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InductionInduction of anesthesia means administering anesthetic drugs to induce a state of anesthesia. It typically implies General anaesthesic and inducing a state of unconsciousness but can also refer to the induction of spinal or regional anaesthesia. GAStandard induction involves:Standard monitoring – sats, BP, HR (ECG)Position the patient in the appropriate position “sniffing position”Baseline vital signsPrior to commencement Machine should be checkedSuction should be on and readily availableAirway equipment should be available (variety including gudels) IV access – freely flowingDrugs – drawn up and available including emergency drugsPreoxygenation – get EtO2 above 70-80% - 3 mins at 100% O2 and high flowsTitrate IV induction agents to effect using dose/weight as a guide as to how much will be requiredInhalational anaesthesia – may not have IV access but need to have IV equipment available to be inserted after inductionChildrenAdults with needle phobiaDifficult IV accessMethod is the same as for Iv except that you titrate inhaled anaesthetics instead of IVSevoflurane is preferable – less pungent and less airway irritationTest eyelash reflex to assess level of consciousnessConfirm ability to ventilate the patientInsert LMA ORAdminister neuromuscular blocking agentMask ventilation – allowing time for NBA to work and also maintaining oxygenationAirway instrumentation – laryngoscope – various typesIntubationConfirm positionFogging of tubeChest rise and fallCO2 on capnographListen to chestMaintenanceDefined as management of physiological functions and the maintenance of surgical anesthesia following induction and until emergence.Involves maintaining the state of surgical anesthesia for the duration of the procedure. Involves administration of volatile or intravenous anesthetic agents.Maintaining hypnosisAgents whose activity is mainly on GABA receptor induce unconsciousnessInhaled anaesthsicsPropofolBenzodiazepinesAmnesia accompanies unconsciousness but benzos can help with thisAnalgesiaSurgical stimuli can induce a neurohumoral response with activation of the sympathetic nervous system (hypertension, tachycardia), the coagulation cascade (hypercoagulable state), and the stress hormone release (hyperglycemia, protein catabolism, immunosuppression).Block nociception – regional anaesthesia or with IV agents - opioids, nitrous oxide, central alpha-2 agonists, and ketamine.Physiological HomeostasisHaemodynamic parametersRespiratoryEndocrineRenal and electrolytestemperatureEmergenceEmergence from GA involves waking the patient up at the end of the procedure and removing the airway device in a manner that is safe and minimizes postoperative complications. Patient can be extubated awake or deep depending on the surgical procedure performed and the impact of extubation ie coughingPlan emergence as you planned induction but in opposit direction100% O2Assess neuromuscular blockade with nerve stimulatorReverse neuromuscular blockade (neostigmine/atropine/glycopyrulate or sugammadex)Turn off anaesthetic agents (IV or Inhaled)Make sure suction has been performed and have suction ready for use if needed againAssess neuromuscular blockade to make sure reversal has occurredAssess if patient is breathingEnsure adequate post operative analegesiaWhen patient shows signs of waking up can extubatebuckingreturn of eyelid reflexprotruding tongueswallowingpurposeful movements – reaching for the tubeFasting RequirementsClear liquids – 2hrsLight meals – 6hrsHeaving meals – 8hrsPeople at risk of aspirationacutely unwell – septicfull stomachsevere refluxpregnantdiabetic – slow gastric emptyingileus or acute abdomenstroke patients with poor swallow reflexRapid Sequence InductionA method of rapidly inducing GA and neuromuscular blockade to quickly provide optimal intubating conditions while minimizing risk of aspirationIndications:Deteriorating clinical situation and acutely unwellSevere refluxPregnant Non-cooperative patientRespiratory and ventilatory compromiseImpaired oxygenationFull stomach (increased risk of regurgitation, vomiting, aspiration)Secretions, blood, vomitus, and