Pharm Quiz 1 Flashcards
What neurotransmitter and receptor sites does benzodiazepines stimulate and what is the mode of action?
GABA, upon activation GABA receptors conduct chloride through the channels in the cell membrane which leads to neuraa hyper polarization—> inhibitory neurotransmitter affects
What are the 5 reasons we give benzodiazepines?
Sedation Anxiolysis Anticonvulsant Skeletal Muscle Relaxation Anterograde amnesia
Multiple drugs interact with GABA receptors through multiple mechanisms, this can lead to what?
Cross tolerance
What is the reversal agent for benzodiazepines?
Flumazenil
Where are the only muscles that contain GABA receptors?
skeletal muscle
How do benzodiazepine compare to barbiturates?
- anything a barb can do a benzo can do better
- less tolerance
- less taxiphalxis
- less abuse potential
- greater margin of safety
- fewer drug reactions
- NO induction of microsomal enzymes
- less addiction potential compared to barbiturates
Benzodiazepines have no retrograde amnesia, true or false?
true—-> it has anterograde amnesia
retrograde = loss of stored information anterograde = forgetting things that happen from the time you receive the benzo
Describe the skeletal muscle relaxation characteristics of benzodiazepines
- No effects at the neuromuscular junction
- the effects are of central origin inadequate for surgey
What are the two most desirous effects preoperatively and intraoperatively for benzodiazepines?
anxiolysis and hypnosis
Are the anticonvulsant effects of benzodiazepines potent enough to stop a grand mal seizure?
yup
Chemically what is the structure of all benzodiazepines?
drugs with a benzene ring fused to a diazepine ring, all clinically useful benzodiazepines contain a 5-aryl substituent and a 1,4 - diazapine ring
What are the most common side affects of benzodiazepines?
- Fatigue and drowsiness are the most common
- sedation usually disappears in 2 weeks
- decreased coordination
- no significant BP or HR effects due to no GABA receptors in the heart or the vascular
- minimal ventilation effects unless lung disease present
- decreased cognitive function
- transient anterograde amnesia
- suppression of adrenal cortisol levels
Dependence may require ___ months of ___ use.
6 months of continuous use(6 months of continuous use of barbs you would probably be dead)
What symptoms may be seen in benzodiazepine withdrawals?
irritability, insomnia, tremulousness
What are the two metabolic pathways of benzodiazepines?
- Glucuronidation
2. Hepatic microsomal enzyme
Glucuronidation is the exclusive metabolic pathway for what 3 benzodiazepines?
- lorazepam
- oxazepam
- temazepam
Are there any ACTIVE benzodiazepine metabolites involved in Glucuronidation?
no
What if any effects by aging on Glucuronidation.
little effect by aging
Are there any ACTIVE benzodiazepine metabolites involved with Hepatic microsomal enzyme metabolism
yes
Describe the process of Hepatic microsomal enzyme metabolism
Oxidative process sensitive to aging, liver disease and anesthetic agent exposure
Can pregnant women receive benzodiazepines?
NO! They are class D and X drugs-potential for harm to unborn demonstrated
exposure to benzodiazepines during pregnancy has resulted in a slight risk of cleft palate in new borns
Midazolam is ___ soluble and it has a ___ ring
Water, imidazole
How much more potent is Midazolam(versed) over Diazepam(valium).
How much affinity does Midazolam have over Diazepam?
2-3X more potent and it has twice the affinity of Diazepam
What is the pKa of Midazolam?
6.1
What happens to the solublility of Midazolam as it reaches physiologic pH?
Midazolam at its pKa is water soluble, when it is injected into the body and reaches physiologic pH is becomes lipid soluble.
What happens to the Imidazole rings in response to pH and solubility?
- ph < than 4.1 Imidazole rings opens and Midazolam is water soluble
- when Midazolam reaches physiologic ph, the Imidazole rings close and it becomes lipid soluble
What impact of being water soluble have on the preparation of Midazolam?
Water soluble preparation means no propylene glycol solution like diazepam and less pain after IV injection
What % of Midazolam is absorbed from first pass clearance when given orally?
50%—>rapid GI absorption
Midazolam has a short duration of action from single dose due to what?
redistribution
By what speed does Midazolam cross the BBB?
