General Anesthetics

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General Anesthetics
Michael H. Ossipov, Ph.D. Department of
Pharmacology
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Surgery Before Anesthesia
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Fun and Frolics led to Early Anesthesia
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History of Anesthesia (150 years old)
Joseph Priestly discovers N2O in 1773 Crawford
W. Long 1842. Country Dr. in Georgia first used
ether for neck surgery. Did not publicize, in
part because of concerns about negative fallout
from frolics. Tried to claim credit after
Mortons demonstration but Important lesson
learned if you dont publish it, it didnt
happen. Sir Humphrey Davy experimented with
N2O, reported loss of pain, euphoria Traveling
shows with N2O (1830s 1840s) Colt (of Colt
45 fame) Horace Wells 1844. Demonstrated N2O for
tooth extraction deemed a failure because
patient reacted.
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History of Anesthesia
William Morton, dentist first demonstration of
successful surgical anesthesia with ether
1846 John C. Warren, surgeon at MGH says
Gentlemen, this is no humbug! birth of modern
anesthesia Dr. John Snow administers chloroform
to Queen Victoria (1853) popularizes anesthesia
for childbirth in UK He becomes the first
anesthesia specialist. Note that ether became
anesthesia of choice in US, chloroform in UK
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Anesthesia

• Allow surgical, obstetrical and diagnostic
  procedures to be performed in a manner which is
  painless to the patient
• Allow control of factors such as physiologic
  functions and patient movement

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Anesthetic techniques

• General anesthesia
• Regional anesthesia
• Local anesthesia
• Conscious Sedation (monitored anesthesia care)

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What is Anesthesia

• No universally accepted definition
• Usually thought to consist of
• Oblivion
• Amnesia
• Analgesia
• Lack of Movement
• Hemodynamic Stability

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What is Anesthesia

• Sensory
• -Absence of intraoperative pain
• Cognitive
• -Absence of intraoperative awareness
• -Absence of recall of intraoperative events
• Motor
• -Absence of movement
• -Adequate muscular relaxation
• Autonomic
• -Absence of hemodynamic response
• -Absence of tearing, flushing, sweating

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Goals of General Anesthesia

• Hypnosis (unconsciousness)
• Amnesia
• Analgesia
• Immobility/decreased muscle tone
• (relaxation of skeletal muscle)
• Inhibition of nociceptive reflexes
• Reduction of certain autonomic reflexes
• (gag reflex, tachycardia, vasoconstriction)

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Desired Effects Of General Anesthesia (Balanced
Anesthesia)

• Rapid induction
• Sleep
• Analgesia
• Secretion control
• Muscle relaxation
• Rapid reversal

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Phases of General Anesthesia
Stages Of General Anesthesia

• Induction- initial entry to surgical anesthesia
• Maintenance- continuous monitoring and medication
• Maintain depth of anesthesia, ventilation, fluid
  balance, hemodynamic control, hoemostasis
• Emergence- resumption of normal CNS function
• Extubation, resumption of normal respiration

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Stages Of General Anesthesia
Phases of General Anesthesia
Stage I Disorientation, altered
consciousness Stage II Excitatory stage,
delirium, uncontrolled movement, irregular
breathing. Goal is to move through this stage as
rapidly as possible. Stage III Surgical
anesthesia return of regular respiration. Plane
1 light anesthesia, reflexes, swallowing
reflexes. Plane 2 Loss of blink reflex,
regular respiration (diaphragmatic and chest).
Surgical procedures can be performed at this
stage. Plane 3 Deep anesthesia. Shallow
breathing, assisted ventilation needed. Level of
anesthesia for painful surgeries (e.g. abdominal
exploratory procedures). Plane 4 Diaphragmatic
respiration only, assisted ventilation is
required. Cardiovascular impairment. Stage IV
Too deep essentially an overdose and represents
anesthetic crisis. This is the stage between
respiratory arrest and death due to circulatory
collapse.
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Routes of Induction

• Intravenous
• Safe, pleasant and rapid
• Mask
• Common for children under 10
• Most inhalational agents are pungent, evoke
  coughing and gagging
• Avoids the need to start an intravenous catheter
  before induction of anesthesia
• Patients may receive oral sedation for separation
  from parents/caregivers
• Intramuscular
• Used in uncooperative patients

