Chapter 7. Inhalation Anesthetics R1

Inhalation anestheticsFirst universally accepted general anesthetics - nitrous oxide, chloroform and ether.

Ethyl chloride, ethylene, and cyclopropane were also used - particularly popular ; fast induction - but toxicity and flammability led to their withdrawal from the market

Methoxyflurane and enflurane are no longer used ; toxicity & efficacy 1) Methoxyflurane : the most potent inhalation agent but vasopressin-resistant, high output, renal failure 2) Enflurane : nonpungent odor and nonflammable at clinical concentration but depresses myocardial contractility, sensitizes the myocardium to epinephrine, increases the secretion of CSF & resistance to CSF outflow

Five inhalation agents continue to be used in clinical anesthesiology : nitrous oxide, halothane, isoflurane, desflurane, and sevoflurane.

Inhalation anestheticsThe course of general anesthesia 1) Induction () 2) Maintenance () 3) Emergence ()

Inhalation anesthetics are particularly useful in the induction of pediatric patients ; it may be difficult to start an iv line.

adults prefer rapid induction with intravenous agents.

regardless of the patients age, anesthesia is often maintained with inhalation agent

emergence depends primarily upon the pulmonary elimination of agents

Inhalation anestheticsPharmacokinetics ()

relationship between a drugs dose, tissue concentration, and elapsed time

how a body affects a drug

Pharmacodynamics() the study of drug action, including toxic responses how a drug affects a body

Clinical pharmacology of individual agents Nitrous oxide, Halothane, Isoflurane, Desflurane, Sevoflurane

Pharmacokinetics of Inhalation anesthetics Although the mechanism of action of inhalation anesthetics remains unknown, it is assumed that their ultimate effect 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

Pharmacokinetics of Inhalation anesthetics

Pharmacokinetics of inhalation anesthetics -Factors affecting inspiratory concentration(FI ) 1) fresh gas flow rate(FGF rate)

2) volume of the breathing system(breathing circuit volume)

3) any absorption by the machine or breathing circuit(circuit absorption)

the higher the FGF rate, the smaller the breathing system volume, the lower the circuit absorption the closer the inspired gas concentration will be to the fresh gas concentration the faster induction, recovery times

Pharmacokinetics of inhalation anesthetics -Factors affecting alveolar concentration(FA )1. Uptake

2. Ventilation

3. Concentration

Pharmacokinetics of inhalation anesthetics -Factors affecting alveolar concentration(FA )1. Uptake

FA/FI FA FA/FI

Pharmacokinetics of inhalation anesthetics -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

Uptake = x Q x (PA-PV) / barometrc pr. (Q : cardiac output)

Pharmacokinetics of inhalation anesthetics -Factors affecting alveolar concentration(FA )1) solubility in the blood ()

Insoluble agents(N2O) soluble agents(halothane) blood N2O FA Halothane FA -> induction

Partition coefficients(:) relative solubilities of an anesthetic in air, blood, and tissues : ( ) . (ex.isoflurane(: 1.4) : blood isoflurane alveolar isoflurane 1.4 )

blood/gas partition coefficient . blood solubility pulmonary circulation (uptake) . solubility alveolar partial pressure induction .

Pharmacokinetics of inhalation anesthetics -Factors affecting alveolar concentration(FA )2) alveolar blood flow

in the absence of pulmonary shunting : equal to cardiac output ex) cardiac output anesthetic uptake , alveolar partial pressure , induction .

insoluble agent alveolar blood flow

soluble agent low cardiac output , solubleagent overdosage

Pharmacokinetics of inhalation anesthetics -Factors affecting alveolar concentration(FA )3) difference in partial pressure between alveolar gas and venous blood

- tissue uptake (tissue uptake Alveolar to venous partial pr.difference 0) -tissue uptake 1) tissue solubility of the agent( tissue/blood partition coefficient) 2) tissue blood flow 3) difference in partial pressure between arterial blood and the tissue

Pharmacokinetics of inhalation anesthetics -Factors affecting alveolar concentration(FA )- tissue solubility blood flow 4 group 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 Vessel-rich group blood tissue perfusion Vessel-poor group blood tissue perfusion .

