vergel lemuel b. habito, m.d.

Inhalation anesthetics are the most common drugs used for the provision of general anesthesia A balanced technique is achieved when combined with intravenous adjuvants such as opioids or benzodiazepines Most popular inhaled anesthetics used in adult surgical procedures are Sevoflurane, Desflurane and Isoflurane In pediatric cases, Halothane and Sevoflurane are used

 It

is an altered physiologic state characterized by reversible loss of consciousness, analgesia of the entire body, amnesia and some degree of muscle relaxation

 volatile anesthetics

in early clinical use

consisted of:
flammable gases x diethyl ether, cyclopropane, divinyl ether non-flammable gases x chloroform, trichloroethylene (associated w/ hepatotoxicity & neurotoxicity)

1930s noncombustible anesthetic gases might be derived using organic fluoride compounds 1940s safe incorporation of Fluorine into molecules of anesthetic gases (lowered the boiling point, increased stability, decreased toxicity, dampened the flammable hydrocarbon of the ether anesthetic framework)

 1951

Halothane was synthesized and tested in animals by Suckling 1956 introduced into clinical practice due to its non-flammability, lower tissue solubility, low pungency, high potency, lower incidence of nausea & vomiting drawbacks: sensitizes the myocardium to catecholamines and later described the role of its intermediate metabolite in hepatic necrosis

 1959

1966

Terrel and colleagues at Ohio Medical Products

synthesized 700 compounds of methyl ethyl ethers which were halogenated with fluorine and chlorine. 347th Enflurane; 469th Isoflurane 653rd Desflurane
1970

Wallin and colleagues at Travenol Laboratories

synthesized Fluorine isopropyl ethers Sevoflurane

 Sevoflurane

July 1990

x Released in Japan for general use 1995 x Introduced in US clinical practice after its safety was established

Study of the relationship between a drugs dose, tissue concentration, & elapsed time How a body affects a drug Four phases:

1. Absorption (Uptake)
x phase in which a drug is transferred from the administration site into the bloodstream

2. Distribution
x phase in which drug is transferred to tissue sites throughout the body

3. Metabolism (Biotransformation)
x physiochemical processes by which substances in a living organism are synthesized (anabolism) or altered (catabolism)

4. Excretion (Elimination)
x phase in which changed or unchanged drug is transferred from tissues or blood into some vehicle (e.g., bile, exhaled air, urine) for removal from the body

 Speed

of action Their existence as gases Administration via the lungs Ability to decrease plasma concentrations as easily and rapidly as they are increased

 GOAL: to

produce the anesthetic state by establishing a specific concentration of anesthetic molecules in the central nervous system (CNS) Achieved by establishing the specific partial pressure of the agent in the lungs, which ultimately equilibrates with the brain and spinal cord At Equilibrium:

Equilibration is a result of three factors: 1. Inhaled anesthetics are gases rapidly transferred bidirectionally via the lungs to and from the bloodstream and subsequently to and from CNS tissues as partial pressures equilibrate 2. Plasma and tissues have a low capacity to absorb the inhaled anesthetics relative to the amount we can deliver to the lungs, allowing us to quickly establish or abolish anesthetizing concentrations of anesthetic in the bloodstream and ultimately the CNS 3. Metabolism, excretion, and redistribution of the inhaled anesthetics are minimal relative to the rate at which they are delivered or removed from the lungs This permits easy maintenance of blood and CNS concentrations

Anesthetic machine to patient via FGO Three tissue groups Vessel-rich groups (brain, heart, liver, kidney, endocrine group)
x 1st to take up appreciable amounts of anesthetic x Moderate solubility and small volume limit the capacity of this group x 1st to fill (arterial P = tissue P)

Muscle groups (skin, muscle) x Not as well perfused, slower uptake x Has greater capacity owing to a larger volume uptake Fat group x Perfusion nearly equals that of the muscle group

 FA/

FI ratio Inhaled anesthetics with the lowest solubilities in blood show the fastest rise in FA/ FI ratio. To speed the uptake and induction of anesthesia Overpressurization Concentration effect

 Along

with the concentration of potent agent in the alveoli via its uptake, there is further concentration via the uptake of Nitrous oxide. The second gas is the potent agent.

anesthetics with very low tissue solubility have an extremely rapid rise in FA/FI with induction. The greater the solubility of an inhaled anesthetic, the more rapidly it is absorbed by the bloodstream.
Inhaled

 Greater

cardiovascular depression reduces anesthetic uptake, thus increases the rate of rise of FA/FI.

