NONVOLATILE ANESTHETIC AGENT

NONVOLATILE ANESTHETIC AGENT R1 신승호 PHARMACOLOGICAL PRINCIPLES PHARMACOKINETICS • Oral, sublingual, rectal, inhalation, transdermal, subcutaneous, IM, IV • Administrarion site  Blood stream • Affected by characteristic of drug, site of absorption Absorption • Bioavailability • Fraction of unchanged drug that reaches the systemic circulation • Oral administration • Convenient, economical, tolerant • Unreliable  Pt’s cooperation, 1st pass hepatic metabolism, gastric pH, enzymes, motility, food, other drug 등에 의해 영향 받음 • Subligual, rectal, buccal administration • 1st pass hepatic metabolism 을 bypass • Transdermal administration • Prolonged and continuous absorption with minimal total dose • Parenteral injection • Subcutaneous, IM,  blood flow, carrier vehicle • IV  completely bypass the process of absorption PHARMACOKINETICS Distribution • Major determinet of end-organ drug concentration • Highly perfused organs  large amount of drug PHARMACOKINETICS Distribution • Plasma protein bounded drug  unavailable for uptake • Albumin  bind acidic drug (eg. Barbiturate) • AAG  bind basic drug (eg. Local anesthetics) • Plasma protein 이 소실 되거나, binding site 가 다른 물질에 의해 occupied 되어 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 • Permeation of CNS  BBB는 ionized drug의 흡수를 방해 • Molecular size • Lipid-solubility • After the highly perfused organs are saturated during initial distribution, the greater mass of the less perfused organs takeup drug from the blood stream • Plasma conc. 이 감소  어떤 drug는 highly perfuse organ에서 방출되 어 equilibrium 유지 • 이러한 redistribution 은 대부분의 마취 약제의 termination 의 기전 PHARMACOKINETICS Distribution • Vd • Volume of distribution  apparent volume into which a drug has been distributed • Dose / Plasma concentration • Drug elimination 과 continual redistribution 을 고려 • A small Vd • relative confinement of the drug to the intravascular space • High protein bounding, ionization • A large Vd • total body water 의 양보다 많을 수도 있음 • High solubility or binding of the drug in tissue other than plasma PHARMACOKINETICS Biotransformation • Metabolic process • Liver 가 primary organ • 대부분 end product 가 water soluble, inactive • Kidney로의 excretion 이 용이한 형태 • Phase I • 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 clearence • • • • Rate of elimination of a drug as a result of liver biotransformation mm/min Hepatic blood flow, hepatic excretion ratio 에 영향 Hepatic enzyme system capacity PHARMACOKINETICS Excretion • The kidney is the principle organ of excretion • Non-protein bound drugs freely cross from plasma into the glomerular filtrate • Non-ionizedfraction  reabsorbed in the renal tube • Ionized portion is excreted in urine  urine pH 에 영향받음 • Kidney active secrete some drug • Renal clearance  the rate of elimination of a drug from kidney excretion • Renal failure  changing pharmacokinetics of drug ; protein bounding, Vd, clearance rates • Relatively few drugs depend on biliary excretion • The lungs  excretion of volatile agents PHARMACOKINETICS Compartment Models • A simple way to characterize the distribution and elimination of drug in the body • Group of tissues that process similar pharmacokinetics • Plasma & vessel rich group  central compartment • Muscle, fat, skin, etc.  pph. compartment • Compartment 는 conceptual  not represent actual tissues • Two compartment model • Correlate well with the distribution and elimination phase of many drugs • 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  elimination of drug from continued but less steep • Elimination half-life of drug • Vd 에 비례, rate of clearance 에 반비례 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 dustribution & biotransformation • First-order kinetics • Constant fraction or percentage