Benzodiazepines Flashcards
sedatives
- a drug that induces calm or sleep.
hypnotics
- a drug that induces hypnosis or sleep.
Why do we say anesthesia is like sleep?
- anesthesia is like sleep because it has some commonalities in the RAS (reticular activating system).
- Anesthesia and sleep inhibit thalmic and mid-brain RAS.
- anesthesia and sleep both reversibly inhibit the central nervous system.
Consciousness in the OR
- from a study that was conducted on patients in the US and Europe, it showed that as many as 1/1,000 to 1/20,000 patients reported having awareness under anesthesia.
- This number isn’t always accurate because patient’s don’t always understand the difference between sedation (where they will remember) and awareness under general anesthesia.
- Some patients also remember emergence from anesthesia in the waking up phase, but not actually being in the OR under general anesthesa.
- consciousness under general anesthesia can give people PTSD to not want to have surgery again.
Describe unconsciousness
- consciousness to unconsciousness is a spectrum or range.
- it is not a yes no question.
- With anesthesia, we are looking at the depth of unsconsciousness. EX: are you so unconscious you are almost dead, or are you almost conscious enough to start moving on the OR table.
What are Freud’s 3 levels of the mind.
- The conscious mind
- the preconscious mind
the unconscious mind
In 1937, what were EEGs used for?
- to measure the effects of anesthesia.
- At this time, we were looking at the EEG waveforms and saying if the waves are doing this, the patient should be awake, and if the waves are doing that, the patient should be sedated.
In 1952, what did we realize about EEGs?
- That the depth of anesthesia correlated with the concentration of ether.
- We were able to see depth of sedation at this point, whether you were a little bit, a lot, or so unconscious you were near death.
- We also knew that cerebral blood flow and cerebral metabolic of oxygen requirements correlated to Eeg activity.
- The EEG looked busier/had more activity if the patient had better cerebral blood flow and they were using more oxygen.
- The EEG had less activity on it if the patient had very little cerebral blood flow and wasn’t having a lot of oxygen required.
- Bedause we knew that anesthesia altered cerbral blood flow and oxygen requirements, we could deduce how much anesthesia was needed and how deeply the patient was sedated based on the EEG.
What does an EEG do?
- It is a continuous measurement of responsiveness and cerebral function.
- The EEG stickers are named after the location on the brain they are measuring
- A normal EEG is impractical in the OR because it is so large.
instead we use a BIS.
When was the BIS created?
- 1996
What is a BIS?
- A processed EEG where they took allthe leads from a regular EEG together into 1 strip that goes across the patient’s forehead.
This is what is used in the OR.
Describe the first BIS study.
- 1500 subjects were tested for a total of 5000 hours.
- They took out all the artifact, the loose wires and needles,and the pacemaker spikes, so that they had a really great EEG waveform.
- The BIS was tested with a variety of anesthetics such as isoflurane/oxygen, propofol/nitrous, propofol/alfentanil, etc.
- They came up with a mathematical algorithm that looked at EEG pattern, time, frequency, and amplitude to get a BIS reading.
What does a BIS show with hypnotic drugs?
- BIS changes correlated with patient movement.
- Hypnotics correlate to the BIS much better than high dose narcotics.
What does a BIS show with high dose narcotics?
In the initial BIS studies, what did a BIS <58 show?
- No pateint with a BIS <58 was conscious.
- This patient will not move, or cough, and their depth of anesthesia is enough.
In the initial BIS studies, what did a BIS of <65 show?
- A BIS of <65 showed that the patient had less than 5% chance of return to consciousness within 50 seconds.
- For a BIS of <65, it will take them a little bit of time to wake up, instead of just waking up the second anesthesia gets turned off.
Descrbide the modern day BIS.
- The bis was named so, because it was the first one of its kind to come out.
- other names for the BIS include PSA, narcotrend, and GE entropy.
What are the 5 things we see on the BIS monitor?
