Benzodiazepines EXAM Review Flashcards
Which chemical group is responsible for the physical properties of midazolam?
Midazolam is unlike other benzodiazepines because it has a substituted imidazole ring and the nitrogen
in this ring has a pK of 6.2, that is protonated (ionized) and the drug is water soluble in the acidic
preparation of the vial.
At physiologic pH 7.4 in the blood, 90% of midazolam is unprotonated (non-ionized) and lipid soluble..
When is midazolam water soluble?
At pH < 4, imidazole ring is OPEN = Water soluble
When is midazolam lipid soluble?
At pH >4, imidazole ring is CLOSED = Lipid soluble *so at pH of 7.4, the ring is closed, so a patient in
acidosis would require a higher dose of midazolam to be effective?
*Midazolam pK is 6.15 which permits the preparation of salts that are water soluble, it is buffered in
solution to a pH of 3.5. So with a pK (6.15) > pH 3.5 the drug is ionized (Midazolam is a base)
Are benzodiazepines highly protein bound? What is the significance of this?
Benzodiazepines are HIGHLY protein bound drugs. Extensive protein binding. In states of low protein
binding, like hypoalbuminemia, there is less binding to protein causing an enhanced clinical effect of
benzos. This effect can be exacerbated in hepatic cirrhosis or CRF due to protein spillage
Does cimetidine prolong the effects of midazolam, diazepam, lorazepam?
It is an inhibitor
Cimetidine is the ONLY H2 Antagonist that inhibits CYP-450 3A. So famotidine and ranitidine are ok to
use. However, cimetidine is a known STRONG INHIBITOR of CYP-450 3A, so this will prolong the effectsof midazolam, diazepam, and lorazepam.
Other inhibitors of CYP-450 3A are: Erythromycin, CCB, fentanyl, fluoxetine, and again cimetidine
**famotidine (Pepcid) DOES NOT delay hepatic clearance of Diazepam
What agent is recommended to reverse the adverse effects of benzodiazepines?
Flumazenil 0.2 mg IV (8-15 mcg/kg IV), if further dosing is required give 0.1 mg IV at 60 sec intervals (
max =1 mg)
Doses of 0.3-0.6 mg IV have been known to reverse the sedative effects (alpha-1 subunits)
Doses of 0.5-1mg IV have been known to abolish the therapeutic dose of benzodiazepines
Which benzodiazepine is associated with a prolonged context sensitive half-life?
Diazepam (similar to fentanyl) > Midazolam
What are common pharmacological effects of benzodiazepines? ASASH
Five principal pharmacological effects: anxiolysis, sedation, hypnosis, anticonvulsant actions, and
skeletal muscle relaxation via spinal-cord mediated
Do benzodiazepines interact with alcohol /opioids?
Alcohol and benzodiazepines have a synergistic effect when in combination
*Also with inhaled volatile anesthetics, opioids, and alpha-2 agonists
What is the least /most potent Benzodiazepine? (LMD)
Most potent = Lorazepam (more sedative than amnestic than midazolam and diazepam)
2nd potent = Midazolam (less sedative than lorazepam, more amnestic)
Least potent = Diazepam
What benzodiazepines are water soluble? What Benzodiazepine does not require the diluent propylene
glycol? What are disadvantages of propylene glycol?
Midazolam is water soluble
Diazepam and lorazepam are not water soluble and require propylene glycol. Propylene glycol can be painful at the IV site and thrombophlebitis
What is the mechanism of action for all benzodiazepines?
Benzos DO NOT activate GABA receptors, they enhance the affinity of the receptors for GABA, this leadsto enhanced opening of the Cl- conductance and causes hyperpolarization of the POST-Synaptic cell membrane, making POST-Synaptic neurons resistant to excitation.
GABA is a large macromolecule that has separate binding site for benzos, barbiturates, etomidate,
propofol, neurosteroids, and alcohol. Therefore since it is the same receptor, but different binding site, benzos, barbs and alcohol can have synergistic effects by acting on the same receptor but at different receptor sites
How are benzodiazepines for advantageous when compared to barbiturates?
Less tendency for tolerance, less potential for abuse, more safety in overdose situations, less drug
interactions, less addicting compared to cocaine, amphetamines, opioids, and barbiturates
What is the mechanism of action of flumazenil? What is the dose of flumazenil? What is the duration ofaction of flumazenil?
MOA = Selective antagonist with high affinity for benzodiazepine receptors, where it exerts minimal
weak agonist activity. As a competitive antagonist, flumazeinil prevents or reverses, in a dose-depedent
manner, all the agonistic effect of benzodiazepines
Dose of Flumazenil
Flumazenil 0.2 mg IV initial dose (8-15 mcg/kg) works within 2 minutes. Can repeat with 0.1 mg IV to a
max of 1 mg if required at 60 second intervals. 0.3-0.6 decreases degree of sedation. 0.5-1 mg abolishes
the therapeutic effects of benzos
Alternative to repeated doses, is a continuous infusion of 0.1-0.4 mg/hr
Duration of action of Flumazenil
30-60 minutes
Do benzodiazepines prevent the sympathetic response to attempted intubation?
No
Midazolam DOES NOT prevent blood pressure and heart rate responses evoked by tracheal intubation.
In fact, mechanical stimulus may offset the blood pressure lowering effects of midazolam.
Midazolam lowers SVR, DOES NOT lower CO, so this agent is useful in the CHF patient who have a weak
heart. Remember, CO and SVR have an inverse relationship
*Opioids will blunt the effects to attempted intubation
What are benefits of lorazepam when compared to diazepam?
Lorazepam is more potent sedative and amnestic than diazepam and midazolam (more amnestic anterograde, thansedative).
All benzos have same effects on ventilation, CV, and skeletal muscles, does not undergo phase I
oxidation or hydrolysis, so it is forced down the phase II pathway of glucuronidation to INACTIVE
metabolites excreted in water soluble form through the kidneys, not entirely dependent on
microsomal enzymes, so this is better for our liver and renal patients (why it is better for the ICU setting)
Metabolism is less influenced in hepatic function, increasing age, or other drugs that inhibit CYP-450 (
cimetidine), has good oral and IM absorption, dose is 50 mcg/kg not to exceed 4 mg, peaks in 2-4 hours,
anterograde amnesia lasting 6 hours without excessive sedation, effective for emergence with ketamine
, produces less pain and venous thrombosis than diazepam
What agent is water soluble? What two are insoluble in water and what do they need to be stable in
solution?
Water soluble =
Insoluble to water =
Midazolam
Diazepam and Lorazepam (requires propylene glycol)
Best thing to do for anxiety:
talk to the patient. Portray confidence and highlight your
qualifications
Lipid soluble drugs action is terminated
•
with redistribution
Water soluble drugs action is terminated with
metabolism
Ketamine does all of the following EXCEPT:
Reduce oral secretions
Which would ketamine be least appropriate for induction:
50 year old with glaucoma because
it increases IOP
True about Propofol
: Allows rapid transition between deep and light anesthesia
Ability of opioid to cross BBB except:
Mu2 activity
Which about opioid N/V is true:
Equipotent doses of opioids cause equal incidence of N/V
Potential Hazards with narcan to reverse opioid induced respiratory depression:
sudden severe pain,
withdrawal in chronic users
late respiratory depression
acute pulmonary edema
***Benzodiazepines DO NOT
induce microsomal activity
Midazolam dose is
0.2mg/kg IV
Midazolam on HR and Bp
Increase; decrease
Ventilation and midazolam
Decrease hypoxic drive
COPD patients and midazolam
Depression of ventilation