of drug is distributed or metabolized per unit of time • Zero-order kinetics • Drug 의 농도가 biotransformation capacity 를 넘어서면 constant amount of drug 만 단위시간당 대사 되는 경우 PHARMACODYNAMICS Dose-Response Curves • Relationship between drug dose and pharmacological effect • Relationship between drug dose and pharmacological effect • X-axis  steady-states plasma conc. • Y-axis  pharmacological • Linear 한 형태나 logarithmic 한 형태 • Curve position  indication of drug potency • Maximal effect of drug  efficacy • Slope of curve  receptor binding character of the drug • ED(50) : median effective dose • LD(50) : median lethal dose • Therapeutic index • Ratio of LD 50:ED 50 PHARMACOKINETICS Drug Receptor • Macromollecules • • • • Protein embedded into cell membrane Endogeneous substance, exogenous eubstance Agonist  receptor와 결합 하여 cell function 에 변화를 주는것 Antagonist  receptor 에 결합 하지만, cell 에 direct effect 가 없음 • 약리학 적으로 agonist substance 의 effect 를 저해 • Competitive antagonist  bind reversibly to receptor, can be displaced by higher conc. of agonist • Non-competitive antagonist  bind to the receptor with high affinity • 높은 농도의 agonist 로도 receptor blockade가 reverse 되지 않음 • 직접 cell function 에 영향을 주는 경우도 있지만, 2nd messenger, cAMP 등의 regulatory molecule을 매개 하는 경우도 있다 SPECIFIC NONVOLATILE ANESTHETIC AGENTS BARBITURATES Mechanism of action • Depress reticular activating system • Brain stem의 complex polysynaptic network of neurons and regulatory centers • Consciousness 를 포함한 몇가지 vital function을 관장 • Axon 보다는 nerve synapse에 영향을 미침 • Excitatory neurotransmitters (Ach)  suppress transmission • Inhibitory neurotransmitters (GABA) enhance transmission BARBITURATES Structure-Activity Relationship 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, secobarbotal • Premedication for all age groups • Distribution • 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 • Redistribution • pph. Compartment(주로 muscle)  20-30분 이내에 peak level 의 10% • 임상적으로 환자가 30초 이내에 의식을 잃고, 20분이내에 awake BARBITURATES Pharmacokinetics • Distribution BARBITURATES Pharmacokinetics • Distribution • Induction dose • BW 와 age 로 결정 (old age 의 경우 dose 를 줄임) • redistribution 이 감소 • Elimination half-life  3-12 h • Thiamylal, methohexital has similar distribution patterns • Less lipid-soluble barbiturate • Much longer distribution half life and duration of action • Biotransformation • Hepatic oxydation • Inactive water soluble metabolites • Methohexital 의 경우, thiopental에 비해 3-4배 hepatic clearnace가 빠름 • Single dose barbiturate 의 awake 는 주로 redistribution 에 의해 좌우 되지 만, psychomotor function의 full recover 는 metabolism 에 의해 영향받음 BARBITURATES Pharmacokinetics • Excretion • Highly protein bound  decrease glomerular filtration • Highly lipid solubility  increase renal tubular reabsorption • Renal excretion 은 water-soluble hepatic metabolites위주로 이루어짐 • Phenobarbital 은 예외 • Methohexital 의 경우 feces 로 excretion BARBITURATES Effects on Organ Systems • Cardiovascular • Induction dose of barbiturates • Fall in BP, elevation HR • Depression of the medullary vasomotor center  pph. Capacitance vessel vasodilation , pph. Pooling of blood & RA 로의 venous return 감 소 • Tachycardia  due to central vagolytic effect • 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 • Slow rate of injection, preoperative hydration BARBITURATES Effects on Organ Systems • Respiratory • Depression of medullary ventilatory center • Decrease the ventilatory response to hypercapnia, hypoxia • Barbiturate sedation • Upper airway obx.  apnea usually follows an induction dose • 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 • Laryngospasm & hiccuping are more common after use of methohexital BARBITURATES Effects on Organ Systems • Cerebral • Constrict the cerebral vasculature • Decreasing