Benzodiazepines Flashcards
What do Benzodiazepines do?
Anxiolysis Sedation Anticonvulsant action Spinal cord mediated skeletal muscle relaxation Anterograde Amnesia
What do we use benzodiazepines for?
Pre-Op sedation
Conscious Sedation
Short Procedures such as regional anesthesia placement
Theoretically can be used for induction of anesthesia
Specific uses
MOA of Benzodiazepines
GABA Molecule
GABAa- pentameric
2 alpha subunits, 2 beta units and 1 gamma
What subunit of benzo causes sedation
alpha-1
5 subunits
What subunit of benzo causes anxiolysis?
Alpha-2
GABA Agonist
binds to GABAa increasing affinity of receptors for GABA
What change opens in GABA channels
Cl, increased frequency of cl channel opening, increased Cl conductance
What occurs with increased Cl conductance
post synaptic membrane hyperpolarization. More resistance to excitation= drug effect we are looking for
Generalizations about Benzos
Highly lipid soluble, protein bound
Higher margin of safety
Fewer/less serious drug interactions (compared to others)
Anticonvulsant, increased seizure threshold in LAST
Depresses swallowing reflex and upper airway activity
synergistic with other CNS depressants
HPA suppression, inhibit platelet aggregation (unsure if clinically relevant)
LAST
Local Anesthetic Systemic Toxicity
Anticonvulsant Characteristics of Benzos
Decreased alpha activity
Increased low voltage rapid beta activity
Unable to produce isoelectric EEG
Benzos in Elderly
Increased sensitivity due to pharmacokinetics, dose dependent
Aging/liver disease effect on glucuronidation
Structure of Midazolam
Substituted imidazole ring makes drug stable in aqueous solution, accounts for rapid metabolism
Water soluble, no preservative, painless injection
Pharmacokinetics of Midazolam (PO)
rapid GI absorption (50% reaches systemic circulation= substantial hepatic first pass)
Hepatic/small intestine metabolism
What enzyme breaks down Midazolam
P450 CYP3A4-> active, inactive metabolites, cleared by kidneys
Midazolam Elimination Time
Elimination 1/2 time 1.9 hours (can be 2x in elderly d/t decreased hepatic BF/Enzyme activity
Midazolam DOA
short (15-80 mins) d/t lipid distribution from brain to inactive tissue sites
Pharmacodynamics of Midazolam (CNS)
decreases CMRO2/CBF
Cerebral vasomotor response to CO2 stays in tact, does NOT prevent increase in ICP with DL, NO neuroprotective qualities
Pharmacodynamics of Midazolam (Respiratory)
DD (0.15 mg/kg) decreases ventilation d/t decreased hypoxic drive
Pharmacodynamics of Midazolam (CV)
decreases SVR (coudn increase CO in CHF) enhanced CV changes with other induction drugs in hypovolemic patients, does not attenuate CV response to DL
MIdazolam IV Dose
1-2.5 mg adults
Midazolam PO Dose
0.5mg/kg q30 mins prior to induction= reliable sedation anxiolysis without delayed wakening
Dose of Midazolam for Paradoxical Vocal Cord Motion Treatment
0.5-1mg
Structure of Diazepam
insoluble in water
must be dissolved in organic solvent such as propylene glycol which causes pain on injection
Lipid emulsion exists which decreases pain but also slightly decreases bioavailability
Pharmacokinetics of Diazepam (PO)
rapid GI absorption crosses placenta (can be equal or greater than maternal)
Two metabolites Diazepam is metabolized into
desmethyldiazepam (elimination 1/2 48-96 hours only slightly less potent then parent drug)
Oxazepam- undergo secondary conjugation to form water soluble glucorinide conjugateives, so if something inhibits oxidative metabolism will have further prolongation of effects
Oxidative pathway of N-desmethylation
metabolism of diazepam
Pharmacodynamics of Diazepam (respiratory)
minima depressant effect
increase PaCO2 not seen until doses reach or exceed 0.2mg/kg
Pharmacodynamics of Diazepam (CV)
transient depression of baroreceptor mediated HR, could theorectically affect hypovolemic patients
no direct action on SNS
Fentanyl given after?- associated with decreased SVR/BP
Uses of Diazepam
treatment of delirium
tremens (severe alcohol withdrawal)
anticonvulsant (0.1mg/kg)
Pharmacokinetics of Lorazepam (metabolism)
conjugated with glucuronic acid in liver makes inactive metabolites then excreted by kidneys
Most potent Benzodiazepine
lorazepam
Pharmacokinetics of Lorazepam (special Characteristics)
not as dependent on liver for metabolism, less issues with age, liver failure, enzyme inhibiting drugs
Slower Clearance d/t
slower hepatic glucoronidation
Compared to Midazolam and Diazepam
Pharmacokinetics of Lorazepam
Slower Onset of Action (1-2mins)
Longer DOA (6-10 h) due to lower lipid solubility/slower entrance into CNS
Reliable PO/IM absorption
PO Pharmacokinetics of Lorazepam
max plasma concentration within 2-4 hours, therapeutic range persists for 24-48 hours
Volume of Distribution PK of Lorazepam
High Vd in Obese= higher elimination 1/2 t
Uses of Lorazepam
limited due to slow onset, long DOA
effective in limiting incidence of emergence reactions s/p ketamine administration
Remimazolam
Organ independent metabolism (carboxylic ester moiety) = rapid degradation= fast recovery
Oxazepam
Active metabolite of diazepam
slow PO absorption
Uses of Oxazepam
insomnia with night wakings, short total sleep time
Alprazolam (Xanax) Uses
primary anxiety, panic attacks,
How Xanax works
inhibition of adrenocorticotrophic hormone/cortisol secretion
Uses of Clonazepam
seizures
uses of flurazepam
insomnia, myoclonic/infantile spasms
+ active metabolite = daytime sleepiness
decreased REM
Use of Temazepam
insonmia
Use of Triazolam
insomnia with difficulty falling asleep
risk of rebound insomnia with DC
Benefits of Ro (investigational)
decreased recovery/time to ambulation post-op/use but did not demonstrate any difference in time to discharge compared to others
Ro (investigational)
similar DOA/onset as otheres, increased plasma clearance
full agonistic activity @ CNS benzodiazepine receptor
Flumazenil
Benzo reversal Agent
Flumazenil Structure
similar to benzo but has carbonyl instead of phenyl group
Efficiency of Flumazenil depends on
amount of free bezno at receptor site
MOA of Flumazenil
competitive antagonist
Use of Flumanzenil
0.2mg (effect within 2 mins)
0.1mg every minute for desired effect
0.3-0.6mg total should abolish sedative effects
0.5-1mg: total should achieve complete reversal
IF you have used 5mg total and still having issues, likely another cause
DOA of Flumazenil
30-60 minutes
be aware could require supplementary doses after this time or low dose infusion (0.1-0.4mg/h) to maintain reversal
C/A of Flumazenil
Benzo reliant patients esp those using for seizures
seizures noted when used in TCA/antidepressant overdose patients
Definition of Benzo
A drug with a chemical structure including benzene and diazepine rings
NOn- benzodiazepine Definition
is a drug with a similar pharmacology but not structure
binds on GABA at same site as benzos
similar effects
increased selectivity for certain GABA subunits= desired effects on sleeping with minimal SE
Examples of Non-Benzo
Zaleplon (Sonata)
Zolpidem (Ambien)
Eszopicalone (Lunesta)