Rapid passage across the BBB
By what speed does Midazolam have effect-site equilibration time?
slow effect-site equilibration time
What should you do knowing the effect-site equilibration time of Midazolam?
Space IV doses to allow peak clinical effects
Does intranasal have any first pass effects?
no
Based upon Midazolam’s extensive plasma protein binding, what effect would it have on someone with hypoalbuminemia?
a does would have an exaggerated affect
How does the sedation 1/2 life of Midazolam compare to diazepam and lorazepam
Its shorter
Is Midazolam the only benzo used for infusions?
yes
What is the elimination 1/2 time of Midazolam?
1-4 hours, but may be doubled in the elderly
How does the volume of distribution of Midaz compare to that of diazepam?
The Vd of midazolam = that of diazepam(valium) due to similar lipid solubility and high protein binding
How does being elder or obese affect the Vd of Versed?
Greater Vd due to increased peripheral tissue distribution aids in prolonging duration of action
How long does it take for mental function to return to baseline after midazolam administration?
4 hours
What is a reason to use versed in kids?
for emergence delirium
How is Midazolam metabolized?
- hydrozylated via cytochrome P-450 to 1 & 4 hydroxymidazolam
- urine excreted as gluduronide conjugates
- minimal pharmacologic activity
Does H2 blockers interfere with midazolam metabolism?
no, unlike diazepam
Drugs inhibiting cytochrome P-450 like EES, Ca++ channel blocker cause _____ midazolam action
increased
Does ESRD have any affect on the metabolism or elimination of versed?
no, inactive metabolites
How does Midazolam effect CNS(5)?
- decreased CMRO2 similar to thiopental and propofol until ceiling effect reached(versed can not produce an isoelectric EEG due to the ceiling effect)
- reduces regional cerebral blood flow in areas involving attention, arousal and memory
- less neural-protective actions due to ceiling effect
- potent anti-confulsant for status epilepticus
- Rare paradoxical excitation—>treatment is flumazenil
- does not alter ICP so it is OK to use with neuro anesthesia inductions
How does Midazolam effect ventilation(4)?
- dose dependent decreases in ventilation
- COPD patients greater ventilatory depression effects
- ventilatory depression effects similar to diazepam
- causes decreased swallowing reflex and decreased upper airway activity
Does versed prevent BP and HR increases with laryngoscopy?
no
By what action does versed drop the SBP?
thought to be vasodilation related to levels of extravascular prostanoids and calcium.(prostanoids-local hormones formed from arachidonic acid including prostaglandins and thromboxane)
CO not altered-lowered BP due to decreased SVR**
no GABA receptors in the heart
What is the pre op (oral)dosage of versed for pediatrics?
0.5 mg/kg - 1 mg/kg(20 mg max) 30 minutes prior to induction gives sedation, anxiolysis without delayed awakening
What is the parenteral versed dose?
0.05 to 0.1 mg/kg IM
Why is there a 20 mg max on pre op oral dosage of versed?
more than that increases danger of vomiting
What are four comparison of versed to valium?
- more rapid onset
- greater amnesia
- less post-op sedation
- slower effect-site equilibration—>so give dose time to work
What is the dose of IV versed given as an induction agent?
0.1 - 0.2 mg/kg given IV over 30-60 seconds
Use decreased doses of midazolam for(2)?
- induction if opioids also used
2. with the elderly
Is MAC increased or reduced when versed is given?
MAC is reduced in a dose related manner until ceiling effect
How does a versed induction affect awakening?
slower induction compared to other induction agents
Has versed awakening been associated with N&V or excitation?
no
How does the duration of action of Diazepam compare to midazolam?
its highly lipid soluble so it has a prolonged action compared to versed
How is Diazepam prepared?
- Dissolved in propylene glycol because of it being water insoluble
- dilution with water causes cloudiness but doesn’t alter potency
- IM or IV may hurt
What is the most common route now for Diazepam?
Oral doses have rapid absorption-oral route often preferred as a pre-op
How long does it take to have a peak affect of oral diazepam?
about an hour; 15-30 minutes pediatrics
Rapid brain uptake of valium followed by _____ to inactive tissues
redistribution
What is the VD of Valium?
