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08. NONVOLATILE ANESTHETIC AGENT

08. NONVOLATILE ANESTHETIC AGENT. R1 윤묘섭. PHARMACOLOGICAL PRINCIPLES. PHARMACOKINETICS. Four Parameters : absorption, distribution, biotransformation, excretion Elimination : biotransformation & excretion Clearance : elimination 의 rate 를 측정. PHARMACOKINETICS. Absorption.

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08. NONVOLATILE ANESTHETIC AGENT

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  1. 08. NONVOLATILE ANESTHETIC AGENT R1 윤묘섭

  2. PHARMACOLOGICAL PRINCIPLES

  3. PHARMACOKINETICS • Four Parameters : absorption, distribution, biotransformation, excretion • Elimination : biotransformation & excretion • Clearance : elimination 의 rate 를 측정

  4. PHARMACOKINETICS Absorption • Oral, sublingual, rectal, inhalation, transdermal, subcutaneous, IM, IV • Administration site  Blood stream • characteristic of drug & site of absorption • Bioavailability • unchanged drug이 systemic circulation 에 도달하는 비 • Oral administration Unreliable  Pt’s 협조 및 1st pass hepatic metabolism, gastric pH, enzymes, motility, food, other drug 등에 의해 영향 받기 때문

  5. PHARMACOKINETICS • Transdermal administration • with minimal total dose로도 Prolonged and continuous absorption • Subligual, rectal, buccal administration • 1st pass hepatic metabolism 을 bypass • Parenteral injection • Subcutaneous, IM,  blood flow • IV  completely bypass the process of absorption

  6. PHARMACOKINETICS Distribution • Major determinant of end-organ drug concentration • Clinical pharmacology 의 Key role • Highly perfused organs  large amount of drug

  7. PHARMACOKINETICS Distribution • Plasma protein bounded drug  uptake불가 • Albumin  bind acidic drug (eg. Barbiturate) • AAG  bind basic drug (eg. Local anesthetics) • Plasma protein 이 소실 되거나, binding site 가 다른 물질에 의해 점유되어 있으면 tissue로 uptake 되는 free drug 는 증가 • Renal dz, liver dz, CHF, malignancy  albumin production 감소 • Trauma , infection, MI, Chr. Pain  AAG 증가 • Availability 외에도 여러 다른 요소들에 의해 drug uptake 가 영향 • CNS에서 BBB는 ionized drug의 흡수를 방해 • Molecular size • Lipid-solubility

  8. PHARMACOKINETICS Distribution(2) • Vd • Volume of distribution  drug distribute 되는volume • Dose / Plasma concentration • A small Vd 비교적 intravascular space에 국한되는 약제 Ex. High protein bounding, ionization되는 약제 • A large Vd • total body water 의 양보다 많을 수도 있음 • High solubility or binding of the drug in tissue other than plasma

  9. PHARMACOKINETICS Biotransformation • Metabolic process • Liver 가 primary organ • 대부분 end product 가 water soluble, inactive • Kidney로의 excretion 이 용이한 형태화 • Phase I • Parent Drug 를 oxidation, reduction, hydrolysis 과정을 거쳐 more polar 한 형태로 변환 • Phase II • Parent drug나 phase I 의 metabolite를 conjugation Glucuronic acid 등과 conjugation 시켜 highly polar end product 형성 • Hepatic clearance • Liver에서 biotransformation 제거되는 drug 의 rate • Hepatic blood flow, hepatic excretion ratio 에 영향받음

  10. PHARMACOKINETICS Excretion • The kidney :principle organ • Non-protein bound drugs은 자유롭게 plasma 에서 glomerular filtrate로 cross • Non-ionized fraction  the renal tube에서 재흡수 • Ionized portion is excreted in urine  urine pH 에 영향받음 • Renal clearance  kidney excretion에 의해 drug이 제거되는 rate • Renal failure  drug의 pharmacokinetics변함 • ex) protein binding, Vd, clearance rates.. • 일부 약물은 biliary excretion: 보통 intestine 에서 재흡수되고 이어서 urine으로 배설. Delayed toxic effect : enterohepatic recirculation • The lungs  volatile agents 제거 담당

