Benzos and Barbs Flashcards
5 Phamacological effects of benzodiazepines?
- Anxiolysis
- Sedation
- Anterograde amnesia
- Anticonvulsant action
- Muscle relaxation (spinal level)
Do benzos produce enough muscle relaxation for surgery?
No
Do benzos alter dose of muscle relaxant needed?
No
Which is great, potential for abuse in opioids or benzos?
Benzos potential for tolerance/ abuse is less
Do benzos induce hepatic enzyme?
No
What is antagonist for benzos?
Flumazenil
What is structure of benzodiazepines?
Benzene ring fused with 7 member diazepine ring (2 rings fused)
What is MOA of benzos?
Facilitate action of Gaba at GABAa -Increases affinity of GABAa for its receptor -DO NOT activate GABAa receptor
What is affect of increase affinity for GABAa by benzos?
-Opening Cl gated channels -Increase Cl conductance -Hyperpolarization of post-synaptic membrane -increased resistance of post-synaptic membrane to excitation
What is principle inhibitory neurotransmitter in CNS?
GABA
What causes differences in different benzos?
-Potency -Lipid solubility -Pharmacokinetics Generally all are highly lipid soluble and highly bound to plasma proteins
Which plasma proteins do benzos bind to?
Albumin
Properties of midazolam?
-Water soluble preparation -Imidazole ring -2-3x potency of diazepam - Extensize first pass effect -90-98% protein bound -Rapid redistribution–> short duration
Effect site equilibrium and t 1/2 elimination of midazolam?
- 0.9-5.6 min effect sit eequilibration - 1-6.5 hours t 1/2 elimination
What is metabolism of midazolam?
-Extensive hepatic metabolism -Hydroxylation to water soluble compounds (1 and 4 hydroxymidazolam) -ACTIVE METABOLITE= 1-hydroxy-midazolam -Conjugated and excreted in urine -Renal failure DOES NOT affect vd, t 1/2 elim, or clearnace
CNS effects of midazolam?
-Decrease CBF, CRMO -Does NOT produce isoelectric EEG -Preserves cerebrovascular response to CO2 - Does NOT attenuate ICP in response to laryngoscopy -Potent anticonvulsant and amnestic -Paradoxical excitement- RARE
Respiratory effects of midazolam
- Dose dependent decrease in ventilation -Hypoxemia and hypoventilation is enhanced when given with opioid -Depress swallowing refelx -Decrease upper airway activity
Cardiovascular effects of midazolam
-Decreases SVR at induction dosage -BP Consequently decreases -CO unchanged -Doesn’t prevent HR and BP changes with intubation
Premedication PO dose for midazolam?
0.25-0.5 mg/kg PO, masx PO dose for peds 20mg
IV sedation dose for midazolam?
1-2.5 mg IV can give as high as 5mg if needed
Induction dose midazolam?
0.1-0.2 mg/kg over 30-60 seconds Maintenance: incremental or infusion
Properties of diazepam?
- Highly lipid soluble with prolonged DOA - Commercially prepared in organic solvents including propylene glycol, benzyl alcohol VERY PAINFUL IV AND IM -Highly protein bound -Rapidly absorbed from GI tract (PO valium better than PO versed) -Viscous, pH 6.6-6.9
Metabolism of diazepam
- Oxidation, n-demethylation to desmethyldiazepam, oxazepam, and temazepam by hepatic microenzymes -Conjugated to glucaronic acid prior to renal excretion -Desmethyldiazepam - oxidized, conjugated and excreted in urine -Cimetidine will impact metabolism of valium
Elimination 1/2 time of diazepam?
21-37 hours in healthy volunteers Desmethyldiazepam- 48-96 hours
Pharmacodynamics of valium?
Cardiac stable= SVR, BP , CO (<20% decrease) Other system effects similar to midazolam
Premed oral/IV dosage for valium?
10-15 mg PO 0.2/kg for IV (reduces MAC)
Induction dose valium?
0.5-1.0 MG/KG IV
Anticonvulsant dose for valium?
