General Anesthetics

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General Anesthetics

• Yacoub M. Irshaid, MD, PhD, ABCP
• Department of Pharmacology

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General Anesthetics

• General anesthesia is typically a state of
  analgesia, amnesia, loss of consciousness,
  inhibition of sensory and autonomic reflexes, and
  skeletal muscle relaxation.
• This is achieved by a combination of intravenous
  and inhaled drugs.

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General Anesthetics

• Types of General Anesthesia
• Intravenous agents used alone, or in combination
  with other anesthetic agents, to achieve an
  anesthetic state or sedation. These drugs
  include
• Barbiturates Thiopental, methohexital.
• Benzodiazepines Midazolam, diazepam.
• Propofol.

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General Anesthetics

• 4. Ketamine.
• Opioid analgesics Morphine, fentanyl,
  sufentanil, alfentanil, remifentanil.
• Miscellaneous sedative-hypnotics Etomidate,
  dexmedetomidine.
• B. Inhaled anesthetics which include
• Volatile liquids Halothane, isoflurane,
  desflurane, enflurane, methoxyflurane, and
  sevoflurane.
• Gases Nitrous oxide.

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General Anesthetics

• Balanced Anesthesia
• Although general anesthesia can be produced by
  only intravenous or only inhaled anesthetic
  agents, modern anesthesia typically involves a
  combination of
• IV agents for induction of anesthesia.
• Inhaled agents for maintenance of anesthesia.
• Muscle relaxants.
• Analgesics.
• Cardiovascular drugs to control autonomic
  responses.

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Inhaled Anesthetics

• Pharmacokinetics
• An adequate depth of anesthesia depends on
  achieving therapeutic concentrations in the
  central nervous system.
• The rate at which an effective brain
  concentration is achieved (time to induction of
  anesthesia) depends on multiple pharmacokinetic
  factors that influence brain uptake and tissue
  distribution of the anesthetic agent

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Inhaled Anesthetics

• Uptake and distribution of inhaled anesthetics
• Achievement of a brain concentration of an
  inhaled anesthetic to provide adequate anesthesia
  requires transfer of the anesthetic from the
  alveolar air to the blood, and from the blood to
  the brain.
• The rate of achievement of such a concentration
  depends on

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Inhaled Anesthetics

• Solubility of the anesthetic
• The bloodgas partition coefficient is a useful
  index of solubility, and defines the relative
  affinity of the anesthetic for the blood compared
  with that of inspired gas.
• The partition coefficients for desflurane and
  nitrous oxide, which are relatively insoluble in
  blood, are extremely low.

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Inhaled Anesthetics

• Thus, when such agents diffuse from the lung into
  the arterial blood, relatively few molecules are
  required to raise its partial pressure, and
  therefore the arterial tension rises rapidly.
• Conversely, for anesthetics with moderate-to-high
  solubility (halothane, isoflurane), more
  molecules dissolve before partial pressure rises
  significantly, and arterial tension of the gas
  increases less rapidly.

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Inhaled Anesthetics

• Nitrous oxide and desflurane (and to a lesser
  extent sevoflurane), with low solubility in
  blood, reaches high arterial tensions rapidly,
  which in turn results in rapid equilibration with
  the brain and faster onset of action.

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Why induction of anesthesia is slower with more
soluble anesthetic gases. In this schematic
diagram, solubility in blood is represented by
the relative size of the blood compartment (the
more soluble, the larger the compartment).
Relative partial pressures of the agents in the
compartments are indicated by the degree of
filling of each compartment. For a given
concentration or partial pressure of the two
anesthetic gases in the inspired air, it will
take much longer for the blood partial pressure
of the more soluble gas (halothane) to rise to
the same partial pressure as in the alveoli.
Since the concentration of the anesthetic agent
in the brain can rise no faster than the
concentration in the blood, the onset of
anesthesia will be slower with halothane than
with nitrous oxide.
12
Tensions of three anesthetic gases in arterial
blood as a function of time after beginning
inhalation. Nitrous oxide is relatively insoluble
(bloodgas partition coefficient 0.47)
methoxyflurane is much more soluble (coefficient
12) and halothane is intermediate (2.3).
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Inhaled Anesthetics

• B. Anesthetic concentration in the inspired air
• The concentration of an inhaled anesthetic in
  the inspired gas mixture has direct effects on
  both the maximum tension in the alveoli and the
  rate of increase in its tension in the arterial
  blood.

