General Anesthetics

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General Anesthetics

• Chapter 25

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Isoflurane

• Chemistry and Physical Properties. Isoflurane
  (FORANE, others) is 1-chloro-2,2,2-trifluoroethyl
  difluoromethyl ether. It is a volatile liquid at
  room temperature and is neither flammable nor
  explosive in mixtures of air or
  oxygen.Pharmacokinetics. Isoflurane has a
  bloodgas partition coefficient substantially
  lower than that of halothane or enflurane.
  Consequently, induction with isoflurane and
  recovery from isoflurane are relatively rapid.
  Changes in anesthetic depth also can be achieved
  more rapidly with isoflurane than with halothane
  or enflurane. More than 99 of inhaled isoflurane
  is excreted unchanged via the lungs.
  Approximately 0.2 of absorbed isoflurane is
  oxidatively metabolized by CYP2E1. The small
  amount of isoflurane degradation products
  produced is insufficient to produce any renal,
  hepatic, or other organ toxicity. Isoflurane does
  not appear to be a mutagen, teratogen, or
  carcinogen.Clinical Use. Isoflurane is a
  commonly used inhalational anesthetic worldwide.
  It is typically used for maintenance of
  anesthesia after induction with other agents
  because of its pungent odor, but induction of
  anesthesia can be achieved in less than 10
  minutes with an inhaled concentration of 3
  isoflurane in O2 this concentration is reduced
  to 1 to 2 for maintenance of anesthesia. The
  use of other drugs such as opioids or nitrous
  oxide reduces the concentration of isoflurane
  required for surgical anesthesia.

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Isoflurane

• Cardiovascular System
• Cardiac output is well maintained
• Decreased systemic vascular resistance
• Coronary steal
• Compensatory mildly elevated heart rate
• Rapid increase
• Sympathetic stimulation
• Tachycardia and hypertension

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Isoflurane

• Respiratory System
• Concentration-dependent depression of ventilation
• Normal respiration rate but a reduced tidal
  volume
• Reduced alveolar ventilation and increased
  arterial CO2
• Depressed response to hypercapnia and hypoxia
• Bronchodilator
• Airway irritant
• Can stimulate airway reflexes during induction of
  anesthesia, producing coughing and laryngospasm.

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Isoflurane

• Nervous System
• Dilates cerebral vasculature
• Less than enflurane or halothane
• Increased intracranial pressure
• Hyperventilation to reduce
• Does not have to be prophylaxis, unlike halothane
• Reduced O2 consumption
• Muscle
• Relaxation
• Enhances depolarizing and nondepolarizing muscle
  relaxants
• More potent than halothane in potentiation of
  neuromuscular blocking agents
• Relaxes uterine smooth muscle
• Not recommended for analgesia or anesthesia for
  labor and vaginal delivery

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Isoflurane

• Kidney
• Reduced renal blood flow and glomerular
  filtration rate
• Small volume of concentrated urine
• Rapidly reversed
• No long-term renal sequelae or toxicities
• Liver and Gastrointestinal Tract
• Concentration dependent splanchnic and hepatic
  blood flow reduction
• LFTs minimally affected by isoflurane
• No reported incidence of hepatic toxicity

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Enflurane

• Chemical and Physical Properties. Enflurane
  (ETHRANE, others) is 2-chloro-1,1,2-trifluoroethyl
  difluoromethyl ether. It is a clear, colorless
  liquid at room temperature with a mild, sweet
  odor. Like other inhalational anesthetics, it is
  volatile and must be stored in a sealed bottle.
  It is nonflammable and nonexplosive in mixtures
  of air or oxygen.Pharmacokinetics. Because of
  its relatively high bloodgas partition
  coefficient, induction of anesthesia and recovery
  from enflurane are relatively slow. Enflurane is
  metabolized to a modest extent, with 2 to 8 of
  absorbed enflurane undergoing oxidative
  metabolism in the liver by CYP2E1. Fluoride ions
  are a by-product of enflurane metabolism, but
  plasma fluoride levels are low and nontoxic.
  Patients taking isoniazid exhibit enhanced
  metabolism of enflurane with significantly
  elevated serum fluoride concentrations.Clinical
  Use. As with isoflurane, enflurane is primarily
  utilized for maintenance rather than induction of
  anesthesia.

