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Anesthesia Agents II. Wayne E. Ellis, Ph.D., CRNA. Minimum Alveolar Concentration (MAC). MAC: MAC that prevents skeletal muscle movement in 50% of patients MAC-Awake: MAC at which 50% of pts will respond to the command “Open your eyes”

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anesthesia agents ii

Anesthesia Agents II

Wayne E. Ellis, Ph.D., CRNA

minimum alveolar concentration mac
Minimum Alveolar Concentration (MAC)

MAC:

MAC that prevents skeletal muscle movement in 50% of patients

MAC-Awake:

MAC at which 50% of pts will respond to the command “Open your eyes”

Usually associated with a loss of recall (~1/3 – ¼ MAC)

MAC-BAR:

MAC necessary to block adrenergic response to skin incision (HR,B/P)

Expressed as MAC-BAR50 or MAC-BAR95

Exceeds the requirement of MAC

inhaled agents
Inhaled Agents:

Agent: MAC% with 60% N2O

Nitrous Oxide 104 ---

Desflurane 6.0 (2.8)

Sevoflurane 2.6 (1.4)

Isoflurane 1.28 (0.56)

Ethrane 1.58 (0.57)

Halothane 0.75 (0.29)

metabolism of volatile anesthetics
Metabolism of volatile anesthetics

Methoxyflurane > Halothane > Sevoflurane > Enflurane > Isoflurane > Desflurane

Desflurane almost totally inert to metabolism

Metabolism

Cytochrome P450 enzymes in liver

Oxidize anesthetics

metabolism toxicity
Metabolism & Toxicity

Liver most susceptible to toxicity

Halothane

Chloroform

Halothane is only anesthetic that undergoes metabolic reduction

Penthrane (Methoxyflurane) Kidneys

inhaled agents metabolized
Inhaled Agents: % Metabolized

Halothane 15.00 – 20.00 %

Sevoflurane 5.00 %

Ethrane 2.00 – 3.00 %

Isoflurane 0.20 %

Desflurane 0.02 %

Nitrous Oxide 0.004 %

ideal volatile anesthetic agent
Ideal Volatile Anesthetic Agent

Rapid Induction and Emergence

Pleasant (non-irritating)

Easily change the depth of anesthesia

Skeletal and smooth muscle relaxation

Low toxicity

Good safety profile (minimal side effects)

Inexpensive (equipotent dosing)

ideal volatile anesthetic agent1
Ideal Volatile Anesthetic Agent

Nonarrhythmogenic

Resistant to biodegradation

Nonflammable

Physically Stable

Short post-operative recovery time

carbon dioxide
Carbon Dioxide

End product of metabolism

Can become anesthetic to CNS at concentrations > 5% inhaled

Normal levels

Arterial 40 mm Hg

Venous 45 mm Hg

Human production 4 ml/kg

Basis of absorption = ability to form carbonic acid in water

carbon dioxide1
Carbon Dioxide

CO2 + H2O <--> H+ + HCO3-

H+ + HCO3- --> 2 H+ + CO3--

Nonvolatile carbonate salts formed with various cations

Reuse of volatile anesthetics dependent on removal of CO2 from circuit

nitrous oxide
Nitrous Oxide

Odorless to sweet smelling

Low Potency, Low blood solubility

Very "fast-on, fast-off"

Inhalation administration well tolerated

<25% remains conscious

Discovered 1772 Joseph Priestly

Clinical Use 1884 Horace Wells

Combined with Ether 1870 Andrews

Greatest advantage:

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properties
Properties

Low molecular weight 44

Vapor pressure 800 torr @ 25 C

Odor Sweet

Stable in Soda Lime

Solubility

Blood/Gas 0.46 – 0.47

Brain/Gas 1.1

Oil/Gas 1.4

MAC 104/105

properties1
Properties

Low molecular weight

Nonflammable

Supports Combustion

Vapor pressure 800 torr @ 25 C

Stable in Soda Lime

Low potency (MAC = 104/105)

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nitrous oxide n 2 o
Nitrous Oxide (N2O)

