GENERAL ANESTHETICS

Dr Joshua Reece

Spring Term 2020 1

 LEARNING OBJECTIVES

By the end of this session the student should be able to:

• Define the terms “general anesthesia” and “balanced anesthesia.”
• Describe the objectives of general anesthesia, the characteristics of
an ideal anesthetic, and the stages of general anesthesia.
• List the drugs commonly used in combination with inhalation
anesthetics in balanced anesthesia.
• Describe the mechanisms of action, adverse effects, drug
interactions and contraindications of general anesthetics.
• Define MAC and explain how MAC is used in anesthesiology.
• Describe how physical properties of inhaled anesthetics influence
potency and onset.
• Compare and contrast inhalation anesthetics with respect to their
pharmacokinetic properties.
• Compare and contrast the properties of IV general anesthetics.
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 GENERAL ANESTHETICS

• The state of “general anesthesia” includes:

• Analgesia
• Amnesia
• Loss of consciousness
• Suppression of reflexes
• Skeletal muscle relaxation

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 BALANCED ANESTHESIA

• No single drug is capable of achieving all of the

desired goals of anesthesia.
• In balanced anesthesia, several drugs are
used in combination to produce the anesthetic
state.

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 BALANCED ANESTHESIA

• The onset of inhalational agents is not rapid:

patients are usually anesthetized with an IV
agent.
• Halogenated hydrocarbons are not good
analgesics: a supplemental analgesic is
required.
• Neuromuscular blockers are used to provide
paralysis adequate for surgical access.

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TYPES OF GENERAL ANESTHETICS

• INHALED ANESTHETICS
• IV ANESTHETICS

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 INHALED ANESTHETICS

• Gases
 N2O
• Volatile halogenated hydrocarbons
 Halothane
 Enflurane
 Isoflurane
 Desflurane
 Sevoflurane
 Methoxyflurane
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 IV ANESTHETICS

Used alone or with other drugs to:

• Achieve anesthesia
• As components of balanced anesthesia
• Sedate patients in ICUs who must be
mechanically ventilated for long periods.

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 IV ANESTHETICS

IV anesthetics include:

• Barbiturates
• Propofol
• Ketamine
• Etomidate

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 INHALED ANESTHETICS

• Used for the maintenance of anesthesia

after administration of an IV agent.

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 INHALED ANESTHETICS

COMMON FEATURES
• Increase perfusion of brain.
• Cause bronchodilation.
• Decrease minute ventilation.
• Potency correlates with liposolubility.
• Rate of onset inversely correlates to blood
solubility.
• Recovery is due to redistribution from the brain.
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 Desflurane Sevoflurane

Isoflurane

Enflurane Halothane

Methoxyflurane 12
PHARMACODYNAMICS

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 MECHANISM OF ACTION

• The actions of inhaled anesthetics are the

consequence of direct interactions with ligand-
gated ion channels.
• Positive modulation of GABAA and glycine
receptors.
• Inhibition of nicotinic receptors.

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POTENCY OF GENERAL ANESTHETICS

• Standard of comparison for potency of general

anesthetics: Minimum alveolar concentration
(MAC).
• MAC is the concentration that results in
immobility in 50% of patients when exposed
to a noxious stimulus such as surgical
incision.
• MAC is expressed as % of the alveolar gas
mixture.

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POTENCY OF GENERAL ANESTHETICS

• MAC is low for potent anesthetics and

large for less potent agents.

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POTENCY OF GENERAL ANESTHETICS

100

50

0
1
MAC
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 POTENCY OF GENERAL ANESTHETICS

• MAC values are additive.

• Nitrous oxide can be used as a “carrier” gas,
decreasing the anesthetic requirement of
other inhaled anesthetics.
• 0.7 MAC of isoflurane and 0.3 MAC of nitrous
oxide yield 1 MAC.

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 SOME MAC VALUES

Anesthetic MAC (%)

Nitrous oxide 104
Desflurane 6
Sevoflurane 2.0
Enflurane 1.7
Isoflurane 1.4
Halothane 0.75
Methoxyflurane 0.16
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 THE MEYER–OVERTON CORRELATION

• The potency of an anesthetic can be predicted

from its liposolubility.
• The oil:gas partition coefficient is a good
measure of the liposolubility.
• The potency of an anesthetic increases as its
solubility in oil increases.
• As λ(oil:gas) increases, the MAC decreases.

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PARTITION COEFFICIENTS: DEFINITION

• The partition coefficient is the ratio of the

concentrations of a compound in one solvent to
the concentration in another solvent.
• For example, an oil:gas partition coefficient of 19
means that the concentration of anesthetic in oil
is 19-fold that present in the alveolar gas when
the partial pressure of the anesthetic is identical
at both sites.

