GERERAL ANESTHESIA AND PHARMACOLOGY OF GENERAL ANESTHETICS

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GERERAL ANESTHESIA AND PHARMACOLOGY OF GENERAL
ANESTHETICS
Amir B. Channa FFARCS,DA(ENG) Department of
Anesthesia Intensive Care King Khalid
University Hospital Riyadh
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Anesthesia Types

• Local Anesthesia loss of sensory perception over
  a small area of the body
• Regional Anesthesia loss of sensation over a
  specific region of the body (e.g. lower trunk)
• General Anesthesia loss of sensory perception of
  the entire body

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Anesthesia
The administration of drugs that alleviate pain
or other sensation and movement
General Effects CNS
Local Effects a specific region of the PNS
General anesthesia is a state of reversible loss
of consciousness for the purpose of carrying out
surgery.
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Desirable components of anesthesia

• Immobility in response to noxious stimulus
• Anxiolysis
• Amnesia
• 3. Analgesia
• 4. Unconsiousness
• 5. Muscle relaxation
• 6. Loss of autonomic reflexes

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Historical Perspectives

• History
• First attempts
• Egyptian - compression
• Grecian - wine and mandragora
• Scythian - hemp
• Indian - hemp
• Chinese - hemp

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Effects of general anesthesia

• High Dose Effects
• Deep sedation
• Muscle relaxation
• Diminished motor responses
• Diminished autonomic responses
• Myocardial protection from ischemia
• Cardiovascular/respiratory depression
• Hypothermia
• Nausea, vomiting
• Death (1 per 250,000)

• Low Dose Effects
• Amnesia
• Euphoria
• Analgesia
• Hypnosis
• Excitation
• Hyperreflexia

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Before Anesthesia

• Surgery uncommon
• Aseptic technique unknown
• Surgical pain relief
• alcohol,
• hashih,
• opium
• physical methods (ice, ischemia)
• unconsiousness (blow to head, strangulation)
• simple restraint most common

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General Anesthetics
Parenteral
Inhalational
Gas
Volatile liquids
Induction Agents Barbiturates eg thiopentone
Propofol etomidate etc
nitrous oxide
halothaneisoflurane,desflurane, sevoflurane
Opioids
(fentanyl) Sufentanil remifentanil
Benzodiazepines
midozolam

• NMRELAXANTs
• Suxa
• Atracurium Cisat

In the beginning there was ether chloroform
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Phases of Anesthesia
Induction putting the patient to
sleep Maintenance keeping the patient asleep
(without awareness) Emergence waking the
patient up (recovery)
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Dose Response Relationships
Barbiturates
Coma
Medullary depression
Benzodiazepines
CNS Effects
Anesthesia
Hypnosis
Possible selective anticonvulsant
muscle-relaxing activity
Sedation, disinhibition, anxiolysis

Increasing dose
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CLASSIFICATION OF GENERAL ANESTHETICS

• 1. Intravenous agents
• primarily used for induction
• Barbiturates thiopentone and methohexitone
• Benzodiazepines midololam lorezepam
• Etomidate
• Ketamine
• Propofol
• TIVA PROPOFOL (total IV anesthesia)

B
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• INTRAVENOUS ANAESTHETICS
• Rapid onset (seconds)
• Rapid awakening (minutes)
• Danger of overdose due to irrevocability of i.v.
  injection
• Redistribution determines duration of action

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GENERAL ANAESTHETICSCLASSIFICATION

• 2. Inhalational agents
• primarily used for maintenance
• 2a Volatile agents
• Isoflurane
• Sevoflurane
• Desflurane
• Halothane, Enflurane
• Diethyl ether, chloroform, cyclopropane
• 2b Anesthetic gases
• Nitrous Oxide- currently used
• Xenon- in the near future?

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Mechanisms of Action

• Enhanced GABA effect on GABAA Receptors
• Inhaled anesthetics - Etomidate
• Barbiturates - Propofol
• Benzodiazepines
• Block nicotinic receptor subtypes (analgesia)
• Moderate to high concs of inhaled anesthetics
• Activate K channels (hyperpolarize Vm)
• Nitrous oxide, ketamine, xenon
• Inhibit NMDA (glutamate) receptors
• Nitrous oxide, ketamine, xenon, high dose
  barbiturates
• Inhibit synaptic proteins (?NT release)(amnesia)
• Enhance glycine effect on glycine Rs
  (immobility)

