Anxiolytic and Hypnotic Drugs Flashcards by Meghan May

How prevelant are anxiety disorders

seen in 28.8 % populaiton in lifetime with 4% at any one time

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Define GAD

• Generalized persistent anxiety for at least 1 months duration.

Absence of the specific symptoms and patterns that characterize other anxiety disorders such as phobias, panic attacks or obsessive-compulsive disorder.

Psychological correlates include apprehensive expectation with worry fear and anticipation of misfortune to self and others, hyperattentiveness, distractibility, difficulty in concentrating, insomnia, feeling on edge and impatience.

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How does the ANS respond to anxiety?

Sweating
Tachycardia and palpitations
Cold clammy hands
Dry mouth and lump in throat feeling
GI upset
Frequent urination and diarrhea

Voluntary Muscle Activation

•Jitteriness and an inability to relax

Complications - Abuse of alcohol, sedatives and antianxiety medications are common

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____ has a role in slow wave sleep while ____ has a role in REM sleep

seratonin

Nepi

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______ - disorders of initiating and maintaining sleep.
______ - disorders of excessive sleep or sleepiness.

Insomnia

Hypersomnia

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Recommended tx for anxiety and insomina

• BENZODIAZEPINES and related drugs

SSRIs are commonly used
BUSPIRONE
CLASSICAL ANTIHISTAMINES

• ALCOHOL, CANNABIS, OPIATES • BARBITURATES

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Whats going on in the GABAergic synapse?

Uptake of glutamate; takes excitatory NT in brain to make the inhibitory NT

GABA is released, binds ot GABA receptors:

GABA-A key in anxiety

GABA-B in msl relaxants

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Where in the brain is GABA localized?

Substantia Nigra
Globus Pallidus •Hippocampus
Limbic structures - Amygdala
Hypothalamus
Spinal cord

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Describe structure of GABA receptor

Has 5 units with 4 groups per unit

forms pore for Cl- to come in, enters and HYPERPolarizes and inhibits

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describe interaction of Benzos on the GABA receptor

Binds to the Gamma subunit and enhances the action of GABA thus increase the Cl-release

works by INCREASING FREQUENCY of opening

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What is the interaction of Barbituates on the GABA receptor?

They bind in allosteric site and increase duration of Cl- Channel opening

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___ is the primary site of alcohol action and inhilation anesthetics

GABA

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DIAZEPAM, ZOLPIDEM are examples of

Bensodiaezepines (work on GABA receptor)

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What is the antagonist that would block benzos at their site of action on a GABA receptor?

Flumazenil

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Partial agonist for 5-HT 1A - inhibition of adenylate cyclase and opens K+ channel

Also binds to dopamine receptors.

Buspirone

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List of Benzos to tx anxiety

Alprazolam (Xanax®)
Diazepam (Valium®)
Lorazepam (Ativan®)
Clonazepam (Klonopin®) •Chlordiazepoxide (Librium®, Limbitrol®) •Clorazepate (Tranxene®)

•Oxazepam (Serax®)

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Alprazolam

mechanism:

CNS effects:

Uses

GABA enhancement

Forebrain depression, dependence

Anxiolytic, antipanic

(short half)

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Diazepam

CNS effects

mechanism

uses

Broad CNS depression, see dependence

GABA enhancement

anxiolytic, sedative, muscle relaxant

Long 1/2

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Buspirone

Mechanism

CNS effects

Uses

5-HT effect

Little sedation, no dependence

Anxiolytic

delayed effect

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What two antioxlytics are used as hynotics, what;s their differences?

Flurazepam: rapid onset, lasts long time

Triazolam: rapid onset, last SHORT

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What is the role of lipophilicity in Diazepam

Fast onset, oral drug

has HIGH solubility thus quick to brain with rapid distribution in one dose

active metabolites change this in mult dose setting

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Role of lipophilicity in Lorezepam (sleep and anxiety)

less lipophilic then diazepam with slower onset of action

longer duraion of action after single dose

no active metabolites

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what are the only two drugs given at their active metabolite?

