General Anesthesia
Physiological state that includes
Analgesia
Amnesia
Loss of conciousness
Inhibition of
o Sensory reflexes
o Autonomic reflexes
 Skeletal muscle relaxation
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An Ideal General Anasthetics
General anasthetics should be able to have all of these
characteristics (even though no anathetics are able to have
all of these properties)
1. Induce smooth and rapid loss of conciousness
2. Allow prompt recovery after its admin is discontinued
3. Possessed
a. Wide margin of saftey
b. Devoid of adverse effects
Types of General Anasthesia ‘
1. Intravenous Anasthesia
a. Can be given either
i. Single agent
ii. Combination with
1. Other anasthesia
2. Analgesics (opioid)
b. Agents
i. Barbiturates
1. Thiopental
2. Methohexital
ii. Benzodiazepine
1. Midazolam
2. Diazepam
iii. Phenols
1. Propofol
iv. Ketamine
v. Opioid Analgesics
1. Morphine
2. Fentanyl
vi. Miscellaneous Sedative-Hypnotic agents
1. Etomidate
2. Dexmedetomidine
2. Inhaled Anastheisa
a. The compound are
i. Highly volatile liquid
ii. Aerosolized in specialized vaporizer delivery systems
b. Agents
i. Isoflurane
ii. Desflurane
iii. Sevoflurane
3. Balanced Anasthesia
a. Involved both methods of admin
i. Intravenous
1. To induce the state of anesthesia
2. *one exception – sevoflurane (inhalation) can sufficiently induce
anasthesia
ii. Inhalation
1. To maintain the state of anasthesia
2. *one exception – Propofol (intravenous) can maintained the
state of anasthesia
Stages of Anasthesia – Guedel signs
Inhaled Anasthetics
1. Stage of Analgesia
a. At first, patient at the state of analgesia without amnesia
b. Later, amnesia comes about
2. Stage of Excitement
a. Patients appear to be
i. Vocalized delirium
ii. Amnesia
iii. Irregular respiration
iv. Retching
v. Vomiting
b. This state can be avoided by giving high concentration
of anasthesia
c. The stage ends when respiration is normalized
3. Stage of Surgical Anasthesia
a. Begins with recurrence of regular respiration
b. Extends to a complete halt in respiration (apnea)
c. Signs appear as changes in
i. Ocular movement
ii. Eye reflexes
iii. Pupil size
4. Stage of Medullary Depression
a. Deep stage of CNS depression
b. Includes
i. Vasomotor center
ii. Respiratory center in the medulla
c. Without respiratory support, death ensures within minutes
Pharmacokinetics
1. Uptake and Distribution of Inhaled Anasthetics
a. Concentration of an inhaled anasthetic is proportional
to its partial pressure
b. Adequate brain concentration is important in order to
determine the depth of general anasthetics
c. The rate of adequate concentration to be achieved in
the brain depends on
i. Solubility
1. Blood:gas partition coefficient is a useful index in
determining the solubility of the inhaled anasthetics
2. Blood:gas partition coefficient
a. Poorly blood soluble anasthetics
i. Requires less amount of molecules to reach the
arterial partial pressure
ii. The levels rises rapidly in the blood
iii. Onset of action in the brain is rapid
iv. Eg. Nitric Oxide
b. Highly blood soluble anasthetics
i. Requires more amount of molecules to reach
the arterial partial pressure
ii. The level in the blood rises very slow
iii. Slow onset of action in the brain
iv. Eg. Halothane
ii. Anasthetic Concentration in the Inhaled Air
1. ↑the conetration of anasthesia inhaled, ↑ the rate
of transfer into the blood
2. Example
a. Moderate blood soluble anasthesia
i. Given in high doses in the induction phase to
reach a rapid increase in blood level
ii. Doss is reduced once the therapeutic level in the
brain is achieved
iii. It often be given with less soluble anasthesia
(Nitric oxide) to ↓time required for
1. Loss of conciousness
2. Achievement the state to surgical anasthesia
iii. Pulmonary Ventilation
1. ↑in rate and depth of ventilation, ↑arterial tension
(level in the blood) of inhaled anasthetics
2. Variability
a. ↑in rate and depth of ventialtion have variable
effects depending on the solubillity of inhaled
anasthetics
i. Poorly soluble anasthetics (Nitric oxide) only has
insignificant increase in arterial gas tension
ii. Highly and moderately soluble anasthetics