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Enflurane

• Cardiovascular System
• Concentration dependent hypotension
• Depressed myocardial contractility
• Peripheral vasodilation
• Minimal effect on heart rate
• Neither the bradycardia seen with halothane nor
  the tachycardia seen with isoflurane

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Enflurane

• Respiratory System
• Similar to halothane
• Rapid, shallow breathing
• Minute ventilation decreased
• PaCO2 of 60 mm Hg with 1 MAC
• Greater depression of the ventilatory responses
  to hypoxia and hypercarbia than halothane or
  isoflurane
• Bronchodilator

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Enflurane

• Nervous System
• Cerebral vasodilator
• Increase intracranial pressure
• Reduced cerebral O2 consumption
• Produces electrical seizure activity
• High concentrations or profound hypocarbia result
  in EEG changes
• Seizure activity may be accompanied by peripheral
  motor manifestations of seizure activity
• Self-limited
• Not thought to produce permanent damage
• Epileptic patients are not particularly
  susceptible
• Generally is not used in patients with seizure
  disorders.

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Enflurane

• Muscle
• Skeletal muscle relaxation
• Enhances the effects of nondepolarizing muscle
  relaxants
• Relaxes uterine smooth muscle
• Not widely used for obstetric anesthesia

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Enflurane

• Kidney
• Reduced renal blood flow, glomerular filtration
  rate, and urinary output
• Rapidly reversed upon drug discontinuation
• High plasma levels of fluoride ions (20 to 40
  mmol) and can produce transient
  urinary-concentrating defects following prolonged
  administration
• Scant evidence of long-term nephrotoxicity
• Safe in renal impairment, provided that the depth
  of enflurane anesthesia and the duration of
  administration are not excessive
• Liver and Gastrointestinal Tract
• Reduces splanchnic and hepatic blood flow
• Does not appear to alter liver function or to be
  hepatotoxic

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Desflurane

• Chemistry and Physical Properties. Desflurane
  (SUPRANE) is difluoromethyl 1-fluoro-2,2,2-trifluo
  romethyl ether. It is a highly volatile liquid at
  room temperature (vapor pressure 681 mm Hg) and
  thus must be stored in tightly sealed bottles.
  Delivery of a precise concentration of desflurane
  requires the use of a specially heated vaporizer
  that delivers pure vapor that then is diluted
  appropriately with other gases (O2, air, or N2O).
  Desflurane is nonflammable and nonexplosive in
  mixtures of air or oxygen.Pharmacokinetics.
  Desflurane has a very low bloodgas partition
  coefficient (0.42) and also is not very soluble
  in fat or other peripheral tissues. For this
  reason, the alveolar (and blood) concentration
  rapidly rises to the level of inspired
  concentration. Indeed, within five minutes of
  administration, the alveolar concentration
  reaches 80 of the inspired concentration. This
  provides for a very rapid induction of anesthesia
  and for rapid changes in depth of anesthesia
  following changes in the inspired concentration.
  Emergence from anesthesia also is very rapid with
  desflurane. The time to awakening following
  desflurane is half as long as with halothane or
  sevoflurane and usually does not exceed 5 to 10
  minutes in the absence of other sedative
  agents.Desflurane is metabolized to a minimal
  extent, and more than 99 of absorbed desflurane
  is eliminated unchanged via the lungs. A small
  amount of absorbed desflurane is oxidatively
  metabolized by hepatic CYPs. Virtually no serum
  fluoride ions are detectable in serum after
  desflurane administration, but low concentrations
  of trifluoroacetic acid are detectable in serum
  and urine.

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Desflurane

• Clinical Use. Desflurane is a widely used
  anesthetic for outpatient surgery because of its
  rapid onset of action and rapid recovery. The
  drug is irritating to the airway in awake
  patients and can provoke coughing, salivation,
  and bronchospasm. Anesthesia therefore usually is
  induced with an intravenous agent, with
  desflurane subsequently administered for
  maintenance of anesthesia. Maintenance of
  anesthesia usually requires inhaled
  concentrations of 6 to 8. Lower concentrations
  of desflurane are required if it is
  coadministered with nitrous oxide or opioids.

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Desflurane

• Cardiovascular System
• Concentration dependent decrease in blood
  pressure
• Cardiac output well preserved as is blood flow to
  the major organ beds (splanchnic, renal,
  cerebral, and coronary)
• Increased heart rate often noted during induction
  and during abrupt increases
• Greater than Isoflurane
• Unlike some inhalational anesthetics, hypotensive
  effects do not wane with increasing duration of
  administration

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Desflurane

• Respiratory System
• Concentration-dependent increase in respiratory
  rate and decrease in tidal volume
• At low concentrations (less than 1 MAC) the net
  effect is to preserve minute ventilation
• Greater than 1 MAC minute ventilation is
  depressed
• Elevated arterial CO2 tension (PaCO2)
• Greater than 1.5 MAC will have extreme elevations
  of PaCO2, may become apneic
• Bronchodilator
• Strong airway irritant, can cause coughing,
  breath-holding, laryngospasm, and excessive
  respiratory secretions
• Because of its irritant properties, desflurane is
  not used for induction of anesthesia