- SQI - signal quality index. Shows you how good the signal is and if you have a bunch of artifact or not.
- EMG - there should be no EMG movement if you have paralyzed the patient because you have inhibited all the neuromuscular blocking receptors, unless your paralytic has worn off and you are not aware and your patient is about to move.
- EEG - the processed brain wave signal
- SR - suppresion ratio. this tells you how much of the time in the last few minutes has the BIS been 0. Your SR should never be 0 unless you know the patient is braindead, in which case you wouldn’t be using sedation or a BIS.
- A number from 0-100
What does a BIS reading of 0 mean?
- No brain wave activity
What does a BIS of 100 mean?
- The patient is awake and alert and talking.
- if you were to close your eyes, take deep breaths, and thing about something calming, you could probably lower your BIS a little bit without any anesthesisa.
- The BIS is just a monitor but not always 100% acurrate.
What is the ideal number range for no recall on the BIS?
- 40-60
- 40 is deeper sedated
- 60 is closer to being awake.
What synergistic drugs will lower your BIS number?
- Hypnotics
- volatiles
- NMBDs
- Opioids
- Any of these when given in combination.
- Beta blockers can falsely lower your BIS number by blocking the peripheral nervous system.
What drugs will falsely increase your BIS?
- sympathimoteics
- ketamine
- Epinephrine
- Anything that increases your heart rate, or stimulates your CNS and causes your CNS to be more active.
What are the 5 pharmacologic effects of benzodiazepines?
- Anxiolytics: Most helpful with chronic anxiety
- Sedation: to relax the patient before surgery. Also used as sedation when the patient is getting a short procedure done and doesn’t need general anesthesia.
- anterograde amnesia: the patient is aware of everything up until the point of getting the benzo (no retrograde) but cant remember afterwards. The anterograde amnesia effect lasts a few hours longer than the sedative affect. Sometimes these people have a problem reme,bering things for a few hours post-op after they have already woken up. Electroconvulsant therapy is the only thing that will cause retrograde amnesia.
- Anticonvolsant actions: Used to treat siezures acutely. Valium is great for this.
- Spinal cord mediated skeletal muscle relaxation: Not adequate for surgery and has no nmbd potentiation.
Compare benzos to barbiturates.
- Benzos have largely replaced barbiturates for preop sedation.
- There is less tolerance with benzos than barbiturates.
- there is a lower potential for abuse with benzos than barbiturates
- benzos have fewer and less serious side effects.
- benzos do not induce hepatic microsomal enzymes
Compare the type of benzos with each other.
EX: versed, valium, ativan
- they are all structurally similar
- they all use flumazenil as their pharmacologic antagonist.
what is the most commonly used benzo in the perioperative period and why?
- midazolam
- because it has a quick on and off, and a prompt recovery.
what benzos are more attractive for sedation post op and why?
- Diazepam and lorazepam.
- they have a much greater half time than midazolam and should be used if you want to keep the patient intubated.
what is the mechanism of action of benzos?
- Benzos facilitate the action opf GABA at GABA-a, which relates to the chloride ion, and it enhances the affinity of the receptor for GABA.
- This then enhances the opening of the chloride channels, which allow more chloride in to hyperpolarize the cell, and post synaptic membrane.
- This makes the cell more resistant to depolarization.
what is GABA?
- the principle inhibitory neurotransmitter in the CNS
what subunits on the GABA receptor can be GABA sites?
- There are 2, alpha-1/beta-2 sites.
what subunits on the GABA receptor can be a benzo site?
- alpha-1/gamma-2
- alpha-2/gamma-2
- a benzo will potentiate the GABA receptor at the benzo site to open up the chloride channel and cause hyperrepolarization.
What benzo effects do we see on the alpha-1 site on the GABA receptor?
- sedative, amnestic, and anticonvulsant. (the stuff you want in preop)
- the most abundant sununit type
- effects the cerebral cortex, cerebellar cortex, and thalamus
What benzo effects do we see on the alpha-2 site on the GABA receptor?
