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Sleep Disorders I. Normal Sleep a. Active suppression of the RAS b. Sleep stages i. Sleep is divided into two stages: 1. Non rapid eye movement (NREM) a. A stage of sleep characterized by slowing of the EEG rhythms, high muscle tone b. Where night terrors can occur c. Absence of eye movements and thought like mental activity d. The brain is inactive while the body is active e. Made up of 4 stages i. Stage 1: disappearance of alpha wave and appearance of theta wave 1. Makes up 5% of sleep time 2. Drowsiness (actually still awake) ii. Stage 2: K complexes (increase in voltage) and sleep spindles (increase in frequency) 1. 12-14 cps 2. 45% of sleep 3. Light sleep 4. Longest of all sleep stages iii. Stage 3: appearance of delta wave 1. 12% of sleep cycle 2. Deep sleep iv. Stage 4: continuation of delta wave 1. 13% 2. Slow wave deep sleep f. Amnesia upon waking, enuresis and somnambulism occur and patients are hardest to arouse in stages 3 and 4 g. Stages 3 and 4 tend to disappear in the elderly 2. Rapid eye movement (REM) a. A stage of sleep characterized by aroused EEG patterns, sexual arousal, saccadic eye movements, generalized muscular atony (deep paralysis) excepted in the middle ear and the eye muscles and dreams b. The brain is active but the body is inactive c. Seen as bursts and sawtooth waves on the EEG d. Makes up 25% of the sleep cycle e. Increased BP, RR, pulse and brain RR f. g. h. i. i. All in a irregular patter Also called paradoxical sleep i. The brain waves look like they do when you are awake ii. Patient is easiest to arouse You remember the dreams you have Men under go partial or full penile erections The amount of REM increases as sleep lengthens i. I.e. it is increased in the second half of the night In children, REM makes up 50% of sleep j. c. Sleep Cycle i. Moves from Stage 1 to 2 to 3 to 4 to 3 to 2 to 1 and lastly to REM ii. Normally under go 4-8 cycles per 8 hour rest iii. REM latency is 90 minutes 1. The period of time from the moment you fall asleep to the first REM period 2. Exception: Depression and narcolepsy a. REM latency is 60 min or less b. The amount of REM increases c. Depression may be alleviated by less sleep iv. REM rebound 1. You can catch up on lost REM but not too much v. Sleep latency 1. The time needed before you actually fall asleep. Typically less than 15 min in most individuals. 2. May be abnormal in many disorders such as insomnia d. Sleep Hygiene i. Arise at the same time daily. ii. Limit daily in bed time to the usual amount present before the sleep disturbance iii. Discontinue CNS acting drugs such as caffeine, nicotine, alcohol and stimulants iv. Avoid daytime naps except when sleep chart shows they induce better night sleep v. Establish physical fitness by means of a graded program of vigorous exercise early in the day vi. Avoid evening stimulation and substitute radio or relaxed reading for television vii. Try very hot, 20 minute body temperature raising bath soaks near bedtime viii. Eat at regular times daily and avoid large meals near bedtime ix. Practice evening relaxation routines such as progressive muscle relaxation or meditation x. Maintain comfortable sleeping conditions e. Characteristics of Sleep i. From infancy to old age 1. The total sleep time decreases 2. REM percentage decrease 3. Stages 3 and 4 vanish f. Neurotransmitters of sleep, etc. i. Serotonin 1. Secreted from the dorsal rapid (sp?) 2. Increased during sleep 3. Initiates sleep (NREM) 4. Tryptophan (precursor of serotonin) increases total sleep time ii. Acetylcholine 1. Increased during sleep 2. Linked to REM sleep iii. Dopamine 1. Increased during sleep 2. Linked to arousal and wakefulness 3. Agonists produce arousal 4. Antagonists decrease arousal and produce sleep iv. Norepinephrine 1. Decreased during sleep 2. Linked to REM sleep 3. Secreted from the Locus Ceruleus 4. Lowering norepinephrine leads to increased REM v. Benzodiazepines 1. Suppress stage 4 and, when used chronically, increase sleep