Morgan & Mikhail Chap 8(Inhalational Anesthetics) Flashcards

1
Q

Currently used inhalational agents

A

Currently used inhalation agents include nitrous oxide, halothane, isoflurane, desflurane, and sevoflurane.

Inhalation anesthetics, notably halothane and sevoflurane, are particularly useful for the inhalation induction of pediatric patients in whom it may be difficult to start an intravenous line. Although adults are usually induced with intravenous agents, the nonpungency and rapid onset of sevoflurane make
inhalation induction practical for them as well. Regardless of the patient’s age, anesthesia is often maintained with inhalation agents.

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2
Q

Emergence from Inhalational Anesthetics

A

Emergence depends primarily
upon redistribution of the agent from the brain, followed by pulmonary elimination.
Because of their unique route of administration, inhalation anesthetics have useful
pharmacological properties not shared by other anesthetic agents.

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3
Q

Flow of Inhalational Agents

A

Pharmacokinetics of Inhalation Anesthetics
Although the mechanism of action of inhalation anesthetics is not yet fully understood, their ultimate effects clearly depend on attaining a therapeutic tissue concentration in the
central nervous system (CNS). There are many steps between the anesthetic vaporizer and the anesthetic’s deposition in the brain (Figure 8–1).

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4
Q

Factors Affecting FI Concentration

A

The fresh gas leaving the anesthesia machine mixes with gases in the breathing circuit before being inspired by the patient. Therefore, the patient is not necessarily receiving the concentration set on the vaporizer. The actual composition of the inspired gas mixture depends mainly on the fresh gas flow rate, the volume of the breathing system, and any absorption by the machine or breathing circuit. The greater the fresh gas flow rate, the smaller the breathing system volume, and the lower the circuit absorption, the
closer the inspired gas concentration will be to the fresh gas concentration.

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5
Q

Factors affecting FA Concentration

A

If there were no uptake of anesthetic agent by the body, the alveolar gas concentration
(FA) would rapidly approach the inspired gas concentration (FI). Because anesthetic agents are taken up by the pulmonary circulation during induction, alveolar concentrations lag behind inspired concentrations (FA/FI <1.0). The greater the uptake,
the slower the rate of rise of the alveolar concentration and the lower the FA:FI ratio.

Because the concentration of a gas is directly proportional to its partial pressure, the alveolar partial pressure will also be slow to rise. The alveolar partial pressure is important because it determines the partial pressure of anesthetic in the
blood and, ultimately, in the brain. Similarly, the partial pressure of the anesthetic in the brain is directly proportional to its brain tissue concentration, which determines the clinical effect.

Three factors affect anesthetic uptake: solubility in the blood, alveolar blood flow, and the difference in partial pressure between alveolar gas and venous blood.

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6
Q

Partition coefficients of volatile anesthetics at 37C affecting FA

A

Relatively insoluble agents, such as nitrous oxide, are taken up by the blood less
avidly than more soluble agents, such as sevoflurane. As a consequence, the alveolar concentration of nitrous oxide rises and achieves a steady state faster than that of sevoflurane. The relative solubilities of an anesthetic in air, blood, and tissues are expressed as partition coefficients (Table 8–1).

Each coefficient is the ratio of the concentrations of the anesthetic gas in each of two phases at steady state. Steady state is defined as equal partial pressures in the two phases. For instance, the blood/gas partition coefficient (λb/g) of nitrous oxide at 37°C is 0.47. In other words, at steady state, 1 mL of blood contains 0.47 as much nitrous oxide as does 1 mL of alveolar gas, even though the partial pressures are the same.

The higher the blood/gas coefficient, the greater the anesthetic’s solubility and the greater its uptake by the pulmonary circulation. As a consequence of this increased solubility, alveolar partial pressure rises to a steady state more slowly. Because fat/blood partition coefficients are greater than 1, blood/gas solubility is increased by postprandial lipidemia and is decreased by anemia.

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7
Q

Blood flow on Pulmonary Uptake

A

The second factor that affects uptake is alveolar blood flow, which—in the absence of pulmonary shunting—is equal to cardiac output. If the cardiac output drops
to zero, so will anesthetic uptake. As cardiac output increases, anesthetic uptake
increases, the rise in alveolar partial pressure slows, and induction is delayed.

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8
Q
A

The final factor affecting the uptake of anesthetic by the pulmonary circulation is the
partial pressure difference between alveolar gas and venous blood. This gradient
depends on tissue uptake. If anesthetics did not pass into organs such as the brain,
venous and alveolar partial pressures would become identical, and there would be no pulmonary uptake.

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9
Q

Tissue Groups based on perfusion and solubility

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10
Q

FA and FI relationship for different gases

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11
Q

Partial Pressure in Tissues

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12
Q

Ventilation on alveolar

A

The lowering of alveolar partial pressure by uptake can be countered by increasing
alveolar ventilation. In other words, constantly replacing anesthetic taken up by the
pulmonary bloodstream results in better maintenance of alveolar concentration. The
effect of increasing ventilation will be most obvious in raising the FA/FI for soluble anesthetics because they are more subject to uptake. Because the FA/FI very rapidly
approaches 1.0 for insoluble agents, increasing ventilation has minimal effect. In
contrast to the effect of anesthetics on cardiac output, anesthetics and other drugs (eg, opioids) that depress spontaneous ventilation will decrease the rate of rise in alveolar concentration and create a negative feedback loop.

