benzo

Benzodiazepines

Overview

Midazolam, Diazepam, and Lorazepam are three commonly used benzodiazepines in anesthesia
o All have a relatively low molecular weight and are lipid soluble
o As a result of their lipid solubility, they have rapid CNS effects and large V_d
o Midazolam is the most lipid soluble
o They can be classified as short-acting (Midazolam), intermediate-acting (Lorazepam), and long-acting (Diazepam) according to their metabolism and plasma clearance
Midazolam has pH dependent solubility and is therefore formulated in an acidic solution so that it is water soluble for injection, but becomes lipid soluble once exposed to plasma
Benzodiazepines produce reliable anxiolysis and anterograde amnesia, which makes them excellent choices for anesthesia premedication
o All benzodiazepines have hypnotic, sedative, amnestic, anxiolytic, and anticonvulsant properties, and cause centrally mediated muscle relaxation
Benzodiazepines can be used for sedation, or the induction and maintenance of anesthesia
o Most commonly used as premedication
Major side effects include
o Respiratory depression
o Tolerance
o Small decrease in blood pressure
o Lorazepam and Diazepam may cause thrombophlebitis
o Prolonged amnesia

Pharmacokinetics

The pharmacokinetic profile of the benzodiazepines is best described using a two or three compartment model
Important Pharmacokinetic Variables
o Midazolam
§ Vd_ss = 1.1-1.7 L/kg
§ Clearance = 6-11 mL/kg/min
§ Alpha Elimination Half-life = 7-15 min
§ Beta Elimination Half-life = 1.7-2.6 hours
§ 94% protein bound
o Diazepam
§ Vd_ss = 0.7-1.7 L/kg
§ Clearance = 0.2-0.5 mL/kg/min
§ Alpha Elimination Half-life = 10-15 min
§ Beta Elimination Half-life = 20-50 hours
§ 98% protein bound
o Lorazepam
§ Vd_ss = 0.8-1.3 L/kg
§ Clearance = 0.8-1.8 mL/kg/min
§ Alpha Elimination Half-life = 3-10 min
§ Beta Elimination Half-life = 11-22 hours
§ 98% protein bound
Metabolism
o metabolized by the liver via two pathways
§ hepatic microsomal oxidation ® Midazolam is rapidly oxidized, which accounts for its greater hepatic clearance compared to diazepam.
§ glucuronide conjugation
o Metabolites
§ Diazepam has two metabolites, which prolong the drug's effects
§ Midazolam forms hydroxymidazolams, which are active and can accumulate with repeated dosing
the metabolites are rapidly conjugated and excreted in the urine - HOWEVER, patients with renal failure can retain a-hydroxymidazolam, leading to prolonged sedation
patients with normal hepatic and renal function clear the metabolites faster than midazolam
§ Lorazepam has five metabolites ® principal metabolite is conjugated to glucuronide, and is inactive, water-soluble, and rapidly excreted renally
Onset and duration of action of a bolus IV administration depends upon lipid solubility of each drug
o Midazolam has a more rapid onset (30-60 sec) and shorter duration of action than Lorazepam (onset of 60-120 sec) due to Midazolam's increased lipid solubility as compared to Lorazepam
o Redistribution from the CNS to lean body mass accounts for most of the termination of action of all three benzodiazepines when a single bolus is given. HOWEVER, after a prolonged, continuous infusion or multiple doses, Midazolam will clear faster due to its faster hepatic clearance (it has a shorter context-sensitive half-time regardless of infusion duration as compared to the other benzodiazepines)
Factors affecting Pharmacokinetics
o age, gender, race, enzyme induction, hepatic and renal disease
o The elderly are particulary sensitive to Diazepam, as increasing age decreases its clearance. Age also affects the clearance of Midazolam, but to a lesser degree
o Lorazepam seems to be resistant to the effects of age, gender and renal disease
o Obesity increases the V_d of these drugs since the benzodiazepines are quite lipophilic. As a result, the elimination half-times are increased (return of drug to the plasma is delayed)