Lorezepam and Oxazepam

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What are teh CNS effects of Benzos?

Decreased Anxiety
Sedation
Hypnosis
Muscle Relaxation
Anterograde Amnesia - IV administration
Anticonvulsant Action
Minimal CV and respiratory actions at therapeutic doses.

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What drug interactions do we need to be aware of when prescribing benzos?

* Produce additive CNS depression with most other depressant drugs such as ethanol, other sedative hypnotics and sedating antihistamines. * Drugs that affect hepatic metabolism such as cimetidine

Clincal uses of Benzos

* Anxiety States * Sleep Disorders * Muscle Relaxant - diazepam * Seizure Treatment * Intravenous Sedation and Anesthesia * Alcohol Withdrawal - chlordiazepoxide • Acute manic episodes - clonazepam

What benzo is used for alcohol withdrawl?

Chlordiazepoxide

What are the recommended benzos to tx anxiety

•Diazepam •Chlordiazepoxide •Alprazolam •Lorazepam •Clonazepam

What signs do we need to be aware of in pt with benzo use that is in withdrawl

* ANXIETY * INSOMNIA * IRRITABILITY * HEADACHE * HYPERACUSIS * HALLUCINATIONS • SEIZURES \*\*Gradual dose reduction. Switch to longer acting drugs.

High affinity for 5-HT1A receptors Less sedating than benzodiazepines No cross-tolerance with benzodiazepines Does not potentiate other sedative-hypnotics and depressants nor suppress symptoms of their withdrawal Used in the treatment of generalized anxiety syndrome. Therapeutic effects may take 1 to 2 weeks to occur

What are some other tx for anxiety

* SSRIs AND SNRIS- panic attacks and Generalized Anxiety Disorder - GAD * Beta-blockers - performance anxiety * Other sedatives - rarely

What are the different dimensions of insomnia

* Symptoms may be mild or severe. Transient, chronic or intermittent. * Can’t fall asleep and/or stay asleep. * Daytime sequelae: tired, fatigued, sleepy, anxious, depressed

What benzos are used to tx insomnia

Flurazepam, Triaxolam, zolpidem, zaleplon and eszopiclone

Benzo used as hypontic with rapid onset of action and long duration of action

Flurazepam

Affects of Benzos on Sleep ## Footnote \_\_\_\_\_\_\_latency to sleep \_\_\_\_\_in stage 1 and 2 sleep;\_\_\_\_\_ time in stage 3 and 4and REM sleep \*\*Rebound insomnia upon withdrawal

Decreased Increases, decreased

What are some adverse effects to treating insomnia with benzos?

* Daytime sedation * Ataxia * Rebound insomnia * Tolerance and dependence * Occasional idiosyncratic excitement and stimulation

Non-Benzodiazepines chemically. Bind to BDZ receptor on GABA receptor complex. Weak anxiolytic, muscle relaxant and anticonvulsant at hypnotic dose.

Zolpidem (Ambien®) and Zaleplon (Sonata®)

What effect does Zolpidem and Zaleplon have on Stages of sleep

Stage 3 and 4 sleep preserved, minor effects on REM sleep. Zolpidem typical duration of action 5-6 hours. Sustained release preparation now available. Duration of action 7 to 8 hours. Now also available as an oral spray targeted at problems of sleep initiation and sublingual tablets for middle of the night waking.

is a hypnotic agent that is similar to zolpidem with a faster onset of action and a shorter terminal elimination half- life compared to zolpidem.

Zaleplon

zolpidem (ambien) and Zalepon are Antagonized by

flumazenil

Similar in mechanism to zolpidem and zaleplon. Is thought to act through an **interaction with the GABA-receptor c**omplex at binding domains located close to or allosterically coupled to the BDZ receptor. Approved for use for six months based on drug company studies. • Low likelihood of dependence and withdrawal. DEA schedule IV drug.

