Pharmacology Specifics – Benzodiazepines Flashcards
What are the six FDA-approved indications for benzodiazepines?
Generalized anxiety disorder
social phobia
panic disorder
insomnia
status epilepticus/seizures
premedication for anesthetic procedures
What are the six non-FDA approved uses of benzodiazepines?
Agitation
alcohol withdrawal symptoms
muscle spasms
sedation
restless legs syndrome
sleepwalking disorder
Benzodiazepines act through which specific receptor? Which ion does it regulate? What does this activity result in for the neuron?
The gamma-aminobutyric acid (GABA) A receptor
It regulates chloride entry into neurons which results in neuronal hyperpolarization
Xanax
Alprazolam
Who manufactures Xanax?
Pfizer, as well as multiple generic manufacturers
What is the route of Xanax ingestion? What three forms does it come in?
PO
tablet ER, tablet ODT, and liquid
Is Xanax expensive?
Yes
What drug class do benzodiazepines belong to?
Anxiolytics
Librium
Chlordiazepoxide
Who makes Librium and in what form is it ingested?
It is made by multiple generic manufacturers
It is ingested PO in the form of a capsule
What is the recommended dose of Librium? What is the maximum amount recommended in a given day?
5 mg, 10 mg, 25 mg
3-4 times a day
Maximum 100 mg per day
Klonopin
Clonazepam
Who makes Klonopin?
Roche & multiple generic manufacturers
What is the route of ingestion for Klonopin?
PO
Tablet ODT
What is the recommended dose of Klonopin? What is the maximum amount recommended per day?
0.5 mg-1 mg (0.5 mg, 1 mg)
3 times a day (TID)
Maximum 20 mg per day
Valium
Diazepam
Who makes Valium?
Roche & Multiple generic manufacturers
Valium is available to patients in what forms? Via what route?
PO
Tablet and liquid
What is the recommended dose of Valium? What is the maximum amount recommended per day?
5 mg-25 mg (2 mg, 5 mg, 10 mg)
3-4 times a day
Maximum 40 mg per day
Ativan
Lorazepam
Who makes Ativan?
Multiple generic manufacturers
What is the route of ingestion of Ativan? In what forms does it come in?
PO
Tablet & liquid
What is the recommended dosage for Ativan?
0.5–1 mg (0.5 mg, 1 mg, 2 mg)
3-4 times a day
Serax
Oxazepam
Who makes Serax?
Multiple generic manufacturers
What is the route of ingestion for Serax?
PO
Capsule
What is the recommended dose for Serax? What is the recommended maximum amount per day?
10 mg – 30 mg (10 mg, 15 mg, 30 mg)
3-4 times a day
Maximum 120 mg per day
What is the recommended initial dose of Klonopin (clonazepam)? What is the interval for increasing the dose and by how much daily?
Klonopin should be started at 0.25 mg daily,
2x a day
The dose can be increased by 0.125–0.25 mg daily or 2x a day every 2-3 days
What is the therapeutic dose of Klonopin?
1–4 mg total per day in divided doses
What is the recommended dose of Xanax (alprazolam)? If the patient needs an increase in medication, what interval and amount per day is recommended?
The initial dose is 0.25 mg 2-3 times per day
The dose can be increased by 0.5-1 mg daily every 3-4 days
What is the usual therapeutic dose of Xanax? What is the maximum dose recommended in a given day?
The usual therapeutic dose is 2–3 mg total per day, 2-3 times per day
The maximum dose is 4 mg per day
What is the recommended initial dose of Ativan (lorazepam)? What is the recommended interval if the patient needs an increase?
The initial dose is 0.5 mg, 2x daily
The dose can be increased by 1 mg daily, divided into doses 2-3 times per day
What is the usual therapeutic dose for Ativan?
2-8 mg total per day, 2-3 times per day dosing
What is the recommended initial dose of Valium (diazepam)? How much can it be safely increased daily?
The initial dose is 2 mg, 2-4 times daily
The dose can be increased by 1-2 mg daily
What is the usual therapeutic dose for Valium?
15-30 mg total per day
2-3 times daily dosing
For alcohol withdrawal, what IM dose of Valium is recommended every 4 hours?
10 mg
What is the initial recommend dose for Librium? How much can it be safely increased by daily?
The initial dose of Librium is 5-10 mg daily, 2x per day
The dose can be increased by 5 mg daily
What is the usual therapeutic dose for Librium?
30-40 mg total per day, with 2-3 times a day dosing
For alcohol withdrawal, what is the recommended intramuscular dose of Librium that should be given every 4 hours?
50-100 mg
What is the recommended initial dose for Serax (Oxazepam)? How much can it safely be increased by per day?
The initial dose is 10-15 mg daily
It can be increased by 10 mg daily in divided doses (3 times per day)
What is the usual therapeutic dose for Serax (Oxazepam)?