  11. PHARMACOKINETICS Compartment Models • 실제 인체에서 drug distribution 과 elimination 을 설명한 model • Plasma & vessel rich group  central compartment • Muscle, fat, skin, etc.  pph. compartment • Compartment 는 conceptual  actual tissue는 아님 • Two compartment model • Drugs의 distribution 과 elimination phase 에 잘 적용됨 • Alpha phase (distribution phase) • Initial rapid decline in plasma conc. (redistribution) • Plasma, vessel rich group of the CNS  less perfused pph. tissue • Beta phase (elimination phase) • Less steep decline in plasma conc. • Distribution slows 약 elimination 은 이어짐 하지만 less steep • Elimination half-life of drug • Vd 에 비례, rate of clearance 에 반비례

  12. PHARMACOKINETICS Compartment Models

  13. PHARMACOKINETICS Compartment Models • Three compartment model • Central compartment + 2 pph. Compartment • Plasma conc. (Cp) • Cp (t) = Ae –at + Be –bt +Ce –rt • A, B, C 는 fractional coefficient • Alpha 는 rapid distribution half-life, beta는 slow distribution half life, gamma 는 terminal distribution half life 를 의미함 • Rates of distribution & biotransformation • First-order kinetics • 일정시간당 일정 부분이나 일정 비율의 약이 distributed or metabolized • Zero-order kinetics • Drug 의 농도가 biotransformation capacity 를 넘어서면 일정 양의 drug 만 단위시간당 대사 되는 경우

  14. PHARMACODYNAMICS • Drugs 의 Therapeutic and toxic organ system effect • efficacy, potency, therapeutic ratio 를 결정

  15. PHARMACODYNAMICS Dose-Response Curves • X-axis  steady-states plasma conc. • Y-axis  pharmacological • Linear(A)한 형태나 logarithmic (B)한 형태 • Curve position  drug potency • Maximal effect of drug  efficacy • Slope of curve  drug의 receptor binding character • ED(50) : median effective dose • LD(50) : median lethal dose • Therapeutic index • Ratio of LD 50:ED 50 • drug dose and pharmacological effect 의 관계

  16. PHARMACODYNAMICS Drug Receptor • Macromollecules • Protein embedded into cell membrane • Agonist  receptor와 결합 하여 cell function 에 변화를 주는것 • Antagonist  receptor 에 결합 하지만, cell 에 직접 효과 없음 • 약리학 적으로 agonist substance 의 effect 를 저해 • Competitive antagonist  receptor에 가역적 결합하며 agonist 가 higher conc. 시 대체가능해짐 • Non-competitive antagonist  receptor 에high affinity하게 결합 따라서 높은 농도의 agonist 로도 receptor blockade가 reverse 되지 않음 • 직접 cell function 에 영향을 주는 경우도 있지만, 2nd messenger, c-AMP 등의 regulatory molecule을 매개 하는 경우도 있다

  17. SPECIFIC NONVOLATILE ANESTHETIC AGENTS

  18. BARBITURATES Mechanism of action • Depress reticular activating system • Brain stem의 neurons and regulatory centers의 complex polysynaptic network • Consciousness 를 포함한 몇가지 vital function을 관장 • Axon 보다는 nerve synapse에 영향을 미침 • Excitatory neurotransmitters (Ach)의 transmission 을suppress • Inhibitory neurotransmitters (GABA) 의transmission을 enhance

  19. BARBITURATES Structure-Activity Relationship

  20. BARBITURATES Pharmacokinetics • Absorption • IV route 를 통해 전신 마취의 induction 시 성인과, IV line을 가진 소아에서 가장 많이 사용되는 약제 • Rectal thiopental, methohexital • 소아의 경우 • IM pentobarbital, secobarbital • Premedication for all age groups

  21. BARBITURATES Pharmacokinetics • Distribution(1) • Highly lipid-soluble barbiturates(thiopental, thiamylal,methohexital) • Duration of action 이 redistribution 에 의해 결정 • Thiopental  highly protein bound, but great lipid solubility, highly nonionized fraction  maximal brain uptake 가 30초 이내 • 만약 central compartment 가 contracted(hypovolemia), low serum albumin level(LC), nonionized fraction 이 증가(acidosis) • 이러한 경우, brain과 heart 에 높은 농도로 thiopental 이 존재 • pph. Compartment(주로 muscle)  20-30분 이내에 peak level 의 10% 가REDISTRIBUTION • 임상적으로 환자가 30초 이내에 의식을 잃고, 20분이내에 awake

