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Sedative Hypnotics & Antianxiety Agents
Dr. Goodman
69
Pharmacology
Undergraduate 3
10/01/2010

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Term
Selective anxiolytic effect
Relieve anxiety without sedative effects.
Definition
BZDs
Term
Were once extensively used for antianxiety and sedation, but have been largely replaced by the benzodiazepines
Definition
Barbiturates
Term
Therapeutic uses of BZDs
Definition
Sedative-Hypnotic: treat insomnia

Anxiolytic (antianxiety): Anxiety (panic, obsessive compulsive disorders, phobias)

Muscle Relaxant: spasticity, dystonias

Anticonvulsant: absence, status epilepticus, and generalized seizures (rapid tolerance develops)

Other Uses:
Pre-operative medication & endoscopic procedures
Withdrawal from chronic use of ethanol and other CNS depressants.
Term
Benzodiazepines are NOT
Definition
Anesthetics
Term
Which BZD when given as I.V. has anesthetic actions
Definition
Diazepam (Valium)
Term
BZD Central Actions MOA
Definition
Term
THE LIMBIC SYSTEM IS COMPOSED OF
Definition
the limbic system (amygdala, septum, hippocampus)
Term
Area of the brain involved in sleep, ataxia, and muscle relaxation
Definition
Sleep involves the ascending reticular formation

Muscle relaxation involves the medulla

Ataxia involves the cerebellum
Term
GABA-A Receptor structure and subunits
Definition
Pentameric structure composed of alpha, beta, delta, and gamma subunits
Term
Binding sites on GABA-A Receptor and actions associated with binding
Definition
•GABA site (there are 2, between A-1 and B2))
Increase GCl-
Hyperpolarization
Inhibition

•Barbiturate site
Increase GABA effect

•Benzodiazepine site (Between A-1 and Gamma 2)
Increase GABA effect

•Picrotoxin site
Block Cl- channel
Term
Actions at the GABA-A Receptor
Agonists: GABA
Definition
GABA binds to GABAA receptors which increases Cl-conductance and hyperpolarizes neurons
Neuronal activity is inhibited by GABA
Term
Actions at the GABA-A Receptor
Antagonists: Bicuculline
Definition
Competitive block of GABA binding
Reduces inhibition and produces convulsions
Term
Actions at the GABA-A Receptor
Antagonists: Picrotoxin
Definition
Non-competitive block of GABA actions
Blocks the chloride channel
Reduces inhibition and produces convulsions
Term
Actions of Benzodiazepines at the GABAA Receptor
Definition
BZs bind to a site on GABAA receptor (ionotropic Cl- channel).

Enhance inhibitory effect of GABA by increasing Cl- influx (hyperpolarization).

BZ’s increase FREQUENCY of Cl- channel opening in the presence of GABA.

BZ’s alone (without GABA) don’t affect Cl-channel function.
Term
Sedative Hypnotics & Antianxiety Agents general definitions
Definition
Sedative: Depress the CNS-Calm down, treat agitation

Hypnotic: Induce sleep
go to sleep fast, feel refreshed tomorrow !!!

Anxiolytic: Reduce anxiety
physical, emotional, cognitive
Term
Actions of Other Agents at the Benzodiazepine Receptor: INVERSE AGONISTS (Beta-carbolines)
Definition
Produce the opposite effects at the BZ binding site
Decrease chloride conductance
Anxiety, irritability, agitation, delirium, convulsions
No therapeutic uses
Term
What are BZD-R Inverse agonists
Definition
Beta Carbolines
Term
Noncompetitive BZD antagonists
Definition
Picrotoxin
Term
Flumazenil (Romazicon)
Definition
BZD receptor antagonist

Blocks both agonist & inverse agonist; Have no biological effect ; Can precipitate withdrawal in dependent persons

High Ist pass metabolism

Only i.v.

Used to reverse BZD anesthesia

BZD over dose
0.2mg/mt→If does not respond suspect other drugs along with BZD like alcohol
Term
competitive BZD antagonists
Definition
Bicuculline
Term
Chlordiazepoxide (Librax, Librium)
Definition
Chlordiazepoxide (Librax or Librium)

Has a medium to long half life, but its active metabolite has a very long half life.
Has amnestic, anxiolytic, hypnotic and skeletal muscle relaxant properties.

