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Chapter 7. Inhalation Anesthetics

Chapter 7. Inhalation Anesthetics. 경희의료원 마취통증의학과 R1 이강우. Inhalation anesthetics. Nitrous oxide, Chloroform and Ether. Ethyl chloride, ethylene, cyclopropane Methoxyflurane and Enflurane Nitrous oxide, Halothane, Isoflurane, Desflurane, and Sevoflurane.

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Chapter 7. Inhalation Anesthetics

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  1. Chapter 7. Inhalation Anesthetics 경희의료원 마취통증의학과 R1 이강우

  2. Inhalation anesthetics Nitrous oxide, Chloroform and Ether. Ethyl chloride, ethylene, cyclopropane Methoxyflurane and Enflurane Nitrous oxide, Halothane, Isoflurane, Desflurane, and Sevoflurane.

  3. Inhalation anesthetics • The course of general anesthesia 1) Induction 2) Maintenance 3) Emergence • Useful in the induction of pediatric patients • Adults prefer rapid induction with intravenous agents.

  4. Inhalation anesthetics Pharmacokinetics (how a body affects a drug) Relationship between a drug’s dose, tissue concentration, and elapsed time Pharmacodynamics (how a drug affects a body) The study of drug action, including toxic responses MAC (Minimum alveolar concentration) Clinical pharmacology of individual agents Nitrous oxide, Halothane, Isoflurane, Desflurane, Sevoflurane

  5. Pharmacokinetics • Mechanism of action of inhalation anesthetics remains unknown • Depends on attainment of a therapeutic tissue concentration in the central nervous system • There many steps, between the administration of an anesthetic from a vaporizer and its deposition in the brain

  6. PharmacokineticsFactors affecting inspiratory concentration(FI ) Fresh gas flow rate (FGF rate) Volume of the breathing system (breathing circuit volume) Any absorption by the machine or breathing circuit (circuit absorption)

  7. Pharmacokinetics Factors affecting alveolar concentration(FA ) Uptake Ventilation Concentration

  8. Pharmacokinetics Factors affecting alveolar concentration(FA ) Uptake 1) FA/FI <1.0 2) Uptake ↑ → Alveolar concentration ↓ → FA/FI ↓ 3)Gasconcentration→ Partial pressure Alveolar partial pressure →Anesthetic partial pressure inblood → Brain tissue concentration 4) Uptake of Anesthetic agent ↑ → Induction ↓

  9. Pharmacokinetics Factors affecting alveolar concentration(FA ) Anesthetic uptake factors 1) Solubility in the blood 2) Alveolar blood flow 3) Difference in partial pressure between alveolar gas and venous blood

  10. Pharmacokinetics Factors affecting alveolar concentration(FA ) Solubility in the blood 1) Solubility : Insoluble agents(N2O)< soluble agents(halothane) FA : Insoluble agents(N2O)> soluble agents(halothane) Induction speed : Insoluble > soluble agents 2)Partition coefficients(λ) Relative solubility of an anesthetic in air, blood, and tissues 3) Blood/gas partition coefficient↑ → Solubility in Blood ↑ → Uptake ↑ → Alveolar partial pr↓→ induction speed ↓

  11. Pharmacokinetics Factors affecting alveolar concentration(FA ) Alveolar blood flow 1) In the absence of pulmonary shunting : ABF = CO CO↑ → Uptake ↑ → Alveolar partial pr↓→ induction speed ↓ 2) Insoluble agent Alveolar blood flow 영향 적음 3)Soluble agent Low CO → Alveolar concentration ↑→ overdosage

  12. Pharmacokinetics Factors affecting alveolar concentration(FA ) Difference in partial pressure between alveolar gas and venous blood 1) No tissue uptake → Alveolar to venous partial pr difference= 0 2) Factors affecting tissue uptake Tissue solubility of the agent( tissue/blood partition coefficient) Tissue blood flow Difference in partial pressure between arterial blood and the tissue