- anxiolytic, and skeletal muscle relaxation
- effects the hyppocampus and amygdala.
Are there benzos that are specific to alpha-1 or alpha-2?
- Not yet.
- At this point in time, benzos hit both subunits so we get all the effects from alpha-1 and alpha-2.
What other medications also affect GABAa?
- alcohol
- volitile anesthetics
- Propofol
- Etomidate
- barbiturates
what are some of the synergistic effects that benzos can have when given with other medications othat also work on the GABA receptor?
- Increased risk of overdose
- cross-tolerance
All benzos are highly…
- Lipid soluble and protein bound (albumin)
- We want to make sure that the patient has enough albumin before giving a benzo.
- the less protein binding we have, the more free drug we have floating around, the more of a toxic dose we could be giving.
- be cautious of patients that have liver cirrhosis and aren’t making as much albumin, and chronic renal failure who might hold onto the drug a little bit longer.
What are the general effects seen on an EEG with benzos?
- On the EEG we see decreased alpha activity.
- some benzos can produce an isoelectric state where they have a flat line EEG. Not versed though because versed has a ceiling.
- Benzos cause antegrade amnesia.
What other drugs cause synergism when given with benzos?
- Other GABA related drugs
- Alcohol, volitiles, injected anesthetics, opioids, and alpha-2 agonists such as precedex and klonidine.
What effects do benzos have on platelet aggregation?
- there are some small studies that show benzos can inhibit the platelet aggregating factor which could potentially cause a small risk for bleeding.
- Benzos can prevent the confirmational change so that platelets don’t aggregate like they should. Platelets don’t get thei pseudopods to grab onto each other.
- these effects are hardly seen and not enough evidence shows any surgical significance.
- We are not going to hold their benzo because of this.
What is another name for versed?
- Midazolam
What kind of chemical structure does midazolam have?
- An imidazole ring.
- this allows for rapid metabolism
- this ring stabilizes the structure.
when is midazolam most often used?
- preoperatively as an anxiolytic
- during conscious/moderate sedation.
what is the potency of midazolam compared to other benzos?
- 2-3 times as potent as diazepam (valium) because it has a greater affinity for the receptor.
what causes the amnesia to be greater than the sedation effect with midazolam?
- the retrograde amnesia
- can last for several hours after the sedative effect has worn off.
- This is why people getting versed need a family member to take them home so the family member can listen to the post op instructions. The patient will still have the amnestic effect.
What kind of solubility does midazolam have?
- water soluble and lipid soluble.
- no solvent has to be added to the bottle. You can pull it straight from the vile and put it straight into the vein.
- the pH of versed is dependent on the imidazole ring opening and shutting.
- if the pH is <3.5, the ring is open, it is water soluble, and protonated/inactive.
if the pH is >4.0, the ring is closed, it is lipid soluble, and unprotonated/active. - in the bottle, the pH is <3.5 which makes it water soluble.
When you inject the versed into the blood and it mixes with the blood pH, your versed now has a pH >4.0 and is lipid soluble at this point so it can cross the cell membrane and go to work.
What is mixed in with midazolam in the vile to make it irritating or painful at the IV site?
- propylene glycol
what is the onset of action for midazolam?
- 1-2 minutes IV
it rapidly moves from the blood, across the lipid barrier to the effector site in the brain and effects GABA rapidly.
What is the percentage that midazolam is protein bound and how much is free floating?
- 96-98% highly protein bound
- 2-4% free floating drug available to bind to the receptor.
what is the peak effect time of midazolam?
- 5 minutes
what is the duration of action for midazolam?
- short duration from brain to hepatic clearance due to lipid solubility and rapid redistribution.
What is the elimination half time for midazolam?
- 2 hours for 50% of the midazolam to be cleared from the plasma. After 50% of the drug is gone, the patient should be somewhat steady on their feet at that point.