Used for short term treatment of anxiety for 2-4 weeks & management of acute alcohol withdrawal syndrome

Similar to Phenobarbital in its anticonvulsant properties. However, it lacks the hypnotic effects of Barbiturates
Term
Short Acting BZDs
Definition
alprazolam= Xanax
oxazepam= Serax
midazolam= Versed
triazolam = Halcion
temazepam= Restoril
Term
Actions of Other Agents at the Benzodiazepine Receptor: Non-BZD Agonists
Definition
Act at BZ receptor to produce pharmacological actions similar to BZDs.
Term
Intermediate Acting BZDs
Definition
lorazepam= Ativan
estazolam= ProSom
temazepam= Restoril
Term
Long Acting BZDs
Definition
chlordiazepoxide= Librium
clonazepam= Klonopin
clorazepate=Tranxene
diazepam= Valium
flurazepam= Dalmane *widely used for primary insomnia and other sleep disorders
temazepam= Restor
Term
BZDs PK
Definition
Lipid-soluble: fast cross blood-brain-barrier: rapid onset of action.
Persist longer in high fat-to-lean body mass
obese, elderly
Abuse liability (Valium)


Biotransformation & Half-Life:
Hepatic oxidation: long-t1/2, active metabolites
Glucuronidation: short-t1/2, no active metabolite
Term
What determines the use of BZD and Barbs
Definition
Dose and Plasma Half Life
Term
BZDs with T1/2=>24hr(long) are usually used for?
Definition
Anxiety, Withdrawal, Muscle Relaxant
Term
BZDs with T1/2=6-24hr(intermediate) are usually used for?
Definition
Insomnia, Anxiety
Term
BZDs with T1/2=2-6hr(short) are usually used for?
Definition
Insomnia
Term
BZDs with T1/2=<2hr(ultra-short) are usually used for?
Definition
Pre-anesthetic Medication
Term
Therapeutic Index of BZD are?
Definition
HIGH
Term
Benzodiazepines: Acute Toxicity Treatment
Definition
TREATMENT:
Support respiration & blood pressure
Gastric lavage, activated charcoal, cathartic (Sorbitol)

Give antagonist: Flumazenil (Romazicon)
Short acting (~2 hr)
Injected IV, quickly reverses BZ-induced respiratory depression.
Term
Which is safer BZDs or BARBS
Definition
BZDs safer. Barbs increased risk of respiratory depression --> coma -->death
Term
Acquisition of tolerance relative to BZD uses
Definition
Anticonvulsant > Sedation >> Muscle Relaxant > Antianxiety
Term
What type of dependence may result from BZDs
Definition
Physical and/or psychological dependence may develop

Physical dependence is present when withdrawal symptoms occur.
Term
Benzodiazepines: Drug Interactions
Definition
Minimal induction of liver drug metabolizing enzymes, therefore few drug interactions are produced.

Additive CNS effects
Severe CNS depression and coma can result from BZs taken with other CNS depressants such as ethanol
Death from BZ overdose is usually associated with ingestion of a CNS depressant
Term
Benzodiazepines Overdose Adverse Effects
Definition
Somnolence (difficulty staying awake)
Mental confusion
Hypotension
Hypoventilation
Impaired motor functions
Impaired reflexes
Impaired coordination
Impaired balance
Dizziness
Muscle weakness
Coma
Term
Increasing doses of BZDs produce
Definition
sedation, hypnosis, and stupor NOT anesthesia
Term
Antagonist that blocks the Cl- channel
Definition
Picrotoxin (Noncompetitive)
Term
Do BZDs independently
Definition
NO only in the presence of GABA
Term
BZD Antagonist that is only given I.V.? Why?
Definition
Flamazenil (Romazicon)
HIGH First pass effect
Term
If Pt. does not responds to Flumazenil it is likely
Definition
to suspect other CNS depressant drugs along with BZD
Term
BZD(s) with *greater efficacy for panic and phobic disorders
Definition
Alprazolam (Xanax, Clonazepam (Klonopin)
Term
BZD(s)widely used for primary insomnia and other sleep disorders
Definition
Triazolam (Halcion), Estazolam (ProSom), Flurazepam (Dalmane)
Term
BZD(s) *used for management of withdrawal states in physiologically dependent on ethanol and other sedative-hypnotics
Definition
Chlordiazepoxide (Librax, Librium)
Term
Adavantages of Barbs
Definition
Barbiturates are effective and relatively inexpensive
Barbiturates have been extensively studied and there is a vast amount of information available related to side effects and toxicity
Term
Therapeutic uses of Barbs
Definition
IV anesthesia: Thiopental (Pentothal) and Methohexital (Brevital)

Convulsions: emergency treatment (eclampsia, tetanus, status epilepticus), but benzodiazepines are preferable.

Epilepsy

Rarely used as a sedative due to the availability of safer benzodiazepine agents.
Term
Peripheral effects of BARB
Definition
Respiration: depression with increasing doses

Cardiovascular: decreased BP and HR at sedative-hypnotic doses

Liver: bind cytochrome P450
Induce drug metabolizing and other enzymes
Increases metabolism of steroids, vitamins K/D, cholesterol and bile salts.
Term
General & Specific MOA of Barbs
Definition
General Mechanisms
Potently depress the activity of neurons in the reticular formation (pons, medulla) and cortex.


Specific Mechanisms
Bind to a site on GABAA receptors while inhibiting excitatory AMPA receptors.

AMPA receptors are the subtype of glutamate receptors sensitive to kainate or quisqualate.