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Desflurane

• Nervous System
• Decreases cerebral vascular resistance and
  cerebral metabolic O2 consumption
• Increased cerebral blood flow
• Increased intracranial pressure
• Hyperventilation to decrease

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Desflurane

• Muscle
• Direct skeletal muscle relaxation
• Enhanced effects of nondepolarizing and
  depolarizing neuromuscular blocking agents
• Kidney
• No reported nephrotoxicity
• Liver and Gastrointestinal Tract
• Not known to affect liver function tests or to
  cause hepatotoxicity

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Sevoflurane

• Chemistry and Physical Properties. Sevoflurane
  (ULTANE) is fluoromethyl 2,2,2-trifluoro-1-triflu
  oromethylethyl ether. It is a clear, colorless,
  volatile liquid at room temperature and must be
  stored in a sealed bottle. It is nonflammable and
  nonexplosive in mixtures of air or oxygen.
• Sevoflurane can undergo an exothermic reaction
  with desiccated CO2 absorbent (BARALYME) to
  produce airway burns or spontaneous ignition,
  explosion and fire. Care must be taken to ensure
  that sevoflurane is not used with an anesthesia
  machine in which the CO2 absorbent has been dried
  by prolonged gas flow through the absorbent.
  Sevoflurane reaction with desiccated CO2
  absorbent also can produce CO, which can result
  in serious patient injury.

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Sevoflurane

• Pharmacokinetics. The low solubility of
  sevoflurane in blood and other tissues provides
  for rapid induction of anesthesia, rapid changes
  in anesthetic depth following changes in
  delivered concentration, and rapid emergence
  following discontinuation of administration.Appro
  ximately 3 of absorbed sevoflurane is
  biotransformed. Sevoflurane is metabolized in the
  liver by CYP2E1, with the predominant product
  being hexafluoroisopropanol. Hepatic metabolism
  of sevoflurane also produces inorganic fluoride.
  Serum fluoride concentrations peak shortly after
  surgery and decline rapidly. Interaction of
  sevoflurane with soda lime also produces
  decomposition products. The major product of
  interest is referred to as compound A and is
  pentafluoroisopropenyl fluoromethyl ether (see
  Kidney, below).
• Clinical Use. Sevoflurane is widely used,
  particularly for outpatient anesthesia, because
  of its rapid recovery profile. It is well-suited
  for inhalation induction of anesthesia
  (particularly in children) because it is not
  irritating to the airway. Induction of anesthesia
  is rapidly achieved using inhaled concentrations
  of 2 to 4 sevoflurane.

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Sevoflurane

• Cardiovascular System
• Concentration dependent decrease in arterial
  blood pressure
• Systemic vasodilation
• Decrease in cardiac output
• Does not produce tachycardia
• May be a preferable agent in patients prone to
  myocardial ischemia

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Sevoflurane

• Respiratory System
• Concentration dependent reduction in tidal volume
  and increase in respiratory rate
• Reduction in minute ventilation and an increase
  in PaCO2
• Not irritating to the airway and is a potent
  bronchodilator
• Most effective clinical bronchodilator of the
  inhalational anesthetics

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Sevoflurane

• Nervous System
• Decreased cerebral vascular resistance
• Decreased cerebral O2 consumption
• Increased cerebral blood flow
• Increase intracranial pressure
• Prevented by hyperventilation
• Muscle
• Skeletal muscle relaxed
• Enhanced effects of nondepolarizing and
  depolarizing neuromuscular blocking agents.
• Similar to those of other halogenated
  inhalational anesthetics

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Sevoflurane

• Kidney
• Production of compound A
• May produce renal toxicity
• Large clinical studies have shown no evidence of
  increased serum creatinine, blood urea nitrogen
• The current recommendation of the FDA is that
  sevoflurane be administered with fresh gas flows
  of at least 2 L/min to minimize accumulation of
  compound A
• Liver and Gastrointestinal Tract
• Not known to cause hepatotoxicity or alterations
  of hepatic function tests.