distorted anatomyCrystalloids vs ColloidsCrystalloidsSolutions of salts and electrolytes commonly used for volume expansion. They do not provide oncotic pressure and only remain in the intravascular space for a short period of time.Pharmaceutic:Pre-made solutionCheapLong shelf-lifePharmacokinetic:Passes readily from intravascular to extravascular space. Rapidly equilibrate with and distribute throughout the entire ECF space within 30 minutes Only about 20% of infused solution remains in intravascular space.Side effect – Hyperchloraemic acidosis (plasma HCO3 decreases as Cl conc increases) ? Increased potential for fluid overload and pulmonary oedemaColloidsHomogenous non-crystalline substances containing large molecules.They have an increased ability to remain in the intravascular space and as such may act as volume expandersPharmaceutic:Pre-made in solutionCheaplong shelf life at room temperatureIsotonicPharmacokinetic:Distribution: low Vd with minimal distribution to ISFMetabolism: slow metabolism to prolong effective time within intravascular compartment.Non-organ dependent metabolism andEliminationGelofusineDegradation of bovine collagen, polydispersed colloidal solutions - oxy, urea crosslinked or succynated gelatinsSmall size = rapid clearance unchanged (80%)Therefore fast t1/2 (1-2/24)No accumulationVolume expansionDilutional coagulopathiesAlbuminPurified from pooled human plasma.Minimal infection riskContains large amount of sodiumUsed in lots of diseases, may result in worse outcomes in burns, hypoproteinaemiaMaintains intravascular volumeRisk of anaphylaxisNot ok for some Jehovas witnessesFluid requirement calculationWater comprises 60% of the lean body mass, ～42 litres in a 70 kg man. Of this, about two-thirds are intracellular (28 litres); therefore, extracellular volume (ECV) comprises 14 litres. The extracellular compartment can be further divided into interstitial (11 litres) and plasma (3 litres) with small amounts of transcellular fluids, for example, intraocular, gastrointestinal secretion, and cerebrospinal fluid completing the distribution.The aim of intraoperative fluid therapy is to maintain an adequate circulating volume to ensure end-organ perfusion and oxygen delivery to the tissues.Estimation of Daily Water Requirements in Unstressed Healthy AdultsBased on metabolic rate 80-110 mls/100kcalsBased on body surface area 1.5 l/m2/dayBased on weight 30-40 mls/kg/dayFluid administration should always be based on clinical circumstances (eg blood loss, internal fluid loss in third spaces, abnormal haemodynamics requiring intravascular volume loading, oliguria with acute renal failure). Components of Daily Obligatory Water LossInsensible loss: 800 mlsMinimal sweat loss: 100 mlsFaecal loss: 200 mlsMinimal urine volume to excrete solute load: 500 mlsTotal: 1,600 mlsNeed to overcome loses but need to use clinical findings to determine the amount of fluid required.Total IVF maintenance requirements = Insensible loss + 3rd space loss requirementsInsensible loss = 1- 2 mL/kg/hr3rd space loss requirements depend on the type of trauma related to the surgical procedure that is being performed.Low risk patient having low risk surgeryN saline or Hartmans (my preference is Hartmans)Fasting patient – 30-40mls/kg/dayIf 70kg need:~2450mls/day waterInsensible losses = 2x70 = 140mls/hrFor this surgery I would give them ~ 150mL/hr and then allow them to eat and drink when they are awake to make up the difference. If clinically it appeared they required more I would increase the rate.Degree of tissue traumaMinimal (i.e. eye cases, laparscopic cholecystectomy) - 1 - 2 mL/kg/hrLow (i.e. arthroscopies, ENT) - 3 - 4 mL/kg/hrModerate (i.e. total joint replacements) - 5 - 6 mL/kg/hrSevere (i.e. bowel resection, total hip replacement) - 7 - 8 mL/kg/hrEmergency - (i.e. gun shot, car accident-severe injuries) - 10 - 15 mL/kg/hrAnxiolytic or Sedative PremedicationRefers to the administrations of a drug in the immediate preoperative period.Principal indication is to allay anxiety.IndicationCalm the patient and aid in restraint, Smooth anesthetic induction and recovery, decrease the dose of general anesthetic, analgesia, block vagal reflexes.ContraindicationsRisk of central depression of respiration (haven’t allowed for adequate preoxygenation)Airway obstructionCardiovascular compromise from traumaDay surgeryPneumoperitoneiumCardiovascularIAP < 10 mm Hg↑ VR ? ↑ COIAP 10–20 mm Hg↑ IAP ? ↓ VR ? ↓ CO↑ IAP ? ↑ SVRBP = ↓ CO × ↑↑ SVR?