latency vi. Alcohol intoxication 1. Suppress REM vii. Barbiturate intoxication 1. Suppresses REM viii. Major depression 1. Shortens REM latency, increased REM time, suppression of delta, multiple awakenings and early morning awakening ix. Melatonin 1. Side effects include hypothermia or low body temperature a. Predisposes the person to infection 2. Low in people with jetlag g. Agents to increase sleep II. i. Antihistamine (OTC) 1. H1 antagonist 2. Not for use in older people or with alcohol ii. Valarian Root 1. Calming effect 2. Decreases sleep latency and increases quality of sleep 3. Not for use in pregnant or nursing women iii. Chamomile 1. Active ingredient is apigehin 2. Acts like a benzodiazopine 3. Also has a coumadin like effect Sleep Disorders a. Affects more than 40 million Americans b. Cost over 16 billion per year c. Classified by the diagnostic and statistical manual of mental disorders (DSM-IV) on the basis of clinical diagnosis and criteria and presumed etiology d. Narcolepsy i. A disorder characterized by excessive daytime sleepiness and abnormalities of REM sleep for a period of greater than 3 months ii. REM sleep occurs in less than 10-20 minutes. Patients feel refreshed upon awakening iii. Presenting symptoms: 1. Sleep attacks (most common) 2. Cataplexy: pathognomonic sigh consisting of a sudden loss of muscle tone which may have been precipitated by a loud noise or intense emotion. a. Patient remains awake if it is a short episode b. Treated with TCA or SSRI 3. Hypnagogic (going to sleep) and hypnopomic (after waking up) hallucinations 4. Sleep paralysis a. Most often occurs during waking when the patient is awake but unable to move 5. Report falling asleep quickly at night 6. HLA-DR2 is a human lymphocyte antigen that is increased in patients with narcolepsy 7. Hypocretin (important for appetite and alertness) is decreased iv. Treatment: 1. Forced naps at a regular time of day 2. Psychostimulants are preferred or if cataplexy is present TCAs are preferred 3. Provigil is an alpha agonist used to treat sleep attacks e. Sleep Apnea i. 18 million Americans have sleep apnea ii. A disorder characterized by the cessation of airflow at the nose or mouth during sleep. iii. Episodes last longer than 10 seconds each iv. Characterized by a loud snore followed by a heavy pause. v. Considered pathologic if the patient has more than 5 episodes an hour or more than 30 episodes during the night. vi. In severe cases, patients may experience more than 300 apneic episodes during the night vii. Pickwickian syndrome is the presence of sleep apnea in obese people viii. Presenting symptoms 1. Usually seen in obese middle aged males (~35 yr old) 2. Sometimes associated with depression, mood changes and daytime sleepiness 3. Spouses typically complain of partner’s snoring and of partner’s restlessness during the night 4. Complain of dry mouth in the morning 5. May have headaches in the morning due to the lack of oxygen 6. Complain of being tired during the day 7. May develop arrhythmias, hypoxemia, pulmonary hypertension and sudden death 8. Central alveolar hypoventilation a. Cannot breathe because of the airways ix. Types 1. Obstructive a. Muscle atonia in oropharynx or nasal, tongue or tonsil obstruction b. Problem with the respiratory structure or due to obesity c. More effort for respiratory action leads to an increase in muscle mass 2. Central a. Due to a lack of respiratory effort b. Problem with the respiratory center of the brain 3. Mixed a. Central at first but prolonged disorder is due to the collapse of the air way x. Treatment 1. Continuous positive airway pressure (CPAP) a. The device used to treat sleep apnea by sending positive airway pressure at a constant continuous pressure to help keep an open airway and allowing the patient to breathe normal through his/her nose and airway 2. Nasal positive airway pressure (NPAP) 3. Weight loss and surgery (for obstructive) f. Insomnia or Dysomnia i. A disorder characterized by difficulties in initiating or maintaining sleep (problem