in cerebral blood flow, ICP • 만약 ICP 가 cerebral ABP 보다 감소하면 cerebral perfusion pressure 는 증 가 • CPP 는 cerebral artery pressure – (greater of cerebral venous pressure or ICP) • 하지만 이러한 cerebral blood flow 의 감소는 유해하지 않음 • Barbiturate 는 cerebral oxygen consumption 을 50% 까지 감소 • EEG changes • Small dose  low-voltage fast activity • High dose ( bolus of 15-40 mg/kg, thiopental)  electrical silence (suppression) • 이러한 effect 는 transient episode of focal ischemia (cerebral embolism) 로 부터 pretect • 하지만 global ischemia (cardiac arrest, etc) 시에는 not protectove • 이러한 EEG suppression dose 시 • Prolonged awakening, delayed extubation, inotropic support need BARBITURATES Effects on Organ Systems • Cerebral • Degree of CNS depression  mild sedation to unconsciousness • Depending on the dose • Garlic or onion sensation during induction with thiopental • Unlike opioids, do not selectively impair the perception of pain • 어떤 경우에는 antianalgesic effect (lowering the pain threshold) • Small dose 시 때때로 excitement, disorientation • Do not produce muscle relaxation, • some induce involuntary skeletal m. contraction 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 • Reduce renal blood flow and GFR • in proportion to the fall in BP • Hepatic • Hepatic blood flow is decreased • Chr. exposure  opposing effect on drug biotransformation • 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 BARBITURATES Effects on Organ Systems • Immunological • Anaphylactic and anaphylactoid allergic reactions are rare • Thiobarbiturates  mast cell histamine release in vitro • Some anesthesiologist • Prefer methohexital over thiopental or thiamylal in asthmatic pt. BARBITURATES Drug Interaction • Contrast media, sulfonamides, etc • Same protein-binding site as thiopental  increase the amount of free drug • Potentiate the organ system effect • Ethanol, opioid, antihistamine, other CNS depressant • Potentiate the sedative effects of barbitura • Common clinical impression • chr. Alcohol abuse  increased thiopental requirements • Lacks scientific proof 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 that effectively reverse most of the CNS effects of benzodiazepines BENZODIAZEPINES Structure-Activity Relationships • Include benzene rings and a seven-member diazepine rings 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 • Intranasal(0.2-0.3mg/kg), buccal(0.07mg/kg), sublingual(0.1mg/kg) • Effective preoperative sedation • IM injection of diazepam is painful and unreliable • Midazolam, lorazepam 은 well absorbed, peak level 에 30-90분 도달 • Midazolam 을 이용한 전신마취의 induction 은 IV administration 이용 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 수 는 없음 • Benzodiazepines are highly protein bound (90-98%) BENZODIAZEPINES Pharmacokinetics • Biotransformation • Rely on liver  water-soluble glucuronide end products • 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) BENZODIAZEPINES Pharmacokinetics • Excretion • Chiefly in the urine • Enterohepatic circulation produce 2nd peak in diazepam plasma conc. (6-12h after administration) • Renal failure  prolonged sedation in Pt receiving midazolam • Accumulation of a conjugated metabolite BENZODIAZEPINES Effects on Organ Systems • 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 • Usually insignificant unless the drug are administered IV or in association with other respiratory depressants • Barbiturate 에 비해 apnea 가 less common 하지만, small dose of diazepam & midazolam 의 IV투여로도 respiratory arrest 가 발생가능 • Steep dose-response curve, slightly prolonged onset and high potency of midazolam • Careful titration to avoid overdosage & apnea • IV benzodiazepines 를 투여 받은 모든 환자는 ventilation monitoring 하 여야 하며, 항시 심폐소생술이 가능한 상태여야 함 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 