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Anesthetic Techniques

• Inhalation anesthesia
• Anesthetics in gaseous state are taken up by
  inhalation
• Total intravenous anesthesia
• Inhalation plus intravenous (Balanced
  Anesthesia)
• Most common

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Anesthetic drugs have rapid onset and offset

• Minute to minute control is the holy grail of
  general anesthesia
• Allows rapid adjustment of the depth of
  anesthesia
• Ability to awaken the patient promptly at the end
  of the surgical procedure
• Requires inhalation anesthetics and short-acting
  intravenous drugs

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Anesthetic Depth

• During the maintenance phase, anesthetic doses
  are adjusted based upon signs of the depth of
  anesthesia
• Most important parameter for monitoring is blood
  pressure
• There is no proven monitor of consciousness

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Selection of anesthetic technique

• Safest for the patient
• Appropriate duration
• i.v. induction agents for short procedures
• Facilitates surgical procedure
• Most acceptable to the patient
• General vs. regional techniques
• Associated costs

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MAC Minimal Alveolar Concentration

• "The alveolar concentration of an inhaled
  anesthetic that prevents movement in 50 of
  patients in response to a standardized stimulus
  (eg, surgical incision)."
• A measure of relative potency and standard for
  experimental studies.
• MAC values remain constant regardless of stimuli,
  weight, sex, and even across species
• Steep DRC 50 respond at 1 MAC but 99 at 1.3
  MAC
• MAC values for different agents are approximately
  additive. (0.7 MAC N2O 0.6 MAC halothane 1.3
  MAC total)
• "MAC awake," (when 50 of patients open their
  eyes on request) is approximately 0.3.
• Light anesthesia is 0.8 to 1.2 MAC, often
  supplemented with adjuvant i.v. drugs

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Factors Affecting MAC

• Circadian rhythm
• Body temperature
• Age
• Other drugs
• Prior use
• Recent use

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How do Inhalational Anesthetics Work?

• Surprisingly, the mechanism of action is still
  largely unknown.
• "Anesthetics have been used for 160 years, and
  how they work is one of the great mysteries of
  neuroscience," James Sonner, M.D. (UCSF)
• Anesthesia research "has been for a long time a
  science of untestable hypotheses," Neil L.
  Harrison, M.D. (Cornell University)

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How do Inhalational Anesthetics Work?
Meyer-Overton observation There is a strong
linear correlation between lipid solubility and
anesthetic potency (MAC)
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How do Inhalational Anesthetics Work?

• Membrane Stabilization Theory
• Site of action in lipid phase of cell membranes
  (membrane stabilizing effect) or
• Hydrophobic regions of membrane-bound proteins
• May induce transition from gel to liquid
  crystalline state of phospholipids
• Supported by NMR and electron-spin resonance
  studies
• Anesthesia can be reduced by high pressure

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How do Inhalational Anesthetics Work?

• Promiscuous Receptor Agonist Theory Anesthetics
  may act at GABA receptors, NMDA receptors, other
  receptors
• May act directly on ion channels
• May act in hydrophobic pouches of proteins
  associated with receptors
• May effect allosteric interaction to alter
  affinity for ligands
• Immobility is due to a spinal mechanism, but site
  is unknown
• Overall, the data can be explained by supposing
  that the primary target sites underlying general
  anesthesia are amphiphilic pockets of
  circumscribed dimensions on particularly
  sensitive proteins in the central nervous
  system. Franks and Lieb, Environmental Health
  Perspectives 87199-205, 1990.

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Receptors Possibly Mediating CNS Effects Of
Inhaled Anesthetics

• Potentiation of inhibitory receptors
• GABAA
• Glycine
• Potassium channels

• Inhibition of excitatory receptors
• NMDA (glutamate)
• AMPA (glutamate)
• Nicotinic acetylcholine
• Sodium channels

Inferred from demonstration of effect on receptor
at clinically relevant concentrations and lack of
effect in absence of receptor
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Inhaled Anesthetics

• Gases
• Nitrous oxide
• Present in the gaseous state at room temperature
  and pressure
• Supplied as compressed gas

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Inhaled Anesthetics

• Volatile anesthetics
• Present as liquids at room temperature and
  pressure
• Vaporized into gases for administration