  22. BARBITURATES Pharmacokinetics • Distribution (2)

  23. Distribution(3) Induction dose BW 와 age 로 결정 (old age 의 경우 dose 를 줄임) Elimination half-life  3-12 h Thiamylal, methohexital 비슷한 distribution patterns Less lipid-soluble barbiturate Much longer distribution half life and duration of action Biotransformation Hepatic oxydation이 관여 Inactive water soluble metabolites생성 Methohexital 의 경우, thiopental에 비해 3-4배 hepatic clearnace가 빠름 Single dose barbiturate 의 awake 는 주로 redistribution 에 의해 좌우 되지만, psychomotor function의 full recover 는 metabolism 에 의해 영향받음 BARBITURATES Pharmacokinetics

  24. BARBITURATES Pharmacokinetics • Excretion • Highly protein bound한 성질은 glomerular filtration줄이고 • Highly lipid solubility한 성질은 renal tubular reabsorption늘림 • Renal excretion 은 water-soluble hepatic metabolites위주로 이루어짐 Methohexital 의 경우 feces 로 excretion

  25. BARBITURATES Effects on Organ Systems • Cardiovascular • Induction dose of barbiturates • Fall in BP, elevation HR medullary vasomotor center억제  pph. capacitance vessel vasodilation , pph. Pooling of blood & RA 로의 venous return 감소 • Tachycardia  central vagolytic effect에 기인 • Sympathetic activity 에 의한 resistance vessel 의 constriction Increase pph. Vascular resistance 하지만 hypovolemia, CHF, BB 등의 baroreceptor response 가 충분하지 않다면 cardiac output, ABP 는 dramtically decreased 이는 충분히 보상되지 못한 pph. pooling effect 와 direct myocardial depression • Pt with poorly controlled HTN • Induction 시 BP의 심한 wide swing • Barbiturate 의 vascular effect • volume state, baseline autonomic tone, preexisting cardiovascular dz • 에의해 달라짐 • Slow rate of injection, preoperative hydration으로 약화 시킬 수 있음

  26. BARBITURATES Effects on Organ Systems • Respiratory • medullary ventilatory center억제 Decrease the ventilatory response to hypercapnia & hypoxia • Barbiturate sedation • Upper airway obx.  induction dose로 apnea가능 • Awakenning  tidal volume, RR decreased • Do not completely depress noxious airway reflex • Bronchospasm  asthma Pt. • Laryngospasm  lightly anesthetize Pt. (cholinergic nerve stimulation, histamine release, direct bronchial smooth m. contraction)  Atropine premedication 으로 예방 • Methohexital 사용시 Laryngospasm & hiccuping 더 흔함

  27. BARBITURATES Effects on Organ Systems • Opioids와 달리 selective하게 pain 줄이진 못함 Small dose 시 때때로 excitement, disorientation • muscle relaxation효과도 없음 some induce involuntary skeletal m. contraction

  28. BARBITURATES Effects on Organ Systems • Cerebral • Small dose of thiopental (50-100mg, iv) • 대부분의 grand mal seizure 를 조절 • Acute tolerance, physiologic dependence on the sedative effect • Renal • BP 하강에 비례해 renal blood flow and GFR 줄어듬 • Hepatic • Hepatic blood flow is decreased • Chr. exposure  drug biotransformation에 opposing effect • Induction of hepatic enzyme • Increase rate of metabolism of some drug (eg, digoxin) • Combination with the CYT P-450 enzyme system • Interfere with the biotransformation of other drug (eg, TCA) • Formation of porphyrin 을 촉진 • Porphyria 유발

  29. BARBITURATES Drug Interaction • Contrast media, sulfonamides, etc • thiopental 과 Same protein-binding site free drug양 늘림 • Ethanol, opioid, antihistamine, other CNS depressant • Potentiate the sedative effects of barbiturate

