General anesthesia is a state of drug-

induced reversible inhibition of central

nervous function

Several categories of drugs are

combined to produce optimal
anesthesia
 Goals of surgical anesthesia
(Luellmann Color Atlas of Pharmacology 3rd ed, 2005)
 Inhaled
Anesthetics

Intravenous
Anesthetics
 Regimen for balanced anesthesia
(Luellmann Color Atlas of Pharmacology 3rd ed, 2005)
Facilitate smooth induction of anesthesia and lower
required anesthetic doses

H2 blockers
Benzodiazepines
Nonopioids or opioids
Antihistamines
Antiemetics
Anticholinergics
 Nonflammable, nonexplosive, and volatile
agents
Primarily for maintenance
Depth of anesthesia depend on
concentration of anesthetic in the CNS
The principal objective of inhalation
anesthesia is a constant and optimal brain
partial pressure (Pbr) of inhaled anesthetic
(partial pressure equilibrium between
alveoli [Palv] and brain [Pbr])
Concentration of anesthetic in the brain is
reached depends on:
Solubility properties of the anesthetic
Concentration in the inspired air
Pulmonary ventilation rate
Pulmonary blood flow
Partial pressure gradient of the
anesthetic between arterial and mixed
venous blood
Why induction of anesthesia is slower with more soluble anesthetic gases
(Katzung Basic & Clinical Pharmacology 9th ed)
 Properties of Inhaled Anesthetics
(Katzung Basic & Clinical Pharmacology 9th ed)
Ventilation rate and arterial anesthetic tensions. Increased ventilation (8 versus 2
L/min) has a much greater effect on equilibration of halothane than nitrous
oxide (Katzung Basic & Clinical Pharmacology 9th ed)
 The minimal alveolar concentration
(MAC) at which 50% of patients remain
immobile following a defined painful
stimulus (skin incision)
MAC is small for potent anesthetics such
as sevoflurane and large for less potent
agents such as nitrous oxide
 Inhaled anesthetics that are relatively
insoluble are eliminated at faster rates
than more soluble anesthetics
The duration of exposure to the
anesthetic can also have a marked
effect on the time of recovery
Clearance of inhaled anesthetics by the
lungs into the expired air is the major
route of their elimination from the body
 Elimination routes of different volatile anesthetics
(Luellmann Color Atlas of Pharmacology 3rd ed, 2005)

The extent of metabolism of inhaled anesthetics, the rank order

is: methoxyflurane > halothane > enflurane > sevoflurane >
isoflurane > desflurane > nitrous oxide (not metabolized)
 No specific receptor has been identified
Variety of molecular mechanisms may
contribute to the activity of general
anesthetics
General anesthetics increase the
sensitivity of the -aminobutyric acid
(GABAA) receptors to the inhibitory
neurotransmitter GABA
 An example of modulation of a ligand-gated membrane channel
modulated by inhaled anesthetics(Lippincot Illustrated Reviews 6th ed, 2015).
 These channels are ubiquitous in the CNS
and are linked to several
neurotransmitters (Ach, dopamine,
norepinephrine, and serotonin)
Nitrous oxide and ketamine inhibition
of the N-methyl-d-aspartate (NMDA)
receptors antagonism of the action of
the excitatory neurotransmitter glutamic
acid
 Potent anesthetic but a relatively weak
analgesic
PK oxidatively metabolized in the
body to tissue-toxic hydrocarbons and
bromide ion fever, followed by
anorexia, nausea, and vomiting, and
possibly signs of hepatitis
 Cardiac arrhythmias, concentration-
dependent hypotension
Hepatotoxicity formation of reactive
metabolites that either cause direct
hepatocellular damage
Malignant hyperthermia th/
dantrolene
 Not toxic to the liver or kidney
Does not induce cardiac arrhythmias or sensitize the heart
to catecholamines
Dose-dependent hypotension
Isoflurane Pungent odor and stimulates respiratory reflexes

Anesthetic for outpatient procedures

Stimulates respiratory reflexes
Relatively expensive
Desflurane
 Low pungency, without irritating the airways
suitable for inhalation induction
Sevoflurane Low blood solubility
Met by the liver