  13. Pharmacokinetics Factors affecting alveolar concentration(FA )

  14. Pharmacokinetics Factors affecting alveolar concentration(FA ) 4 group of tissue by solubility and blood flow 1) Vessel-rich group ex) brain, heart, liver, kidney, endocrine organ 2) Muscle group ex) skin, muscle 3) Fat group 4) Vessel-poor group ex) bone, ligament, teeth, hair, cartilage

  15. Pharmacokinetics Factors affecting alveolar concentration(FA )

  16. Pharmacokinetics Factors affecting alveolar concentration(FA )

  17. Pharmacokinetics Factors affecting alveolar concentration(FA ) Ventilation Constantly replacing anesthetics taken up by pul bloodstream → FA/FI↑ for soluble agent

  18. Pharmacokinetics Factors affecting alveolar concentration(FA ) Concentration 1) Concentration effect Concentrating effect Augmented inflow effect 2) Second gas effect

  19. Pharmacokinetics Factors affecting alveolar concentration(FA ) (Anesthetic gas50% uptake) 10/90=11% 40/60=66% → Concentrating effect → →

  20. Pharmacokinetics Factors affecting alveolar concentration(FA ) 1% of second gas 1% of second gas (1.7%) 1% of second gas 0.4% of second gas - → Second gas effect

  21. Pharmacokinetics Factors affecting alveolar concentration(FA ) Alveolar partial pr > Arterial partial pr → Alveolar-arterial difference 1) Venous admixture 2) Alveolar dead space 3) Nonuniform alveolar gas distribution 4) Ventilation/perfusion mismatch (ex: atelectasis, emphysema, neumonia)

  22. Pharmacokinetics Factors affecting alveolar concentration(FA ) Recovery from anesthesia - Anesthetic concentration in brain tissue ↓ Anesthetics can be eliminated by 1) biotransformation 2) transcutaneous 3) exhalation

  23. Pharmacokinetics Factors affecting elimination Induction을 촉진시키는 요소들은 Recovery도 촉진 Rebreathing High Fresh gas flows Low Anesthetic-circuit volume Low absorption by the Anesthetic-circuit Decreased Solubility High CBF(Cerebral Blood Flow) - Increased Ventilation

  24. Pharmacokinetics Factors affecting elimination • Diffusion hypoxia 1) Directly affect oxygenation by displacing O2 2) diluting alveolar CO2 → respiratory drive ↓ → prevent : 100% O2 5~10min

  25. PharmacodynamicsTheories of anesthetic action Pharmacodynamics the study of drug action, including toxic responses how a drug affects a body General anesthesia reversible loss of consciousness analgesia of the entire body amnesia muscle relaxation General anesthesia agent inert elements ( ex: xenon ) simple inorganic compounds ( ex: nitrous oxide) halogenated hydrocarbons ( ex: halothane ) complex organic structures (ex: barbiturate )

  26. PharmacodynamicsTheories of anesthetic action Agent-specific theory   Unitary hypothesis Critical volume hypothesis Fluidization theory of anesthesia Lat phase separation theory

  27. PharmacodynamicsMAC(Minimum alveolar concentration) Alveolar concentration that prevents movement in 50% of patients in response to a standardized stimulation MAC is useful measure brain partial pressure 반영 agents 간의potency 비교 experimental evaluation의 기준 제공 The MAC value for different anesthetics are roughly additive The sameMAC ≠ CNSdepression ≠ Myocardial depression

  28. PharmacodynamicsMAC(Minimum alveolar concentration) Point on dose-response curve → ED50,( median effective dose) 1.3 MACof any of the volatile anesthetics prevent movement in about 95% patientssurgical incision ≒ ED95 MAC Awake = 0.3 ~ 0.4 MAC One of the most striking is the 6% decrease in MAC per decade of age, regardless of volatile anesthetic Unaffected by species, sex, or duration of anesthesia