  30. BENZODIAZEPINES Mechanism of Action • Interact with specific receptors in CNS, cerebral cortex • Inhibitory effect of various neurotransmitters • Ficilitate GABA-receptor binding  increase membrane conductance of chloride ions  membrane polarization change inhibits normal neuronal function • Flumazenil • Specific benzodiazepine-receptor antagonist • Effectively reverse most of the CNS effects of benzodiazepines

  31. BENZODIAZEPINES Structure-Activity Relationships • benzene rings and a seven-member diazepine rings

  32. BENZODIAZEPINES Pharmacokinetics • Absorption • Benzodiazepines 는 대개 PO, IM, IV 형태로 투여 • Sedation 및 전신 마취시 induction • Diazepam, lorazepam  GI tract 에서 well absorbed • Peak plasma level 에 1-2 시간 경에 도달 • Oral midazolam 은 FDA 에서 공인되지 않았지만, 소아의 premedication 에 널리 쓰임 • IM injection of diazepam is painful and unreliable • Midazolam, lorazepam 은흡수 잘되어, peak level 에 30-90분 도달 • Midazolam 을 이용한 전신마취의 induction 은 IV administration 이용

  33. BENZODIAZEPINES Pharmacokinetics • Distribution • Diazepam 은 lipid soluble  BBB 를 쉽게 통과 • Midazolam 은 low pH 에서 water soluble • But physiologic pH  increase lipid solubility • Lorazepam  modest lipid solubility • Slower brain uptake and onset of action • Redistribution of benzodiazepines • Rapid ( initial distribution half life is 3-5 min) • Responsible for awakening • Midazolam 이 종종 induction agent 로 사용됨 • 하지만 thiopental 의 rapid onset과 short duration of action 을 대체 할 수는 없음 • Benzodiazepines are highly protein bound (90-98%)

  34. BENZODIAZEPINES Pharmacokinetics • Biotransformation • Rely on liver  water-soluble glucuronide end products로 전환 • Phase I metabolites of diazepam are phramacologically active • Slow hepatic extraction and a large Vd result in a long elimination half-life for diazepam (30h) • Lorazepam also has a low hepatic extraction ratiio • Lower lipid solubility limits it’s Vd, shorter elimination half-life(15h) • Clinical duration of lorazepam  too long due to a high affinity • Midazolam 의 경우 diazepam 의 Vd를 공유 하지만 high hepatic extraction ratio 를 가지므로 half life 가 짧다 (2h)

  35. BENZODIAZEPINES Pharmacokinetics • Excretion • Chiefly in the URINE • Enterohepatic circulation produce 2nd peak in diazepam plasma conc. (6-12h after administration) • Renal failure시  prolonged sedation in Pt receiving midazolam • Accumulation of a conjugated metabolite

  36. BENZODIAZEPINES Effects on Organ Systems(1) • Cardiovascular • Minimal cardiovascular depressant effect at induced doses • ABP, cardiac output, pph. Vascular resistance decline slightly • HR 는 때때로 증가 • Midazolam 의 cardiovascular effect 가 diazepam 보다 크다. • Midazolam 투여시의 HR change는 decreased vagal tone 이 원인 • Respiratory • Depress ventilatory response to CO2 • drug are administered IV나 다른 respiratory depressants없음 별문제 없다 • Barbiturate 에 비해 apnea 가 less common 하지만, small dose of diazepam & midazolam 의 IV투여로도 respiratory arrest 가 발생가능 Careful titration to avoid overdosage & apnea • IV benzodiazepines 를 투여 받은 모든 환자는 ventilation monitoring 하여야 하며, 항시 심폐소생술이 가능한 상태여야 함

  37. BENZODIAZEPINES Effects on Organ Systems • Cerebral • Reduce cerebral oxygen consumption, cerebral blood flow, ICP • Barbiturate 의 효과 보다는 적다 • Grand mal seizure 에 효과적 • Oral sedative dose  often antegrade amnesia, useful premedication • Mild muscle relaxant property of these drugs is mediated at the spinal cord level, not the NM junction • Low dose  antianxiety, amnesic, sedative effect • Induction dose  stupor and unconsciousness • Thiopental 과 비교해서, benzodiazepines 에 의한 induction • Slower loss of consciousness and longer recovery • No direct analgesic properties

