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77 Cards in this Set
- Front
- Back
What are the 5 principal pharmacologic effects of benzodiazepines?
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1. Sedation
2. Anxiolysis 3. Anticonvulsant actions 4. Spinal cord-mediated skeletal muscle relaxation 5. Anterograde amnesia |
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What percent of the population use benzodiazepines as sleep aids?
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4%
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Benzodiazepines versus barbiturates: tolerance
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Benzodiazepines have less tendency to produce tolerance than barbiturates
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Benzodiazepines versus barbiturates: abuse
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Benzodiazepines have less potential for abuse than barbiturates
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Benzodiazepines versus barbiturates: margin of safety with overdose
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Benzodiazepines have a greater margin of safety after overdose than barbiturates
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Benzodiazepines versus barbiturates: drug interactions
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Benzodiazepines have fewer and less serious drug interactions than barbiturates
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What are the 3 main benzodiazepines?
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1. Diazepam
2. Midazolam 3. Lorazepam |
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What is the chemical structure of benzodiazepines?
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A benzene ring and a 7 member diazepine ring
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What do substitutions on the chemical structure of benzodiazepines affect?
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Potency and biotransformation
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What does the imidazole ring on midazolam contribute to?
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Water solubility at a low pH
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What occurs to midazolam at physiologic pH?
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An intramolecular rearrangement, which changes the physiochemical properties, making it extremely lipid soluble
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What is the mechanism of action of benzodiazepines?
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Facilitation of gamma-aminobutyric acid (GABA)
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What is GABA?
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The principal inhibitory neurotransmitter in the central nervous system
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What is GABA's effect at the receptor?
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1. GABA binds to the receptor, enhancing the opening of chloride channels
2. Increased chloride conductance causes hyperpolarization of the postsynaptic cell membrane 3. Resistance to excitation |
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Where is the highest density of GABA receptors located?
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Cerebral cortex
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Suggested effects of benzodiazepine receptor occupancy at 20%, 30-50%, and >60%
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20% = anxiolysis
30-50% = sedation >60% = unconsciousness |
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What was the original parenteral benzodiazepine?
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Diazepam
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Is diazepam water or lipid soluble and what does this entail?
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Insoluble in water: dissolved in organic solvents for IV use
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What is the most common organic solvent diazepam is dissolved in and what is this associated with?
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Propylene glycol: associated with pain on injection and thrombophlebitis
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What occurs with diazepam administration after PO administration? When are peak plasma levels?
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Rapid absorption from GI tract: peak plasma levels in 60 minutes
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After IV administration of diazepam, what accounts for termination of action?
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Redistribution of drug (from CNS) to inactive tissue depots
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Does diazepam have a low or high volume of distribution and what does this reflect?
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Large volume of distribution: reflecting its high lipid solubility (1-1.5 L/kg)
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Where does extensive uptake of diazepam occur?
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Adipose tissue
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Does diazepam cross the placenta?
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Yes, rapidly crosses the placenta
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Is diazepam protein-bound? How much?
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Extensively protein-bound: >96%
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What is diazepam primarily bound to in plasma?
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Albumin
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What disease states may increase the free fraction of diazepam?
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Cirrhosis or renal failure
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What kind of metabolism does diazepam undergo? Through what pathway?
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Primary hepatic oxidation:
N-demethylation oxidative pathway |
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What are the 2 principal metabolites of diazepam? Are they active or inactive?
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Oxazepam
Desmethyldiazepam (both active) |
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What is the elimination half-time of diazepam?
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21-37 hours
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What occurs to the elimination half-time of diazepam in the presence of cirrhosis? What does this reflect and result in?
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Increased 5 times
Reflects increase in the volume of distribution secondary to decreased protein binding-- decreased hepatic clearance |
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What is the elimination half-time of the active metabolite desmethyldiazepam?
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48-96 hours
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How long may drug clearance take for patients on chronic diazepam therapy?
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May take a week or more to clear all metabolites after discontinuation of therapy
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Where are diazepam metabolites cleared and how?
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Cleared in the urine as conjugates of glucuronic acid
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What drug delays clearance of diazepam and desmethyldiazepam? Why does this occur? What does this result in?
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Cimetidine: inhibition of hepatic microsomal enzymes
Results in an increased elimination half-time (due to reduced clearance) |
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What are 4 clinical uses of diazepam?
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1. Preoperative anxiolysis
2. Treatment of delirium tremens 3. Treatment of local anesthetic induced seizures 4. Skeletal muscle relaxant in treatment of lumbar disc disease |
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What is the maximum drug dose of lidocaine with epinephrine?
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7 mg/kg
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What is the maximum drug dose of lidocaine without epinephrine?