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Nitrous Oxide

• Chemical and Physical Properties. Nitrous oxide
  (dinitrogen monoxide N2O) is a colorless,
  odorless gas at room temperature. It is sold in
  steel cylinders and must be delivered through
  calibrated flow meters provided on all anesthesia
  machines. Nitrous oxide is neither flammable nor
  explosive, but it does support combustion as
  actively as oxygen does when it is present in
  proper concentration with a flammable anesthetic
  or material.Pharmacokinetics. Nitrous oxide is
  very insoluble in blood and other tissues. This
  results in rapid equilibration between delivered
  and alveolar anesthetic concentrations and
  provides for rapid induction of anesthesia and
  rapid emergence following discontinuation of
  administration. The rapid uptake of N2O from
  alveolar gas serves to concentrate coadministered
  halogenated anesthetics this effect (the "second
  gas effect") speeds induction of anesthesia. On
  discontinuation of N2O administration, nitrous
  oxide gas can diffuse from blood to the alveoli,
  diluting O2 in the lung. This can produce an
  effect called diffusional hypoxia. To avoid
  hypoxia, 100 O2 rather than air should be
  administered when N2O is discontinued.Nitrous
  oxide is almost completely eliminated by the
  lungs, with some minimal diffusion through the
  skin. Nitrous oxide is not biotransformed by
  enzymatic action in human tissue, and 99.9 of
  absorbed nitrous oxide is eliminated unchanged.
  Nitrous oxide can be degraded by interaction with
  vitamin B12 in intestinal bacteria. This results
  in inactivation of methionine synthesis and can
  produce signs of vitamin B12 deficiency
  (megaloblastic anemia and peripheral neuropathy)
  following long-term nitrous oxide administration.
  For this reason, N2O is not used as a chronic
  analgesic or as a sedative in critical care
  settings.

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Nitrous Oxide

• Clinical Use. Nitrous oxide is a weak anesthetic
  agent and produces reliable surgical anesthesia
  only under hyperbaric conditions. It does produce
  significant analgesia at concentrations as low as
  20 and usually produces sedation in
  concentrations between 30 and 80. It frequently
  is used in concentrations of approximately 50 to
  provide analgesia and sedation in outpatient
  dentistry. Nitrous oxide cannot be used at
  concentrations above 80 because this limits the
  delivery of an adequate amount of oxygen. Because
  of this limitation, nitrous oxide is used
  primarily as an adjunct to other inhalational or
  intravenous anesthetics. Nitrous oxide
  substantially reduces the requirement for
  inhalational anesthetics. For example, at 70
  nitrous oxide, the MAC for other inhalational
  agents is reduced by about 60, allowing for
  lower concentrations of halogenated anesthetics
  and a lesser degree of side effects.One major
  problem with N2O is that it will exchange with N2
  in any air-containing cavity in the body.
  Moreover, because of their differential bloodgas
  partition coefficients, nitrous oxide will enter
  the cavity faster than nitrogen escapes, thereby
  increasing the volume and/or pressure in this
  cavity. Examples of air collections that can be
  expanded by nitrous oxide include a pneumothorax,
  an obstructed middle ear, an air embolus, an
  obstructed loop of bowel, an intraocular air
  bubble, a pulmonary bulla, and intracranial air.
  Nitrous oxide should be avoided in these clinical
  settings.

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Nitrous Oxide

• Cardiovascular System
• Cardiac function generally preserved
• When administered with halogenated inhalational
  anesthetics, it generally produces an increase in
  heart rate, arterial blood pressure, and cardiac
  output
• When administered with an opioid, it generally
  decreases arterial blood pressure and cardiac
  output
• Increased venous tone in both the peripheral and
  pulmonary vasculature
• Pulmonary vascular resistance can be exaggerated
  in patients with pre-existing pulmonary
  hypertension and the drug generally is not used
  in these patients

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Nitrous Oxide

• Respiratory System
• Modest increases in respiratory rate and
  decreases in tidal volume
• Minute ventilation is not significantly changed
  and PaCO2 remains normal
• Depressed ventilatory response to hypoxia
• Monitor arterial O2 saturation directly in
  patients receiving or recovering from nitrous
  oxide

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Nitrous Oxide

• Nervous System
• Increased cerebral blood flow and intracranial
  pressure
• Administered with intravenous anesthetic agents,
  increases in cerebral blood flow are attenuated
  or abolished
• Administered with halogenated inhalational
  anesthetic, vasodilatory effect on the cerebral
  vasculature is slightly reduced
• Muscle
• Does not relax skeletal muscle
• Does not enhance neuromuscular blocking drugs
• Does not trigger malignant hyperthermia
• Kidney, Liver, and Gastrointestinal Tract
• Neither nephrotoxic nor hepatotoxic