Pharmacokinetics of inhalation anesthetics -Factors affecting alveolar concentration(FA )Initial rise of rate of FA/FI : induction uptake ventilation FA/FI ventilation increase FA/FI alveolar/venous partial pr. difference uptake FA/FI solubility level

Pharmacokinetics of inhalation anesthetics -Factors affecting alveolar concentration(FA )- tissue group

Pharmacokinetics of inhalation anesthetics -Factors affecting alveolar concentration(FA )

2. Ventilation

pul. blood stream alveolar concentration . (ventilation soluble agent FA/ FI )

Pharmacokinetics of inhalation anesthetics -Factors affecting alveolar concentration(FA ) 3. Concentration Concentration Effect :inspired anesthetic concentration alveolar concentration& FA/FI

Pharmacokinetics of inhalation anesthetics -Factors affecting alveolar concentration(FA ) Anesthetic gas 50%

10/90=11% 40/60=66% :Anesthetic gas concentration 4 alveolar concentration 6

Anesthetic gas: 80O2:20

Gas : 40O2:20

Anesthetic gas : 20

O2:80

Gas : 10O2:80

Pharmacokinetics of inhalation anesthetics -Factors affecting alveolar concentration(FA )Second gas effect : () solubility () 1% of second gas 1% of second gas (1.7%) 1% of second gas

uptake of half of the N2O absorbed gases replaced by added ventilation

0.4% of second gas

O2 : 19%

N2O : 80%

O2 : 19(31.7%)

N2O: 40(66.7%)

O2 :19%N20 : 40%O2 : 7.6%N2O : 32%

Pharmacokinetics of inhalation anesthetics-Factors affecting arterial concentration(Fa )Ventilation/perfusion mismatch alveolar anesthetic partial pr. arterial anesthetic partial pr. arterial partial pr. end-expiratory gas . venous admixture alveolar dead space nonuniform alveolar gas distribution ventilation/perfusion mismatching ->alveolar- arterial difference . V/Q mismatching(ex.Atelectasis,emphysema,pneumonia) alveolar partial pr.,alterial partial pr. : poorly soluble agent alveolar gas arterial blood pr.

Pharmacokinetics of inhalation anesthetics-Factors affecting eliminationRecovery from anesthesia brain tissue anesthetic concentration .

Anesthetics can be eliminated by 1) biotransformation alveolar partial pr. . Methoxyflurane soluble anesthetics elimination 2) transcutaneous loss diffusion through the skin : insignificant 3) exhalation Induction Recovery . - Rebreathing Elimination - high Fresh gas flows - low Anesthetic-circuit volume - low absorption by the Anesthetic-circuit - decreased Solubility - high CBF(Cerebral Blood Flow) - increased Ventilation

Pharmacokinetics of inhalation anesthetics-Factors affecting eliminationDiffusion hypoxia on recovery from anesthesia with N2O room air N2O Diffusion hypoxia . 1`. Directly affect oxygenation by displacing O2 2. diluting alveolar CO2 respiratory drive

N2O 100% O2 5~10 .

Pharmacodynamics of inhalation anesthetics-Theories of anesthetic actionPharmacodynamics() the study of drug action, including toxic responses how a drug affects a body

General anesthesia 1) reversible loss of consciousness 2) analgesia of the entire body 3) amnesia 4) muscle relaxation altered physiological state

General anesthesia 1) inert elements ( ex) xenon ) 2) simple inorganic compounds ( ex) nitrous oxide) 3) halogenated hydrocarbons ( ex) halothane ) 4) complex organic structures ( ex) barbiturate )

Pharmacodynamics of inhalation anesthetics-Theories of anesthetic action 1) Agent-specific theory 2) Unitary hypothesis 3) Critical volume hypothesis 4) Fluidization theory of anesthesia

Pharmacodynamics of inhalation anesthetics-Minimum Alveolar Concentration(MAC)MAC (Minimum alveolar concentration)

: surgical incision standardized stimulus 50% alveolar concentration.