  38. BENZODIAZEPINES Drug Interactions • Cimetidine binds to CYT P-450, reduce metabolism of diazepam • Erythromycin inhibits metabolism of midazolam Cause 2-3 fold prolongation and intensification of effects • Heparin은 diazepam 을 protein-binding site에서 분리해냄 Increase drug conc. (200% increase after 1000 units of heparin) • Combination of opioids and diazepam Markedly reduces ABP, & pph. Vascular resistanc Pronounced in Pt with ischemic heart dz, or valvular heart dz • Benzodiazepines reduce the MAC of volatile agents (30%) • Ethanol, barbiturates, other CNS depressants potentiate the sedative effects of the benzodiazepines

  39. BENZODIAZEPINES Uses and Dosee of Commonly used Benzodiazepines

  40. Opioids Mechanisms of action • Specific receptors located CNS & other tissues • Mu, kappa, delta, sigma

  41. Opioids Mechanisms of action • Binding 하는 receptor의 종류, affinity, receptor activation의 여부에 의해 pharmacodynamic property 가 결정 • Agonist 만이 receptor activation • Agonist-antagonist (nalbuphine, nalophine, butorphanpl, pentazoxin) 등은 서로 다른 receptor 에서 opposite action을 보임 • Naloxone  pure opioid antagonist • Opioid receptor 에 결합하는 endogenous peptides • Endorphins, enkephalins, dynorphins • 작용기전 • Opiate receptor activation은 excitatory neurotransmitter (Ach, substance P) 등의 presynaptic release 와 postsynaptic response 를 억제 • Potassium, calcium ion conduction 에 변화에도 관여

  42. Opioids Mechanisms of action • 기전(2) Pain impulse는 dorsal horn of the spinal cord level 에서, intrathecal, epidural 로의 opioid 투여에 의해 억제됨 • CNS 뿐만 아니라, somatic, sympathetic pph. Nerve 에서도 opiate receptor 가 존재

  43. Opioids Structure-Activity Relationships • Opiate-receptor interaction은 화학적으로 다양한 group의 compound 에 의해 공유됨 • 하지만 common structural characteristics 를 가짐

  44. Opioids Pharmacokinetics • Absorption • IM morphine, meperidine • Rapid absorption, (20-60min) • Fentanyl citrate , oral transmucosal • Analgesia, sedation (10분이내) • Children (15-20 micrograms/kg), adult (200-800 micrograms) • Fentanyl • 적은 분자량, 높은 lipid solubility • Transdermal absorption 가능 Surface area의 크기, local skin condition 등에 영향 받음 • Upper dermis가 reservoir of drug이며 이로써 흡수 속도가 느려지고 오래 작용할 수 있음 • Serum conc  14-24h 후 plateau 형성,72시간 까지 지속 • High incidence of nause, variable blood level

  45. Opioids Pharmacokinetics • Distribution • Half-life  5-20 분 ,매우 빠름 • Morphine 의 경우, fat solubility 가 낮아 BBB 통과가 느림, onset of action이 느리고 오랜 기간 지속 • Fentanyl 과 sufentanil 은 높은 지질 용해도를 가져, rapid onset 과 short duratio보임 • Alfentanil 는 fentanyl에 비해 지질 용해도는 낮지만, nonionized fraction 이 많아서 onset 과 duration 이 짧다. • Lipid soluble opioid는 liver 에서 retained (1st-pass uptake)되며 이후, 다시 systemic circulation으로 감 Pul. Uptake 가 증가하는경우 • Smoking, 흡입마취제 감소하는 경우 • 다른 drug 가 이미 accumulation 된경우 • 적은 양의 drug dose는 Redistribution에 의해 termination 되며 • 많은 양의 drug 는 biotransformation 에 의해 plasma level 결정됨