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Inhaled Anesthetics

• Volatile anesthetics
• Present as liquids at room temperature and
  pressure BUT NOT ALWAYS!
• Vaporized into gases for administration

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Concentration of Inhaled Anesthetics Determines
Dose

• Partial pressure (mmHg)
• Applies to gas phase or to dissolved gases
• Volumes
• Percentage of total gas volume contributed by
  anesthetic
• Percentage of total gas molecules contributed by
  anesthetic
• Partial pressure/atmospheric pressure

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Solubility of Inhaled Anesthetics Determines Dose
and Time-course

• Ratio of concentration in one phase to that in a
  second phase at equilibrium
• Important solubility coefficients for inhaled
  anesthetics
• Lower blood-gas partition coefficient leads to
  faster induction and emergence
• Higher oil-gas partition coefficient leads to
  increased potency

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Chemistry
(CF3)2CH-O-CH3 10, excellent anesthesia CF3CHFC
F2-O-CH3 5, light anesthesia,
tremors CF3CH2-O-CF2CH2F 3, convulsions CF3CH2
-O-CH2CF3 (Indoklon) 0.25, marked
convulsions CF3CF2-O-CF2CF3 Inert
From F.G. Rudo and J.C. Krantz, Br. J. Anaesth.
(1974), 46, 181
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Inhaled Anesthetics
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Inhaled Anesthetics - Historical

• Ether Slow onset, recovery, explosive
• Chloroform Slow onset, very toxic
• Cyclopropane Fast onset, but very explosive
• Halothane (Fluothane) first halogenated ether
  (non-flammable)
• 50 metabolism by P450, induction of hepatic
  microsomal enzymes TFA, chloride, bromide
  released
• Myocardial depressant (SA node), sensitization of
  myocardium to catecholamines
• Hepatotoxic
• Methoxyflurane (Penthrane) - 50 to 70
  metabolized
• Diffuses into fatty tissue
• Releases fluoride, oxalic acid
• Renotoxic

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Inhaled Anesthetics Currently

• Enflurane (Ethrane) Rapid, smooth induction and
  maintenance
• 2-10 metabolized in liver
• Introduced as replacement for halothane,
  canabilized to make way for isoflurane
• Isoflurane (Forane) smooth and rapid induction
  and emergence
• Very little metabolism (0.2)
• Control of Cerebral blood flow and Intracranial
  pressure
• Potentiates muscle relaxants, Uterine relaxation
• CO maintained, arrhythmias uncommon, epinephrine
  can be used with isoflurane Preferential
  vasodilation of small coronary vessels can lead
  to coronary steal
• No reports of hepatotoxicity or renotoxicity
• Most widely employed

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Inhaled Anesthetics New Kids on the Block

• Desflurane (Suprane) Very fast onset and offset
  (minute-to minute control) because of its low
  solubility in blood
• Differs from isoflurane by replacing one Cl with
  F
• Minimal metabolism
• Very pungent - breath holding, coughing, and
  laryngeal spasm not used for induction
• No change in cardiac output tachycardia with
  rapid increase in concentration, No coronary
  steal
• Degrades to form CO in dessicated soda-lime
  (Ba2OH /NaOH/KOH not Ca2OH)
• Fast recovery responsive within 5-10 minutes

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Inhaled Anesthetics New Kids on the Block

• Sevoflurane (Ultane) Low solubility and low
  pungency excellent induction agent
• Significant metabolism (5 10x gt isoflurane)
  forms inorganic fluoride and hexafluoroisoproprano
  lol
• No tachycardia, Prolong Q-T interval, reduce CO,
  little tachycardia
• Soda-lime (not Ca2OH) degrades sevoflurane into
  Compound A
• Nephrotoxic in rats
• Occurs with dessicated CO2 absorbant
• Increased at higher temp, high conc, time
• No evidence of clinical toxicity
• Metallic/environmental impurities can form HF

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Inhaled Anesthetics Currently

• Nitrous Oxide is still widely used
• Potent analgesic (NMDA antagonist)
• MAC 120
• Used ad adjunct to supplement other inhalationals
• Xenon
• Also a potent analgesia (NMDA antagonist)
• MAC is around 80
• Just an atom what about mechanism of action?