↑ BPIAP > 20 mm Hg↓↓ VR ? ↓↓↓ CO↓ BPRespiratoryLung volumes esp FRC↓Airway resistance↑Pulmonary compliance↓Airway pressure↑Risk of barotrauma↑V/Q mismatch↑RenalRenal function↓GastrointestinalRisk of regurgitation↑NeurologicalICP?↑Cerebral Perfusion P?↓RenalMarkedly increased IAP reduces renal function and urine output owing to an increase in renal vascular resistance and reduction in glomerular filtration rate (GFR). This is compounded by the reduction in cardiac output.GastrointestinalIncreased IAP may cause regurgitation of gastric contents with associated risk of pulmonary aspiration. This is particularly significant in the obese patient.PositionTrendelenburg (head down)Reverse TrendelenburgSupineProneLateralLithotomyCardiovascularVR↑↓↑↓increaseCO↑↓↑↓Increases transientBP?↓↓ pressure on IVCIncrease transientRespiratoryLung volumes↓?↓↓V/Q mismatch↑?↑increaseincreaseincreaseFRC↓↓increase↓compliance↓↓↓Atelectasis↑?↑increaseSupine – redistribution of pooled blood from lower limbs – increased VR and COLateral - the dependent lung is relatively under-ventilated and over-perfused, while the non-dependent lung is over-ventilated and under-perfused. This leads to a generally well tolerated increase in ventilation-perfusion inequality but can cause hypoxaemia in compromised patients.Prone - compression of the inferior vena cava (IVC) reducing venous return to the heart.Increase FRC and oxygen tensionImprove V/Q mismatchPost Operative Nausea and VomitingIntraoperatively Given antiemetic prophylaxis if patient at high risk of PONVPrevious Hx of PONVFemaleNon-smokerInvasive surgeryGynaecologicalUrologicalGastroenterologicalAnticipation of high opioid requirement intraoperativelyUse of Nitrous OxideUse of volatile anaesthetic agentsCombination therapy is the accepted way of controlling PONV.Incidence of PONV is significant and remains of major concern to patients.Start with a 5HT antagonist such as Granisetron, tropisetron or ondansetron. Inhibit the actions of serotonin receptor. Most effective antiemetics to date. Lack of extrapyramidal side effects and longer duration of action. DoseGranisetron 1mg BDTropisetron 2mg BDOndansetron 4-8mg TDSThen use Droperidol. D2 (dopamine) receptor antagonist at the Chemoreceptor Trigger Zone (CTZ). Can be just as effective as 5HT receptor antagonist. There are side effects – EPSE, sedation at high doses, neuroleptic malignant syndrome. Dose 0.25 – 0.5mg 8hrly.Then use steroid. Dexamethasone – in combination with other antiemetic drugs, dexamethasone is also effective for PONV. Dose 4-8mg IV single dose. Side effects include increase in BSL.During all of this I would ensure that the patient had adequate hydration and appropriate pain relief. I would also want to make sure that the cause of the PONV was not due to obstruction or ileus is GI surgery.Safety to ExtubateAbsence of threat of airway soiling, or Ability to protect the airwayAdequate spontaneous ventilationAdequate oxygenationAbility to clear secretionsCriteria for Extubation Specific FIO2 <50% PEEP < 5cmH2O PaO2 > 60mmHg PaCO2 < 50mmHg Resolving CXR No other major organ system failure or instabilityFailure to WakeKnown as delayed emergence.Need to rule out:HypercarbiaHypoxiaHypotensionHypothermia IntoxicationInadequate or delayed NMB reversal (sux apnoea)If residual block, need to keep the patient asleepMetabolicHyper/hyponatremiaHyper/hypoglycemiaNeurologicStrokeResidual anaestheticVolatilePropofolKetamineExcess opioidsMay require reversal with naloxoneCare must be taken as this will reverse the analgesic effects of opioids and the patient will wake up in pain and angry!!Excess preoperative sedativesManagementABCsReintubate if extubated deepO2 and ensure adequate respirationCirculationVital signs (including temperature)Review preoperative history and anaesthetic recordsAssess for persistent NM blockade – nerve stimulatorNeurologic