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Inhaled Anesthetics

• Increases in the inspired anesthetic
  concentration increases the rate of induction of
  anesthesia.
• Advantage is taken of this effect in anesthetic
  practice. For example, a high concentration of
  isoflurane (1.5) is used for an increased rate
  of induction, which is then reduced (0.75-1) for
  maintenance of anesthesia.

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Inhaled Anesthetics

• Similarly, moderately soluble anesthetics are
  often administered in combination with a less
  soluble agents to reduce the time needed for loss
  of consciousness and achievement of a surgical
  depth of anesthesia. (nitrous oxide halothane).

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Inhaled Anesthetics

• C. Pulmonary ventilation
• The rate of rise of anesthetic gas tension in
  arterial blood is directly dependent on both the
  rate and depth of ventilation. The magnitude of
  the effect depends on bloodgas partition
  coefficient.
• An increase in pulmonary ventilation is
  accompanied by only a slight increase in arterial
  tension of an anesthetic with low blood
  solubility, but can significantly increase
  tension of agents with moderate-to-high blood
  solubility.

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Inhaled Anesthetics

• Fore example, a 4-fold increase in ventilation
  rate almost doubles arterial tension of halothane
  during the first 10 minutes of anesthesia but
  increases the arterial tension of nitrous oxide
  by only 15.

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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.
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Inhaled Anesthetics

• Therefore, hyperventilation increases the speed
  of induction of anesthesia with inhaled
  anesthetics that would normally have a slow
  onset.
• Depression of respiration by opioid analgesics
  slows the onset of anesthesia of inhaled
  anesthetics if ventilation is not manually or
  mechanically assisted.

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Inhaled Anesthetics

• D. Pulmonary blood flow
• Changes in blood flow to and from the lungs
  influence transfer processes of anesthetic gases.
• An increase in pulmonary blood flow slows the
  rate of rise in arterial tension, particularly
  for agents with moderate-to-high blood
  solubility.

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Inhaled Anesthetics

• Increased pulmonary blood flow exposes a large
  volume of blood to the anesthetic thus, blood
  capacity increases and the anesthetic tension
  rises slowly.
• A decrease in pulmonary blood flow has the
  opposite effect, increasing the rate of rise of
  arterial tension of inhaled anesthetics.

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Inhaled Anesthetics

• In patients with circulatory shock, the combined
  effect of decreased cardiac output and increased
  ventilation will accelerate induction of
  anesthesia with halothane and isoflurane. This is
  less likely with less soluble agents such as
  nitrous oxide and desflurane.

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Inhaled Anesthetics

• E. Arteriovenous concentration gradient
• The anesthetic concentration gradient between
  arterial and mixed venous blood is dependent
  mainly on the uptake of anesthetic by the tissue
• Venous blood returning to the lungs may contain
  significantly less anesthetic than arterial
  blood.
• The greater this difference, the more time it
  will take to achieve equilibrium with brain
  tissue.

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Inhaled Anesthetics

• 2. Elimination of inhaled anesthetics
• The time of recovery from inhalation anesthesia
  depends on the rate of elimination of the
  anesthetic from the brain.
• Many of the processes of anesthetic transfer
  during recovery are simply the reverse of those
  that occur during induction of anesthesia.

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Inhaled Anesthetics

• The bloodgas partition coefficient of the
  anesthetic is one of the most important factors
  governing recovery, which include pulmonary blood
  flow, ventilation magnitude, and tissue
  solubility of the anesthetic.
• Two features of recovery are different from what
  happens during induction

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Inhaled Anesthetics

1. Although the transfer of the anesthetic from the
   lungs to the blood can be enhanced by increasing
   its concentration in inspired air, the reverse
   can not be enhanced, because the concentration in
   the lung can not be reduced below zero.
2. At the beginning of recovery, the anesthetic gas
   tension in different tissues may be variable. In
   contrast, with induction the initial anesthetic
   tension is zero in all tissues.