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13
Q

Concentration on alveolar

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14
Q

FACTORS AFFECTING ARTERIAL CONCENTRATION (Fa)

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15
Q

FACTORS AFFECTING ELIMINATION

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16
Q

Pharmacodynamics of Inhalation Anesthetics

A

MAC
Indeed, measures of minimum alveolar concentration (MAC), the anesthetic concentration that prevents movement in 50% of subjects or animals, are dependent upon anesthetic effects at the spinal cord and not at the cortex

The MAC of an inhaled anesthetic is the alveolar concentration that prevents
movement in 50% of patients in response to a standardized stimulus (eg, surgical incision). MAC is a useful measure because it mirrors brain partial pressure, allows
comparisons of potency between agents, and provides a standard for experimental
evaluations

The MAC values for anesthetic combinations are roughly additive. For example, a mixture of 0.5 MAC of nitrous oxide (53%) and 0.5 MAC of isoflurane (0.6%) produces the same likelihood that movement in response to surgical incision will be
suppressed as 1.0 MAC of isoflurane (1.2%) or 1.0 MAC of any other single agent.

MAC can be altered by several physiological and pharmacologic variables (Table 8–4). One of the most striking is the 6% decrease in MAC per decade of age,
regardless of volatile anesthetic. MAC is relatively unaffected by species, sex, or
duration of anesthesia. Further, as noted earlier, MAC is not altered after spinal cord
transection in rats, leading to the hypothesis that the site of anesthetic inhibition of motor
responses lies in the spinal cord.

17
Q

Factors Effecting MAC

18
Q

Clinical Pharmacology of Inhalation Anesthetics: N2O

A

Nitrous oxide (N2O; laughing gas) is colorless and essentially odorless. Although
nonexplosive and nonflammable, nitrous oxide is as capable as oxygen of supporting combustion. Unlike the potent volatile agents, nitrous oxide is a gas at room temperature
and ambient pressure. It can be kept as a liquid under pressure because its critical
temperature (the temperature at which a substance cannot be kept as a liquid irrespective of the pressure applied) lies above room temperature. Nitrous oxide is a relatively inexpensive anesthetic; however, concerns regarding its safety have led to continued interest in alternatives such as xenon (Table 8–5). As noted earlier, nitrous oxide, like xenon, is an NMDA receptor antagonist.

During emergence, almost all nitrous oxide is eliminated by exhalation. A small amount
diffuses out through the skin. Biotransformation is limited to the less than 0.01% that
undergoes reductive metabolism in the gastrointestinal tract by anaerobic bacteria.
By irreversibly oxidizing the cobalt atom in vitamin B12, nitrous oxide inhibits
enzymes that are vitamin B12 dependent. These enzymes include methionine synthetase,
which is necessary for myelin formation, and thymidylate synthetase, which is necessary
for DNA synthesis. Prolonged exposure to anesthetic concentrations of nitrous oxide can result in bone marrow depression (megaloblastic anemia) and even neurologic
deficiencies (peripheral neuropathies). However, administration of nitrous oxide for bone marrow harvest does not seem to affect the viability of bone marrow mononuclear
cells. Because of possible teratogenic effects, nitrous oxide is often avoided in pregnant patients who are not yet in the third trimester. Nitrous oxide may also alter the immunologic response to infection by affecting chemotaxis and motility of
polymorphonuclear leukocytes.

Examples of conditions in which nitrous oxide might be hazardous include venous or arterial air embolism, pneumothorax, acute intestinal obstruction with bowel distention, intracranial air (pneumocephalus following dural closure or
pneumoencephalography), pulmonary air cysts, intraocular air bubbles, and
tympanic membrane grafting. Nitrous oxide will even diffuse into tracheal tube cuffs,
increasing the pressure against the tracheal mucosa.

Obviously, nitrous oxide is of
limited value in patients requiring increased inspired oxygen concentrations.

Nitrous oxide is an ozone-depleting gas with greenhouse effects.

19
Q

Clinical Pharmacology of Inhalation Anesthetics: Halothane

A

Halothane is a halogenated alkane (see Table 8–3). Carbon–fluoride bonds are
responsible for its nonflammable and nonexplosive nature.

C. Cerebral
By dilating cerebral vessels, halothane lowers cerebral vascular resistance and
increases cerebral blood volume and CBF. Autoregulation, the maintenance of constant
CBF during changes in arterial blood pressure, is blunted. Concomitant rises in
intracranial pressure can be prevented by establishing hyperventilation before
administration of halothane. Cerebral activity is decreased, leading to electroencephalographic slowing and modest reductions in metabolic oxygen requirements.