with normal sleep cycle) ii. Typically associated with some form of anxiety or anticipatory anxiety iii. Many patients have underlying psychiatric disorders such as depression (more frequently in women) iv. Other causative conditions include PTSD, OCD and eating disorders v. Primary lasts for at least 1 month and occurs 3x a week vi. Secondary is due to a psychiatric disorder vii. Can be due to jet lag (2-7 days [change meal time to fool body]), changing jobs, pregnancy, menstrual irregularity, pain, infection, tumor and/or vascular lesion viii. Symptoms 1. Predominant complaint is difficulty initiation or maintaining sleep 2. Affects the patients level of functioning 3. Frequent yawning and tiredness during the day 4. Sleep state misperceptions ix. Treatment 1. Consider good sleep hygiene 2. Consider behavioral modification techniques such as stimulus control 3. If medication are to be used consider benzodiazepines for a short period of time (max = 2 wks) a. DOC = ambian or triazolam if they can not fall asleep and florezapan if the wake up in the middle of the night 4. Warm socks may help some people fall asleep x. Differential diagnosis 1. Medical: a. Pain, CNS lesions, endocrine diseases, aging, brain stem lesions, alcohol, diet or medications 2. Psychiatric: a. Anxiety, tension, depression and environmental changes or other sleep disorders g. Parasomnias i. Nightmares 1. Occur during REM 2. Patient has a memory of the event upon awakening 3. Increased during times of stress 4. Reported by 50% of the population 5. Usually not treated but you could use a REM suppressant such as a TCA ii. Night terror 1. Occurs during Stages 3 & 4 2. Awakening by scream or intense anxiety 3. NO memory of the event the following day 4. Seen more frequently in children 5. More common in boys 6. Runs in families 7. Treatment is rarely required but if medication is needed consider benzodiazepines 8. Closely related to sleep walking and temporal epilepsy iii. Sleep talking 1. Occurs in all stages of sleep 2. Common in children and tired people 3. Usually involves a few words 4. May accompany night terrors and sleepwalking 5. No treatment is necessary iv. Sleepwalking 1. Also known as somnambulism 2. Occurs in stages 3 & 4 3. Sequence of behaviors with out full consciousness 4. May perform preservative behaviors 5. Usually terminates in awaking followed by confusion 6. May return to sleep without any memory of the event 7. Begins at a young age (4-8) and prevalence increases at 12 years of age 8. More common in boys 9. May find neurological condition 10. Sleep deprivation and stress my exacerbate 11. Need to assure patient safety 12. Use drugs to suppress stages 3 and 4 such as benzodiazepines v. Restless leg syndrome 1. Sensation of deep leg movement III. 2. Alleviated by leg massage vi. Sleep seizure 1. Form of epilepsy exacerbated by sleep Sedative-hypnotic drugs a. Includes benzodiazepines (15 types--alprazolam, diazepam, etc), barbiturates (phenobarbital) and alcohols b. Used to eliminate anxiety and increase sleepiness c. Benzodiazepines are used the most d. Barbituates were the first drugs used clinically e. Alcohol was the first ever used f. Most of the drugs that are used for anxiety states cause dose-dependent depression of the CNS that extends to sleep inducing effects (hypnosis) and possible anesthesia g. In overdose, depression of respiratory and vasomotor centers, dose response relationship is better for the benzodiazepines than for alcohol and barbiturates h. Other actions include anticonvulsant and muscle relaxing effects i. Drug induced sleep changes REM and suppresses the amount of REM j. All the drugs have differing levels of psychomotor depression k. Alcohol with increase the CNS effects l. MOA: i. Most facilitate the action of GABA 1. GABAA receptor activation leads to increased Cl ion influx and GABAB receptor activation causes an increase in the efflux of K a. Both lead to membrane hyperpolarization ii. The pentapeptide structure of the GABAA receptor has binding sites for benzodiazepines (BZ) and for barbiturates and alcohol 1. All different sites for each 2. Can be used to prevent OD of a specific drug 3. 