- 4 hours for people with malnutrition/low albumin levels, elderly patients with low cardiac output, liver failure due to hepatic flow and enzymatic activity and the liver isn’t able to metabolize the drug.
- Patients in renal failure or who have poor kidney function are not able to clear the drug as easily.
what is the volume of distribution for midazolam?
- 1-1.5L/kg which is large.
- We see a greater volume of distribution in morbidly obese patients because they have more peripheral fat tissue to get through.
- the volume of distribution might be a lot less in an elderly person who is cachetic and they have less fat and tissue to go through.
How is midazolam metabolized?
- by hepatic and intestinal cytochrome P-450 enzymes
- CYP3A4
What drugs cause inhibition of CYP450 enzymes (these decrease the metabolism of benzos)
- cimetidine (tagament)
- eythromycin
- calcium channel blockers (common)
- Antifungals
- fentanyl (common)
- Because these drugs inhibit the CYP450 enzymes, it delays the half life of versed when given together.
what is the clearance rate for midazolam?
- 5x faster than lorazepam
- 10x faster than diazepam
What metabolites does midazolam metabolize to?
- 1-hydroxymidazolam
- the active metabolite is conjugated and cleared by the kidneys
- This metabolite only has half the activity as the parent drug midazolam.
- midazolam also produces some inactive metabolites that get cleared by the kidneys.
what effects does midazolam have on the central nervous system?
- Decreases cerebral blood flow (dose dependent)
- decreases CMRO2 (dose dependent)
- Does not produce an isoelectric EEG due to the ceiling effect.
- Is a potent anticonvulsant even in statis epilepticus.
- preserves vasomotor response to CO2. The vasomotor response means that if CO2 goes up we visodilate and if CO2 goes down we vasoconstrict. Versed preserves this vasomotor ability.
- Has no change in ICP if decreased intracranial compliance. Is good for induction with neuro pathology patients.
What effects does midazolam have on the pulmonary system?
- A dose dependent decrease in ventilation. the more versed you give, the less you’ll be able to ventilate.
- decreases hypoxic drive which is even worse in copd patients
- transient apnea if rapid IV bolus, especially if given with an opioid.
- depresses swallowing reflex. Makes the patient at risk for aspiration.
- decreases upper airway activity.
What effects does midazolam have on the cardiovascular system?
- dose dependent in crease in heart and decrease in blood pressure. The heart rate increases to compensate for the blood pressure being low.
- cardiac output is unchanged.
- SVR is decreased
- Midazolam will cause enhanced hypotension in already hypovolemic patients.
- Could be helpful in patients with CHF.
does not inhibit the response to intubation. if you have someone that doesn’t have much anesthetic on board (just a little bit of versed) and you put the cold blade in their mouth, their heart rate and blood pressure are going to sky rocket.
What is the midazolam dosing for kids for sedation in pre-op?
- 0.25-0.5mg/kg oral as a liquid.
- goes through the first pass effect in the liver.
- Peaks in about 20-30 minutes.
What is the midazolam dosing for adults for sedation in pre-op?
- 1-5mg IV
- peaks in 5 minutes
- Onset is 1-2 minutes
- Half life is 2 hours
- Elderly patients may require a decreased dose due to greater CNs sensativity.
describe the midazolam safety in children
- must be given in preop PO, 30 minutes before induction.
- start on the lower end with your dosing at 0.25mg/kg.
- Per the graph, there were hardly any changes between times for end of surgery to pacu, pacu to eye opening, and time to pacu, there were no changes in times when kids got 0.25/kg - 1mg/kg.
midazolam is very safe in chilren.
what is the dosing for midazolam for induction?
- we typically will not use versed for induction.
- 0.1-0.2mg/kg given IV over 30-60 seconds.
- this is facilitated by a preceding dose of opioid, typically fentanyl 50-100mcg given over 1-3 minutes.