90 mg total per day
3 times per day dosing
What patient population often requires lower benzodiazepine doses? Why?
The elderly population
They metabolize these drugs slower
For Xanax and Klonopin, what type of dose adjustment is needed in the geriatric population?
No dose adjustment is needed; increase as needed/tolerated
For Chlordiazepoxide, how should the usual dose be modified for the geriatric population?
The usual dose should be decreased by 50%
For diazepam, what initial dose should be used in the geriatric population?
Use 2 mg daily initially, and increase as needed/tolerated
This is the normal starting dose
What should be the initial dose of Ativan when used in the geriatric population?
Use an initial dose of 1 mg per day in divided doses, and increase as needed/tolerated
For Oxazepam, what is the maximum dose that should be used in the geriatric population?
45-60 mg total per day, in divided doses
What type of renal adjustment is needed for Xanax, Klonopin, Valium, and Serax?
No dose adjustment is needed; increase as needed/tolerated
For patients with renal impairment, (CrCl less than 10 mL per minute), how should Librium be adjusted?
Patients with renal impairment should have their doses decreased by 50%
How should Ativan be adjusted for patients with mild-to-moderate renal impairment? How does this differ from the recommendation for patients with renal failure?
No dose adjustment is needed for mild-to-moderate renal impairment
It’s not recommended for patients with renal failure
What type of hepatic dosing adjustment is recommended for Xanax, Klonopin, and Serax?
No dose adjustment is needed; increase as needed/tolerated
What should be the maximum dose of Librium given to a patient per day to a patient with hepatic insufficiency?
20 mg total per day
How much should the usual dose of Valium be reduced in a patient with hepatic insufficiency?
50%
Similar to patients with renal insufficiency, how much does Ativan need to be adjusted for patients with mild-to-moderate liver impairment? How does this differ in patients with hepatic failure?
No adjustment needed for mild-to-moderate liver impairment
Ativan is not recommended for patients with liver failure
With regard to pregnancy, what category are benzodiazepines in? What are the 3 primary teratogenic concerns?
Category D
Cleft lip/palate, and urogenital and neurological malformations
Recent literature, however, does not show an increased risk of these
Bellantuono C et al.: Benzodiazepine exposure in pregnancy and risk of major malformations: a critical overview. Gen Hosp psychiatry 35:3, 2013 January – February
When possible, during which trimester should the use of benzodiazepines be avoided?
The first trimester
What type of benzodiazepine should be used if necessary?
Consider an agent with a short half-life, and use sparingly and intermittently
What other category of medications should be considered in pregnancy? Which one of these types of medications is the exception?
Consider an antidepressant agent
With the exception of paroxetine (Paxil) (category D), all of the antidepressants are in category C
And what point during pregnancy should benzodiazepines be avoided? Why?
Avoid use near the time of delivery
The baby may experience withdrawal symptoms
Do benzodiazepines cross into the breastmilk? What are the long-term effects of benzodiazepine exposure in babies?
Yes, benzodiazepines can cross into the breastmilk
The long-term effects of this are unknown
What side effects may occur in the baby with prolonged benzodiazepine use in the mother?
“Floppy baby syndrome” type of effects
Respiratory depression, sedation, difficulty breast-feeding and hypotonia
Generally speaking, do benzodiazepines have a longer half-life in babies? Why?
Yes; they have not developed the mechanisms for metabolism
If a benzodiazepine must be used in a mother who is breast-feeding, what is the best type of agent to choose?
Choose an agent with a shorter half-life
What is known about the safe use of Xanax, Klonopin, and Ativan in the pediatric population?
Safety has not been established in children
What do we know about the safe use of Serax (Oxazepam) in children under six years of age? In children between 6 and 12 years of age? How do we use this medication in children over 12 years of age?
Safety has not been established for children under 6 years of age
No guideline has been established for children between 6 and 12 years of age
For children over 12 years of age, use 10-15 mg, 3-4 times per day
What is the recommendation for the use of Librium (Chlordiazepoxide) in children younger than 6 years of age? How about older than 6 years of age? What’s the maximum dose for children older than 6 years of age?
Librium is not recommended for children younger than 6 years of age
For children older than 6 years of age
5 mg, 2-4 times a day
This can be increased to 10 mg, 2-3 times a day
What is the recommended dose of diazepam (Valium) in the pediatric population?
Start at 1 mg, 2-4 times per day
Increase gradually as needed/tolerated
What type of adjustment is needed for a pediatric patient with renal insufficiency who is taking Valium or Serax (Oxazepam)?
No dose adjustment needed
Is a dose adjustment needed for Librium (Chlordiazepoxide) use in pediatric patients with renal impairment?
Dose adjustment may be needed in children with renal impairment
What’s a sexual side effect occasionally seen with Xanax?
