Anxiolytic and Hypnotic Drugs Flashcards
How prevelant are anxiety disorders
seen in 28.8 % populaiton in lifetime with 4% at any one time
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.
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
____ has a role in slow wave sleep while ____ has a role in REM sleep
seratonin
Nepi
- ______ - disorders of initiating and maintaining sleep.
- ______ - disorders of excessive sleep or sleepiness.
Insomnia
Hypersomnia
Recommended tx for anxiety and insomina
• BENZODIAZEPINES and related drugs
- SSRIs are commonly used
- BUSPIRONE
- CLASSICAL ANTIHISTAMINES
• ALCOHOL, CANNABIS, OPIATES • BARBITURATES
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
Where in the brain is GABA localized?
- Substantia Nigra
- Globus Pallidus •Hippocampus
- Limbic structures - Amygdala
- Hypothalamus
- Spinal cord
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
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
What is the interaction of Barbituates on the GABA receptor?
They bind in allosteric site and increase duration of Cl- Channel opening
___ is the primary site of alcohol action and inhilation anesthetics
GABA
DIAZEPAM, ZOLPIDEM are examples of
Bensodiaezepines (work on GABA receptor)
What is the antagonist that would block benzos at their site of action on a GABA receptor?
Flumazenil
Partial agonist for 5-HT 1A - inhibition of adenylate cyclase and opens K+ channel
Also binds to dopamine receptors.
Buspirone
List of Benzos to tx anxiety
- Alprazolam (Xanax®)
- Diazepam (Valium®)
- Lorazepam (Ativan®)
- Clonazepam (Klonopin®) •Chlordiazepoxide (Librium®, Limbitrol®) •Clorazepate (Tranxene®)
•Oxazepam (Serax®)
Alprazolam
mechanism:
CNS effects:
Uses
GABA enhancement
Forebrain depression, dependence
Anxiolytic, antipanic
(short half)
Diazepam
CNS effects
mechanism
uses
Broad CNS depression, see dependence
GABA enhancement
anxiolytic, sedative, muscle relaxant
Long 1/2
Buspirone
Mechanism
CNS effects
Uses
5-HT effect
Little sedation, no dependence
Anxiolytic
delayed effect
What two antioxlytics are used as hynotics, what;s their differences?
Flurazepam: rapid onset, lasts long time
Triazolam: rapid onset, last SHORT
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
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
what are the only two drugs given at their active metabolite?
Lorezepam and Oxazepam
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.
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
_______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 complex 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
- ______ 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)
