Benzodiazepines: Pharmacology of Anesthesia Agents

Out of diazepam, midazolam, & Lorazepam which one is the most stable in solution?
Midazolam

What benzodiazepine is the best for terminating seizure activity?
Lorazepam

What are the 5 main pharmacologic effects of benzodiazepines?
1. Anxiolysis
2. Sedation
3. Anticonvulsant
4. Anterograde Amnesia
5. Skeletal muscle relaxation

If a pt has received a benzo preoperatively, should they receive an increased, decreased, or normal dose of paralytic for induction?
Normal

If a pt has developed a LA toxicity, why would it be a good idea to give them a benzo?
Increase seizure threshold = decreased risk for seizures

What agent would have a greater tendency for tolerance: benzo or barb?
barb

What agent has a lesser abuse potential: benzo or barb?
Benzo

What agent (when not combined with any other agent) is safer in OD situations: Benzo or barb?
Benzo

True or False: Benzodiazepines are *more* addicting than opioids, cocaine, amphetamine, & barbs
False

True or False: Benzodiazepines are water soluble
False (they are lipid soluble)

True or False: Benzos have *low* protein binding
False (they are highly protein bound drugs)

Should a pt with hypoalbuminemia receive an increased, decreased, or normal dose of Benzo?
Decreased dose (hypoalbuminemia will enhance the effect of benzos)

True or False: Benzos *activate* GABA receptors
False

True or False: Benzos *enhance* the affinity of the receptors for GABA
True

What effect is brought about by benzo induced enhancement of GABA?
Increased Cl- influx –> hyperpolarization of postsynaptic cell –> increased resistance to excitation

GABA receptors have *separate* binding sites for what 6 substances?
1. Benzodiazepines
2. Barbiturates
3. Etomidate
4. Propofol
5. Neurosteroids
6. Alcohol

True or False: Benzos, barbs, & alcohol act *synergistically* when given concomittently
True

What is the most abundant GABA receptor subunit?
Alpha 1 subunit

The sedative effect of benzos come from activation of what GABA subunit?
Alpha 1 subunit

The anxiolytic & amnestic effects of benos come from activation of what GABA subunit?
Alpha 2 subunit

What effect do benzos have on the nucleoside transporter? How does this effect adenosine degradation?
1. Inhibits nucleoside transporter
2. Decreases degradation of adenosine

Why is adenosine considered cardioprotective during myocardial ischemia?
It causes coronary vasodilation

True or False Midazolam can produce an isoelectric EEG?
False

Describe the anterograde amnesia that is caused by benzos.
Cannot remember events that take place after the benzo is administered, until it starts to wear off.

True or False: Benzos have the ability to suppress the hypothalamic-pituitary-adrenal axis
True

How is Lorazepam metabolized? Does it have active metabolites?
1. Hepatic glucuronidation (conjugation reaction)
2. No active metabolites

How is diazepam metabolized? does it have active metabolites?
1. Hepatic microsomal enzymes
2. Does have *active* metabolites

How is Midazolam metabolized?
Hepatic hydroxylation (CYP-450 3A)

List the 3 benzos in this lecture in order of most potent to least potent.
Lorazepam > Midazolam > Diazepam

Describe the solubility of midazolam.
*At pH < 4*: Water soluble (ionized) *At pH > 4*: Highly lipid soluble (nonionized)

Why doesn’t midazolam generally cause injection site pain?
It doesn’t contain the solubilizing agent propylene glycol

Does versed cross the BBB?
yes

What is the bioavailability of oral versed d/t first pass hepatic effect?
50%

True or False: Midazolam’s context sensitive half time is shorter than both diazepam & Lorazepam
True

Why does obesity & elderly age generally increase benzo Vd?
Increased adipose tissue

List the 3 main benzos from this lecture in order of greatest hepatic clearance to least (aka shortest half-life)
1. Midazolam
2. Lorazepam
3. Diazepam

What effect does midazolam have on CMRO2 & CBF?
Decreases both

True or False Midazolam causes a dose dependent decrease in ventilation?
true

True or False: Benzos can depress the swallowing reflex & decrease upper airway activity
True

True or False: Midazolam is effective in preventing the increased BP & HR responses evoked during laryngoscopy
False (Use esmolol, lidocaine, or fentanyl for this purpose)

What is the induction dose of midazolam?
0.1-0.2 mg/kg over 30-60 seconds

What is the induction dose for Diazepam?
0.5-1 mg/kg

What is flumazenil?
Competitive selective benzodiazepine GABA receptor antagonist

What is the dose for flumazenil?
0.1-0.2 mg IV up to 1 mg total (titrate to effect)

What is the infusion range for flumazenil?
0.1-0.4 mg/hr

In what type of situation might the administration of flumazenil precipitate seizure activity?
Chronic benzo use

True or False: Context sensitive half time of benzos increases with increased duration of infusion
True

Why aren’t benzos generally dialyzable?
Because they are highly protein bound

If you gave a normal dose of benzo to a pt with liver failure or kidney failure, what would you expect to happen? why?
Increased effect of the drug & increased side effects d/t decreased protein binding

What are the 3 active metabolites of diazepam?
1. Desmethyldiazepam
2. Oxazepam
3. Temazepam

What would you expect to happen if diazepam & cimetidine were given concomitantly?
Cimetidine causes delayed hepatic metabolism —> increased effect & prolonged elimination half life of diazepam & desmethyldiazepam

True or False: N2O can be safely used without adverse cardiac changes after induction with diazepam
true

True or False: Administration of N2O after opioid induction can cause myocardial depressant activity
True

Are diazepam’s skeletal muscle relaxant effects d/t actions on spinal neurons or actions at the NMJ?
Actions on spinal neurons

True or False: Tolerance to the skeletal muscle relaxant effects of diazepam does not typically occur
False

True or False: Massive OD on benzos generally won’t lead to serious negative outcomes as long as cardiac & pulmonary functions are supported, and other CNS depressants are not present
True

The metabolism of what benzo is *least* likely to be affected by alteration in hepatic function, increasing age, or CYP-450 inhibitors like cimetidine?
Lorazepam

What benzo is the most potent sedative & amnestic?
Lorazepam

Why isn’t lorazepam used for IV induction or sedation for RA?
Slow onset

Lorazepam and Diazepam both contain propylene glycol to increase aqueous solubility. Which one generally causes greater injection site pain?
Diazepam

What are the indications for Anti-Anxiety Benzodiazepines? Reduce anxiety, Induce sedation, Relax Muscles, Inhibit Convulsions, Treat A ETHOL and drug withdrawal symptoms, Safer than Sedative-Hypnotics What are the reactions for the Anti-Anxiety Benzodiazepines? Sedation, Drowsiness, Ataxia, Dizziness, Irritability, Blood dycrasias, …

Lorazepam (Ativan) Mechanism of Action 1/2 Binds to the benzodiazepan receptor and enhances the effects of the brain chemical GABA, an inhibitory transmitter Lorazepam (Ativan) Mechanism of Action 2/2 And may result in a state of sedation, hypnosis, skeletal muscle …

Etomidate: definition, duration of action, complications, patients to use it in Definition: induction agent Duration of action: 5mn Complications: minimal hepatic and renal effects Good for patients with decreased cardiac output; bad for patients less drug binding –> increased unbound …

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Diazepam (Valium) Mechanism of Action 1/3 Binds to the benzodiazepan receptor and enhances the effects of GABA. Diazepam (Valium) Mechanism of Action 2/3 Benzodiazepines act at the level of the Limbic, Thalamic, and Hypothalmic regions of the CNS WE WILL …

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