Midazolam
List the: Mechanism of Action, Onset, and Duration of Midazolam
MOA: GABA-A agonist
Onset: 30-60 seconds
Duration: 20-60 mins (very short with single doses because it redistributes quickly)
Diazepam is an effective anticonvulsant. What three specific conditions can it treat, and what dose should be used? <conditions listed in ppt>
Treats lidocaine toxicity, delirium tremens (alcohol withdrawal), and status epilepticus
0.1mg/kg
Facilitates GABA at alpha 1,2,5 receptors, must be followed up with long-acting anti-epileptic agent
**Bonus answer: it can be given with ketamine to prevent emergence delirium
What is the onset, peak, and duration for IV lorazepam? Typical dose? What condition can prolong sedation?
onset: 1-2 mins
peak: 20-30 mins
duration: 6-10 hrs
typical dose: 1-4mg
Sedation can be prolonged by obesity
Rank Lorazepam, Midazolam, and Diazepam from shortest to longest elimination half life.
Midazolam (1.9 hours, high affinity for protein binding)
Lorazepam (14 hrs)
Diazepam (40-43hrs, desmethyldiazepam = 48-96hrs)
**Diazepam undergoes enterohepatic recirculation which explains why it remains in the body for such a long time (elimination t1/2 = 43hrs)
-->Remember that all are metabolized by liver and are highly protein bound so therefore cirrhosis will lead to higher levels of unbound active drug for longer
Which population do we need to be careful with when giving benzos? Why?
Use caution with the elderly d/t decreased levels of albumin for benzos to bind to, slower metabolism, and decreased hepatic blood flow
In addition, worried about gait instability, acceleration of cognitive decline with long term use, and confusion during withdrawl from benzos
Name a unique characteristic of the chemical structure of midazolam and its significance
The imidazole ring makes midaz unique. The nitrogen component causes midaz to have a pKa of 6.2.
When this midaz is exposed to an acidic pH (ppt says <4), the imidazole ring opens which increases the water solubility. (the nitrogen component is protonated)
When midaz is exposed to a physiologic pH (ppt says >4), the imidazole ring closes which increases it lipid solubility (the nitrogen component is 90% UNprotonated)
*According to Stoletings, the opening and closing only occurs in about 10% of midaz molecules and is not the major determinant of lipid/water solubility
What type of surgery is diazepam especially helpful for? Why?
Diazepam is used a lot in extensive spinal cases or in cases in which skeletal muscle relaxation would be particularly helpful. Skeletal muscle spasm is what contributes most to post-op discomfort and diazepam can help with this.
- It works on interneuron in the spinal cord, NOT at the neuromuscular junction
Compared to midazolam and diazepam, where does lorazepam rank in lipid solubility, passage into the CNS, and onset of action?
Loarzepam has the lowest lipid solubility, slowest passage into CNS, and slowest onset of action of the three.
For this reason it is not suitable as an induction agent, anticonvulsant (umm what, we literally do this in the ICU but sure), or for sedation with regional anesthesia
Let's Play: DOES IT BURN?!
- Midazolam, Diazepam, and Lorazepam
Midazolam: NO (already water soluble so it does NOT require a solubilizing agent)
Diazepam: YES (insoluble in water so it requires a solvent, propylene glycol, that produces burning on injection, might also look cloudy upon injection though this does NOT affect efficacy)
Lorazepam: YES (but less than diazepam according to ppt, no explanation why given)
The reversal agent for benzos: MOA, dosing, duration
Flumazenil! Competitive antagonist with dose-dependent effects, reverses CNS effects in 2 mins with 30-60 mins duration of action
Initial dose: 0.2 mg IV (8-15 mcg/kg IV)
Increments of 0.1 mg IV q60 seconds
Total: 1mg
Dose dependent effects: 0.3-0.6 mg decreases sedation, 0.5-1mg completely reverses therapeutic effects (as an infusion: 0.1-0.4 mg/hr)
- midaz can cause rare paradoxical excitement that is reversible with flumazenil
What is the oral preop dose of midaz for pediatric patients?
.25 mg/kg in a 2mg/ml suspension
- Minimal effects on ventilation and oxygenation up to 1mg/kg
- 0.5 mg/kg po 30 mins pre-anesthesia will give reliable sedation without delayed awakening with amnesia when given within 10 mins before surgery
- Recommended 20 mins before surgery
- PO bioavailability of 50% d/t first-pass according to APEX, oral doses are therefore much higher than IV
How long does it take to reach peak concentration in adults vs children when taken orally?
adults = 1hr
children = 15-30 mins
- Rapidly absorbed from the GI tract, rapid uptake in brain
When should you expect the peak plasma concentration of lorazepam when taken orally? What is the oral pre-op dose?
Peak plasma concentration in 2-4 hrs
50mcg/kg to max of 4mg
Therapeutic level lasts for 24-48 hrs
Maximal anterograde amnesia for 6 hrs
Explain the MOA of benzos:
Where do they bind on the receptor?
What happens to the ion channel when they bind to their receptor?
What is the overall effect of benzos binding to their receptor
Benzos are GABA-A agonists.