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 POTENCY & LIPOSOLUBILITY

ANESTHETIC MAC (%) (oil:gas)

Nitrous oxide 104 1.4
Desflurane 6 19
Sevoflurane 2 51
Enflurane 1.7 98
Isoflurane 1.4 98
Halothane 0.75 224
Methoxuflurane 0.16 960
The potency of an anesthetic increases as
its liposolubility increases. 22
 POTENCY & LIPOSOLUBILITY
Oil/Gas Partition Coefficient

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MAC (%)
 Questions

• Describe the mechanism of action of inhaled

anesthetics.
• Define MAC.
• Explain how MAC is used in anesthesiology.

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PHARMACOKINETICS: ANESTHETIC INDUCTION

• Anesthesia requires transfer of anesthetic

from the alveolar air to the blood and then
to the brain.

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 ANESTHETIC INDUCTION

Anesthetic gas

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 ANESTHETIC INDUCTION

• The rate at which a given concentration of

anesthetic in the brain is reached depends on:
• Solubility of the anesthetic
• Its concentration in the inspired air
• Pulmonary ventilation rate
• Pulmonary blood flow
• Arteriovenous concentration gradient

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 SOLUBILITY IN BLOOD

• The blood:gas partition coefficient () is a useful

index of solubility.
• It defines the relative solubility of an anesthetic
in the blood compared to air.

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 SOLUBILITY IN BLOOD

• When an anesthetic with low solubility in blood

reaches the arterial blood the arterial tension of
the anesthetic rises quickly.

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 SOLUBILITY IN BLOOD

• Conversely, if an anesthetic has high solubility in

blood, more molecules of the anesthetic will
dissolve in blood before the partial pressure
increases significantly.
• Consequently, the arterial tension of the gas
increases less rapidly.

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 SOLUBILITY IN BLOOD

• Therefore there is an inverse relationship

between the blood solubility of an anesthetic and
the rate of rise of its tension in arterial blood.
• A low blood:gas partition coefficient
determines a faster onset of anesthesia.

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 SOLUBILITY IN BLOOD

ANESTHETIC (blood:gas)
Nitrous oxide 0.47
Desflurane 0.45
Sevoflurane 0.65
Enflurane 1.8
Isoflurane 1.4
Halothane 2.3
Methoxyflurane 12
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THE BLOOD:GAS PARTITION COEFFICIENT

Halothane Nitrous oxide

(blood:gas) = 2.3 (blood:gas) = 0.47

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 THE BLOOD:GAS PARTITION COEFFICIENT

Alveolus Blood Brain

N2O 0.47

Halothane 2.3

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 THE BLOOD:GAS PARTITION COEFFICIENT

1 N2O
Ratio of arterial 0.8 Sevoflurane
anesthetic tension Isoflurane
to inspired
0.6
anesthetic tension Halothane

0.4
Methoxyflurane
0.2

0
0 10 20 30
Minutes of Administration
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ANESTHETIC MAC (%) (oil:gas) (blood:gas)

Nitrous oxide 104 1.4 0.47

Desflurane 6 19 0.45
Sevoflurane 2 51 0.65
Enflurane 1.7 98 1.8
Isoflurane 1.4 98 1.4
Halothane 0.75 224 2.3
Methoxyflurane 0.16 960 12
• Anesthetics with large λ(oil:gas) have large λ(blood:gas).
• High potency correlates with slow onset.
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 ANESTHETIC CONCENTRATION
IN THE INSPIRED AIR
• Increase in anesthetic concentration increases
the rate of induction.

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 VENTILATION RATE

Anesthetic gas • Increase in ventilation rate

increases rate of induction.

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 PULMONARY BLOOD FLOW

• An increase in pulmonary blood flow (increased

cardiac output) slows the rate of induction.
• This is because increased pulmonary blood flow
exposes a larger volume of blood to the
anesthetic.
• Blood “capacity” increases and tension rises
slowly.

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ARTERIOVENOUS CONCENTRATION GRADIENT

• Difference between the concentration of

anesthetic in arterial and venous blood.
• Reflects the solubility of the anesthetic in
the tissues.
• Uptake by tissues slows down onset and
recovery.

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Anesthetic gas
Other Tissues

Lung Blood Brain

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 ELIMINATION

• Elimination of inhalational anesthetics is largely

the reverse process of uptake.

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 ELIMINATION

• For agents with low blood and tissue solubility,

recovery from anesthesia mirrors anesthetic
induction, regardless of the duration of
anesthetic administration.

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 ELIMINATION

• For agents with high blood and tissue solubility,

recovery depends on the duration of anesthetic
administration.
• This is because the anesthetic accumulates in
fat.

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ELIMINATION & RATE OF RECOVERY

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 Questions

• Describe how physical properties of inhaled

anesthetics correlate with potency and
onset.

