Pharm Review PDF

Friendly Reminders-DONT FORGET TO LOOK OVER THE PHARM FINAL REVIEW PPTS AND QUIZLETS, NEW MATERIAL/QUIZLETS, PKa, MATH, DRUG DOSES - RR TV MV OPIOIDS DECREASED INCREASED DECREASED VOLATILES INCREASED DECREASED DECREASED IV SEDATIVES DECREASED DECREASED DECREASED Drugs that blunt hemodynamic response...

Friendly Reminders-DONT FORGET TO LOOK OVER THE PHARM FINAL REVIEW PPTS AND QUIZLETS, NEW MATERIAL/QUIZLETS, PKa, MATH, DRUG DOSES - RR TV MV OPIOIDS DECREASED INCREASED DECREASED VOLATILES INCREASED DECREASED DECREASED IV SEDATIVES DECREASED DECREASED DECREASED Drugs that blunt hemodynamic response to laryngoscopy = propofol, precedex, fentanyl, lidocaine, drugs that don’t blunt (so add opioid along with)= etomidate, benzo’s Test 1 Material Pharm Review (3 questions) Key Points GABA is the primary inhibitory neurotransmitter in the brain. Activation of the Gaba (A) receptor results in influx of chloride and hyperpolarization of the cell Efficacy of the drug is the maximal response when all receptor sites are occupied and is a function of the nature of the drug as a full, partial, or inverse agonist The primary mechanism of termination of action of a bolus dose of an anesthetic induction agent is redistribution to the vessel intermediate group Vd is the dosage divided by the initial plasma concentration of the drug and is a model used to explain the measured concentration in the central compartment following a given dose. It does not represent actual volume. Clearance of a high HER drug is dependent on liver blood flow while that of low HER drugs is more dependent on enzyme activity GFR is considered the best measure of renal function and creatinine clearance is the most reliable measure of GFR The pharmacokinetics of most anesthetic drugs can be adequate;y described by a 2 or 3 compartment model When a sedative-hypnotic drug is delivered into the central circulation, equilibration with the effect site is so rapid as to be indistinguishable from a pharmacokinetic standpoint. Lag between peak plasma concentration and peak effect (hysteresis/biophase/k) is a pharmacodynamic effect. The Vd at time of peak effect (Vdpe) provides a more useful guideline for determining proper bolus dosing Context-sensitive decrement time provides us useful info about termination of effect following a drug infusion of a given duration Wide interpatient variability exists (much of which is unpredictable) emphasizing the need to individualize and titrate both bolus and infusion dosing Ligand-gated ion channels ○ Excitatory Glutamate receptors (NMDA, AMPA, Kainate) Nicotinic acetylcholine receptors (CNS and NMJ) Serotonin ○ Inhibitory GABA, glycine ○ Glutamate is the primary excitatory NT in the CNS ○ GABA receptor (inhibitory ligand-gated ion channel) Benzos-increase sensitivity of receptor to endogenous GABA Prop, etomidate, thiopental-increase sensitivity of receptor to GABA, high concentrations can directly open the Cl- channel ○ Graph given comparing efficacy and potency (slide 23) (compare competitive vs. non competitive antagonist) A,B,C A-presence of a competitive antagonist? B-presence of a competitive antagonist? C-partial agonist, non-competitive antagonist? B is less potent than A ○ Agonists are characterized by: Efficacy and Potency Efficacy-maximal response when all receptor sites are occupied, reflects the agonists ability to activate the receptor, the maximum effect the drug can produce, full agonist = high efficacy, partial agonist= low efficacy Potency- defined by the dose (or concentration) needed to produce a defined effect (ED50 or EC50), dose required to produce a given effect ○ Competitive antagonist (decreases potency, doesnt affect efficacy) Binds at the orthosteric site (where primary ligand binds) but doesnt activate the receptor Binding of the agonist and competitive antagonist is mutually exclusive Can be overcome by large doses of agonist ○ Noncompetitive antagonist (decreases potency, decreases efficacy) Binds at an allosteric site Can bind whether the orthosteric site is bound by an agonist or not Agonist binding is not affected, but receptor activation is blocked Can not be overcome by large doses of agonist ○ REVIEW of pKa For a weak acid, the protonated form is non-ionized-so the greater the pKa than the pH, the more protonated, non-ionized, form is present For a weak base, the protonated form is ionized-so the greater the pKa than the pH, the more protonated, ionized form is present ○ Primary mechanism of termination of action of a bolus dose of induction agent is REDISTRIBUTION to other tissues, primary muscle (vessel intermediate, V2) ○ Clearance can only occur out of the central compartment ○ V1-central compartment (brain, heart, lungs, kidneys) ○ V2-vessel intermediate group (muscle) ○ V3-slowly equilibrating compartment, vessel poor group (fat, bone) ○ K1E-hysteresis, doesnt actually exist in the body, PHARMACODYNAMIC effect ○ K10-clearance out of central compartment ○ Propofol-low K31, high K10 ○ Vd=amount of drug administered/initial drug plasma concentration ○ Loading dose= Vd X target concentration Hepatic clearance ○ Rate of metabolism occurring in the liver is the difference between the concentration entering the liver and the concentration exiting the liver times the blood flow through the liver, R=Q (Cinflow-Coutflow) ○ HER is the fraction of the drug entering the liver which is removed, ER=Cinflow-Coutflow/Cinflow ○ Clearance is the amount of the blood cleared of drug per unit time, Clearance=QXER=Q (Cinflow-Coutflow/Cinflow) High HER drugs-metabolism is “flow limited” Low HER drugs-metabolism is “capacity-limited” Renal clearance ○ Creatinine clearance (ml/min)= (140-age) X lean body mass (kg)/plasma creatinine concentrationX72 ○ Normal values: Female-85-125 ml/min, Male-95-140 ml/min, decreases with age Zero-order process-rate of change is constant, fixed amount of drug is removed per unit time First-order process-rate of change is proportional to the amount of drug present IV-Sedative Hypnotics (4 Q’s) Key Points Propofol, the most commonly used induction agent, increases the affinity of the GABAa receptor for GABA. In higher concentrations it may directly activate the receptor. After prolonged propofol infusion awakening occurs rapidly due to clearance which exceeds the rate of return of drug from the slow peripheral compartment (fat) to the central compartment Propofol is unique in having distinct antiemetic properties Propofol and midazolam are equally effective in producing memory impairment at similar sedation levels Of the induction agents, propofol produces the greatest degree of hypotension and apnea Etomidate provides unequaled CV stability as an induction agent A significant disadvantage to the use of etomidate, particularly as an infusion, is adrenal suppression The benzodiazepines have five principal effects: anxiolysis, sedation, anticonvulsant activity, skeletal muscle relaxation, and amnesia The barbiturates act primarily at the GABAa receptor, enhancing the affinity for GABA, and at high doses, directly activate the receptor Awakening from the barbiturates occurs prior to return of normal respirations and respiratory drive Ketamine, a drug with intrinsic analgesic properties, produces a dissociative state The dominant CV effect of ketamine, in a patient with an intact ANS and adequate catecholamine stores, is hypertension and tachycardia Dexmedetomidine, a potent a2 agonist, inhibits the release of NE from the locus coeruleus Dexmedetomidine, as an adjunct to GA, markedly reduces MAC but is associated with a high incidence of bradycardia AAASS GABA agonists-Propofol, etomidate, benzos, barbs Non-GABA agonists-Ketamine, dex, scopolamine, droperidol Most commonly used induction agents-prop, etomidate, ketamine, barbs (thio,meth) All have short duration following a bolus dose d/t redistribution from the central compartment to peripheral tissues Propofol MOA/Pharmacokinetics Decreases the rate of dissociation of GABA from the GABAa receptor ○ Increases the duration of GABA-activated opening of the chloride channel (hyperpolarizes the postsynaptic cell membrane) ○ Higher concentrations thought to directly activate GABAa receptor channels Also GABA ○ Increased affinity of glycine receptor for glycine GLYCIN ○ Inhibition of NMDA receptors ○ Ion channel blocking of the nicotinic acetylcholine receptors in the brain NMDA Clearance exceeds hepatic blood flow NACHR ○ High HER drug (little change in propofol pharmacokinetics with hepatic/renal dysfunction) ○ Tissue uptake and elimination in the lungs contributes to the rapid clearance (makes it unique) CSHT graph: diazepam > thiopental > midazolam > ketamine > propofol > etomidate Propogol has a very high K10 but K31 is very low Doses ○ Healthy adult: 1.5-1.2 mg/kg 1.5 2.5mg ○ Morbidly obese based on lean BW ○ Children: 2-3 mg/kg ○ Elderly requires a 25-50% reduction in dose Taffinity O WW kg ○ Maintenance of anesthesia: 100-300 mcg/kg/min (usually 100-200 mcg/kg/min) ○ Sedation: 25-100 mcg/kg/min Dosing variables: younger children have an increased central compartment and increased clearance Antiemetic effect ○ Postop N/V is reduced when used as a component of any anesthetic technique ○ Postop N/V in PACU (bolus 10-15 mg +/- infusion at 10 mcg/kg/min) ○ Useful in prevention and treatment of chemotherapy related N/V ○ When used for induction and maintenance of anesthesia, as efficacious as ondansetron Antipruritic, anticonvulsant (not good for ECT), attenuation of bronchoconstriction (with EDTA preservative, not generic form with metabisulfite preservative), analgesia (not acute but maybe neuropathic pain states) Decreased CMRO2, decreased CBF, decreased ICP Blunted tachycardic response to hypotension Propofol induced hypotension is