M.

Babbini, MD, PhD General Anesthetics

General Anesthetics
Drug Classes and Drugs to consider *
Inhalational Anesthetics Intravenous Anesthetics
Volatile liquids Gas Barbiturates Benzodiazepines Others
Halothane Nitrous oxide Thiopental (Midazolam) Propofol
Isoflurane Etomidate
Sevoflurane Ketamine
Opioids (morphine,
fentanyl)

* Drugs in brackets have been already mentioned elsewhere

Learning Objectives
Mechanism of action
- Define the term "general anesthesia”
- Describe the stages of general anesthesia
- List the main general anesthetics which are presently in clinical use
- Explain the mechanisms of action of general anesthetics
- Define the term ‘minimal alveolar concentration
Actions on organ systems
- Describe the pharmacodynamics of halothane, isoflurane, sevoflurane and nitrous oxide
- Describe the pharmacodynamics of propofol, etomidate and ketamine
- Describe the general anesthetics properties of barbiturates , benzodiazepines and opioids
Pharmacokinetics
- Describe the pharmacokinetics of inhaled anesthetics
- Explain the relationship between the blood/gas partition coefficient and speed of induction and recovery
Adverse effects, drug interactions and contraindications
.- Describe the main features of halothane hepatitis.
.- Describe the main features of malignant hyperthermia.
Therapeutic uses
- Outline the procedures of balanced general anesthesia, conscious sedation, neuroleptanalgesia and
.neuroleptanesthesia.
-

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M. Babbini, MD, PhD General Anesthetics

General anesthesia
may be defined as a state which includes

1) loss of consciousness (a coma state which is not reversible as long

as the drug is in the body)

2) inhibition of sensory and autonomic reflexes (including

nociceptive reflexes, i.e. analgesia

3) skeletal muscle relaxation

4) anterograde amnesia (upon recovery)

[the extent to which any individual anesthetic drug can exert these
effects depend upon the drug, the dose, and the clinical circumstances}

SIGNS AND STAGES OF GENERAL ANESTHESIA

I. Stage of analgesia
- Analgesia
- Unaltered consciousness
- Normal pupils
II. Stage of excitement
- Disturbed consciousness (uncoordinated movements, incoherent talk)
- Irregular respiration
- Retching and vomiting
- Incontinence (sometimes)
- Increased blood pressure
- Mydriasis
III. Stage of surgical anesthesia
- Loss of consciousness
- Regular respiration
- Progressive decrease of skeletal muscle tone
- Progressive loss of somatic and autonomic reflexes
- Progressive decrease in blood pressure
- Miosis
IV. Stage of medullary depression
- Loss of consciousness
- No spontaneous respiration
- Cardiovascular collapse
- Mydriasis

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M. Babbini, MD, PhD General Anesthetics

PHARMACOKINETICS OF INHALATIONAL ANESTHETICS (1)

ABSORPTION AND DISTRIBUTION

- The concentration of a gas in an environment is proportional to its

partial pressure or tension (these two terms are often used
interchangeably)

- Depth of anesthesia is determined by the concentration of the

anesthetic in CNS.

- In order to reach the CNS the anesthetic must be transferred from the
alveolar air to blood and from blood to brain. This transfer is influenced
by:

1) Solubility in blood (blood/gas partition coefficient)

The more soluble an anesthetic is in blood, the more of it must be
dissolved in blood to rise its partial pressure. Therefore the higher the
blood/gas partition coefficient, the slower the induction and recovery of
anesthesia.

2) Anesthetic partial pressure in the inspired air:

The anesthetic tension in the alveoli and the rate of rise of this tension in
the arterial blood are directly proportional to the anesthetic tension in the
inspired air. Therefore the higher the partial pressure of the anesthetic in
the inspired air, the faster the achievement of anesthetic levels in the
blood and therefore the faster induction of anesthesia.

3) Pulmonary ventilation
The rate of rise of the anesthetic gas tension in the arterial blood is
directly proportional to the lung ventilation. Therefore the faster the
ventilation, the faster the induction of anesthesia.

4) Pulmonary blood flow

An increase in pulmonary blood flow slows the rate of rise in arterial
tension of the anesthetic. Therefore the faster the pulmonary blood flow
the slower the induction of anesthesia.

5) Uptake of the anesthetic by the tissues

It depends on tissue/blood partition coefficient and tissue blood flow.
It regulates the arteriovenous concentration gradient of the drug. The
greater this gradient the more time it takes to achieve equilibrium, and
therefore the slower the induction of anesthesia

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M. Babbini, MD, PhD General Anesthetics

Why induction of anesthesia is slower with more soluble anesthetic

gases

PHARMACOKINETICS OF INHALATIONAL ANESTHETICS (2)

ELIMINATION

- Inhaled anesthetics are mainly eliminated by respiratory route.

- Respiratory elimination is affected by the same kinetic variables which

affect absorption. The three most important are pulmonary ventilation,
blood flow and solubility in blood and tissues.
- When the administration of an inhaled anesthetic is discontinued,
tension of the anesthetic in brain decreases rapidly, because of the
high brain blood flow

- On the contrary the anesthetic will persist for a longer time in tissue
with lower blood flow such as skeletal muscle or very low blood flow like
adipose tissue

- Anesthetics which are relatively insoluble in blood and brain are

eliminated faster than more soluble anesthetics.

- Metabolism may contribute to the elimination of some inhaled

anesthetics (.20 % of halothane, . 3% of sevoflurane are
biotransformed).
. Some metabolites may be toxic for liver and other organs.

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M. Babbini, MD, PhD General Anesthetics

GENERAL ANESTHETICS: MECHANISM OF ACTION

At the neurophysiological level
- Early depressive effect on substantia gelatinosa

- Blockade of small inhibitory neurons (e.g Golgi type II cells) in several

brain areas.

