Benzodiazepines, Pharm Ii

Front 1

Benzodiazepines exert 5 prinicipal pharmacologic effects, what are they?

Back 1

1. Sedation
2. Anxiolysis
3. Anticonvulsant actions
4. Spinal cord mediated skeletal muscle relaxation
5. Anterograde amnesia

Front 2

What % of the population uses benzodiazepines for sleep aids?

Back 2

4%

Front 3

When comparing benzo's to barb's, what is different (4)?

Back 3

1. Less tendency to produce tolerance
2. Less potential for abuse
3. Greater margin of safety after overdose
4. Fewer and less serious drug interactions

Front 4

Name 3 benzodiazepines

Back 4

1. Diazepam
2. Midazolam
3. Lorazepam

Front 5

All benzodiazepines consist of what two structures?

Back 5

Benzene ring and a seven member diazepine ring

Front 6

What do substitutions at various portions on these rings affect?

Back 6

Potency and biotransformation

Front 7

What is special about midazolam?

Back 7

the imidazole ring contributes to its water solubility at low pH

Front 8

What happens at physiologic pH with midazolam?

Back 8

an intramolecular rearrangement occurs which changes the physiochemical properties, making it extremely lipid soluble (rendering it to rapid metabolism)

Front 9

What is the mechanism of action of benzo's?

Back 9

facilitation of gamma-aminobutyric acid (GABA)

Front 10

What is the principal inhibitory neurotransmitter in the CNS?

Back 10

GABA

Front 11

How specifically does GABA work?

Back 11

it binds to the receptor- enhanced opening of chloride channels-increased chloride conductance-hyperpolarization of the postsynaptic cell membrane-resistance to excitation

Front 12

Where is the highest density of GABA receptors?

Back 12

in the cerebral cortex

Front 13

Where else are GABA receptors found?

Back 13

hypothalamus, cerebellum, midbrain, hippocampus, medulla and spinal cord

Front 14

What is the suggested benzo receptor occupancy for, anxiolysis, sedation and unconsciousness?

Back 14

20%- Anxiolysis
30-50%- Sedation
>60%- Unconsciousness

Front 15

Diazepam is _____ in water.

Back 15

insoluble

Front 16

Since diazepam is insoluble in water, how can it be administered IV?

Back 16

it is dissolved in organic solvents

Front 17

Which drug was the original parenteral benzo?

Back 17

diazepam

Front 18

What organic solvent is most likely used with diazepam? and it is associated with?

Back 18

propylene gylcol, pain on injection and thrombophlebitis

Front 19

Describe the pharmacokinetics of diazepam, when given orally. Peak plasma levels within?

Back 19

Undergoes rapid absorption from the GI tract following oral administration, in 60 minutes in adults

Front 20

When administered IV, diazepam's action is terminated from the result of?

Back 20

redistribution to inactive tissue depots

Front 21

Does diazepam have a large or small volume of distribution? and why?

Back 21

large, high lipid solubility (1-1.5L/kg)
-extensive uptake into adipose tissue
-rapidly crosses the placenta

Front 22

Diazepam is also highly ______ _____.

Back 22

protein bound, >96%

Front 23

Diazepam is primarly bound to?

Back 23

albumin in the plasma

Front 24

What may increase the free fraction of the drug?why?

Back 24

cirrhosis or renal failure
Cirrhosis: less binding d/t less protein
Renal failure: uremic plasma-compete for binding

Front 25

What type of metabolism does diazepam undergo? via?

Back 25

primary hepatic oxidation via the N-demethylation oxidative pathway (P450)

Front 26

What are the two principal metabolites from diazepam?

Back 26

oxazepam and desmethyldiazepam

Front 27

What is the elimination half-life of diazepam?

Back 27

21-37 hours

Front 28

What type of variables affect elimination half-life?

Back 28

1. Directly proportional to volume of distribution
2. Inversely proportional to rate of clearance

Front 29

In cirrhosis, the elimination half-life may be increased by how much? and why?

Back 29

5x, reflects increase in the volume of distribution secondary to decreased protein binding and decreased hepatic clearance

Front 30

What is the elimiation half-life of desmethyldiazepam?

Back 30

48-96 hours

Front 31

What three things affect volume of distribution?

Back 31

1. Lipid solubility
2. Protein binding
3. Ionized or nonionized

Front 32

Patients on chronic diazepam therapy, the metabolites may take how long to clear after discontinuation of therapy?

Back 32

a week or more

Front 33

What drug delays the hepatic clearance of both diazepam and desmethyldiazepam?