 Mainly

thru the LUNGS Recovery from anesthesia depends on anesthetic solubility, cardiac output and minute ventilation. Solubility is the primary determinant of the rate of fall of FA Rate of Induction > Rate of Recovery

phenomenon during recovery from anesthesia wherein washout of high concentrations of Nitrous Oxide can lower alveolar concentrations of Oxygen and Carbon dioxide.

 The

pharmacodynamic effects of inhaled anesthetics must be based on a dose, and this dose is the minimum alveolar concentration (MAC) At 1 atm (1 atm = 760 mm Hg) Prevents movement in response to a surgical stimulus in 50% of patients (analogous to an ED50 for injected drugs)

 Consistently

prevents patient movement during surgical stimulation - 1.2 to 1.3 MAC Self-awareness and recall are prevented by 0.4 to 0.5 MAC

Temperature: Hypothermia Hyperthermia Age: Young Elderly Alcohol: Acute intoxication Chronic abuse Anemia: Hematocrit <10% PaO2 < 40mmHg PaCO2 >95mmHg Thyroid: Hyperthyroid Hypothyroid BP MAP<40mmHg Electrolytes: Hypercalcemia Hypernatremia Hypernatremia Pregnancy Drugs Local anesthetics Opiods Ketamine Barbiturates BDZ Verapamil Lithium Sympatholytics Methyldopa Clonidine Dexmedotomidine Sympathomimetics Amphetamine Chronic Acute Cocaine Ephedrine No change No change

if > 42 C

Caused by <pH in CSF

Caused by altered CSF Caused by altered CSF MAC decreased by 1/3 at 8wks AOG; Normal by 72h postpartum Except cocaine

 the study of drug action, including toxic

responses how a drug affects the body

 UNITARY

HYPOTHESIS All inhalational agents share a common mechanism of action at molecular level MEYER-OVERTON RULE - Anesthetic potency of inhalation agents correlates directly with their lipid solubility

1. Be pleasant to inhale, permitting a smooth induction and emergence 2. Be potent to allow the concomitant administration of high oxygen 3. Rapid induction and emergence (low solubility) 4. Be easy to administer and analyze

5. Be easily and cheaply prepared in pure form 6. Be stable in storage and with soda-lime, not flammable, not metabolized. 7. Act at specific CNS sites to cause unconsciousness 8. No CV or respiratory effects, non-toxic to organ systems 9. Provide postoperative pain relief

Nitrous Oxide Halothane Methoxyflurane Enflurane Isoflurane Desflurane Sevoflurane

 Inorganic Colorless

gas

Sweet-smelling Non-explosive

and non-flammable Insoluble in blood A gas at room temperature and ambient pressure Relatively inexpensive

CARDIOVASCULAR Stimulate sympathetic nervous system Depresses myocardial contractility in vitro Arterial BP, cardiac output and heart rate are essentially unchanged or slightly elevated in vivo May be associated with epinephrine-induced arrythmias

RESPIRATORY Increases respiratory rate and decreases tidal volume HYPOXIC DRIVE
the

ventilatory response to arterial hypoxia mediated by peripheral chemoreceptors in carotid bodies, markedly depressed by Nitrous Oxide

CEREBRAL Produces a mild elevation of intracranial pressure It preserves CBF but increases CMRO2 It has an antineuroprotective effect

NEUROMUSCULAR Does not provide significant muscle relaxation RENAL Decrease renal blood flow by increasing renal vascular resistance

HEPATIC Hepatic blood flow probably falls but to a lesser extent GASTROINTESTINAL Implicated as a cause of post-operative nausea and vomiting

 Almost

all N2O is eliminated by EXHALATION Biotransformation is limited to less than 0.01% by reductive metabolism in GIT by anaerobic bacteria By irreversibly oxidizing Cobalt ion in Vit. B12, may inhibit enzymes that are Vit. B12dependent Has an effect on embryonic development

 N2O

is 35x more soluble than Nitrogen in the blood Has tendency to diffuse into air-containing cavities
Air embolism Pneumothorax Intracranial air Pulmonary air cysts Intraocular air bubble Tympanic membrane grafting

relatively high MAC (105) prevents its use as a complete general anesthetic, used in combination to a more potent volatile anesthetic Attenuates the circulatory and respiratory effects of volatile anesthetics Potentiates neuromuscular blockade
Its

a halogenated alkane The MOST POTENT volatile anesthetic Non-flammable and non-explosive nature Vapor pressure = 243mmHg at 20C Thymol preservative and amber-colored bottles retard oxidative decomposition Least expensive volatile anesthetic
Is

CARDIOVASCULAR Direct myocardial depression decrease in arterial BP Decreases coronary blood flow Slows SA node conduction resulting in bradycardia Sensitizes the heart to the dysrhythmogenic effects of Epinephrine Associated with bradycardia in the pediatric population

