patients taking BZRAs should allow for adequate sleep time and not take BZRAs in combination with other sedatives, alcohol, or sleep restriction.

  18. Side Effects of BZRAs • Zolpidem is the BZRA most often associated with sleepwalking and sleep-related eating disorder , but these manifestations may occur with other BZRAs as well. • Residual sedation is another important side effect of BZRAs. shorter-acting medications are less likely to cause residual sedation. Women metabolize zolpidem more slowly compared with men and are especially at risk for impairment • Respiratory depression caused by the BZRA hypnotics alone is uncommon. However, caution is advised with the use of hypnotics in patients with hypoventilation, OSA, and severe lung disease.

  19. Side Effects of BZRAs • Drugs with high receptor binding affinity such as lorazepam, midazolam,and triazolam cause more side effects on withdrawal. • Triazolam causes rebound insomnia and is no longer recommended as a first-line hypnotic. • Significant rebound insomnia has not been noted in most studies of zaleplon, zolpidem, and eszopiclone. • withdrawal side effects and rebound insomnia may potentially occur with all BZRAs, and slow withdrawal, if possible, is recommended.

  20. Using BZRA Hypnotics • The hypnotics are grouped into non benzodiazepines and BZs. • Ideally,hypnotics should be used on a short-term or intermittent basis at the lowest effective dose. • A lower dose and more caution is indicated in older adults and in patients with impaired hepatic function because most BZRAs undergo hepatic metabolism. • The FDA approved indication for most hypnotics is for short-term use. The exact treatment duration is not specified. • The FDA indication for eszopiclone does not specify short term use. New studies have documented effectiveness of some hypnotic medications (eszopiclone, zolpidem CR) for 6 months or longer.

  21. Using BZRA Hypnotics • It is recommended that BZRA hypnotics be used in as low a dose as possible for as short a time as possible. • The clinician should also remember thatcognitive behavioral treatment of insomnia is an effective alternative to hypnotics.

  22. Choice of BZRA Hypnotic Medication • The major characteristic of BZRA medications to consider in choosing a hypnotic is the duration of action. • Short-acting medications work in the treatment for sleep-onset insomnia but may not work for sleep-maintenance insomnia. • Triazolam has a short duration of action and is associated with significant rebound insomnia. • Zaleplon has a very short duration of action and may be useful as a “rescue medication” for middle of the night dosing(as long as 4–6 hours of potential sleep remain).

  23. Choice of BZRA Hypnotic Medication • Zolpidem has a short to intermediate action and may work for some but not all patients as treatment of sleep maintenance insomnia. • Intermediate-acting medications are indicated for sleep-onset and sleep-maintenance insomnia but may cause daytime sedation in some patients. Temazepam, eszopiclone, and zolpidem CR are in this category. • Temazepam has a long onset of action in some patients and may not be effective for treating sleep-onset insomnia in those individuals.

  24. Choice of BZRA Hypnotic Medication • Long-acting medications have an increased risk of daytime sedation and other residual effects. • Flurazepam has a long half life and also has active metabolites. • Sometimes patients who fail to respond to a given BZRA will respond to an alternate BZRA. • Lorazepam (Ativan) and clonazepam (Klonopin) are two BZ BZRAs that are not FDA approved for primary insomnia treatment. • Lorazepam is approved for treatment of insomnia coexists with anxiety. Although the standard dose for anxiety is 2 to 4 mg, lower doses (0.5–1 mg) of lorazepam may work as a hypnotic.

  25. Choice of BZRA Hypnotic Medication • Clonazepam(amotril,apetryl) is a potent BZRA with a very long half-life and is commonly associated with morning grogginess. Starting with the lowest possible dose and having patients plan on a long sleep period is prudent. An occasional patient requires up to 2 mg of clonazepam for sleep maintenance insomnia. • Alprazolam (Xanax)is FDA approved for the treatment of anxiety and panic disorder.Although the medication’s half-life is fairly long, it is usually prescribed with dosing two or three times daily. If used as a hypnotic, the duration of effect may not last the entire night. An extended-release preparation is available.

