unit 9 Flashcards
glutamate
ubiquitous excitatory neurotransmitter - causes EPSPs
- involved in every behavior and cognitive process
- why? because nearly every, if not every, neuron in the CNS has glutamate receptors
- Glutamate is by a wide margin the most abundant neurotransmitter in the vertebrate nervous system that causes excitation . It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain.
glutamate receptors
- NMDA – ionotropic
- AMPA – ionotropic
- Kainate - ionotropic
- Metabotropic glutamate receptors – G-protein coupled receptors (AKA metabotropic receptors; there are 8 subtypes )
- the most important are ionotropic
glutamatergic synapse
processes of glutamate synthesis and metabolism, neuronal and glial glutamate uptake, and vesicular glutamate uptake and release. Pre- and postsynaptic excitatory amino acid receptors are also shown. The table lists important glutamatergic receptor agonists and antagonists. Note the interesting property that not only can the neuron use re-uptake of glutamate for repackaging, but glial cells can also take in glutamate. The glial cells then metabolize the glutamate (via glutamine synthetase) to glutamine, release the glutamine, and neurons take up the glutamine for synthesis (via glutaminase) back into glutamate for repackaging.
criteria glutamate has met to be considered a neurotransmitter
It is localized presynaptically in specific neurons where it is stored and released from synaptic vesicles.
It is released by a calcium-dependent mechanism by physiologically relevant stimuli in amounts sufficient to elicit postsynaptic responses.
A mechanism (reuptake) exits that will rapidly terminate its transmitter action.
It demonstrates pharmacological identity with the naturally occurring transmitter.
Receptors
pathways using excitatory amino acid neurotransmitters
There is no need to know the location of all of these glutamatergic/aspartaminergic neurotransmitter pathways. Just be aware that these excitatory neurotransmitters, especially glutamate are very widely distributed throughout the brain.
structural and functional properties of glutamate receptors
It is only necessary to know that there are 3 types of ionic glutamate receptors – AMPA, Kainate, and NMDA and that there are metabotropic receptors.
- AMPA - ligand gated channel superfamily => cation selectivity = Na+, K+
- Kainate - ligand-gated channel superfamily => cation selectivity = Na+, K+
- NMDA - ligand-gated channel => cation selectivity => Na+, K+, Ca2+
schematic representation of NMDA receptor complex
The NMDA receptor is very important for controlling synaptic plasticity and memory function. It has some unique features.
1) The NMDAR selectively binds the molecule N-methyl-D-aspartate (NMDA).
2) The ligand gating requires co-activation by two ligands: glutamate plus glycine or D-serine (possibly two molecules of each!)
3) The channel can be blocked by Mg2+ under resting conditions.
4) Depolarization dislodges the Mg2+ allowing Na+ and Ca2+ to enter and K+ to exit.
The NMDA receptor complex possesses a glutamate recognition site to which receptor agonists and competitive antagonists bind, as well as other binding sites for glycine, polyamines such as spermine and spermidine, phencyclidine (PCP) and related drugs, Mg2+, and Zn2+. Channel opening permits an influx of Na+ and Ca2+ ions, and efflux of K+ ions.
biochemical processes hypothesized to underlie ischemic neuronal injury and death
Overactivation of NMDA receptors can lead to neuroexcitotoxicity. This happens by relieving the Mg2+ block and causing excessive influx of Ca2+. Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases.
Ischemia is a restriction in blood supply to tissues, causing a shortage of oxygen that is needed for cellular metabolism. Reduced cellular energy metabolism during ischemia causes increased release and decreased reuptake of glutamate, as well as increased extracellular K+ concentrations due to inhibition of the Na+-K+ ATPase.
Neurons are strongly depolarized by glutamate stimulation of AMPA and kainate receptors and by exposure to the elevated extracellular K+ levels. Persistent glutamate activation of NMDA receptors with simultaneous membrane depolarization leads to a prolonged opening of NMDA receptor channels, permitting massive Ca2+ influx across the membrane. Depolarization is also thought to cause additional Ca2+ entry into the cell through voltage-operated Ca2+ channels (VOCC). Elevated intracellular Ca2+ levels activate a variety of Ca2+-dependent processes, including specific proteases and endonucleases; phospholipase A2 (PLA2), which liberates arachidonic acid (AA) from membrane lipids; nitric oxide synthase (NOS), which catalyzes the formation of nitric oxide (NO); and ornithine decarboxylase (ODC), which mediates polyamine biosynthesis. Ca2+ accumulation in mitochondria can also lead to severe damage to these organelles.