D. Neuromuscular
Halothane relaxes skeletal muscle and potentiates nondepolarizing neuromuscularblocking
agents (NMBAs). Like the other potent volatile anesthetics, it is a trigger for malignant hyperthermia.

E. Renal
Halothane reduces renal blood flow, glomerular filtration rate, and urinary output. Part
of this decrease can be explained by a fall in arterial blood pressure and cardiac output. Because the reduction in renal blood flow is greater than the reduction in glomerular filtration rate, the filtration fraction is increased. Preoperative hydration limits these changes.

F. Hepatic
Halothane decreases hepatic blood flow in proportion to the depression of cardiac output. Hepatic artery vasospasm has been reported during halothane anesthesia. The
metabolism and clearance of some drugs (eg, fentanyl, phenytoin, verapamil) seem to be impaired by halothane. Other evidence of hepatic cellular dysfunction includes
sulfobromophthalein (BSP) dye retention and minor liver transaminase elevations.

Postoperative hepatic dysfunction has several causes: viral hepatitis, impaired
hepatic perfusion, preexisting liver disease, hepatocyte hypoxia, sepsis, hemolysis,
benign postoperative intrahepatic cholestasis, and drug-induced hepatitis. “Halothane hepatitis” is extremely rare. Patients exposed to multiple halothane anesthetics at short intervals, middle-aged obese women, and persons with a familial predisposition to halothane toxicity or a personal history of toxicity are considered to be at increased risk.

It is prudent to withhold halothane from patients with unexplained liver dysfunction
following previous anesthetic exposure.

Hypovolemic patients and some patients with severe reductions in left ventricular
function may not tolerate halothane’s negative inotropic effects

The myocardial depression seen with halothane is exacerbated by β-adrenergic
blocking agents and calcium channel blocking agents.

20
Q

Clinical Pharmacology of Inhalation Anesthetics: Isoflurane

A

Isoflurane is a nonflammable volatile anesthetic with a pungent ethereal odor

Biotransformation & Toxicity
Isoflurane is metabolized to trifluoroacetic acid. Although serum fluoride fluid levels
may rise, nephrotoxicity is extremely unlikely, even in the presence of enzyme inducers.
Prolonged sedation (>24 h at 0.1–0.6% isoflurane) of critically ill patients has resulted
in elevated plasma fluoride levels (15–50 μmol/L) without evidence of kidney impairment. Similarly, up to 20 MAC-hours of isoflurane may lead to fluoride levels exceeding 50 μmol/L without detectable postoperative kidney dysfunction. Its limited
oxidative metabolism also minimizes any possible risk of significant hepatic dysfunction.

Contraindications
Isoflurane presents no unique contraindications. Patients with severe hypovolemia may
not tolerate its vasodilating effects. It can trigger malignant hyperthermia.

Drug Interactions
Epinephrine can be safely administered in doses up to 4.5 mcg/kg. Nondepolarizing
NMBAs are potentiated by isoflurane.

21
Q

Clinical Pharmacology of Inhalation Anesthetics: Desflurane

A

For instance, because the vapor pressure of desflurane at 20°C is 681 mm Hg, at high
altitudes (eg, Denver, Colorado) it boils at room temperature. This problem
necessitated the development of a special desflurane vaporizer. Furthermore, the low solubility of desflurane in blood and body tissues causes very rapid induction of and
emergence from anesthesia. Therefore, the alveolar concentration of desflurane
approaches the inspired concentration more rapidly than with the other volatile agents, providing tighter control over anesthetic concentrations. Wakeup times are approximately 50% less than those observed following isoflurane.

Although desflurane is roughly one-fourth as potent as the other volatile agents, it is 17 times more potent than nitrous oxide. A high vapor
pressure, an ultrashort duration of action, and moderate potency are the most characteristic features of desflurane.

Desflurane undergoes minimal metabolism in humans.

Desflurane is the most
ozone-depleting of the inhalation anesthetics.

Contraindications
Desflurane shares many of the contraindications of other modern volatile anesthetics:
severe hypovolemia, malignant hyperthermia, and intracranial hypertension.

Desflurane potentiates nondepolarizing neuromuscular blocking agents to the same
extent as isoflurane

Desflurane emergence has been associated with delirium in some pediatric patients.

22
Q

Clinical Pharmacology of Inhalation Anesthetics: Sevoflurane

A

Nonpungency and rapid increases in alveolar anesthetic concentration make sevoflurane
an excellent choice for smooth and rapid inhalation inductions in pediatric and adult patients.

No study has associated sevoflurane with any detectable postoperative renal toxicity or injury. Nonetheless, some clinicians recommend that fresh gas flows be at least 2 L/min for anesthetics lasting more than a few hours

Contraindications include severe hypovolemia, susceptibility to malignant
hyperthermia, and intracranial hypertension.

Drug Interactions
Like other volatile anesthetics, sevoflurane potentiates NMBAs. It does not sensitize the heart to catecholamine-induced arrhythmias.

23
Q

Clinical Pharmacology of Inhalation Anesthetics: Xenon

24
Q

Clinical Pharmacology of Inhalation Anesthetics Summation Table