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Malignant Hyperthermia
Malignant hyperthermia (MH) is a pharmacogenetic
hypermetabolic state of skeletal muscle induced
in susceptible individuals by inhalational
anesthetics and/or succinylcholine (and maybe by
stress or exercise).

• Genetic susceptibility-Ca channel defect
  (CACNA1S) or RYR1 (ryanodine receptor)
• Excess calcium ion leads to excessive ATP
  breakdown/depletion, lactate production,
  increased CO2 production, increased VO2, and,
  eventually, to myonecrosis and rhabdomyolysis,
  arrhythmias, renal failure
• May be fatal if not treated with dantrolene
  increases reuptake of Ca in Sarcoplasmic
  Reticulum
• Signs tachycardia tachypnea ETCO2 increasing
  metabolic acidosis also hyperthermia, muscle
  rigidity, sweating, arrhythmia
• Detection
• Caffeine-halothane contracture testing (CHCT) of
  biopsied muscle
• Genetic testing for 19 known mutations associated
  with MH

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Intravenous Anesthetics

• Most exert their actions by potentiating GABAA
  receptor
• GABAergic actions may be similar to those of
  volatile anesthetics, but act at different sites
  on receptor
• High-efficacy opiods (fentanyl series) also
  employed
• Malignant hyperthermia is NOT a factor with these

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Intravenous Anesthetics
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Organ Effects

• Most decrease cerebral metabolism and
  intracranial pressure. Often used in the
  treatment of patients at risk for cerebral
  ischemia or intracranial hypertension.
• Most cause respiratory depression
• May cause apnea after induction of anesthesia

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Cardiovascular Effects

• Barbiturates, benzodiazepines and propofol cause
  cardiovascular depression.
• Those drugs which do not typically depress the
  cardiovascular system can do so in a patient who
  is compromised but compensating using increased
  sympathetic nervous system activity.

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Intravenous Anesthetics - Barbiturates
Ideal Rapid Onset, short-acting Thiopental
(pentathol)- previously almost universally
used For over 60 years was the standard against
which other injectable induction
agents/anesthetics were compared Others
Suritol (thiamylal) Brevital (methohexital) Act
at GABA receptors (inhibitory), potentiate
endogenous GABA activity at the receptor, direct
effect on Cl channel at higher concentrations. Ef
fect terminated not by metabolism but by
redistribution repeated administration or
prolonged infusion approached equlibrium at
redistribution sites. Redistribution not
effective in terminating action, led to many
deaths. Build-up in adipose tissue very long
emergence from anesthesia (e.g. one case took 4
days to emerge)
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Propofol (Diprivan)

• Originally formulated in egg lecithin emulsion
• anaphylactoid reactions
• Current formulation 1 propofol in 10 soybean
  oil, 2.25 glycerol, 1.2 egg phosphatide
• Pain on injection
• Onset within 1 minute of injection
• Not analgesic
• Enhances activity of GABA receptors (probably)
• Vasodilation, respiratory depression, apnea (25
  to 40)
• Induction and maintenance of anesthesia or
  sedation
• Rapid emergence from anesthesia
• Antiemetic effect
• Feeling of well-being
• Widely used for ambulatory surgery

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Etomidate (Amidate)

• Insoluble in water, formulated in 35 propylene
  glycol (pain on injection)
• Little respiratory depression
• Minimal cardiovascular effects
• Rapid induction (arm-to-brain time), duration 5
  to 15 minutes
• Most commonly used for induction of anesthesia in
  patients with cardiovascular compromise or where
  cardiovascular stability is most important
• Metabolized to carboxylic acid, 85 excreted in
  urine, 15 in bile
• Rapid emergence from anesthesia
• Adverse effects Pain, emesis, involuntary
  myoclonic movements, inhibition of adrenal
  steroid synthesis

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Ketamine

• Chemically and pharmacologically related to PCP
• Inhibits NMDA receptors
• Analgesic, dissociative anesthesia
• Cataleptic appearance, eyes open, reflexes
  intact, purposeless but coordinated movements
• Stimulates sympathetic nervous system
• Indirectly stimulates cardiovascular system,
  Direct myocardial depressant
• Increases cerebral metabolism and intracranial
  pressure
• Lowers seizure threshold
• Psychomimetic emergence reactions
• vivid dreaming extracorporeal (floating
  "out-of-body") experience misperceptions,
  misinterpretations, illusions
• may be associated with euphoria, excitement,
  confusion, fear