- Progressive depression of the ascending pathways in the reticular

activating system.

At the cellular level

- Depression of synaptic transmission (the main cellular effect).
Neurons are hyperpolarized and their threshold for firing is increased.

- Depression of axonal conduction.

At the molecular level

-The primary molecular target of many general anesthetics is the
GABAA receptor-chloride channel.

-Halogenated anesthetics, benzodiazepines, barbiturates, etomidate

and propofol, all facilitate GABA-mediated inhibition at GABAA receptor
site.

- Many general anesthetics seem also to cause membrane

hyperpolarization via their activation of ligand gated K+ channels.

-Some general anesthetics (ketamine, nitrous oxide) seem to inhibit a

different type of ligand gated ion channel, namely the NMDA receptor.

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M. Babbini, MD, PhD General Anesthetics

THE MINIMUM ALVEOLAR ANESTHETIC CONCENTRATION

- During general anesthesia the partial pressure of an anesthetic in the
brain equal that in the lung when equilibrium is reached.

- Therefore the measurement of the steady state alveolar concentration

of different anesthetic provides a measure of their relative potencies.

- The Minimum Alveolar Anesthetic Concentration (MAC) is

defined as the concentration of the anesthetic that results in the
immobility of 50% of patients when exposed to a noxious
stimulus.

- Thus MAC represent the ED50 on a conventional quantal dose-

response curve, and is therefore a measure of the potency of the
inhaled anesthetic..
- A MAC > 100% indicates that even when all the molecules of the
inspired gas are molecules of the anesthetic, the concentration is not
able to cause immobility in 50% of patients.

- MAC decreases in elderly patients and in the presence of certain

adjuvant drugs (opioids, benzodiazepines, barbiturates, etc.)

- MACs of inhaled general anesthetic are additive.

SOME FEATURES OF INHALATIONAL ANESTHETICS

Drug B/G * MAC(%) B(%)** Onset Recovery
Nitrous oxide 0.47 >100 none rapid rapid
Sevoflurane 0.69 2.0 <3 rapid rapid
Isoflurane 1.40 1.2 <2 medium medium
halothane 2.30 0.75 40 slow slow
* Blood/gas partition coefficient
** biotransformation
# poor induction because of irritant properties

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M. Babbini, MD, PhD General Anesthetics

HALOTHANE PHARMACOLOGY
Chemistry
-A halogenated ether, volatile liquid at room temperature.
-
Pharmacodynamics
[most effects are concentration dependent, that is they increase as the partial
pressure in the target tissue increases]

Nervous system effects

- Slow induction and recovery (if given alone)
- Partial loss of nociceptive reflexes
- Good postoperative amnesia

Skeletal muscle effects

- Modest relaxation of skeletal muscle
- Enhancement of the action of nondepolarizing skeletal muscle
relaxants

Cardiovascular effects
- Direct depression of myocardial contractility and rate
- Increase in cardiac automaticity
- 5-10% reduction of cardiac output
- Sensitization of myocardium to catecholamines
- Little changes in total peripheral resistance
- Decreased brain vascular resistance
- Reduction of blood pressure due mainly to:
a) reduced cardiac output
b) impairment of normal baroreceptor response

Respiratory effects
- Decrease in tidal volume
- Increase in respiratory rate
- Decrease in minute ventilation (the increased rate cannot compensate
for the decreased tidal volume)
- Ventilatory response to CO2 is decreased
- Ventilatory response to hypoxia is decreased
[all these effects can be overcome by assisting the ventilation]
- Bronchodilation
- Depression of mucociliary clearance

Gastrointestinal effects
- Postoperative nausea and vomiting (. 15%)

Urogenital effects
- Decreased renal blood flow
- Decreased glomerular filtration rate
- Pronounced relaxation of the uterus

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M. Babbini, MD, PhD General Anesthetics

HALOTHANE HEPATITIS
Occurrence
- It is very low (1:35000), but the risk seems to increase after repeated
exposures.

Etiology
- Halothane is partially (. 30%) metabolized to trifluoroacetic acid,
bromide and chloride ions, which have been implicated as causative
factors in halothane hepatitis.

Pathogenesis
- The mechanism of hepatotoxicity remains obscure. Two hypotheses
are :
1) an allergic reaction (an immune response to certain
fluoroacetylated liver enzymes) .
2) an idiosyncratic reaction (a genetically determined defect in
hepatic cell membranes that make these cells more susceptible to
halothane-induced injury).

Pathology
- The syndrome is histologically indistinguishable from viral hepatitis.

Symptoms and signs

- Anorexia, nausea and vomiting, fever.

Clinical course and prognosis

-The syndrome typically starts 3-5 days after anesthesia and may
progress to hepatic failure. The prognosis is poor (death occurs in .
50% of these patients).

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M. Babbini, MD, PhD General Anesthetics

ISOFLURANE PHARMACOLOGY
Chemistry
-A halogenated ether, volatile liquid at room temperature.