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ORGAN EFFECTS OF INHALED
ANESTHETICS

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 CARDIOVASCULAR EFFECTS

• Most inhaled anesthetics depress normal

cardiac contractility.
• As a result, they tend to decrease mean arterial
pressure.

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 CARDIOVASCULAR EFFECTS

• Halothane and enflurane reduce MAP mainly

by myocardial depression, with little effect on
PVR.
• Isoflurane, desflurane and sevoflurane
produce vasodilation and have minimal effect on
cardiac output.
• Isoflurane, desflurane and sevoflurane may
be better choices for patients with impaired
myocardial function.
• N2O lowers blood pressure less than other
inhaled anesthetics. 49
 CARDIOVASCULAR EFFECTS

• Halothane sensitizes the myocardium to

circulating catecholamines, which may lead to
ventricular arrhythmias.
• This effect is less marked for isoflurane,
sevoflurane and desflurane.

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 RESPIRATORY EFFECTS

• Volatile anesthetics are bronchodilators.

• Volatile anesthetics are respiratory depressants.
• Isoflurane and enflurane are the most depressant.
• N2O is the least depressant.

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 CNS EFFECTS

• Inhaled anesthetics increase intracranial pressure.

• Undesirable in patients who already have
increased intracranial pressure because of brain
tumor or head injury.
• N2O increases blood flow the least.
• Enflurane at high concentrations may cause tonic-
clonic movements.

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 OTHER EFFECTS

• N2O exchanges with nitrogen in air-containing

cavities in the body.
• N2O enters the cavity faster than nitrogen
escapes.
• Therefore, it increases the volume and/or
pressure of the cavity.

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 OTHER EFFECTS

• N2O should be avoided in the following clinical

settings:
• Pneumothorax
• Obstructed middle ear
• Air embolus
• Obstructed loop of bowel
• Intraocular air bubble
• Pulmonary bulla
• Intracranial air 54
TOXICITY

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 HEPATOTOXICITY (HALOTHANE)

• Some individuals exposed to halothane may

develop a potentially severe and life-threatening
hepatitis.
• There is no specific treatment
• Liver transplantation may be required.

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 NEPHROTOXICITY

• Methoxyflurane has nephrotoxic potential.

• Due to fluoride released during
metabolism.

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 MALIGNANT HYPERTHERMIA

• Potentially fatal genetic disorder of skeletal

muscle.
• Triggered in susceptible individuals by volatile
inhalation anesthetics, such as halothane, and
depolarizing skeletal muscle relaxants, such as
succinylcholine.

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 MALIGNANT HYPERTHERMIA

• Transmitted as an autosomal dominant trait.

• Incidence is about 1:12,000.
• Malignant hyperthermia is one of the main
causes of death due to anesthesia.

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 MALIGNANT HYPERTHERMIA

• The malignant hyperthermia syndrome includes:

• Tachycardia
• Hypertension
• Severe muscle rigidity
• Hyperthermia
• Hyperkalemia
• Acidosis

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 MALIGNANT HYPERTHERMIA

• Malignant hyperthermia results from altered

control of Ca2+ release from the SR.
• In most cases, the syndrome is caused by a
defect in the ryanodine receptor gene (RYR1).
• Abnormal RYR receptors trigger unregulated
release of calcium from the SR, which may lead
to an acute malignant hyperthermia crisis.

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 MALIGNANT HYPERTHERMIA

Sarcolemma

DHPR RYR Ca2+

SR
T-Tubule
 MALIGNANT HYPERTHERMIA

Sarcolemma

Depolarization

DHPR RYR Ca2+

SR
T-Tubule
 MALIGNANT HYPERTHERMIA

Sarcolemma

Depolarization

DHPR RYR
Ca2+
SR
T-Tubule
 MALIGNANT HYPERTHERMIA

Sarcolemma

Depolarization

DHPR RYR
Ca2+
SR
T-Tubule
Ca2+
 MALIGNANT HYPERTHERMIA

• The increased Ca2+ concentration causes

increased muscle contraction which generates
heat.
• Increased levels of aerobic metabolism produce
CO2 and deplete O2 and ATP.
• A switch to anaerobic metabolism worsens
acidosis with the production of lactate.
• Energy stores get depleted.
• Muscle fibers die leading to hyperkalemia and
myoglobinuria.
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MALIGNANT HYPERTHERMIA: TREATMENT

• Dantrolene: blocks Ca2+ release from the

sarcoplasmic reticulum.
• Measures to reduce body temperature and
restore electrolyte and acid-base balance.

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 THE CAFFEINE-HALOTHANE MUSCLE
CONTRACTURE TEST

• The most reliable test to establish susceptibility

to malignant hyperthermia.
• A muscle sample is removed from the thigh.
• The response to halothane and caffeine is
assessed.