Exam (pupils, cranial nerves, reflexes, response to pain)Check glucoseABG with electrolytesMay need to make arrangement for reversal agentsNaloxoneFlumazenilNeostigmineSugammadexArrange imaging if concerned about cerebral event, may need CT or MRI. Post-operative DeliriumPatients with cognitive impairment are known to be at greater risk of post operative delirium.Risk factors:Old agePre-existing dementiaDrugsAnticholinergic drugs including some antiemeticsPsychoactive drugsBenzodiazepinesOpioidsWithdrawal from alcoholInfectionFluid and electrolyte disturbanceHypoxemiaSevere painMultiple concurrent medical problemsMultiple concurrent medicationsManagementEnsure adequate oxygen delivery to tissues.Avoid hypoxia, hypotension, and severe anemia.Maintain fluid and electrolyte balance.Monitor fluid status to avoid volume depletion and fluid overload.Ensure adequate pain management while minimizing opioid use if suspected to be cause of deliriumReview medicationDiscontinue unnecessary medicationsDiscontinue or minimize use of anticholinergics, antihistamines, and benzodiazepines.Maintain bowel and bladder function.Avoid stimulating precipitantsUrinary catheterMobilize patients earlyOptimize environmental stimuliMaintain sleep/wake cycleQuiet single roomFamily members at bedside when possible, other familiar objects in patient’s room otherwise need supportive and understanding nursing staff.Treat agitated deliriumLow dose atypical antipsychotic such as quetiapine 12.5–25 mg nightly or as needed.Consider low dose haloperidol 0.25 mgOlanzapine wafer 5-10mgAvoid restraintsPharmacologySedative/hypnotic agentsPropofolThiopentoneMidazolamKetamineInhalational agentsSevofluraneIsofluraneDesfluraneNitrous OxideHalothaneOpioidsOxycodoneFentanylMorphineBuprenorphineCodeineTramadolMuscle RelaxantsDepolarisingSuxamethoniumNon-DepolarisingAminosterroidsRocuroniumVecuroniumPancuroniumBenzylisoquinolonesAtracuriumCisatracuriumMivatracuirumTubocurarineReversal DrugsNeostigmineSugammadexAntiemetic agentsAntidopaminergicDroperidolProchlorperazineMetaclopramideAntiserotinergicOndansetronTropisetronGranisetronAnticholinergicHyoscineAntihistaminesPromethazineCyclizineSteroidsDexamethasoneSedative/hypnotic agentsPropofolSterically hindered phenol used for induction and maintenance of anaesthesia and for sedation in both theatre and ICU. It also has a use in status epilepticus when other agents have failed.Insoluble in water but highly soluble in fat and requires preparation as a lipid emulsion.Mechanism of ActionThe action of propofol involves a positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABA-A receptors.Induction Dose1.5-2.5mg/kgMaintenanceUp to 4mg/kg but can be higher in younger patientsPharmacokineticsPreparation10mg/mlIsotonic emulsion in soyabean, glycerol, purified egg lecithin and sodium hydroxide to adjust pHpKa = 11AbsorptionIV onlyRapid - time to onset of unconsciousness is 15-30 seconds, due to rapid distribution from plasma to the CNS. Distribution is so rapid that peak plasma concentrations cannot be readily measured. Duration of action is 5-10 minutes.DistributionVd = 4L/kg98% bound to albuminhighly lipophilicDistribution Half-life = 1-2mins – accounts for the rapid fall in plasma levels with a short duration of actionMetabolismHepatic - CYP450To inactive metabolitesClearance 23 – 50 mL/kg/minEliminationIt is chiefly eliminated by hepatic conjugation to inactive metabolites, which are excreted by the kidneyElimination Half-life = 5-12hrsDecreased renal function leads to a decreased rate of elimination but does not effect the action of the drugPharmacodynamicsCNS:Mech. Unclear, perhaps: potentiates effects of GABA on it’s A receptorAlso glycine (?NMDA) receptors, and nAChRSmooth onset/offset, no hangoverMyoclonic movementsDec. CMRO2, CPP, ICPAutoregulation not alteredAnticonvulsant – ECT, care.CVS:Dec. SV, SVR (inc. NO release), HR, MAP, contractility, sympathetic outflow resp to hypoxia/hypercapnoeaHr maintainedResp:Dec. TV, MV, laryngeal reflexesInc RR, ApnoeaBronchodilatorHPV maintainedGIT:Antiemetic (D2 receptor, possibly)No hepatic effectsRenal: no effectsTrigliceridaemiaAdverse effects:Pain – direct neural stimulationPropofol infusion syndrome – green urine/hairNot used in pregnancy/deliveryNot commonly used in paediatrics – unproved safety profileThiopentoneSulphur analogue of the oxybarbituate pentobarbitone.Mechanism of ActionThe action of barbituates involves a positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABA-A receptors.Induction Dose3-7mg/kgPharmacokineticsPreparationSodium salt and presented as a pale yellow powderVial contains sodium carbonate and nitrogen which improve solubility of the solutionpKa = 7.6AbsorptionIV onlyRapid - time to onset of unconsciousness is 30 seconds, DistributionVd = 2.5L/kg75% bound to albuminhighly lipophilicDistribution Half-life = 8.5 mins MetabolismHepatic, oxidation, conjugation, inactive metabolites, unless high dose (phenobarbitone)Thiopentylecarboxylic acidHydroxythiopentylePhentobarbityle EliminationCl 3.4mL/kg/minRenal elimination <1% unchangedElimination Half-life = 5-15hrsPharmacodynamicsCNS:Increased duration of GABA A channel opening (binds to β subunit)Sudden onset, hangover effectDec. CMRO2, CBF, ICP, sympathetic outflowAnticonvulsantPain increased at low dosesCVS:Dec. contractility, SNS outflow, SVR, MAPInc. HR, myocardial oxygen demand, coronary blood flowMore CVS benign than propofolResp:Dec. TV, MV, RR, resp to hypoxia/hypercapnoeaApnoeaMild suppression of resp reflexes – may cause broncho/laryngospasm (histamine rel), incompatible with LMA for this reasonMaintained HPVGIT:Dec Hepatic blood flowSplanchnic vasoconstrictionRenal:Dec RBF/GFRInc ADHTherefore dec UOutputOther: Non trigger for MHAdrenal suppressionPorphyria triggerTissue damage in extravasationThrombosis in intraarterial injectionNo effects on gravid uterusMidazolamBenzodiazepine commonly used in anaesthesia as premedication and to sedate patients during minor surgery.Can also be used as an anxiolytic, hypnotic and an anticonvulsant.Mechanism of ActionModulate the effects of GABA at the GABA A receptorsBenzodiazepines are thought to act via specific benzodiazepine receptors found at synapses throughout the central nervous system, but concentrated especially in the cortex and midbrain. Benzodiazepine receptors are closely linked with GABA receptors, and appear to facilitate the activity of the latter. Activated GABA receptors open chloride ion channels which then either hyperpolarise or shortcircuit the synaptic membrane.PharmacokineticsPreparationClear solutionStructure is dependent on the surrounding pHAbsorptionOral bioavailability 44%IM 80-100%Distribution96% protein boundVd 1-1.5L/kgMetabolismCompletely metabolised in the liver to hydroxylated derivatives.Undergoes extensive hydroxylation by hepatic microsomal oxidative mechanisms (cytochrome P-4503A) to form 1-hydroxymidazolam and 4-hydroxymidazolam, which are then conjuated to a glucuronide) Metabolites bind to CNS benzodiazepine receptors and are pharmacologically active.EliminationOccurs in the urine, predominantly as the hydroxylated derivativesRenal impairment has little effect. Cl = 5.89ml/min/kg Elimination half-life is 1.53.5 hours. PharmacodynamicsCNS:Increased affinity of GABA binding to GABA A receptorAmnesia, hypnosis, sedn, anticonvulsant, no analgesiaDec. CBF, CMRO2, ICP, EEG suppressionCVS:Dec. SVR, MAP, Coronary O2 consumptionInc. coronary vessel size, HR – BRR maintainedSympathetics intact – hypertension to laryngoscopy maintainedResp:Dec. MV, apnoea, airway reflexesDec. Hepatic blood flow, RBF, GFR, UOutput, platelet activitySynergysm with other CNS depressantsHas a specific antidote (100mcg aliquots of flumazenil – has a shorter halt life than midaz [naloxone like precautions])KetamineKetamine is a non-competitive NMDA receptor antagonist. Used for induction of anaesthesia, sedation and pain relief at low doses.PreparationPhencyclidine derivative10/50/100mg/ml racemic (R & S) ketamine-HCl(+) isomer 3-5times more potentBenzethonium-Chloride preservativepH 3.5-5.5pKa = 7.5Easy to draw up, not a conduit for bacterial growth, stable in solution. Compatible with other solutions.AbsorptionOral bioavailability 20%, well absorbed IMTherefore there are may forms in which the drug can be given. For induction ketamine can be given IM if IV access is difficult to establish.DistributionVd = 3L/kgDistribution half time = t1/2? = 10minsHighly lipid solubleRapidly distributed to highly perfused tissues such as brain where the peak concentration may be 4-5 times that present in the plasma.Rapid transfer across the BBBThis allows for fast onset and fast offset of the drug. MetabolismMetabolised exclusively by hepatic microsomal enzymesHepatic metabolism hydroxylation or N-demethylation, conjugationActive: Norketamine (30% as potent) – has analgesic propertiesEliminationElimination half time = 11/2??