dose-dependent May suppress SVT (not typically drug of choice in the EP lab) Induction apnea is highest with prop and lowest with ketamine No inhibition of HPV No potentiation of NMBs, not a trigger for MH Pain on injection: etomidate = methohexital > prop > thiopental Propofol infusion syndrome ○ Associated with infusion at >/= 75 mcg/kg/min for > 24 hrs ○ Clinical features severe , refractory bradycardia Cardiomyopathy with acute HF Metabolic acidosis (high HR that cant be attributed to something else) Skeletal myopathy Hyperkalemia Hepatomegaly Lipemia Etomidate MOA/Pharmacokinetics Enhances the affinity of GABAa receptor for GABA At supra-clinical doses, may activate the GABAa receptor directly 75% protein bound Induction dose: 0.2-0.4 mg/kg Beneficial in these settings ○ Compromised CV status ○ Questionable intravascular volume status ○ Elevated ICP ○ ECT ○ Mapping of epileptogenic foci Unlikely will see as an infusion due to adrenocortical suppression ○ ○ Acts through inhibition of 11B-hydroxylase suppression of adrenal steroidgenesis-cortisol and mineralcorticoids (glucocorticoids, mineralcorticoids) ○ May be problematic with septic shock Cerebral vasoconstriction (CBF decreased), CMRO2 decreased Maintained or improved CPP bc little to no decrease in MAP, reduction in ICP due to decreased CBF d/t lack of effect on the SNS and baroreceptor function, induction doses of etomidate produce minimal changes in: HR, SV, CO, MAP Does not induce histamine release Causes myoclonus Benzodiazepines MOA: enhances the affinity of GABAa receptors for GABA directymulate Increased opening of the chloride channels->increased chloride conductance->hyperpolarization of the postsynaptic cell membrane->greater resistance to excitation Drug effect is a function of receptor occupancy ○ 60% unconsciousness Clearance: midazolam > lorazepam > diazepam ○ Lorazepam has a higher affinity for the receptor but is cleared faster than diazepam ○ Despite higher clearance and similar Vd of lorazepam vs diazepam, effects of lorazepam last longer due to its higher affinity for the GABA receptor (may result in delayed emergence from sedation and prolonged amnesia) ○ Midazolam is the fastest working and shortest duration relative to other benzos Rapid redistribution from the central compartment High HER ○ BUT FLUMAZENIL IS THE SHORTEST DURATION (watch for resedation) Preop anxiolysis ○ Oral premed in adults: 5-15 mg diazepam ○ Oral premed in children: 0.25-1 mg/kg midazolam (0.5 mg/kg sweet spot) ○ Nasal premed: 0.2 mg/kg midazolam ○ Induction: 0.05-0.15 mg/kg midazolam ○ Sedation: 0.5-1mg repeated midazolam, 0.07 mg/kg IM midazolam Skeletal muscle relaxation (occurs via interaction of benzos with the spinal internuncial neurons NOT at the NMJ) or lumbar disc disease (not paralysis) Little or no change in ICP, cannot produce an isoelectric EEG NMS Flumazenil-FASTEST WORKING BENZO, competitive antagonist that binds at the allosteric site ○ Dose: 0.2-0.5 mg incrementally to a total dose of 3.0 mg, every 2-3 mins, dont get the abrupt reversal like narcan our spine ○ Short half life-WATCH FOR RENARC Barbiturates MOA Low concentrations: enhance effect of GABA by decreasing rate of dissociation of GABA from receptor High concentrations: mimic effect of GABA by directly activating the opening of the chloride channels Thiopental CSHT: can shift from first order to zero order kinetics ○ First-order = constant fraction of drug cleared over time ○ Zero-order = constant amount of drug cleared over time ○ May have anti analgesic effect at low blood levels Thiopental induction dose: Adult 3-5 mg/kg Methohexital: adult induction dose is 1-2 mg/kg ○ Drug of choice for ECT Proportional decreases in CMRO2 and CBF resulting in decreased ICP Investigated and found to be CI following resuscitation from cardiac arrest Peripheral vasodilation with venous pooling Decreased contractility, increased HR, decreased CO, MAP unchanged or slightly decreased All IV induction agents, with the exception of ketamine and etomidate, produce a dose-dependent respiratory depression Porphyria Potential triggers: barbs, etomidate, ketamine, ketorolac, amio, some CCBs, fasting, stress-PROPOFOL IS NOT A TRIGGER Ketamine Ketamine Ketorolac Supplied in 3 strengths: 1%,5%,10% S (+) isomer CCBS ○ 4x greater affinity for phenycyclidine binding site on the NMDA receptor than R Fasting (-)-3x greater potency than racemic mixture Stress ○ More intense analgesia ○ 20% quicker metabolism and quicker return of cognitive function than racemic mixture ○ Decreased salivation ○ Decreased incidence of emergence reactions (hallucinations, nightmares, impaired memory and cognition, mood disorder) ○ Better accepted by patients ○ Only racemic mixture is approved in the US Produces a dose-dependent CNS depression resulting in a “dissociative state” NMDA receptor antagonist ○ Inhibits binding of glutamate with receptor ○ Inhibits release of glutamate from the presynaptic nerve terminal Rapid onset of action (characteristics related to these things NOT high HER) ○ High lipid solubility ○ Highly unionized Barbs Etom Amio r punts ○ Poorly protein bound ○ Increased CBF could speed delivery to brain Brief duration of action ○ Initially due to redistribution (large Vd) ○ High HER ○ Rapid clearance in the liver Dosing ○ 1-2 mg/kg IV ○ 4-8 mg/kg IM Sub-anesthetic doses may reduce the incidence of acute opioid tolerance Potential value of ketamine in depression and OCD Increased CMRO2, CBF, ICP Emergence reactions: 10-30% incidence in adults in whom ketamine is a major portion of the anesthetic ○ Adults > children ○ Female > male ○ Certain personality types (high psychotism score) Burst suppression of the EEG at high doses Bronchodilatory effect Dexmedetomidine MOA: A2 agonism Sedation and hypnosis, sympatholysis, analgesia Sedation in the locus coeruleus Analgesia primarily at the spinal cord Bradycardia sympatholysis at the heart Hypotension central > peripheral effects Near complete hepatic biotransformation ○ Direct glucuronidation and metabolism by CYP450 enzymes Renal excretion ○ No effect of renal disease on pharmacokinetics Renal doesnt effect the drug, liver problems does effect the drug CSHT is 4 mins following 10 min infusion but 250 mins following an 8 hour infusion Anxiolysis, sedation, analgesia, sympatholysis, decreased salivation, minimal depression of ventilation Good for awake airway management, probably not best for a trauma patient dltsympatholysis Reduces MAC of iso by 35-50% Attenuation of baroreceptor reflexes Vasoconstriction in the cerebral vessels and a decrease in CBF, no change in CMRO2 Tehoprotective (uncoupled) tho Diuretic effect by opposing the action of vasopressin Scopolamine Naturally occurring anticholinergic alkaloid derived from the balladonna plant Tertiary amine, lipid soluble 100X the potency of atropine in the reticular activating system ffffpy f rophy tx tratumcorneum 3X the potency of atropine as an antisialogogue (more mydriasis, cycloplegia) Less likely to produce tachycardia SEs: mydriasis/cycloplegia, central anticholinergic syndrome, atropine fever ○ Give physostigmine for central anticholinergic syndrome and atropine fever Droperidol A butyrophenone, derived from haloperidol Previously combined with fentanyl to produce neuroleptanalgesia ○ innovar=droperidol+fentanyl Used as an antiemetic ○ Dose: 0.625 mg-1.25 mg ○ Efficacy improved when used in combo with serotonin antagonists or dexamethasone or both Mechanisms of Anesthesia and Consciousness (0 Q’s apparently)-refer to final review ppt. Test 2 material Inhaled anesthetics (7 Q’s) Key Points The low boiling point of desflurane requires a special vaporizer to assure delivery of desired concentration Preferred inhalation induction = sevoflurane d/t low pungency, low blood:gas solubility All volatiles will trigger MH in a susceptible patient, while nitrous & xenon do not MAC of the inhalation agents is increased or decreased by multiple factors Cerebral blood flow is increased & CMRO2 decreased by the VA’s The volatile anesthetics produce predictable effects on evoked potential monitoring which vary by type of monitor The volatile anesthetics all produce similar decreases in blood pressure secondary to relaxation of vascular smooth muscle The volatile anesthetics trigger a cascade of intracellular events similar to that produced by a brief ischemic period. This results in some degree of protection from ischemia for the myocardium & potentially other organ systems preconditioning VA’s produce a dose-dependent decrease in compensatory autonomic nervous system response inhalation agents produce a dose-dependent decrease in TV w/ an incomplete tachypneic compensation resulting in decreased minute ventilation VA’s produce a dose-dependent decrease in uterine smooth muscle tone Degradation of VA’s in CO2 absorbents may result in production of Compound A & carbon monoxide ischemic des sero Current Inhaled Anesthetics ○ Volatile agents include sero OE Nzo ○ Gases BP VP N D I Halothane Isoflurane (Forane) Desflurane (Suprane) Sevoflurane (Ultane) J S H Nitrous oxide Xenon Property HALOTHANE ISO SEVO DES NITROUS MAC B:G 0.75 2.5 1.17 1.46 1.8 0.65 6.6 0.42 104 0.46 Vapor pressure (lowest to highest) 3 4 5 (highest boiling point/lowest VP) 2 1 (lowest boiling point/highest VP) **the Lower the boiling point, the higher the vapor pressure Halothane ○ significantly metabolized (20%)—more than others ○ highest blood solubility out of other volatile agents so you have to give more to get Pcns partial pressure ○ produces greater reduction of hepatic blood flow Most metabolized to trifluroacetylated intermediates (so not the volatile of choice with cirrhosis) ○ good for inhalation induction (also sevoflurane) d/t low pungency Isoflurane ○ most potent of the current