(Halothane) has a very significant increase in
arterial gas tension up to fourfolds
iv. Pulmonary Blood Flow
1. ↑in cardiac output will lead to
a. ↑pulmonary perfusion
b. Exposes larger volume of blood
c. ↑blood carrying capacity
d. ↓rate of rise in the anasthetic tension in the blood
2. ↓in cardiac output
a. ↓pulmonary perfusion
b. Exposes fewer volume of blood
c. ↓blood carrying capacity
d. ↑rate of rise in the anasthetic tension in the blood
v. Arteriovenous Concentration Gradient
1. Distribution of inhaled anasthetics to the peripheral
tissues depends on
a. Solubility of the agent
i. Lipid soluble more likely to accumulate in tissue
b. Concentration gradient of drugs between blood
and tissues
i. ↑concentration gradient, ↑accumulation in
peripheral tissues
c. Tissue blood flow
i. Highly perfused organs tend to accumulate the
drugs
1. Brain
2. Heart
3. Liver
4. Kidneys
5. Splanchnic bed
d. If the distribution of drugs in the peripheral tissues
are high, less venous concentration of drugs
i. Due to this, rate of achieving the arterial blood
tension is slower due to less drugs remain in the
blood to achieve the therapeutic effects
2. Elimination
a. Recovery phase depends on the rate of elimination of
anasthetics from the brain
b. Two distinctive features of the recovery phase
compared to that of induction phase
i. Transfer of drugs from the blood back to the lung
cannot be increased as drugs in the lungs cannot be
reduced to zero level
1. While induction phase, transfer of drugs from the
lung to the blood can be increased by ↑rate and
depth of ventilation
ii. Anasthetics gas tension in different tissues are variable
in the recovery phase
1. While during induction phase, all tissues anasthetics
gas tension remains at zero level
c. Factors governing the rate of elimination are
i. Blood:gas partition coefficient of anasthetics
1. ↑blood solubility, ↓rate of elimination
ii. Duration of exposure
1. ↑duration of exposure, ↓rate of elimination as drugs
have already accumulated in various tissues
iii. Pulmonary clearence is the principal route of
elimination. Somehow, liver also plays important role I
elimination
1. Halothane is metabolized in toxic metabolite
called the Chlorotriflouroethyl free radical
a. May lead to Halothane-induced Hepatitis
2. The rank in susceptibility to hepatic metabolism
a. Methoxyflurane  Halothane  Enflurane 
Sevoflurane  Isoflurane  Desflurane  Nitric
Oxide
Systemic Effects of Inhaled Anasthetics
1. Cardiovascular Effects
a. Blood pressure
i. ↓BP proportionate to dose
1. Due to ↑ individual vascular beds (cerebral artery)
with little change in systemic vascular resistance that
leads to ↓cardiac output
a. Halothane
b. Enflurane
2. Due to ↑TPR with slightly ↓in cardiac output
a. Isoflurane
b. Desflurane
c. Sevoflurane
b. Heart rate
i. Bradycardia
1. Due to direct vagal stimulation
a. Halothane
ii. Tachycardia
1. Due to transient stimulation of sympathetic outflow
a. Desflurane
c. ↓myocardial oxygen consumption
2. Respiratory Effects
a. ↑ventilation rate
b. ↓tidal volume
c. ↑arterial PCO2 level
d. ↓mucocilliary function
3. Brain Effects
a. ↓metabolic activity of the brain
b. ↑intracranial pressure secondary to ↑cerebral blood flow
i. Nitirc oxide it the least likely to cause this
c. CNS depression
i. At higher dose
ii. Myoclonic activity
iii. Seizure like activity may also appear
4. Kidneys Effects
a. Solely depends on the dose given
b. ↓glomerular filtration rate
c. ↓renal blood flow
d. ↑filtration fraction
Toxicity
1. Acute Toxicity
a. Halothane-Induced Hepatitis
i. Halothane
b. Nephrotoxicity
i. Formations of floride metabolites in
1. Methoxyflurane
2. Enflurane
3. Sevoflurane
c. Malignant Hyperthermia
i. If given together with muscle relaxant (Succinylcholine)
ii. Treated with Dentrolene
2. Chronic Toxicity
a. Mutagenicity
b. Carcinogenicity
c. Problems with reproductive system
d. Heamatotoxicity
i. Megaloblastic anemia
Mechanism of Actions of General Anasthetics
1. Lipid Solubility-Anaesthetic Potency Correlation (the MeyerOverton correlation)
a. May act by dissolving in the fatty fraction of brain cells
and removing fatty constituents from them,
i.