0.1 mg/kg IV Inhibit activity in hippocampus and limbic system
Properties of Ativan?
Lorazepam 5-10x more potent than diazepam - NO ACTIVE METABOLITES - Most potent of bnzs in anethesia practice -Hurts IV d/t propylene glycol - less influenced by alteration in hepatic function, age and other drugs
t 1/2 life for lorazepam
10-20 hours
Onset of lorazepam?
peak 2 hours (not very utilized in OR setting)
Premed/PO dose for lorazepam?
50 mcg/kg (MAX 4MG)
What is flumazenil?
Imidazobenzodiazepine derivative -Specific competitive benzos antagonist with high affinity for bnz receptors - No adverse S/E
DOA of flumazenil
30-60 minutes, may need to repeat/supplement
Dose of flumazenil
0.2 mg IV initial, wait 2 min 0.1 mg IV subsequent doses at 60 second intervals MAX 3 MG
Infusion dose of flumazenil?
0.1-0.4 mg/hr (0.1-0.5 mcg/kg/min)
How is flumazenil metabolized?
Hepatic metabolism and renal excretion
Why does flumazenil not cause acute anxiety and neuroendocrine stress response?
Flumazenil mimics benzos
What other use is flumazenil used for?
Antiabuse- alcohol/benzos
Properties of barbiturates?
- Sodium salts -Highly alkaline- bacteriostatic but NATURE of drug is acid (acidic pt, acidic drug= more nonionized= reduce dose) - Racemic mixture, but levo isomer is potent one -Derived from barbituric acid -Urea+malonic acid= barbituric acid
Barbiturates with substitutions at carbon #2, #5 have what?
Sedative, hypnotic properties
Barbiturates with branches chain at #5 increases which activity?
Hypnotic
Phenyl group at C#5 on barbituate increases which activity?
anticonvulsant activity
Methyl radical on barbiturate imparts ____ activity.
Convulsant (used in ECT)
What does sulfuration do to barbiturates?
Increases fat solubility -Shorter duration of action -More rapid onset -Increased potency
Long branched chain on barbiturate is ____ potent than straight chain
More
Potency of levo isomers vs destro isomers?
Levo isomers are 2x potent of dextro-isomers
If oxygen is at C#2, we call the barbiturate a ______
oxybarbiturate
If sulfur at #2, we cal the barbiturate a _____
thiobarbiturate
What is relative potency of the barbiturates?
Thiopental- (TPL/STP)=1 Thiamylal (Surital)=1.1 Methohexital (Brevital)= 2.5
MOA of barbiturates?
- Decreases rate at which GABA dissociated from its receptor–> increases duration of GABA activated Cl- opening (enhances GABA activity) -Mimics GABA at receptor (direct activation of Cl-channels) -Decreases sympathetic ganglia- hypotension -Decreases postsynaptic membrane sensitivity to ACh–> some muscle relaxation -Produces functional inhibition of post-synaptic neuron -Depresses RAS (Reticular activating system)
Pharmacokinetics of barbiturates?
-Rapid onset of aciton (one arm–> brain) -Redistribution= rapid termination of effect -Extensive metabolism
TPL Protein binding/fat:blood partition coefficient? ionization?
- TPL 70-85% protein bound F/B coefficient= 11 Ionization TPL pK= 7.6 (mainly non-ionized at physio pH)
What type of metabolism does oxybarbiturates go through
hepatic only
What type of metaboism does thiobarbiturates go through?
hepatic+ some extra hepatic (GI)
How is pharmacological activity of barbiturates terminated?
Side chain oxidation at C#5 to carboxylic acid
How is barbiturate ring opened?
Desulfuration Hydrolysis
How are barbs ultimately excreted?
Changed to water soluble compound during metabolism -Renal excretion primarily <1% excreted unchanged Methohexital also excreted in feces
Does CO/HBF have any effect on barbs?
Methohexital is more influenced by HBF compared to TPL
What is T 1/2 elimination TPL or methohexital?
TPL= 11.6 hours Prolonged in pregnancy due to increased protein binding Methohexital= 3.9 hours
CNS effects of barbs?