GABA
Ubiquitous inhibitory neurotransmitter
- Involved in every behavior
GABAa – Ionotrophic (chloride ion influx)
GABAb – Metabotropic
GABA essentially acts as a “brake” in the central nervous system
Drugs that promote GABA activity have been used to treat anxiety and sleep disordersgamma-Aminobutyric acid, or GABA is the chief “inhibitory neurotransmitter” in the mammalian central nervous system.
Two general classes of GABA receptor are known:
1) GABAA in which the receptor is part of a ligand-gated ion channel (permitting Cl- ion influx)
2) GABAB metabotropic receptors, which are G protein-coupled receptors.
Its principal role is reducing neuronal excitability throughout the nervous system.
In humans, GABA is also directly responsible for the regulation of muscle tone.
GABA synthesis
Note that the most important so-called “excitatory” neurotransmitter in the brain is the precursor molecule to the most important “inhibitory” neurotransmitter in the brain with the use of the appropriate enzyme.
GABA synapse
, illustrating the processes of -aminobutyric acid (GABA) synthesis and metabolism, neuronal and glial GABA uptake, and vesicular GABA uptake and release. Pre- and post-synaptic GABA receptors and sites of action of some GABAergic drugs are also shown. The table lists important GABAergic receptor agonists and antagonists.
the interplay between neurons and glia in GABA metabolism
Glial cells play an important role in controlling the amount of GABA in neurons and in the extracellular space.
techniques used to localize GABA pathways
Immunohistochemical localization of glutamic acid decarboxylase (GAD).
Immunohistochemical localization of GABA itself.
Histochemical localization of the GABA-destroying enzyme GABA aminotransferase (GABA-T).
Uptake of labeled GABA followed by autoradiography.
GABAa receptor complex
is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is GABA, and its activation inhibits neurotransmission. Upon activation, the GABAA receptor selectively conducts Cl- through its pore and hyperpolarizing the cell. The figure shows the different sites of action where neural depressants bind to activate the GABAA receptor.
therapeutic uses of sedative-hypnotics and anxiolytics
Insomnia
Anxiety
Epilepsy
Muscle spasticity
Induction of amnesia
As preanesthetic medication
Adjunct in alcohol withdrawal
classifications of sedative-hypnotics and anxiolytics
barbiturates, benzodiazepines, non-barbiturates/non-benzodiazepines
barbiturates
- Thiopental
- Secobarbital
- Pentobarbital
- Phenobarbital
benzodiazepines
- Chlordiazepoxide (Librium)
- Diazepam (Valium)
- Oxazepam
- Others
non-barbiturates/non-benzodiazepines
- Chloral hydrate
- Carbamates (e.g., meprobamate)
- Buspirone
- beta-blockers (propranolol); alpha2-adrenergic receptor agonist (clonidine)]
characteristics of barbituates
*all general, non-selective CNS depressants
*relatively low therapeutic indices
*drug interactions – induce liver enzymes(involved in metabolizing drugs)
*all derived from barbituric acid
absorption and distribution of barbituates
*administered as water-soluble free acid
*oral – when used to treat anxiety or sleep disorders
*intravenously – when used as adjuncts to general anesthesia
*thiobarbiturates are very lipid soluble and have a very rapid onset of action because of high rate of entry into CNS; but they also rapidly redistribute from CNS to highly perfused tissues and then to fat thus rapidly terminating their CNS effects.
CNS actions of barbituates
*decrease the amount of neurotransmitter released in excitatory neurons
*barbiturates interact with GABA to enhance postsynaptic inhibition
*increases the duration of GABA-Cl channel opening
*depresses the reticular activating system and excitability of cortical cells
*sedation – drowsy, aroused by external stimuli
*hypnosis – sleep, aroused by external stimuli
*coma – not aroused by external stimuli
*death – not aroused by external stimuli
*anticonvulsant action: best anti-epileptics are phenobarbital, mephobarbital and metharbital; they have rather selective actions as patient can be seizure-free and functional
*analgesia – very weak or none
respiratory, cardiovascular, and autonomic effects of barbituates
*depress respiratory drive and rhythm
*cross placental membrane and may depress fetal respiration
*at sedative-hypnotic doses, there is only a slight fall in blood pressure and heart rate
*blockade of sympathetic ganglionic transmission
cautions, side effects and contraindications of barbituates
*spatial judgment impaired
*drug interactions – augmentation of CNS depressive effects of ethyl alcohol; phenothiazine (antipsychotics); antihistamines; and antihypertensives
*contraindicated in certain pathological states (e.g., pulmonary insufficiency and emphysema)
*contraindicated in patients with previous allergic reactions
*drug interactions - enzymes
tolerance of barbituates
tolerance develops to the sedative-hypnotic effects of barbiturates
*metabolic tolerance – enzyme induction
*pharmacodynamic tolerance – adaptation of nervous tissue to drug presence
physical dependence of barbituates
*large problem!!
