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BarbiturateThiopental (Pentothal)Methohexital (Brevital)Clinical UseInduction of General AnesthesiaTreatment of inc. ICP/Cerebral protectionInduction of General Anesthesia Used for ECTMechanism of ActionGABA receptor activation – prolong GABA inhibitory effectsDepress the RASDecreased transmission in SNS gangliaHigh doses effect the NMJ-postsynaptic membrane decreased sensitivity to AChGABA receptor activation – prolong GABA inhibitory effectsDepress the RASDecreased transmission in SNS gangliaHigh doses effect the NMJ-postsynaptic membrane decrease sensitivity to AChDosing2.5% solution (pH 10.5)3-5 mg/kg** dose according to lean body mass to avoid overdose***Stable 2 wks. In fridge; 6 days room temp1% solution1.0 – 1.5 mg/kgStable 6 wks.StructureDerived from Barbituric AcidChained substitution at #5C and sulfur atom at #2CIncreased lipid solubilityRacemic mixture - S(-) isomer 2x as potent as R(+) isomerDerived from Barbituric AcidChained substitution at #5C, oxygen at #2C, and methyl group #3CConvulsive ActivityRacemic mixture - S(-) isomer 4-5x as potent as R(+) isomerIonizationMetabolic Δ in pH has > effect on distribution than respiratory ΔAlkalosis favors ionized fractionDecreased barbiturate effectAcidosis favors nonionized fraction > access to CNS b/c of ↑ lipid solubilityIncreased barbiturate effectSameUptakeMaximal brain uptake – 30 sec/one arm to brain circulation timeRapid effect site equilibrationSameDistributionDistribution Determined byLipid solubility Non-lipid soluble portion binds to albumin in plasmaProtein bindingDegree of ionization – pK of 7.6 (see above)Alteration in Blood VolumeHemorrhage- ↓ BV = ↑ drug conc. In bloodAlteration in Blood FlowShock - ↓BF to SM and fat, but adequate BF to brain = stronger drug effectHypovolemia – exaggerated cerebral and cardiac depressionSame BarbiturateThiopental (Pentothal)Methohexital (Brevital)Distribution Cont.Brain (30 sec)→skeletal muscle (equilibrates in 15 min) →Fat (cont. to ↑after 30 min)Prolonged context sensitive half-time r/t distribution in fat cellsPrompt awakening after single IV dose r/t redistribution from brain to inactive tissues (SM and fat) = Large VdFat:blood partition coefficient is 11 – thiopental will move from blood to fat as long as conc. In fat is < 11xs that in blood------------------------------------------MetabolismHepatocytes – will need large liver dysfunction to see a change in metabolismSide chain oxidation at #5C to yield carboxylic acidMetabolized slower than methohexital b/c it is more lipid solubleExtrahepatic sites – kidneys and CNSHepatocytes – will need large liver dysfunction to see a change in metabolismSide chain oxidation at #5 C to yield carboxylic acidElimination<1% excreted unchanged in urineLow hepatic extraction ratioCapacity dependantInfluenced by enzyme activityElderly = slower movement betw. Compartments = ↑plasma conc. so use smaller dosesPedi. – short E1/2 time b/c of rapid hepatic clearancePregnancy – prolonged E1/2 time b/c ↑ Vd and protein bindingObesity – prolonged E1/2x b/c increased VdSame Except:High hepatic extraction ratioCO and blood flow dependantGreater hepatic clearance (shorter E1/2x) than pentothal = faster recoveryCardiovascularTransient ↓ BP r/t ↓SNS outflow from CNS(do not use in Pt. w/CAD) Peripheral vasodilation b/c of depression of medullary vasomotor center→ ↓CO↓venous return → ↓ COCompensatory ↑HR – carotid sinus baroreceptor driven (↑peripheral SNS activity)Myocardial depression w/overdose and large doses to tx. ICPHypovolemia = exaggerated ↓ in BP (less able to compensate for peripheral