PHARMACODYNAMICS
[most effects are concentration dependent, that is they increase as the partial
pressure in the target tissue increases]

Nervous system effects

- Medium induction and recovery (if given alone)
- Partial loss of nociceptive reflexes
- Good postoperative amnesia

Skeletal muscle effects

- Good relaxation of skeletal muscle
- Enhancement of the action of nondepolarizing skeletal muscle
relaxants.
Cardiovascular effects
- Reflex increase in cardiac rate
- Cardiac automaticity is not affected
- Cardiac output is well maintained
- Decreased total peripheral resistance
- Decreased brain vascular resistance
- Reduction of blood pressure (due mainly to the decrease in TPR)

Respiratory effects
- Decrease in tidal volume
- No change respiratory rate
- Minute ventilation is decreased
- Ventilatory response to CO2 is decreased
- Ventilatory response to hypoxia is decreased
[all these effects are lessened by surgical stimulation and can be
overcome by assisting the ventilation]
- Bronchodilation
- Depression of mucociliary clearance

Gastrointestinal effects
- Postoperative nausea and vomiting (. 15%)

Urogenital effects
- Decreased renal blood flow
- Decreased glomerular filtration rate
- Pronounced relaxation of the uterus

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M. Babbini, MD, PhD General Anesthetics

PHARMACOLOGY OF SEVOFLURANE
- Sevoflurane is a halogenated anesthetic that resembles isoflurane in
most of its pharmacological properties. The main difference is the more
rapid induction and recovery (blood/gas partition coefficient is 0.69)

- Sevoflurane comes close to have the characteristic of an ideal

inhaled anesthetic. (its potential nephrotoxicity due to some
degradation product is not supported by large clinical studies)

MALIGNANT HYPERTHERMIA
Occurrence: is very low (1:20000)

Etiology
- General anesthesia with all halogenated anesthetics, especially
when supplemented with depolarizing muscle relaxants seems to be the
causative factor.

Pathogenesis
- Malignant hyperthermia is an autosomal dominant disorder (a mutation
in the gene encoding the skeletal muscle ryanodine receptor) which
arises from a stimulus-elicited excessive release of CA++ from the
sarcoplasmic reticulum.

Symptoms and signs

- Hyperthermia, muscular rigidity, acidosis, tachycardia and shock.
- Hyperkalemia, hypercalcemia and myoglobinuria usually occur.
- Creatinine kinase levels are hugely elevated.

Clinical course and prognosis

- The syndrome can start during surgery or few days later, progresses
rapidly and can be fatal (death occurs in 10-20% of these patients).
Therapy
- Dantrolene is the drug of choice

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M. Babbini, MD, PhD General Anesthetics

NITROUS OXIDE PHARMACOLOGY

Chemistry
- A gas (N2 O) without odor or taste.
- Blood/gas partition coefficient = 0.47

Mechanism of action
- Nitrous oxide is a potent and selective inhibitor of NMDA activated
current, suggesting that its CNS depressants effects are produced via a
non competitive antagonistic activity at NMDA receptors.

Nervous system effect

-The MAC is >100%, therefore surgical anesthesia can be reached only
when is administered under hyperbaric conditions.
.- Induction and recovery are very rapid
- Postsurgical amnesia is incomplete
- When given in subanesthetic doses:
euphoria is usually present,
analgesia is very good with 20% concentration

Skeletal muscle effects

- Negligible effects on skeletal muscle tone.
- No interaction with nondepolarizing skeletal muscle relaxants

Cardiovascular Effects
Direct depressant effect on the heart are counteracted by a
sympathetic stimulation. Therefore:

- No change or increase in heart rate.

- No effect on cardiac automaticity.
- Negligible effects on cardiac output and blood pressure.

Respiratory effects
- Respiration is well maintained
- Respiratory depressant effects of other anesthetics are enhanced.

Gastrointestinal effects
- Postoperative nausea and vomiting (. 15%)

Other effects
- Megaloblastic anemia (after prolonged exposure, due to oxidation of
the cobalt atom in Vit.B12)
-Increased incidence of spontaneous abortion after long term-exposure
of subanesthetic doses.

Clinical uses
- As a sole agent to provide analgesia for dental procedures and minor
surgery.
- For general anesthesia, in combination with other inhalational
anesthetics (the drug substantially reduce the requirement for these
anesthetics, so allowing the use of lower concentrations).

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M. Babbini, MD, PhD General Anesthetics

COMPARATIVE PHARMACOLOGICAL PROPERTIES OF SOME

INHALED ANESTHETICS
Effect on Halothane Isoflurane N2 O
CNS
-Analgesia Incomplete Incomplete Very good
Heart
-contractility ú 0 0,ü
-frequency ú ü ü
-automaticity ü 0 0
-cardiac output ú 0 0
-sensitization to catecholamines Yes Yes No
Total peripheral resistance 0 ú 0,ü
Blood pressure úú ú 0
Baroreceptor reflex ú ú 0
Respiration ú úú 0
Cerebral blood flow üü ü 0,ü
Renal blood flow ú ú 0,ú
Skeletal muscle tone ú úú 0
Uterine tone ú ú 0
Nausea and vomiting ü ü ü
ü = increased ; ú = decreased ; 0 = negligible effect

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M. Babbini, MD, PhD General Anesthetics

INTRAVENOUS ANESTHETICS: BARBITURATES

Drugs
Thiopental sodium is the agents most commonly used.

Mechanism of action
- Facilitation of GABA-mediated inhibition at GABA-A receptors
(opening of Cl- channels is prolonged by GABA action)
- Direct opening of Cl- channels (at high doses).

Nervous system effects

- Following a standard IV dose:
unconsciousness occurs in 10-20 sec.
recovery occurs15-20 minutes (due to the redistribution process)
- Inhibition of sensory and autonomic reflexes (including nociceptive
reflexes) is negligible
- Therefore choreiform movements, vocalization and sympathetic
responses can occur in response to surgery.