MAC is a useful measure ; brain partial pressure agents potency . experimental evaluation . Mac value ex) 0.5 MAC N2O (53%) 0.5 MAC Halothane (0.37%) mixture CNS depression 1.0 MAC isoflurane(1.7%) . MAC CNS depression Myocardial depression ex) 0.5 MAC Halothane 0.5MAC N2O Myocardial depression .

Pharmacodynamics of inhalation anesthetics-Minimum Alveolar Concentration(MAC) MAC dose-response curve . ED50,( median effective dose)

1.3 MAC surgical incision standardized stimulus , 95% alveolar concentration MAC Awake = 0.3 ~ 0.4 MAC Physiological and pharmacological variables MAC . 10 MAC 6% .

MAC , , .

Pharmacodynamics of inhalation anesthetics-Minimum Alveolar Concentration(MAC)

Clinical pharmacology of inhalation anesthetics1. Nitrous oxide ( N2O) ( N2O:laughing gas) 1) physical properties inorganic anesthetic gas , , O2 , gas , N2O

Clinical pharmacology of inhalation anesthetics2) effect on organ systems A. Cardiovascular system - N2O stimulate the sympathetic nervous system in vitro, N2O (myocardial contractility) direct depress but, in vivo, N2O catecholamines stimulation arterial blood pressure cardiac output heart rate

- N2O Myocardial depression unmasked coronary artery diseases severe hypovolemia BP myocardial ischemia

- pulmonary vascular smooth muscle constriction pulmonary vascular resistance -> Rt. Ventricular end-diastolic pr.

- endogenous catecholamine level epinephrine induced arrhythmia higher incidence

Clinical pharmacology of inhalation anestheticsB. respiratory

- N2O CNS stimulation, pulmonary stretch receptors activation -> increase respiratory rate ( tachypnea) decrease tidal volume : net effect -> minimal change in minute ventilation and resting arterial CO2 level

- Hypoxic drive : carotid bodies peripheral chemoreceptor arterial hypoxia ventilatory response N2O hypoxic drive depression .

C. cerebral

increasing cerebral blood flow & cerebral blood volume -> mild elevation of intracranial pressure increase CMRO2 ( cerebral oxygen consumption ) MAC N2O level dental surgery minor procedures analgesia .

Clinical pharmacology of inhalation anesthetics D. neuromuscular - not provide significant muscle relaxation - not a triggering agent of malignant hyperthermia

E. Renal - N2O renal vascular resistance renal blood flow : glomerular filtration rate(GFR) & urinary output

F. hepatic - N2O hepatic blood flow but other volatile agent . G. gastrointestinal - N2O is cause of postoperative nausea & vomiting ( activation of the chemoreceptor trigger zone and the vomiting center in the medulla)

Clinical pharmacology of inhalation anesthetics3) Biotransformation & toxicity - emergence() N2O is eliminated by exhalation : diffuses out through skin : biotransformation : 0.01%

- N2O Vitamine B12 cobalt Vitamine B12 enzyme Myelin methionine synthetase DNA thymidylate synthetase N2O Bone marrow depression( ex) megaloblastic anemia ) Neurological deficiencies ( ex) peripheral neuropathie pernicious anemia) - teratogenic effect : - Polymorphonuclear leukocytes chemotaxis motility infection immunological response

Clinical pharmacology of inhalation anesthetics4) contraindication

air embolism pneumothorax acute intestinal obstruction, intracranial air ( ex) dural closure pneumoencephalus tension pneumocephalus) pul. air cyst intraocular air bubble tympanic membrane grafting Pulmonary HTN ( N2O pulmonary vasculature resistance

Clinical pharmacology of inhalation anesthetics5) drug interactions

- N2O MAC more potent volatile agents

- N2O neuromuscular blockade , (volatile agents) - vaporizer N2O .