available VA’s ○ isoflurane & desflurane increase HR 5-10% may see > increase with rapid increase in delivered concentration ○ Does not increase respiratory rate beyond 1 MAC with compensatory mechanism for increase in PaCO2 unlike all volatile agents & N2O ○ produces greater & longer lasting reduction in ventilatory drive to hypoxia than sevoflurane & desflurane ○ hepatic arterial buffer response preserved with isoflurane & sevoflurane Desflurane ○ is the MOST pungent of the volatile agents (may result in coughing, breath holding, salivation, laryngospasm) in neuro not ○ essentially ZERO metabolism to trifluoroacetate ○ degrades to carbon monoxide in a dry CO2 absorber ○ lowest potency & lowest blood solubility of VA’s ○ unique in producing an increase in sympathetic nervous system outflow despite this increase, BP is decreased similarity to the other volatile agents ○ produces a transient significant surge in catecholamine 5 10 Fluothane Forane suprane great THR cases ○ f only Desflurane produced significant QT prolongation (no increase in dysrhythmias notes) ○ isoflurane & desflurane increase HR 5-10% may see > increase with rapid increase in delivered concentration ○ less reduction in airway resistance with desflurane d/t direct effect on bronchial smooth muscle d/t it’s pungency so not the drug of choice with bronchoconstriction ○ at 1 MAC of Desflurane —> reduces hepatic blood flow by 30% ○ can produce carbon monoxide Sevoflurane ○ Least amount of airway irritation of VA’s good for inhalation induction (also halothane) d/t low pungency ○ Metabolism 2-5% metabolized which is much greater than isoflurane or desflurane (but has not been associated with injury to renal concentrating mechanisms in humans) ○ not metabolized to triflouroacetate does not produce a renal concentrating injury ○ no change in HR @ < 1 MAC modest increase @ greater concentrations ○ smallest reduction in hepatic blood flow, regardless of dose hepatic arterial buffer response preserved with isoflurane & sevoflurane ○ 0% metabolized to trifluroacetylated intermediates volatile of choice with cirrhosis ○ Can produce Compound A & produces greatest heat when degraded Nitrous Oxide ○ Concerns increased postoperative n/v of inactivation of vitamin B12 anti-neuroprotective effect DNAmyelin expansion of an air-filled structure or bubble effects on embryonic development ○ causes less decrease in minute ventilation & increase in PaCO2 than the volatile agents d/t less decrease in tidal volume greater increase in respiratory rate Xenon ○ no significant myocardial depression or change in coronary blood flow ○ provides some analgesia, less than nitrous Minimum alveolar concentration (MAC) ○ defined as the alveolar concentration of an anesthetic at 1 atmosphere that prevents movement in response to a surgical stimulus in 50% of patients ○ MAC values are roughly additive Things that increase MAC analgesic effects ultane methionine Sythetase activity ○ increased CNS neurotransmitter levels acute cocaine or amphetamine intoxication ○ upregulation of CNS response due to chronically reduced neurotransmitter levels ○ hyperthermia ○ hypernatremia ○ red hair (19% increase in MAC) Things that decrease MAC ○ increasing age (BIGGEST ONE) ○ metabolic acidosis ○ hypoxia ○ alpha-2 agonists ○ hypothermia ○ hyponatremia ○ pregnancy (30% decrease, d/t progesterone) MAC-awake & MAC-BAR ○ MAC-awake = alveolar concentration @ which the patient opens eyes to command ○ MAC-BAR = alveolar concentration that blunts adrenergic response to noxious stimuli 1.5 MAC CMRO2 & EEG ○ CMRO2 decrease consistent with the decrease in spontaneous cortical neuronal activity once an isoelectric EEG is attained, no further decrease in CMRO2 occurs isoflurane, desflurane, sevoflurane ○ neither isoflurane, desflurane, or sevoflurane produces seizure activity on the EEG CBF, coupling, & autoregulation ○ Cerebral blood flow Iso, Des, & Sevo all produce dose-dependent increases but at < 1 MAC, increases in CBF are minimal Isoflurane will produce GREATEST increase in CBF ○ Uncoupling of CMRO2 & CBF? CBF increases despite decreases in CMRO2 uncoupling versus 2 separate effects ○ intrinsic autoregulation of CBF is diminished in dose-dependent fashion by volatile agents d/t direct vasodilation produced CBF normally remains constant within a range of MAP 50-150 mmHg. In the presence of high concentrations of volatile, CBF becomes pressure dependent takeaway = autoregulation > impaired @ higher MAC values Intracranial pressure luxury perfusion ○ At >1 MAC, isoflurane, desflurane, & sevoflurane begin to produce similar mild increases in ICP desflurane might produce slightly greater increase (pungency?) sevoflurane is the LEAST pungent & produces the LEAST airway irritation, so may produce less coughing or bucking on the tube which can markedly increase ICP This increased ICP may be blunted by hyperventilation or the co-administration of propofol or barbiturates DO NOT HYPERVENTILATE a TBI patient, HYPOCAPNIA contraindicated CSF production & resorption ○ changes in CSF production & resorption play an insignificant role relative to ICP changes associated with changes in cerebral blood flow CBF response to hyper & hypocapnia ○ cerebral blood flow changes 3% from baseline for each 1 mmHg change in PCO2 ○ hypocapnia will BLUNT the increase in CBF seen with volatile agents ○ should not decrease CO2 below 30-35 mmHg Cerebral protection ○ when anesthetic agents are used to lower blood pressure, isoflurane & other volatile agents appear to improve cerebral tissue oxygenation vs. the sedative-hypnotics the difference is likely d/t the reduction in CMRO2 combined with maintenance of, or a modest increase in, cerebral blood flow VA’s & IV sedatives decrease CMRO2 VA’s increase CBF Neuromonitoring ○ Evoked potentials ○ sensory-evoked potentials all volatiles cause a dose-dependent increase in latency & decrease in amplitude of all cortical SEP’s ○ motor-evoked potentials Nitrous Oxide ○ Data on effects of nitrous oxide on CBF, CMRO2, & ICP is conflicting ○ injury is greater in the face of temporary ischemia when nitrous oxide is added to isoflurane conditioning negates ○ Typically increases PVR only slightly, but may be markedly increased with pre-existing pulmonary hypertension neonates ○ Does not provide direct relaxation of skeletal muscle ○ nitrous oxide decreases the activity of methionine synthetase which is involved in the formation of myelin & DNA Hemodynamics ○ Blood pressure dose related decrease due to: preischemic effects potent relaxation of vascular smooth muscle no significant differences between volatiles nitrous oxide may increase BP slightly d/t sympathetic stimulation Contractility ○ healthy patient = no reduction in contractility by any of the volatiles ○ cardiac patient (EF < 40%) = slight reduction in contractility, no impairment of functional reserve ○ ventricular response to acute increase in preload volatiles — no change propofol — reduced Other circulatory effects ○ automaticity & conduction slow SA node discharge rate slowed conduction in His-purkinje & ventricular conduction pathways ○ prolongation of the QT interval all volatiles may slightly prolong QT intervals only Desflurane produced significant prolongation (no increase in dysrhythmias notes) Coronary steal, ischemia, & cardiac outcomes ○ most studies suggest that determinant of myocardial oxygen supply & demand rather than the anesthetic, are of far greater importance to patient outcomes Cardioprotection — ischemic conditioning ○ preconditioning following a brief period of coronary occlusion & ischemia ischemia signals a cascade of intracellular events which reduced myocardial injury from ischemia provides 2-3 hours of protection ○ Greatest benefit for pre-ischemic conditioning = volatile given before, during, & after ○ other drugs which also create ischemic preconditioning adenosine, opioid agonists, K-ATP channel openers ○ sulfonylurea drugs close K-ATP channels, abolishing preconditioning & should be discontinued 24-48 hours preop in high risk patients Autonomic nervous system ○ the volatile anesthetics produce a dose-dependent impairment of reflex control mechanisms patient’s ability to compensate for hypovolemia with vasoconstriction & tachycardia is reduced ○ Baroreflex function returns to normal more rapidly following discontinuation of the less blood soluble agents sevoflurane & desflurane faster than isoflurane Ventilatory effects ○ all volatile agents & N2O produce a dose-dependent reduction in minute ventilation & subsequent increase in PaCO2 via: decreased tidal volume an incomplete increase in respiratory rate ○ general anesthesia produces a reduction in FRC children have INCREASED MV:FRC ratio ○ Inspiration 40% intercostal muscles (compromised with analgesia) 60% diaphragm (remains essentially intact) Response to CO2 ○ all inhaled anesthetics produce a dose-dependent reduction in ventilator response to hypercarbia ○ apneic threshold PaCO2 below which respiratory drive ceases 505 mmHg below resting PaCO2 in a spontaneously breathing patient Response to hypoxia ○ all inhaled agents produce a dose-dependent reduction in the ventilator response to hypoxia Bronchioles smooth muscle tone ○ volatile agents relax airway smooth muscle Pulmonary vascular Resistance & HPV ○ VA’s = minimal to no effects on PVR ○ HPV is impaired to some extent by all the inhaled agents Hepatic Effects ○ all VA’s reduce hepatic blood flow to some extent Neuromuscular effects ○ 30-40% reduction in rocuronium in presence of VA’s mechanism = postsynaptically @ the nicotinic Ach receptor of NMJ Malignant Hyperthermia ○ uncontrolled release of calcium ○ s/s = increased ETCO2 (early sign), tachycardia, tachypnea, metabolic acidosis, muscle rigidity, rhabdomyolysis potentially, increased