Book reading of Miller

1
Book reading of Miller

• Chapter 10 
•  Intravenous Nonopioid Anesthetics

J.G. Reves   Peter S.A. Glass   David
A. Lubarsky   Matthew D. McEvoy

R1 ???/VS??? ??
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 Intravenous Nonopioid Anesthetics

• Ideal anesthetics ? hypnosis, amnesia, analgesia,
  and muscle
  relaxation without
  undesirable cardiac and respiratory
  depression.
• Thiopental and other barbiturates, however, are
  not ideal intravenous anesthetics ? provide only
  hypnosis
• Simultaneous use of several drugs-- each
  provides some or all desired effects,combined
  with inhaled anesthetics.
• -- the skillful use of multiple intravenous
  anesthetics is not only possible but
  preferable. ( safer than the use of only one or
  two drugs )

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Intravenous Nonopioid Anesthetics
PROPOFOL

• PROPOFOL
• The most frequently used intravenous anesthetic
  today.
• The potential as an anesthetic induction agent
  confirmed by Kay and Rolly in 1977.
• Insoluble in water and was therefore initially
  prepared with Cremophor EL (BASF A.G.). ?
  reformulated as an emulsion due to anaphylactoid
  reactions.

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PROPOFOL
PROPOFOL

• Physicochemical Characteristics
• A group of alkylphenols oils at room
  temperature and insoluble in aqueous solution.
• Several formulations available today? 1
  propofol, 10 soybean oil, 2.25 glycerol, and
  1.2 purified egg phosphatide disodium edetate
  (0.005) was added to prevent microbial growth.
  Viscous, milky-like appearance
• All formulations available commercially are
  stable at room temperature and are not light
  sensitive.
• If a dilute solution of propofol is required, it
  is compatible with D5W.

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Intravenous Nonopioid Anesthetics
PROPOFOL

• PROPOFOL
• Rapidly metabolized in the liver ( conjugation to
  glucuronide and sulfate? produce water-soluble
  compounds ), excreted by the kidneys.
• Extrahepatic metabolism or extrarenal elimination
  has been suggested (confirmed during the
  anhepatic phase of patients receiving a
  transplanted liver) The lungs seem to play
  an important role.
  a 20 to 30 decrease in propofol concentration
  
• measured
  across the lung.
  The kidney and small intestine
  showed an ability to form propofol
  glucuronide.

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Intravenous Nonopioid Anesthetics
PROPOFOL
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Intravenous Nonopioid Anesthetics
PROPOFOL
After a single bolus injection, whole blood
propofol levels decrease rapidly as a result of
both redistribution and elimination.
Figure 10-2  Simulated time course of whole
blood levels of propofol after an induction dose
of 2.0 mg/kg. Blood levels required for
anesthesia during surgery are 2 to 5 µg/mL, with
awakening usually occurring at a blood level
lower than 1.5 µg/mL.
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Intravenous Nonopioid Anesthetics
PROPOFOL

• Altered factors of the pharmacokinetics of
  propofol (gender, weight, preexisting disease,
  age, concomitant medication)? ?clearance by
  decreasing hepatic blood flow (propofols
• own effect)? ?C.O leads to a decrease
  in propofol plasma concentration ? womenhigh
  clearance? The elderly have decreased clearance
  rates
• ? Children have a larger central
  compartment volume and
• more rapid clearance ? Propofol
  kinetics is unaltered by renal disease

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Intravenous Nonopioid Anesthetics
PROPOFOL

• Effect with fentanyl ? controversalwhen propofol
  is administered immediately after fentanyl, ?
  ?pulmonary uptake of propofol by 30, but not if
  administered 3 minutes later.
• Propofol is primarily a hypnotic. The machenism
  was suggestedmediated by potentiating the
  ?-aminobutyric acid (GABA)-induced chloride
  current through binding to the ß-subunit of the
  GABAA receptor. Through GABAA receptor in the
  hippocampus, propofol ?Ach release in the
  hippocampus and prefrontal cortex. ? produce
  sedative effects.
• Two interesting side effects of propofol are its
  antiemetic effect and the sense of well-being
  noted after administration. ( by ?serotonin
  level? )
• At subhypnotic doses, propofol provides sedation
  and amnesia.
• Awareness during surgery at higher infusion rates
  has been reported.

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Intravenous Nonopioid Anesthetics
PROPOFOL

• The effect of propofol on the EEG after the
  administration of 2.5 mg/kg followed by an
  infusion demonstrates an initial increase in a
  rhythm followed by a shift to ? frequency.
• The effect of propofol on epileptogenic EEG
  activity ?controversalSeveral study showed a
  direct anticonvulsant effect of propofol that is
  dose dependent.
• Interestingly, propofol has been associated with
  grand mal seizures and has been used for cortical
  mapping of epileptogenic foci.

