Benzos and Barbs Flashcards
Do benzos potentiate the neuromuscular blockade?
Nope
Do benzos induce hepatic enzymes?
Nope
We’re having fun now, aren’t we? Riiiiiight?!?
Nope
Benzodiazepine structure?
Benzene ring fused with 7-member diazepine ring
Benzodiazepine MOA
Facilitate action of GABA and GABA-A receptor, enhance affinity of GABA to the receptor
(but DOES NOT activate GABA-A receptor)
This leads to Cl channels open, inc conductance, hyperpolarization of post-synaptic membrane, increased resistance of post-synaptic membrane to excitation
Benzos are highly _____ (water/lipid) soluble and _____ (high/low) protein binding
Lipid soluble
High PB
Structure of midazolam (versed)?
Water soluble preparation Imidazole ring (same compound that etomidate has)
How does potency of midazolam compare to diazepam?
Midazolam is 2-3x more potent than diazepam
Midazolam metabolism?
Extensive hepatic metabolism
ACTIVE METABOLITE: 1-hydroxy-midazolam
Conjugated and excreted in the urine
Renal failure doesn’t effect VD, E1/2t, or clearance
Midazolam CNS effects?
Decreases CBF and CMRO2
Does NOT attenuate ICP response to laryngoscopy
Anticonvulsant and amnestic
Midazolam respiratory effects?
Decrease in ventilation
Hypoxemia and hypoventilation enhanced in presence of opioid
Depress swallow reflex
Midazolam CV effects?
Cardio stable; CO unchanged
Dec SVR at induction dosage
Dec BP from anxiolysis
Doesn’t attenuate laryngoscopy HR/BP changes
Dosage of midazolam for…
Premedication peds
IV sedation adults
Induction
Premed peds: 0.25-0.5 mg/kg po (not on drug cards)
Peds po dose max 20mg
IV sedation adults (premedication): 0.5-5 mg IV or 0.04-0.08 mg/kg
Induction: 0.05-0.35 mg/kg over 30-60 sec
*Per drug cards, not powerpoint
Diazepam is prepared in what solvents?
Propylene glycol
Benzyl alcohol
Painful IV/IM injection
Diazepam metabolism?
Oxidation, n-demethylation to desmethyldiazepam (ACTIVE METABOLITE) which is oxidized, conjugated, and excreted in the urine
Diazepam E1/2t?
Diazepam is a day (21-37h) with prolonged DOA
Desmethyldiazepam is 2-4 days!
Diazepam dosages for… premedication oral and IV; induction; anticonvulsant?
Premedication oral: 10-15mg
Premedication IV: 0.2 mg/kg (reduces MAC)
Induction: 0.5-1 mg/kg IV
Anticonvulsant: 0.1 mg/kg IV
Which benzodiazepine is most potent?
Lorazepam (ativan)
It is 5-10x more potent than diazepam
Lorazepam metabolism and e1/2t?
Metabolites are INACTIVE
Metabolism effected by hepatic function and age
E1/2t 10-20h
Slow onset, IV takes 20-30 min to peak, not used as often in OR
Lorazepam solvent?
Propylene glycol
Lorazepam premedication/po dosage?
50 MCG/kg (max 4 mg)
What is the reversal for benzodiazepines?
Flumazenil (Romazicon)
Specific, competitive benzo antagonist with high affinity for benzo receptors
What is flumazenil (romazicon) a derivative of?
Imidazobenzodiazepine
Flumazenil DOA? Metabolism?
30-60 min, meaning you may need to redose
Hepatic metabolism, renal excretion
Flumazenil (romazicon) dose?
0.2 mg IV, wait 2 min, 0.1 mg IV subsequent doses at 60 sec intervals to max total 3 mg
Infusion: 0.1-0.4 mg/h
Flumazenil antagonizes what effects of benzos?
Antagonizes depression of ventilation and sedation
Benzodiazepines 5 pharmacological effects?
Anxiolysis Asleep (sedation) Anterograde Amnesia Anticonvulsant Muscle Relaxation- spinal
What is the order of benzos from least to most potent?
DiVA
Diazepam, versed, ativan
Etomidate and midazolam have an imidazole compound that makes the drug ____ soluble at an acidic pH and ____ soluble at physiologic pH (water/lipid soluble)
Water soluble at an acidic pH
Lipid soluble at physiologic pH
Barbiturates are ____ (acidic/alkaline) drugs, but when prepared in ____ solution, they are weak ___
They are acidic drugs
Prepared in highly alkaline solution (bacteriostatic)
Actually are weak acids, not bases
All barbiturates are derived from what?