temperature (late finding) ○ N2O & xenon are considered non-triggers Maternal Effects ○ dose-dependent decrease uterine smooth muscle tone ○ at > 1 MAC uterine atony may be a problem when this is bad — following delivery when uterine contraction is important in reducing ongoing blood loss (impairs the response to oxytocin) when this is good — need for brief uterine relaxation (eg. Retained placenta following delivery Fetal effects ○ neonatal effects of anesthesia for cesarean section APGAR score — no difference between general anesthesia & regional anesthesia more sensitive tests reveal transient depression following general anesthesia (NOT REGIONAL) which resolves by 24 hours in fetus Degradation ○ Compound A produces renal injury in rats a vinyl ether produced from breakdown of sevoflurane in CO2 absorbents increased production in: ○ low-flow or closed circuit anesthesia ○ warm or desiccated CO2 absorbents ○ bara lime > soda lime > absorb humans Zero case reports of renal injury attributable to sevoflurane since its introduction FDA recommendation ○ >/ 1 L/min fresh gas flow up to 2 MAC hours ○ >/ 2 L/min fresh gas flow after 2 MAC hours ○ Carbon monoxide & Heat Carbon monoxide production Bara lime > soda lime > ambsorb Desflurane >> Sevoflurane increased a higher absorbent temperatures greatly increased with desiccated absorbent Heat produced by interaction of volatile with absorbent, particularly desiccated absorbent ○ greatest with sevoflurane ○ greatest with bara lime Metabolism ○ metabolism of some of the volatile anesthetics produces significant fluoride concentrations &, in some cases, injury to the renal collecting tubules ○ methoxyflurane & enflurane can produce a high output renal insufficiency thought related to: peak serum fluoride concentration duration of elevated fluoride concentration Clinical uses — induction ○ halothane or sevoflurane good for inhalation induction d/t low pungency & high acceptance ○ advantages of inhalation induction maintenance of spontaneous respirations self-limiting generally well-accepted Clinical uses — maintenance ○ advantages of volatile agents for anesthetic maintenance easily administered easy & rapid titration of deep anesthesia highly effective in preventing recall easily monitored via end-tidal concentrations ○ additional benefits relaxation of skeletal muscle typically well preserved cardiac output & CBF predictable recovery provide some protection from ischemic injury MAC #’s to know ○ 0.1 MAC = will reduce ventilator drive to hypoxia by 25-75% ○ 0.15-0.5 MAC = MAC-awake, hysteresis exists between losing & regaining consciousness ○ 1 MAC = isoflurane, desflurane, & sevoflurane begin to produce similar mild increases in ICP 1 MAC of desflurane reduces hepatic blood flow by 30% direct relaxation of skeletal muscle — effect most pronounced at > 1 MAC of volatile Uterine atony may be a problem ○ 1.3 MAC = will prevent movement in patients, but not universally ○ 1.5 MAC = MAC-BAR burst suppression occurs ○ 2 MAC = EEG becomes isoelectric Uptake & distribution (6 Q’s) Key points At equilibrium P CNS = P blood = P alveoli modern vaporizers are described as flow compensated, variable bypass, out-of-circuit, agent specific, flow-over, temperature & pressure compensated Gases equilibrate based on PARTIAL PRESSURES rather than concentration The partial pressure of a gas in solution is defined by the partial pressure in the gas phase with which it is in equilibrium. When there is no gas phase the partial pressure reflects a force to escape out of solution the rate of rise of FA/FI helps us understand the uptake & distribution of inhaled anesthetics, & FA is a useful alternative to direct measurement of brain concentration of inhaled anesthetic In first-order kinetics the time constant can be simply described as volume/flow. Rate of ride of FA/FI can be increased by decreasing the time constant uptake of inhaled anesthetic from the alveoli to the blood has the greatest effect on rate of rise of FA/FI the 2nd gas effect states that the larger volume uptake of a gas (ex- nitrous) will accelerate the rate of rise of FA of companion (2nd) gas washout of the less-soluble inhaled anesthetics is more rapid than that of the more-soluble agents washout of large volumes of nitrous oxide @ the conclusion of an anesthetic may reduce alveolar oxygen concentration resulting in hypoxia (aka diffusion hypoxia) Physical characteristics ○ P CNS = P blood = P alveoli ○ inhaled anesthetics are rapidly transferred bi-directionally from alveoli to blood to CNS ○ anesthetizing concentrations of volatile anesthetic can be rapidly achieved in the CNS d/t low capacity of the plasma & tissues to absorb them ○ rate of delivery & removal from the lungs far exceeds the effects of metabolism, excretion, & redistribution on the VA’s Vapor Pressure ○ the VA’s are liquid @ 20 degrees Celsius ○ in a closed container molecules will equilibrate between the gas & the liquid phases ○ vapor pressure is the pressure exerted by molecular collisions of the gas against the walls of a closed container independent of the volume of liquid in the container proportional to temperature Latent heat of vaporization ○ The amount of energy consumed when a liquid concerts to a vapor the # of calories required to change 1 gram of liquid into vapor without a change in temperature ○ as liquid moves to vapor energy is consumed temperature drops vapor pressure drops vaporizer output is decreased ○ result in the need for temperature compensation in the vaporizer Anesthetic vaporizer ○ flow compensated the % coming out of the vaporizer is consistent, despite changes in fresh gas flow ○ variable bypass allows only a portion of fresh gas flow to flow through the vaporizing chamber ○ out-of-circuit located outside of the breathing circuit as opposed to a draw-over system anesthetic is introduced to the circuit through a fresh gas line ○ agent specific calibrated for a specific agent filling a vaporizer with an agent having higher vapor pressure than it is designed for will result in delivery of greater than expected concentrations of agents Sevoflurane put in Isoflurane vaporizer = UNDERDOSE Isoflurane put in Sevoflurane vaporizer = OVERDOSE ○ flow-over a portion of the fresh gas flows over the liquid reservoir, picking up vaporized agent depending on the vapor pressure & temperature of the liquid agent ○ temperature compensated accounts for changes in ambient temperature &, more importantly, changes in anesthetic temperature d/t latent heat of vaporization ○ pressure compensated to minimize pressure buildup in the vaporizer d/t positive pressure ventilation or use of the O2 flush &/or one way check valve Gases in solution ○ gases equilibrate based on partial pressures rather than concentration ○ Inhaled anesthetics equilibrate based on their partial pressures in each tissue compartment, not based on their concentrations ○ the partial pressure of a gas in solution is defined by the partial pressure in the gas phase with which it is in equilibrium. Where there is no gas phase the partial pressure reflects a force to escape out of solution ○ the partial pressure of anesthetic in a tissue depends on its concentration & solubility Transfer of anesthetic ○ machine to alveoli is dependent on Fresh gas flows concentration delivered by vaporizer ○ dilution in circuit airway dead space (we can’t do much about this) alveoli (we can decrease by having patient force exhale to get rid of expiratory reserve volume) ○ alveoli to blood diffusion across the alveolar-capillary membrane dependent on: partial pressure difference blood solubility of agent additional dilution in blood ○ vessel-rich group consists of CNS (tissues of desired effect), heart, kidney, liver, GI tract, & glandular tissues majority of cardiac output goes to vessel-rich group (75%), then muscle (19%), then fat (6%) ○ blood to tissues dependent on tissue blood flows (MOST IMPORTANT) partial pressure differences tissue:blood solubilities Why FA/FI ○ the faster we can increase FA relative to FI, the more rapidly induction occurs ○ FA becomes our proxy for measuring concentration of inhaled anesthetic in the brain time constants ○ = volume/flow ○ 1 time constants = 63% ○ 2 time constants = 86% ○ 3 time constants = 95% ○ rate of rise of FA/FI can be increased by decreasing the time constant increasing alveolar ventilation decreasing the FRC — can be achieved by having the patient forcefully exhale prior to initiating the first inhalation of agent Pediatric inhalation induction is faster than adults d/t their smaller FRC relative to their minute ventilation Rise of FA in the presence of uptake ○ the uptake of anesthetic from alveoli into the blood is the most important determinant of the rate of rise of Fa/FI ○ uptake into blood is proportional to solubility of the agent in blood cardiac output/pulmonary blood flow alveolar to mixed venous partial pressure difference ○ solubility the higher the solubility of an agent in blood, the slower the rate of rise of FA/FI more agent is leaving the alveoli & entering the blood REMEMBER gases equilibrate based on partial pressure, NOT concentration the partial pressure is the force the gas is exerting to leave the liquid phase & enter the non-existent gas phase increasing solubility in blood means that more agent will be accommodated in the blood before partial pressures equalize between the alveoli & the blood ○ cardiac output increasing cardiac output exposes more blood to the alveolar to mixed venous partial pressure difference which is driving agent into the blood, so slows the rise of FA/FI ○ alveolar to mixed venous partial pressure difference (PA-PV) the driving force for movement of agent into blood over time, as blood levels begin to be achieved, less agent