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Intravenous Nonopioid Anesthetics
PROPOFOL

• Propofol decreases intracranial pressure (ICP) in
  patients with either normal or increased ICP?
  In patients with normal ICP, the decrease in ICP
  (30) is associated with a small decrease
  in cerebral perfusion pressure (10) ? In
  patients with elevated ICP, the decrease in ICP
  (30 to 50) is associated with significant
  decreases in cerebral perfusion pressure.
  May not be beneficial !
• Propofol produces a larger decrease in
  intraocular pressure? effective in preventing a
  rise in intraocular pressure secondary to
  endotracheal intubation.

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Intravenous Nonopioid Anesthetics
PROPOFOL

• Effects on the Respiratory System
• Apnea occurs after an induction dose of propofol,
  the incidence and duration of which appear to be
  dependent on the dose, speed of injection, and
  concomitant premedication.
• The incidence of prolonged apnea (gt30 seconds) is
  further increased by the addition of an opiate.
• The onset of apnea is usually preceded by a
  marked reduction in tidal volume and tachypnea.
• The ventilatory response to carbon dioxide is
  also decreased during a maintenance infusion of
  propofol.
• Propofol, 1.5 to 2.5 mg/kg, results in an acute
  (13 to 22) rise in PaCO2 and a decrease in pH.
• Propofol induces bronchodilation in patients with
  COPD.

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Intravenous Nonopioid Anesthetics
PROPOFOL

• Effects on the Cardiovascular System
• The most prominent effect of propofol is a
  decrease in arterial blood pressure during
  induction of anesthesia. Independent of the
  presence of cardiovascular disease.
• ?cardiac output (15) ?stroke volume (20)
  ?systemic vascular resistance (15-25)
• Vasodilatory effect ? due to reduction in
  sympathetic activity.
• The heart rate does not change significantly
  after induction of propofol.

Mean and diastolic pressure?
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Intravenous Nonopioid Anesthetics
PROPOFOL

• Effects on the Cardiovascular System
• Propofol either resets or inhibits the
  baroreflex, thus reducing the tachycardic
  response to hypotension.
• Propofol attenuates the heart rate response to
  atropine in a dose-dependent manner.
• The heart rate may increase, decrease, or remain
  unchanged when anesthesia is maintained with
  propofol.
• A significant reduction in both myocardial blood
  flow and myocardial oxygen consumption.

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Intravenous Nonopioid Anesthetics
PROPOFOL

• Other effect
• Propofol does not affect corticosteroid synthesis
  or alter the normal response to
  adrenocorticotropic hormone (ACTH) stimulation.
• Propofol does not alter hepatic, hematologic, or
  fibrinolytic function.
• In patients with multiple drug allergies,
  propofol should be used with caution.
• Propofol also possesses significant antiemetic
  activity at low (subhypnotic) doses. It has been
  used successfully to treat postoperative nausea
  in a bolus dose of 10 mg.
• Ever reported to relieve cholestatic pruritus?

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Intravenous Nonopioid Anesthetics
PROPOFOL

• For short (lt1 hour) body surface procedures, the
  advantages of more rapid recovery and decreased
  nausea and vomiting are still evident. However,
  if propofol is used only for induction in longer
  or major procedures, both speed of recovery and
  the incidence of nausea and vomiting are similar
  to those after thiopental/isoflurane anesthesia.
• Total intravenous anesthesia with propofol plus
  an opiate results in similar recovery but reduces
  the incidence of postoperative nausea and
  vomiting in the first 72 hours by 15 to 20 when
  compared with an isoflurane-based anesthetic.

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Intravenous Nonopioid Anesthetics
PROPOFOL

• Other effect
• Propofol decreases polymorphonuclear leukocyte
  chemotaxis
• Propofol inhibits phagocytosis and killing of
  Staphylococcus aureus and Escherichia coli. ?
  increased life-threatening systemic infections
  associated with the use of propofol.
• The Intralipid that acts as the solvent for
  propofol is an excellent culture medium.

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Intravenous Nonopioid Anesthetics
PROPOFOL

• A dose of 1 mg/kg (with premedication) to 1.75
  mg/kg (without premedication) is recommended for
  inducing anesthesia in patients older than 60
  years.
• Propofol results in significantly quicker
  recovery and earlier return of psychomotor
  function than thiopental does.
• For maintenance, its more suitable to administer
  propofol as a continuous infusion.
• After an induction dose, an infusion of 100 to
  200 µg/kg/min is usually needed.