*withdrawal symptoms may be severe (e.g., seizures)
barbiturate poisoning
*moderate intoxication similar to alcoholic inebriation
*symptoms of severe intoxication: coma – can last up to five days with phenobarbital; constricted pupils dilation due to hypoxia; breathing slow or rapid and shallow; shock syndrome may develop (fall in blood pressure)
*death may be due to respiratory depression or complications of prolonged coma (pulmonary edema)
*treatment – charcoal lavage; intensive support therapy (respiratory); no stimulants; hemodialysis
duration of action of barbiturates
uses boil down to some basic pharmacokinetics: their lipid solubility. The higher the lipid solubility, the quicker the onset of action and shorter the duration of effect.
Thiopental is used to help you relax before you receive general anesthesia with an inhaled medication. It was once thought to be “truth serum”.
Secobarbital and Pentobarbital are used short-term to treat insomnia, an emergency treatment for seizures, or as a sedative before surgery.
Phenobarbital is a treatment of certain types of epilepsy in developing countries and commonly used to treat seizures in young children.
Secobarbital, Pentobarbital and Phenobarbital used in the US for physician-assisted suicide and executions of criminals.
tolerance and therapeutic index
Metabolic tolerance is an issue with barbiturates. With repeated use there is substantial increase in liver microsomal enzymes which increases drug metabolism and thus requiring more drug to give the desired effect. Note here that, while more drug is required to get the desired effect, the dose for respiratory depression does not change! Thus, the therapeutic index and margin of safety shrinks.
The above are theoretical dose-response curves for the barbiturate-induced desired effect (e.g., mood change or sedation) and lethal respiratory depression. The top panel shows that with early drug use (non-tolerant) the individual experiences mood effects without significant respiratory depression. However, as tolerance develops with repeated use (bottom panel), larger amounts of drug are needed to experience the mood change (the curve shifts to the right) but no change in the dose causing depression of respiration occurs. The margin of safety (i.e., therapeutic index) shrinks dramatically in the tolerant individual.
effects of acute and chronic barbiturate administration on sleep architecture
Another problem with barbiturates is that they promote sleep, but not normal, restful sleep. They disrupt typical sleep architecture.
Recall that sleep stages are cycled-through about 4-5 times per night with several bouts of REM sleep.
The left panel shows the initial effects of pentobarbital, which include a short onset of sleep and few spontaneous awakenings. The right panel shows the changes after chronic nightly use of the drug. Tolerance is shown by the long onset of sleep (1 hour) and the 12 spontaneously awakenings during the night. Both REM and stages 3 and 4 sleep are suppressed
blood levels of secobarbital in mothers and newborn infants
Effect of barbiturate on mothers in labor. Blood levels of secobarbital in mothers and their newborn infants after intravenous administration of the drug to the mothers. Each point represents one subject (circles, mothers; asterisks, infants).
characteristics of benzodiazepines
*today, the most commonly used sedative - hypnotics
mechanism of action for benzodiazepines
*preferentially act on the limbic system (septum, amygdala and hippocampus) where they potentiate GABAergic inhibitory neurotransmission
*increases the frequency of GABA-Cl channel opening
absorption and distribution of benzodiazepines
- benzodiazepines are weakly basic (therefore absorbed better in duodenum)
- several are metabolized to active forms
- the more lipophilic benzodiazepines have shorter onset and duration of action
advantages of benzodiazepines over barbiturates
*safer, higher therapeutic index
*less depression of respiration
*less induction of hepatic drug-metabolizing enzymes
*slower development of tolerance
*lower risk of physical dependence, withdrawal symptoms not severe
*less depression of REM sleep
major therapeutic uses of benzodiazepines
- Chlordiazepoxide
* Anticonvulsant, muscle relaxing properties, sedative and hypnotic effects. Used primarily in anxiety and muscular-skeletal disorders, and alcohol withdrawal syndromes; premedical treatment to anesthesia.- is used for treatment of prolonged anxiety, because of its long duration of action
- is similar to meprobamate and barbiturates in general; cumulative effect and the withdrawal symptoms
2. Diazepam
* an anticonvulsant and treatment of status epilepticus
* used as an amnesic agent in dental surgery and for possible amnesic effects in procedures such as endoscopy and bronchoscopy
* useful in acute alcohol withdrawal
3. Oxazepam
* is an metabolite of diazepam with short duration of action
major complications/concerns of benzodiazepines
*tolerance, physical dependence and cross tolerance occur with benzodiazepines and ALL other sedative-hypnotics including ethanol
*tolerance is common. and overdoses are frequent. However, serious consequences are rare. Treatment includes support of respiration and cardiovascular functions.