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Inhalational Agents
Halogenated hydrocarbons (Volatile)
Nitrous oxide (Gas)
N
N
O
Anesthesia machine work station
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Preanesthetic Medications

• Benzodiazepines
• Reduce anxiety
• Midazolam, diazepam
• Barbiturates
• Sedation
• Pentobarbital
• Antihistamines
• Prevention of allergic reactions
• Diphenhydramine
• Antiemetics
• Prevent aspiration of stomach contents
• Reduce postsurgical nausea and vomiting
• Ondansetrone

• Opioids
• Provide analgesia
• Fentanyl
• Anticholinergics
• Amnesia, prevent bradycardia, and fluid secretion
• Scopolamine
• Muscle relaxants
• Facilitation of intubation

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CHARACTERSITICS OF ANIDEAL ANAESTHETIC

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• Rapid and pleasant induction
• Rapid changes in the depth of anesthesia
• Adequate muscle relaxation
• Wide margin of safety
• Absence of toxic/adverse effects
• No emergence problems 

No single agent yet identified is an ideal
anesthetic
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Anesthetic Uptake and Distribution

• Vessel Rich Group (VRG)
• CNS and visceral organs
• High blood flow (75) and low capacity
• Muscle Group (MG)
• Skin and muscle
• Moderate flow and high capacity
• Fat Group (FG)
• Low flow and high capacity
• Vessel Poor Group
• Bone, cartilage, ligaments
• Low flow and low capacity

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Search for the molecular mechanism(s) of general
anesthesia
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Mechanism of action Intravenous Anesthetics

• Cause anesthesia via GABAa receptors
• Specific selective targets
• Specific sites for specific effects
• Different anesthetics have different mechanisms

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Anesthetic of the Future Xenon

• Rare gas extracted from air
• Very expensive to produce
• Close to ideal anesthetic
• Low blood and tissue solubility
• (rapid induction/recovery)
• Potent
• Not metabolized (totatally inert)
• Nonflammable
• Minimal side effects

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THERAPEUTIC GASES Oxygen

• Administered to prevent hypoxic injury
• Hypoxia can result from
• Hypoxemia (problem with lungs)
• Inadequate delivery to tissues
• Impaired utilization
• Can have toxic effects
• Due to free radical generation

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THERAPEUTIC GASES Nitric Oxide

• Important cell signalling molecule
• Can selectively dilate pulmonary vasculature
• Administered to newborns with persistent
  pulmonary hypertension
• Under investigation for many disease states
• Can have toxic effects

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Regional Effects

• Immobilization in response to surgical incision
  (spinal cord)
• Sedation, loss of consciousness (?thalamic
  firing)
• Amnesia (?hippocampal neurotransmission)

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Parenteral Anesthetics (Intravenous)

• Most commonly used drugs to induce anesthesia
• Barbiturates (Thiopental Methohexital)
• Benzodiazepines (Midazolam)
• Opioids (Morphine Fentanyl)
• Propofol
• Etomidate

Most commonly used for induction
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Barbiturates Benzodiazepines MOA

• 1) Both bind to GABAA receptors, at different
  sites
• Both cause increase Cl- influx in presence of
  GABA
• BNZ binding can be blocked by flumazenil
• 2) Barbs at high doses - are also GABA mimetic,
  block Na channels NMDA/glutamate Rs

(w/ ??)
-
O
Flumazenil
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Classic Stages of Anesthesia

• Stage 1 Analgesia
• decreased awareness of pain, amnesia
• Stage 2 Disinhibition
• delirium excitation, enhanced reflexes,
  retching, incontinence, irregular respiration
• Stage 3 Surgical Anesthesia
• unconscious, no pain reflexes, regular
  respiration, BP is maintained
• Stage 4 Medullary Depression
• respiratory CV depression requiring ventilation
  pharmacologic support.

Seen mainly with Ether. Not all stages are
observed with modern GAs.
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Barbiturates

• Thiopental methohexital are highly lipid
  soluble can produce unconsciousness surgical
  anesthesia in lt1 min.
• Rx induction of anesthesia short procedures
• Actions are terminated by redistribution
• With single bolus - emergence from GA occurs in
  10 mins
• Hepatic metabolism is required for elimination

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Thiopental (Pentothal )

• Barbs are respiratory circulatory depressants
• (Contraindicated hypovolemia,
  cardiomyopathy, beta-blockade,etc.)
• Psychomotor impairment may last for days after
  use of a single high dose
• Taste of garlic prior to anesthesia
• Potentially fatal attacks of porphyria in pts
  with a history of acute or intermittent
  porphyria.
• Delay giving other drugs (e.g. NMJ blockers)
  until barb has cleared the i.v. line to avoid
  precipitation.