  46. Opioids Pharmacokinetics • Biotransformation • Primarily on the liver • High hepatic extraction ratio가지며, clearance 는 hepatic blood flow 에 의해 좌우됨 • Alfentanil 은 small Vd이므로, short elimination half-life (1.5h) • Morphine  glucuronic conjugation • Meperidine  N-demethylated 되어 normeperidine됨(active metabolite) • Fentanyl, alfentanil, sufentanil Inactive metabolite로 biotransformation • Remifentanil • Ultrashort-acting opioid 로 terminal elimination half-life 은 10min이내  blood, tissue의 non-specific esterase 에 의해 hydolysis • remifentanyl infusion의 Duration 은 wake-up time에 거의 영향을 미치지 않음 • Context/sensitive half-time (infusion 후, 약물의 혈장 농도가 50%로 감소하는데 필요한 시간) 약 3분, (infusion 의 duration 에 영향받지 않음)

  47. Opioids Pharmacokinetics • Biotransformation • Remifentanil 은 repeated bolus, prolonged infusion, 에 의해서도 accumulation 효과 가 거의 없음 • 다른 opioid 와는 다른 특성 • Extra hepatic metabolism • Metabolic toxicity 가 거의 없고,hepatic dysfunction 시에도 유용하게 사용가능 • Pseudocholinesterase deficiency 의 경우에도 normal response

  48. Opioids Pharmacokinetics • Excretion • End product of morphine and meperidine eliminated by kidney • 10% 미만은 biliary excretion • 5-10 % 의 morphine 은 unchanged 형태로 kidney 로 배설 • Renal failure 시 약물의 duration 증가 • Accumulation of morphine metabolite in renal failure • Narcosis, ventilatory depression • 오히려 metabolite 가 more potent opioid receptor agonist • Normeperidine ( metabolite of meperidine) • CNS excitatory effects • Myoclonic activity, seizure 유발 • Not reversed by naloxone • Fentanyl • IV 4시간후 late 2nd peak in plasma level Enterohepatic recirculation과 mobilization of drug 에 의한 것 • Sufentanil  metabolite 가 urine 과 bile 로 배설 • Remifentanil  metabolite 의 effect 는 매우 미약 • Severe liver disease pt 의 경우에도 pharmacodynamics 나 pharmakokinetics 에 거의 영향이 없다

  49. Opioids Effects on Organ systems • Cardiovascular • 대개 opioids 는 심각한 심혈관계 기능 저하가 없음 • Meperidine 은 HR 증가 (atrophine 과 구조가 유사), high dose of morphine, fentanyl, sufentanil, remifentanil , alfentanil 는 vagus mediated bradycardia 유발 • Meperidine 을 제외 하고, 모든 opioid 는 cardiac contractility 를 depression 시키지 않음 • 하지만, ABP 는 bradycardia, venodilation, decrease sympathetic reflex 에 의해 종종감소 • Meperidine, morphine 는 어떤 환자의 경우, histamine release 유발 • Systemic vascular resistance 및, ABP 를 심하게 감소 시킴 • Slow infusion, 충분한 intravascular volume 유지, H1, H2 histamine antagonist 의 pretreatment 로 예방 • opioid anesthesia 중 Intraoperative HTN 특히 morphine, meperidine의 경우 드물지 않게 발생 주로 마취 심도가 낮아서 발생하며 vasodilater 나 흡입 마취제의 투여로 조절가능 • Opioid 와 다른 마취약제 (nitrous oxide, benzodiazepines, barbiturates, volatile agents) 의 병행 사용은 심각한 myocardial depression을 유발 할 수 있음

  50. Opioids Effects on Organ systems • Respiratory • Ventilation&respiratory rate억제 • Resting PaCO2 는 증가, PaCO2 증가에 대한 response 는 감소 • CO2 response curve 가 우하향으로 이동 • Brainstem 의 respiratory center 에 작용 • Apneic threshold 가 증가, hypoxic drive 는 감소 • 여자의 경우가 more depressed • Morphine, meperidine • Histamine-induced bronchospasm 유발가능 • Opioids, particularly fentanyl, shfentanil, alfentanil • Chest wall rigidity 유발  ventilation 을 방해 • 주로 large bolus dose 에 의해 유발 • 근이완제로 효과적으로 치료가능 • Opioids 는 효과적으로 bronchoconstrictive response 를 억제 (intubation자극 등)

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