Clinical pharmacology of inhalation anesthetics2. Halothane 1) physical properties halogenated alkane

Clinical pharmacology of inhalation anesthetics2) effects on organ systems

A. cardiovascular

dose-dependent reduction of arterial blood pressure Halothane coronary artery vasodilator Systemic arterial pressure coronary blood flow

aortic arch carotid bifurcation baroreceptor vagal stimulation heart rate halothane reflex , sinoatrial node conduction , Junctional rhythm bradycardia

: &

Halothane cardiac arrhythmia Halothane epinephrine arrhythmogenic effects epinethrine 1.5g/kg

Clinical pharmacology of inhalation anesthetics B. respiratory

Halothane tidal volume alveolar ventilation , resting PaCO2 Halothane ventilatory effect central mechanism (medullary depression) peripheral mechanism (intercostal muscle dysfunction) pre-existing lung disease , surgical stimulation

Hypoxic drive 0.1 MAC Halothane . Halothane a potent bronchodilators ( Halothane Airway reflex , bronchial smooth muscle ) Halothane mucociliary function postoperative hypoxia & atelectasis

Clinical pharmacology of inhalation anesthetics C. cerebral

- cerebral vessels dilating cerebral vascular resistance , CBF ( arterial blood pressure CBF autoregulation .) - intracranial pressure Halothane Hyperventilation

D. neuromuscular

- , non-depolarizing neuromuscular-blocking agents (NMBA) - malignant hyperthermia

Clinical pharmacology of inhalation anesthetics E. renal

- Halothane renal blood flow, GFR(glomelular filtration rate), urinary output ( Halothane arterial blood pressure cardiac output ) - GFR renal blood flow filtration fraction : Preoperative hydration

F. hepatic

- cardiac output hepatic blood flow - hepatic artery vasospasm . - fentanyl, phenytoin, verapamil .

3) biotransformation & toxicity

halothane (liver) trifluoroacetic acid cytochrome P450(2EI) disulfiram .

postoperative hepatic dysfunction viral hepatitis, impaired hepatic perfusion, hepatocyte hypoxia, sepsis, hemolysis, benign postoperative intrahepatic cholestasis, drug induced hepatitis , halothane hepatitis .

Halothane hepatitis is increased risk at : halothane : : halothane : halothane Hx(+)

Clinical pharmacology of inhalation anesthetics

Clinical pharmacology of inhalation anesthetics4) contraindication

Halothane intracranial mass lesion intracranial hypertension hypovolemic pt.

severe cardiac disease ( ex) aortic stenosis ) epinephrine

Pheochromocytoma

Clinical pharmacology of inhalation anesthetics5) drug interactions

Halothane - adrenergic blocking agent(propranolol) Ca++ channel blocking agent(verapamil) myocardiac depression Tricyclic antidepressants, MAO inhibitor fluctuations in blood pressure & arrhythmias ( but not absolute contraindication)

Halothane aminophylline ventricular arrhythmias

Clinical pharmacology of inhalation anesthetics3. Isoflurane

1) physical properties nonflammable volatile anesthetic pungent ethereal oder Enflurane chemical isomer, 2) effects on organ systems A. cardiovascular mild cardiac depression but carotid baroreflex heart rate , cardiac output -adrenergic stimulation skeletal muscle blood flow, systemic vascular resistance arterial blood pressure Isoflurane heart rate , arterial blood pressure , norepinephrine plasma level dilates coronary arteries

Clinical pharmacology of inhalation anestheticsB. Respiratory

respiratory depression (resembles that of other volatile anesthetics) -> minute ventilation 0.1MAC Isoflurane hypoxia hypercapnia good bronchodilator

C. Cerebral

>1.0 MAC : CBF & intracranial pressure ( but, Halothane ,Hyperventilation . ) O2 2.0 MAC , electrically silent electroencephalogram(EEG) EEG suppression cerebral ischemia brain protection