  26. MELATONIN RECEPTOR AGONIST RAMELTEON (ROZEREM) • Ramelteon(Rozerem)is the first melatonin (MT) receptor agonist approved in the United States for treatment of insomnia.It is an MT1/MT2 receptor agonist. • The effects at MT1 are thought to inhibit neuronal firing of the suprachiasmatic nucleus (SCN), effectively turning off the alerting signal and allowing sleep to occur. In contrast, MT2 receptor effects are thought to mediate melatonin’s phase shifting effects on circadian rhythms. • Ramelteon is about 17 times more potent at the MT1/MT2 receptors than melatonin.

  27. RAMELTEON (ROZEREM) A MELATONIN RECEPTOR AGONIST • Ramelteonis available as a 8-mg tablet and the dose is 8 mg taken 30 minutes before bedtime. • An absence of next day residual effects, withdrawal, or rebound effects,lacks abuse potential. • Most effects of ramelteon being on sleep latency. • Ramelteon is FDA approved for sleep onset insomnia. The medication has a short half-life. • Side effects of ramelteon include headache, nausea, dizziness, somnolence, nightmares, hallucinations,and rarely suicidal ideation. Arthralgia and myalgia may also occur.

  28. MELATONIN RECEPTOR AGONIST RAMELTEON (ROZEREM) • Because ramelteon has no dependence potential, it may be a good choice for patients with alcohol or drug dependency. • Ramelteonundergoes hepatic metabolism and should be avoided in patients with severe liver disease. • Use of ramelteon is contraindicated in patients taking luvoxamine because this antidepressant significantly increases the levels of ramelteon in blood.

  29. SEDATING ANTIDEPRESSANTS • Sedating antidepressants used in doses lower than used for antidepressant effects are widely used as hypnotics . • Relatively little evidence has demonstrated their effectiveness as hypnotics in patients without depression. The sedative effects of trazodone are caused byits antihistamine activity. • Trazodone(trittico) is a sedating antidepressant with minimal anticholinergic activity that is frequently used as a hypnotic. It is a reasonable hypnotic in comorbid depression , in patients with significant sleep apnea, or in patients with a history of medication dependence. • The sedative effects of trazodone are caused by its antihistamine activity . Its main side effects are priapism (1 in 8000) and postural hypotension. • The usual dose is 25 to 100 mg at bedtime.

  30. SEDATING ANTIDEPRESSANTS • Mirtazapine (Remeron)antagonizes alpha-2 receptors and serotonin (5HT2) receptors, is used in low doses as a hypnotic. lower doses (7.5 mg and 15 mg) are sometimes more sedating than higher doses. • The major side effect is weight gain. • Doxepin (Sinequan, Silenor) and amitriptyline (Elavil)are sedating tricyclic antidepressants (TCAs) that have been used in low doses as hypnotics. • Sedating TCAs have significant anticholinergic side effects (dry mouth, constipation,urinary retention).

  31. SEDATING ANTIDEPRESSANTS • Lower doses avoid significant anticholinergic side effects. It is important to recall that TCAs are very dangerous in overdose. • very low dose doxepin (1, 3, 6 mg) has been evaluated as a hypnotic. • The major significant effect was a decrease in WASO. The mechanism of hypnotic action of doxepin is antagonism of histamine (H1) receptors. • Doxepin (Silenor) is available as 3-mg and 6-mg tablets is approved by the FDA for treatment of sleep-maintenance insomnia.

  32. ANTIPSYCHOTICS • Quetiapine (Seroquel) is a second-generation antipsychotic medications that antagonizes histamine, dopamine D2, and serotonin receptors. • At low doses, the medication’s main effect is as an antihistamine. • Quetiapine is indicated for treatment of schizophrenia and bipolar disorder. • Side effects include Q–T interval prolongation, weight gain, extrapyramidal symptoms, headache, cataracts, and a decreased white blood cell count. • Because of its side effects, this medication is usually not used in patients without significant psychiatric disorders.