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Benzodiazepines

• Diazepam (Valium, requires non-aqueous vehicle,
  pain on injection) Replaced by Midazolam
  (Versed) which is water-soluble.
• Rapidly redistributed, but slowly metabolized
• Useful for sedation, amnesia
• Not analgesic, can be sole anesthetic for
  non-painful procedures (endoscopies, cardiac
  catheterization)
• Does not produce surgical anesthesia alone
• Commonly used for preoperative sedation and
  anxiolysis
• Can be used for induction of anesthesia
• Safe minimal respiratory and cardiovascular
  depression when used alone, but they can
  potentiate effects of other anesthetics (e.g.
  opioids)
• Rapid administration can cause transient apnea

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Opioids

• i.v. fentanyl, sufentanil, alfentanil,
  remifentanyl or morphine
• Usually in combination with inhalant or
  benzodiazepine
• Respiratory depression, delayed recovery, nausea
  and vomiting post-op
• Little cardiovascular depression Provide more
  stable hemodynamics
• Smooth emergence (except for N V)
• Excellent Analgesic intra-operative analgesia
  and decrease early postoperative pain
• Remifentanil has ester linkage, metabolized
  rapidly by nonspecific esterases (t1/2 4
  minutes fentanyl t1/2 3.5 hours)
• Rapid onset and recovery
• Recovery is independent of dose and duration
  offers the high degree of minute to minute
  control

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Conscious sedation

• A term used to describe sedation for diagnostic
  and therapeutic procedures throughout the
  hospital.
• Ambiguous because no one really knows how to
  measure consciousness in the setting of a patient
  receiving sedation.

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Depth of sedation
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Conscious sedation

• Each health care facility should have policies
  and procedures defining conscious sedation and
  specifying the procedures and training required
  for its use.
• Before sedating patients one should review and
  follow these policies and procedures.
• One should also understand sedative medications
  and have the knowledge and skills required for
  the treatment of possible complications (e.g.
  apnea).

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Conscious sedation

• The most common mistake is to over-sedate the
  patient. If the patient is comfortable, there is
  no need for more medication.
• The safest method of sedation is to carefully
  titrate sedative medications in divided doses.
• Allow enough time between doses to assess the
  effects of the previous dose.
• Administer medications until the desired level of
  sedation is reached, but not past the point where
  the patient is capable of responding verbally.
• Midazolam and fentanyl are among the easiest
  drugs to use. Midazolam provides sedation and
  anxiolysis and fentanyl provides analgesia.

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What is Balanced Anesthesia?

• Use specific drugs for each component
• Sensory
• N20, opioids, ketamine for analgesia
• Cognitive
• Produce amnesia, and preferably unconsciousness,
  with N2O, .25-.5 MAC of an inhaled agent, or an
  IV hypnotic (propofol, midazolam, diazepam,
  thiopental)
• Motor
• Muscle relaxants as needed
• Autonomic
• If sensory and cognitive components are adequate,
  usually no additional medication will be needed
  for autonomic stability. If some is needed,
  often a beta blocker /- vasodilator is used.

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What is Balanced Anesthesia?

• Garbage Anesthesia (everything but the kitchen
  sink)
• LOT2 (Little Of This, Little of That)
• Mixed Technique
• The Usual

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MAC Reduction
Lang et al, Anesthesiology 85, 721-728, 1996
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Bolus Dose Equivalents

• Fentanyl 100 mg (1.5 mg/kg)
• Remifentanil 35 mg (0.5 mg/kg)
• Alfentanil 500 mg (7 mg/kg)
• Sufentanil 12 mg (0.2 mg/kg)

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What is the role of N2O?

• Excellent analgesic in sub-MAC doses
• MAC is around 110.
• MACasleep tends to be about 60 of MAC.
• MACasleep for N2O is 68-73
• Well tolerated by most patients but bad news if
  you are subject to migraine.
• At N2O concentrations of 70, there may be no
  need for additional drugs to ensure lack of
  awareness.
• Has the fastest elimination of any hypnotic agent
  used in anesthesia.
• If you want your patients to wake up quickly,
  keep them within N2O of being awake!