They bind between the alpha and gamma subints of the GABAa receptor
Benzos binding to the GABAa receptor leads to an increased frequency of the Cl- channel opening (Of note: most GABAa agonists increase the amount of time the channel is open, rather than the frequency like benzos)
The increased influx of Cl- leads to hyperpolarization of the membrane
Which benzo is the most potent sedative and amnestic of the three?
Lorazepam!
lorazepam>midazolam>diazepam
List the IV sedation and IV induction doses for midaz:
What are their respective respiratory and CV effects?
IV sedation: 0.01-0.1 mg/kg OR 1-2.5 mg IV (both listed in ppt and APEX) <kids IV sedation: 0.05-0.1 mg/kg>
- minimal CV effects, minimal respiratory effects (can see resp. depression when given with opioids)
IV induction: 0.1-0.2 mg/kg IV over 30-60 seconds
- increased HR, decreased BP and SVR w/ respiratory depression
- increased speed when opioid given 1-3 mins previously, decrease dose if other CNS depressants are being used
- Of note: Patients with COPD are more sensitive to the respiratory depressant effects
- Potential for peripheral vasodilation, hypotension and delayed emergence
- Decreased incidence of N/V and emergence delirium
What are the three metabolites of diazepam? What is notable about its most prominent metabolite
1. Desmethyldiazepam (nordazepam): has an elimination half life of 48-96 hrs and can outlast the parent drug. It is slowly metabolized with a potency similar to its parent drug. Expect return of drowsiness 6-8 hours after parent drug effect. Nordazepam can accumulate with sustained use and is sequestered into fat from which it can reenter circulation. Because of this, it can take a week to clear!
2. Oxazepam: aka Serax, commercially available for insomnia, mentioned at end of ppt, low oral absorption with duration of 5-15hrs
3. Temazepam: aka Restoril, commercially available for insomnia, reliable onset after 2.5hrs, elimination ½ 15hrs
What are the active metabolites of lorazepam?
Sorry yall, trick question! There are none
What are the active metabolite for midaz? Potency? Things to watch for?
1-hydroxymidazolam is the most common active metabolite of midaz
- 0.5x potency of midaz, rapidly conjugated to an inactive compound
- Further broken down to 1-hydroxymidazolam glucuronide which is cleared by the kidneys and can accumulate with renal failure and exert synergistic effects with continuous infusion
4-hydroxymidazolam also exists but is barely detectable
**Due to extensive hepatic metabolism w/ CYP450 3A (5x >loraz, 10x >diaz), clearance is not effected by renal failure as long as the med is not given as a continuous infusion
Which medication's CNS effects makes it a good pick for neuro cases? Why?
Midazolam! Midaz decreases CMRO2 (cerebral metabolic rate of oxygen) and cerebral blood flow, which protects injured brain tissue and decreases ICP
Midaz does NOT affect the vasomotor response to changes in PaCO2 and does NOT prevent the increased ICP caused by direct laryngoscopy (still need another agent)
Midaz has anticonvulsant effects
What does it mean that midazolam has a slow effect site equilibration?
This means that it takes about 5 mins to reach it's peak effect. Wait to redose until 5 mins to avoid delivering too high of a dose of midaz
- Remember that this is a matter of seconds for propofol
You are a CRNA in the ED
A patient comes in after a suspected OD with diazepam after being found down next to their new empty bottle of pills. What medication should you give, and how much? If after the max dose of this medication, the patient is still unarousable, what do you suspect?
Flumazenil!
Initial dose 0.2 mg IV (8-15mcg/kg IV), Increments of 0.1mg IV q 60 seconds, Total: 1-5mg
0.3-0.6mg decreases sedation, 0.5-1mg reverses therapeutic effects
Should see reversal of CNS effects in 2 mins and the reversal should last 30-60 mins. Will likely need a drip for this pt (0.1-0.4 mg/hr)
If the pt still does not wake up, suspect that other substances not reversed with flumazenil have been taken
Describe the metabolism of lorazepam:
- slow process that does NOT involve hepatic enzymes (no CYP450)
- it is conjugated in the liver and excreted in the urine 80%
- metabolism is less sensitive to liver function, age, and drugs that inhibit CYP 450
Low doses of which med can be effective in treating paradoxical vocal cord dysfunction?
Midazolam! Paradoxical motion of the vocal cords can occur with anxiety pre-op or post-op leading to an upper airway obstruction and stridor. Giving sedation in this situation might seem counterintuitive, but actually small doses of midaz can help :) Think 0.5-1mg IV Plus, what do we really know anyway?!
List four of the six extended benzo family memebers
(Remember that some are directly related to our parent meds)
1. Oxazepam (Serax): metabolite of diazepam, insomnia, duration 5-15hrs
2. Alprazolam (Xanax): anxiety and panic attacks, greater adrenocorticotropic and cortisol suppression than than all benzos including midazolam
3. Clonazepam (Klonopin): good oral absorption, long elimination half life of 24-48hrs, effective for seizure control and prevention
4. Flurazepam (Dalmane): insomnia, onset in 15-25 mins, active metabolite of this med causes hangover and cumulative sedation
5. Temazepam (Restoril): active metabolite of diazepam, for insomnia, reliable but long onset 2.5hrs, elimination ½ 15 hrs
6. Triazolam (Halcion): shortest acting (½ life 1.7 hrs), good for difficulty falling asleep, associated with bizarre behaviors