vasodilation↓ dose and inject slowlySameBarbiturateThiopental (Pentothal)Methohexital (Brevital)CNSCerebral protective b/c causes vasoconstriction = ↓CBF, ICP and cerebral metabolic O2 requirementsCan cause injury r/t hypotensionNeed functioning EEG to have cerebral protection- not post arrest patients*used more now– hyperventilate to cause vasoconstriction and give diuretics to ↓brain volume *Clouding of consciousness, sedation, unconsciousnessDecreases increased ICP – by ↓CBV through cerebral vascular vasoconstrictionClouding of consciousness, sedation, unconsciousnessMore rapid recovery of consciousness than thiopentalPulmonaryDose-dep. depression of medullary + pontine vent. centersApnea when combined w/other depressant pre-op meds↓RR and VT in spontaneously breathing patientLaryngosmasm or bronchospasm possible with stimulation of upper airwaySameLiverModest ↓in hepatic blood flowStimulates hepatic microsomal enzyme activity/induction – have to give more of drug that undergoes microsomal enzyme activityAfter 2-7 D of sustained drug administration – persists for 30 days after drug d/cPhenobarbital most potent for causing enzyme inductionAffects oral anticoagulants, phenytoin, tricyclics, endogenous corticosteroids, bile salts, Vit. KSamePlacental TransferReadily crosses placenta – Category CAffects placental blood flowFetal plasma levels less than maternalSameMisc.Impairement of neutrophil function – pt. susceptible to infection↓autotissue injury + organ dysfunction (good)Heat loss and decreased. body temp. r/t peripheral vasodilationIntraarterial InjectionIntense vasoconstriction and pain – observe distal pulses, blanching, and cyanosisInflammation and arteritisTreatment Inject saline to dilute drugInject lidocaine to prevent arterial spasm + produce vasodilationUrokinase to improve distal blood flowSameBarbiturateThiopental (Pentothal)Methohexital (Brevital)Misc.Venous Thrombosisr/t crystal formation in the veinsnot as detrimental as intraarterial injectionimportant to use dilute solutionAntianalgesicIf pt in pain when given will not be able to sedate with pentothal (can sedate w/versed)“Hangover”- r/t redistribution from fat and SKMPorphyria – defect in enzymes involved w/HgB synthesisBarbs. Stimulate aminolevulinic acid synthetase – causes ↑ rate of heme productionS/S- abd. Pain, Δ MS, dark urine, vomitingFatal neuro/CV complications can occurTreatment – IV glucose + heme infusion, opiods (only pure agonsists), phenothiazine for N/V, chloral hydrate or low dose benzos. For insomniaSameDrug InteractionsWill precipitate in solution at lower pHOpiodsNuromuscular Blocking AgentsCatecholaminesSameAllergic ReactionsAnaphylaxisTx. With IVF and epinephrineHigh mortality rateAnaphylactoidHistamine ReleaseSameEffect on EEGSmall dosesIncrease low-voltage, fast Beta wave activityProduces clouding of consciousnessLarger dosesHigh-voltage, slow Delta wave activitySimilar to physiological sleepLoss of consciousness – have arousal w/painful stimuliSomatosensory Evoke potentials remain intactContinuous infusion can produce isoelectric EEG↓CMO2 requirements to about 55%Reflects ↓neuronal but not metabolic need for O2Hypothermia=only way to ↓basal cellular metabolic O2 requirementSameNon-barbituratePropofolKetamineEtomidateClinical UseInduction of AnesthesiaSedationTIVA/MACAntiemetic (low dose)Antipuritic w/neuraxial opiodsInduction of AnesthesiaSedationAnalgesia (profound)AmnesiaInduction of Anesthesia***use with cardiac and unstable patients***Poor analgesic and amnestic propertiesDosingInduction = 1.5 – 2.5 mg/kgIV sedation = 25 – 100 mcg/kg/minMaint. of anesth = 100 – 300 mcg/kg/minElderly – hypotension – smaller doses↓central distribution volume and clearance ratePeds – higher ind. Dose (mg/kg basis) ↑ central distribution volume and clearance rateAnalgesia = 0.2 – 0.5 mg/kgInduction = 1-2 mg/kg IV = 4 – 8 mg/kg IM ( 1-2 mg/kg w/ general anesthesia)Duration of action IV = 5-15 min IM= 12-25 min.Induction = 0.2 – 0.4 mg/kgOnset = 30 – 60 secondsMyoclonic movements normalMechanism of ActionGABA receptor interaction – prolong GABA inhibitory effectsDecreases the rate of dissociation of GABA from the receptorNoncompetitive attachment to phencyclidine (PCP) recognition sites on NMDA receptorsInhibits activation of receptor by glutamateDecreases pre-synaptic release of glutamatePotentiates effect of GABA(weak action at GABA receptors)Exerts effect at receptor sites:Opioid – ?, Δ ,Κ, Σ(delirium)MAO – antinociceptive actionMuscarinic – anticholinergic,bronchodilation, HTN, delirium, ↑HRVS Na channels – acts like local anestheticGABA receptor interaction – prolong GABA inhibitory effectsNon-barbituratePropofolKetamineEtomidateStructureSubstituted IsopropylphenolOnly one not a chiral compoundLipid egg soy emulsion b/c it is insolubleRelated to phencyclidineRacemic mixtureS(+) more active isomerCarboxylated Imidazole compoundAdministered as single isomer R(+)Water soluble @ Acidic pH (ring open)Lipid soluble @ phys. pH (ring closed)Uptake +DistributionShort effect-site equilibration time30 sec. brain effect after dosingAwakening faster and completeTissue uptake = lungs = large VdLungs are inactive storage siteIf fentanyl given first = less uptake into the lungs r/t binding site competitionRapid onset = high lipid solubilityShort duration of action= 5-15 min.Rapid brain penetrationRedistributes to inactive sites = large VdRapid brain penetration – peak brain level in 1 minuteRapid awakening = redistribution to inactive sitesSignificant tissue uptake = Large VdWeak base, 99% unionized pH 7.4Bound to albumin = ↓albumin will ↑unbound active drug = > drug effectMetabolismBoth hepatic + extrahep. ClearanceHepatic metabolism = rapid and extensiveExtrahepatic = pulm. Uptake, first pass elimination and renal excretionFirst pass hepatic effectHepatic microsomal enzymeslong term use leads to enzyme inductionhalothane and valium slow metabolism Hepatic microsomal enzymes and plasma esterases (quickly metabolized)EliminationMetabolites excreted by kidneysClearance and elim. not affected by cirrhosis/renal dysfunctionHigh hepatic extraction ratio – clearance rate affected by blood flowPlacental TransferCategory B – not FDA approved for C-section and pregnancy (pentothal is)Crosses placentaClears rapidly from neonatesCardiovascular↓BP, CO and SVR (do not use w/CAD or angina) – r/t vasodilation b/c of SNS inhibitionNegative inotropeMay ↓SNS > PNSBradycardia and asystolePropofol + fentanyl = profound bradycardia; may need to give glycopyrolate (anticholinergic)Can tx. With B-agonist (isoproterenol)Resembles SNS stimulation (30 min)Direct negative inotrope (when SNS stimulation ceases)↑ arterial BP, HR, and MRO2 (do not use w/ CAD)Inhibits catecholamine uptake postganglionic SNSResponse blunted w/ prior admin. Of benzo, or together w/ IA/nitrousAt induction doses = CV stabilityMinimal Δ to HR, SV, COAcute hypovolemia ↓ SVR = possible sudden ↓BPNon-barbituratePropofolKetamineEtomidateCNS↓ CMRO2, CBF, and ICPMemory impairment = MidazolamEEG changes similar to ThiopentalDoes not affect SSEPsGive physostigmine to reverse adverse CNS effect (delirium r/t muscarinic receptor effect)↑ ICP in spontaneously breathing Pt.Potent vasodilator = ↑CBF and CMRO2↓ CMRO2, CBF, and ICP – potent direct