Skeletal muscle effects

- Negligible effects on skeletal muscle tone

Cardiovascular effects
- Dose-dependent decrease in cardiac contractility
- Dose dependent decrease in total peripheral resistance.
(The above mentioned action cause a dose dependent decrease in
cardiac output and blood pressure)
- Brain blood flow is decreased
- Intracranial pressure is markedly reduced

Respiratory effects
- Dose-dependent depression of the respiratory center can be marked
and can cause a decrease in:
a) minute ventilation;
b)ventilatory response to CO2 ;
c) ventilatory response to hypoxia
- Coughing, bronchospasm and laryngospasm can occur (the basis of
these reactions is unknown)

Gastrointestinal effects
- Postanesthetic nausea and vomiting is . 15%
- Induction of P450 system in the liver

Other effects
- Anaphylactoid reaction (due to histamine release)

Use in anesthesia
- As a sole agent in case of short surgery.
- For induction of anesthesia, in combination with inhaled anesthetics.

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M. Babbini, MD, PhD General Anesthetics

INTRAVENOUS ANESTHETICS: PROPOFOL

Mechanism of action
- The same as that of thiopental.

Central nervous system effects

- Following a standard IV dose:
unconsciousness occurs in 10-20 seconds
recovery occurs in about 2 minutes (due to the redistribution
process and to its half life of about 10 minutes)
- Inhibition of sensory reflexes (including nociceptive reflexes) is
negligible
- Therefore choreiform movements, vocalization and sympathetic
responses can occur in response to surgery.

Skeletal muscle effects

- Negligible effects on skeletal muscle tone.

Cardiovascular effects
- Dose-dependent decrease in TPR.
- Dose dependent decrease in blood pressure (greater than with
thiopental).
- Brain blood flow is decreased and intracranial pressure is markedly
reduced.

Respiratory effects
- Dose-dependent depression of the respiratory center can be marked.
- Bronchospasm is negligible

Gastrointestinal effects
- Pronounced antiemetic activity.

Other effects
-Anaphylactoid reaction
-Propofol infusion syndrome (metabolic acidosis, hyperlipidemia,
rhabdomyolysis). It is rare, but can be fatal.
Use in anesthesia
- The drug is the most commonly used parenteral anesthetic in the U.S.
- Used as a sole agent in case of short surgery.
- For induction of anesthesia, in combination with inhaled anesthetics.
- Sometimes used to obtain prolonged sedation in critically ill patients.

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M. Babbini, MD, PhD General Anesthetics

MINOR INTRAVENOUS ANESTHETICS: ETOMIDATE

Mechanism of action
-Facilitation of GABA-mediated inhibition at GABA-A receptors.

Central nervous system effects

Following a standard IV dose:
- Unconsciousness occurs in 10-20 seconds
- Recovery occurs in about 3-5 minutes (due to the redistribution
process)
- Inhibition of sensory reflexes (including nociceptive reflexes) is
negligible
.- Involuntary movements (myoclonus) occur in .40% of patients

Skeletal muscle effects

- Negligible effects on skeletal muscle tone.
Cardiovascular effects
- Heart rate and cardiac output are well maintained.
- Blood pressure is normal or slightly reduced

Respiratory effects
- Respiration is minimally affected.

Gastrointestinal effects
- Postanesthetic nausea and vomiting occur in > 30% of patients

Other effects
-Inhibition of adrenal steroid synthesis (it can cause adrenal
insufficiency in patient at risk)

Use in anesthesia
- Used as a sole agent in case of short surgery.
- For induction of anesthesia mainly in patients with serious
cardiovascular disease.

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M. Babbini, MD, PhD General Anesthetics

MINOR INTRAVENOUS ANESTHETICS: KETAMINE

Mechanism of action
- Blockade NMDA-type glutamate receptors (the mechanism is quite
similar to that of the psychedelic drug phencyclidine)

Central nervous system effects

- The drug induces a cataleptic state of immobility without loss of
consciousness, accompanied by very profound analgesia, open eyes,
nystagmus, mydriasis, salivation and spontaneous limb movements.
The state has been called dissociative anesthesia.
- Anterograde amnesia is present.
- Postoperative delusions and hallucinations (so called emergence
phenomena) occur in . 30% of adult patients.
- Flash-backs (hallucinations can recur weeks later)

Skeletal muscle effects

- Overall muscle tone is increased (catatonia can occur)

Cardiovascular effects
- Increased heart rate, cardiac output and blood pressure
- Increased intracranial pressure.
(all these effects are due to central sympathetic stimulation)

Respiratory effects
- Respiration is well maintained

Gastrointestinal effects
- Postoperative nausea and vomiting (. 15%)

Use in anesthesia
- In high-risk patients or patients with shock
- In young children
- Low doses (in combination with other anesthetics) as an alternative to
opioids, to achieve pronounced analgesia without respiratory
depression.

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M. Babbini, MD, PhD General Anesthetics

COMPARATIVE PHARMACOLOGICAL PROPERTIES OF SOME

INTRAVENOUS ANESTHETICS
Effects Thi. Pro. Eto. Ket.
CNS
-Analgesia 0 0 0 very good
Heart
-contractility ú ú 0 0,ü
-frequency 0,ü 0 0 ü
-automaticity 0,ü 0 0 ü
-cardiac output ú ú 0 ü
-sensitization to catecholamines No No No No
TPR ü úú 0 ü
Blood pressure ú úú 0,ú ü
Baroreceptor reflex 0 0 0 0
Respiration úú úú 0 0
Cerebral blood flow ú ú ú üü
Intracranial pressure úú ú ú 0,ü
Renal blood flow ú ú 0 0
Skeletal muscle tone 0 0 0 ü
Uterine tone 0 0 0 0
Nausea and vomiting ü ú üü ü
Thi = Thiopental ; Pro = Propofol ; Eto = Etomidate ; Ket = Ketamine
ü = increased
ú = decreased
0 = negligible effect

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M. Babbini, MD, PhD General Anesthetics

BENZODIAZEPINES AS GENERAL ANESTHETIC DRUGS

Drugs
-Certain benzodiazepines (e.g. diazepam, lorazepam, midazolam) are
used in anesthetic procedures.