= 2-3hrsExcreted in urinePharmacodynamicsCVSKetamine is relatively cardio protective and as such it is a good IV induction drug to use in patients who are hameodynamically unstableHR/SV/contractilitynegative inotrope activitydirect stimulation of SNS there fore increasedhigh doses exhaust catecholamines and therefore unmask the negative inotropic effects.CO – increasedMAP – increasedSVR – no change or increased Myocardial O2 consumption – increasedResp.While there may be an increase in secretions these can easily be dealt with, with suction. Bronchodilation may be of benefit in those with asthma. The other issue is that the airway reflexes are maintained and as such other drug such as a paralyzing agent will be required to overcome this to avoid laryngospasm.Retention of airway reflexes in low doseIncreased secretionsBronchodilationIncreased resp rateCNSDissociative anaesthesiaInhibits thalamic transmission to cortexIncreased CBF, ICP, IOPHallunications on emergence – decreased by benzodiazepine or opioid useGITN&V increased compared to propofolOtherIncreased uterine toneDecreased tourniquet hypertensionDecreased inotropic requirement in septic patientsInhalational agentsHalothaneEnfluraneIsofluraneSevofluraneDesfluraneNitrous OxideMAC0.751.71.12.26103Solubility in Soda LimeYes/noyesyesNo – Compound AYes – Carbon MonoxidePreservativeThymolPrevents liberation of brominenonenonenonenoneBlood/gas pc2.31.91.40.70.50.47Oil/gas pc224989853191.4Vapour P at 20deg243175250160670-Boiling Point50 deg56 deg48 deg58 deg23.5 deg-88.5 degSpecific Gravity1.811.521.52MW = 200MW = 168MW = 44Metabolism20-50% oxid/redn2/oxid0.2% oxid2-5% oxidNo metabolism0.004% GITCNSCBF++++++++++CMRO2------------0EEG inc silence3.5 MACDoesn’t happen1.5 MAC1.5 MAC1.5 MACnoSeizures0>2MAC0/-000ICP++++++++0CSF production+ ?absorb++?absorb0?absorb000CVSBP-?contrac--?contact-?SVR-?SVR-?SVR0/+HR0/-++++++0/+CO--0000/+RAP+0+0++SVR0-------0Pulm Vasc Pressure00000++Arrhythmia++++0/+0/+0/+0Coronary Blood flowAutoreg intactAutoreg intactCoronary seal vasodilation +++Autroreg intact++0RespRate+++++++++++TV----------0Resp depression++++++++++0Airway resistance--------0HepaticBlood Flow--0/-0/-0/-0Toxicity+++0/+0000RenalBlood Flow-----0Toxicity0+0potential00Skeletal Muscle relaxation+++?muscle blood flow++?muscle blood flow++rigidityMH+++++++0Uterine relaxation++++++0OpioidsDrugs produce their effect by acting as agonists at opioid receptors, which are found in the brain, spinal cord and sites outside of the central nervous system including urinary and GI tract, lung and peripheral nerve endings.There are three principal types of opioid receptors:MuAnalgesiaRespiratory depressionEuphoriaBradycardiaPruritisMiosisNausea and vomitingInhibition of gut motilityPhysical dependenceDeltaAnalgesia KappaAnalgesiaSedationPsychotomimetic effectsDysphoriaDiuresisMorphine is considered the prototypical opioid against which all others are compared.OxycodonePotent opioid agonistMetabolized in liver to noroxycodone relies on CYP3A4 only weakly active and oxymorphone (more potent) and relies on CYP2D6FentanylHighly potentMetabolized in liver to minimally active metabolitesMorphinePrototypical opioidSyntheticMetabolised in liverMorphine 6 glucoronide (active)Morphine 3 glucoronideBuprenorphineSemi-syntheticPartial mu opioid agonistKappa opioid receptor antagonistHigh affinity and slow dissociation from mu receptorMetabolized in liver and gut wall via glucoronidation to inactive metabolite buprenorphine 3 glucoronide and via CYP3A4 to norbuprenorphineCodeineWeak opioidWeak mu receptor agonistAnalgesia dependent on its metabolism to morphine via CYP 2D6Approx. 