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Inhaled Anesthetics

• Inhaled anesthetics that are relatively insoluble
  in blood (low bloodgas partition coefficient)
  and brain (?) are eliminated at faster rates than
  more soluble anesthetics. The washout of nitrous
  oxide, desflurane, and sevoflurane occurs at a
  rapid rate ? more rapid recovery from their
  anesthetic effect compared to halothane and
  isoflurane.

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Inhaled Anesthetics

• Halothane is twice as soluble in brain tissue
  and 5X more soluble in blood than nitrous oxide
  and desflurane ? more slow elimination and less
  rapid recovery from halothane anesthesia.
• The duration of exposure to the anesthetic can
  have a marked effect on recovery time, especially
  for more soluble anesthetics.

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Inhaled Anesthetics

• Accumulation of (isoflurane) in muscle, skin and
  fat increases with prolonged inhalation, and
  blood tension may decline slowly during recovery.
• When the exposure is short, recovery may be rapid
  even with the more soluble agents.
• Clearance of the inhaled anesthetics by the lungs
  is the major route of elimination from the body.

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Inhaled Anesthetics

• Hepatic metabolism may also contribute to the
  elimination of halothane ( 40 during an average
  anesthetic procedure).
• Oxidative metabolism (CYP2E1) of halothane
  results in formation of trifluoroacetic acid and
  release of chloride and bromide ions.

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Inhaled Anesthetics

• Under conditions of low oxygen tension, halothane
  is metabolized to the chlorotrifluoroethyl free
  radical which is capable of reacting with hepatic
  cell membrane and producing halothane hepatitis.
• lt 10 of enflurane is metabolized.
• Isoflurane and desflurane are the least
  metabolized of fluorinated anesthetics.

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Inhaled Anesthetics

• The metabolism of methoxyflurane (70) results in
  elevation of renal fluoride levels and
  nephrotoxicity.
• Enflurane and sevoflurane metabolism leads to
  formation of fluoride ions but do not reach toxic
  levels.
• Nitrous oxide is not metabolized by human
  tissues, but can be metabolized by bacteria in
  the GIT.

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Inhaled Anesthetics

• Sevoflurane is degraded by contact with the
  carbon dioxide absorbent (soda lime Ca(OH)2
  (about 75), H2O (about 20), NaOH (about 3),
  KOH (about 1)) in anesthesia machines yielding a
  vinyl ether which can cause renal damage if high
  concentrations are absorbed.

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General Anesthetics

• Pharmacodynamics
• Both the inhaled and intravenous anesthetics can
  depress spontaneous and evoked activity of
  neurons in many regions of the brain, with
  several potential molecular targets for
  anesthetic actions.

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General Anesthetics

• Interaction of the anesthetics with specific
  nerve membrane components results in modification
  of ion currents, particularly the ligand-gated
  ion channel family.

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General Anesthetics

• A primary molecular target of general anesthetics
  (halogenated inhalational agents, propofol,
  barbiturates, etomidate, ..) is the GABAA
  receptor-chloride channel, a major mediators of
  inhibitory synaptic transmission. Either it is
  directly activated or facilitated.

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General Anesthetics

• Glycine receptor is another target for inhaled
  anesthetics.
• Inhalational agents enhance the capacity of
  glycine to activate glycine-gated chloride
  channels ? inhibitory neurotransmission in spinal
  cord and brain stem.

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General Anesthetics

• Propofol and barbiturates, but not etomidate and
  ketamine, also potentiate glycine-gated currents.
• The only general anesthetics that do not have
  significant effects on GABAA or glycine
  receptors are nitrous oxide and ketamine, which
  act on calcium selective NMDA glutamate receptor.

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General Anesthetics

• Neuronal nicotinic acetylcholine receptors
  inhibition by inhalational agents do not mediate
  anesthetic effect but mediate analgesia and
  amnesia.
• Certain inhalational anesthetics may cause
  membrane hyperpolarization by activation of
  potassium channels.
• Inhalational agents can produce presynaptic
  inhibition of neurotransmitter release in the
  hippocampus contributing to the amnesic effect of
  these agents.