Vd is large as highly lipophilic valium is taken up into fat tissue
What can’t Diazepam be hemodialysis in cases of overdose?
it is too highly protein bound
What is the treatment of a Diazepam OD?
flumazenil
Protein binding of diazepam parallels its ___ ___.
lipid solubility
How does cirrhosis, ESRD and hypoalbuminemia affect diazepam?
decreased diazepam albumin binding and exaggerated diazepam effects
How is Diazepam metabolized?
hepatic microsomal enzymes using oxidative pathways
What are the 2 principle metabolites of diazepam?
desmethyldiazepam and oxazepam
- Desmethyldiazepam only slightly less potent than diazepam
- Desmethyldiazepam metabolized slower than oxazepam
- Desmethyldiazepam causes second wave of sedation 6-8 hours after valium administration
This class of drugs delays hepatic clearance and elimination of diazepam and desmethylidazepam due to inhibition of microsomal enzymes necessary for metabolism.
H2 blockers
What is the elimination 1/2 time for Diazepams?
21 - 37 hours
may be 5 times longer in cirrhosis patients due to decreased protein binding, decreased hepatic blood flow and greater Vd
Should the elderly receive valium?
blue hair = no valium —> increases their hospital stay
diazepam elimination slower in the elderly resulting in a > duration of action
What is the elimination 1/2 time of Desmethyldiazepam?
48 - 96 hours; much longer than the elimination 1/2 time of diazepam
At what dosages of diazepam might you see increases in PaCO2?
> than 0.2 mg/kg
What effect does Diazepam have on the sympathetic nervous system?
no direct action; no GABA receptors there
What is the cardiac induction dose of Diazepam?
0.2 - 0.5 mg/kg with minimal alterations in BP, CO and SVR similar to changes seen with natural sleep
By what action does skeletal muscle relaxation occur with Diazepam?
due to spinal internuncial neurons and not the NMJ, tolerance to this effect occurs
Does valium decrease MAC?
minimally decrease…not as much as opioids; in a dose related fashion up to a dose of 0.2 mg/kg when a ceiling effect occurs
Are massive valium OD fata?
not fatal if other CNS depressants not involved and cardiopulmonary functions are supported
What are the desired affects for giving valium(3)?
- anxiolytic
- amnesic
- hypnotic
What is the preferred route and how much is absorbed ?
PO; 94% absorbed with peak {} in < 1 hour
What dose of Diazepam abolished seizures by facilitating the inhibitory actions of GABA, especially in the hippocampus?
0.1 mg/kg
What is the principle metabolite of diazepam?
desmethyldiazepam also with strong anticonvulsant activity
What diazepam metabolite does lorazepam resemble?
Oxazepam
What is the most potent benzodiazapine amnesic?
Lorazepam
Does H2blockers or age alter the metabolism of Lorazepam?
no
How does lorazepam compare to diazepam in relation to elimination 1/2 time and duration of action?
shorter elimination 1/2 time than diazepam but longer effects due to greater affinity for GABA receptor
What is the peak time for PO and how long does the therapeutic {} last for lorazepam?
2-4 hours; 1-2 days
Pre-op dose ___ mcg/kg or ____mg gives anterograde amnesia lasting up to 6 hours without excessive sedation.
50; 1-4
Prolonged ___ of ___ delays wake-up at surgery end thus ___ ____.
duration of action;limiting use
Are there any risk of paradoxical reactions with lorazepam?
yup
How is lorazepam prepared?
insoluble in water it requires a solvent like propylene glycol.
Is there any pain with lorazepam injection?
despite the need for a solvent, there is minimal pain on injection and minimum venous thrombosis
What is the elimination 1/2 time of lorazepam?
10-20 hours(shorter than diazepam) but due to greater GABA receptor binding, clinical effects last longer than diazepam
What is the mechanism of action of flumazenil?
specific and exclusive benzodiazepine antagonist; competitive antagonist-in dose dependent manner, prevents all bento agonist effects; reverses bento component of ventilatory depression during combo benzo/opioid administration
What is the recommended initial dose of flumazenil?
0.2 mg(8-15 mcg/kg)
What is the speed of action and duration of action?
will reverse benzo CNS effects within 2 minutes; duration of action only 30-60 minutes, additional doses may be required
What is the risk of using flumazenil?
risk of withdrawal symptoms in bento addicts despite flumazenil’s weak bento agonist actions.