5 transmembrane domains a. Activation of any opens the Cl channel iii. BZs potentate GABA by increasing the frequency of Cl ion channel opening 1. This action is blocked by flumazenil, a BZ receptor antagonist iv. Barbiturates increase the duration of Cl ion channel opening and at a high dose, they also open Cl ion channels and block Na channels 1. Flumazenil does not block the effects of barbiturates and ethanol v. BZ receptor mechanisms are heterogeneous. 1. BZ1 receptors mediate hypnotic actions a. Zolpedidem is not an BZ but binds to the BZ receptor 2. BZ2 receptor may play a role in memory, sensor motor and cognitive functions m. Benzodiazepins i. Uses and Effects 1. They enhance the function of GABA in the CNS 2. They are useful in treating the anxiety that accompines some forms of depression and schizophrenia 3. Should not be used to alleviate the normal stress of everyday life because of addiction potential and should only be used for short periods of time 4. CNS depression occurs (sedation, disinhibition, nystagmus, ataxia, respiratory depression) at very high doses 5. Additive with other CNS depressants including ethanol 6. Drug over dose is seldom lethal unless other CNS depressants are taken concurrently 7. Flumazenil IV reverses it’s effects a. Possible anterograde amnesia at conventional doses ii. Flunitrozepam 1. Date rape drug iii. Metabolites 1. Are lipophilic and are rapidly and completely absorbed after oral administration 2. Metabolized in the liver the form active metabolites 3. They are excreted in the urine as glucoronides or oxidized metabolites 4. Three BZ under go extrahepatic metabolism and do not form active metabolites a. Oxazepam, Temazepam and Lorazepan i. OTL: outside the liver iv. Tolerance and Dependency 1. It may occur if high doses of the drug are given over a prolonged period. 2. Cross tolerance can occur a. Individuals tolerant to one drug will be tolerant to other drugs in the same class but not to drugs in other classes 3. Abrupt discontinuation of drug results in withdrawal symptoms after a number of days (long t ½) 4. Tolerance is possibly due to a down regulation of BZ receptors a. The antianxiety effects are less subject to tolerance than the sedative and hypnotic effects 5. Drugs that are more potent and rapidly eliminated (lorazepam and triazolam) have more frequent and severe withdrawal problems 6. The less potent and more slowly eliminated drugs (flurazepam and quazepam) continue to improve sleep even after discontinuation 7. May disturb intellectual functioning and moter dexterity v. Specific Drugs 1. Alprazolam a. Used for short and long term treatment b. Used for anxiety, panic disorders (DOC) and phobias c. Most commonly used anxiolytic 2. Diazepam a. Very similar to cholordiazepoxide, clorazepate and oxazepam b. Used for anxiety (primary use), preoperative sedation, muscle relaxation (treating spasticity form degenerative disorders such as MS and cerebral palsy) c. DOC for terminating grand mal epileptic seizures and status epilepticus and acute treatment of alcohol withdrawal d. Longest acting BZ e. Forms 3 metabolites 3. Lorazepam a. Used for anxiety, preoperative sedation and status epilepticus (primarly) b. No active metabolites 4. Flurazepam a. Helps people fall asleep b. Used for sleep disorders (reduces both sleep induction time and the number of awakenings and increases the duration of sleep c. Lng acting with little rebound insomnia d. Effective up to 4 weeks e. T ½ = 85 hours 5. Temazepam a. Used for sleep disorders (reduces frequent awakening and inability to stay asleep) b. Taken several hours before bedtime c. Intermediate acting d. Slow oral absorption e. Peak sedative effect occurs 2-3 hours after oral dose IV. 6. Triazolam (Halicon) a. Causes significant amnesia b. Must be used carefully in elderly patients c. Used to induce sleep in patients with recurring insomnia and