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 CHRONIC TOXICITY

Hematotoxicity
• Prolonged exposure to N2O decreases
methionine synthase activity and causes
megaloblastic anemia.
• Potential occupational hazard for staff
working in poorly ventilated dental
operating suites.

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INTRAVENOUS ANESTHETICS

 Barbiturates
 Propofol
 Ketamine
 Etomidate

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ULTRA-SHORT ACTING BARBITURATES

Thiopental and Methohexital

• Used for induction of anesthesia and for
short surgical procedures.

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 ULTRA-SHORT ACTING BARBITURATES

• Their anesthetic effects are terminated by

redistribution from the brain to other tissues, but
hepatic metabolism is required for their
elimination from the body.
Percent of Dose

Blood MG
• VRG: brain, liver, kidneys
VRG
• MG: muscle, skin
FG • FG: fat

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Time
ULTRA-SHORT ACTING BARBITURATES

• They decrease intracranial pressure.

• They do not produce analgesia.
• They may cause hyperalgesia.
• May cause apnea, coughing, chest wall spasm,
laryngospasm and bronchospasm: a concern for
asthmatic patients.

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 PROPOFOL

• Postoperative vomiting is uncommon. Antiemetic.

• Used for induction and maintenance of anesthesia.
• Produces no analgesia.
• Rapidly metabolized in the liver.
• Potent respiratory depressant.
• Reduces intracranial pressure.
• Causes hypotension through decreased PVR.
• Fospropofol: prodrug converted to propofol in vivo.

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 ETOMIDATE

• Primarily used for anesthetic induction of patients at

risk for hypotension.
• Causes minimal CV and respiratory depression.
• No analgesic effects.
• Reduces intracranial pressure.
• Associated with nausea and vomiting.

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 KETAMINE

• Produces dissociative anesthesia,

characterized by catatonia, amnesia and
analgesia, with or without loss of consciousness.
• Mechanism of action may involve blockade of
NMDA receptors.
• Only IV anesthetic that possesses both
analgesic properties and the ability to produce
CV stimulation.

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 KETAMINE

• Increases intracranial pressure.

• Causes sensory and perceptual illusions, and
vivid dreams (‘emergence phenomena’).
• Diazepam, midazolam, or propofol reduce the
incidence of these phenomena.

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 Questions

• Describe the adverse effects of general

anesthetics.
• Explain the pathophysiology of malignant
hyperthermia and its pharmacological
management.
• Describe the test to establish susceptibility
to malignant hyperthermia.

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NEUROLEPTIC-OPIOID COMBINATIONS

Neuroleptic-Opioid Combinations
• When a potent opioid analgesic, such as
fentanyl, is combined with a neuroleptic such as
droperidol, neurolept analgesia is established.
• Neurolept analgesia can be converted to
neurolept anesthesia by the concurrent
administration of 65% N2O in O2.

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 ADJUVANT DRUGS

• Adjuvant drugs provide additional effects that

are desirable during surgery but are not
necessarily provided by the general anesthetics.

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 ADJUNCTS TO ANESTHETICS

• Benzodiazepines. For their anxiolytic and

anterograde amnesic properties.
• Opioids. For analgesia.
• Neuromuscular blockers. To achieve muscle
relaxation.

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 ADJUNCTS TO ANESTHETICS

• Antiemetics, eg ondansetron. To prevent

possible aspiration of stomach contents.

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 ADJUNCTS TO ANESTHETICS

• Antimuscarinics, eg scopolamine
• For its amnesic effects
• To prevent salivation and bronchial secretions
• To protect the heart from bradycardia caused
by inhalation agents and neuromuscular
blockers.

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 Questions

• List the drugs used in combination with

inhalation anesthetics in balanced anesthesia.

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 Questions

Antiemetic properties

A. Halothane
B. Propofol
C. Etomidate
D. Ketamine
E. Apomorphine
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 Questions

Minimal cardiovascular depression

A. Propofol
B. Etomidate
C. Halothane
D. Enflurane

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 Questions

CV stimulation

A. Ketamine
B. Propofol
C. Etomidate
D. Fentanyl
E. Halothane
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 Questions

Hepatotoxic

A. Desflurane
B. Enflurane
C. Isoflurane
D. Propofol
E. Halothane
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 Questions

Decreases intracraneal pressure

A. Ketamine
B. Propofol
C. Halothane
D. Enflurane
E. Isoflurane
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 Questions

Decreases cardiac output

A. Enflurane
B. Isoflurane
C. Desflurane
D. Sevoflurane
E. Nitrous oxide
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 Questions

Treatment for malignant hyperthermia

A. Physiostigmine
B. Dantrolene
C. Bromocriptine
D. Atropine
E. Dopamine

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THE END

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