active metabolites of some benzodiazepines extend their duration of action
Long-acting benzodiazepines undergo several metabolic changes (phase 1) that create active metabolites(A) before being conjugated (phase II) with glucuronide to form a water-soluble inactive metabolite for excretion. (UDP= uridine diphosphate) Not important to know the name of the conjugate or the product excreted.
chloral hydrate
non-barbiturates/non-benzodiazepine
* chemically reduced to the active metabolite in liver
* the same sedative-hypnotic properties as barbiturates
* currently used as pre-medication for children and elderly
carbamates - meprobamate
non-barbiturates/non-benzodiazepine
*possess sedative-hypnotic, anticonvulsant and muscle relaxing properties; used primarily in anxiety and muscular-skeletal disorders (e.g., muscle spasm); of no value in treating psychoses; suppresses REM sleep
*ability to produce habituation and physical dependence similar to that for barbiturates; toxicity includes sleepiness, ataxia, hypotension; and massive overdose results in coma, shock, pulmonary edema and respiratory depression. The dose necessary to produce profound CNS depression is usually considered to be very much greater than that of a barbiturate.
*the drug should be withdrawn gradually and slowly
*the locus and mechanism of action are unknown
buspirone (second generation anxiolytic)
*it is an effective anti-anxiety drug and is a 5-HT1A receptor agonist
*has no effect on GABA or benzodiazepine binding
*has little interaction with CNS depressants, but caution must be
exercised with alcohol
*possesses no anticonvulsant properties
*has lower risk of dependence
*has no effect on panic disorder
*elicits no cross tolerance with other anti-anxiety drugs
time course of brain and venous ethanol concentrations
After administration of ethanol (2 g/kg i.p.) to mice, the brain ethanol concentration reached its peak in about 15 min, and did not equate with ethanol levels in venous blood taken from the tip of the tail until 60 min had passed.
- the alcohol molecule is both hydrophilic and lipophilic
relationship between blood alcohol concentration and signs of intoxication
After three doses of alcohol (1.0 g/kg at time a, and 0.25 g/kg at times b and c), signs of intoxication appeared during the rising phase of the blood alcohol concentration (BAC) curve when the BAC was about 200 mg/dl. However, when the BAC was declining, the subject became sober even though the BAC was about 265 mg/dl.
- tolerance is quicker
ethanol effects at glutamate synapse
Alcohol also inhibits glutamate, particularly at the N-methyl-d-aspartate (NMDA) glutamate receptor.
It does this by two means. First, it inhibits NMDA receptors so that the channels do not fully open so that there is less entry of sodium (Na+) and calcium (Ca2+) into the cell for less excitation. Secondly, alcohol may also increase activity of presynaptic metabotropic glutamate receptors to decrease glutamate release. Therefore, alcohol has two ways to inhibit the main “excitatory” transmitter in the brain.
acute cellular effects of glutamate
receptor antagonism and reduced glutamate release
behavioral effects of glutamate
memory loss, rebound hyperexcitability of the abstinence syndrome
acute cellular effects of GABA
increase in GABA-induced CL= influx to hyperpolarize
behavioral effects of GABA
sedative effects, anxiety reduction, sedation, incoordination, memory impairment, tolerance and signs of hyperexcitability during withdrawal
acute effects of dopamine
increase in dopamine transmission in mesolimbic tract
behavioral effects of dopamine
reinforcement, negative affect as a sign of withdrawal
acute cellular effects of opiods
increase in endogenous opioid synthesis and release
chronic cellular effects of opiods
neuroadaptive decrease in endorphin levels
behavioral effects of opioids
reinforcement and dysphoria
inverse agonists acting on BDZ receptor
can have anxiogenic effects or even convulsive effects
metabolism of ethanol
Ethanol is oxidated by the enzyme alcohol dehydrogenase using NAD+ as a cofactor to form acetaldehyde. A second oxidative step converts acetaldehyde to acetic acid, which, in turn, is broken down to carbon dioxide and water. The first step involving alcohol dehydrogenase is the rate-limiting step. The drug disulfiram (Antabuse) blocks the second step by blocking the activity of aldehyde dehydrogenase. This is important to know this two step process.