  29. PharmacodynamicsMAC(Minimum alveolar concentration)

  30. Nitrous oxidePhysical properties 임상에서 쓰이는 유일한 inorganic anesthetic gas 무색, 무취 폭발성 無, 인화성 無 이나 O2연소에 도움을 주는 물질 상온, 대기압에서 gas형태로 존재, 일정 압력하에서 액체상태로 보관이 가능 비교적 저렴

  31. Nitrous oxideEffect on organ system- Cardiovascular In vitro- stimulate the sympathetic nervous system in vitro, direct depression of myocardial contractility In vivo- Stimulation of catecholamine → ABP, CO, HR Unchanged or slightly↑ N2O의 Myocardial depression이 unmasked 되는 경우 Coronary artery diseases Severe hypovolemia ∴ BP ↓  myocardial ischemia Constriction pulmonary vascular smooth muscle → pulmonary vascular resistance ↑ → Rt. Ventricular end-diastolic pr. ↑ Endogenous catecholamine level ↑ → epinephrine induced arrhythmia↑

  32. Nitrous oxideEffect on organ system- Respiratory CNS stimulation, pulmonary stretch receptor activation → respiratory rate↑(tachypnea) & tidal volume↓ : net effect -> minimal change in minute ventilation and resting arterial CO2 level Hypoxic drive↓

  33. Nitrous oxideEffect on organ system- Cerebral Cerebral blood flow & Cerebral blood volume↑ → Intracranial pressure mild↑ CMOR2(Cerebral oxygen consumption)↑ Levels of nitrous oxide below MAC provide analgesia in dental surgery and other minor procedures

  34. Nitrous oxideEffect on organ system- Etc. Neuromuscular not provide significant muscle relaxation not a triggering agent of malignant hyperthermia Renal Renal vascular resistance ↑ → renal blood flow ↓ : glomerular filtration rate(GFR) & urinary output ↓ Hepatic Hepatic blood flow ↓ Gastrointestinal Activation of the chemoreceptor trigger zone and the vomiting center in the medulla →Postoperative nausea & vomiting

  35. Nitrous oxideBiotransformation & toxicity Eliminated by exhalation : almost diffuses out through skin :small amount biotransformation : than less 0.01% Vit B12내부의 cobalt 원자의 비가역적 산화 → Vit B12 dependentenzyme ↓ →① Myelin형성에 필요한 methionine synthetase ↓ ② DNA합성에 필요한 thymidylate synthetase ↓ ∴ Prolonged exposure of anesthetic level →① Bone marrow depression(ex: megaloblastic anemia ) ② Neurological deficiencies (ex:peripheral neuropathiesandpernicious anemia) Teratogenic effect Polymorphonuclear leukocytes 의chemotaxis와 motility에 영향 → immunological responsechange

  36. Nitrous oxideContraindication Air embolism Pneumothorax Acute intestinal obstruction Intracranial air ( ex: dural closure or pneumoencephalus로 인한 tension pneumocephalus) Pul. air cyst Intraocular air bubble Tympanic membrane grafting Pulmonary HTNpatient

  37. Nitrous oxideDrug interaction MAC = 105 vol% → combination with the more potent volatile agent Neuromuscular blockade↑ (but effect : N2O< volatile agents) Requirements of other agents↓ Second gas effect

  38. HalothanePhysical properties Halogenated alkane Nonexplosive Nonflammable Least expensive volatile anesthetics

  39. HalothaneEffect on organ system- Cardiovascular Dose-dependent reduction of arterial blood pressure → Myocardial depression (2.0MAC : BP 50%↓) Coronary artery vasodilator But Systemic arterial pressure ↓ → coronary blood flow ↓ Hypotension → Vagal stimulation ↓, HR↑ But this reflex↓, sinoatrial node conduction slowing →Junctional rhythmandbradycardia In infant: HR↓& myocardial contratility↓→ CO↓ Sensitize the heart to the arrhythmogenic effects to epinephrine : epinephrine1.5μg/kg 이상 사용금기

