General Anesthetics - PowerPoint PPT Presentation

About This Presentation
Title:

General Anesthetics

Description:

General Anesthetics Chapter 25 Pharmacokinetics Small, hydrophobic, substituted aromatic or heterocyclic compounds Hydrophobicity is the key factor governing their ... – PowerPoint PPT presentation

Number of Views:251
Avg rating:3.0/5.0
Slides: 65
Provided by: Kend163
Category:

less

Transcript and Presenter's Notes

Title: General Anesthetics


1
General Anesthetics
  • Chapter 25

2
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.

3
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

4
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.

5
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

6
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

7
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.

8
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

9
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

10
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.

11
Enflurane
  • Muscle
  • Skeletal muscle relaxation
  • Enhances the effects of nondepolarizing muscle
    relaxants
  • Relaxes uterine smooth muscle
  • Not widely used for obstetric anesthesia

12
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

13
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.

14
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.

15
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

16
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

17
Desflurane
  • Nervous System
  • Decreases cerebral vascular resistance and
    cerebral metabolic O2 consumption
  • Increased cerebral blood flow
  • Increased intracranial pressure
  • Hyperventilation to decrease

18
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

19
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.

20
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.

21
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

22
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

23
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

24
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.

25
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.

26
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.

27
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

28
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

29
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

30
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.

31
Structures of IV General Anesthetics
32
(No Transcript)
33
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

34
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

35
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

36
  • 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.

37
(No Transcript)
38
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.

39
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

40
Barbiturates Methohexital
  • More potent
  • Pain in injection
  • Can produce excitement phenomena such as muscle
    tremor, hypertonus, and hiccups
  • Rapid clearance

41
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

42
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

43
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

44
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

45
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.

46
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.

47
  • 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.

48
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

49
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

50
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

51
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

52
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.
Write a Comment
User Comments (0)
About PowerShow.com