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 • Heparin displaces diazepam from protein-binding site • Increase drug conc. (200% increase after 1000 units of heparin) • Combination of opioids and diazepam • Markedly reduces ABP, pph. Vascular resistance • 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 BENZODIAZEPINES Uses and Dosee of Commonly used Benzodiazepines Opioids Mechanisms of action • Specific receptors located CNS & other tissues • Mu, kappa, delta, sigma Opioids Mechanisms of action • Provide some degree of sedation, • Most effective at analgesia • Binding 하는 receptor의 종류, affinity, receptor activation의 여 부에 의해 pharmacodynamic property 가 결정 • Agonist 만이 receptor activation • Agonist-antagonist (nalbuphine, nalophine, butorphanpl, pentazoxin) 등은 서로다른 receptor 에서 opposite action을 보임 • Naloxone  pure opioid antagonist • Opioid receptor 에 결합하는 endogenous peptides • Endorphins, enkephalins, dynorphins • 기전 • Opiate receptor activation은 excitatory neurotransmitter (Ach, substance P) 등의 presynaptic release 와 postsynaptic response 를 억제 • Potassium, calcium ion conduction 에 변화 Opioids Mechanisms of action • 기전 • Pain impulse는 dorsal horn of the spinal cord level 에서, intrathecal, epidural 로의 opioid 투여에 의해 억제됨 • 또한 periaqueductal gray 에서 nucleus raphae 를 경유해서 dorsal horn으로 도달하는 경로를 가진 descending inhibitory pathway 의 modulation 도 중요한 역할을 함 • CNS 뿐만 아니라, somatic, sympathetic pph. Nerve 에서도 opiate receptor 가 존재 Opioids Structure-Activity Relationships • Opiate-receptor interaction은 화학적 으로 다양한 group의 compound 에 의 해 공유됨 • 하지만 common structural characteristics 를 가짐 • 약간의 molecular change 에 의해서도 agonist 가 antagonist 로 변환될수 있 음 • L-isomer 가 d-isomer 보다 more potent 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 dermis  reservoir of drug 흡수 속도가 느려지고 오래 작용할 수있음 Serum conc  14-24h 후 plateau 형성,72시간 까지 지속 High incidence of nause, variable blood level Opioids • Distribution Pharmacokinetics • Half-life  5-20 분 ,매우 빠름 • Morphine 의 경우, fat solubility 가 낮 아 BBB 통과가 느림, onset of action이 느리고 오랜 기간 지속 • Fentanyl 과 sufentanil 은 높은 지질 용 해도를 가져, rapid onset 과 short duratio • Alfentanil 는 fentanyl에 비해 지질 용해 도는 낮지만, nonionized fraction 이 많 아서 onset 과 duration 이 짧다. • Lipid soluble opioid는 liver 에서 retained (1st-pass uptake), • 이후, 다시 systemic circulation으로 • Pul. Uptake 가 증가하는경우 • 감소하는 경우 • Smoking, 흡입마취제 • 다른 drug 가 이미 accumulation 된경우 • Redistribution small dose of drug 를 termination,하지만 많은 양의 drug 는 biotransformation 에 의해 termination Opioids Pharmacokinetics • Biotransformation • Primarily on the liver • High hepatic extraction ratio, clearance 는 hepatic blood flow 에 의해 좌우 • Alfentanil 은 small Vd,  short elimination half-life (1.5h) • Morphine  glucuronic conjugation • Meperidine  N-demethylated to normeperidine, active metabolite, • Fentanyl, alfentanil, sufentanil • Inactive metabolite • Remifentanil • Ultrashort-acting opioid with a terminal elimination half-life of less than 10min  non-specific esterase in blood, tissue 에 의해 hydolysis • Duration of remifentanyl infusion 은 wake-up time 에 거의 영향을 미치지 않음 • Context/sensitive half-time (infusion 후, 약물의 혈장 농도가 50%로 감소하는 데 필요한 시간) • 약 3분, infusion 의 duration 에 영향받지 않음 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 없 고,hepatic dysfunction 시에도 유용하게 사용가능 • Pseudocholinesterase deficiency 의 경우에도 normal response 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 recirculation, mobilization of drug • 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 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 • Slow infusion, 충분한 intravascular volume 유지, H1, H2 histamine antagonist 의 pretreatment 로 예방 • Intraoperative HTN during opioid anesthesia • 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 Opioids Effects on Organ systems • Respiratory • Depress ventilation, particularly respiratory rate • Resting PaCO2 는 증가, PaCO2 증가에 대한 response 는 감소 • CO2 response curve 가 downward and to the right • Brainstem 의 respiratory center 에 작용 • Apneic threshold 가 증가, hypoxic drive 는 감 소 • 여자의 경우가 more depressed • Morphine, meperidine • Histamine-induced bronchospasm • 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 (intubation 등) Opioids Effects on Organ systems • Cerebral • Cerebral perfusion 과 ICP 에 대한 영향은 variable • Cerebral oxygen consumption, cerebral blood flow, ICP 를 감소 • Barbiturate 나 benzodiazepines 의 효과 보다는 미약 • Artificail ventilation 시에는 normocarbia 유지 • Opioids bolus 후 Brain tumor 나 head trauma 시 점진적이고 경도의 cerebral blood flow velocity 와 ICP 의 증가가 보고 되기도 함 • Opioids 는 mild 한 MAP 감소 • CPP 를 감소  abnormal intracranial elastance 를 보이는 환자에게서 심각한 수준으로 감소 될 수 있음 • Opioid 는 mild 한 ICP 증가 효과 • 하지만 불충분한 마취시 intubation 자극에 의한 ICP 증가에 비해서는 미미 • Stimulation of the medullary chemoreceotor trigger zone • High incidence of nausea and vomiting • Physical dependence • 반복적인 투여 시 incidence 증가 Opioids Effects on Organ systems • Cerebral • Do not produce amnesia • Barbiturate 나 benzodiazeoines 와 달리, pt 를 unconscious 하게 만들 기 위해서는 비교적 large dose 의 opioid가 필요 • IV meperidine (25 mg) 은 shivering을 감소시키는데 있어 most effective 한 opioid • Gatrointestinal • Reducing peristalsis • Slow gastric emptying time • Biliary colic • Opioid-induced contraction of Sphincter of Oddi • Biliary spasm 은 naloxone 에 의해 reversed • Long term opioid therapy 환자의 경우 • Constipation 을 제외한 대부분의 side effect 에 tolerance Opioids Effects on Organ systems Opioids Effects on Organ systems • Endocrine • Stress response to surgical stimulation • Secretion of cathecholamine, ADH, cortisol • Opioids 는 흡입마취제 보다 이러한 호르몬 등의 분비를 억제하는 효과가 크다 • 특히 more potent opioids인 fentanyl, alfentanil, sufentanil, remifentanil 에서 이러한 효과가 두드러진다. • Ischemic heart dz 환자에게 이러한 stress response 에 대한 효과는 benifitial Opioids Drug Interactions • Combination of opioids (particulary meperidine) and MAO inhibitor • Respiratory arrest, Hypertension, hypotension, coma, hyperpyrexia 등 유발 가능 • Barbiturate, benzodiazepines, other CNS depressants • Synergistic cardiovascular , respiratory, sedative effect with opioid • Alfentanil 의 경우 erythromycin 투여 후 prolonged sedation, respiratory depression effect KETAMINE Mechanisms of action • Multiple effects on CNS • • • • Spinal cord  blocking polysynaptic reflex Brain  inhibiting excitatoryneurotransmitter Barbiturate  depression of the reticular activationg system Ketamine  functionally “dissociate” the thalamus from the limbic cortex • Some brain neurons inhibited but others are tonically excited • This state of dissiciative anesthesia cause the patient to appear conscious (eye eye opening, swallowing, muscle contracture) , but unable to process or respond to sensory input KETAMINE Structure-Activity Relationships • Analogue of phencyclidine • One-tenth s potent, retain many of phencyclidine’s psychotomimetic effects • Subtherapeutic dose • Can cause hallucinogenic effects KETAMINE Pharmacokinetics • Absorption • IV or IM • Peak plasma level  10-15min after IM injection • Distribution • Thiopental 에 비해 more lipid soluble, less protein bound • Increase in cerebral blood flow, cardiac output • Rapid brain uptake, subsequent redistributin (distribution half life 10-15 min) • Awakening is due to redistribution to pph compartment KETAMINE Effects on Organ Systems • Cardiovascular • Increase ABP, HR, Cardiac output • Central stimulation of the sympathetic nervous system, inhibition of the reuptake of norepinephrine • Increase in pulmonary artery pressure, myocardial work • Avoided in coronary artery dz, uncontrolled HTN, CHF, arterial aneurysm • Direct myocardial