Test 1: Benzodiazepines Flashcards
Which Benzos are associated with pain on injection?
Diazepam and lorazepam are lipophilic and are traditionally formulated in propylene glycol because they are not soluble in water. These formulations are associated with pain on injection.
Why does Midazolam NOT cause pain on injection?
The imidazole ring of midazolam allows the preparation of acidic aqueous solutions, which cause minimal pain on injection.
-Does not require a lipoidal vehicle (such as propylene glycol) for parenteral use
-Once in a physiologic solution with a pH > 4.0, the ring CLOSES and midazolam becomes lipophilic, and can gain rapid access to the CNS.
What GABA A receptor subunits do Benzos act on?
Benzodiazepines are thought to interact with GABAA receptors between the α and γ subunits. The binding pocket appears to be at the interface of the α and γ2 subunits in receptors containing α1, α2, α3, or α5 subunits.
What do the α1 subunits mediate with Benzos?
α1-containing subunits are important mediators of the sedative, amnestic, and anticonvulsive effects of benzodiazepines.
What do the α2 subunits mediate with Benzos?
α2-containing receptors play an important role in anxiolysis, anti-hyperalgesia, and centrally mediated muscle relaxation.
What are the Active Properties of Benzodiazepines?
-Anxiolytic
-Sedative
-Hypnotic
-Amnestic (Anterograde: Valium & Versed; Retrograde ?)
-Anticonvulsant
-Centrally mediated muscle relaxation
What is important to know regarding anesthetic use of Versed?
-Premedication is the primary use for Versed.
-Combining Versed with another induction agent offers improved increased hemodynamic stability without affecting emergence
-High Induction doses of Versed delay emergence (unless surgery is of prolonged duration)
What is the MOA of Benzos?
Benzodiazepines act on a subset of GABAA receptors containing γ subunits to potentiate chloride conductance upon GABA binding.
-Allosterically increase GABAA’s affinity for GABA (!!)
-Modulatory effect: Increases the polarization of the nerve cell and Decreases the nerve cell’s ability to respond to an impulse/signal.
-Increases the FREQUENCY of chloride channel opening, which results in postsynaptic membrane hyperpolarization, and neuronal transmission is inhibited.
-Enhances the inhibitory effects of GABA
What is the “ceiling effect” associated with Benzos?
Benzodiazepines act on a subset of GABAA receptors containing γ subunits to potentiate chloride conductance upon GABA binding.
-Benzos work allosterically to enhance endogenous GABA binding, they do not work directly.
-This modulatory mode of action is postulated to create a “ceiling effect” that limits CNS depression, although when combined with other drugs, benzodiazepines can lead to dangerous respiratory depression.
-Lower doses = anxiolysis
-Higher doses = sedation
-Considered to be safer and lower toxicity due to built-in limit on their effect.
-Midazolam shown to be unable to produce an isoelectric EEG.
Why is there a concern for “stacking” doses of Midazolam?
Intravenous midazolam does not reach peak effect site concentration until nearly 10 minutes after administration. When titrating midazolam, one must therefore be patient to avoid “stacking” the doses and oversedating the patient.
What are the Pharmacokinetics associated with Diazepam (Valium)?
-Onset of Action = almost immediate (fast onset, almost 100% bioavailable)
-PO dose is more reliable than IM
-Duration of Action = 20-30 minutes
-90-98% protein bound
-Metabolism = hepatic and enterohepatic (CYP)
-Active metabolite = Desmethylmedazolam to Nordiazepam to Oxazepam
-Secondary peak in plasma concentrations 6-12 hours later
-1/2 life = 30-50 hours (1/2 life = the patient’s age in years)
What is the premed dose of Diazepam?
Administer 60-90 minutes prior to procedure
Adult:
-PO 2-10 mg
-IV 5-7.5 mg
Child:
-PO 0.2 - 0.3 mg/kg up to 10 mg
-IV 0.04 - 0.3 mg/kg
What are the contraindications for the use of Diazepam?
-Interactions with erythromycin and anti-fungals
-Elderly (POCD)
-Acute Porphyrias
-Risk for unexpected respiratory depression and oversedation
What are the Pharmacokinetics associated with Midazolam (Versed)?