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Intravenous Nonopioid Anesthetics
PROPOFOL

• Uses- Induction and Maintenance of
  AnesthesiaPropofol is suitable for both
  induction and maintenance of anesthesia and has
  also been approved for use in neurologic and
  cardiac anesthesia.

Physiologic characteristics that best determine
the induction dose are age, lean body mass, and
central blood volume.
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Intravenous Nonopioid Anesthetics
PROPOFOL

• Propofol has been evaluated for sedation during
  surgical procedures and in mechanically
  ventilated patients in the intensive care unit
  (ICU). Propofol by continuous infusion provides a
  readily titratable level of sedation and rapid
  recovery once the infusion is terminated,
  irrespective of the duration of the infusion.
• Propofol has also been used successfully in
  patient-controlled sedation.

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Intravenous Nonopioid Anesthetics
PROPOFOL

• Side effect and contraindications
• pain on injection, myoclonus, apnea, decrease in
  arterial blood pressure, and rarely
  thrombophlebitis.
• Apnea after induction with propofol is common.
  The incidence of apnea may be similar to that
  after thiopental or methohexital however,
  propofol produces a greater incidence of apnea
  lasting longer than 30 seconds.
• The most significant side effect on induction is
  the decrease in systemic blood pressure.

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Intravenous Nonopioid Anesthetics
PROPOFOL

• Side effect and contraindications
• Propofol infusion syndrome is a rare, but
  lethal syndrome. Clinical features include
  cardiomyopathy with acute cardiac failure,
  metabolic acidosis, skeletal myopathy,
  hyperkalemia, hepatomegaly.

Present evidence suggests that this syndrome
occurs as a result of failure of free fatty acid
metabolism because of inhibition of free fatty
acid entry into mitochondria and failure of the
mitochondrial respiratory chain.
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Barbiturates
24
Barbiturates

• history
• --Barbituric acid??sedation
• --Barbital (diethylbarbituric
  acid)?sedation??.?
• ???
• --Somnifen, a mixture of the barbiturate
  salts of
• diethylbarbituratic and diallylbarbituratic
  
• acids1920?.iv form??????
• --Thiopental????.????

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Barbiturates

• Chemistry and Formulation
• -- hypnotically active hydrogen attached to
  the carbon atom in
• position 5 by aryl or alkyl groups
• -- only the thiobarbiturates thiopental and
  thiamylal and the oxybarbiturate methohexital are
  commonly used for induction of anesthesia
• -- ????LR????????
• -- ??????
• pancuronium, vecuronium, atracurium,
  alfentanil, sufentanil, and midazolam(???IV,
  RSI???)

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Chemistry and Formulation
Hypnotically active barbiturates listed according
to duration of action
Only the ultrashort-acting drugs are commonly
used for induction.
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Barbiturates

• Structure-Activity Relationships
• --Substitutions at position 5 either aryl or
  
• alkyl groups-- hypnotic and sedative
• --?? phenyl groupanticonvulsant
• C2 sulfur-- more rapid onset
• C1 methyl or ethyl group--
  more rapid onset but excitatory side effects,
  including tremor, hypertonus, and involuntary
  movement

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Barbiturates

• Stereoisomerism
• --stereoisomers of the same drug can have
  different CNS potency and activity ?thiopental,
  thiamylal, methohexital, secobarbital, and
  pentobarbital?C5????????
• --the duration of action is dependent on the
  summation of the duration of effects of each
  isomer

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(No Transcript)
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Barbiturates

• Metabolism
• --Phenobarbital(60 to 90??????. ????????
• --hepatically metabolized.??????.???.???
• --biotransformed by four processes
• (1) oxidation(???) produces polar
  (charged) alcohols,
• ketones, phenols, or carboxylic acids
  excreted in urine
• or as glucuronic acid conjugates in
  bile
• (2) N-dealkylation
• (3) desulfuration of the thiobarbiturates at
  C2
• (4) destruction of the barbituric acid ring.
• --Methohexital???.?thiopental???

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Barbiturates

• Pharmacokinetics
• quick distribution of the drug to the highly
  perfused, low-volume tissues (i.e., brain) and
  slower redistribution of the drug to lean tissue
  (muscle), which terminates the effect
• thiopental??????????.??????
• affinity for fat, relatively large volume of
  distribution, and low rate of hepatic clearance?
  ???????

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Barbiturates

• Pharmacology
• --GABAA receptor of CNS
• (1) enhancement of the synaptic actions of
  inhibitory neurotransmitters
• (2) blockade of the synaptic actions of
  excitatory neurotransmitters
• --GABA???????????????. ??GABAA
  ?barbiturates??. ????????hyperpolarization.
• --????glutamate and acetylcholine??????