Clinical pharmacology of inhalation anestheticsD. neuromuscular - relax skeletal muscles

E. renal - renal blood flow , glomerular filtration rate , urinary output

F. hepatic - Total hepatic flow - Hepatic oxygen supply : better maintained than with Halothane ( Isoflurane hepatic artery perfusion hepatic venouse O2 saturation )

Clinical pharmacology of inhalation anesthetics3) biotransformation & toxicity

trifluoroacetic acid serum fluoride fluid level , .

4) Contraindications

: Isoflurane .

5) Drug interactions

Epinephrine 4.5 g/kg nondepolarizing NMBAs Isoflurane

Clinical pharmacology of inhalation anesthetics4. Desflurane

1) physical properties

Isoflurane

Vapor pressure 20 681 mmHg

low solubility in blood and body tissues -> ultrashort duration -> very rapid wash in and wash out of anesthetic

Moderate potency

Clinical pharmacology of inhalation anesthetics2) effects on organ systems

A. cardiovascular

Isoflurane

systemic vascular resistance arterial blood pressure

cardiac output or (1~2 MAC)

heart rate, central venous pressure, pulmonary artery pressure: moderate rise

desflurane heart rate, BP, catecholamine level .

fentanyl, esmolol, clonidine .

coronary blood flow .

Clinical pharmacology of inhalation anesthetics B. respiratory

tidal volume respiratory rate Alveolar ventilation resting PaCO 2 ventilatory response pungency and airway irritation during desflurane induction salivation, breath-holding, coughing, laryngospasm

C. Cerebral

directly vasodilates the cerebral vasculature, increasing CBF & intracranial pressure cerebral metabolic rate of oxygen(CMRO2) cerebral vasoconstriction & increase in CBF cerebral oxygen consumption during periods of desflurane-induced hypotension, CBF is adequate to maintain

Clinical pharmacology of inhalation anesthetics D. neuromuscular : dose-dependent

E. renal : no evidence of any nephrotoxic effects F. hepatic : no evidence of hepatic injury

Clinical pharmacology of inhalation anesthetics 3) biotransformation & toxicity

minimal metabolism insignificant percutaneous loss CO poisoning : disposing of dried out absorbent or use of calcium hydroxide minimize the risk

4) Contraindications

severe hypovolemia malignant hyperthermia intracranial hypertension

5) drug interactions

potentiates nondepolarizing neuromuscular blocking agents Epinephrine 4~5 g/kg . associated with delirium in some pediatric patients

Clinical pharmacology of inhalation anesthetics5. sevoflurane

1) physical properties

nonpungency & rapid increase in alveolar anesthetic concentration excellent choice for smooth & rapid inhalation induction

rapid emergence than isoflurane

greater incidence of delirium in some pediatric pt. ( faster emergence) treated with 1.0~2.0 g/kg of fentanyl

Clinical pharmacology of inhalation anesthetics2) effects on organ systems A. cardiovascular mildly depresses myocardial contractility. systemic vascular resistance & arterial blood pr. prolong the QT interval

B. respiratory : depresses respiration , vagus n. bronchospasm

Clinical pharmacology of inhalation anesthetics3) biotransformation & toxicity

Liver microsomal enzyme P-450(2E1) inorganic fluoride : nephrotoxicity but significant renal dysfunction . Barium hydroxide lime soda lime Alkali Sevoflurane . ( Compound A, fluorometal-2, 2-difluoro-1-vinylether) Compound A - Respiratory gas temperature - Low-flow anesthesia - barium hydroxide (Barakyme) - Sevoflurane -

Clinical pharmacology of inhalation anesthetics Hydrogen fluoride Acid burn

4) Contraindications Severe hypovolemia malignant hyperthermia intracranial hypertension

5) Drug interactions potentiates NMBAs catecholamine-induced arrhythmia

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