RESPIRATORY Causes rapid shallow breathing Increased respiratory rate is not enough to counter the decreased tidal volume Alveolar ventilation drops and resting PaCO2 is elevated A potent bronchodilator

CEREBRAL Lowers cerebral vascular resistance, increases cerebral blood flow and ICP Decreases CSF volume at 1 MAC (decrease production, increase resorption) NEUROMUSCULAR Relaxes skeletal muscle and potentiates nondepolarizing neuromuscular blocking drugs

RENAL Reduces renal blood flow, glomerular filtration rate and urine output HEPATIC Decrease in hepatic blood flow (Portal vein) in proportion to decrease in cardiac output Also causes hepatic artery vasoconstriction

is oxidized in the LIVER to its principal metabolite -- TRIFLUOROACETIC ACID (TFA) In the absence of Oxygen, reductive metabolism may result in small amounts of hepatotoxic end products HALOTHANE HEPATITIS- extremely rare (1 per 35,000) Can be degraded to BCDFE in dry soda lime
It

 Withhold

Halothane from patients with unexplained liver dysfunction It should be used with caution in patients with intracranial mass lesions, hypovolemic and with severe cardiac disease Myocardial depression is exacerbated by Bblockers and Ca-channel blocking agents

 Halothane

+ Tricyclic anti-depressants and MAO inhibitors has been associated with BP fluctuations and dysrrhythmias Halothane + Aminophylline has resulted in serious ventricular dysrrhythmias

halogenated methylethyl ether, a colorless anesthetic with sweet, fruity odor Light-sensitive and stabilized with butylated hydroxytoluene Non-explosive and nonflammable It is the MOST POTENT inhalational gas Its high solubility and low vapor pressure limit its rate of induction

CARDIOVASCULAR It depresses cardiac contractility It does not alter the carotid baroreflex and heart rate usually rises

RESPIRATORY Increases in RR It reduces minute ventilation by lowering tidal volume It has mild bronchodilating properties

CEREBRAL Vasodilates cerebral vasculature, increasing cerebral blood flow and intracranial pressure NEUROMUSCULAR Relaxes skeletal muscle

RENAL It causes a fall in renal blood flow and GFR It has been implicated for post-operative highoutput renal failure HEPATIC Depresses hepatic blood flow

 Extensively

metabolized due to cytochrome P450 liver microsomal enzyme activity Oxidative metabolites include free-fluoride and oxalic acid which are Nephrotoxic Fluoride is responsible for the vasopressinresistant high-output renal failure

 Contraindication: Any

degree of pre-existing

renal dysfunction Methoxyflurane should be avoided in patients receiving nephrotoxic drugs Phenobarbital, isoniazid, and ethanol ENHANCES methoxyflurane metabolism MF enhances non-depolarizing muscle relaxants

halogenated methyl ethyl ether An ISOMER of Isoflurane Vapor pressure = 175 mmHg at 20C Pungent Nonflammable

CARDIOVASCULAR Depresses myocardial contractility Decreases systemic vascular resistance; the heart rate usually rises Sensitizes the heart to the dysrhythmogenic effects of epinephrine but doses up to 4.5 mcg/ kg are usually well-tolerated

RESPIRATORY Decrease minute ventilation despite an increase in respiratory rate, increased resting PaCO2 (60mmHg at 1 MAC) Decreased response to hypercapnia and abolishment of hypoxic drive Depressed mucociliary function and bronchodilation

CEREBRAL Increases cerebral blood flow and intracranial pressure Increases CSF secretion and the resistance to CSF outflow May produce spike-and-wave pattern in EEG culminating in frank TONIC-CLONIC SEIZURES

NEUROMUSCULAR Relaxes skeletal smooth muscle RENAL Renal blood flow, GFR, and urine output fall It has a nephrotoxic metabolite HEPATIC Decreases hepatic blood flow

 Fluoride is

an end-product of Enflurane metabolism but defluorination is less than methoxyflurane After 10 MAC hours, Fluoride concentrations in healthy patients average less than 40 mol/L causing mild reduction in renal concentrating ability

should be avoided in patients with preexisting kidney disease and those with seizure disorders Isoniazid induces Enflurane defluorination Enflurane potentiates nondepolarizing blocking agents
It

halogenated methyl ethyl ether The SECOND MOST POTENT volatile anesthetic Clear, non-flammable volatile anesthetic with a pungent ethereal odor Vapor pressure = 240mmHg at 20C a chemical ISOMER of ENFLURANE but with different physicochemical properties

CARDIOVASCULAR Causes minimal cardiac depression in vivo Cardiac output is maintained by a rise in heart rate due to partial preservation of carotid baroreflexes HR increases 10-20%