Decreased libido
What’s an occasional sexual and physiologic side effect seen in women who take Librium?
Irregular menses and decreased libido
What’s a psychiatric side effect occasionally seen with the use of Klonopin?
Suicidal ideation
What musculoskeletal and respiratory side effect can be seen with Valium use?
Muscle weakness and respiratory depression
Rash and diarrhea with rectal gel use can be seen if used with which benzodiazepine?
Diazepam (Valium)
What occasional side effect can be seen in elderly patients with the use of Ativan?
Delirium
Weakness can also be seen
What rare skin and abdominal side effect can be seen with the use of Xanax?
Stevens-Johnson syndrome and liver failure
What rare hematologic and abdominal side effect can be seen with the use of Librium?
Agranulocytosis and liver failure
What is a rarely seen hematologic side effect of Valium?
Neutropenia
What is a rarely seen metabolic side effect of the use of Ativan?
Acidosis
Are benzodiazepines well absorbed orally?
Yes
What is the bioavailability of Xanax, Klonopin, Valium, and Ativan?
90%
What is the bioavailability of Serax (Oxazepam)?
93%
Which benzodiazepine has the most rapid time to peak concentration?
Valium
0.5-6 hours
Both Xanax and Ativan exhibit what time to peak concentration?
1-2 hours
This is considered intermediate
What is the time to peak concentration for Klonopin?
1-4 hours
What is the time to peak concentration for Serax (Oxazepam)?
Time to peak concentration is 3 hours
What is the time to peak concentration for Librium?
Several hours
Where is Xanax, Librium, Klonopin, Valium, Ativan, and Serax metabolized in the body?
The liver
Both Xanax and Klonopin are metabolized by which specific liver enzyme?
CYP3A4
In addition to CYP3A4, What other specific enzyme is Valium metabolized by in the liver?
CYP2C19
Via CYP3A4, what 2 specific biochemical reactions does Klonopin undergo in the liver?
Oxidation and reduction
Via CYP3A4 and CYP2C19, which 4 specific biochemical reactions does Valium undergo in the liver?
Glucuronidation, methylation, oxidation, and hydroxylation
What specific biochemical reaction does Ativan undergo in the liver?
Glucuronidation
In addition to all being metabolized by the liver, are Xanax, Librium, Klonopin, Valium, Ativan, and Serax all excreted primarily by the kidneys?
Yes
Which two benzodiazepines are also excreted some via feces?
Ativan and Xanax
What percentage of Xanax is protein-bound in the body?
80%
What percentage of Klonopin is protein-bound in the body?
85%
What percentage of Ativan is protein-bound in the body?
85-91%
What percentage of Oxazepam is protein bound in the body?
94-97%
What percentage of Valium is protein-bound in the body?
95-98%
What percentage of Librium is protein-bound in the body?
96%
What is the half-life of Serax?
5-11 hours
What is the half-life of Xanax?
12-15 hours
What is the half-life of Ativan?
10-20 hours
What is the half-life of Klonopin?
18-50 hours
What is the half-life of Valium?
20-80 hours
What is the half-life of Librium?
24-48 hours
What is the distribution of Librium?
0.25-0.5 L/kg
What is the distribution of Serax?
0.59 L/kg
What is the distribution of Xanax?
0.8-1.3 L/kg
What is the distribution of Valium?
1 L/kg
What is the distribution of Ativan?
1.3 L/kg
What is the distribution of Klonopin?
1.5-4.4 L/kg
Benzodiazepines are often used to “bridge” patients who are starting what category of medications for anxiety?
why are they used for this purpose?
What type of side effects do patients initially experience?
Antidepressants
They are used this way because the therapeutic effects of antidepressants may be delayed
Patients may experience stimulating side effects initially
Benzodiazepines may be more effective than antidepressants for what specific disorder?
Social anxiety disorder
In patients with social anxiety disorder, benzodiazepines may worsen symptoms if these patients present with which 2 comorbid conditions?
Depression
“Offidani E et al: Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. Psychother Psychosom 82:355, 2013”
PTSD
“Davidson JR: Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry 65 Suppl 5:29, 2004”
Why is the long-term use of benzodiazepines not recommended?
The risk of dependence
Is tolerance to the anxiolytic effects of benzodiazepines common?
No
What patient population should the use of benzodiazepines be avoided in?
Patients with a history of substance use disorder
Which type of benzodiazepines have the highest risk of dependence?
What are 2 examples
The agents that are rapidly absorbed and have shorter half-lives
Xanax and Valium
True or false: benzodiazepines may be beneficial for long term use in refractory cases
True
Why are Ativan and Serax preferred by many physicians?
2 reasons
Both are metabolized through conjugation
They don’t produce active metabolites
Fewer CYP 450 drug interactions