depressant effect of large doses of ketamine • Inhibition of calcium transients (unmasked by sympathetic blockade) • Exhaustion of catechlolamine store (eg. Severe end-stage shock) • Indirect stimulatory effecs • Often benificial to Pt with acute hypovolemic shock KETAMINE Effects on Organ Systems • Respiratory • Ventilatory drive is minimally affected (customary induction dose) • Rapid IV bolus, pretreatment with opioids occasionally produce apnea • Ketamine is a potent bronchodilator • Good induction agent for asthmatic Pt • Upper airway reflex remain largely intact • 하지만 aspiration Pn. Risk 가 있는 환자의 경우 반드시 intubation • Ketamine 에 의한 salivation 증가 • Premedication with an anticholinergic agent KETAMINE Effects on Organ Systems • Cerebral • Increase cerebral oxygen consumption, cerebral blood flow, ICP • Space-occupying intracranial lesions 시 사용이 불가 • Myoclonic activity  increased subcortical electrical activity • Undesirable psychotomimetic side effects • Illusions, disturbing dreams, delirium during emergence and recovery • Less common in chlidren and in Pt with benzodiazepines premedication • Of the nonvolatile agents, ketamine may be the closet to being a “complete” anesthetic as it induce analgesia, amnesia, and unconsciousness KETAMINE Effects on Organ Systems KETAMINE Drug Interactions • Nondepolarizing neuromuscular blocking agnets are potenciated by ketamine • Theophylline 과 ketamine 의 병행 투여는 seizure 의 발생확률 증가 • Diazepam 은 ketamine의 cardiostimulatory effects 를 감소 시키 고 elimination half life 를 증가 • Propranolol, phenoxybenzamine, 기타 다른 sympathetic antagonist 는 ketamine의 direct myocardial depressant effect 를 unmasking • Halothane 등 으로 마취된 환자에서 ketamine 투여시 종종 myocardial depression 이 발생 ETOMIDATE Mechanisms of Action • Depress the reticular activating system and mimics the inhibitory effects of GABA • Bind to a subunits of the GABA type A receptor • Barbiturate 와는 달리 extrapyramidal motor activity 의 inhibitory effect 는 없음 • 이 disinhibition 은 30-60 % 의 myoclonus incidence 의 원인 ETOMIDATE Structure-Activity Relationships • Carboxylated imidazole 은 구조적으로 다른 anesthetic agents 와 구조적 으로 연관이 없다 • Imidazole ring • Water solubility in acidic solution, lipid solubility at physiologic pH • Ethmidate 는 propylene glycol 에 용해된 상태 • Cause pain on injectin • Reduced by a prior injection of lidocaine ETOMIDATE Pharmacokinetics • Absorption • Only for intravenous administration • Used primarily for induction of general anesthesia • Distribution • Highly protein bound, 하지만 높은 lipid soulubility, large nonionized fraction(at physiologic pH) 때문에 매우 빠른 onset 을 보임 • Redistribution • Awakening level 로의 plasma concentration 의 감소 • Biotransformation • Hepatic microsomal enzymes and plasma esterases • Rapidly hydrolyze etomidate to an inactice metabolite • Biotransformation rate 는 barbiturate 의 약 5배 • Excretion • 주로 kidney 에서 metabolite 가 배설 ETOMIDATE Effects on Organ Systems • Cardiovascular • Minimal effects on the cardiovascular system • Mild reduction in pph. vascular resistance • Slight decline in ABP • Myocardial contractility, cardiac output • Usually unchanged • Dose not release histamine • Respiratory • Affected less with ethmidate than with barbiturates or benzodiazepines • Induction dose 로도 대개 apnea 를 유발 하지 않음 • Opioids 가 같이 투여시 apnea 유발 가능 ETOMIDATE Effects on Organ Systems • Cerebral • Decrease cerebral metabolic rate, cerebral blood flow, ICP • Same extent as thiopental • Cardiovascular effects 가 작기 때문에 CPP는 intact • Postoperative nausea, vomiting • More common than barbiturate induction • Can be minimized by antiemetic medication • Sedative-hypnotic but lacks analgesic properties • Endocrine • Transiently inhibit enzymes involved in cortisol and aldosterone synthesis • Long-term infusions lead to