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Simple Combinations

• Morphine
• 10 mg iv 3-5 minutes prior to induction
• Additional 5 mg 45 minutes before the end of the
  procedure, if it lasts longer than 2 hours
• Propofol
• 2-3 mg/kg on induction
• N2O
• 70
• Sevoflurane
• 0.3-0.6
• Relaxant of choice

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Simple Combinations

• Fentanyl
• 75-150 on induction
• 25-50 mg now and then during the case
• Propofol
• 2-3 mg/kg on induction
• N2O
• 70
• Sevoflurane
• 0.3-0.6
• Relaxant of choice

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Local/Regional Anesthetics
Michael H. Ossipov, Ph.D. Department of
Pharmacology
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General concepts

• Cocaine isolated from Erythroxylon coca plant in
  Andes
• Von Anrep (1880) discovers local anesthetic
  property, suggests clinical use
• Koller introduces cocaine in opthalmology
• Freud uses cocaine to wean Karl Koller off
  morphine
• Halstead demonstrates infiltration anesthesia
  with cocaine
• Rapidly accepted in dentistry

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General concepts

• Halstead (1885) shows cocaine blocks nerve
  conduction in nerve trunks
• Corning (1885) demonstrates spinal block in dogs
• 1905 Procaine (NOVOCAINE) synthesized
• analog of cocaine but without euphoric effects,
  retains vasoconstrictor effect
• Slow onset, fast offset, ester-type (allergic
  reactions)

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General concepts

• First modern LA (1940s) lidocaine (lignocaine
  in UK XYLOCAINE)
• Amide type (hypoallergenic)
• Quick onset, fairly long duration (hrs)
• Most widely used local anesthetic in US today,
  along with bupivacaine and tetracaine

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General concepts

• Cause transient and reversible loss of sensation
  in a circumscribed area of the body
• Very safe, almost no reports of permanent nerve
  damage from local anesthetics
• Interfere with nerve conduction
• Block all types of fibers (axons) in a nerve
  (sensory, motor, autonomic)

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Local anesthetics Uses

• Topical anesthesia (cream, ointments, EMLA)
• Peripheral nerve blockade
• Intravenous regional anesthesia
• Spinal and epidural anesthesia
• Systemic uses (antiarrhythmics, treatment of pain
  syndromes)

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Structure

• All local anesthetics are weak bases. They all
  contain
• An aromatic group (confers lipophilicity)
• - diffusion across membranes, duration,
  toxicity increases with lipophilicity
• An intermediate chain, either an ester or an
  amide and
• An amine group (confers hydrophilic properties)
• charged form is the major active form

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Structure

• Formulated as HCl salt (acidic) for solubility,
  stability
• But, uncharged (unprotonated N) form required to
  traverse tissue to site of action
• pH of formulation is irrelevant since drug ends
  up in interstitial fluid
• Quaternary analogs, low pH bathing medium
  suggests major form active at site is cationic,
  but both charged and uncharged species are active

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O
?

COCH
H
N
CH
N
H

H
2
2
2
Nonionized base
Cationic acid
1.0
Base
Log
Lipoid barriers
(nerve sheath)
pH p
K
a
Acid
(Henderson-Hasselbalch equation)
Extracellular
Base Acid
1.0
fluid
For procaine (p
K
8.9)
a
at tissue pH (7.4)
Nerve membrane
3.1

Base
Axoplasm
Base Acid
2.5

0.03
Acid
71
Structure

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Structure

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Mode of action

• Block sodium channels
• Bind to specific sites on channel protein
• Prevent formation of open channel
• Inhibit influx of sodium ions into the neuron
• Reduce depolarization of membrane in response to
  action potential
• Prevent propagation of action potential

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Mode of action
75
Mode of action
76
Mode of action
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Sensitivity of fiber types

• Unmyelinated are more sensitive than myelinated
  nerve fibers
• Smaller fibers are generally more sensitive than
  large-diameter peripheral nerve trunks
• Smaller fibers have smaller critical lengths
  than larger fibers (mm range)
• Accounts for faster onset, slower offset of local
  anesthesia
• Overlap between block of C-fibers and Ad-fibers.