Mechanism of action
- Neurophysiological: increased activity of small inhibitory GABAergic
neurons in several brain areas
- Molecular: facilitation of GABA-mediated inhibition at GABA-A
receptors (the frequency of opening of Cl- channels is increased by
facilitating GABA action)

Nervous system effects

- Following a 70 mg IV dose of diazepam drowsiness occurs in 2-3
minutes, but a complete unconsciousness is not achieved
- Recovery from drowsiness is slow
- Anterograde amnesia occurs in > 50% of patients (likely due to
impairment of hippocampal function)
- Analgesic effect is negligible.

Effects on other organs

- Respiration and circulation are only moderately depressed, but
cardiovascular and respiratory depression produced by other drugs are
enhanced

- Skeletal muscle tone is moderately reduced by a centrally mediated

action. The effect of curare-like drugs is not modified.

- Renal and hepatic function are not affected.

-Postoperative nausea and vomiting are rare.

Use in anesthesia
- As adjuvant agents during surgical procedures performed under local
anaesthesia.
- For induction of anesthesia, in combination with inhaled anesthetics
(but propofol and thiopental il largely preferred)
- In the preanesthetic medication (they are considered drugs of choice
because of their anxiolytic, sedative and amnestic properties).

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M. Babbini, MD, PhD General Anesthetics

OPIOIDS AS GENERAL ANESTHETIC DRUGS

Drugs
- Morphine, fentanyl, sulfentanil, alfentanil

Central nervous system effects

In some situations very large dose of opioids may be infused to obtain
anesthesia.
- Large IV doses of morphine or fentanyl administered slowly induce
unconsciousness and profound analgesia.
- With fentanyl unconsciousness occurs in 10-20 seconds and returns
in about 30 minutes (due to a redistribution process).
- Anterograde amnesia is negligible and postoperative recall of
events may occur.

Cardiovascular effects
- Cardiovascular system is moderately depressed with morphine (due
to histamine release) and unaffected by fentanyl and congeners.

Skeletal muscle effects

- Rigidity of respiratory muscle may be prominent and administration of
a muscle relaxant may be necessary to permit artificial respiration.

Respiratory effects
- Respiration is severely depressed and ventilation must be
mechanically controlled.

Gastrointestinal effects
- Postoperative nausea and vomiting are frequent

Use in anesthesia
- They are used (often together with nitrous oxide) in cardiac surgery or
for surgery in patients with very serious cardiac disease.
- They are used widely to provide relief from pain during general
anesthesia of all types.
- They are frequently used as preanesthetic medication in order to
decrease pain-anticipatory anxiety.

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M. Babbini, MD, PhD General Anesthetics

CONSCIOUS SEDATION
- Conscious sedation refers to a state of altered consciousness
induced by drugs with the following features:

1) Consciousness is not lost (patient can respond to verbal commands)

2) A patent airway is maintained (patient do not have to be ventilated)
3) Cardiovascular effects are generally not marked.
4) Anxiety is alleviated
5) Pain is relieved.
6) Some degree of anterograde amnesia is present.

- The technique typically involve the use of one or more parenteral

anesthetic agents given IV injection of infusion.

- A wide variety of IV anesthetic agents (benzodiazepines, etomidate,

propofol, opioids, ketamine) have been used. Benzodiazepines and
opioids have the advantage that their effects can be easily reversed by
the use of specific receptor antagonists.

- When a potent opioid (fentanyl) is combined with a potent neuroleptic

compound (droperidol) the conscious sedation is called
neuroleptanalgesia. This is a state of quiescence due mainly to
indifference to the surrounding, accompanied by profound analgesia.

- Neuroleptanalgesia can be converted to neuroleptanesthesia by the

concurrent administration of 65-70% of nitrous oxide

- Conscious sedation can be used for many diagnostic and minor

surgical procedures.

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M. Babbini, MD, PhD General Anesthetics

THE MODERN BALANCED GENERAL ANESTHESIA

Phases Drugs
Preanesthetic -Diazepam, lorazepam
care -Chlorpromazine, haloperidol
-Atropine
-Morphine, meperidine

Induction of -Thiopental (propofol or etomidate or midazolam

anesthesia may be alternative drugs)

followed by

-one or two inhaled anesthetics (loading dose)

Maintenance of - One or two inhaled anesthetics (maintenance

anesthesia dose)

-Adjuvant drugs (neuromuscular blocking agents,

opioids)
Postanesthetic To prevent nausea and vomiting
care
- Serotonin antagonists (ondansetron)
- Glucocorticoids (dexamethasone)

To allay pain

- Opioids
- Analgesic antipyretics
To reduce gastric acidity and prevent
aspiration pneumonia
- Proton pump inhibitors (omeprazole)

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M. Babbini, MD, PhD General Anesthetics

General Anesthetics
(Practice questions)

Directions: 1-5
Match each anesthetic drug with the appropriate description (each lettered option can be
selected once, more than once, or not at all).

A) Halothane
B) Sevoflurane
C) Nitrous oxide
D) Thiopental
E) Propofol
F) Etomidate
G) Ketamine
H) Midazolam
I) Fentanyl
1) An halogenated anesthetic that causes fast induction and recovery

2) This drug can trigger an attack of acute porphyria in risk patients.

3) This drug has the highest incidence of postanesthetic nausea and vomiting.

4) This inhaled anesthetic substantially reduced the needed concentration of other inhaled
anesthetics given concomitantly

5) This drug causes a cataleptic state called dissociative anesthesia

6) New potential general anesthetics were tested in laboratory animals. The minimum
alveolar concentration (MAC) of each drug is reported in the table below:

Drug MAC
A 5.5
B 45.2
C 12.7
D 0.9
E 3.2

Which of the following drug has the highest potency?