adrenocortical supression • Critically ill Pt 에서 mortality rate 증가 ETOMIDATE Drug Interaction • Frentanyl increase the plasma level and prolong the elimination half-life of etomidate • Opioid decrease the myoclonus characteristic of an etomidate induction PROPOFOL Mechanisms of Action • Involce facilitation of inhibitory neurotransmission mediated by GABA PROPOFOL Structure-Activity relationships • Phenol ring with two isopropyl groups attached • Altering the side-chain length of this alkylphenol influence potency, induction, recovery characteristics • Not water soluble, 1% aqueous solution (10mg/mm) • Soybean oil, glycerol, egg lecithin 을 함유한 oil-in water emulsion 형태로 IV 로 투여가능 • History of egg allergy • Non CIx of propofol : 대부분의 egg allergy 는 주로 egg white 에 들어 있는 albunin이 관여 • Egg lecithin 은 egg york 에서 추출 • 투여시 pain 유발 • Elderly 의 경우 pain 이 덜함 • Prior lidocaine injection, mixing with lidocaine (2ml of 1% lidocaine + 18ml propofol) PROPOFOL Structure-Activity Relationship • Support the growth of bacteria • • • • So good sterile technique is needed Cleaning the rubber stopper or ample neck with an alcohol swab Ample 개봉후 6시간 내에 투여가 이루어 져야 함 0.025 % sodium metabisulfite 을 함유시킴 • 미생물의 번식을 억제 PROPOFOL Pharmacokinetics • Absorption • Only for IV administration for induction of GA and for moderate to deep sedation • Distribution • High lipid-solubility • Onset of action : almost as rapid as that of thiopental • Awakening from single bolus dose : rapid • Very short initial distribution half-life(2-8 min) • Good agent for outpatient anesthesia • Thiopental, etomidate 등에 비해 recovery 가 빠르고 잔존효과가 적음 • Lower induction dose is recommended in elderly patient • Elderly pt 의 경우 Vd 가 적기 때문 • Women may require a higher dose of propofol PROPOFOL Pharmacokinetics • Biotransformation • Clearance of propofol 이 hepatic blood flow 를 넘어섬 • Implying the existence of extrahepatic metabolism • High clearance rate (thiopental 의 10배 ) • Relatively rapid recovery after a continuous infusion • Liver conjugation  inactive metabolite 는 kidney 에서 elimination • Do not affected by moderate cirrhosis • Long term sedation of critically ill children, neurosurgical pt, (young adult) • long-term propofol infusion 시 lipemia, metabolic acidosis, death 유발 • Excretion • Primarily excreted in the urine, but CRF 시 영향 받지 않음 PROPOFOL Effects On Organ System • Cardiovascular • Decrease in ABP : systemic vascular resistance 감소 (inhibition of sympathetic vasoconstrictor activity), cardiac contractility, preload 감소 • Thiopental 에 비해 hypotension 이 두드러짐 • 하지만 laryngoscopy, intubation 자극에 의해 쉽게 reversed • Hypotension 을 조장 하는 factor • Large dose, rapid injection, old age • Markdly impair the normal arterial baroreflex response to hypotension- 특히 normocarbia 나 hypocarbia 시 • Marked drop in preload  vagally mediated bradycardia • 이러한 HR, cardiac output 의 변화는 health pt 에 있어 대부분 점진적 이 고, 큰 위험성은 없으나, 어떠한 경우에는 (특히 고령환자, negative chronotrophics 복용시, oculocardiac reflex 와 연관된 surgical procedure 등) asystole 까지 유발 할 위험성이 존재 • Impaired ventricular function  ventricular filling pr., contractility 감소 때문에 심각하게 cardiac output 감소 • PROPOFOL Effects On Organ System • Respiratory • Barbiturate 와 마찬가지로 profound respiratory depression • cause apnea following induction dose • Conscious sedation 을 위한subanesthetic dose 로도 hypoxic ventilatory drive 를 감소시켜 hypercarbia 에 대한 normal response를 억제 • 따라서 이러한 technique 는 trained doctor 에 의해서만 시행되어야 함 • Upper airway reflex depression • Thiopental 에 의한 효과 보다 강력  helpful during intubation, or laryngeal mask placement • Can cause histamine release • 하지만 barbiturate나 etomidate 에 비해 asthma 환자나, 일반인 모두에게 있어 wheezing 의 incidence 가 낮다 • Asthma 환자에 있어서 propofol은 금기가 아니다. PROPOFOL Effects On Organ System • Cerebral • Cerebral