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Choice of local anesthetics

• Onset
• Duration
• Regional anesthetic technique
• Sensory vs. motor block
• Potential for toxicity

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Clinical use
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Choice of local anesthetics
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Factors influencing anesthetic activity

• Needle in appropriate location (most important)
• Dose of local anesthetic
• Time since injection
• Use of vasoconstrictors
• pH adjustment
• Nerve block enhanced in pregnancy

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Redistribution and metabolism

• Rapidly redistributed
• More slowly metabolized and eliminated
• Esters hydrolyzed by plasma cholinesterase
• Amides primarily metabolized in the liver

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Local anesthetic toxicity

• Allergy
• CNS toxicity
• Cardiovascular toxicity

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Allergy

• Ester local anesthetics may produce true allergic
  reactions
• Typically manifested as skin rashes or
  bronchospasm. May be as severe as anaphylaxis
• Due to metabolism to ?-aminobenzoic acid
• True allergic reactions to amides are extremely
  rare.

87
Systemic toxicity

• Results from high systemic levels
• First symptoms are generally CNS disturbances
  (restlessness, tremor, convulsions) - treat with
  benzodiazepines
• Cardiovascular toxicity generally later

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CNS symptoms

• Tinnitus
• Lightheadedness, Dizziness
• Numbness of the mouth and tongue, metal taste in
  the mouth
• Muscle twitching
• Irrational behavior and speech
• Generalized seizures
• Coma

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Cardiovascular toxicity

• Depressed myocardial contractility
• Systemic vasodilation
• Hypotension
• Arrhythmias, including ventricular fibrillation
  (bupivicaine)

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Avoiding systemic toxicity

• Use acceptable total dose
• Avoid intravascular administration (aspirate
  before injecting)
• Administer drug in divided doses

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Maximum safe doses of local anesthetics in adults
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Uses of Local Anesthetics

• Topical anesthesia
• - Anesthesia of mucous membranes (ears, nose,
  mouth, genitourinary, bronchotrachial)
• - Lidocaine, tetracaine, cocaine (ENT only)
• EMLA (eutectic mixture of local anesthetics)
• cream formed from lidocaine (2.5) prilocaine
  (2.5) penetrates skin to 5mm within 1 hr,
  permits superficial procedures, skin graft
  harvesting
• Infiltration Anesthesia
• - lidocaine, procaine, bupivacaine (with or w/o
  epinephrine)
• - block nerve at relatively small area
• - anesthesia without immobilization or
  disruption of bodily functions
• - use of epinephrine at end arteries (i.e.
  fingers, toes) can cause severe vasoconstriction
  leading to gangrene

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Uses of Local Anesthetics

• Nerve block anesthesia
• - Inject anesthetic around plexus (e.g.
  brachial plexus for shoulder and upper arm) to
  anesthetize a larger area
• - Lidocaine, mepivacaine for blocks of 2 to 4
  hrs, bupivacaine for longer
• Bier Block (intravenous)
• - useful for arms, possible in legs
• - Lidocaine is drug of choice, prilocaine can
  be used
• - limb is exsanguinated with elastic bandage,
  infiltrated with anesthetic
• - tourniquet restricts circulation
• - done for less than 2 hrs due to ischemia,
  pain from touniquet

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Uses of Local Anesthetics

• Spinal anesthesia
• - Inject anesthetic into lower CSF (below L2)
• - used mainly for lower abdomen, legs, saddle
  block
• - Lidocaine (short procedures), bupivacaine
  (intermediate to long), tetracaine (long
  procedures)
• - Rostral spread causes sympathetic block,
  desirable for bowel surgery
• - risk of respiratory depression, postural
  headache

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Uses of Local Anesthetics

• Epidural anesthesia
• - Inject anesthetic into epidural space
• - Bupivacaine, lidocaine, etidocaine,
  chloroprocaine
• - selective action of spinal nerve roots in
  area of injection
• - selectively anesthetize sacral, lumbar,
  thoracic or cervical regions
• - nerve affected can be determined by
  concentration
• - High conc sympathetic, somatic sensory,
  somatic motor
• - Intermediate somatic sensory, no motor block
• - low conc preganglionic sympathetic fibers
• - used mainly for lower abdomen, legs, saddle
  block
• - Lidocaine (short procedures), bupivacaine
  (intermediate to long), tetracaine (long
  procedures)
• - Rostral spread causes sympathetic block,
  desirable for bowel surgery
• - risk of respiratory depression, postural
  headache