CARDIOVASCULAR Mild -adrenergic stimulation increases skeletal muscle blood flow, decreases systemic vascular resistance and lowers BP Dilates coronary arteries

RESPIRATORY Respiratory depression resembles that of the other anesthetics except that tachypnea is less pronounced There is a more pronounced fall in minute ventilation A tendency to irritate airway but a good bronchodilator

CEREBRAL At concentrations greater than 1 MAC it increase cerebral blood flow and ICP It reduces cerebral metabolic requirements At 2 MAC it produces electrically silent EEG, EEG suppression Provides some degree of brain protection

NEUROMUSCULAR Relaxes skeletal muscle RENAL Decreases renal blood flow, GFR, and urine output HEPATIC Hepatic blood flow is reduced

 Metabolized

to 1/10th the extent of Enflurane Trifluoroacetic acid (TFA) is the principal end product Limited metabolism minimizes any possible risk of hepatic dysfunction

 No

unique contraindications other than the controversy regarding CORONARY STEAL SYNDROME Epinephrine can be safely administered in doses up to 4.5mcg/kg It potentiates non-depolarizing agents

has similar structure with Isoflurane differs only in the substitution of fluorine atom in Isofluranes chlorine atom It has as a high vapor pressure, low solubility and ultra-short duration of action It has a rapid wash-in and wash-out in tissues The MOST PUNGENT volatile anesthetic
It

CARDIOVASCULAR Increasing dose, decline in systemic vascular resistance, decrease in BP Cardiac output remains relatively unchanged or slightly depressed at 1-2 MAC It does not increase coronary artery blood flow It increases heart rate

RESPIRATORY It causes a decrease in tidal volume and increase in respiratory rate It decreases ventilatory response to increasing PaCO2 Pungency and airway irritation can be manifested by salivation, breath-holding, coughing and laryngospasm

CEREBRAL Decreases cerebral vascular resistance Increases cerebral blood flow Associated with increase in intracranial pressure

NEUROMUSCULAR Associated with a dose-dependent decrease in response to train-of-four and tetanic peripheral nerve stimulation

RENAL No evidence of nephrotoxic effects HEPATIC Hepatic function test are unaffected

 Has

a near-absent metabolism to serum Trifluoroacetate (TFA) Serum and urine fluoride levels are essentially unchanged at pre-anesthetic levels There is insignificant percutaneous loss

 Degraded

to potentially harmful levels of CARBON MONOXIDE by desiccated carbon dioxide absorbent especially by barium hydroxide lime, but also
by sodium and potassium hydroxide
use of calcium hydroxide minimizes this

degradation problem

 Contraindications

Severe hypovolemia Malignant hyperthermia Intracranial hypertension

potentiates non-depolarizing muscle relaxants Epinephrine can be safely administered in doses up to 4.5 g/kg
It

 Completely

fluorinated methyl isopropyl ether Sweet-smelling Vapor pressure = 160 mmHg at 20C (most similar to that of Enflurane) It is non-pungent and achieves rapid increases in alveolar anesthetic concentration Potent bronchodilator

CARDIOVASCULAR Mildly depresses myocardial contractility Systemic vascular resistance and arterial BP decline slightly than isoflurane and desflurane Provides a relative stable heart rate Cardiac output is not as well-maintained as with isoflurane or desflurane

RESPIRATORY Depresses respiration and reverses bronchospasm to an extent similar to isoflurane CEREBRAL Slight increase in cerebral blood flow and ICP It decreases CMRO2 It depresses CSF production up to 40% at 1 MAC

NEUROMUSCULAR Produces adequate muscle relaxation for intubation RENAL Slightly decreases renal blood flow Its metabolism with fluoride impairs renal tubular function

HEPATIC Decreases portal vein blood flow but increases hepatic artery blood flow

 Rate

of metabolism = 5% (ten times that of Isoflurane) Liver microsomal enzyme P450 metabolizes Sevoflurane at a rate similar to Enflurane It has a potential nephrotoxicity It can be avoided in patients with impaired kidney function

is metabolized to acyl halide (hexafluoroisopropanol) Barium hydroxide > Soda lime can degrade Sevoflurane to Compound A, a vinyl ether FGF less than 2 L/min are not recommended
It

 Contraindication:

Severe hypovolemia Susceptibility to malignant hyperthermia Intracranial hypertension

Potentiates

non-depolarizing muscle relaxants It does not sensitize the heart to cathecolamineinduced dysrhythmias

 An

inert gas Provides some degree of analgesia Non-explosive Non-pungent Odorless MAC in humans: 71% Does not produce significant myocardial depression