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5 mg/kg
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What is the maximum drug dose of bupivicane (cardiotoxic) with epinephrine?
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3 mcg/kg
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What is the maximum drug dose of bupivicane (cardiotoxic) without epinephrine?
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2 mcg/kg
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What is the most popular benzodiazepine for preoperative anxiolysis or conscious sedation?
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Midazolam
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How potent is midazolam compared to diazepam?
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2-3 times more potent than diazepam
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What pH is the parenteral solution of midazolam buffered to?
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pH = 3.5
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What is the chemical structure of midazolam characterized by?
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A pH dependent ring opening phenomenon
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What pH values does midazolam's imidazole ring remain open at? What does this maintain?
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pH values < 4
Maintains the water solubility of the drug |
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At what pH value does midazolam's imidazole ring close and what does this do to the drug?
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pH values > 4
Converts midazolam into an extremely lipid soluble drug |
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Because of midazolam's water solubility at pH < 4, what does this necessitate, and what does this cause?
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A dissolving agent
Little to no venoirritation or thrombophlebitis |
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What occurs to midazolam after PO administration?
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Rapid absorption from the GI tract
Substantial first pass hepatic elimination-- 50% of dose reaches systemic circulation |
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Is midazolam protein-bound?
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Extensively bound to plasma proteins (>96%)
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What is midazolam's volume of distribution and elimination half-time? Compared to diazepam?
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Large volume of distribution
Relatively short elimination half-time: greater hepatic clearance than diazepam Elimination half-time: 1-4 hours |
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What kind of metabolism does midazolam undergo?
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Extensive hydroxylation by hepatic microsomal enzymes (cytochrome P450)
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How are midazolam's (weakly active) metabolites excreted?
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In the urine as glucuronic conjugates
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Do H2 receptor antagonists interfere with the metabolism of midazolam?
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No
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What 2 drugs decrease cytochrome P450 enzyme activity that may decrease hepatic clearance of midazolam?
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Erythromycin
Calcium channel blockers |
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What are the 5 clinical uses of midazolam?
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1. Preoperative anxiolysis
2. Sedation of pediatric patients 3. Adjunct for MAC cases 4. Induction of GA 5. Continuous infusion for facilitation of mechanical ventilation |
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What is the pediatric dose of midazolam?
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0.5 mg/kg PO
30 minutes prior to induction |
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What is the potency of lorazepam compared to diazepam and midazolam?
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More potent amnestic agent than diazepam or midazolam
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What kind of metabolism does lorazepam undergo?
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Hepatic oxidation
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Does lorazepam have active or inactive metabolites and how are they excreted?
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Inactive metabolites
Excreted in urine as glucuronide conjugates |
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What is the oral dose for lorazepam for preoperative anxiolysis?
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50 mcg/kg
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How long does lorazepam provide anterograde amnesia?
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Up to 6 hours
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What are some other benzodiazepines used to treat insomnia, anxiety, or seizure disorders?
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Oxazepam
Clonazepam Flurazepam Temazepam Triazolam Quazepam Alprazolam |
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How do benzodiazepines affect:
-Cerebral vessels/CBF -CMRO2 |
Cerebral vasoconstriction- reduction in CBF (by 34%)
Reduction in CMRO2 |
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What happens to the CBF to CMRO2 ratio with benzodiazepines?
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Remains normal
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What is the affect of benzodiazepines and seizure activity?
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Potent anticonvulsants: increase seizure threshold to local anesthetics
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What is the affect of benzodiazepines and EEG activity?
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Do not produce burst suppression or an isoelectric EEG
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What do benzodiazepines do to MAC for inhaled anesthetics?
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Reduce MAC
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What is the affect of benzodiazepines on respiration?
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Dose-related central respiratory depression
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Do benzodiazepines cause apnea?
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Possible, but not common
Obstruction more likely |
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What do benzodiazepines have a synergistic effect with?
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Opioids
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What affect do benzodiazepines have on hemodynamics?
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Little to no effect
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What affect do benzodiazepines have on blood pressure?
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May cause slight reduction in BP
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Are homeostatic reflex mechanisms affected by benzodiazepines?
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Homeostatic reflex mechanisms are maintained
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What is flumazenil?
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Specific and exclusive benzodiazepine antagonist
Competitive antagonist: prevents or reverses all benzodiazepine agonist effects |
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What is the dosing for flumazenil?
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Initial: 0.2 mg IV
Additional 0.1 mg IV until desired effect reached |
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What is the duration of action of flumazenil?
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30-60 minutes
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Flumazenil induced benzodiazepine antagonism is NOT associated with what?
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Acute anxiety
Hypertension Tachycardia |