Thus changing activity of brain cells and inducing
anaesthesia
b. The greater is the lipid solubility of the compound, the
greater is its anaesthetic potency
2. Lipid Hypotheses of General Anaesthetic Action
a. Hydrophobic anaesthetic molecules accumulate inside
the hydrophobic (or lipophilic) regions of neuronal lipid
membrane causing its distortion and expansion
(thickening) due to volume displacement
b. Accumulation of critical amounts of anaesthetic causes
membrane thickening sufficient to reversibly alter
function of membrane ion channels thus providing
anaesthetic effect
c. This hypotheses is now rejected
3. Modern Lipid Hypotheses
a. Anaesthetic effect happens if solubilization of general
anaesthetic in the bilayer causes redistribution of
membrane lateral pressures
b. According to modern lipid hypothesis change in
membrane lateral pressure profile shifts the
conformational equilibrium of certain membrane proteins
known to be affected by clinical concentrations of
anaesthetics such as ligand-gated ion channels
4. Membrane Protein Hypothesis of General Anaesthetic
action
a. According to this theory general anaesthetics are much
more selective than in the frame of lipid hypothesis and
they bind directly only to small number of targets in CNS
mostly
i.
ligand(neurotransmitter)-gated ion channels in
synapse
ii.
G-protein coupled receptors altering their ion flux
b. Particularly Cys-loop receptors are plausible targets for
general anaesthetics that bind at the interface between
the subunits.
c. The Cys-loop receptor superfamily includes
i.
Inhibitory receptors
1. GABAA receptors
2. GABAC receptors
3. Glycine receptors and
ii.
Excitatory receptors
1. Acetylcholine receptors
2. 5-HT3 serotonin receptors
d. General anaesthetics can
e. Inhibit the channel functions of excitatory receptors
f. Potentiate functions of inhibitory receptors
Intravenous General Anasthetics
Differences of IV anasthetics compared to Inhalation
 Doesn’t need specialized vaporiser machine
 Rapid onset of action
o Use during induction phase
o Benzodiazepine is exception cause it has slow onset of
action
 Rapid recovery
o Enables use in short ambulatory surgical procedure
Agents
Barbiturates
Thiopental
Contraindication
 Severe hypotension
 Addison disease
 Liver disease
 Breathing disorder
Pharmacokinetics
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Upon admin, rapidly crosses
the BBB
With sufficient dose, loss of
conciousness ensures in a
single cardiac cycle
sufficient
Highly lipid soluble
o Plasma:brain equilibrium
reaches very rapidly
o High Vd, redistributed to
almost all body
compartment
o Due to rapid redistribution
(clearence from brain),
duration of action is short
Metabolized in the liver
Excreted through urine
 Lacks of Antinoceptive activity
Adjuvant Therapy
 Opioid
o Combined with
 Fentanyl
 Morphine
 Sufentanyl
o ↑cardiac stability
o ↑respiratory depressive effects
o ↑postoperative emesis
Pharmacological Effects
1. CVS effects (dose dependent)
o ↓BP
o ↓Cardiac output
o ↓stroke volume
o ↑venous capacity (venodilation)
2. Respiratory effects
o Potent respiratory depressor
o Produces
 Transient apnea
 ↓sensitivity of respiratory center
to changes in PCO2
3. CNS effects
o ↓in cerebral
 Metabolism
 Oxygen consumption
o ↓cerebral blow flow
 Can be given in pts with ↑ICP
4. Hepatic and Renal Effects
o ↓hepatic and renal blood flow
Adverse Effects
1.
2.
3.
4.
5.
6.