- Depress LOC - Cerebravasoconstriction, reduced CBF, decreased ICP, and CMRO2 -Can produce isolectric EEG - Paradoxical excitement -Methohexital can cause excitatory skeletal movemnets (myoclonus and hiccups) -Does not preclude SSEP monitoring -Small doses decrease pain threshold (anti analgesic) -No skeletal muscle relaxation -Decrease IOP -Cerebral protection
CV effect of barbs?
- Depression of medullary vasomotor center & decreased SNS outflow form CNS–> peripheral vasodilation–> preload decreases -SBP decreases, compensatory increase HR in normovolemic patients -Myocardial depression is minimal - If SNS not intact OR hypovolemia OR large doses given to reduce ICP will see SIGNIFICANT decrease in BP and myocardial depression - Histamine release with rapid IV admin
When is SNS not intact?
“Extremes of age” i.e. elderly and children If SNS not intact, can see significant decrease in BP and myocardial depression with barbs
Respiratory effects of barbs?
- Dose dependent depression of medullary and pontine ventilatory centers - Decreased ventilatory response to hypoxia and hypercapnia -Apnea -Depression of laryngeal and cough reflexes are incomplete (can cause laryngospasm/bronchospasm)
Other special effects of barbs?
Hepatic enzyme induction with chronic use, phenobarb is most potent inducer! -Increase metabolism of oral anticoags, phenytoin, TCA, corticosteroids and vit K. -Accelerated production of heme by stimulation of enzyme d-aminolevulinic acid synthetase -Venous thrombosis -Readily crosses placenta
What can we expect with patients treated with barbs for sz disorders?
-Metabolize drug about 2x as fast as expected -Especially evident in muscle relaxants
Barbituates N&V incidence?
Higher than midaz and propfol but lower than etomidate, ketamine and volatiles
Tolerance and barbituates?
Tolerance develops rapidly Induction of hepatic enzymes, dose requirements may increase 6 fold
Allergies with barbituates?
1:30,000 HIGH mortality - Presents as anaphylaxis -Allergy in atopic pt (mulitple allergies, asthma, previous TPL exposure)
Induction dose for TPl and methohexital?
TPL 3-5 mg/kg - decreaes dose with age (30% decrease in elderly) and first trimester (protein bound) - Increase dose in peds (5-6 mg/kg); infanct 7-8 mg/kg Methohexital -1-2 mg/kg IV OR 20-30 mg/kg PR in peds
Duration of single dose barb for IV induction? Why?
5-8 minutes d/t rapid redistribution
How to prepare barbs?
DO NOT mix with LR–> precipitate Only use sterile H2O and NSS Dont’ mix with opioids, catechols, NMB, midazolam, which are acidic
What happens during intra-arterial injection of barbs? What to do with intra-arterial injection barb?
- Immediate intense vasoconstriction and pain -Crystalline precipitation in arterial vessel, inflammatory response, vasoconstriction, microembolization Treatment - dilute with NSS - Phenoxybenzamine- alpha antagonist -Prevent thromosis - heparin, urokinase -Brachial plexus or stellate ganglion block (block SNS response) -Papaverine (Vasodilates) 40-80 mg in 10-20 mL or 5-10 mL lidocaine 1%
What is porphyrias?
-Group of inborn errors of metabolism: deficiency in enzymes in heme biosynthetic pathway -Triggers when there’s an event that decreases heme concentration in body will cause accumulation of precursors of heme
What does porphyrins do in humans?
- Main precurors of heme- essential constituent
What is gene expression of porphyria
-Non-sex linked autosomal dominant, variable expression (chromosome 11) -Attacks more frequent in femalse, 3rd 4th decade)
S/S of porphyria
- Severe abdominal pain with D/V - ANS instabiity- tachycardia, HTN -Electrolyte disturbances -Skeletal muscle weakness, respiratory failure -Seizure -neuropsychiatric disturbances
Triggers for porphyria
Thiopental Thiamylal Methohexital Etomidate
What do barbs increase metabolism of?
oral anticoags, phenytoin, TCA, corticosteroids and vit K