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Xenon

• Xenon is an inert gas that first was identified
  as an anesthetic agent in 1951. It is not
  approved for use in the United States and is
  unlikely to enjoy widespread use because it is a
  rare gas that cannot be manufactured and must be
  extracted from air. This limits the quantities of
  available xenon gas and renders xenon very
  expensive. Despite these shortcomings, xenon has
  properties that make it a virtually ideal
  anesthetic gas that ultimately may be used in
  critical situations.Xenon is extremely
  insoluble in blood and other tissues, providing
  for rapid induction and emergence from
  anesthesia. It is sufficiently potent to produce
  surgical anesthesia when administered with 30
  oxygen. Most importantly, xenon has minimal side
  effects. It has no effects on cardiac output or
  cardiac rhythm and is not thought to have a
  significant effect on systemic vascular
  resistance. It also does not affect pulmonary
  function and is not known to have any hepatic or
  renal toxicity. Finally, xenon is not metabolized
  in the human body. Xenon is an anesthetic that
  may be available in the future if limitations on
  its availability and its high cost can be
  overcome.

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Structures of IV General Anesthetics
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Induction of Anesthesia

• Parenteral anesthetics
• Rapid onset and short duration after a single
  bolus dose
• Accumulate in fatty tissue
• Prolonging recovery if multiple doses or infusion
  are given
• Particularly for drugs with lower rates of
  clearance
• Each has its own unique set of properties and
  side effects
• Propofol most commonly used parenteral agent
• Thiopental slightly reduced hypotension, good
  track record
• Etomidate usually is reserved for patients at
  risk for hypotension and/or myocardial ischemia
• Ketamine is best suited for patients with asthma
  or for children undergoing short, painful
  procedures

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Pharmacokinetics

• Small, hydrophobic, substituted aromatic or
  heterocyclic compounds
• Hydrophobicity is the key factor governing their
  pharmacokinetics
• Partition into the highly perfused and lipophilic
  tissues of the brain and spinal cord
• Produce anesthesia within a single circulation
  time
• Blood levels fall rapidly
• Diffuses into less perfused tissues such as
  muscle and viscera
• Finally, the poorly perfused but very hydrophobic
  adipose tissue

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Pharmacokinetics

• Redistribution out of the CNS back into the blood
• Termination of anesthesia after single boluses
  primarily reflects redistribution out of the CNS
  rather than metabolism
• After redistribution, blood levels fall according
  to a complex interaction between the metabolic
  rate and the amount and lipophilicity of the drug
  stored in the peripheral compartments
• Half-lives are "context-sensitive

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• For example, after a single bolus of thiopental,
  patients usually emerge from anesthesia within 10
  minutes however, a patient may require more than
  a day to awaken from a prolonged thiopental
  infusion. Most individual variability in
  sensitivity to parenteral anesthetics can be
  accounted for by pharmacokinetic factors. For
  example, in patients with lower cardiac output,
  the relative perfusion of and fraction of
  anesthetic dose delivered to the brain is higher
  thus, patients in septic shock or with
  cardiomyopathy usually require lower doses of
  anesthetic. The elderly also typically require a
  smaller anesthetic dose, primarily because of a
  smaller initial volume of distribution.

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Barbiturates

• Chemistry and Formulations. Anesthetic
  barbiturates are derivatives of barbituric acid
  (2,4,6-trioxohexahydropyrimidine), with either an
  oxygen or sulfur at the 2-position. The three
  barbiturates used for clinical anesthesia are
  sodium thiopental, thiamylal, and methohexital.
  Sodium thiopental (PENTOTHAL) has been used most
  frequently for inducing anesthesia. The
  barbiturate anesthetics are supplied as racemic
  mixtures despite enantioselectivity in their
  anesthetic potency. Barbiturates are formulated
  as the sodium salts with 6 sodium carbonate and
  reconstituted in water or isotonic saline to
  produce 1 (methohexital), 2 (thiamylal), or
  2.5 (thiopental) alkaline solutions with pHs of
  10 to 11. Once reconstituted, thiobarbiturates
  are stable in solution for up to 1 week,
  methohexital for up to 6 weeks if refrigerated.
  Mixing with more acidic drugs commonly used
  during anesthetic induction can result in
  precipitation of the barbiturate as the free
  acid thus, standard practice is to delay the
  administration of other drugs until the
  barbiturate has cleared the intravenous tubing.