will enter the blood factors that increase rate of rise FA/FI ○ FGF’s high high flows (>4 L/min) minimize mixing of exhaled gas with fresh gas, reducing dilution, & speeding the rate of rise of FA) ○ Decreased FRC Decreased FRC decreases volume in the volume/flow equation, resulting in a shorter time constant ○ Alveolar ventilation increased increases flow in the volume/flow equation, resulting in a shorter time constant ○ Second gas effect the large volume uptake of 1 gas (the first gas) accelerates the rate of rise of FA of a companion gas (the 2nd gas) ○ Low blood solubility decreases uptake into blood ○ Cardiac output decreased less mixed venous blood per time is exposed to the alveoli so less uptake into blood occurs ○ Inspired concentration increased overpressurization — giving a higher inspired concentration (FI) than the desired alveolar concentration (FA) Concentration effect — the loss of anesthetic from alveoli into blood produces 2 effects concentration of the remaining gas in a smaller volume augmented inflow of new gas d/t the loss of volume into the blood ○ is clinically insignificant with the volatiles, only makes a difference with an agent given in high concentrations such as nitrous oxide ○ Alveolar to mixed venous partial pressure difference increased greater partial pressure difference equals > driving force, thus initially when Pv is zero there is a rapid change in Pv, producing a rapid reduction in PA-PV it is the rapid reduction in PA-PV which produces the > change in FA/FI ○ Spontaneous respiration vs. controlled In a spontaneously breathing patient, respirations are depressed by increasing concentration of volatile anesthetics this respiratory depression (decreased alveolar ventilation) will slow the rate of rise of FA offers some safety in preselecting overdose in a spontaneously breathing patient by controlling the patient’s respirations it is possible to more rapidly obtain a deeper level of anesthesia but you give up the negative feedback safety feature of spontaneous respirations Perfusion Effects ○ reducing cardiac output increases the rate of rise of FA/FI having the > effect on the more soluble agents ○ cardiovascular depression related to high concentrations of volatile agents may result in a positive feedback loop & further increase the alveolar partial pressure V/Q mismatch right-to-left shunt ○ R-L shunt reduces the amount of blood traversing the pulmonary capillaries for alveolar exchange ○ 2 effects occur a more rapid rise in FA d/t what looks to the alveoli like decreased CO a decrease in arterial partial pressure of agent (Fa) d/t mixing of blood which bypasses the lungs with blood traversing the lungs for exchange ○ Result induction is delayed, despite the increased FA effect is greater with the less-soluble agents Metabolism (biotransformation) ○ metabolic pathways for the inhalation anesthetics are rapidly saturated & result in minimal metabolism of drug ○ the pharmacokinetics of inhalational agents are best described by a 5 compartment model Alveoli, VRG, muscle, fat, & adipose adjacent to lean tissue Exhalation & Recovery ○ typically describes as the ratio of FA/FA0 FA0 being the FA @ the time the agent was discontinues washout of the anesthetic is much more rapid with the less soluble anesthetics desflurane, sevoflurane, & nitrous PCNS falls rapidly due not only to the declining FA, but also continuing redistribution to the muscle & fat emergence typically requires an 80-90% reduction in P CNS Diffusion Hypoxia ○ washout of large volume of nitrous oxide when discontinued can reduce alveolar partial pressures of: oxygen (resulting in hypoxia) carbon dioxide (reducing respiratory drive & potentially worsening any hypoxemia) ○ 100% oxygen should be used when discontinuing nitrous oxide @ the end of an anesthetic Stages of Anesthesia ○ Stage I — analgesia or discontinuation ○ Stage II — excitement or delirium eyelash reflex disappears but other reflexes remain intact & coughing, vomiting, & struggling may occur ○ Stage III — surgical anesthesia from onset of autonomic respiration to respiratory paralysis where we want to be ○ Stage IV — from stoppage of respiration til death anesthetic overdose causes medullary paralysis with respiratory arrest & vasomotor collapse pupils are widely dilated & muscles are relaxed Test 3 material Opioids MOA of opioids = antinociception ○ presynaptic action results in hyperpolarization & decreased release of NT —> G protein coupled receptor binding —> Ca++ channel suppression/K+ channel activation —> hyperpolarized membrane —> decreased release of excitatory NT’s (Ach, NE, dopamine, glutamate, substance P) Opioid Receptors ○ Mu1 = euphoria, bradycardia ○ Mu2 = depression of ventilation ○ Mu3 = dysphoria, sedation, diuresis Opioids CV effects ○ morphine-induced bradycardia d/t stimulation of vagal nuclei in medulla ○ Morphine-induced histamine release —> results in decreased venous tone variable decreases in SVR, MAP Opioids Ventilation effects ○ all opioids produce dose-dependent ventilatory depression ○ mu receptor activation results in direct depression of ventilation centers in brainstem ○ increase in resting PaCO2 with shift of CO2 response curve to right ○ incomplete compensatory increase in TV, evidenced by predictable increase in PaCO2 Opioids Cough suppression ○ direct depressant effects on medullary cough centers Opioids can cause “wooden chest syndrome”, but likely r/t laryngeal musculature contraction/upper airway issues CNS effects ○ increased vagal tone, decreased sympathetic tone ○ In ABSENCE of hypoventilation; decreased cerebral blood flow, possible decrease in ICP. Hypoventilation —> hypercapnia which can increase CBF/ICP, caution in head injury Opioids show no indication of seizure activity with occasional myoclonus Opioids can cause MIOSIS via excitatory stimulation of ANS component Edinger-Westphal nucleus in oculomotor nerve Opioids precede production of analgesia, not tied to analgesic effect (pt. Can be very sleepy w/o relief of pain) Opioids can cause biliary smooth muscle spasm (largest contributor with fentanyl), increased biliary pressure, epigastric distress ○ caution use if planned intraop cholangiogram ○ tx = naloxone, nitroglycerin, glucagon Opioids can delay gastric emptying d/t increased pyloric tone (aspiration risk), constipation d/t decreased peristalsis & prolonged transit time Opioids effects on N/V ○ direct stimulation of CTZ by acting as partial agonist @ dopamine (d2) receptor ○ effect on vestibular apparatus ○ depresses vomiting center in medulla ○ increased GI secretions & delayed transit Opioids that have provocation of cough = fentanyl, sufentanil, alfentanil ALL opioids readily transported across placenta ○ neonatal depression from placental transfer ○ dependency with chronic maternal use Opioid overdose s/s = hypoventilation, miosis, coma ○ tx= airway management—> ventilatory support —> opioid antagonist Opioid agonists listed most potent to least ○ Sufentanil (most potent) don’t give with impaired renal function rapid onset is r/t lipid solubility more rapid induction/emergence, earlier extubation vs. fentanyl/morphine ○ Remifentanil safe to use in liver/renal disease metabolism decreased by 20% with hypothermia abrupt discontinuation of analgesia —> OIH ○ Fentanyl highly lipid soluble —> rapid onset, large volume of distribution, long elimination half time Shorter duration r/t rapid redistribution to fat, skeletal muscle Metabolism dependent on CYP3A marked reduction in MAC of VA or dose of propofol for GA, blunts hemodynamic response to laryngoscopy & surgical incision bradycardia d/t depression of carotid sinus baroreceptor reflex Benzos + fentanyl = marked synergism in hypnotic & ventilators depression effects —> decreased protocol requirements for GA ○ Buprenorphine ○ Alfentanil rapid onset d/t LOW pka, thus high degree of non-ionized drug @ physiologic pH metabolism = wide interindividual variability r/t hepatic enzyme activity smaller/more rapid equilibration of Vd SE = potential for acute dystonia in untreated Parkinson’s disease ○ Hydromorphone Primary conjugation with glucuronide acid in liver metabolite = hydromorphone-3-glucuronide —> neuroexcitatory effects Suitable for PCA ○ Morphine Dull pain relieved more effectively than sharp, intermittent pain, effective against visceral & somatic pain Less than 0.1% of IV morphine gains access to CSF @ time of peak plasma concentration d/t: poor lipid solubility, high degree of ionization @ physiologic pH, protein binding, rapid conjugation with glucuronic acid (glucuronidation—this is the primary reason there’s a rapid decrease in plasma concentration) peak pharmacological effects lag behind peak plasma concentration (HYSTERESIS) Metabolites = morphine-3 glucuronide (75-85% most common, inactive), morphine-6 glucuronide (5-10%, 650x analgesic potency, active) accumulation of morphine-6-glucuronide is significant issue with renal dysfunction Minimal excretion/low excretion in breast milk ○ Meperidine (least potent) mu & kappa opioid receptor agonist similar structure to local anesthetics & atropine —> Increased HR metabolite = normeperidine 50% analgesic properties of meperidine CNS stimulant (myoclonus, seizures, delirium, confusion, hallucinations) don’t use in renal patients commonly used in postoperative shivering Opioids associated with pulmonary uptake = sufentanil & fentanyl elimination half-time of opioids from greatest to least ○ fentanyl, sufentanil, alfentanil, remifentanil context sensitive half-time greatest to least ○ fentanyl, alfentanil, sufentanil, remifentanil (basically context-insensitive) Pentazocine & Butorphanol —> increase in plasma catecholamines (increased HR & BP) Nalbuphine —> NO evidence of catecholamines release Naloxone concerns with