Nonirritating potent analgesic, but a weak

Nitrous general anesthetic
Alone cannot produce surgical anesthesia
oxide combined with other more potent agents
Probably the safest of these anesthetics
 Cause rapid induction often occurring
within one armbrain circulation time
Have an onset of anesthetic action
faster than the fastest of the inhaled
gaseous
May be used as sole agents for short
procedures or administered as infusions
to help maintain anesthesia during
longer cases
 Induction unbound, lipid-soluble,
nonionized molecules cross into the brain
most quickly
The exact MoA of IV anesthetics is
unknown
Recovery from IV anesthetics is due to
redistribution from sites in the CNS
 Termination of drug effect by redistribution
(Luellmann Color Atlas of Pharmacology 3rd ed, 2005)
 When CO is reduced, the body
compensates by diverting more CO to
the cerebral circulation
Decreased CO causes prolonged
circulation time
The slow titration of a reduced dose of an
IV anesthetic is key to a safe induction in
patients with reduced CO
Propofol Barbiturates Benzodiazepines

Opioids Etomidate Ketamine

Dexmedetomidine
 IV sedative/hypnotic used for induction
and/or maintenance of anesthesia
Widely used and has replaced thiopental
as the first choice for induction of general
anesthesia and sedation
PKs distribution half-life is 28 minutes; the
elimination half-life is approximately 3060
minutes, rapidly met in the liver, excr in the
urine as glucuronide and sulfate conjugates
 Induction is smooth and occurs 30-40 s
after adm, rapid equilibration between
the plasma and brain, plasma levels
decline rapidly as a result of redistribution
CNS, BP without myocardium
Does not provide analgesia
The incidence of postoperative nausea
and vomiting is very low
 Characteristics of Some Intravenous Anesthetics

Drugs Action Effect

Barbiturates Thiopental, Ultrashort-acting, Potent anesthetic
methohexital high lipid solubility but a weak
analgesic
Benzodiazepines Midazolam, GABA Anterograde
diazepam, amnesia while
lorazepam causing sedation
Opioids Fentanyl, Analgesic
sufentanil,
remifentanil
Etomidate Rapid, short-acting, Hypnotic, lacks
little to no effect on analgesic activity
the heart and
circulation
Ketamine Short-acting, BP and Analgesia, sedation,
CO, bronchodilator amnesia, immobility
Dexmedetomidine 2 receptor agonist in Sedative, analgesic,
certain parts of the sympatholytic, and
brain anxiolytic
effects
 Characteristics of Some Intravenous Anesthetics

PKs AEs

Barbiturates Remain in the body Apnea, coughing, chest wall

for long periods spasm, laryngospasm, and
Met by the liver bronchospasm
Benzodiazepines Met by the liver Minimal cardiovascular depressant,
potential respiratory depressants
Opioids Adm intravenously, Hypotension, respiratory
epidurally, or depression, muscle rigidity,
intrathecally postanesthetic nausea and
vomiting
Etomidate Decreased plasma cortisol and
aldosterone levels
Ketamine Lipophilic and enters Hallucinations
the brain very quickly
Dexmedetomidine
 Abolish reflexes to facilitate tracheal
intubation and provide muscle
relaxation
MoA blockade of nicotinic
acetylcholine receptors in the
neuromuscular junction
Cisatracurium, pancuronium,
rocuronium, succinylcholine, and
vecuronium
 )

Mode of action of muscle relaxants

(A Textbook of Clinical Pharmacology and Therapeutics, 2008)
 Mechanism of action of non-depolarizing and depolarizing
neuromuscular-blocking drugs (Lippincot Illustrated Reviews 6th ed, 2015).
 Lippincott Illustrated Reviews:
Pharmacology. 6th ed. 2015.
Betram G. Katzung Basic & Clinical
Pharmacology. 9th ed.
A Textbook of Clinical Pharmacology
and Therapeutics. 5th ed. 2008.
Luellmann Color Atlas of
Pharmacology. 3rd ed. 2005.
End.
THX U