N = N+ - O- <--> N- = N+= O

Resonance structure

Incomplete anesthetic

MAC = 105%

Synthesized in 1776

Demonstrated at Mass General Hospital 1845

Considered failure

Reintroduced in 1863

nitrous oxide1
Nitrous Oxide

Most commonly used inhalant adjunct to general anesthetic agents

Reduce amount of other agent

Supports combustion

Oxidant

Supplied in Blue cylinders

745 psi

Boiling point -88o C

Low solubility, High volatility

properties2
Properties

Solubility

Blood/gas coefficient 0.47

Oil/gas coefficient 1.4

Poor blood solubility

No preservative

Stored as a liquid under pressure

745 psi

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properties3
Properties

Low blood solubility

Raid induction and emergence

No preservative

Nonflammable

Supports Combustion

Stored as a liquid under pressure (750 psi)

Blue Tank

How do you calculate remaining quantity of N2O in tank

advantages
Advantages

Little to no depression of cardiovascular and respiratory systems

With volatile agent

Reduction in amount of volatile anesthetic requirement

Reduce unwanted effects of the agent

Hypotension

Cardiac depression

Speed of induction improved

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advantages1
Advantages

Analgesic effects prominent

Analgesia may involve

Release of endogenous opioids

Enhancement of nervous pathways

Irregular depression of cortical brain

No depression of vital centers in absence of hypoxia

Minimal biodegradation

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advantages2
Advantages

Promotes amnesia (usually 60 to 70%)

Used in combination with narcotic and muscle relaxant

Nitrous-narcotic technique

Include benzodiazepine for amnesia

No effect on skeletal muscle

No effect on kidneys

Does not cross placenta

Eliminated via lungs

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advantages3
Advantages

Little to no depression of cardiovascular and respiratory systems

With volatile agent

Reduction in amount of volatile anesthetic requirement (2nd Gas Effect)

Reduce unwanted effects of the agent

Hypotension

Cardiac depression

Speed of induction improved

advantages4
Advantages

Analgesia may involve

Release of endogenous opioids

Enhancement of nervous pathways

No depression of vital centers in absence of hypoxia

Minimal biodegradation

No effect on kidneys

Eliminated via lungs

disadvantages
Disadvantages

Irregular depression of cortical brain

Increased heart rate and blood pressure

Increased cerebral blood flow and intracranial pressure

Predisposition to atelectasis

0.1-0.4 MAC depress central responsiveness to Hypoxia

Increased muscle tone in larynx and abdomen

“Tight Chest” possible

Skeletal muscle relaxation is absent

Inactivates B12

disadvantages1
Disadvantages

Increased heart rate and blood pressure

Increased cerebral blood flow and intracranial pressure

Predisposition to atelectasis

0.1-0.4 MAC depress responsiveness to Hypoxia

Increased muscle tone in larynx and abdomen

“Tight Chest” possible

Skeletal muscle relaxation is absent

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disadvantages2
Disadvantages

75% causes reduction in fetal oxygenation

Decreased APGAR Scores

Lower neurobehavioral scores

Enlargement of closed air spaces

Endotracheal tube cuffs

Middle ear procedures

Nitrous Oxide off > 30 minutes before graft placed

Pneumothorax

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disadvantages3
Disadvantages

Air emboli

Nitrogen (B/g of 0.015) does not leave as fast as nitrous oxide enters

Volume expands rapidly

Avoid in patients with potential for air emboli or with methyl methacrylate

Increased incidence of nausea (> 15%)

Supports combustion

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disadvantages4
Disadvantages

Possibility of problems with DNA synthesis

Potential for increased spontaneous abortion

Potential for Diffusion Hypoxia

Decreased DNA Synthesis (50% for 2 hrs < DNA synthesis 1-6 days)

Can be abused by practitioners

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disadvantages5
Disadvantages

Decreased DNA Synthesis (50% for 2 hrs < DNA synthesis 1-6 days)

Possibility of problems with DNA synthesis following the 7th day

Potential for increased spontaneous abortion

Potential for Diffusion Hypoxia

Abused Drug by practitioners

diethyl ether us
Diethyl ether (US)

CH3CH2OCH2CH3

First complete anesthetic

Demonstrated in 1846 (Crawford Long)

More potent than nitrous oxide

Flammable/explosive

Stimulates emesis

diethyl ether us1
Diethyl ether (US)