renarcotization d/t duration of agonist > duration of antagonist Opioid tolerance mechanism is not a function of enzyme induction (no increase in the metabolism of opioids) opioid agonists-antagonists ○ analgesia with less depression of ventilation, less potential for dependence Mechanisms of Pain Perception likely occurs in thalamus, discrimination occurs in cortex 4 components of nociceptors = transduction, transmission, modulation, perception afferent pathways ○ 1st-order neurons = cell body in DRG ○ 2nd-order neurons = cell body is dorsal horn ○ 3rd-order neurons = cell body in thalamus nerve stimulator modulates pain via gate theory ○ gate theory = large myelinated A beta fibers dominate communication & inhibit transmission of A delta/C primary hyperalgesia occurs @ site of injury secondary hyperalgesia increases size of “wound” to include adjacent, non-injured tissue central sensitization - alterations in the excitability and response of 2nd-order neurons/interneurons in the spinal cord the longer acute pain is present the higher the likelihood of developing chronic pain CRPS I develops after an initiating noxious event, CRPS II develops after nerve injury greatest benefit of regional anesthesia is in patients at highest risk of complication Local Anesthetics Onset, duration, & potency are related to pKa, lipid solubility, protein binding, concentration/dose, vasoactive properties ○ higher pKA slower onset increased lipid solubility delays onset of action, increases duration of action, equates to increased potency increased protein binding correlates with increased duration of action increasing dose/concentration results in more rapid onset vasodilation reduces duration of action increased myelination = more rapid conduction, increased diameter = more rapid conduction drugs that alter RMP = opioids, alter TP = IV anesthetics, VA’s local anesthetic decrease rate of depolarization by preventing Na+ influx such that THRESHOLD POTENTIAL is NEVER reached. LA’s DO NOT alter RMP or TP local anesthetics can access the intracellular receptor in voltage-gated sodium channels only when the channel is in the active-open state Tonic inhibition vs. phasic inhibition ○ tonic = slower firing fibers are less susceptible to blockade ○ phasic = faster firing fibers are more susceptible to blockade Fibers affected in differential blockade ○ 1st = B preganglionic sympathetic ○ 2nd = A delta ○ 3rd = A alpha ○ 4th = C sensory Rates of absorption from greatest to least = ICEBS ○ intercostal > caudal > epidural > brachial plexus > femoral/sciatic nerve ○ site of injection most important in absorption Esters/amides are not affected by renal failure ○ amides are dependent on hepatic blood flow ○ esters subject to hydrolysis by plasma cholinesterase Amides are slower & more complex than esters —> GREATER chance for cumulative effects & systemic toxicity Chloroprocaine ○ rapid onset despite high pKa, attributed to INCREASED CONCENTRATION ○ rapid metabolism, able to deliver in HIGH concentrations (2-3%) ○ reduces effects of concurrent/subsequent epidural bupivicaine, opioids Benzocaine ○ potential to produce methemoglobinemia (doses > 300 mg, neonates) can also occurs with cetacaine Prilocaine ○ metabolite = o-toluidine can accumulate after large doses (>600 mg) & precipitate methemoglobinemia Bupivicaine ○ selective cardiotoxicity, high affinity for Na+ channels in cardiac muscle cells ○ highly protein bound, very lipid soluble Ropivicaine ○ decreased potential for neurotoxicity & cardiotoxicity compared to bupivicaine d/t missing alkyl/methyl group Infiltration analgesia ○ bupivicaine max dose = 2 mg/kg, 3mg/kg with epi never give > 175 mg ○ lidocaine max dose = 5 mg/kg, 7 mg/kg with epi never give > 300 mg Bier Block ○ most common LA = lidocaine ○ alternative LA = prilocaine, mepivicaine DO NOT USE BUPIVICAINE!! ○ at least 20 minutes of tourniquet time lessens systemic toxicity concerns, effective surgical time window properties of individual LA (more effective in short/moderate duration), site of injection (more effective in infiltration & peripheral nerve injection) PH adjustment ○ speeds onset of block, increases depth/density of block, increases segmental spread of epidural block ○ increases the fraction of non-ionized drug molecules Toxicities of LAs are additive, not independent or synergistic Allergic reactions with LA’s are most commonly d/t esters secondary to para-aminobenzoic (PABA). There is no cross-sensitivity between esters & amides Neural tissue toxicity ○ spinal nerves & nerve roots are much more susceptible than peripheral nerves ○ LA-induced increases in intracellular Ca++ concentrations may be responsible ○ permanent neurological injury after regional anesthesia very rare event Transient neurological symptoms (TNS) is associated with normal sensory/motor exam ○ occurs after SAB injection of LA Cauda equine syndrome ○ results from diffuse injury across lumbosacral plexus ○ presents as various degrees of sensory loss, bowel/bladder dysfunction, paraplegia Methemoglobinemia is implicated with topical administration of prilocaine, benzocaine, cetacaine ○ otaludine metabolite in prilocaine Potency for CNS & CV toxicity correlates with potency of LA Increasing concentration of Bupivicaine (more potent LA) often produces CV collapse Bupivicaine produces significantly > effect on cardiac electrophysiology, has much higher affinity for resting & inactive cardiac Na+ channels, bupivicaine dissociates from receptor much more slowly during repolarization & diastole Treatment of LAST ○ airway management ○ suppression of seizure activity ○ smaller doses of epi ○ avoid vaso, beta blockers, ca++ channel blockers Test 4 Material NMBs and Reversal (4 Q’s) Key Points Many different conditions are associated with change in the makeup of the nicotinic acetylcholine (NAChrs) and will effect response to both depolarizing and nondepolarizing NMBs An increase in the “immature” forms of NAChRs may result in excessive potassium release following administration of a depolarizing NMB Both succinylcholine and the non-depolarizing NMBs act via binding the alpha subunits of the NAChRs Other than the distinction between the depolarizing and non-depolarizing, the NMBs are typically classified based on onset and DOA Succinylcholine results in the fastest onset with the least variability and shortest duration of the NMBs. Monitoring of the typical succinylcholine block reveals no fade on TOF monitoring, and no Post-tetanic facilitation. There are significant side effects with all NMBs, with distinct differences between succinylcholine and the non-depolarizing NMBs Succinylcholine is a trigger for MH which may occur due to mutation in the ryanodine receptor resulting in excessive calcium release While widely used previously, it is now believed that routine use of succinylcholine in otherwise healthy children is contraindicated. non-depolarizing NMB results from competitive antagonism of Ach binding the NAChR. Monitoring of non-depolarizing block reveals fade with repetitive stimulation and the presence of post-tetanic facilitation. As a general rule, decreased potency results in a more rapid onset of NMB The volatile anesthetics produce a dose-dependent potentiation of the NMBs resulting in reduction in necessary dosage and prolongation of effect Clinical assessment of recovery from NM blockade is unreliable at best and predisposes the patient to residual postoperative neuromuscular blockade and a marked increase in morbidity Even in the use of a nerve stimulator, in the absence of objective measurement, results in a marked increase in the likelihood of residual paralysis and the associated complications Various muscles have differing sensitivity to, and recovery from, NMB and monitoring at particular sites may under or over estimate onset and recovery from block The non-depolarizing NMBs may be antagonized with an anticholinesterase which results in increased levels of Ach at the NMJ to compete with the NMB drug for the alpha subunit of the NAChR The anticholinesterases are paired with an antimuscarinic for reversal of neuromuscular blockade to prevent the unwanted muscarinic effects of increased acetylcholine. It is important to match the appropriate antimuscarinic with the anticholinesterase to match the onset of effect The selective relaxant binding agent (SRBA) sugammadex encapsulates and renders ineffective the aminosteroidal NMBs, in particular rocuronium and vecuronium The availability of sugammadex changes the way we think about a difficult airway scenario, CICO, and certain neuromuscular disorders, in that recovery from neuromuscular block with rocuronium and sugammadex may be more rapid than spontaneous recovery from succinylcholine Significant consequences exist for patients with inadequate reversal of muscle relaxant at the conclusion of surgery Prolonged use of neuromuscular blockade in the ICU is associated with multiple concerns, including myopathy, polyneuropathy, and the potential for hyperkalemic arrest following use of succinylcholine for emergent reintubation LOOK AT 2023 ASA practice guidelines (slide on ppt) ○ Highlights This practice guideline provides evidence-based recommendations on the management of neuromuscular monitoring and antagonism of neuromuscular blocking agents. The objective is to guide practice that will enhance patient safety by reducing residual neuromuscular blockade. It is recommended to use quantitative neuromuscular monitoring at the adductor pollicis and to confirm a recovery of train-of-four ratio greater than or equal to 0.9 before extubation. Sugammadex is recommended from deep, moderate, and shallow levels of neuromuscular blockade that is induced by rocuronium or vecuronium. Neostigmine is a reasonable alternative from