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Barbiturates Thiopental and Thiamylal

• Produces unconsciousness in 10 to 30 seconds with
  a peak effect in 1 minute and duration of
  anesthesia of 5 to 8 minutes
• Neonates require higher dose
• Elderly/pregnant require lower dose
• Doses can be reduced by 10 to 50 after
  premedication with benzodiazepines, opiates, or
  a2 adrenergic agonists
• Thiopental produces garlic taste prior to
  induction
• Intra-arterial injection of thiobarbiturates can
  induce a severe inflammatory and potentially
  necrotic reaction and should be avoided

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Barbiturates Methohexital

• More potent
• Pain in injection
• Can produce excitement phenomena such as muscle
  tremor, hypertonus, and hiccups
• Rapid clearance

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Barbiturates PK

• Primarily eliminated by hepatic metabolism
• Renal excretion of inactive metabolites
• Small fraction of thiopental undergoes
  desulfuration to the longer-acting hypnotic
  pentobarbital
• Highly protein bound
• Hepatic disease or other conditions that reduce
  serum protein concentration will increase the
  initial free concentration and hypnotic effect of
  an induction dose

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Barbiturates

• Nervous System
• Dose dependent reduction of cerebral O2
  consumption
• Cerebral blood flow and intracranial pressure are
  similarly reduced
• Thiopental has been used as a protectant against
  cerebral ischemia
• At least one human study suggests that thiopental
  may be efficacious in ameliorating ischemic
  damage in the perioperative setting
• Reduced intraocular pressure
• Anticonvulsant
• Thiopental in particular is a proven medication
  in the treatment of status epilepticus

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Barbiturates

• Cardiovascular
• Dose-dependent decrease in blood pressure
• Vasodilation, particularly venodilation
• Direct decrease in cardiac contractility
• Heart rate increases as a compensatory response
  to a lower blood pressure
• Baroreceptor reflex blunted
• Hypotension can be severe in patients with an
  impaired ability to compensate for venodilation
  such as those with hypovolemia, cardiomyopathy,
  valvular heart disease, coronary artery disease,
  cardiac tamponade, or b adrenergic blockade
• Not contraindicated in patients with coronary
  artery disease
• None of the barbiturates has been shown to be
  arrhythmogenic

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Barbiturates

• Respiratory
• Respiratory depression
• Decreased minute ventilation and tidal volume
  with a smaller and inconsistent decrease in
  respiratory rate
• Reflexes to hypercarbia and hypoxia are
  diminished
• Little effect on bronchomotor tone and can be
  used safely in asthmatics

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Barbiturates

• Other Side Effects
• Short-term administration of barbiturates has no
  clinically significant effect on the hepatic,
  renal, or endocrine systems
• Single induction dose of thiopental does not
  alter tone of the gravid uterus, but may produce
  mild transient depression of newborn activity
• True allergies to barbiturates are rare however,
  direct drug-induced histamine release is
  occasionally seen
• Can induce fatal attacks of porphyria in patients
  with acute intermittent or variegate porphyria
  and are contraindicated in such patients.

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Propofol

• Chemistry and Formulations
• Propofol now is the most commonly used
  parenteral anesthetic in the United States. The
  active ingredient in propofol, 2,6-diisopropylphen
  ol, is essentially insoluble in aqueous solutions
  and is formulated only for IV administration as a
  1 (10 mg/ml) emulsion in 10 soybean oil, 2.25
  glycerol, and 1.2 purified egg phosphatide. In
  the United States, disodium EDTA (0.05 mg/ml) or
  sodium metabisulfite (0.25 mg/ml) is added to
  inhibit bacterial growth. Nevertheless,
  significant bacterial contamination of open
  containers has been associated with serious
  patient infection propofol should be either
  administered or discarded shortly after removal
  from sterile packaging.

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• Dosage and Clinical Use. The induction dose of
  propofol (DIPRIVAN) in a healthy adult is 1.5 to
  2.5 mg/kg and it has an onset and duration of
  anesthesia similar to thiopental. As with
  barbiturates, dosages should be reduced in the
  elderly and in the presence of other sedatives
  and increased in young children. Because of its
  reasonably short elimination half-life, propofol
  often is used for maintenance of anesthesia as
  well as for induction. For short procedures,
  small boluses (10 to 50 of the induction dose)
  every 5 minutes or as needed are effective. An
  infusion of propofol produces a more stable drug
  level (100 to 300 mg/kg per minute) and is better
  suited for longer-term anesthetic maintenance.
  Infusion rates should be tailored to patient
  response and the levels of other hypnotics.
  Sedating doses of propofol are 20 to 50 of
  those required for general anesthesia. However,
  even at these lower doses, caregivers should be
  vigilant and prepared for all of the side effects
  of propofol discussed below, particularly airway
  obstruction and apnea. Propofol elicits pain on
  injection that can be reduced with lidocaine and
  the use of larger arm and antecubital veins.
  Excitatory phenomena during induction with
  propofol occur at about the same frequency as
  with thiopental, but much less frequently than
  with methohexital.