What is the maintenance dosing of a midazolam drip?
- Very uncommon to use a versed gtt in the OR.
- can be used to suppliment opioids, propofol, and volitiles.
- decreases the requirements for volitiles, used in a dose dependent mannor.
- is rarely associated with n/v or emergence excitement/craziness
What is the dosing for midazolam when used postoperatively as a maintenance gtt?
- 1-7mg/hr IV
- Will show markedly delayed awakening because the active metabolites accumulate over time. 9contect sensative half life)
- Clearance for the gtt depends on hepatic metabolism and not redistribution.
- there is some t-cell suppression and delayed healing if you leave someone on a versed drip past 2-3 days. not a huge clinical significance though.
what is another name for diazepam?
Valium
What type of solubility is diazepam?
- highly lipid soluble
What is the duration of action time for diazepam?
- it has a more prolonged duration of action than midazolam.
How often is diazepam used in the OR?
- hardly ever used in anesthesia because versed is much more beneficial.
How is diazepam prepared?
- It is dissolved in organic solvents.
- it is insoluble in water because it is highly lipid soluble.
- if mixed with propylene glycol it can cause pain with injection and glycol toxicity.
- if it is mixed with a soybean formulation, it is much less painful with injection.
What is the onset of action with diazepam?
- 1-5 minutes
What is the half-time with diazepam?
- 20-40 hours before 50% of the drug is cleared from the body. Not the best option for the OR.
- diazepam is extensively protein bound.
What is the volume of distribution for diazepam?
- very similar to midazolam due to the high lipid solubility.
There is a larger volume of distribution in women versus men for diazepam. - 1-1.5L/kg which is large.
- We see a greater volume of distribution in morbidly obese patients because they have more peripheral fat tissue to get through.
- the volume of distribution might be a lot less in an elderly person who is cachetic and they have less fat and tissue to go through.
what causes prolonged effects with diazepam use?
- hepatic failure
- liver cirrhosis
- Old age
What are diazepams effects on GABAa?
- It dissociates from GABAa faster than lorazepam.
- it has a shorter duration of action but much longer elimination half-time. So its around longer, just not on the receptor as long.
How is diazepam metabolized?
- by hepatic and intestinal cytochrome P-450 enzymes
- CYP3A4
what are the active metabolites of diazepam?
- Desmethyldiazepam (48-96 hours0 and oxazepam.
- Both are almost as potent as the parent drug diazepam.
- because of these metabolites, the patient could have a return of drowsiness 6-8 hours later.
what drug interactions does diazepam have?
- cimetidine (tagament)
- eythromycin
- calcium channel blockers (common)
- Antifungals
- fentanyl (common)
- Because these drugs inhibit the CYP450 enzymes, it delays the half life of versed when given together.
what effects does diazepam have on the central nervous system?
- decreases cerebral blood flow and cmro2 (dose dependent). The more you give, the greater the decrease.
- Is a potent anticonvulsant when given at 0.1mg/kg Iv. Abolishes DT’s, status epilepticus, and lidocaine toxicity related to seizures. is a longer acting antiepileptic drug.
can produce an isoelectric/flatline EEEG reading.
what effects does diazepam have on the pulmonary system?
- Minimal effects on ventilation
- produces a slight decrease in VT
- After 0.2mg/kg is given iV there is an increase in PaCO2, which can be exaggerated when given with opioids, in people who drink alcohol, and patients with COPD.
- ventilatory depressant effects are reversed by surgical stimulation.
- very minimal effects on pulmonary status.
What effects does diazepam have on the cardiovascular system?
- a minimal decrease in blood pressure, cardiac output, and SVR even with induction doses.
- blood pressure changes that do occur happen when given with an opioid, the BP will decrease.
- Blood pressure is unchanged with the addition of nitrous.
- used to be given back in the day in large doses for cardiac surgery patients.
what effects does diazepam have on the neuromuscular system?