  33. OTHER MEDIATIONS USED FOR INSOMNIA • Gabapentin(Pregavalex)(an anticonvulsant structural analog of GABA that binds the alpha-2-delta subunit of voltage-gated calcium channels) is used for chronic pain and restless legs syndrome (RLS). • The half-life of gabapentin is approximately 5 to 9 hours, and it is excreted by the kidneys unchanged. • Because of the sedative properties of gabapentin, the medication may be used as an alternative hypnotic treatment in patients who do not respond to or tolerate traditional hypnotic medications.

  34. OTHER MEDIATIONS USED FOR INSOMNIA • The usual dose is 300 to 900 mg at bedtime. • Side effects include dizziness, ataxia, weight gain, and, less commonly, leukopenia. • Gabapentin could potentially be useful in patients with insomnia associated with pain. • Gabapentin may increase the amount stage N3 sleep. • Melatoninis a naturally occurring substance available as an over-the-counter (OTC) sleeping pill. It appears to have a small effect on sleep latency with little effect on WASO or TST.

  35. OTHER MEDIATIONS USED FOR INSOMNIA • Ramelteon is a melatonin receptor agonist (MT1, MT2) that is FDA approved for the treatment of sleep onset insomnia. • One problem with both ramelteon and melatonin as hypnotics is that the endogenous melatonin levels are already elevated during the dark hours. Melatonin also has a short half-life. • The hypnotic dose of melatonin is 3 to 5 mg. • Antihistamines as diphenhydramine(benalex) and doxylamine(donormyl) are the primary ingredients in OTC sleep aids. Some limited evidence exists for their efficacy. The main problem is that they have considerable anticholinergic activity (urinary retention) and may cause daytime sedation.

  36. PHARMACOTHERAPY FOR PATIENTS WITH DEPENDENCE ISSUES • In patients with a history of past or current alcohol or BZ dependence, the use of BZRAs is problematic. For these patients, use of 1- Ramelteon (no abuse potential), 2-Low dose of a sedating antidepressant, or 3- Cognitive-behavioral treatment of insomnia are the best treatment options.

  37. OVERALL STRATEGY • It is always important to ask patients about prior treatment failures and side effects. • Drug interactions should also be considered. • In patients with sleep-onset insomnia, treatment could be started with ramelteon or zaleplon. • The cost of these medications may not be acceptable. • A lower dose of a longer-acting medication could be tried. The duration of action depends on both the dose and the elimination half-life.

  38. OVERALL STRATEGY • If sleep-maintenance insomnia is a problem, use of zolpidem, zolpidem CR, eszopiclone, or temazepam could be considered. • In older adult patients or those with impaired hepatic metabolism, a lower hypnotic dose is prudent. • If the duration of action is not long enough, a switch to a longer-acting medication should be made . • If the duration of action is too long (morning sedation), a switch to a shorter-acting medication or a reduction in dose of the current medication could be tried.

  39. OVERALL STRATEGY • If the medication is not effective, a switch to an alternative BZRA could be considered. • If anxiety is a major component of insomnia, use of a traditional BZ or eszopiclone with more anxiolytic activity might be more effective. • If the current hypnotic medication is not tolerated because of side effects, a switch to an alternative BZRA could also be tried. • If treatment with standard BZRA hypnotics is not successful, a sedating antidepressant could be tried.

  40. OVERALL STRATEGY • Given the minimal anticholinergic effects associated with trazodone , most physicians would start with this medication when using a sedating antidepressant. • low-dose doxepin or amitriptyline may be effective in some patients. • If sedating antidepressants are not effective (or tolerated at an effective dose), the combination of a BZRA and a sedating antidepressant could be tried (e.g., zolpidem and trazodone). • If a significant pain component to insomnia is present, gabapentin could be tried for its sedating as well as analgesic effects.

  41. OVERALL STRATEGY • If anxiety is a major component of the insomnia or the traditional BZRA hypnotics are not effective, use of lorazepam, alprazolam, or clonazepam could be tried. • Sedating antipsychotic (quetiapine) have major side effects and are generally to be avoided unless a mental disorder is present or all other options have failed.

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