Treatments for Insomnia. Alejandro M. Ramirez BLA April 2007

Transcription

1 Treatments for Insomnia Alejandro M. Ramirez BLA April 2007

2 Sleeping Disorders Insomnia Sleep Apnea Restless Legs Syndrome Narcolepsy

3 Insomnia Transient: Short time Intermittent: Comes and goes Chronic: Occurs most nights for periods longer than a month Primary Secondary

4 Insomnia, Introduction 40% of American adults suffer from intermittent insomnia 10-15% suffer from chronic insomnia A person suffering from chronic insomnia experiences on frequent basis: Problems falling asleep. Problems staying asleep Experiences nonrestorative sleep

5 Introduction 7.5 hours is the average amount of sleep required by an individual. Decreased amount of sleep leads to decreased amount of energy, mental alertness, and mood levels. Immune response is bolstered by sleep, therefore health is affected as well.

6 Consecuences People with chronic insomnia are more likely to develop psychiatric problems. Long-term sleep deprivation may increase the severity of chronic diseases, such as high blood pressure and diabetes. According to the National Highway Traffic Safety Administration, more than 100,000 crashes each year are due to drivers falling asleep at the wheel.

7 Causes Anxiety Depression Stimulants Change in environment Change in schedule Long term use of sleep medications Medical conditions causing pain Eating too much before sleeping

8 Causes, Age As age increases, changes occur which may affect sleep Change in sleep patterns Change in activity Change in health

9 Treatment Abstention Relaxation therapy Sleep restriction Reconditioning Drugs Barbiturates Benzodiazepines Miscellaneous Sedatives and hypnotics

10 Barbiturates Amobarbital (Amytal) Butabarbital (Butisol) Pentobarbital (Nembutal) Phenobarbital (Solfoton) Secobarbital (Seconal) Produce drowsiness and prolong sleep duration by slowing CNS functioning. Cause mild sedation and a hypnotic state. Short term use

11 Benzodiazepines Estozolam (ProSom) Ability to: Flurazepam (Dalmane) Quazapam (Doral) Temazepam (Restoril) Triazolam (Halcion) speed sleep onset Reduce number of awakenings Increase total sleep duration Should not discontinue abruptly because of rebound insomnia.

12 Miscellaneous Sedatives and Hypnotics Eszopiclone (Lunesta) Ramelteon (Rozerem) Zaleplon (Sonata) Zolpidem (Ambien and Ambien CR) Difficult to group together Different mechanisms Mechanisms unknown

13 Inhibitory Neurotransmitters GABA Serotonin Glycine Taurine

14 Excitatory Neurotransmitters Acetylcholine Glutamate Norepinephrine Epinephrine Phenylethylamine Histamine Dopamine

15 Stimulatory, Excitatory

16 Serotonin

17 Dopamine

18 GABA

19 Glycine, Histamine

20 Thalamus, Hypothalamus and Brainstem

21 Hypothalamus Serotoninergic, adrenergic, and histamminergic activity is high during wakeful states, decreases during NREM, and is almost eliminated with REM sleep. Cholinergic activity remains high in the brainstem during REM sleep. Posterior and midbrain hypothalamic junction lesions result in sleepiness. Anterior inflammation resulted in insomniac state.

22 Superchiasmatic Nuclei Light has important role in circadian clock

23 GABA-A Receptor Mediates tonic inhibition Alpha, beta, delta, and gamma subunits Alpha, beta, and gamma are encoded by same cluster of genes on chromosome 5. Composition of these subunits determines affinity of the receptor to ligand Distribution of subunits also varies depending on tissue and location

24 GABA-A Receptor Five protein subunits. Form central pore permeable in the most part to Chloride ions. GABA, benzodiazepines, barbiturates and anaesthetic steroids bind to Chloride channel. GABA is the most improtant inhibitory transmitter in the CNS, and is virtually absent outside the brain and spinal chord.

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26 Some Methods for Studying GABA- A Receptors Immunohistochemistry Knock-out, knock-in mice PCR, RT-PCR

27 Immunohistochemistry

28 GABA-A Receptor, Subunits

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30 Benzodiazepines Benzodiazepines do not open the chloride channel directly. Binds indirectly to alpha and increases the capacity of GABA to bind to it s receptor on the beta subunit.

31 Benzodiazepines Produce their therapeutic effect on the GABA-A receptors, but tolerance and dependence are more complicated than simply downregulating. Long term exposure causes differential changes in the expression of GABA-A receptor genes. Poor memory and loss of motor function from abuse. e.g. Flunitrazepam (Rophypnol).

32 GABAergic vs. Cholinergic Study Cholinergic system in nucleus pontis oralis (NPO) is critically important in production of REM sleep. Ach release in NPO is greater during REM sleep. Neurons show increased dischrge rate during sleep. Lesions to such cholinergic neurons eliminate REM sleep.

33 GABAergic vs. Cholinergic Study GABA mediated inhibition has negative effect on pre-synaptic release of ACh in the NPO. Pontine GABAergic system functions to suppress active sleep and promote wakefulness. Cholinergic activation of Pontine waves stem from the pons to the hippocampus and amygdala.

34 How? Use cholinergic and Gabaergic agonists and antagonists: Muscimol: GABA-A agonist Bicuculline: GABA-A antagonist Carbachol: mach receptor agonist Scopolamine: mach receptor antagonist

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39 Reference a.htm erstanding_sleep.htm y332/salinas/neurotransmitters/slide14.gif