Barbituric acid urea and malonic acid
Barbiturates with branched substitutes at carbon #5 increases ____ activity
Barbiturates with phenyl group at carbon #5 increases ____ activity
Branched chain at 5 increases HYPNOTIC activity
Phenyl group at 5 increases ANTICONVULSANT activity (phenobarbital)
Methyl radical on a barbiurates imparts what activity (methohexital)
CONVULSANT activity
Sulfuration increases what?
Sulfuration: fat soluble
As lipid solubility increases, shorter duration, more rapid onset, and increased potency
What is more potent, a long branched chain or a straight chain? Levo-isomers or dextro-isomers?
Long branched chain is more potent
Levo-isomers are twice as potent as dextro-isomers
Barbiturate MOA?
Decreases rate that GABA dissociates from receptor (increases duration of GABA), Cl channel opens, decreased postsynaptic sensitive to Ach, some muscle relaxation
Mimics GABA at receptor DIRECTLY
Decreases trasmission in the sympathetic ganglia leading to hypotension
Depresses RAS -> sleep
Barbiturate pharmacokinetics?
Rapid onset Redistribution is rapid, terminates effect Extensive metabolism Highly protein bound Ionization of TPL: pK is 7.6
Oxybarbiturates have a oxygen at carbon #___, has what metabolism?
Thiobarbiturate has a ____ at carbon #2, has what metabolism?
Oxy: O2 at carbon #2, hepatic metabolism only
Thio: Sulfur at carbon #2, hepatic and extra hepatic (GI) metabolism
Barbiturate metabolism?
Side chain oxidation at carbon 5 to carboxylic acid terminates pharmacologic activity
Desulfuration, hydrolysis opens ring to water soluble compounds
Renal excretion
E1/2t in TPL vs methohexital?
TPL 11.6h
Prolonged in pregnancy due to increased protein binding
Methohexital 3.9h
Barbiturate CNS effects?
Depress LOC Cerebral vasoconstriction, dec CBF, ICP, CMRO2, IOP Can produce isoelectric EEG (coma) Paradoxical excitement Methohexital: myoclonus and hiccups Does NOT interfere with SSEP monitoring
Barbiturate CV effects?
Depression of medullary vasomotor center and decreased SNS outflow, peripheral vasodilation (dec afterload), dec preload
Dec SBP -> compensatory HR increase
Minimal myocardial depression (more depression if SNS not intact, hypovolemia, or large doses)
Histamine release with rapid IV admin (more hypotension)
Barbiturate respiratory effects?
Depression of medullary and pontine ventilatory centers, decrease response to hypoxia and hypercapnia
APNEA
Incomplete depression laryngeal and cough reflexes (laryngospasm, bronchospasm)
Are barbiturates hepatic enzyme inducers?
YES, phenobarb is the most potent inducer
As a hepatic inducer, barbiturates increase metabolism of what drugs?
Oral anticoagulants Phenytoin TCAs Corticosteroids Vit K Muscle relaxants? Look up.
Why is tolerance an issue with barbs?
As good enzyme inducers, they metabolize themselves well, tolerance builds, they need more drug for more effect,
Other side effects not mentioned yet of barbs?
Venous thrombosis
Crosses placenta
N/V
Accelerated production of heme by stimulation of an enzyme, D-aminolevulinic acid synthetase (caution in porphyria)
Induction of GA dosages for TPL and methohexital?
TPL 3-5 mg/kg IV (dec dose for elderly and first trimester pregnancy, inc dose for kids)
Methohexital 1-2 mg/kg IV or 20-30 mg/kg po in peds
Duration 5-8 min (that’s when it redistributes)
Barb interactions?
Opioids, catecholemines, NMBs, midazolam (these are acidic): pancuronium, vecuronium, atracurium, alfentanil, sufentanil, midazolam
LR solution is too acidic (precipitates)
What happens if barbs are given intra-arterially? Treatment?
IMMEDIATE, intense vasoconstriction and pain
Mechanism: crystalline precipitation in artery, inflammatory response, vasoconstriction, microembolization (loss of limb is possible!)
Treatment: Dilute with NS, phenoxybenzamine, prevent thrombosis (heparin), brachial plexus block, papaverine 40-80mg or lidocaine
What is porphyrin a precursor to?
Heme, which is a component of hemoglobin, myoglobin, catalase, peroxidase, respiratory and P450 liver cytochromes
What is porphyria?
Attacks precipitated by events that decrease heme concentration (drugs, hormones, fasting, stress)
Autosomal dominant, linked to chromosome 11
S/S of porphyria attack?
Severe abd pain, diarrhea, vomiting, ANS instability (tachycardia, HTN), electrolyte disturbances, seizure, resp failure, skeletal muscle weakness, neuropsychiatric disturbances
Drugs to avoid giving people with porphyria?
Barbs Etomidate Diazepam Sulfonamide antibiotic Phenytoin Alcohol Nifedipine Ketorolac