  40. HalothaneEffect on organ system- Respiratory Rapid, shallow breathing – Not enough to counter TV↓ → alveolar ventilation↓, resting PaCO2↑ * Cause of ventilatory effect central mechanism (medullary depression) peripheral mechanism (intercostal muscle dysfunction) ↗: pre-existing lung disease ↘: surgical stimulation Hypoxic drive↓ A potent bronchodilators (∵ Airway reflex ↓, bronchial smooth muscle 이완 ) Mucociliary function ↓ → postoperative hypoxia & atelectasis촉진

  41. HalothaneEffect on organ system- Cerebral Cerebral vesselsdilating → cerebral vascular resistance↓ , CBF ↑ Autoregulation (Arterial blood pressure의 변화에도 CBF를 유지하는 작용)→ Intracranial pressure↑ Prevent: Hyperventilation

  42. HalothaneEffect on organ system- Etc. Neuromuscular Skeletal muscle relaxation Non-depolarizing neuromuscular-blocking agents (NMBA)effect↑ Malignant hyperthermia Renal Renal blood flow, GFR(glomelular filtration rate), urinary output ↓ (∵ Arterial blood pressure & cardiac output ↓) GFR↓ <Renal blood flow↓ → Filtration fraction↑ Prevent: Preoperative hydration Hepatic CO↓ ∝ hepatic blood flow↓ Hepatic artery vasospasm The metabolism and clearance of Fentanyl, phenytoin, verapamil↓

  43. HalothaneBiotransformation & toxicity Be oxidized in the liver by a cytochrome P450 (2EI) → trifluoroacetic acid : Inhibited bypretreatment with disulfiram viral hepatitis, impaired hepatic perfusion, hepatocyte hypoxia, sepsis, hemolysis, benign postoperative intrahepatic cholestasis, drug induced hepatitis → postoperative hepatic dysfunction Halothane hepatitisis extremely rare (1/35000 ) - Hepatitis is increased risk at : halothane 마취에 짧은 간격으로 여러 차례 노출 : 중년의 비만한 여성 : Halothane 독성에 노출된 가족력이 있는 환자 : 개인적으로 halothane 독성에 대한 Hx(+)인 환자

  44. HalothaneContraindication Halothane에 폭로된 과거력을 가진 환자 중 설명이 불가능한 간 기능 장애를 보일 때 Intracranial mass lesion → Intracranial hypertension Hypovolemic pt. Severe cardiac disease ( ex: aortic stenosis ) Epinephrine이 외부에서 주입된 환자 Pheochromocytoma

  45. HalothaneDrug interaction β- adrenergic blocking agent (propranolol), Ca++ channel blocking agent (verapamil) → Myocardial depression↑ Tricyclic antidepressants, MAO inhibitor → fluctuations in blood pressure & arrhythmias ( but not absolute contraindication) Aminophylline → Severeventricular arrhythmias

  46. IsofluranePhysical properties Nonflammable volatile anesthetic Pungent ethereal oder Chemical isomer of enflurane but different physiochemical property

  47. IsofluraneEffects on organ system- Cardiovascular Minimal cardiac depression but carotid baroreflex → HR↑→ CO유지 β-adrenergic stimulation → skeletal muscle blood flow↑ systemic vascular resistance↓ arterial blood pressure ↓ Isoflurane농도를 급격히 증가 → HR ↑, arterial blood pressure↑, norepinephrine의 plasma level↑ Dilates coronary arteries

  48. IsofluraneEffects on organ system- Respiratory Respiratory depression, Tachypnea ( less pronounced) → minute ventilation↓( more pronounced) 0.1MAC정도 소량의 Isoflurane도 hypoxia나 hypercapnia에 대한 정상적인 호흡 반응을 둔화시킴 Good bronchodilator

  49. IsofluraneEffects on organ system- Cerebral >1.0 MAC : CBF & intracranial pressure↑ but Isoflurane < Halothane Reversed by hyperventilation Cerebral metabolic oxygen requirement↓ 2.0 MAC → electrically silent electroencephalogram(EEG) : EEG suppression → cerebral ischemia시 brain protection

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