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2. Hypnotic Agents A dose-related, generalized depression (more than seen with anti-anxiety sedative drugs) of the CNS that produces drowsiness and induces sleep Often an increase in the dosage of a sedative agent will produce hypnotic activity Ideal hypnotic agent would produce drowsiness and facilitate the onset and maintenance of sleep that resembles natural sleep in its electroencephalographic characteristics and from which the recipient can be aroused easily No next-day effects such as rebound anxiety or continued sedation (Hang Over) Chronic use without dependence or rebound insomnia on discontinuation Insomnia is one of the most common complaints in general medical practice Treatment is predicated upon proper diagnosis Regular moderate exercise is the best treatment for insomnia

3. Hypnotic Agents Management of insomnia is controversial Pharmacological versus non-pharmacological treatment Use of short-acting versus long acting hypnotic agents Search for specific causes of the problem: use non-pharmacologic treatments when possible. Are there drug causes for insomnia? ethanol use, caffeine containing products or OTC medications such as decongestants Sleep hygiene education-no caffeine or decongestants, no ethanol, adequate exercise, regular sleep and waking times Types of insomnia Transient – less than 3 days and caused by brief environmental or situational stress Short-term – 3 days to 3 weeks caused by stressors such as illness, grief or job problems Long-term insomnia – lasting for more than 3 weeks

4. Hypnotic Agents Causes of long-term insomnia Major psychiatric illnesses and drugs used to treat Depression: SSRI’s in initial stages but will disappear as the depression is treated - if insomnia continues trazodone may improve sleep Anxiety disorders, psychosis such as schizophrenia - insomnia often disappears as they begin treatment with dopamine blocking agents—if agitation continues benzodiazepines are useful adjuncts Insomnia due to CHF, asthma, COPD, chronic pain in terminal cancer (adequate pain control usually resolves the insomnia) Conditioned or learned insomnia – patients associate the bedroom with activities other than sleep NO TV, reading, or computer use! Sleep state misperceptions – feel they do not sleep but it is an illusion Sleep apnea (hypnotics are CONTRAINDICATED): sleep studies Long-term insomnia patients must also adhere to non-pcol treatments Sleep restriction therapy, go to bed only when sleepy, leave the bedroom if sleep does not come in 15-20 minutes, arise at the same time, avoid naps

5. Hypnotic Agents Side-Effects of hypnotic agents limit their usefulness Decreased effectiveness over time Rebound insomnia on discontinuation All these drugs change sleep architecture Barbiturates decrease REM sleep Benzodiazepines reduce slow-wave non-REM sleep Benzodiazepines produce cognitive changes - next day confusion, increased rate of falls in the elderly, rebound next-day anxiety, amnesia, worsening of sleep apnea Short-acting agents - rapid sleep but often wake up after 3-4 hours and can not get back to sleep Elderly: – polyphasic sleep pattern (napping) - siesta Altered pharmacokinetic activity due to reduced body water (diuretics), reduced renal function, increased body fat greatly increased the half-life for benzodiazepines Week 1: pleasant sleep and adequate daytime wakefulness Week 3: may produce daytime confusion, amnesia, cognitive impairment and impair quality of life

6. Hypnotic Agents Management of patients on long-term treatment In elderly: termination of benzodiazepines will be a long, involved process Seizures, rebound insomnia, altered sleep patterns Patients taking these drugs for months or years are a special problem group If taking for more than 2 weeks the drug must be tapered slowly without abrupt discontinuation In patients on short half-life agents: Easier to switch them to a long half-life agent and taper dosage Remember that the withdrawal of long-acting agents will have DELAYED withdrawal side effects Use extreme care in discontinuation in patients with known seizure disorders

7. Hypnotic Agents Prescribing Guidelines Benzodiazepines, zolpidem, and zaleplon are preferred over barbiturates: greater therapeutic index Benzodiazepines with a short half-life are favored in patients with sleep-onset insomnia and no daytime anxiety Benzodiazepines with a longer half-life are preferred if daytime anxiety is present, tolerate next-day sedation Start at small dose and incrementally increase as necessary Long half-life agents can accumulate and after 2-4 weeks Cause next-day cognitive impairment or delayed daytime cognitive impairment Benzodiazepines are preferred in the elderly Less risk of falls and respiratory depression Caution: early morning wakening, rebound daytime anxiety and amnesic episodes - more common at higher dosage Avoid barbiturates, glutethimide and meprobamate (anti-anxiety agent) for insomnia management High abuse potential and very easy to overdose

8. Barbituate Sedative Hypnotics These agents have largely been replaced by the benzodiazepines due to a higher margin of safety As hypnotic agents used only for short-term treatment of insomnia - less than 2 weeks All are absorbed orally and distributed to all tissues and body fluids Lipid solubility as determined by the partition coeffficient correlates with the pharmacology one observes - higher the lipid solubility the faster the onset and the shorter the duration of action High lipid solubility or hydrophobicity leads to extensive plasma protein binding - acidic drugs will result in displacement and increased CNS depression – drug-drug displacement drug interactions Tissue redistribution is a result of lipid solubility differences and the extent of plasma protein binding - influences rate of excretion

9. Barbituate Sedative Hypnotics Sedative (Anxiolytics) and hypnotics are short and intermediate agents with rapid onset and short duration Side-effects Decreases the incidence of REM sleep Problems are dose-related: respiratory depression, suicide Idiosyncrasy: excitation and hypersensitivity are possible Acute overdose coupled with ethanol or other CNS depressant use is a leading cause of death Chronic use ? psychological and physical dependence Other properties Anesthesia – ultra-short acting agents quickly cross BBB then less rapidly redistribute to other tissues poor analgesic Anti-epileptic and anti-seizure - primarily now used in a prophylactic treatment to prevent future seizures

10. Barbituate Sedative Hypnotics Metabolism is via CYP450: extent is a function of the drug itself Inducers or stimulators of increased production of these enzymes leading eventually to metabolic tolerance Induction leads to increased porphyrin and heme synthesis and finally the intact CYP450 enzyme Cross tolerance does develop between the various agents Any drug that is metabolized by an induced enzyme as a result of barbiturate use will be cleared from the body at a higher than normal rate Excretion of the free drug and the metabolites occurs renally as the free acid Urinary alkalinization will increase the rate of only phenobarbital due to a favorable pKa value Alkalinization will not increase excretion of the other barbiturate due to high pKa values MOA: mimics GABA enhancing inhibitory effects of GABA by binding the GABA receptor-chloride channel complex

19. Insomnia MoA – unknown: believed to result from GABA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors. Metabolized by CYP3A4 and CYP2E1 via demethylation and oxidation - Interactions

22. New for 2005 Rozerem (ramelteon) Tablets Approved: July 22, 2005 Company: Takeda Pharmaceuticals North America, Inc. Treatment for: InsomniaRozerem is the first and only prescription sleep medication that has shown no evidence of abuse and dependence, and is therefore not designated as a controlled substance. Rozerem is indicated for the treatment of adults with insomnia characterized by difficulty with sleep onset, and can be prescribed for long-term use.

23. Ramelton - Rozerem® Indication: treatment of adults with insomnia characterized by difficulty with sleep onset, and can be prescribed for long-term use. MoA: Melatonin receptor agonist at the MT1 and MT2 receptors Metabolized primarily by CYP1A2, also 3A4 and 2C families to a lesser degree. Warnings: Not used in renal impairment, can cause cognitive impairment, Not to be taken with alcohol, appears to decrease tesosterone and increase prolactin. No data yet for pediatric use