A) Drug A
B) Drug B
C) Drug C

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M. Babbini, MD, PhD General Anesthetics
D) Drug D
E) Drug E

7) A 43-year-old man underwent surgery to remove a prostatic cancer. Sevoflurane was used
for general anesthesia. The drug has a minimum alveolar concentration (MAC) of 2.0. Which
of the following phrases best describes the MAC of an inhalational anesthetic?

A) The blood/gas partition coefficient of the anesthetic

B) The concentration of anesthetic needed for short surgery
C) The ED50 on a conventional quantal dose-response curve
D) The maximal efficacy of the anesthetic
E) The concentration of anesthetic in the inspired air

8) A 48-year-old woman underwent surgery to remove an uterine myoma. General anesthesia

was induced with propofol and maintained by sevoflurane and nitrous oxide. The blockade
of which of the following receptors most likely mediated the effectiveness of nitrous oxide in
this patient?
A) Nm cholinergic
B) Alpha-1 adrenergic
C) NMDA glutamatergic
D) GABAergic
E) 5-HT3 serotonergic

9) A 44-year-old man underwent surgery because of a prolapsed intervertebral disk. General

anesthesia was induced with propofol and maintained with sevoflurane. When
administration of sevoflurane was discontinued the patient regained consciousness in few
minutes. Which of the following statements best explains why sevoflurane caused a rapid
anesthetic recovery?

A) It redistributed rapidly to the lipid tissue

B) It is rapidly metabolized
C) It has a low MAC value
D) It has a low blood/gas partition coefficient
E) It concentrates mainly into the cerebral cortex

10) A 63-year-old woman underwent surgery to remove a vulvar cancer. The patient was a
heavy smoker and had been suffering from chronic obstructive pulmonary disease for 20
years. General Anesthesia was induced with propofol and maintained with sevoflurane.
Which of the following sevoflurane effects most likely occurred during surgery?

A) Decreased cardiac output

B) Increased ventilatory response to carbon dioxide
C) Bronchodilation
D) Increased skeletal muscle tone
E) Increased uterine tone

11) A 52-year-old woman underwent hysterectomy to remove an endometrial carcinoma.

Anesthesia was induced with thiopental and maintained with nitrous oxide and halothane.
Which of the following statements best explains why another anesthetic like halothane was

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M. Babbini, MD, PhD General Anesthetics
added to nitrous oxide ?

A) To achieve a more complete analgesia

B) To maintain unconsciousness and muscle relaxation
C) To prevent sensitization of the myocardium to catecholamines
D) To prevent anesthesia induced respiratory depression
E) To prevent post anesthetic nausea and vomiting

12) A 12-year-old was admitted to the hospital with the admitting diagnosis of acute
appendicitis. Family history of the patient indicated that his father underwent surgery few
years ago ad suffered a serious disorder just after the beginning of general anesthesia.
Further analysis indicated that the disorder was an inherited autosomal dominant disease.
Because of this the anesthesiologist avoided the use of halogenated anaesthetics in this
boy. Which of the following was most likely the disorder suffered by the patient’s father?

A) Acute intermittent porphyria

B) Malignant hyperthermia
C) Acute hepatitis
D) Hemolytic anemia
E) Myasthenia gravis

13) A 43-year-old woman underwent dilation and curettage because of an abnormal vaginal
bleeding. General anesthesia was performed with thiopental. The patient lost consciousness
in about 10 seconds and regained it 15 minutes later. Which of the following phrases best
explains why general anesthesia induced by a standard dose of thiopental lasts 5-15
minutes?

A) Slow distribution of the drug into the CNS

B) Fast elimination of the drug from the body
C) Redistribution of the drug into peripheral tissues
D) Rapid biotransformation of the drug by the brain
E) Poor diffusion of the drug into the central neurons

14) A 61-year-old man underwent surgery to remove a prostate cancer. An IV injection of

thiopental was performed and the patient lost consciousness in 10 seconds. Which of the
following mechanism of action most likely mediated the anesthetic effect of the drug?

A) Increased affinity of GABA for its GABA-A receptor

B) Enhancement of beta-carboline affinity for GABA-A receptor
C) Blockade of NMDA glutamate receptors in the CNS
D) Enhancement of Cl- channel opening in the absence of GABA
E) Activation of GABA-B receptors on presynaptic terminals

15) A 61-year-old woman underwent colonoscopy because of rectal bleeding. The woman
was very afraid of the procedure and asked for a general anesthesia. Since she had been
suffering from coronary artery disease for seven years, etomidate was chosen for
anesthesia. Which of the following effects most likely occurred in this patient during the
postanesthetic period?

A) Nausea and vomiting

B) Delusions

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M. Babbini, MD, PhD General Anesthetics
C) Respiratory depression
D) Increased blood pressure
E) Decreased heart rate

16) A 4-year-old girl, who had been suffering from asthma for six months, was scheduled for
a short suture procedure that was anticipated to take approximately 10 minutes. She was
brought to the operation room by her parents and was in distress over parting from them
and afraid of the doctors. Which of the following drugs would be appropriate for providing
sedation and analgesia to this girl?

A) Ketamine
B) Thiopental
C) Fentanyl
D) Halothane
E) Sevoflurane

17) A 49-year-old woman underwent abdominal surgery to remove a colon cancer. The
anesthesia was performed with thiopental, fentanyl and nitrous oxide. Which of the following
adverse effects was most likely to occur shortly after the recovery from anesthesia?