Hypotension
Apnea
Airway obstruction
Emergence delirium
Prolonged somnolence
Nausea
Agents
Benzodiazepines
Pharmacokinetics
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1. Diazepam
2. Lorazepam
3. Midazolam
Clinical Uses
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Preanasthetic
medications
Adjuvant during
surgical procedures
performed under
local anasthesia
Contraindication
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Pregnancy
Myasthenia gravis
COPD
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Solubility
o Non-water soluble
 Agents
 Diazepam
 Lorazepam
 Formulate in non-aquous
vehicles which can lead to local
irritation
o Water soluble
 Agent
 Midazolam
 Prepared in aquous solution; the
drug of choice to be given
parenterally
All drugs can become lipid soluble in
the physiological pH
Readily crosses the BBB
The slowest onset among other IV
general anasthetics
o Reaches plateau CNS effects too
early that it is inadequate for
surgical anasthesia
o Further ↑in dose will lead to
 Prolong postanasthetic recovery
period
 High incidence of anterograde
amnesia
Midazolam has the most rapid onset
among other Benzodiazepine
Pharmacological Effects
1. CNS effects
a. Sedative
b. Anxiolytic
c. Amnestic properties
d. Ability to control acute
agitation
2. Respiratory effects
a. Respiratory depression
Adverse Effects
1. Pradoxical Effects
a. Aggression
b. Violence,
c. Impulsivity
d. Irritability
e. Suicidal behavior
sometimes occur
2. Cognitive Effects
a. Anterograde amnesia
3. May develop
a. Tolerence
b. Depedency
c. Withdrawal syndrome
Agents
Propofol
Pharmacokinetics
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Clinical Uses
 Induction phase of
anasthesia
 Maintainance
phase of anasthesia
 Can be either
o Total IV procedure
o Balanced
procedure
 The most suitable for
ambulatory surgical 
procedures
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Rapid onset
Rapid recovery rate
If given through prolong infusion
o Cumulative effects may produce
including
 Delayed recovery phase
 ↑serum lipid level (since
propofol often formulated in
lipid vehicles)
 Severe acidosis in children
 Respiratory infections may
also presented
Upon admin, half life is about 2-8
minutes
o But after redistribution to
peripheral tissues, half life
elevated to 30-60 minutes
Metabolize through Glucuronidation
phase in the liver and other
extrahepatic metabolic system
o May be useful for pts with hepatic
insufficiency
Excreted via urine
Pharmacological Effects
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CNS effects
o Reduction in the
postoperative
 Nausea
 Vomiting
o Improve sense of wellbeing
o Effective in producing
prolonged sedation
Respiratory Effects
o Produces
 Transient apnea
 ↓sensitivity of
respiratory center to
changes in PCO2
CVS effects
o Marked ↓in BP due to
↓TPR
o Venodilation
o Negative inotropic
effects
Adverse Effects
1.
2.
3.
4.
5.
6.
Pain at the site of injection
Hypotonus
Tremor (rare)
Hypotension
Apnea
Airway obstruction
Agents
Etomidate
Clinical Use
 Induction phase of
anasthesia
Pharmacokinetics
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Ketamine
Clinical Uses
 Due to its
cardiostimulatory
effects, useful in
o Cardiogenic
shock
o Septic shock
 Given with propofol
in ambulatory
surgery
Contraindication
 ↑ICP
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Rapid loss of conciousness
o With minimal hypotension
Rapid biphasic distribution to the
peripheral tissues
o Initial distribution
 Half life – 3 minutes
o Intermediate distribution
 Half life – 29 minutes
Rapid redistribution to peripheral
tissues leads to rapid short
duration of action
Extensive hepatic metabolism
Excreted via urine
Highly lipophilic, distributed
extensively in highlyperfused
organs
o Brain
o Liver
o Kidneys
Fast induction phase
Slow recovery
Redistribution to other peripheral
tissues happens after prolonged
use
Metabolized in the liver
Excreted through
o Bile
o Urine
Pharmacological Effects
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Adverse Effects
Minimal CVS and Respiratory
depression
o Doesn’t change the heart rate
o Apnea is very seldom
No analgesic property
1. Prolonged infusion will
lead to
a. Hypotension
b. Electrolyte
imbalance
c. Oliguria
CNS effects
o Dissociative Anasthetic State
 Catatonia
 Behavioral abnormalities
 Stupor
 Amnesia
 Analgesia
 With/out loss of conciousness
o ↑cerebal blood flow
CVS effects
o ↑in sympathetic outflow leads to
 ↑TPR
 ↑heart rate
 ↑cardiac output
 ↑BP
o This is due to
 Stimulation of central sympathetic
nervous system
 Inhibition of reuptake of
norepinephrine in the presynaptic
terminal
Respiratory Effects
o Minimal respiratory depression
1. Postoperative psychic
phenomena
a. Disorientation
b. Sensory and
perceptual illusions
c. Vivid dream
d. Delirium
e. Hallucination
2. Hypertension
3. ↑salivation