CH3CH2 - O - CH2CH3

First complete anesthetic

Demonstrated in 1846 (Crawford Long)

More potent than nitrous oxide

Flammable/explosive

Stimulates emesis

chloroform
Chloroform

Trichloromethane

CHCl3

Introduced

Animals 1847 (Flourens)

Man 1848 (Simpson)

First halogenated anesthetic

Pleasant odor

What movies were made of

Nonflammable

Liver Toxicity

cyclopropane
Cyclopropane

C3H6

Hydrocarbons without halogen burn quickly

Discovered in 1929

Tested at University of Wisconsin

Used clinically for > 30 years

Flammable and explosive

halogenated structure provides
Halogenated structure provides

Nonflammable

Intermediate blood solubility

Anesthetic potency

Molecular stability

04/15/96

WEE / UIOWA / CON

9

modern fluorinated anesthetics
Modern Fluorinated Anesthetics

Goals when making anesthetics

Reduce or eliminate toxicity (metabolism)

Reduce or eliminate flammability

Increase speed of induction and recovery

Basic structures

Ethane (Halothane)

Methyl ethyl ethers

Propyl methyl ether

halothane fluothane
Halothane (Fluothane)

Only ethane anesthetic

Non-ether

Simply halogenated hydrocarbon

Added halogens to eliminate flammability, increase potency, increase tolerance of patient to inhalation

halothane
Halogenated alkane

2-bromo-2chloro-1,1,1-trifluoroethane (CF3CHClBr)

Synthesized 1951

Clinical use 1956

Clear, nonflammable liquid

Volatile at room temperature

Intermediate solubility, High potency

Results in rapid onset and recovery from anesthesia

Halothane

04/15/96

WEE / UIOWA / CON

8

properties4
Properties

Molecular weight 197

Boiling Point 50.2 oC

Vapor pressure 244 torr @ 20 C

Odor Sweet, non pungent

Partition Coefficients

Blood/gas 2.3 - 2.54

Brain/gas 1.9

Oil/Gas 224

MAC

Nitrous Oxide 0.29

Oxygen 0.75 - 0.77

Not stable in soda lime

Contains 0.01% thymol as inhibitor (preservative, antioxidant)

halothane1
Halothane

Halogenated alkane

Synthesized 1951

Clinical use 1956

Sweet, nonpugent odor

Intermediate solubility

High potency

Results in rapid onset and recovery from anesthesia

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halothane2
Halothane

Introduced in 1956

Sweetish odor, non pungent

2-bromo-2chloro-1,1,1-trifluoroethane (CF3CHClBr)

Contains 0.01% thymol as inhibitor (preservative, antioxidant)

halothane3
Halothane

Boiling Point 50.2o C

MAC 0.74%

Halothane Hepatitis

1:30,000

Related to metabolism

Coupled with hypotension, hypovolemia, and aminoglycocides

halothane4
Halothane

Halogenated structure would provide nonflammablility, intermediate blood solubility, anesthetic potency, and molecular stability

Carbon-fluorine decreases flammability

Triflurocarbon contributes to the molecular stability

Carbon-chlorine and carbon-bromine bond plus the retention of a hydrogen atom ensures anesthetic potency

advantages5
Advantages

Sweet, nonpungent odor - well suited for inhalation induction

Less incidence of tachycardia

Depression of Carotid Sinus baroreceptors

Decreased firing of Sinus node

"Inhalation Inderal"

Decreased BP accompanied by a stable or decreased HR

Less depression of ventilation, best suited for the spontaneous breathing patient

advantages6
Advantages

Sweet, nonpungent odor - well suited for inhalation induction

Less incidence of tachycardia

Depression of Carotid Sinus baroreceptors

Decreased firing of Sinus node

"Inhalation Inderal"