Back 33

Cimetidine, inhibition of hepatic microsomal enzymes (P450)

Front 34

Does Cimetidine increase or decrease elimination half-life of diazepam?

Back 34

increase

Front 35

WHat are clinical uses for diazepam?

Back 35

Preoperative anxiolysis, treatment of delerium tremens (DT's), treatment of local anesthetic induced seizures, skeletal muscle relaxant in treatment of lumbar disc disease

Front 36

Midazolam is how many times more potent that diazepam?

Back 36

2-3 times more potent

Front 37

The parenteral solution of midazolam is buffered to what pH?

Back 37

3.5

Front 38

How is midazolam described structurally?

Back 38

by a pH dependant ring opening phenomenon

Front 39

The imidazole ring remains open at pH values of? This maintains?

Back 39

<4, water solubility of the drug

Front 40

What happens at pH values >4 for midazolam?

Back 40

the ring closes, converts midazolam into an extremely lipid soluble drug

Front 41

What does the water solubility at pH <4 obviate the need for?

Back 41

a dissolving agent, little to no venoirritation or thrombophlebitis

Front 42

After oral administration of midazolam, it undergoes?

Back 42

rapid absorption from the GI tract, substantial first pass hepatic extraction (only 50% of dose reaches systemic circ)

Front 43

Is midazolam bound to plasma proteins?

Back 43

yes, extensively (>96%)

Front 44

Midazolam has a ____ volume of distribution.

Back 44

large

Front 45

Midazolam has a relatively ____ elimination half-life.

Back 45

short

Front 46

What is the elimination half-life for midazolam? Why is it shorter than diazepam?

Back 46

1-4 hours, greater hepatic clearance

Front 47

Midazolam undergoes extensive _________ by hepatic microsomal enzymes.

Back 47

hydroxylation
-cytochrome P450

Front 48

What receptor antagonists do not interfere with the metabolism of midazolam?

Back 48

H2 antagonists

Front 49

What other drugs that decrease the cytochrome P450 enzyme activity decrease hepatic clearance of midazolam?

Back 49

Erythromycin
Calcium channel blockers

Front 50

What are the most common clinical uses of midazolam?

Back 50

preoperative anxiolysis, sedation of pediatric patients, adjunct for MAC cases

Front 51

What is the pediatric does of midazolam 30 minutes prior to induction?

Back 51

0.5mg/kg po

Front 52

What are other uses does midazolam have?

Back 52

continuous infusion for facilitation of mechanical ventilation

Front 53

T or F. Lorazepam is a more potent amnestic agent than diazepam or midazolam.

Back 53

True

Front 54

Lorazepam undergoes _______ oxidation with ______ metabolites excreted in the ______ as ______ ______.

Back 54

hepatic, inactive, glucuronide conjugates

Front 55

Lorazepam causes anterograde amnesia for up to _____ hours?

Back 55

6

Front 56

What are the most common uses of lorazepam?

Back 56

insomnia, anxiety, or seizure disorders

Front 57

Benzodiazepines and effects on the CNS

Back 57

1. Cerebral vasoconstriction- reduction in CBF (up to 34%)
2. Reduction in CRMO2
-ratio of CBF to CMRO2 remains normal
3. Potent anticonvulsants
4. Do not produce burst suppression or an isoelectric EEG
5. Reduce MAC for inhaled anesthetics

Front 58

Benzodiazepines increase the seizure threshold with?

Back 58

local anesthetics

Front 59

Benzodiazepines and effects on respiratory system

Back 59

1. Dose related central respiratory depression
-apnea is possible but not common
-airway obstruction occurs
2. Synergistic effect when used concurrenlty with opioids

Front 60

Benzodiazepines and effects on cardiovascular

Back 60

1. Slight reduction in arterial blood pressure (when used alone produce little to no hemodynamic effects)
2. Homeostatic reflex mechanisms are maintained

Front 61

Flumazenil

Back 61

specific and exclusive benzodiazepine antagonist

Front 62

Flumazenil is what type of antagonist?

Back 62

competitive, prevents or reverses all benzodiazepine agonist effects

Front 63

Flumazenil dosing

Back 63

initial dose: 0.2mg IV
additional dose: 0.1mg IV until desired endpoint met

Front 64

What is the duration of action of flumazenil?

Back 64

30-60 minutes

Front 65

Flumazenil induced benzodiazepine antagonism is NOT associated with?

Back 65

Acute anxiety, hypertension, tachycardia