Pharmacodynamics

CNS
o Classified as GABA_A receptor agonists
§ The benzodiazepines alter the conformation of the GABA_Areceptor so that GABA binds with increased affinity, resulting in opening of the Cl^- channel and neuron hyperpolarization
o They have high affinity for the benzodiazepine receptor (subunit of the GABA_A receptor):
§ Order of receptor affinity ® lorazepam > midazolam > diazepam
o Effects (anxiolysis, sedation, unconsciousness) depend upon drug level:
§ <20% occupancy of the benzodiazepine receptor by agonist results in anxiolysis
§ 30-50% occupancy results in sedation
§ >60% results in unconciousness
o Long-term use of BDZs produces tolerance. Beware, if a patient takes a BDZ at home, the patient will have an increased dose requirement for anesthesia
o Effects on Cerebral Metabolism
§ dose-related decrease in cerebral metabolic O₂ consumption rate (CRMO₂) and the CBF
§ Midazolam and diazepam maintain normal ratio of CBF to CRMO₂
o Midazolam, diazepam, and lorazepam increase seizure threshold (anticonvulsant)
o NO antiemetic effects
Respiratory system
o Dose-related central respiratory depression
o Slopes of the ventilatory response curves to CO₂ are flatter than controls, but they are not shifted to the right, as with opioids. In other words, the response to CO₂ is diminished, but the CO₂ threshold for triggering ventilation is not changed.
o Peak onset of ventilatory depression with midazolam is about 3 min., and significant depression remains for 60-120 min.
o In patients with COPD, respiratory depression is more severe and of longer duration
o BDZs and opioids produce additive or even synergistic respiratory depression
§ BDZs produce dose-dependent apnea (20% incidence with Midazolam) - apnea more likely with co-administration of opioids
Cardiovascular system
o Prominent hemodynamic change is a small reduction in MAP, due to a decrease in SVR
o Hemodynamics remain relatively stable since homeostatic reflex mechanisms are preserved (although the baroreflex may be impaired by midazolam and diazepam, such that the HR does not increase with a decrease in BP)
o Hemodynamic effects of midazolam and diazepam are dose-related at lower doses, but the effects plateau at high doses
o HR, ventricular filling pressures, and CO are maintained after induction with BDZs
o Synergistic hemodynamic effects with opioids (greater decrease in BP than with each drug alone) ® synergism is likely related to a reduction in sympathetic tone when the drugs are given together

Uses

Advantages: amnesia, anxiolysis, and hemodynamic stability
Disadvantage, as compared to propofol, is longer time to recovery after prolonged infusion
Sedation
o Can be used as preoperative premedication, intraoperatively during regional or local anesthesia, or postoperatively
o Good drugs for conscious sedation due to degree of sedation, reliable amnesia and relative lack of respiratory and cardiovascular depression.
o Onset of action most rapid with midazolam, with the peak effect within 2-3 min.
o There is often a disparity between the level of sedation and amnesia, with patients seemingly coherent and awake, but are amnestic for events or instructions
o Longer term sedation can be achieved with these drugs (i.e. ICU patients). HOWEVER, BDZs tend to accumulate (metabolite of midazolam also accumulates). Accumulation of drug results in a longer time to recovery after termination of an infusion.
o Recent studies indicate that midazolam may be used for maternal sedation
§ Only 0.005% of maternal dose reaches breast milk
o Oral formulation of midazolam is available (0.5 mg/kg), and provides reliable amnesia within 10 min. and effectively sedates children for induction
Induction of anesthesia
o Midazolam is the BDZ of choice
o Amnesia is more reliable (lasts about 1-2 hours), but induction and emergence are less rapid than with thiopental or propofol
o Rapidity of action depends upon several factors:
§ Dose, speed of injection, degree of premedication, age (elderly require smaller doses), ASA status, and concurrent anesthetic drugs
§ Induction of anesthesia occurs in 28 sec in adequately premedicated, healthy patients
§ Patients >55 yo, and ASA physical status >III need 20% less midazolam for induction
o With induction dose of 0.15 mg/kg, awakening occurs in healthy patients in approximately 17 min.
Maintenance of anesthesia
o BDZs provide hypnosis and amnesia, but lack analgesia, so they must be used with analgesic drugs during maintenance
o Midazolam infusions reduce opioid requirements
o MAC is reduced with midazolam
o BEWARE: Midazolam, diazepam, and lorazepam accumulate in the blood with repeated boluses and continuous infusions, resulting in prolonged arousal time (less of a problem with midazolam than with diazepam or lorazepam due to the greater clearance of midazolam)
Dosing for Various Uses
o Induction
§ Midazolam 0.05-0.15 mg/kg
§ Diazepam 0.3-0.5 mg/kg
§ Lorazepam 0.1 mg/kg
o Maintenance
§ Midazolam 0.05 mg/kg prn (1 mg/kg/min)
§ Diazepam 0.1 mg/kg prn
§ Lorazepam 0.02 mg/kg prn
o Sedation
§ Midazolam 0.5-1 mg repeated
§ Diazepam 2 mg repeated
§ Lorazepam 0.25 mg repeated

Side Effects/Contraindications

Most significant problem with midazolam is respiratory depression
BDZs cause relatively little change in hemodynamics
Lorazepam and Diazepam cause, in addition to respiratory depression, venous irritation and thrombophlebitis, due to solvents used in their formulation (both are highly water insoluble)
Amnesia may be prolonged, despite a lack of sedation!

Otherwise, the BDZs are very well tolerated

Anesthesiology Rotation & Elective