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Inhaled Anesthetics

• Organ System Effects of Inhaled Anesthetics
• Effects on the Cardiovascular System
• Halothane and enflurane reduce arterial pressure
  by reduction of cardiac output.
• Isoflurane, desflurane, and sevoflurane reduce
  arterial blood pressure by decreasing systemic
  vascular resistance.

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Inhaled Anesthetics

• Halothane may cause bradycardia probably because
  of direct vagal stimulation.
• Desflurane and isoflurane increase heart rate.
• All depress myocardial function, including
  nitrous oxide.
• Halothane, and to a lesser effect isoflurane
  sensitize the myocardium to circulating
  catecholamines ? ventricular arrhythmias.

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Inhaled Anesthetics

• B. Effects on the Respiratory System
• All except nitrous oxide decrease tidal volume
  and increase respiratory rate
• All volatile anesthetics are respiratory
  depressants and reduce the response to increased
  levels of carbon dioxide.
• All volatile anesthetics increase the resting
  levels of PaCO2.

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Inhaled Anesthetics

• The respiratory depressant effect is overcome by
  assisted or controlled ventilation.
• Inhaled anesthetics depress mucociliary function
  of airways ? pooling of mucus ? atelectasis and
  postoperative respiratory infection.
• Halothane and sevoflurane have bronchodilating
  action (?).
• Airway irritation with desflurane.

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Inhaled Anesthetics

• C. Effects on the Brain
• Decrease metabolic rate of the brain.
• Increase cerebral blood flow by decreasing
  cerebrovascular resistance (not desirable in
  patients with increased intracranial pressure).
  Nitrous oxide is the least likely to do so.
• If the patient is hyperventilated before the
  volatile agent is administered, the increase in
  ICP can be minimized (by inducing hypocapnoeic
  vasoconstriction).

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Inhaled Anesthetics

• Nitrous oxide has analgesic and amnesic
  properties.
• D. Effects on the Kidney
• Decrease GFR and renal blood flow, and increase
  the filtration fraction.
• Impair autoregulation of RBF.
• E. Effects on the Liver
• Reduce hepatic blood flow.

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Inhaled Anesthetics

• F. Effects on Uterine Smooth Muscle
• Nitrous oxide has little effect.
• Halogenated anesthetics are potent uterine muscle
  relaxants.

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Inhaled Anesthetics

• Toxicity
• Hepatotoxicity
• Potentially life-threatening in subjects
  previously exposed to halothane.
• Incidence is 120,000 35,000.
• Obese patients are most susceptible.
• Mechanism is unclear, but may be
• a. Direct hepatocellular damage by reactive
  metabolites (free radicals).

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Inhaled Anesthetics

• b. Initiation of immune-mediated responses by
  reactive metabolites. Serum of patients with
  halothane hepatitis contain a variety of
  autoantibodies against hepatic proteins.
• Trifluoroacetylated proteins in the liver could
  be formed in hepatocytes during halothane
  biotransformation. They are also found in the
  sera of patients who did NOT develop hepatitis
  after halothane anesthesia.

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Inhaled Anesthetics

• 2. Nephrotoxicity
• Prolonged exposure to methoxyflurane and
  enflurane leads to formation of fluoride ions
  intrarenally by the renal enzyme ß-lyase ?
  changes in renal concentrating ability (?
  proximal tubular necrosis).

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Inhaled Anesthetics

• 3. Malignant hyperthermia
• Is an autosomal dominant genetic disorder of
  skeletal muscle that occurs in individuals
  undergoing general anesthesia with volatile
  agents succinylcholine.
• It consists of rapid onset of tachycardia and
  hypertension, severe muscle rigidity,
  hyperthermia, hyperkalemia, and acidosis.
• It is rare but is an important cause of
  anesthetic morbidity and mortality.

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Inhaled Anesthetics

• Associated with increased calcium concentration
  in skeletal muscle cells (from the sarcoplasmic
  reticulum). Reduced by dantrolene.
• 4. Prolonged exposure to nitrous oxide decrease
  methionine synthase activity and can potentially
  cause megaloblastic anemia in inadequately
  ventilated operating room personnel.

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Intravenous Anesthetics

• Are commonly used for induction of general
  anesthesia because of more rapid onset than
  inhaled agents.
• Recovery is rapid and permits their use for short
  procedures.