A) Watery diarrhea
B) Malignant hyperthermia
C) Hallucinations
D) Nausea and vomiting
E) Strong pain

18) A 52-year-old man underwent liver biopsy for a suspected liver cancer. Conscious
sedation was induced with a drug combination that has the advantage of being reversible by
the administration of specific receptor antagonists. Which of the following pairs of drugs
was most likely administered ?

A) Fentanyl and thiopental

B) Fentanyl and midazolam
C) Fentanyl and ketamine
D) Thiopental and midazolam
E) Thiopental and ketamine

19) A 57-year-old man was undergoing surgery to remove a kidney carcinoma. The
anesthesia was induced withy propofol, maintained with halothane, and supplemented by
succinylcholine. A few minutes into the operation the patient exhibited fever of 104° F,
skeletal muscle contracture, and profuse diaphoresis. His blood pressure dropped to 80/50
mm Hg and the heart rate was 125 bpm. Which of the following molecular actions best
explains the signs and symptoms of the patient?

A) Excessive release of acetylcholine from motor neuron terminals

B) Opening of K+ channels in skeletal muscle membrane
C) Excessive release of Ca++ from sarcoplasmic reticulum
D) Blockade of Ca++ channel in skeletal muscle membrane
E) Opening of Cl- channels in motor end plate
.

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M. Babbini, MD, PhD General Anesthetics

20) A 63-year-old man underwent surgery to remove a laringeal carcinoma. The man was an
heavy smoker and had been suffering from COPD for 15 years. General anesthesia was
induced by propofol and maintained by sevoflurane and nitrous oxide. A low dose of
ketamine was added to provide additional analgesia. The blockade of which of the following
receptors most likely mediated the therapeutic efficacy of ketamine in this patient?

A) Nm cholinergic
B) Alpha-1 adrenergic
C) NMDA glutamatergic
D) GABAergic
E) Endorphinergic

General Anesthetics
(Answers and explanations)

Directions: 1-5
Match each anesthetic drug with the appropriate description (each lettered option can be
selected once, more than once, or not at all).

A) Halothane
B) Sevoflurane
C) Nitrous oxide
D) Thiopental
E) Propofol
F) Etomidate
G) Ketamine
H) Midazolam
I) Fentanyl

1) An halogenated anesthetic that causes fast induction and recovery (B)

2) This drug can trigger an attack of acute porphyria in risk patients.(D)

3) This drug has the highest incidence of postanesthetic nausea and vomiting.(F)

4) This inhaled anesthetic substantially reduced the needed concentration of other inhaled
anesthetics given concomitantly (C)

5) This drug causes a cataleptic state called dissociative anesthesia (G)

6) Learning objective: explain the meaning of the minimum alveolar concentration (MAC) of
inhalational anesthetics
Answer: D
During general anesthesia the partial pressure of an anesthetic in the brain equal that in the lung
when equilibrium is reached. Therefore the measurement of the steady state alveolar concentration
of different anesthetic provides a measure of their relative potencies. The Minimum Alveolar

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M. Babbini, MD, PhD General Anesthetics
Anesthetic Concentration (MAC) is defined as the concentration of the anesthetic that results in the
immobility of 50% of patients when exposed to a noxious stimulus. Thus MAC represent the ED50
on a conventional quantal dose-response curve, and is therefore a measure of the potency of the
inhaled anesthetic. The lower the MAC, the higher the potency.
A, B, C, E) (see explanation above)

7) Learning objective: explain the meaning of the minimum alveolar concentration (MAC) of
inhalational anesthetics
Answer: C
The Minimum Alveolar Anesthetic Concentration (MAC) is defined as the concentration of the
anesthetic that results in the immobility of 50% of patients when exposed to a noxious stimulus.
Thus MAC represent the ED50 on a conventional quantal dose-response curve, and is therefore a
measure of the potency of the inhaled anesthetic.

8) Learning objective: explain the mechanism of action of nitrous oxide

Answer: C
Nitrous oxide is a potent and selective inhibitor of NMDA activated current, suggesting that its CNS
depressants effects are produced via a non competitive antagonistic activity at NMDA receptors
A, B, D, E) (see explanation above)

9) Learning objective: describe the relationship between blood/gas partition coefficient and speed
of induction and recovery from general anesthesia.
Answer: D
Sevoflurane has a blood/gas partition coefficient of 0.69. Since the speed of induction and
recovery of anesthesia is inversely proportional to the blood/gas partition coefficient, sevoflurane
causes a rapid anesthetic induction and recovery.
A) Redistribution can be a factor that speed up the recovery from anesthesia but sevoflurane has
low lipid solubility and therefore redistribution into lipid tissue is minimal.
B) Metabolism of sevoflurane is very low (about 3%).
C) The MAC of an inhalational anesthetic is a measure of the potency of the drug i.e. it is a
pharmacodynamic variable. The speed of induction is dependent upon pharmacokinetic variables.
E) Inhalational anesthetics distribute uniformly into the brain. They are not concentrated in a
specific region of the brain.

10) Learning objective: describe the pharmacological effects of isoflurane.

Answer: C
All halogenated anesthetics have bronchodilating properties, an effect of value in patients with
underlying airway problems, like in the present case.
A) Cardiac output is minimally affected by sevoflurane.
B, D, E) In fact sevoflurane has effects opposite to those listed.

11) Answer: B
Unconsciousness, which is usually achieved with thiopental, cannot be maintained with nitrous
oxide alone (the drug has a MAC higher than 100%) and therefore another potent anesthetic is
needed. Moreover nitrous oxide nas negligible effects on skeletal muscle tone and therefore an
halogenated anesthetic is given together, most of the time (all halogenated anesthetics cause
relaxation of skeletal muscle and enhance the effects of neuromuscular blocking agents).
A) Actually the nitrous oxide induced analgesia is excellent, even at low concentration of the gas.
C, D, E) Actually halothane can cause, not prevent, all these listed effects.