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Barbiturates

• Effects on Cerebral Metabolism
• --dose-related depression ?slowing of the EEG,
  reduction in the rate of ATP consumption ,
  protection from incomplete cerebral ischemia
• --??????????(??50).?????????
• --decreased cerebral blood flow (CBF) and ICP,
  but reserving cerebral perfusion pressure

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Barbiturates

• Pharmacodynamics
• -- loss of consciousness, amnesia, and
  respiratory and cardiovascular depression
• -- ?????????
• -- amnesic effect less pronounced than that
  produced by the benzodiazepines

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Barbiturates

• Onset of Central Nervous System Effects
• -- ???BBB??????????.???.????.?????.
• --gt?????.???
• methohexital gtThiopental gt pentobarbital
• -- patients with acidosis require the
  administration of less barbiturate
• -- The degree of protein binding of a drug is
  influenced by the physiologic pH and disease
  state
• -- The two primary determinants of the plasma
  concentration are the dose administered and the
  rate (speed) of administration

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Barbiturates

• Termination of Effect
• --???onset????Protein binding is less .
• --???thiopental 5 to 10 minutes
• --In the case of constant infusion or repeated
  dosing with saturation of all tissue sites,
  patients awake at a much delayed rate
• --?????.???
• --Methohexital?Thiopental??.?????????psychomotor
  ??.???????.?????????????.?Methohexital???????????
  ?.???propofol

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Barbiturates

• Uses
• -- induction and maintenance
• -- thiopental onset (15 to 30 seconds),
  excellent hypnotic, amnesia, ???
• -- Methohexital ??????. ???,?maintain, recovery
  from infusion titrated to maintain hypnosis is
  similar to propofol,
• -- NS?????24 mg/kg?seizures.
• -- in pediatric patients as a rectal
  premedication(25 mg/kg by rectal instillation
  (10 solution through a 14 French catheter, 7 cm
  into the rectum)

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Barbiturates

• Dosing
• -- thiopental (3 to 4 mg/kg,onset 5 to 15
  seconds),
• thiamylal (3 to 4 mg/kg)
• methohexital (1.0 to 2.0 mg/kg)
• higher doses are needed to reliably induce
  anesthesia in all patients.
• ?interpatient variability(??BZD?)

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Barbiturates

• Side Effects and Contraindications
• -- a garlic or onion taste (40 of patients),
  allergic reactions, local tissue irritation, and
  rarely, tissue necrosis. An urticarial rash that
  lasts a few minutes may develop on the head,
  neck, and trunk. More severe reactions such as
  facial edema, hives, bronchospasm, and
  anaphylaxis
• -- cough, hiccough, tremors, and twitching are
  produced approximately five times more often with
  methohexital

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Barbiturates

• accidental intra-arterial injection can occur
• Treatment consists of
• (1) dilution of the drug by the administration
  of saline into the artery, (2) heparinization to
  prevent thrombosis, and (3) brachial plexus
  block(?)
• proper intravenous administration of thiopental
  is remarkably free of local toxicity

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Benzodiazepines

• Three benzodiazepine receptor agonists are
  commonly used midazolam, diazepam, and
  lorazepam.
• small and lipid soluble at physiologic pH
• Midazolam is the most lipid soluble of
  the
• three drugs -- pH-dependent solubility
• water soluble when pH 3.5

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Benzodiazepines
43
Benzodiazepines

• Metabolism
• Biotransformation of the benzodiazepines
  
• occurs in the liver.

hepatic microsomal oxidation
glucuronide conjugation
susceptible to outside influences and can be
impaired by certain population characteristics,
disease, or the coadministration of other drugs
that can impair oxidizing capacity
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Benzodiazepines

• Metabolism
• rapid oxidation accounts for the
  greater
• hepatic clearance of midazolam, and
  alcohol
• consumption increases the clearance
• Lorazepam is less affected by enzyme
• induction and some of the other factors
  
• known to alter the cytochrome P450
• Age decreases and smoking increases the
  
• clearance of diazepam,34 but not to
  midazolam
• biotransformation
• Race, because of differences in the
  isoenzymes
• responsible for hydroxylation, produces
  genetic
• differences in drug metabolism

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Benzodiazepines

• metabolites
• Diazepam forms two active metabolites,
• oxazepam and desmethyldiazepam
• Midazolam is biotransformed to
• hydroxymidazolams
• Lorazepam has five metabolites, inactive,
  