10% of population are non-metabolisersTramadolAtypically centrally acting analgesic because of its action as an opioid agonist and a serotonin and noradrenaline reuptake inhibitorNot adequate if used as a sole agentSynthetic cyclohexanol derivativeRacemic mixture with each enantiomer producing specific actionsPresentation: available as tablet, capsule or sachets in various strengths for PO, IV and IM administrationDose 50-100mg QIDPharmacokineticsAbsorptionWell absorbed orally – 70% bioavailability, which increases to 90% with repeated dosesDistributionVd = ~4L/kg20% protein boundpKa = 9.4MetabolismIn the liver by demethylation and subsequent glucoronidation to mostly inactive metabolites.Active metabolite – O-desmethyltramadol has analgesic activityUp to 10% of population are non-metabolizers – decreased analgesic effect due to no O-desmethyltramadol being formedEliminationT1/2 = 5-6hrsMetabolites excreted in urine 95% and faeces 5%T1/2 prolonged in renal failure – care taken in renal failurePharmacodynamicCommonly used analgesicAgonist properties at all opioid receptors but particularly the mu receptorsInhibits re-uptake of noradrenaline and 5HT and stimulates presynaptic 5HT release (alternative pathway for analgesia involving descending inhibitory pathways within the spinal cord)Potency: 1/5th to 1/10th that of morphineCNS:Activation of μ-receptorsDifferent enantiomers have different actions:(-) enantiomer → ↓Noradrenaline re-uptake(+) enantiomer → ↓5HT re-uptake and ↑pre-synaptic releaseAnalgesicSedatingN&V commonDue to the release of 5HT Resp:Less respiratory depression than morphineIf respiratory depression occurs – can be reversed by naloxoneCVS:Minimal effectsGIT:Slows gastric emptying but this effect and resultant constipation is less than other opioids such as morphineInteractions:Care must be taken if administered with TCA, SSRI, SNRI as it may result in serotonin syndrome, which presents with haemodynamic instability, seizures and agitation.Should not be used in patients with epilepsyRisk of dependence is low with TramadolMorphinePharmacokinetic Absorption:Well absorbed IM, also used IV, neuraxial Peak effect IV ~15-30minUnreliable PO absorptionDistribution:Basic drug pKa = 7.9 (23% unionized at pH 7.4) Vd = ~3L/kg↓ in renal failure 35% protein-bound Octanol:H2O coefficient = 1 (relatively lipid insoluble cf other opioids)<0.1% IV morph crosses BBB 2° rel poor lipid sol, 77% ionized, protein-binding, rapid metabolism↑with alkalosis (↓ionization) – small effect↑↑ w respiratory acidosis2° ↑CBF with ↑PaCO2Accumulates rapidly in periphery Kidney, liver, skeletal mm Crosses placenta readilyMetabolism:Glucoronidation = main pathHepatic + extra-hepatic (1° kidney)Kidney is significant contributor ~80% morphine-3-glucoronide (inactive)5-10% morphine-6-glucoronide (active)Analgesic/↓MV via μ-receptor activation>potent, ↑duration of action cf morphine ↓with MAO-IElimination:Normorphine1° via urineImpaired excretion in renal failureelimination t1?2 = ~2hrs PharmacodynamicMechanism of action: acts 1° at μ-receptors -Pre- and post-synapticCNS↓CBFIn normocapnoeic PtsCaution - with head injury Drug affect on consciousness (GCS) Meiosis ↓MV → ↑PaCO2 → ↑CBF 2° vasodilation → ↑ICP ?↑sensitivity morphine 2° disturbed BBBEEGα-waves →δ waves (resemble sleep)°epileptiform activity occasional myoclonus → not reflected in EEGSkeletal mm rigidity- interaction with basal ganglia Da/GABAergic neurons - may affect IPPV (thoracic)Meiosis- excitatory action (↑ACh) parasymp portion of E-W nucleusCVS↓HRDirect vagal nucleus stimulation Direct depression SA node Slow conduction AV node↓MAP-Not in normovolaemic PtsOrthostatic↓MAP-2° histamine release → vasodilation-2° inhibit SNS activity → vasodilation Minimised by (a) limit rate infusion 5mg/min, (b) supine, (c) normovolaemiaResp↓MV- Dose-dependent -Direct μ-receptor activation→ depress ventilation centre- ↓RR -Compensatory ↑TV (not as much as ↓RR)↑PaCO2-2° hypoventilation-↓medullary response↓Ciliary motion- Dose-dependent↑Bronchial tone- Direct effect bronchial smooth mm -Indirect 2° histamine releaseGITBiliary