Benzodiazepines Flashcards
Benzodiazepines
Few interactions
High safety margin
Specific, reversible antagonist
Benzodiazepine MOA
Indirectly activate GABA receptors
5 Principle Pharmacologic Effects
Anxiolysis Sedation & hypnosis Anterograde amnesia Anticonvulsant Spinal cord mediated skeletal muscle relaxation
Midazolam (Versed)
pH 3.5 pKa 6.15
Water-soluble Benzo w/ imidazole ring - rapid metabolism & minimal to no discomfort on injection
Amnestic > sedative effects
Midazolam PK
Metabolism by CYP450 via oxidation Two active metabolites Metabolism slowed by CYP inhibitors Elimination not altered by renal failure Rapid absorption from GI tract and prompt passage to blood-brain barrier Extensively bound to plasma proteins Single dose short action d/t lipid solubility (rapid redistribution) Elimination half-time 1.9hrs Increased Vd in elderly and obese
Midazolam PD
CNS: ↓ CMRO2 ↓ CBF
Cerebral vasomotor responsiveness preserved
Does not prevent ↑ ICP w/ laryngoscopy
No neuroprotective activity
Encephalopathy following withdrawal
Respiratory: Dose dependent (>0.15mg/kg) decrease in ventilation ↓ hypoxic drive, synergistic w/ Fentanyl, depresses swallowing reflex & upper airway activity
Cardiac: 0.2mg/kg produces ↓ BP ↑ HR
CO not altered
Changes d/t SVR
Does not attenuate responses to intubation
Midazolam Dose
Pre-op anxiolysis, amnestic, sedation IV 0.02-0.04mg/kg onset 30-60sec PO 0.4-0.8mg/kg administer 30min prior to induced Post-op sedation 0.5-4mg loading dose Infusion 1-7mg/hr
Midazolam SE
Antegrade amnesia (increased w/ ETOH consumption)
Fatigue & drowsiness more common w/ chronic usage
Meals/antacids may decrease absorption
Strong synergistic effect w/ opioids (respiratory depression)
Dependency after >6mos usage
Aging & liver disease affect glucuronidation
Inhibit platelet-activating factor
Contraindication: Acute porphyrias
Diazepam (Valium)
Highly lipid soluble
Insoluble in water (propylene glycol & sodium benzonate) painful on injection
Diazepam PK
Rapidly absorbed in GI tract
Large Vd - extensive tissue uptake
Extensively protein bound (Albumin)
Cirrhosis & renal insufficiency result in ↑ unbound drug w/ ↑ SE
Metabolism: Hepatic microsomal enzymes using oxidative N-methylation pathway
Desmethyldiazepam & Oxazepam (metabolites)
Elimination half-life prolonged >40hrs
Linear relationship
Diazepam PD
Minimal depressive effects on ventilation
Exaggerated when combined w/ opioids or alcohol
Prolonged ventilation depression in COPD
Minimal decreases in BP/CO/SVR
+ Nitrous oxide associated w/ adverse cardiac changes
+ Fentanyl = ↓ BP/SVR
Diazepam Other Uses
Anticonvulsant
IV 0.1mg/kg
Lorazepam (Ativan)
More potent sedative & amnestic than Midazolam or Diazepam
Slower onset
Insoluble in water (requires propylene glycol)
Lorazepam PK
IV onset 1-2min w/ peak effect 20-30min
Max plasma concentration 2-4hrs after PO admin
Antegrade amnesia up to 6hrs w/ minimal sedation (PO)
Conjugated w/ glucuronic acid in liver
Inactive metabolites
Less likely to be influence by liver function alteration, age, or drugs that inhibit CYP450
Slower metabolic clearance
Sedative effect duration 6-10hrs
Elimination half-time 14hrs
Lorazepam Clinical App
Economic alternative
Delayed emergence
Amnestic effects last several days
Delay weaning from ventilator