minimal blockade (train-of-four ratio in the range of 0.4 to less than 0.9). Patients with adequate spontaneous recovery to train-of-four ratio greater than or equal to 0.9 can be identified with quantitative monitoring, and these patients do not require pharmacological antagonism. Nicotinic Ach Receptor Isoforms ○ Mature (epsilon)-confined to the end-plate region of the muscle membrane ○ Immature (gamma)-may be expressed anywhere in the muscle membrane ○ A7-immature ones that proliferate, expressed throughout the muscle membrane in response to denervation/injury Choline acts as a full agonist at the A7 receptor (works here only) Prolonged presence of agonist (choline) does not produce desensitization of the A7 receptor, can lead to excessive K+ release Receptor regulation ○ Upregulation-increase in the number of “immature” Ach receptors (and A7 receptors), both junctional and extrajunctional in response to decreased stimulation of the NMJ (immobilization, severe injury) Increased sensitivity to Ach and succ (Na/K channels stay open longer) Resistance to non-depolarizers (increased A7s, partial agonist of some NDMRs at “immature” receptors) ○ Downregulation-secondary to presence of excess agonist over time Resistance to succ Sensitivity to non-depolarizers Anticholinesterase use for MG Organophosphate poisoning Anticholinesterase poisoning Agonism of A7 reduces organ system damage in abdominal sepsis Safe to use succ during the first 24-48 hours post-burn Conservative approach: avoid succ after 24 hours and for at least 1 year afterwards Resistance to all NDNMBs in burns > 30% TBSA beginning at 1 week post-injury and peaking 5-6 weeks ○ Onset is delayed (can be partially overcome with increased doses) ○ Recovery from NDNMB is more rapid ED50 and ED95 Dosages required to reduce single twitch height by 50% and 95% from baseline Onset time Time from administration to disappearance of single twitch Inversely related to dose Duration of Action Directly related to dose DUR 25% Time from administration to return to 25% of baseline twitch height DUR 0.90 or total duration of action Time from administration to return of TOF ratio to 0.90 Succinylcholine Acts like acetylcholine to activate the nACH receptor Hydrolyzed in the plasma by pseudocholinesterase (aka plasma cholinesterase, butyrylcholinesterase) Fastest onset, shortest duration, most reliable (least amount of variation in onset time) Dose-dependent reduction in single-twitch height, lack of fade on TOF monitoring, does not exhibit post-tetanic facilitation Phase II block may result from: large bolus dose (> 10X ED95), repeated boluses, prolonged infusion Phase II block exhibits fade on TOF and post-tetanic facilitation Intubating dose: 1-1.5 mg/kg Atypical butyrylcholinesterase/Dibucaine # ○ dibucaine-LA which inhibits normal butyrylcholinesterase to a greater extent than it does typical cholinesterase ○ Homozygous typical-dibucaine number 70-80, normal duration of block ○ Heterozygous atypical-incidence 1:480, dibucaine number 50-60, increased duration of block by 50-100% ○ Homozygous atypical-incidence 1:3200, dibucaine number 20-30, increases duration of block to 4-8 hours SEs: bradydysrhythmias, ventricular dysrhythmias, fasciculations, myalgias,increased intragastric pressure, increase IOP, increased ICP, hyperkalemia, masseter spasm, MH Myalgias more common in: women, minor procedures, ambulatory (outpatient) surgery Increased IOP question: picture of guy….ALWAYS AIRWAY FIRST! ○ Transient increase by up to 15 mmHg ○ Attenuated by lidocaine and opioid ○ Concern over extrusion of ocular contents with an open globe injury BLACK BOX WARNING: succ administration may result in rhabdo and fatal hyperkalemia in children with myotonia and muscular dystrophies which may be undiagnosed, FDA states succ should only be used for emergency intubation ○ The routine administration of succ to healthy children should be discontinued. In apparently healthy children, intractable cardiac arrest with hyperkalemia, rhabdomyolysis, and acidosis may develop after succ administration, particularly in children with unsuspected muscular dystrophy of the Duchenne type. NOT A FUNCTION OF THE RYANODINE RECEPTOR. WE TYPED IN DUCHENNE AND BECKERS! Masseter spasm (trismus) ○ Jaw muscle rigidity with limb muscle flaccidity following admin of succ ○ >80% of time not associated with rigidity of other muscles ○ Association with rigidity of other muscles is an early warning sign for MH ○ MHAUS suggests: close observation of patient with masseter spasm for at least 12 hours, follow CK and urine myoglobin at 6 hour intervals for 36 hours ○ Miller: currently no indication exists to change to a “non-triggering” anesthetic in instances of isolated masseter spasm BUT really just probably dont use VAs (according to Ron) MH-effects the ryanodine receptor resulting in excessive Ca++ release ○ Addition of succ to VAs markedly increases the incidence of MH relative to VAs alone Following use of anticholinesterase drugs…(patient scenario question on test?) ○ Neostigmine and pyridostigmine inhibit butyrylcholinesterase ○ Duration of succ NMB will be significantly increased if given after an anticholinesterase 90 mins following neostigmine, butyrylcholinesterase activity is still bronchoconstriction Atracurium (Tracrium) Intubating dose: 0.5 mg/kg Onset: 3-5 mins Metabolism ○ Ester hydrolysis ○ Hoffman elimination ○ Renal 10% Metabolites: laudanosine and acrylate Hemodynamics: at higher doses may see hypotension and tachycardia secondary to histamine release Question: cardiac s/s are due to histamine release!! Ester hydrolysis: non-specific esterases which also degrade remifentanil, esmolol, tamiflu Hoffman elimination ○ Non-enzymatic ○ pH and temp dependent ○ Metabolism increased at higher temperature and higher pH (alkalosis) Cisatracurium (Nimbex) Intubating dose: 0.15-0.2 mg/kg Onset: 4-7 mins Predictable and independent of liver fx Metabolism: hoffman elimination, organ dependent (renal) Metabolites: laudanosine and acrylate Hemodynamics are stable, MINIMAL HISTAMINE RELEASE Mivacurium (Mivacron) Intubating dose: 0.2 mg/kg Histamine release can become an issue!! Histamine release like atracurium! Metabolism: plasma cholinesterase (like SUCC!) Hemodynamics: potential for hypotension and tachycardia with histamine release Duration prolonged with atypical pseudocholinesterase Combining 2 drugs of the same class tends to produce an additive effect Combining drugs from different classes will result in a synergistic effect If a drug with markedly different duration is added for maintenance after blockade with a different drug, recover will be more like that of the initial drug administered (the bulk of the receptors were bound by the 1st drug) ○ Example: give pavulon, run out and give roc, going to look more like the 1st drug (synergistic effect) Combo of non-depol. And depol. ○ If succ is used for intubation and a non-depol is given following recovery from the succ, the non-depol will perform just as you anticipate ○ A non-depol given prior to succ as a defasciculating dose will slow onset of succ and shorten its duration ○ MUST recover from succ before you give NPNMB because if not then you dont know atypical pseudo. Vs paralyzed Priming technique with a Non-depol ○ Administration of a sub-paralyzing dose (10% of the intubating dose) 2-4 mins prior to intubating dose ○ Reduces onset time by 30-60 seconds ○ NMB are not an induction agent!! ○ Not done much anymore because of roc High vs low dose non-depolarizer-mostly done with rocuronium Inhaled anesthetics potentiate NMBs ○ Decreased dose, prolonged DOA ○ Desflurane > sevo > iso > halo > nitrous oxide ○ Proposed mechanisms: inhibition of postsynaptic nACHRs LAs-potentiate effects of succ and non-depol Anticonvulsants (phenytoin, carbamazepine) ○ Acute administration potentiates the non-depolarizers ○ Chronic admin increases the clearance and shortens DOA of NDPNMBs ○ Slight prolongation of succ Magnesium ○ Markedly potentiates the NDPs More rapid onset, prolonged recovery time, impairs reversal with anticholinsterase ○ Presynpatic Magnesium induced impairment of Ca++ channels reduces Ach release ○ Postsynaptic Magnesium decreases membrane excitability by inhibiting postsynaptic potentials Hypercalcemia- decreases sensitivity to NDPs due to increased presynaptic release of Ach Lithium- potentiates both succ and NDPs (decreased dose and careful titration) Corticosteroids- long-term therapy in the critically ill concurrent with NMB markedly increases the incidence of critical illness myopathy Dantrolene- “who cares” -RON Critical illness myopathy-diffuse flaccid weakness sometimes including the diaphragm and facial muscles ○ Associated with Prolonged immobilization Prolonged NMB used (particularly aminosteroids, also reported with bezylisoquinoliniums) Corticosteroid use Hypothermia prolongs duration due to impairment of hoffman elimination Elderly patients-smaller dose initially and less frequent dosing needed due to smaller Vd and decreased CO/liver blood flow/GFR (aminosteroids specifically?) Acidosis, hypercarbia, hypokalemia, hypermag-impairs reversal of NDP block with an anticholinesterase Hypokalemia-potentiates NDP block Hepatorenal dysfunction- impaired metabolism and prolonged duration of the aminosteroid NMBs in particular Increased risk of MH-duchenne and beckers No increased risk of MH-myotonic dystrophy Residual paralysis is considered to be a TOF ratio 0.9), no fade here 70-75% receptors blocked-begin to see fade of T4 Tetanus ○ Current supplied at frequencies > 30 Hz produce sustained contraction ○ Fades with NDPNMB ○ Delivered for 5 secs ○ NMJ at ach can increase for 1-3 mins ○ Post tetanic count (PTC) Single twitches delivered 3 secs after tetanus at 1Hz Inversely