Decreased BP accompanied by a stable or decreased HR

Less depression of ventilation, best suited for the spontaneous breathing patient

thymol
Used as inhibitor or preservative in Halothane

Sticky, yellow deposit as halothane vaporized

Thymol
thymol1
Thymol

Anti- oxidant

Used as inhibitor or preservative in Halothane

Sticky, yellow deposit as halothane vaporized

Requires that vaporizers be cleaned, restrung, and recalibrated annually

OH

OH

CH

CH3

CH3

properties5
Properties

Clear, nonflammable liquid

Volatile at room temperature

Molecular weight 197

Vapor pressure 244 torr @ 20 C

Solubility

Blood/gas 2.3

Oil/gas 224

MAC

70% Nitrous Oxide = 0.29

100 % Oxygen = 0.77

Not stable in soda lime

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halothane5
Halothane

Halogenated structure provides

Nonflammablility

Intermediate blood solubility

Anesthetic potency

Molecular stability

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halothane6
Halothane

Carbon-fluorine decreases flammability

Triflurocarbon contributes to the molecular stability

Carbon-chlorine and carbon-bromine bond plus the retention of a hydrogen atom ensures anesthetic potency

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oxidation and decomposition
Susceptible to spontaneous oxidation

Hydrochloric acid

Hydrobromic acid

Chloride

Bromide

Phosgene

Stored in amber colored bottles (sensitive to UV Light)

Oxidation and Decomposition

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oxidation and decomposition1
Halothane is stored in amber colored bottles

Thymol is added as a preservative

Prevent spontaneous oxidative decomposition

Thymol remains in the vaporizers

Causes "gumming" of vaporizers

Oxidation and Decomposition
advantages7
Advantages

Sweet, nonpungent odor

Suited for inhalation induction

Less incidence of tachycardia

"Inhalation Inderal"

Decreased BP

Stable or decreased HR

Actions in CV system at Sinus node

Less depression of ventilation

Spontaneous breathing patient

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disadvantages6
Disadvantages

Arrhythmogenic potential

Used with epinephrine

Blunts the baroreceptor reflex

> isoflurane

> enflurane

Sinus arrest

Undesirable if want an increased HR

Infant

Rate dependent cardiac output

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disadvantages7
Disadvantages

Rare incidence of liver dysfunction

Solubility

Blood

> enflurane, isoflurane and desflurane

Tissue

> enflurane, isoflurane and desflurane

disadvantages8
Disadvantages

More blood soluble than enflurane, isoflurane and desflurane

More tissue soluble than enflurane, isoflurane and desflurane

Arrhythmogenic potential when used with epinephrine

disadvantages9
Disadvantages

Blunts the baroreceptor reflex more than isoflurane and enflurane

Undesirable if want an increased HR

Such as in an infant who depends on HR for maintenance of cardiac output

Rare incidence of liver dysfunction

halothane7
Halothane

Susceptible to spontaneous oxidation

Hydrochloric acid

hydrobromic acid

Chloride

Bromide

Phosgene

Stored in amber colored bottles (sensitive to UV Light)

disadvantages10
Disadvantages

Rare incidence of liver dysfunction

Solubility

Blood

> enflurane, isoflurane and desflurane

Tissue

> enflurane, isoflurane and desflurane

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halothane epinephrine
Halothane / Epinephrine

Maximum adult dose of Epinephrine with Halothane is 1mcg/kg

2 to 3mcg/kg with any other agent

Children less sensitive to Epi/Halothane; max epi 1.5mcg/kg

3mcg/kg with other agents

Avoid using aminophylline with Halothane.

Aminophylline triggers the release of norepinephrine.

Halothane sensitizes myocardium to catecholamines.

Limit Epinephrine, norepi, Isoproterenol, and dopamine use.

halothane epinephrine1
Halothane / Epinephrine

Dysrhythmias are easily induced.

Avoid Halothane in patients with acute cocaine intoxication.

Cocaine blocks reuptake of norepinephrine.

hepatotoxicity
Hepatotoxicity

Hepatitic Necrosis

Rare, but can be fatal

Two types:

1. Mild

2. Fulminant

fulminant type
Fulminant Type

Metabolites bind to liver proteins

Form trifluroracetylated proteins

Stimulate antibodies

With future exposure, leads to massive hepatic necrosis and death

occurrence of hepatic necrosis
Occurrence of Hepatic Necrosis

Halothane is most common cause

Common events

Halogenated exposure

Reduced liver blood flow

Aminoglycosides

Halothane > Ethrane > Forane > Desflurane

No clinical concern with Desflurane

Very small percent of Desflurane is metabolized

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