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Propofol (Diprivan )

• Produces anesthesia as rapidly as i.v. barbs
  but recovery is more rapid than w/ barbs.
• Recovery is not delayed after prolonged infusion
  (due to more rapid clearance).
• Patients are able to ambulate sooner patients
  feel better in the post-op period compared to
  other i.v. anesthetics.
• Antiemetic effects (pts w/ ?risk of nausea)
• Can cause marked hypotension (gtbarbs)
• Commonly used as component of balanced
  anesthesia for maintenance of anesthesia
  following induction of anesthesia.

More rapid discharge from the recovery room
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Etomidate (Amidate )

• Rapid induction (1 min)
• Used as a supplement with nitrous oxide for short
  surgical procedures
• Short duration of action (3-5 mins)
• Hypnotic, but not analgesic
• Little effect on CV Respiration
• Can cause post-op nausea decrease cortisol
  production w/ long term infusion.
• Primarily used in pts w/ limited cardiac or
  respiratory reserve (safer than barbs or propofol
  in pts w/ coronary artery dx., cardiomyopathy,
  etc.)

increased mortality
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Benzodiazepines

• Midazolam (gt Diazepam Lorazepam)
• Used to produce anxiolysis, amnesia sedation
  prior to induction of GA w/ another agent.
• Sedative doses achieved w/in 2 min, w/ 30 min
  duration of action (short duration).
• Effects are reversed with flumazenil.

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Opioids (Morphine, Fentanyl Remifentanil)

• GAs do not produce effective analgesia (except
  for ketamine).
• Given before surgery to minimize hemodynamic
  changes produced by painful stimuli. This reduces
  GA requirements.
• High doses can cause chest wall rigidity
  post-op respiratory depression
• Therapeutic doses will inhibit respiration (?CO2)
• Used for post-op analgesia
• Remifentanil is an ester opioid metabolized by
  plasma esterases. It is very potent but w/ a
  short t1/2 (3-10 mins).

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Ketamine

• A dissociative anesthetic that produces a
  cataleptic state that includes intense analgesia,
  amnesia, eyes open, involuntary limb movement,
  unresponsive to commands or pain.
• Increases heart rate blood pressure (opposite
  of other GAs)
• Can be used in shock states (hypotensive) or
  patients at risk for bronchospasm.
• Used in children young adults for short
  procedures
• Side Effects nystagmus, pupillary dilation,
  salivation,
• Hallucinations vivid dreams emergence delirium

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Inhaled Anesthetics

• Easily vaporized liquid halogenated hydrocarbons
• Administered as gases

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Inhaled Anesthetics

• Partial pressure or tension in inspired air is
  a measure of their concentration
• The speed of induction of anesthesia depends on
• Inspired gas partial pressure (GA concentration)
• Ventilation rate
• GA solubility (less soluble GAs equilibrate more
  quickly with blood into tissues such as the
  brain)

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Minimum Alveolar Concentration

• The minimum alveolar anesthetic concentration
  required to eliminate the response to a painful
  stimulus in 50 of patients
• A measure of GA potency.
• Its a population average.
• 1.3 MAC - 100 will not respond to stimuli.
• When several GAs are mixed, their MAC values are
  additive (e.g. nitrous oxide is commonly mixed w/
  other anesthetics).

MAC Nitrous Oxide gt100Halothane 0.75Methox
yflurane 0.16
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MAC Patient Conditions

• Pregnancy - ? MAC (elevated progesterone)
• Elderly - ? MAC (less brain activity)
• Chronic Alcoholics - ?MAC (cross-tolerance)
• Acute alcohol poisoning - ? MAC (additive)

Bispectral Index Monitor (EEG) is used to
measure a patients anesthetic depth.
BIS LEVEL CLINICAL STATE
100 80 60 40 0
Awake Sedated Moderate hypnotic level (no
recall) Deep hynotic level Isoelectric EEG
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Elimination

• Anesthesia is most commonly terminated by
  redistribution of drug from brain to the blood
  out through the lungs.
• The rate of recovery from anesthesia for GAs
  with low bloodgas PCs is faster than for
  highly soluble Gas.
• - Time is in the O.R. recovery room
• BloodGas PCoeff
• Haltothane 2.30
• Desflurane 0.42
• Sevoflurane 0.69
• Halothane methoxyflurane undergo hepatic
  metabolism can cause liver kidney
  toxicity.respectively