vasoconstrictorEnhances SSEP – monitoring is more reliableExcitatory Effect – myoclonus, dystonia and tremorsOpioids and/or Benzo pre-med may decrease excitationCan activate seizure foci – caution w/epilepsyCan terminate status epilepticusPulmonaryDose-dependent depression of ventilationApnea 25-35% of patients w/induction Bronchodilation – good for asthmatics; breaks bronchoconstriction (new preservative metabisulfite may cause bronchoconstriction)↓ response to CO2 and hypoxemiaNo alteration in hypoxic pulmonary vasoconstrictionNo significant depression –apnea if give rapidlyMaintains airway reflexesBronchodilator – good for asthmatics/bronchospasmDo not need adjunct airwayInduction agent of choice with bronchospasmLess Depressant effects than barbituratesApnea possible w/rapid injection↓ VT offset by ↑ RRSide EffectsAllergic reaction to componentsEggs, soy or sulfitesLactic acidosis - Propofol infusion syndrome– r/t phenol portion – affect mitochondriaOccurs w/ prolonged high dose infusion (>75 mcg/kg/min >24H)Abnormal lipid metabolism in cardiac and skeletal muscleUnexplained ? HR should be evaluatedABG = met. acidosisMyoclonus on induction with SSRISupports Bacterial growthPain in injection – give lido in IVPossible histamine release r/t additivesDirect myocardial depressant in critically ill = ↓BP and COEnhanced arrhythmia effects of EpinephrineIncreases oral secretions – pre-treat with glyco. to ?coughing/laryngospasmIncreases intraocular pressure – do not use with open globe injuriesEmergence DeliriumMisinterpretation of aud./vis. StimuliLoss of skin/Musc.skel. sensationsDreams + hallucinations up to 24 HIncidence - Age >15, female, and dose >2mg/kg, personality disorders, vivid dreamers, PTSDPrevention – pre-med w/benzosOr w/ thiopental/IAMay activate seizure foci – use cautiously in pt. w/focal seizuresAdrenocortical suppression d/t dose dependent inhibition of the conversion of cholesterol to cortisolenzyme inhibition lasts 4-8 Hif pt. on chronic steroids, hemorrhage, or sepsis – give stress dose steroids to avoid hemodynamic instabilityNon-barbituratePropofolKetamineEtomidateDrug interactionsinhaled anesthetics = depressed hemodynamicsenhances effect of non-depolarizersverapamil = blunts ↑ in BP and enhances ↑ HRaminophylline = ↓ seizure thresholdMisc.Not a MH triggerAntiemetic at low doses- 10 – 15 mgAntipruritic with neuraxial opioids (10 mg)Anticonvulsant - ↓seizure duration in pt’s undergoing ECT↑ Oculocardiac Reflex in pedi strabismus surgeryFive and Dime response = asystoleVagal stimulationInc. potential of this w/propofolAquavan – H2O soluble prodrug that becomes propofol in the bodyDoes not cause same anesthetic effect, pain on injection, infection, hypertriglyceridemia as propofolHas a large Vd and higher potency than propofolProlonged infusion can have green urine (r/t phenols) or cloudy urine (r/t uric acid crystals) – both not harmfulProduces “dissociative anesthesia”Dissociation between Thalamocortical + limbic systemCataleptic state = eyes open with slow nystagmic gazeAmnestic and analgesic Does not trigger MHNo histamine releaseCan use with acute hypovolemiaDo not use with critically ill pt. b/c of ↓ catecholamine storesInhibits platelet aggregationAnalgesia –at subanesthetic dosesGood for somatic painInhibits spinal NMDA receptorsAnalgesia during labor w/o neonate depressionNot for first option interventionVarying degree of hypertonus and purposeful skeletal muscle movement independent of surgical stimulationDoes not trigger MHIncreased incidence of PONVDoes not produce analgesiaPain on injection ................
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