Pharm Chapter 22- Sedative Hypnotics

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Pharmacokinetics of sedative-hypnotics

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lipid-soluble, absorbed well from GI tract, good distribution to the brain

Front 2

drug with the highest lipid solubility

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thiopental; enters CNS rapidly and can be used as induction agent in anesthesia

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CNS effects of thiopental terminated how

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rapid redistribution of the drug from brain to other highly perfused tissues

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other drugs with rapid onset of CNS action

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eszopiclone, zaleplon, zolpidem

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metabolism and excretion of sedative-hypnotics

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metabolized before elimination by hepatic enzymes;

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cause of excessive sedation via metabolism

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diazepam and flurazepam are converted initially to active metabolites which build up

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lorazepam and oxazepam metabolism

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extrahepatic conjugation; do not form active metabolites

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chloral hydrate metabolized to what

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oxidized to trichloroethanol- active metabolite

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reason for short duration of action of zolpidem

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rapid liver metabolism

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metabolism of zaleplon

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very rapid by aldehyde oxidase and cytochrome P450

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duration of action of CNS sedative-hypnotic drugs

a few hours

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zaleplon <zolidem = traizolam = eszopiclone <chloral hydrate

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duration of action of CNS sedative-hypnotic drugs-more than 30 h

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chlordiazepoxide, clorazepate, diazepam, phenobarbital

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location of benzo receptors

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thalamus, limbic structures, cerebral cortex

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benzo receptor structure

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part of a GABAa receptor-chloride ion channel complex

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binding of benzos=what effect

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facilitates the inhibitory actions of GABA through increased chloride ion conductance

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MOA benzos

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increase the frequency of GABA-mediated chloride ion channel opening

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Flumazenil

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reverses the CNS effects of benzos and is classified as an antagonist at receptors

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inverse agonist

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B-carbolines that have a high affinity for BZ receptors and can elicit anxiogenic and convulsant effects

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barbiturates MOA

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depress neuronal activity in midbrain reticular formation, facilitating and prolonging the inhibitory effects of GABA and glycine

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barbiturates MOA continued

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bind multiple isoforms of GABAa receptor but at different sites than benzos so no block by flumazenil
-increased the duration of GABA-mediated chloride ion channel opening
-may block excitatory glutamic acid and at high concentration, sodium channels

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zolpidem, zaleplon, eszopiclone

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not benzos, but exert CNS effects via interaction with certain benzo receptors
-bind more selectively, interacting only with GABAa receptors that contain a1 subunits; antagonized by flumazenil

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which drugs cause sedation

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all in this class

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sedative-hypnotic effect on sleep

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can promote sleep onset and increase duration of the sleep state

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high doses of most older sedative hypnotics?

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loss of consciousness, with amnesia and suppression of reflexes

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benzodiazepines in high doses cause what type of amnesia

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anterograde amnesia

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drugs of this class used in status epilepticus

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diazepam, lorazepam, phenobarbital

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cerebral palsy drug and why

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diazepam; effective at sedative dose levels for specific spasticity states

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meprobamate

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some selectivity as a muscle relaxant

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medullary depression

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high levels of sedative-hypnotics, especially alcohols and barbiturates can cause depression of medullary neurons, leading to respiratory arrest, hypotension, and CV collapse
-cause of death in suicide OD

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psychologic dependence...why

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manifested by the compulsive use of these drugs to reduce anxiety

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withdrawal signs

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anxiety, tremors, hyperreflexia, seizures
-more common with shorter acting drugs

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clinical uses of sedative-hypnotics

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anxiety states, sleep disorders, sedation, hypnosis, muscle relaxation, anticonvulsant, anesthesia

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benzos with the best efficacy in rapid control of panic attacks

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alprazolam, clonazepam

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benzos used in primary insomnia

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estazolam, flurazepam, triazolam

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recent insomnia benzos

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zolpidem, zaleplon, eszopiclone because they have rapid onset with minimal effects on sleep patterns and cause less daytime cognitive impairment

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sedative-hypnotics are not recommended for what kind of sleep disorder

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breathing-related sleep disorder

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thiopental use?

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induction of anesthesia

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day surgery anesthesia?

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diazepam, midazolam

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clonazepam, phenobarbital special uses

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seizure disorders and bipolar disorders

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longer acting benzos that are used in the management of withdrawal states in persons psychologically dependent on ethanol etc

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chlordiazepoxide, diazepam

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toxicity (psychomotor dysfunction)

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cognitive impairment, decreased psychomotor skills, unwanted daytime sedation

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side effects of all drugs used as sleep aids

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functional impairment, "sleep driving"- driving not fully awake with no memory of event

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additive CNS depression

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when sedative-hypnotics are used with other drugs in this class as well as with alcohol, antihistamines, antipsychotic drugs, opioid analgesics, and TCAs

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overdose of sedative-hypnotics

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severe respiratory and CV depression; more likely to occur with alcohols, barbiturates, and carbamates than with benzos or newer ones like zolpidem

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flumazenil can reverse CNS depression with which drugs

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benzos, eszopiclone, zolpidem, zaleplon

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other adverse effects of barbiturates and carbamates

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induce the formation of the liver microsomal enzymes that metabolize drugs--> leads to multiple drug interactions

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what RBC disorder can barbiturates precipitate in susceptible patients

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acute intermittent porphyria

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which can displace coumadin from plasma proteins and increase coagulation

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chloral hydrate

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buspirone

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selective anxiolytic with minimal CNS depressant effects

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what we know of buspirone MOA

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interacts with 5-HT1a serotonin receptors as a partial agonist

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use of buspirone

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slow onset of action and used in generalized anxiety disorders
-tolerance is minimal with chronic use and there is little withdrawal

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metabolism of buspirone

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CYP3A4
-plasma levels markedly increased by drugs such as erythromycin and keconazole

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side effects of busprione

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tachycardia, paresthesias, pupillary constriction, GI distress

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Ramelteon

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hypnotic drug that activates melatonin receptors in the suprachiasmatic nuclei of the CNS decreases the latency of sleep onset with minimal rebound insomnia or withdrawal symptoms

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metabolism of ramelteon

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hepatic cytochrome P450 forming active metabolite

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what CYP inducer markedly reduces plasma levels of ramelteon

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rifampin

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adverse effects of ramelteon

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dizziness, fatigue, endocrine changes including decreased testosterone and increased prolactin