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Neuromuscular Blocking Drugs
Michael H. Ossipov, Ph.D. Department of
Pharmacology
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Neuromuscular blocking drugs
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• Extract of vines (Strychnos toxifera also
  Chondrodendron species)
• Used by indegenous peoples of Amazon basin in
  poison arrows (not orally active, so food is safe
  to eat)
• Brought to Europe by Sir Walter Raleigh, others
• Curare-type drugs Tubocurare (bamboo tubes),
  Gourd curare, Pot curare
• Brody (1811) showed curare is not lethal is
  animal is ventilated
• Harley (1850) used curare for tetanus and
  strychnine poisoning
• Harold King (1935) isolates d-tubocurarine from a
  museum sample determines structure.

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Neuromuscular blocking drugs
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• Block synaptic transmission at the neuromuscular
  junction
• Affect synaptic transmission only at skeletal
  muscle
• Does not affect nerve transmission, action
  potential generation
• Act at nicotinic acetylcholine receptor NII

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Neuromuscular blocking drugs
0
(CH3)3N-(CH2)6-N(CH3)3 Hexamethonium (ganglionic
)
(CH3)3N-(CH2)10-N(CH3)3 Decamethonium (motor
endplate)
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Neuromuscular blocking drugs
0

• Acetylcholine is released from motor neurons in
  discrete quanta
• Causes all-or-none rapid opening of Na/K
  channels (duration 1 msec)
• Development of miniature end-plate potentials
  (mEPP)
• Summate to form EPP and muscle action potential
  results in muscle contraction
• ACh is rapidly hydrolyzed by acetylcholinesterase
  no rebinding to receptor occurs unless AChE
  inhibitor is present

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Non-depolarizing Neuromuscular blocking drugs
0

• Competetive antagonist of the nicotinic 2
  receptor
• Blocks ACh from acting at motor end-plate
• Reduction to 70 of initial EPP needed to prevent
  muscle action potential
• Muscle is insensitive to added Ach, but reactive
  to K or electrical current
• AChE inhibitors increase presence of ACh,
  shifting equilibrium to favor displacing the
  antagonist from motor end-plate

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Nondepolarizing drugs Metabolism
0

• Important in patients with impaired organ
  clearance or plasmacholinesterase deficiency
• Hepatic metabolism and renal excretion (most
  common)
• Atracurium, cis-atracurium nonenzymatic (Hoffman
  elimination)
• Mivacurium plasma cholinesterase

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Depolarizing Neuromuscular blocking drugs
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• Succinylcholine, decamethonium
• Bind to motor end-plate and cause immediate and
  persistent depolarization
• Initial contraction, fasciculations
• Muscle is then in a depolarized, refractory state
• Desensitization of Ach receptors
• Insensitive to K, electrical stimulation
• Paralyzes skeletal more than respiratory muscles

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Succinlycholine Pharmacokinetics
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• Fast onset (1 min)
• Short duration of action (2 to 3 min)
• Rapidly hydrolyzed by plasma cholinesterase

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Succinlycholine Clinical uses
0

• Tracheal intubation
• Indicated when rapid onset is desired (patient
  with a full stomach)
• Indicated when a short duration is desired
  (potentially difficult airway)

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Succinylcholine Side effects
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• Prolonged neuromuscular blockade
• In patients lacking pseudocholinesterase
• Treat by maintaining ventilation until it wears
  off hours later

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Succinylcholine Phase II block
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• Prolonged exposure to succinlycholine
• Features of nondepolarizing blockade
• May take several hours to resolve
• May occur in patients unable to metabolize
  succinylcholine (cholinesterase defects,
  inhibitors)
• Harmless if recognized

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Acetylcholinesterase inhibitors
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• Acetylcholinesterase inhibitors have muscarinic
  effects
• Bronchospasm
• Urination
• Intestinal cramping
• Bradycardia
• Prevented by muscarinic blocking agent

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Selection of muscle relexant
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• Onset and duration
• Route of metabolism and elimination

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Monitoring NM blockade
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• Stimulate nerve
• Measure motor response (twitch)
• Depolarizing neuromuscular blocker
• Strength of twitch
• Nondepolarizing neuromuscular blocker
• Strength of twitch
• Decrease in strength of twitch with repeated
  stimulation

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