- decreases tonic effect on spinal neurons.
- skeletal muscle tone is decreased.
- No action at the neuromuscular junction/not paralysis.
- does cause neuromuscular relaxation.
what is the induction dose for diazepam?
- 0.5-1mg/kg IV
- Decrease the induction dose by 20-25% in the elderly, liver disease patients, and in the presence of opioids.
what is another name for lorazepam?
ativan
What is its potency compared to midazolam and diazepam?
- it is a more potent sedative and amnestic
- you can give a small dose to get a very potent effect.
What does lorazepma resemble?
- it resembles oxazepam (serax) because it has an extra Cl- atom.
What is the solubility of lorazepam?
- lipid soluble but not as much as diazepam.
The lower lipid solubility causes it to have a slower entrance into the CNS and a slower metabolic clearance.
how is lorazepam prepared?
- because it is insoluble in water, it requires the solvent polyethyline glycol which can sting when given IV.
what is the onset of action of lorazepam?
- slower onset of action than midazolam and diazepam.
what is the peak effect of lorazepam?
- 20-30 minutes with IV dose.
It has limited usefulness for induction, conscious sedation, and anticonvulsant therapy because the peak effect is so long. - lorazepam is better for longterm use not short term use.
what is the dosage of lorazepam?
- 1-4mg given IV for a single dose.
Does lorazepam produce active metabolites?
- No it produces inactive metabolites that get excreted out by the kidneys.
What is the elimination half time for lorazepam?
- 14 hours for the 50% oif the drug to be cleared from the body.
- slower half time than versed, but not as long as valium.
- glucuronidation is slower than oxidative hydroxylation.
how is lorazepam metabolized?
- It is not entirely dependent on the CYP450 hepatic enzymes so it is good for older patients and people with liver disease.
what are the organ system effects of lorazepam?
- similar to valium.
what is the cost of lorazepam compared to the other benzos?
- Much cheaper and cost effective than versed, valium, and other sedatives.
what is another name for flumazenil?
- romazicon
what does flumazenil antagonize/reverse?
- All benzos. it is not specific.
How does flumazenil work?
- it is a competitive antagonist that has a high affinity for the benzo receptor.
- It prevents and reverses all agonist activity of benzos.
what chemical structure does flumazenil have?
- 1,4 imidazobenzodiazepine derivitive.
How is flumazenil metabolized?
- it metabolizes into inactive metabolites by the cyp450 hepatic microsomal enzymes.
What is the dosing for flumazenil?
- 0.2mg IV and titrated by 0.1mg every minute to a total of 1mg until the patient is conscious.
- You will need multiple doses to get rid of the benzo. The sedative effect of the benzo will outlast the flumazenil.
How much flumazenil do you need to give to reverse over sedation from an iv push?
- 0.3-0.6mg
How much flumazenil do you need to give to reverse someone who is on a chronic or therapeutic dose of a benzo (i.e they are taking valium daily)?
- 0.5-1mg
if you give a whole 1mg of flumazenil and the patient still hasnt returned to consciousness, what do you do next?
- you have to consider that something else in their system at this point besides benzos. it could be narcotics, alcohol etc.
what is the duration of action for flumazenil?
- 30-60 minutes.
- if you are having to give supplimental doses, you may want to do a continuous infucion at 0.1-0.4mg/hr instead.
- if you have only given 1mg of versed and the peak effect is 5 minutes, and then you give the flumazenil that has a peak effect of 30-60 minutes, by the time you have reached the 30 minutes, you have probably outlasted the sedative effect of the 1mg of versed.
- when you have given multiple doses of versed you will probably have to give repeat doses of flumazenil before you outlast the sedative effect.
What side effects does flumazenil have?
- none other than reversing the benzo which could give the patient acute anxiety, hypertension, and tachycardia.
When is flumazenil contraindicated?
- when patients are using benzos for seizures because it could precipitate a seizure.