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Propofol PK

• Onset and duration of anesthesia similar to
  thiopental
• Recovery much faster after propofol than after
  thiopental or even methohexital
• Very high clearance
• Slow diffusion from the peripheral to the central
  compartment
• Less severe hangover compared with barbiturates
• Metabolized in the liver to less active
  metabolites that are renally excreted
• Clearance exceeds hepatic blood flow, and
  anhepatic metabolism has been demonstrated
• Highly protein bound, and its pharmacokinetics,
  like those of the barbiturates, may be affected
  by conditions that alter serum protein levels

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Propofol

• Nervous System
• Decreased cerebral O2 demand, cerebral blood
  flow, and intracranial and intraocular pressures
  by about the same amount as thiopental
• Has been used in patients at risk for cerebral
  ischemia
• No human outcome studies have been performed to
  determine its efficacy as a neuroprotectant
• Anticonvulsant effects of propofol have been
  mixed
• Some data even suggest it has proconvulsant
  activity when combined with other drugs

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Propofol

• Cardiovascular
• Dose dependent decrease in blood pressure
  significantly greater than that of thiopental
• Vasodilation and mild depression of myocardial
  contractility
• Blunted baroreceptor reflex or is direct
  vagotonic activity
• Smaller increases in heart rate are seen for any
  given drop in blood pressure after doses of
  propofol

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Propofol

• Respiratory and Other Side Effects
• Slightly greater respiratory depression than
  thiopental
• Less likely than barbiturates to provoke
  bronchospasm
• No clinically significant effects on hepatic,
  renal, or endocrine organ systems
• Significant anti-emetic action and is a good
  choice for sedation or anesthesia of patients at
  high risk for nausea and vomiting
• Anaphylactoid reactions and histamine release at
  about the same low frequency as thiopental
• Although crosses placental membranes, considered
  safe for use in pregnant women
• Only transiently depresses activity in the newborn

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Etomidate

• Chemistry and Formulation. Etomidate is a
  substituted imidazole that is supplied as the
  active D-isomer. Etomidate is poorly soluble in
  water and is formulated as a 2 mg/ml solution in
  35 propylene glycol. Unlike thiopental,
  etomidate does not induce precipitation of
  neuromuscular blockers or other drugs frequently
  given during anesthetic induction.Dosage and
  Clinical Use. Etomidate (AMIDATE) is primarily
  used for anesthetic induction of patients at risk
  for hypotension.Induction doses of etomidate
  (0.2 to 0.4 mg/kg) have a rapid onset and short
  duration of action and are accompanied by a high
  incidence of pain on injection and myoclonic
  movements. Lidocaine effectively reduces the pain
  of injection, while myoclonic movements can be
  reduced by premedication with either
  benzodiazepines or opiates. Etomidate is
  pharmacokinetically suitable for infusion for
  anesthetic maintenance (10 mg/kg per minute) or
  sedation (5 mg/kg per minute) however, long-term
  infusions are not recommended for reasons
  discussed below. Etomidate also may be given
  rectally (6.5 mg/kg) with an onset of about 5
  minutes.

53

• Pharmacokinetics and Metabolism. An induction
  dose of etomidate has a rapid onset
  redistribution limits the duration of action.
  Metabolism occurs in the liver, primarily to
  inactive compounds. Elimination is both renal
  (78) and biliary (22). Compared to thiopental,
  the duration of action of etomidate increases
  less with repeated doses. The plasma protein
  binding of etomidate is high but less than that
  of barbiturates and propofol.

54
Etomidate PK

• Rapid onset
• Redistribution limits the duration of action
• Hepatic metabolism, primarily to inactive
  compounds
• Elimination is renal (78) and biliary (22)
• Compared to thiopental, the duration of action
  increases less with repeated doses
• Plasma protein binding of etomidate is high but
  less than that of barbiturates and propofol

55
Etomidate

• Nervous System
• Cerebral blood flow, metabolism, intracranial and
  intraocular pressures are similar to those of
  thiopental
• Has been used as a protectant against cerebral
  ischemia
• Animal studies have failed to show a consistent
  beneficial effect
• No controlled human trials have been performed
• Proconvulsant

56
Etomidate

• Cardiovascular
• Cardiovascular stability after induction is a
  major advantage
• Typically produce a small increase in heart rate
  and little or no decrease in blood pressure or
  cardiac output
• Little effect on coronary perfusion pressure
  while reducing myocardial oxygen consumption
• Best suited to maintain cardiovascular stability
  in patients with coronary artery disease,
  cardiomyopathy, cerebral vascular disease, or
  hypovolemia