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M. Babbini, MD, PhD General Anesthetics
12) Learning objective: describe the anesthetic-induced malignant hypertermia.
Answer: B
In genetically susceptible patients, all halogenated anesthetics can trigger malignant hyperthermia,
a autosomal dominant disorder characterized by severe muscle contraction, rapid development of
hyperthermia and a massive increase in metabolic rate. The syndrome is frequently fatal.
A) Acute intermittent porphyria is an idiosyncratic disorder that can be triggered by barbiturates,
not by halogenated anesthetics.
C) Acute hepatitis is a rare disease that can be induced by halothane but not by other halogenated
anesthetics. Moreover it is not a genetic disorder.
D, E) These diseases are not genetically determined and are not induced by halogenated
anesthetics

13) Learning objective: explain the reason of the short duration of anesthesia induced by
thiopental.
Answer: C
Thiopental rapidly diffuses out of the brain and other highly vascularized tissues and is
redistributed to muscle, fat and eventually to all body tissues. This is the principal mechanism
limiting anesthetic duration after a single anesthetic dose.
A, E) Actually thiopental distributes very rapidly into the CNS. Since it is very lipid soluble, diffusion
into the CNS neurons is very good.
B, D) Thiopental half life is about 12 hours, which indicates that the elimination of the drug from the
body is very slow.

14) Learning objective: describe the mechanism of action of barbiturates.

Answer: D
All barbiturates increase the affinity of GABA for its GABA-A receptor but, unlike benzodiazepines,
they can enhance Cl- channel opening in the absence of GABA, when given at high doses. Since
the dose of thiopental was high enough to lose consciousness the mechanism of this action was
most likely an Enhancement of Cl- channel opening in the absence of GABA.
A, B, C, E) (see explanation above)

15) Learning objective: describe the pharmacological effects of etomidate.

Answer: A
Among general anesthetics etomidate is the drug with the highest incidence of postoperative
nausea and vomiting (>30% of cases).
B, C, D, E) Actually etomidate doesn’t cause delusion and provokes minimal cardiovascular and
respiratory depression.

16) Learning objective: outline the therapeutic uses of ketamine.

Answer: A
Ketamine is a general anesthetic that induces a state of sedation, characterized by immobility,
profound analgesia, anterograde amnesia and a strong feeling of dissociation from the
environment without complete loss of consciousness. This state has been termed dissociative
anesthesia. Since it can provoke postoperative disorientation, perceptual illusions and vivid
dreams, it is not commonly used in general surgery. The drug causes negligible respiratory
depression and significant sympathetic stimulation. It is used in case of short, painful procedures in
children (who are less involved in the mental effect of the drug) especially when they have
respiratory problems, like in the present case.
B, C) These drugs can cause significant respiratory depression
D, E) Halogenated anesthetics are not suitable for minor surgical procedures.

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M. Babbini, MD, PhD General Anesthetics

17) Learning objective: describe the adverse effects of general anesthesia

Answer: D
All the drugs used in the patient’s anesthetic protocol can cause postoperative nausea and
vomiting by an action on the chemoreceptor trigger zone and on the brainstem vomiting center. The
incidence of vomiting in the postoperative period with these drugs is about 15%.
A) Opioids actually tend to cause constipation
B) Halogenated anesthetic can very rarely cause malignant hyperthermia
C) Ketamine is the only anesthetic agent that has been associated with postoperative perceptual
illusion and hallucinations.
E) Postoperative strong pain is quite unlikely when a strong opioid like fentanyl has been used in
the anesthetic protocol.

18) Learning objective: describe the drug used for conscious sedation that have the advantage of
being reversible by the administration of specific receptor antagonists.
Answer: B
Conscious sedation refers to a drug-induced state of altered consciousness with the following
features:
-Consciousness is not lost (patient can respond to verbal commands)
-A patent airway is maintained (patient do not have to be ventilated)
-Cardiovascular effects are generally not marked.
-Anxiety is alleviated
-Pain is relieved.
-Some degree of anterograde amnesia is present.
A wide variety of IV anesthetic agents (benzodiazepines, propofol, opioids) have been used.
Benzodiazepines and opioids have the advantage that their effects can be easily reversed by the
use of specific receptor antagonists (flumazenil and naloxone).
A, C, D, E) There are not specific antagonists for thiopental and ketamine

19) Learning objective: describe the pathophysiology of malignant hyperthermia.

Answer: C
The signs of the patient strongly suggest that he was suffering from malignant hyperthermia, a rare
autosomal dominant disorder that can be triggered by the administration of halogenated
anesthetics and/or succinylcholine. The pathogenesis of the disease is thought to involve a
mutation in the gene encoding the skeletal muscle ryanodine receptor, a channel responsible for
the regulation of Ca++ release from the sarcoplasmic reticulum. This mutation would result in an
excessive release of CA++ which would be the main cause of the symptoms and signs of malignant
hyperthermia.
A, B, D, E) All these actions do not cause the syndrome exhibited by the patient.

20) Learning objective: explain the mechanism of action of ketamine

Answer: C
The mechanism of action of ketamine most likely involves a blockade of NMDA-type glutamate
receptors, a mechanism quite close to that of the psychedelic drug phencyclidine. In fact ketamine
itself has gained popularity as a drug of abuse (it is commonly known as “special K” or “K”).
A, B, D, E) (see explanation above)

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M. Babbini, MD, PhD General Anesthetics

GENERAL ANESTHETICS
Answer key
1) B 6) D 11) B 16) A
2) D 7) C 12) B 17) D
3) F 8) C 13) C 18) B
4) C 9) D 14) D 19) C
5) G 10) C 15) A 20) C

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