• water soluble, and rapidly excreted by
  the
• kidney

46
Benzodiazepines
47
Benzodiazepines

• Pharmacokinetics
• short midazolam
• intermediate lorazepam
• long lasting diazepam
• Factors to influence the
  pharmacokinetics
• are age, gender, race, enzyme induction,
  
• hepatic and renal disease.
• all affected by obesity

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Benzodiazepines

• Pharmacology
• hypnotic, sedative, anxiolytic, amnesic,
  
• anticonvulsant, and centrally produced
  
• muscle relaxant properties
• receptor affinity
• lorazepam gt midazolam gt diazepam

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Benzodiazepines

• Pharmacology
• More is understood about the mechanism
• of benzodiazepines than otherc
  anesthetics
• GABAA subtypes mediate the different
• effects (amnesic, anticonvulsant,
  anxiolytic,
• and sleep).
• anxiolytic less than 20
• sedation 30 to 50
• unconsciousness 60 or higher --
  occupation of
• benzodiazepine agonist receptors

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Benzodiazepines

• Pharmacology
• GABAA receptor a, ß, and ?
• They produce their
• actions by occupying the
• benzodiazepine receptor
• With activation of the GABAA receptor,
  gating of the channel for chloride ions is
  triggered. The cell becomes hyperpolarized and
  therefore resistant to neuronal excitation.
• hypnotic effects of benzodiazepines are
  mediated by alterations in the potential-dependent
  calcium ion flux.

benzodiazepine ?2-subunit
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Benzodiazepines

• Pharmacology
• Long-term administration of
• benzodiazepines produces tolerance
• _at_downregulation of the
  benzodiazepine-GABAA
• receptor complex
• _at_ after the cessation of long-term
  use of
• benzodiazepines, the receptor
  complex becomes
• upregulated

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Benzodiazepines

• Pharmacology
• The more rapid redistribution of
  midazolam and
• diazepam than that of lorazepam
  accounts for
• the shorter duration of their
  actions.
• half-life two
  times longer
• midazolam
  diazepam
• 
  potency six times

53
Benzodiazepines

• Effects on the Central Nervous System
• Midazolam, diazepam, and lorazepam all
  increase the seizure initiation threshold of
  local anesthetics.
• Midazolam and diazepam induce protective
  effect against cerebral hypoxia(less than that of
  pentobarbital).
• Antiemetic effects are not a prominent
  action.

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Benzodiazepines

• Effects on the Respiratory System
• respiratory depression is greater
  with
• midazolam than with diazepam and
  lorazepam
• midazolam is 5 to 9 times as potent as
  diazepam, peak onset of ventilatory depression is
  rapid (about 3 minutes), and significant
  depression remains for 60 to 120 minutes
• the faster the drug is given, the
  more quickly this
• peak depression occurs
• benzodiazepines and opioids produce
  additive or
• supra-additive (synergistic)
  respiratory depression

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Benzodiazepines

• Effects on the Respiratory System
• Apnea is related to the dose of the
  benzodiazepine and is more likely to occur in the
  presence of opioids. Old age, debilitating
  disease, and other respiratory depressant drugs
  probably also increase the incidence and degree
  of respiratory depression and apnea with
  benzodiazepines.

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Benzodiazepines

• Effects on the Cardiovascular System
• modest hemodynamic effects
• Midazolam causes greater decrease in
• arterial blood, but the hypotensive
  effect
• is minimal as seen with thiopental.
• combination of benzodiazepines with
• opioids products synergistic
  hemodynamic
• effect

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Benzodiazepines

• Uses should be titrated
• Intravenous Sedation, Oral Sedation,
• Induction and Maintenance of Anesthesia
• anxiolysis, amnesia, and elevation of
  the
• local anesthetic seizure threshold
• midazolam onset ??. Lorazepam??.?
• ?recovery is similar
• sedation and reliable amnesia
• Prolonged infusion will result in
  accumulation
• in the case of midazolam, significant
• concentration of the active metabolite.

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Benzodiazepines

• Uses
• Dosing should be reduced over time.
• ?????hemodynamic status,
• amnesia
• ???????????.???
• midazolam ???????
• dose, speed of injection, degree of
  
• premedication, age, ASA physical
  status, and
• concurrent anesthetic drugs

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Benzodiazepines

• Side Effects and Contraindications
• Benzodiazepines are remarkably safe
  drugs.
• most significant problem with midazolam
  is
• respiratory depression
• The major side effects of lorazepam and
• diazepam, in addition to respiratory
• depression, are venous irritation and
• thrombophlebitis

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• For me, the Miller is the best way to induction!
• ??????