Induction Agents, Benzos, & Barbs Flashcards
thiopental (MOA,PK/PD, induction doses, volume of distribution, half-life)
PKA:
MOA: Potentiate GABA receptors (gamma-aminobutyric acid) (allosteric)
PK:
▾Weak acid
▾Effects terminated by rapid distribution
▾Oxidized in liver
▾Long elimination half-life
▾Pentobarbital is a metabolite
▾Elimination 1/2 time is shorter in kids
▾1/2 time prolonged in pregnancy
-Causes enzyme induction (more rapid metabolism of other drugs)
PD:
▾Inhibit excitatory pathway mediated by glutamate
▾CNS (Burst suppression, isometrics EEG, decrease CMRO2, CBF, ICP, reverse steal effect, monitor SSEP’s)
▾CV (decrease MAP, CO, negative ionotropic effects, decrease venous vascular tone) ▾Resp (Central apnea 1 min-baseline 6 min shorter than propofol, not much bronchodilation, airway reflexes maintained
Induction Dose: 2.5-5 mg/kg IV
Volume of Distribution (L/kg): ________
Half-Life (hours): LONG, longer in pregnancy, shorter in peds
PK - think of…
think ADME, dose-concentration relationship (plasma concentration curve)
PD - think of…
think receptors, plasma effect site relationship, efficacy-potency, dose-response curve, how the drug affects all the body’s systems
Thiopental (in general)
barbiturate (so an acid), allosteric GABA, Phase I - CYP450, enzyme inducer, “long” half-life, burst suppression, isoelectric EEG, decreased CBF and therefore ICP/CMRO2
increases IPSPs (inhibitory postsynaptic potentials)
Methohexital (in general)
decreases the sz threshold, so used in procedures like ECT to elicit sz’s. Metho-hexital myo-clonus. Just think of excitatory phenomena like muscle movements or hiccoughs.
Methohexital (MOA,PK/PD, induction doses, volume of distribution, half-life)
MOA: Potentiate GABA receptors (gamma-aminobutyric acid) (allosteric)
PK:
▾Weak acid
Oxidized in liver by CYP450 enzymes
• All Barbiturates cause enzyme induction (more rapid metab of other drugs)
PD:
▾Lowers seizure threshold/myoclonus
Induction Dose:
▾1-2 mg/kg IV
▾25mg/kg Rectal (peds)
▾infusion for sedation/general anesthesia – 50-150 mcg/kg/min
Volume of Distribution (L/kg):
Half-Life (hours):
PKA:
Propofol (in general)
-Agonist for GABA (IPSPs)
neuro protective (dose-dependent decreases) but doesn’t affect spinal neuron excitability, myoclonus (less than etom), bronchodilation, dose-dependent respiratory depression (transient but more pronounced than etom)
Propofol (MOA, PK/PD, induction dose, volume of distribution, half-life)
PKA: 11, pH 7-8.5 (Diprivan), or pH 4.5-6.4 (Propofol)
MOA: Selective modulator of GABAa receptor (gamma-aminobutyric acid) (GABA a major inhibitory transmitter in CNS), spinal motor neuron excitability is not altered
• Agonist for GABA (which sends IPSPs – inhibitory postsynaptic potentials)
PK:
▾Clearance exceeds hepatic blood flow (1st pass tissue uptake in the lungs, extensive hepatic metabolism CYP450)
▾Active metabolite (4-hydroxypropofol)
▾Not influenced by hepatic/renal dysfunction
o Decreased rate of plasma clearance in pts older than 60
o Decreased albumin, increased free drug –> exaggerated response
▾Decreased rate of plasma clearance in pts >60
▾Binds reversibly to (erythrocytes + plasma proteins 50%, plasma albumin 48%, free 2%) ▾Increase free fraction seen in severe hepatic/renal disease and pregnancy
Readily crosses the placenta, but is cleared from fetal circ quickly
PD:
▾Weak acid
▾Rapid & pleasant loss & return of consciousness ~ 4 min
▾May induce myoclonus (less than etomidate, mainly seen in younger ppl)
▾Mild-moderate decrease in BP secondary to (decrease in SNS tone & vasodilation, CNS, cardiac & baroreceptor depression), and bradycardia secondary to vasodilation
▾Neuro protective (dose-dependent reductions of CBF, CMRO2, ICP, CPP, EEG, intraocular pressure d/t decrease in MAP, metabolic rate and cerebral vasoconstriction)
▾Resp depression (dose dependent w/ infusions secondary to decreased sensitivity of resp center to CO2) - transient but more pronounced than with etomidate
▾Minimal bronchodilation
Induction Dose: 1.5-2.5mg/kg, maintenance of anesthesia 100-300 mcg/kg/min
Decrease dose in elderly, increase dose in peds
Volume of Distribution (L/kg): 3.5-4.5
Half-life(hours): 0.5-1.5 11
CS half-time is 40 minutes
Etomidate (in general)
-Agonist for GABA (IPSPs)
emergence in 5-15 minutes, ester hydrolysis and hepatic microsomal enzymes/Phase I, myoclonic movements common.