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Intravenous Anesthetics
54
Barbiturates

• Thiopental is the barbiturate that is commonly
  used for induction of anesthesia.
• Thiamylal is similar in pharmacokinetics and
  pharmacodynamics.
• Methohexital is shorter-acting.
• Very highly lipid soluble.
• After an IV bolus injection, thiopental rapidly
  crosses the blood-brain barrier, and can produce
  hypnosis in one circulation time. Bloodbrain
  equilibrium occurs rapidly (lt 1 min).

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Barbiturates

• Thiopental rapidly diffuses out of the brain and
  other highly vascular tissues and is
  redistributed to muscle and fat ? a brief period
  of unconsciousness.
• 12-16 of the dose is metabolized.
• With large doses, or a continuous infusion,
  thiopental produces dose-dependent decreases in
  arterial blood pressure, stroke volume, and
  cardiac output. Most likely due to myocardial
  depression and increased venous capacitance.

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Barbiturates

• Thiopental is also a potent respiratory
  depressant ? transient apnea and lowering the
  sensitivity of the medullary respiratory center
  to carbon dioxide.
• Cerebral metabolism and oxygen utilization are
  decreased after barbiturate administration in
  proportion to the degree of cerebral depression.
  Cerebral blood flow is decreased but less than
  oxygen consumption.

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Barbiturates

• Thiopental does not increase intracranial
  pressure and volume (unlike volatile
  anesthetics), and is desirable for patients with
  cerebral swelling.
• Methohexital can cause central excitatory
  activity (myoclonus), but it also has
  anti-seizure activity.
• Occasionally these agents precipitate porphyric
  crisis during induction in susceptible
  individuals.

58
Benzodiazepines

• Diazepam, lorazepam, and midazoloam are used in
  anesthesia primarily as premedications, because
  of their sedative, anxiolytic and amnestic
  properties, and to control acute agitation.
• Compared with IV barbiturates, these drugs
  produce a slower onset of CNS depression with a
  depth inadequate for surgical anesthesia.
• Large doses that achieve deep sedation prolong
  postanesthetic recovery period and can produce
  anterograde amnesia.

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Opioid Analgesics

• Highly potent agents include fentanyl,
  sufentanil, and remifentanil.
• Remifentanyl is an extremely short-acting opioid,
  and has been used to minimize residual
  ventilatory depression.
• Awareness during anesthesia and unpleasant
  postoperative recall can occur.
• Large doses can produce chest wall and laryngeal
  rigidity, thereby acutely impairing ventilation
  and produce tolerance ? increasing postoperative
  opioid requirements.

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Opioid Analgesics

• Have been used in premedications as well as
  adjunct to both IV and inhalational anesthesia to
  provide perioperative analgesia.
• The shorter-acting alfentanil and remifentanil
  have been used as co-induction agents with IV
  sedative-hypnotic anesthetics.
• Remifentanil is rapidly metabolized by esterases
  in blood (not plasma cholinesterase) and muscle
  tissue ? extremely rapid recovery.

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Opioid Analgesics

• Can be administered in very low doses into
  epidural and subarachnoid space to produce
  excellent postoperative analgesia.
• Fentanyl and droperidol (related to haloperidol)
  are administered together to produce analgesia
  and amnesia (neuroleptanalgesia), and combined
  with nitrous oxide to produce neuroleptanesthesia
  .

62
Propofol

• The most popular IV anesthetic.
• Its rate of onset of action is similar to IV
  barbiturates but recovery is more rapid and
  patient ambulation is earlier.
• The patient subjectively feel better in the
  immediate postoperative period because of the
  reduction in postoperative nausea and vomiting.
• It is the agent of choice for ambulatory surgery.

63
Propofol

• It is used for both induction and maintenance of
  anesthesia as part of total intravenous or
  balanced anesthesia.
• It is effective in producing prolonged sedation
  in patients in critical care setting, but
  cumulative effect can lead to delayed arousal.
• Prolonged administration of conventional emulsion
  formulation can raise serum lipids.