spasm- low incidence -Sphincter of Oddi reversed with naloxone or glucagonGI spasm-↓GI motility (constipation) ↑tone pylorus (↓gastric emptying), ileocaecal valve, anus Nil tolerance effectN&V-Partial dopamine agonist at CTZ -↓gastric emptying - ↑secretionsGURetention-↑internal sphincter tone-Neuraxial: direct parasymp inhibition of sacral plexusUreteric spasm↑ADH-questionable in humans, shown only in animalsDrug Interaction-↓↓MV: amphetamines, phenothiazine, MAO-I, TCA -↑Analgesia: sympathomimetics, AChE (physostigmine)-Antanalgesic: atropineMuscle RelaxantsDepolarisingSuxamethoniumMimic the action of Ach by attaching to the nicotininc Ach receptor and causing membrane depolarization. Duration of action is longer than Ach because hydrolyzing enzyme is not present at the NMJ.Only 20% of dose reaches the NMJ as it is rapidly hydrolised by the plasma and pseudocholinesterases (enzyme of liver and plasma).Hydrolised to choline and succinylmonocholine which is weakly active. Succinylmonocholine is further metabolized by plasma cholinesterase to succinic acid and choline.Effects:ArrythmiasSinus or nodal bradycardia and ventricular arrhythmias via stimulation of muscarinic receptors in the sinus nodeHyperkalemiaDepolarization involves K efflux into ECFMyalgiaIncreased IOPIncreased gastric pressuresAnaphylaxisMHProlonged neuromuscular block – sux apnoeaNon-DepolarisingInhibit the actions of Ach at the NMJ by binding competitively to the alpha subunit of the nicotinic Ach receptor on the post-junctional membrane.AminosterroidsMinimal cardiovascular effectsCan cause increased HRRocuroniumVecuroniumPancuroniumBenzylisoquinolonesAtracuriumMay precipitate the release of histamine – bronchospasmMyopathyMetabolismEster hydrolysisHoffman eliminationCisatracuriumDoes not undergo hydrolysisMivatracuirumTubocurarineReversal AgentsNeostigmineQuaternary aminePKlow oral bioavailabilityminimally protein boundlow Vdpartially metabolized by liver55% excreted unchanged in urinePDCVSPrecipitates bradycardiaRespMay precipitate bronchospasm in asthmaticsGUTIncreases salivationIncreases intestinal motility – abdominal crampsSugammadexSugammadex is a synthetic, modified gamma-cyclodextrin and is the first and only selective relaxant binding agent (SRBA).1,2 Sugammadex is a unique reversal agent because it encapsulates and then inactivates rocuronium and vecuronium rather than counteracting their effects.Sugammadex forms a complex with the neuromuscular blocking agents (NMBAs) rocuronium or vecuronium in the plasma. By forming complexes with these NMBAs, sugammadex reduces their ability to bind to nicotinic receptors in the neuromuscular junction and thereby reverses neuromuscular blockade. ??Upon injection of sugammadex, any rocuronium or vecuronium molecules present in the plasma are attracted to sugammadex via lipophilic interactions and are bound in a ratio of one sugammadex molecule to one molecule of the NMBA.Distribution?Sugammadex has a steady-state volume of distribution of approximately 11–14 litres. Neither sugammadex nor the complex of sugammadex and rocuronium bind to plasma proteins or erythrocytes. Metabolism ?In preclinical and clinical studies no metabolites of sugammadex have been observed and only renal excretion of the unchanged product was observed as the route of elimination.Elimination ?The elimination half-life of sugammadex is 1.8 hours Estimated clearance = 88 ml/minAlmost all (>90%) sugammadex is excreted within 24 hours of administrationAntiemetic agentsAntidopaminergic (Dopamine antagonists)DroperidolProchlorperazineMetaclopramideAntiserotinergic (serotonin antagonists)OndansetronTropisetronGranisetronAnticholinergic (antagonists against muscarinic receptors, act centrally)HyoscineAntihistamines (histamine antagonist, also have anticholinercgic properites)PromethazineCyclizineSteroidsDexamethasoneDopamine and Serotonin are both neurotransmitters that act at the CTZ (chemoreceptor triggering zone). CTZ is rich in dopamine D2 receptors and serotonin receptors.The treatment of N&V is aimed at reducing the afferent supply to the vomiting center. ................
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