difficulty in going to sleep d. Short acting e. Possibility for early A.M. waking f. Sever rebound insomnia g. Must be used intermittently 7. Zolpidem a. Not a BZ but acts on the BZ receptors b. Used for sleep disorders c. BZ1 selective d. Causes less dependence, tolerance and abuse e. Not effective in chronic anxiety seizure disorders or muscle relaxation 8. Zaleplon a. Not a BZ b. Used for sleep disorders c. Use possibly for early awakenings d. Very short acting e. Causes daytime sedation f. Not effective in chronic anxiety seizure disorders or muscle relaxation g. Causes less dependence, tolerance and abuse vi. Duration of Action 1. Short acting a. 3-8 hours b. Oxazepam and Triazolam 2. Intermediate acting a. 10-20 hours b. Alprazolam, Estazolam, Lorazepam and Temazepam 3. Long acting a. 1-3 days b. Clorazepate, chlordiazepoxide, diazepam, flurazepam, quazepam Other drugs a. Buspirone i. No effects on GABA systems ii. Possible partial agonist at 5HT1A receptors iii. There are some affinities of DA2 dopamine receptors and 5HT2 serotonin receptors iv. No sedating and no additive CNS depression with other drugs v. vi. vii. viii. ix. No muscle relaxant and no anticonvulsant activity Useful for GAD Does not cause dependence Should not be used with a MAOI (causes hypertension) Useful in long term therapy of chronic anxiety with the symptoms of irritability and hostility b. Antihistamines i. Hydroxylzine is useful in patients with anxiety who have a history of drug abuse ii. Often used for sedation prior to dental procedures or surgery c. Opioid analgesics promote sedation and sleep d. Barbiturates i. Uses: 1. Dose dependent CNS depression a. Respiratory, coma and possible mortality b. No specific antidote for OD 2. Additive CNS depression with other drugs 3. All end in “tal” and all (except thiopental and methohexital) end in “barbital” ii. Metabolites 1. Hepatic metabolism leads to active metabolites 2. Induction of Cyp450 is characteristic and my lead to drug interactions 3. Increases heme synthesis and so is contraindicated in porphyries iii. Tolerance and dependence 1. Occurs with chronic use 2. Withdrawal symptoms may be severe, especially with short acting barbiturates a. Anxiety, agitation, hyperflexia, seizures and post seizure depression of vital functions b. TX: long acting BZs such as diazepam iv. Duration of Action 1. Long acting a. 1-2 days b. Phenobarbital 2. Short acting a. 3-8 hours b. Pentobarbital, secobarbital, amobarbital (useful for unexplained muteness) 3. Ultra short acting a. 20 minutes b. Thiopental (anesthetic agent) e. Alcohols i. 1st historic use ii. Ethylene glycol 1. Antifreeze 2. Sweet taste 3. Converted to glycoaldehyde (toxic) and then glycolic and oxalic acid by alcohol dehydrogenase 4. Causes CNS depression, metabolic acidosis and nephrotoxicity 5. OD treatment is fomepizole, a long acting inhibitor of alcohol dehydrogenase and hemodialysis a. Ethanol can be used as a competitive inhibitor iii. Methanol 1. Converted to formaldehyde (toxic) and formic acid by alcohol dehydrogenase 2. Causes severe anion gap metabolic acidosis, ocular damage (blindness) and respiratory failure 3. OD treatment is fomepizole, a long acting inhibitor of alcohol dehydrogenase and hemodialysis a. Ethanol can be used as a competitive inhibitor iv. Ethanol 1. Converted to acetaldehyde by dehydrogenase in the cytoplasm a. Causes N&V, headache, hypotension b. Combines with foliate and inactivates it c. Combines with thiamine to decrease availability 2. Acetaldehyde is converted to acetic acid by dehydrogenase in the mitochondria a. Inhibited by disulfiram i. Used to treat alcoholism ii. Many drugs can have a disulfiram like reaction 3. Increasing plasma levels of alcohol can lead to a. Sociability, Gait disturbances, decreased reaction time, ataxia, impaired motor and mental skills, impaired memory, coma and death b. Also causes hypoglycemia, fatty liver and lipemia, muscle wasting (long term alcoholic and poor food intake) and gout (lactate competes with urate for excretion)