Onset of action:
-IV 1-5 minutes to around 10 minutes
-IM 15 minutes (peaks at 30 min)
-PO 10 min (peaks at 20-30 min)
-45% bioavailable
-Duration of action = 2 hours (IM can be up to 6 hrs)
-95% protein bound
-Metabolism: Extensive hepatic via CYP, high hepatic extraction ratio
-Active metabolite = 1-hydroxymidazolam
-Half-life = 1-4 hours
What is the premedication dose of Midazolam?
Adult: 0.5 - 2.0 mg, up to 5 mg
Children:
-PO 0.25 - 0.5 mg/kg up to 20 mg
-IV < 6 years 0.05 - 0.1 mg/kg
-IV > 6 years dose as adults
What are the contraindications for the use of Midazolam?
-Pregnancy
-Interactions with erythromycin and anti-fungals
-Elderly
Why do you avoid Benzo use in the elderly?
Elderly have:
-Increased adipose tissue in body mass
-Decreased plasma proteins
-Decreased hepatic blood flow
-Decreased metabolism
-Decreased CO
-Decreased circulation time (slower onset and higher plasma drug level that remains in the CNS longer before it redistributes)
Expect slowed absorption, increased DOA, and exaggerated effects of the drug.
-Also, benzos are associated with development of delirium
What are the neuro effects of Benzos?
Dose-dependent CNS depressant effects of the benzodiazepines, from anxiolysis to sedation, sleep, and with high enough doses, anesthesia.
-Dose related decrease in CBF, CMRO2 & ICP
-OK for Neuro cases
-Anticonvulsant activity (increases the seizure threshold)
-Anxiolysis, sedation, and anterograde amnesia
-Centrally mediated muscle relaxation
-Does not produce isoelectric EEG
What are the CV effects associated with Benzos?
-Hemodynamic effects are dose related
-Decrease in ABP, CO, and PVR with high (induction doses) or repeated doses
-Occasional dec in BP with Midazolam + opioids in patients with Heart Dz or elderly
What are the Respiratory effects associated with Benzos?
-Dose-dependent decrease in the central respiratory system
-Greatest and longest with Midazolam (Do NOT leave the patient unattended after Versed administration!)
-Depression of airway muscle reflexes and tone (Caution in OSA, can cause patients to obstruct/obtund)
-Potent synergism with opioids = respiratory depression & apnea
What other misc side effects are associated with Benzos?
-Pain on injection (NOT midazolam)
-Depressed cellular immunity
What is important to know with Benzos and Renal Failure?
Benzos are renally excreted. Use caution in renal patients.
-Metabolites can prolong DOA if not being excreted.
What is Flumazenil (Romazicon)?
A competitive benzodiazepine antagonist.
-Inhibits the activity at the Benzo recognition site of the GABAA Receptor.
-Chemically similar to Benzos, with the absence of a phenyl group that is replaced by a carboxyl group.
-RAPID REVERSAL OF CNS EFFECTS
-Short acting, possibility of resedation
What are the new theories of the MOA of Flumazenil (Romazicon)?
-May have partial or mixed effects on the GABAA receptor in the absence of benzos (has anticonvulsant properties)
-High doses can potentiate hypnosis caused by other GABAA agonists (such as Propofol)
What are the Pharmacokinetics of Flumazenil (Romazicon)?
-Onset: 1-2 minutes
-54-64% protein bound
-Metabolism: Liver
-1/2 life: 41 - 79 minutes (short acting: possibility of resedation)
What is the dose of Flumazenil (Romazicon)?
-IV 0.2 mg up to 1 mg total, titrate to desired level of consciousness
->0.6mg indicates that the patient has an additional issue
What are the effects of Flumazenil administration?
-Reverses respiratory depression from Benzos
-Reverses anticonvulsant effects (Proconvulsant = risk of seizure)
-N&V, agitation, confusion, dizziness
-Document a 2 hour stay in the PACU/Recovery room after administration to guard against resedation
-Careful monitoring up to 120 minutes after admin
What are contraindications to the use of Flumazenil?
-Long term Benzo use = withdrawal reaction
-Patients with tricyclic and antidepressant OD = seizures
-Patients with history of seizures (avoid, pro-convulsant)
What are the effects associated with Flumazenil overdose?
Anxiety, agitation, convulsions
What is the induction dose of Diazepam? (Katzung)
0.3 - 0.6 mg/kg IV
What is the DOA of Diazepam? (Katzung)
15-30 min
What is the induction dose of Midazolam? (Katzung)
0.1 - 0.3 mg/kg IV
What is the DOA of Midazolam? (Katzung)
15 - 20 min