Eszopiclone - Lunesta

* melatonin MT1 and MT2 receptor-agonist. * It is specifically indicated for the treatment of insomnia characterized by **difficulty in falling asleep**. It is not a controlled substance.

Ramelteon - Rozerem

Secobarbital and Phenobarbital are both

Barbituates: huge OD issue and used in death penalty

Barbituates are ## Footnote * \_\_\_\_\_\_ absorbed and distributed. * Highly lipid soluble compounds such as thiopental distribute rapidly to brain. Action terminated by\_\_\_\_\_\_,

Rapidly redistribution

What is special about barbituate metabolism?

Can induce own metabolism and that of other drugs. • Eliminated primarily by renal excretion.

What are the CNS effects of Barbituates

Sedation, Hypnot action, Anesthesia \*\*\*Respiratory distress High dose causes sustained decrease in mean arterial and pulse pressure induction of hepatic metabolism

Do we see tolerance or physical dependence in Barbituates?

see metabolic and pharmacodynamic tolerance as well as physical dependence; pts will have symptos of withdrawl such as anxiety, aggitation, insomnia, tremo and life threatening seizures

What happesn in acute poisoning from barbituaties

stupor, coma and respiratory distress

What kind of drug interactions do we see in Barbituates?

* Additive with other CNS depressants such as alcohol, other sedative hypnotics and antihistamines. * Drugs that affect microsomal drug metabolism

Short to intermediate acting barb with moderate lipid solubioity and onset of 10 mins; treats insomnia, lasts 3-4 hrs

Secobarbital

Long acting barb with low lipid solubility, takes 60 mins to work, lats 10-12 hrs and is for seizures and insomnia

Phenobarbital

Ultrashort acting barb with High lipid solubility, onse it 30 secs and lasts for 12 mins for induction of anesthesia, or seizure tx

thiopental

Aldehyde hydrate with pungent taste and somewhat caustic taste. a. Metabolized to trichloroethanol which is the active form of the drug. b. Pharmacology similar to barbiturates. c. Less effects on stages of sleep than benzodiazepines and barbiturates.

Chloral hydrate

• New hypnotic approved 2014. Orexin receptor (OX1 and OX2) antagonist. Orexins are neuropeptide central promoters of wakefulness through excitement of brain regions involved in arousal and attention

Suvorexant

Drugs used to reduce muscle tone associated with spasticity related to multiple sclerosis injuries and other muscular skeletal disorders

SKELETAL MUSCLE RELAXANTS

is characterized by increases in tonic stretch reflexes and flexor muscle spasms, together with a possible muscle weakness

Spasticity

Mech of Spasticity

Mechanisms underlying spasticity involve both the stretch reflex arc itself and higher centers in the brain. Pharmacological treatment of spasticity targets both sites.

GABAergic agents as muscle relaxants

Diazepam and Baclofen

Its action in reducing spasticity is at least partly mediated in the spinal cord. It can be used in patients with muscle spasm of almost any origin including local trauma. It produces sedation in most patients at the doses required to reduce muscle tone.

Diazepam

GABA-mimetic agent that works at GABAB receptors. This results in hyperpolarization, causing presynaptic inhibition. This can result in decreased release of excitatory transmitters such as glutamate. is at least as effective as diazepam in reducing spasticity and produces much less sedation.

Baclofen

\_\_\_\_\_ interferes with releaes of excitatory transmitters \_\_\_\_\_ facilitates GABA mediated presynpatic inhibition

baclofen diazepam

an alpha2 - adrenergic agonist that is related to clonidine. It may enhance both presynaptic and postsynaptic inhibition.

Tizanidine

Efficacy of Tizanidine compared to Diazepam and Baclofen Side effects

May have similar efficacy to diazepam and baclofen in relieving muscle spasm. Side effects include drowsiness, hypotension, dry mouth and asthenia.

Tizanidine interacts with

Interacts with ciprofloxacin and fluvoxamine (CYP1A2 inhibitors)