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Propofol

• When used in critically ill young children for
  sedation, it has caused severe acidosis in the
  presence of respiratory infection and to possible
  neurologic sequelae upon withdrawal.
• After IV administration, the distribution
  half-life is 2-8 minutes and the redistribution
  half life is 30-60 minutes.

65
Propofol

• It is rapidly metabolized in the liver and
  excreted in urine as glucuronide and sulfate
  conjugates.
• Extrahepatic mechanisms may be involved in
  elimination.
• Less than 1 of the drug is excreted unchanged in
  urine.
• It produces depression of central ventilatory
  drive and apnea.

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Propofol

• Produces a marked decrease in blood pressure
  during induction of anesthesia through arterial
  and veno dilation.
• It has the greatest direct negative inotropic
  effect than other IV anesthetics.
• Pain at the site of injection is the most common
  adverse effect after IV bolus administration
  (reduced by admixture with lidocaine).

67
Propofol

• Muscle movements, hypotonus and rarely tremors
  have been reported after prolonged use.

68
Etomidate

• It is used for induction of anesthesia in
  patients with limited cardiovascular reserve,
  because it causes minimal cardiovascular and
  respiratory depression and minimal hypotension.
• It produces rapid loss of consciousness.
• It has no analgesic effects.
• Recovery is less rapid than that of propofol.

69
Etomidate

• Distribution of etomidate is rapid, with a
  biphasic plasma concentration curve showing
  initial and intermediate distribution half-lives
  of 3 29 minutes, respectively.
• Redistribution of the drug from the brain to
  highly perfused tissues is responsible for the
  short duration of action.
• It is extensively metabolized in the liver and
  plasma and only 2 of the drug is excreted
  unchanged in urine.

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Etomidate

• Adverse effects
• High incidence of pain on injection.
• Myoclonic activity.
• Postoperative nausea and vomiting.
• Inhibition of steroidogenesis with decreased
  plasma levels of cortisol and hypoadrenalism
  ?hypotension, electrolyte imbalance and oliguria.

71
Ketamine

• It produces a dissociative anesthetic state
  characterized by catatonia (muscular rigidity and
  mental stupor, sometimes alternating with great
  excitement and confusion), amnesia and analgesia,
  with or without loss of consciousness.
• It is chemically related to phencyclidine, a
  psychoactive drug with high abuse potential.

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Ketamine

• Mechanism of Action
• May involve blockade of the membrane effects of
  the excitatory neurotransmitter glutamic acid at
  the NMDA receptor subtype.
• Pharmacokinetics
• It is highly lipid soluble and rapidly
  distributed into well-perfused organs, including
  brain, liver, and kidney.
• It is then redistributed to less well perfused
  tissues, with hepatic metabolism followed by
  hepatic and biliary excretion.

73
Ketamine

• Pharmacodynamics
• It is the only IV anesthetic that have both
  analgesic properties and the ability to produce
  dose-related cardiovascular stimulation.
• It stimulates the central sympathetic nervous
  system and, to a lesser extent, inhibits the
  reuptake of norepinephrine at sympathetic nerve
  terminals.

74
Ketamine

• It increases heart rate, cardiac output and
  arterial blood pressure which reach a peak in 2-4
  minutes and decline back to baseline over the
  next 10-20 minutes.
• It increases cerebral blood flow, oxygen
  consumption, and intracranial pressure. Thus, it
  is potentially dangerous in patients with
  elevated intracranial pressure.

75
Ketamine

• It decreases respiratory rate but upper airway
  muscle tone is well maintained and airway
  reflexes are usually preserved.
• Its use has been associated with postoperative
  disorientation, sensory and perceptual illusions,
  and vivid dreams (called emergence phenomena).

76
Ketamine

• These effects can be reduced by premedication
  with a benzodiazepine (diazepam, midazolam).
• It is specially useful in patients undergoing
  painful procedures such as burn dressing.

77
Dexmedetomidine

• Sedative effects of the intravenous anesthetic
  dexmedetomidine are produced via actions in the
  locus ceruleus.
• It stimulates a2-adrenergic receptors at this
  site and reduces central sympathetic output,
  resulting in increased firing of inhibitory
  neurons.
• In the dorsal horn of the spinal cord it
  modulates release of substance P ? analgesic
  effects.