proportional to depth of block Useful in evaluating ability to reverse with an anticholinesterase or determining sugammadex dose Double burst stimulation (DBS)-alot like TOF but more defined, makes it easier to visualize fade ○ 2 short bursts of current separated by 750 msecs ○ DBS 3,3-2 bursts of 3 stimuli each ○ DBS 3,2-2 burst of 3 followed by a burst of 2 ○ Fade of DBS 3,3 is identical to fade of TOF, DBS 3,2 is better to see fade ○ Able to visualize or feel fade in DBS at a TOF ratio < 0.6 versus 0.4 in standard TOF monitoring ○ some what uncomfortable for the waking patient Desire a TOF ratio of >0.9 to assure adequate neuromuscular recovery Adequate depth of block ○ Moderate (1-2 TOF at APM) Adequate for most surgical procedures ○ Deep (0 TOF at APM) (1-2 PTC at APM) Return of diaphragmatic movement possible ○ Intense (0 PTC) diaphragmatic/laryngeal muscle paralysis Ideal intubating conditions Adductor Pollicis Muscle (facial nerve) ○ Most commonly used, electrode placement is critical ○ Delayed onset relative to diaphragm and laryngeal muscles Decreased tissue blood flows If APM paralyzed, know these are too ○ Delayed recovery relative to diaphragm and laryngeal muscles Due to greater sensitivity of APM If APM has recovered, know these have too Flexor hallucis brevis (medial plantar nerve) ○ Similar to APM Facial (facial nerve), 5-fold increase in facial paralysis here ○ Orbicularis oculi (moves eyelid) Similar to APM ○ Corrugator Supercilii (furrowing brow, squinting) Similar to diaphragm and laryngeal muscles Diaphragm is hard to block because of spare receptors REFER TO REVERSAL CHART FOR NEOSTIGMINE AND SUGAMMADEX!!! (slide 122) Must have at least 2 twitches to reverse with anticholinesterase Anticholinesterase- inhibition of acetylcholinesterase increases the concentration of Ach at the NMJ allowing greater competition with the non-depol NMB Anticholinesterases ○ Quaternary-edrophonium (weak, shallow block, fast but not as effective), neo, pyridostigmine (MG treatment) ○ Tertiary-Physostigmine (not used for reversal because crosses BBB) Neostigmine Inhibition is concentration-dependent Very high concentrations may directly block the ACH receptor Dose > 70 mcg/kg not recommended Ceiling effect such that very dense block can not be antagonized Administration of excessive neostigmine when recover is near complete may result in weakness and upper airway collapse (low dose 20-30 mcg/kg) Acetylcholinesterase throughout the body is inhibited resulting in a need to co-administer with an anticholinergic to avoid excessive PSNS effects Ideally have 3 twitches for reversal, MUST HAVE 2 Dose: 20-70 mcg/kg depending on degree of block Even a small dose may induce weakness so complete spontaneous recovery dont give any Doses greater than the max may induce weakness through block of receptors Reversal is more effective and complete with the intermediate-acting than with the long-acting NMBs IV agents have minimal to no effect on reversal Inhalation agents potentiate NMB and prolong reversal Reversal is faster and more complete in children, slower in elderly Neostigmine is most often paired with glycopyrrolate ○ Onset matches ○ Less tachy than atropine ○ Doesnt cross BBB Increased salivation, increased bowel motility No conclusive association with increase in PONV Edrophonium Weaker bond than seen with neostigmine r/t neostigmine ○ Much more rapid onset ○ Shorter time to peak effect ○ Similar, only slightly shorter DOA Typically administered with atropine due to its rapid onset (NOT ANYTHING WITH HR) ○ Prolonged impairment of baroreceptor sensitivity with atropine Neostigmine 3-5 mg: glyco 0.6-1 mg (5:1 ratio) Neostigmine (20-70 mcg/kg), supplied as 1 mg/ml Glyco 20-25% of the neo dose (supplied as 0.2 mg/ml) Edrophonium (0.5-1 mg/kg), supplied as 10 mg/ml Atropine 10-20 mcg/kg (check concentration) May be adjusted based off patients HR Sugammadex Selective relaxant binding agent (SRBA) Encapsulates steroidal NMBAs Roc > vec >> panc = pipe Effective for roc and vec Affinity for vec is ⅓ that for roc, less molecules of vec so almost as effective Higher potency of vec means less molecules are present that need to be encapsulated, so efficacy of reversal is similar Re establishment of roc block following sugammadex reversal with sugammadex ○ Recommendation to wait 24 hours before re-administering roc ○ May be acceptable sooner in the absence of high-dose sugammadex reversal (use lower doses) ○ On test-pt scenario that was reversed with sug….now give atracurium and cisatracurium because sug doesnt work on those… SEs: no hemodynamic effects, hypersensitivity reactions, coagulation (brief increase in PT/PTT lasting < 60 mins), slight increase in reversal time if patient hypothermic, interferes with oral contraceptives (equivalent to missing one dose, alternative means of BC for one week after sug) Recovery of NM function may be prolonged in: elderly (over 75 years), BMI > 40, pulm/cardiac/ renal disease PONV and pulm complications reduced with sug versus an anticholinesterase Probably not cost effective for routine use but certainly valuable in many situations (CICO, dense block, pt predisposed to residual NM block/postop resp complications) Laparoscopy ○ Deeper level of NM block provides improves surgical conditions at a lower insufflation pressure May prevent hemodynamic consequences by avoiding excessive pneumoperitoneum pressures in selected patients and types of surgeries Has not been shown to be of clear benefit in all cases GUIDELINES FOR PREVENTING SIGNIFICANT RESIDUAL PARALYSIS IN THE ABSENCE OF QUANTITATIVE NEUROMUSCULAR MONITORING Long-acting neuromuscular blocking drugs should be avoided Tactile response to TOF stimulation should be evaluated during surgery If possible, total twitch suppression should be avoided. Neuromuscular block should be managed so there are always 1-2 tactile TOF responses The block should be antagonized at the end of the procedure, preferably with sugammadex if rocuronium or vecuronium have been used. When using neostigmine, reversal should not be initiated before at least 2-4 responses to TOF stimulation are present During recovery, tactile evaluation of the response to DBS is preferable to tactile evaluation to TOF stimulation because it is easier to manually assess fade in the DBS than the TOF response Clinician should recognize that the absence of tactile fade in both the TOF and DBS responses does not exclude significant residual block Some General Guidelines Do not attempt reversal with neostigmine unless a TOFC of 2-4 is present or there are obvious clinical signs of returning neuromuscular function Only a TOF ratio of 0.90 – 1.0 (measured objectively) assures a minimal risk of clinically significant residual block Following use of an intermediate-acting NMB such as rocuronium, a median time of 90-120 minutes is required to achieve a TOF ratio > 0.90 in 95% of patients in the absence of reversal, sug 2-3 mins Median time to reversal to a TOF ratio >0.90 from a TOFC of 2-4 with neostigmine is 15-20 minutes Exceeding the maximum dose limits of anticholinesterase (60-80 mcg/kg neostigmine or 1.0-1.5 mg/kg edrophonium) provides no further benefit Increased incidence of persistent weakness in patients who received NDPNMBs for >2 days ○ More common in: asthmatic patients receiving high dose steroids, renal failure, steroidal NMBs Association of prolonged use of NMBs with critical illness myopathy (CIM) and polyneuropathy (CIP) In ICU: NM monitoring should be used, periodic return of muscle function should be allowed Recommendations for NMBs in ICU ○ Avoid use by maximum use of analgesics and sedatives, manipulation of vent parameters/modes ○ Minimize dose of NMB by Peripheral nerve stimulator with TOF usage No more than 2 days continuously Bolus rather than infusion Administer only when required for a well-defined goal Continually allow recovery from paralysis Consider alternative therapies Can intubate without a NMB (remifentanil, alfentanil) possible board Q’s for EXAMS 1-4 ○ ○ ○ ○ ○ ○ At low blood levels thiopental has been described as having an anti-analgesic effect ketamine active metabolite = nor ketamine (20-30% the activity of the parent compound) prior to 1 year of age, MAC is decreased. MAC decreases 6% per decade from 1 year of age onward type of surgical stimulation & thyroid function DO NOT change MAC Evoked potentials from most to least sensitive = motor > visual > somatosensory > brainstem auditory evoked (BAEP) Nitrous oxide decreases the activity of methionine syntheses ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ isoflurane may have increased CSF resorption NIOSH has set exposure limits at volatile anesthetics 2 ppm nitrous oxide 25 ppm nitrous oxide decreases the activity of methionine synthetase which is involved in the formation of myelin & DNA FDA recommendation (incr FGF for 4 hours) >/ 1 L/min fresh gas flow up to 2 MAC hours >/ 2 L/min fresh gas flow after 2 MAC hours most likely place to have a leak in anesthesia machine = between flow meters to common gas outlet check valve necessitates the negative pressure leak test for each vaporizer sevo put in iso vaporizer = UNDERDOSE iso put in sevo vaporizer = OVERDOSE Morphine-induced bradycardia is d/t stimulation of vagal nuclei in medulla “Wooden chest syndrome” seen with opioids likely related to laryngeal muscular (upper airway) contraction miosis seen with opioids is d/t excitatory stimulation of ANS component of edinger-westphal nucleus in oculomotor nerve (CN 3) Rates of absorption from greatest to least = ICEBS intercostal > caudal > epidural > brachial plexus > femoral/sciatic nerve site of injection most important in absorption Metabolite of atracurium = laudanosine & acrylate laudanosine can cause seizures if it accumulates