“Muscle movement, but no movement of VS”
Adrenocortical suppresion - 11B-hydroxylase
Etomidate (MOA, PK/PD, induction dose, volume of distribution, half-life)
PKA: 4.2, pH 8.1
Imidazole class – is a carboxylated imidazole
MOA: Selective modulator (allosteric) of GABAa receptor (Chiral: admin as single R+ isomer 5x more potent).
Agonist for GABA (IPSPs – inhibitory postsynaptic potentials) – receptor has an ↑d affinity for GABA
PK:
▾Moderate lipid solubility (weak base) 75% bound to plasma albumin (decreased albumin increases active fraction) - H2O-soluble at acidic pH, lipid-soluble at physiologic pH
▾Prompt emergence 2nd to redistribution to tissues & rapid metabolism
▾Metabolized by ester hydrolysis (phase I) (plasma esterases & microsomal enzymes in liver)
▾Eliminated 10% bile, 13% feces, the rest via kidneys
PD:
▾Rapid onset – 1 “arm-to-brain circulation” – brain [ ] goes up within 1 min
▾Return to consciousness 5-15 min (> propofol)
▾CBF & CMRO2 decrease (decrease ICP while maintaining CPP-remember MAP doesn’t ↓) and ↓ IOP
▾Involuntary myoclonic movements common - ↓ incidence by administering fentanyl/benzos (2nd to distribution to deep cerebral and brainstem, decrease amplitude and increase latency OF AUDITORY EVOKED POTENTIALS – avoid EMG monitoring, affects height) -SSEPs enhanced by etom, while MEPs are suppressed (MEPs more suppressed by propofol)
• may activate sz’s in specific populations, but has been shown to terminate status epilepticus
▾Maintain hemodynamic stability (act on alpha2 B-adrenergic receptors which mediates BP)
▾Minute volume decreases but RR increases - Apnea can occur bc of rapid injection
▾↑ incidence of PONV
Induction Dose: 0.2-0.4 mg/kg IV
Can remember this dose bc (doses up to 0.3 mg/kg have minimal CV effects, but) doses > 0.45 mg/kg result in ↓BP, CO
Volume of Distribution(L/kg): 2.2-4.5 (means significant tissue uptake)
Half-life (hours): 2-5
Ketamine (in general)
Antagonist for NMDA (n-methyl-d-aspartate) receptors, to which glutamate binds to cause EPSPs (excitatory postsynaptic potentials)
“dissociative amnesia”, good for trauma (bc of hyperdynamic state) but not for closed head injury (bc of hyperdynamic state in the brain), lacrimation/salivation
Ketamine (MOA, PK/PD, induction dose, volume of distribution, half-life)
PKA: 7.5, pH 3.5-5.5
MOA: “antagonist for glutamate/NMDA” (which cause EPSPs – excitatory postsynaptic potentials)
produces dissociative anesthesia and analgesia. It binds non-competitively to the phenylcyclidine site of N-methyl-D-aspartate (NMDA) receptors (agonist-glutamate) (bc its structure resembles phenylcyclidine) → inhibits activation of NMDA receptors by glutamate AND decreases presynaptic release of glutamate
exerts effects on opioid, monoaminergic (activation of descending inhibitory monoaminergic pain pathways), muscarinic receptors, VG Na+ receptors, L-type Ca+2 channels, nACH receptors, inhibition of cytokines contribute to analgesia, limbic system activated - suppresses neutrophil production of inflammatory mediators and improves blood flow (more of these details on St. pg 475)
▾Weak actions on GABAa receptors
• ketamine interacts with multiple CNS receptors but there’s no clear association between receptor interaction and specific behavior
PK:
▾Not significantly bound to plasma protein (12%); rapid distribution to tissues
▾Highly lipid soluble; rapid transfer BBB
▾Demethylation of ketamine by CYP450 – PHASE I (metabolism dependent hepatic flow)
High hepatic clearance rate – 1L/min
▾Norketamine is an active metabolite (broken down to form H2O soluble and inactive metabolites)
• Peak plasma concentration in 1 minute after IV admin, and 5 minutes after IM injection
PD:
▾Produces a dissociative state (cataleptic, eyes open, pupils reactive, corneal reflex intact, nystagmus present, lacrimation and blinking continue)
▾↑CBF, CMRO2, ICP (attenuated with benzo/opioid) – potent cerebral dilator, must give with BZ or thiopental
▾Produces nystagmus (↑IOP)
▾↑HR, BP, SVR - SNS activation
▾Maintain spontaneous respirations
▾Bronchodilator (not effective as sole agent)
▾analgesic effects! (through inhibition of cytokines?)
▾increased PO secretions
▾hypertonus and skeletal muscle movements independent of surgical stimulation (st p472)
Induction Dose:
▾Adult dose (2-3min IV): 1-2.5mg/kg IV
▾4-8mg/kg IM (<10 min)
▾10mg/kg PO (10-20 min)
Volume of Distribution(L/kg): 2.5-3.5
Half-life (hours): 2-3
Diazepam (in general)
linear half-life with age, extremely lipophilic, anticonvulsant/CNS depressant, sk. muscle relaxant, but minimal effects on BP (unless given with opioids), Phase I oxidative pathway of N-methylation
Diazepam (MOA, PK/PD, dosing, volume of distribution, half-life)
PKA:
MOA: Facilitate GABA (gamma-aminobutyric acid) - allosteric
5 main effects: anxiolysis, sedation & hypnotics, anticonvulsant activity, spinal-cord mediated muscle relaxation, anterograde amnesia
PK:
▾highly lipid soluble – crosses BBB
▾Rapidly absorbed in GI
▾Large Vd- extensive tissue (women tend to have larger Vd than men, crosses placenta)
▾Extensively protein bound (~98%) - Cirrhosis and renal insufficiency increase unbound diazepam -increases side effects
▾Metabolized by hepatic microsomal enzymes use oxidative pathway of N-methylation – PHASE I
High hepatic extraction
▾Two active metabolites: Desmethyldiazepam (nordiazepam), Oxazepam
Oxazepam metabolized by glucuronidation
▾Near linear relationship b/w elimination 1/2 life and pt. age
▾Elderly: Slow drug absorption, increased adipose tissue, decreased plasma proteins, decreased hepatic blood flow & metabolism, decrease CO, prolonged circulation = slower onset, remains longer in CNS
PD:
▾Resp: In sedative doses produces minimal ventilation depression (exaggerated when combined with opioids & ETOH, COPD may cause prolonged ventilatory depression)
▾CV: Induction doses cause minimal decrease in BP, CO, SVR (Nitrous Oxide not associated with adverse cardiac changes, concomitant use of fentanyl results in ↓ BP & SVR)
▾MSK – skeletal muscle relaxation, good for tetany
▾CNS: anticonvulsant, dose-dependent CNS depression (from anxiolysis –> sedation), anterograde amnesia
Dosing: (anticonvulsant dose) 0.1 mg/kg IV to abolish sz activity (q10-15 min, max dose of 30 mg – St. p857)
Volume of Distribution(L/kg): 1.1
Half-life (hours): >40 hours (linear with age) – low hepatic extraction ratio
insoluble in H2O - pain on injection
Lorazepam (in general)
14-hr half-life, onset 1-2 min, peak 20-30 min (!!), effects last 6 hours
phase II glucuronidation!