ethanol is oxidized by
the enzyme alcohol dehydrogenase using NAD+ as a cofactor to form acetaldehyde. A second oxidative step converts acetaldehyde to acetic acid, which, in turn, is broken down to carbon dioxide and water. The first step involving alcohol dehydrogenase is the rate-limiting step. The drug disulfiram (Antabuse) blocks the second step by blocking the activity of aldehyde dehydrogenase.
metabolism of ethanol and the use of the aldehyde dehydrogenase inhibitor, disulfiram
Ethanol is oxidated by the enzyme alcohol dehydrogenase using NAD+ as a cofactor to form acetaldehyde. A second oxidative step converts acetaldehyde to acetic acid, which, in turn, is broken down to carbon dioxide and water. The first step involving alcohol dehydrogenase is the rate-limiting step. The drug disulfiram (Antabuse) blocks the second step by blocking the activity of aldehyde dehydrogenase.
analgesics, narcotic with alcohol
- when used alone, either alcohol or narcotic drugs cause a reduction in the function of the central nervous system. when they are used together is effect is even greater and may lead to loss of effective breathing function (respiratory arrest) death may occur
FAS signs and symptoms
- Intellectual disability and developmental delays
- Low birthweight
- Neurological disorders (tremor, irritability auditory hypersensitivity, etc.)
- Craniofacial malformations
- Assorted physical abnormalities
alcohol (ETOH) use and abuse
In U.S. nearly 75% of adults drink ETOH.
15% of ETOH users in the U.S. are considered to have a drinking problem or are subject to alcoholism.
10 million Americans are classified as alcoholics.
Alcoholism is most severe of all substance abuse in USA.
More people become dependent on ETOH, become psychotic through excessive use of it and are killed or disabled by it than by all other abused drugs (except nicotine via tobacco) put together.
11 million accidents each year are ETOH-related.
Alcohol Abuse Disorder costs the U.S. economy $136 billion.
alcoholism
an illness characterized by preoccupation with alcohol and loss of control over its consumption such as to lead usually to intoxication if drinking is begun; the condition is chronic, progressive, and has a tendency toward relapse. It is typically associated with physical disability and impaired emotional, occupational, and/or social adjustments as a direct consequence of persistent and excessive use of alcohol.
three-factor vulnerability model
Biological, psychological, and sociocultural influences contribute to the development of alcohol abuse.
epilepsy
Epilepsy affects about 0.5% of the population.
The characteristic event is the seizure, which is often associated with convulsions, but may occur in many other forms.
The seizure is caused by an abnormal high frequency discharge of a group of neurons, starting locally and spreading to a varying extent to affect other parts of the brain.
Seizures may be partial or generalized depending on the location and spread of the abnormal neuronal discharge. The attack may involve mainly motor, sensory or behavioral phenomena. Unconsciousness occurs when the reticular formation is involved.
Partial seizures are often associated with damage to the brain, whereas generalized seizures occur without obvious cause.
Two common forms of generalized epilepsy are the tonic-clonic fit (grand mal) and the absence seizure (petit mal).
The neurochemical basis of the abnormal discharge is not well understood. It may be associated with enhanced excitatory amino acid transmission, impaired inhibitory transmission, or abnormal electrical properties of the affected cells.
Prolonged epileptic discharge (status epilepticus) can cause neuronal death (excitotoxicity).
Current drug therapy is effective in 70-80% of epileptic patients.
tonic-clonic seizures
generalized seizures, i.e. they spread through or affect the entire brain. A patient experiencing a grand mal seizure may experience an aura before the seizure begins. The person experiencing a grand mal seizure collapses, loses consciousness and goes into convulsions. The patient is often unconscious after the seizure’s end.
During a petit mal seizure, the patient loses consciousness for 10 to 15 seconds and then makes a complete recovery, while a person having an “absence seizure” may suddenly stop and stare into space. Someone witnessing such a seizure may think the person has simply stopped paying attention or is daydreaming. After the seizure is over, the sufferer has no memory of it. The patient has no need for medical attention or special care during or after the seizure.
relations among cortical EEG, extracellular and intracellular recordings in a seizure
With Tonic-Clonic Seizures, the tonic phase is typically short duration (a few second) during which the subject tenses and may lose consciousness. Then, during the clonic phase, the subject will shake uncontrollably. The main point here is the the neural excitability—the high-frequency firing of the neuron.