Increase the open time of Cl- channels in the presence of GABA.
Increases Cl- influx
Enhances the inhibitory effects of GABA

At high concentrations directly increase Cl- conductance in the absence of GABA (act as GABAmimetics).
Term
At high concentrations can directly increase Cl- conductance in the ABSENCE of GABA
Definition
Barbs
Term
Barb with the highest lipid solubility that is used as an inducting agent in anesthesia
Definition
Thiopental (Pentothal)
Term
How are MOST barbs with the exception os Phenobarbital (Luminal) metabolized?

How is Luminal metabolized?
Definition
With the exception of Phenobarbital, which is excreted partly unchanged in the urine, the BARBs are extensively metabolized via oxidation at the C5 position.

Most barbiturates are dealkylated

Conjugation by glucuronidation

Renal excretion
Term
Barbs with T1/2=80-120hr (long) are usually used for?
Definition
Anticonvulsant
Term
Barbs with T1/2=15-50 or ~10hr (Intermediate-short) are usually used for?
Definition
Preoperative sedation
Term
Barbs with T1/2=>3-10hr (ultra-short) are usually used for?
Definition
Anesthesia induction
Term
Common side effects & Contraindications of BARBS
Definition
SIDE EFFECTS:
Common Effects: Sedation & confusion

CONTRAINDICATIONS:
Pain: can increase sensitivity to painful situation resulting in restlessness, excitement and delirium.
Pulmonary insufficiency: respiratory depression.
Term
BARBS drug interactions
Definition
Enhance CNS depressive effects of:
Antipsychotics, antihistamines, ethanol, and tricyclic antidepressants.

Accelerate metabolism of:
Beta-blockers, Ca2+-channel blockers, corticosteroids, estrogens, phenothiazines, valproic acid and theophylline.
Term
What kind of dependence is common with Barbs?
Definition
Physical manifested by withdrawal symptoms
Term
Newer NonBZD/NonBarb Hypnotic Agents
Definition
Zolpidem (Ambien), Eszopiclone (Lunesta), Zaleplon (Sonata)
Term
Chloral Hydrate use
Definition
Used for the short-term treatment of Insomnia and as a sedative before minor medical or pediatric dentistry for diagnostic imaging procedures

Today, it is commonly used as an ingredient in the veterinary anesthetic Equithesin (mixture of chloral hydrate, magnesium sulfate and pentobarbital sodium)
Term
Metabolic produces of chloral hydrate
Definition
trichloroethanol and trichloroacetic acid
Term
Discontinued Hypnotic agents
Definition
Ethanol, barbs (avoided), Meprobamate (Equanil)
Term
BZDs commonly used for the management of generalized anxiety disorders?
Definition
Chlordiazepoxide (Librium)
Diazepam (Valium)
Oxazepam (Serax)
Clorazepate (Tranxene)
Lorazepam (Ativan)
Alprazolam (Xanax)
Halazepam (Paxipam)
Term
Busprione(BuSpar)
Definition
Miscellaneous Anxiolytic agent

Buspirone
Has selective affinity of 5-HT1A (mixed agonist antagonist activity), is a relatively new anxiolytic.

Seems most effective in mild and generalized anxiety and is not effective compared to benzodiazepines and certain antidepressant agents in treatment of panic disorder.

Does not exhibit cross-tolerance with benzodiazepines or other sedative-hypnotics. No physical dependence. No sedation or impaired cognition occurs with this drug.

No anticonvulsant activity, will not protect from withdrawal symptoms

Start 5 mg tid, max 60 mg/day. Onset of action is 1 to 3 weeks; limits it usefulness.

No additive depression with ethanol
Term
If Pt. cannot give up alcohol and is sufferring from anxiety which anxiolytic agent would you suggest?
Definition
Buspirone (BuSpar)
-No additive depression with ethanol
Term
Antihistamines used to tx anxiety & insomnia
Definition
Diphenhydramine [Benadryl]
25-100 mg hs sleep OR 10-25 mgr prn anxiety

Hydroxyzine [Atarax]
25-100 mg hs sleep
10-25 mg 1-4 times/day
Term
Beta-Blocker useful to tx anxiety (esp. performance anxiety)
Definition
Physiologic component of anxiety:
tachycardia, palpitations, tremor, sweating

No CNS depression
non-addicting, no drowsiness

Do not use in asthma, diabetes, CHF
monitor BP and pulse

Helpful for performance anxiety:
Propranolol 10 mg prn
Term
Class of drugs that are preferable used as:1. Sedatives, 2. Hypnotics and 3. Anxiolytics
Definition
Sedatives
Benzodiazepines
Antipsychotics

Hypnotics (Non-pharmacological 1st)
Antihistamines
Zolpidem
Benzodiazepines (rapid onset, short t1/2)

Anxiolytics
Benzodiazepines (acute)
Antidepressants (chronic)
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