57
Etomidate

• Respiratory and Other Side Effects
• Respiratory depression less than thiopental
• May induce hiccups
• Does not significantly stimulate histamine
  release
• Associated with nausea and vomiting
• Inhibits adrenal biosynthetic enzymes required
  for the production of cortisol and some other
  steroids, possibly inhibiting the adrenocortical
  stress response
• Single induction dose may transiently reduce
  cortisol levels
• No significant differences in outcome after
  short-term administration
• Not recommended for long-term infusion

58
Ketamine

• Chemistry and Formulation. Ketamine is an
  arylcyclohexylamine, a congener of phencyclidine.
  It is supplied as a racemic mixture even though
  the S-isomer is more potent with fewer side
  effects. Although more lipophilic than
  thiopental, ketamine is water soluble and
  available as 10-, 50-, and 100-mg/ml solutions in
  sodium chloride plus the preservative
  benzethonium chloride.Dosage and Clinical Use.
  Ketamine (KETALAR, others) has unique properties
  that make it useful for anesthetizing patients at
  risk for hypotension and bronchospasm and for
  certain pediatric procedures. However,
  significant side effects limit its routine use.
  Ketamine rapidly produces a hypnotic state quite
  distinct from that of other anesthetics. Patients
  have profound analgesia, unresponsiveness to
  commands, and amnesia, but may have their eyes
  open, move their limbs involuntarily, and breathe
  spontaneously. This cataleptic state has been
  termed dissociative anesthesia.

59

• Ketamine typically is administered intravenously
  but also is effective by intramuscular, oral, and
  rectal routes. The induction doses are 0.5 to 1.5
  mg/kg IV, 4 to 6 mg/kg IM, and 8 to 10 mg/kg PR.
  Onset of action after an intravenous dose is
  similar to that of the other parenteral
  anesthetics, but the duration of anesthesia of a
  single dose is longer. For anesthetic
  maintenance, ketamine occasionally is continued
  as an infusion (25 to 100 mg/kg per minute).
  Ketamine does not elicit pain on injection or
  true excitatory behavior as described for
  methohexital, although involuntary movements
  produced by ketamine can be mistaken for
  anesthetic excitement.

60
Ketamine PK

• Onset and duration determined by the same
  distribution/redistribution mechanism operant for
  all the other parenteral anesthetics
• Hepatically metabolized to norketamine, which has
  reduced CNS activity
• Norketamine metabolized and excreted in urine and
  bile
• Large volume of distribution and rapid clearance
• Suitable for continuous infusion without the
  drastic lengthening in duration of action seen
  with thiopental
• Protein binding is much lower with ketamine than
  with the other parenteral anesthetics

61
Ketamine

• Nervous System
• Indirect sympathomimetic activity
• Produces cataleptic state is accompanied by
  nystagmus with pupillary dilation, salivation,
  lacrimation, and spontaneous limb movements with
  increased overall muscle tone
• Patients are amnestic and unresponsive to painful
  stimuli
• Profound analgesia, a distinct advantage over
  other parenteral anesthetics
• Increases cerebral blood flow and intracranial
  pressure with minimal alteration of cerebral
  metabolism
• Can be attenuated by concurrent administration of
  thiopental and/or benzodiazepines along with
  hyperventilation

62
Ketamine

• Nervous System
• Relative contraindication for patients with
  increased intracranial pressure or those at risk
  for cerebral ischemia
• Increased intraocular pressure, and its use for
  induction of patients with open eye injuries is
  controversial
• Seizure activity appear mixed, without either
  strong pro- or anticonvulsant activity
• Emergence delirium characterized by
  hallucinations, vivid dreams, and illusions is a
  frequent
• Most frequent in the first hour after emergence
  and appear to occur less frequently in children
• Benzodiazepines reduce the incidence of emergence
  delirium

63
Ketamine

• Cardiovascular
• Increase blood pressure, heart rate, and cardiac
  output
• Mediated by inhibition of both central and
  peripheral catecholamine reuptake
• Direct negative inotropic and vasodilating
  activity
• Overwhelmed by the indirect sympathomimetic
  action.
• Useful for patients at risk for hypotension
• Not arrhythmogenic
• Increases myocardial oxygen consumption and is
  not an ideal drug for patients at risk for
  myocardial ischemia

64
Ketamine

• Respiratory
• Small, transient decrease in minute ventilation
• Respiratory depression is less severe than with
  other general anesthetics
• Potent bronchodilator
• Well-suited for anesthetizing patients at high
  risk for bronchospasm.