A paroxysmal depolarizing shift (PDS) or depolarizing shift is a cellular manifestation of epilepsy. First, there is a Ca mediated depolarization, which causes voltage gated Na to open, resulting in action potentials. This depolarization is followed by a period of hyper-polarization mediated by Ca-dependent K channels or GABA-activated Cl influx.
The extracellular recording was made through a high-pass filter. Note the high-frequency firing of the neuron evident in both extracellular and intracellular recording during the paroxysmal depolarization shift (
agents acting to: enhance Na+ channel inactivation
phenytoin, carbamazepine, valproate
agents acting to: enhance GABAergic tranmission
phenobarbital, clonzepam, vigabatrin, tiagabine, gabapentin
inhibit Ca2+ channels
ethosuximide
pharmacological treatment of epilepsy
enhance Na+ channel inactivation, enhance GABAergic transmission, inhibit Ca2+ channels
- Note that a commonality of antiseizure drugs is to inhibit depolarization of cells, or increase polarization, by acting on ionic receptors. Thus drugs such as carbamazepine and valproate inactivate sodium channels so less positive charge enters the cell. Phenobarbital and clonazepam stimulate the GABA receptor. Ethosuximide inhibits Calcium channels.
antiseizure drug-enhanced Na+ channel inactivation and drug-induced reduction of current through T-type Ca2+ channels
Carbamazepine and Valproate are antiseizure drugs (shown in blue text) that prolong the inactivation of the Na+ channels, thereby reducing the ability of neurons to fire at high frequencies. Note that the inactivated channel itself appears to remain open but is blocked by the inactivation gate (I). A, activation gate.
valproate
stimulates production of GABA, and inhibits breakdown of the chemical.
In the presence of GABA, the GABAA receptor allows an influx of Cl-, which in turn increases membrane polarization. Some antiseizure drugs act by reducing the metabolism of GABA. Others act at the GABAA receptor, enhancing Cl- influx. GABA-T, GABA transaminase; GAT-1, GABA transporter.
in the presence of GABA, the GABAa receptor
is following an influx of Cl-, which in turn increases membrane polarization. Some antiseizure drugs act by reducing the metabolism of GABA. Others act at the GABAA receptor, enhancing Cl- influx. Gabapentin acts presynaptically to promote GABA release; its molecular target is currently under investigation. GABA-T, GABA transaminase; GAT-1, GABA transporter.
estazolam
insomnia therapy
- intermediate half-life
- some daytime sedation and performance decrements
flurazepam
insomnia therapy
- long half life
advantage = delayed rebound insomnia
disadvantage = daytime sedation - high risk of falls and driving errors
tempazepam
insomnia therapy
- intermediate half-life
- some daytime sedation and performance decrements
triazolam
insomnia therapy
- short half-life
- no day-time sedation
disadvantage = rebound insomnia
zolpidem
insomnia therapy
- short half-life
- no daytime sedation
disadvantage = rebound insomnia
benzodiazepines for insomnia therapy
estazolam, flurazepam, temazepam, triazolam, zolpidem
non-benzodiazepine therapy for insomnia
antidepressants (amitriptyline, doxepin, trazodone)
antipsychotics (haloperidol, chlorpromazine)
barbiturates
antihistamines (diphenhydramine)
mental illness and insomnia are often co-morbid
and insomnia is a symptom of most mental illnesses. This type of insomnia is properly secondary insomnia – the cause is the mental illness and the insomnia will be relieved if the underlying illness is cleared up.
insomnia and depression
have been linked for some time and most sleep specialists believe that insomnia is often a secondary symptom to clinical depression. A number of anti-depressant drugs are notable for applications as sleep aids. Trazodone is one of the most popular.
haldol (haloperidol) and chlorpromazine
are medications commonly used to treat schizophrenia and sometimes acute psychosis.
antihistamines
can make you feel drowsy, and therefore help you get to sleep for two to three nights — but regular use can make insomnia worse. Diphenhydramine is sold as Benadryl.
haloperiodol
advantages in insomnia therapy = no tolerance, few anticholinergic effects
disadvantages = extrapyramidal effects; increased risk of falls; limited sedation
chlopromazine
advantages in insomnia therapy = no tolerance
disadvantages = extrapyramidal effects, increased risk of falls, anticholinergic delirium