blood flow, ICP 감소 • ICP 증가 된 환자에 있어, 만약 MAP 가 적정하게 유지 되지 않는 다면 propofol 은 CPP 를 심각하게 감소 시킬 수 있음 • Propofol 은 thiopental 과 동등한 정도로 focal ischemia 에 대한 protection 효과 • Antipruritic, antiemetic effect • Outpatient anesthesia 에 효과적인 특성 • Induction 시 muscle twitching, spontaneous movement, opisthotonus, hiccupping 등의 excitatory phenomena 를 보임 • Subcortical gylcine antagonism • But 이러한 현상이 , tonic-clonic seizure 와 유사하지만 propofol 은 anticonvulsant effect 를 보여, status epilepticus 에 효과적 • Intraocular pr 를 감소시킴 • Long-term infusion 시에도 tolerance 유발하지 않음 PROPOFOL Drug Interactions • Nodipolarizing neuromuscular blocking agent 의 경우, 이전의 propofol fomula (Cremophor 함유) 의 경우, propofol의 effect를 potentiate (하지만 새로운 fomula 의 경우 이러한 효과가 없음) • Fentanyl, alfentanil 의 농도는 propofol 의 부가적이 투여로 증가 • 어떤 마취의사 들은 Propofol induction 전, midazolam 의 pretreatment (30 micrograms / kg)는 synergistic effect 를 유발 한다고 주장 • 하지만, 이러한 “coinduction” technique는 questionable efficacy DROPERIDOL Mechanisms of Action • Antagonism of dopamine receptors • CNS system 에서 caudate nucleus, medullary chemoreceptor zone 등이 영향받음 • Serotonin, norepinephrine, GABA 등에 의한 transmission 을 차단 • Tranquilizer, antiemetic properties • Pph alpha-adrenergic blockade DROPERIDOL Structure-Activity Relationships • Droperidol,(butyrophenone ) 은 구조적으로 haloperidol 과 연관 • 이 두가지 drug 의 구조적인 차이 • Haloperidol : neuroleptic • Droperidol : antipsychotic DROPERIDOL Pharmacokinetics • Absorption • Premedication 시 IM inj. 하는 경우도 있으나 대부분 IV 로 투여 • Distribution • Repid distribution phase (약 10분) 을 가지지만, sedative effect 는 높 은 molecular weight, extensice protein binding 등에 의해 delayed • Duration of action : 약 3-24h 정도로 긴편 • Biotransformation • Extensively metabolized in the liver • Hepatic clearance 는 ketamine, etomidate 등과 유사하게 빠른 대사 • Excretion • Biotransformation 의 end product는 urine 으로 배출 DROPERIDOL Effects On Organ System • Cardiovascular • Mild alpha agonist blocking effecs • Decrease ABP, pph vasodilation • Hypovolemic pt 의 경우, 이러한 ABP decline effect 가 더욱 두드러짐 • 이러한 alpha agonist blocking effect 는 antiarrhythmatic effect 를 가지기 도 하는데, 특히 QT interval prolongation, torsades de pointes 등에 연관이 있음 • Droperidol 투여 전에 항상 12 lead ECG 가 기록 되어야 함 • 만약 QT interval 이 440 ms (men), 450 ms (women) 이상이면 droperidol 의 투여 는 중지 되어야 함 • QT interval 이 정상이고 droperidol 이 투여된 상태 라면, ECG monitoring (2-3h) 하 여야 함 • Pheochromocytoma Pt • Droperidol 의 투여는 adrenal medulla 에서 catecholamine release 를 induce 하 여 severe HTN 유발 • 따라서 droporidol 의 투여는 금기 DROPERIDOL Effects On Organ System • Respiratory • Droperidol 의 투여는 resiration 의 심각한 depression 을 유발 하지 않음 • Cerebral • Decrease cerebral blood flow, ICP  by inducing cerebral vasoconstriction • Barbiturate, benzodiazepines, etomidate 등과 같은 cerebral oxygen consumption 감소는 없음 • Droperidol is potent antiemetic • Delayed awakening • Antidopaminergic activity of droperidol rarely precipitates extrapytamidal reactions (eg, oculogyric crises, torticollis, agitation) • Pakinson dz, restless leg syndrome, neurologically mediated movement disorder pt 의 경우 droperidol 사용을 피해야 함 • Premedication 시 apprehensive, fearful • 단독적인 premedication 은 피해야 함 • Opioid 의 병행 투여는 dysphoria 의 incidence 를 감소 DROPERIDOL Effects On Organ System • Cerebral • droperidol is a tranqulilizer • Does not produce analgesia, amnesia, or unconscious at usual dose • Combination of fentanyl and droperidol • Analgesia, immobility, variable amnesia (neuroleptanalgesia) • Nitrous oxide 나 hypnotic agent 의 병행 투여는 ketamine 과 유사 한 disscociative state 를 유발하여 unconsciousness 나 GA 유발 DROPERIDOL Drug Interactions • Antagonize the effects of levodopa, precipitate parkinsonian symptoms • Dopamine 의 renal effect 감소 • Clonidine 의 alpha adrenergic action을 antagonize • Ketamine 의 cardiovascular effects 를 저해