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Properties of Inhaled anesthetics

• Nitrous Oxide
• MAC gt 100 Incomplete anesthetic
• Good analgesia
• No metabolism
• Rapid onset recovery
• Used along w/ other anesthetic fast induction
  recovery
• Halothane
• The first halogenated inhalational anesthetic
• Not pungent (use for induction w/ children)
• Medium rate of onset recovery
• Although inexpensive, its use has declined
• Sensitizes the heart to epi-induced arrhythmias
• Rare halothane induced hepatitis

fewer side effects also seen in children
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Properties of Inhaled anesthetics

• Desflurane
• Most rapid onset of action recovery of the
  halogenated GAs (low PC)
• Widely used for outpatient surgery
• Irritating to the airway in awake patients
  causes coughing, salivation bronchospasm (poor
  induction agent)
• Used for maintenance of anesthesia
• Sevoflurane
• Very low bloodgas partition coefficient w/
  relatively rapid onset of action recovery
• Widely used for outpatient surgery
• Not irritating to the airway
• Useful induction agent, particularly in children

Similar to Desflurane
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Properties of Inhaled anesthetics

• Isoflurane
• Medium rate of onset recovery
• Used for induction maintenance of anesthesia
• Isoflurane was the most commonly used
  inhalational GA in the US. Has been largely
  replaced by Desflurane.
• Methoxyflurane
• Now widely considered obsolete
• Slow onset recovery
• Extensive hepatic/renal metabolism, w/ release of
  F- ion causing renal dysfunction

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Toxicity

• Malignant Hyperthermia
• Esp. when halogenated GA used with
  succinylcholine
• Rx dantrolene (immediately)
• Halothane
• Halothane undergoes gt40 hepatic metabolism
• Rare cases of postoperative hepatitis occur
• Halothane can sensitize the heart to Epi
  (arrhythmias)
• Methoxyflurane
• F release during metabolism (gt70) may cause
  renal insufficiency after prolonged exposure.
• Nitrous oxide
• Megoblastic anemia may occur after prolonged
  exposure due to decreases in methionine synthase
  activity (Vit B12 deficiency).

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MUSCLE PHYSIOLOGY

• Neuromuscular Junction
• Skeletal muscles stimulated by motor neurons
• Components of somatic nervous system
• Nerves reside in brain or spinal cord
• Threadlike extensions travel to muscle cells
• Axon
• Divides profusely as it enters the muscle
• Each axonal ending forms branching neuromuscular
  junction with a single muscle fiber
• Only one neuromuscular junction per muscle fiber

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MUSCLE PHYSIOLOGY

• Neuromuscular Junction
• Axonal ending and muscle fiber very close
• Not touching
• 1 2 nanometers (nm) apart
• Separating space termed synaptic cleft
• Gel-like extracellular substance rich in
  glycoproteins

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NMJ Blockers(TWO TYPES) Depolarising
Nondepolarising

• Depolarising Agent Succinylcholine,
• Non Depolarising Agent Curare Type ie
• Atracurium
• Cisatracurium Rocuronium
• relax skeletal muscle
• facilitate intubation
• insure immobility
• Reversed by neostigmine glycopyrrolate during
  post-op period

quaternary drugs intubation is usually
needed for airway maintenance to prevent
aspiration.
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DEPOLARIZER
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NON-DEPOLARIZERS
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NON-DEPOLARIZERS

• Reversal
• NEOSTIGMINE AND ARTROOINE
• OR NEOSTIGMINE AND GLYCOPYROLATE

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Dantrolene

• Interfers with the release of calcium from the
  sarcoplasmic reticulum through the SR calcium
  channel complex.
• Used to prevent or reverse malignant hyperthermia
  (which is otherwise fatal in 50 of cases w/o
  dantrolene).
• Given by i.v. push at the onset of symptoms (e.g.
  an unexpected rise in CO2 levels)
• Supportive measures 100 O2 are also used to
  treat malignant hyperthermia

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Nausea Vomiting

• General anesthetics effect the chemoreceptor
  trigger zone brainstem vomiting center (cause
  nausea vomiting)
• Rx
• - Ondansetron (5-HT3 antagonist) to prevent
• - Avoidance of N2O
• - Propofol for induction
• - Keterolac vs. opioid for analgesia
• - Droperidol, metaclopromide dexamethasone

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The End