2.

3-01
August 14, 2013
Frederick C. Loyola, M.D. CNS Pharmacology II:
"The state should, I think, be called 'anesthesia.' This signifies insensibility." –W. G. General Anesthesia
Morton, a dentist who first publicly demonstrated the use of ether as an anesthetic

SECTION PAGE ‒ Retain ability to maintain patent airway

I. Overview of General Anesthesia ‒ Respond to verbal commands
A. Modern Practice of Anesthesiology 1  Extensive surgical procedures
o Preoperative benzodiazepines
B. Stages of Anesthesia (Guedel's Signs) 1
o Induction of anesthesia with intravenous anesthetic
C. Mechanism of General Anesthetic Action 1-2
o Maintenance of anesthesia with a combination of
D. Types of General Anesthesia 2 inhaled and intravenous anesthetics
II. Inhaled Anesthetics  Adjuncts
A. Dose-Response Characteristics 2 o Muscle relaxants
B. Pharmacokinetics 3  Facilitate tracheal intubation
1. Uptake and Distribution 3-4  Optimize intra-operative surgical conditions
2. Elimination 4-5 o Opioid analgesics and cardiovascular agents (β-
C. Pharmacodynamics 5 blockers, α2 agonists, Ca2+ channel blockers)
D. Organ-Level Effects 5  Control transient autonomic responses to noxious
stimuli
E. Toxicity 5
F. Clinical Uses 5
STAGES OF ANESTHESIA (GUEDEL'S SIGNS)
III. Intravenous Anesthetics
 Derived from observations of effects of diethyl ether
A. Barbiturates 5-6
 Divided into four stages of increasing depth of central
B. Propofol 6-7
nervous system depression
C. Benzodiazepines 7  Distinctive signs per stage usually obscured because of:
D. Ketamine 7 o More rapid onset of action of modern anesthetics
E. Fentanyl 7-8 o Mechanical control of ventilation
F. Etomidate 8 o Pre-operative or intra-operative agents which can
G. Dexmedetomidine 8 alter clinical signs of anesthesia
IV. Review Questions 9  Atropine and glycopyrrolate
‒  secretions
TRANSMASTER'S NOTE ‒ Treatment for bradycardia
 Muscle relaxants
References: Katzung 10th and 12th, lecture, 2C 2015 trans
‒  muscle tone
‒ Prevent purposeful movements
 Italic – transmaster's notes
 Opioid analgesics
 * – not in lecture ** – 2015 trans
‒ Respiratory and cardiac depression

OVERVIEW OF GENERAL ANESTHESIA STAGES SIGNS

 Induces a physiologic state of: ANALGESIA
o Analgesia Initial  Analgesia (loss of pain
o Amnesia perception) without amnesia
o Loss of consciousness I
o Inhibition of sensory and autonomic reflexes Late  Analgesia with amnesia
o Skeletal muscle relaxation (memory loss)
 Extent of effects depends on specific drug, dosage, and  Appears delirious
clinical situation  Vocalization
 Criteria of ideal anesthetic agent:  Amnesia
o Smooth, rapid induction (loss of consciousness)  Retching and vomiting
o Prompt recovery of cognitive function after II EXCITEMENT  Irregular respiration (in volume
discontinuation of administration and rate)  resumption of regular
o Wide margin of safety respiration
o Devoid of adverse effects  Management entails shortening
 No single anesthetic agent capable of achieving all of the or limiting stage II duration
above desired effects without some disadvantages  Recurrence of regular breathing 
apnea (complete cessation of
MODERN PRACTICE OF ANESTHESIOLOGY spontaneous respiration)
SURGICAL
 Balanced anesthesia III
ANESTHESIA
o Combination of:  No response to noxious stimuli
 Intravenous anesthetics (e.g. trapezius muscle squeeze) –
 Inhalational anesthetics reliable indication
o Taking advantage of individual favorable properties MEDULLARY  Severe depression of vasomotor
IV
while minimizing adverse reactions DEPRESSION and respiratory centers in medulla
 Choice of anesthetic technique determined by type of
diagnostic, therapeutic, or surgical intervention MECHANISM OF GENERAL ANESTHETIC ACTION
 Minor superficial or invasive diagnostic procedures
o Oral or parenteral sedatives in combination with local EFFECTS ON NEURONS
anesthetics  Presynaptic action
 Produce analgesia but patient can still: o Alter neurotransmitter release

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 CNS Pharmacology II: General Anesthesia

 Postsynaptic action TYPES OF GENERAL ANESTHESIA

o Change frequency or amplitude of impulses

ORGAN LEVEL EFFECTS

 Strengthen inhibition or diminish excitation in CNS
o Impairment of excitation > potentiation of inhibition

CANDIDATES OF ANESTHETIC ACTION

 Primary inhibitory ion channels
o Chloride channels mediated by:
 GABAA receptors
 Glycine receptors
o Potassium channels (K2P, KV, KATP)

INHALED ANESTHETICS

DOSE-RESPONSE CHARACTERISTICS
 Difficult to measure under clinical conditions
 Very low gas concentrations  pain awareness
 High concentrations  high risk of severe cardiovascular
and respiratory depression
 Quantal dose-response principles – useful in estimating
anesthetic potency

MINIMAL ALVEOLAR CONCENTRATION (MAC)

 Measure of anesthetic potency
 Minimal alveolar anesthetic concentration (% anesthetic in
inspired air) that results in immobility in 50% of patients
when exposed to surgical stimulus
 Additive
 Excitatory ion channels  Lower in elderly
o Channels activated by:  Reduced by opioids and sedative-hypnotics
 Acetylcholine (nicotinic and muscarinic)   MAC value   potency
 AMPA o MAC value of nitrous oxide – greater than 100%
 Kainate (making it the least potent inhaled anesthetic)
 NMDA
 Serotonin (5-HT2 and 5-HT3) SIGNIFICANCE OF MAC IN BALANCED ANESTHESIA

Remember, there is no single anesthetic that is effective

yet devoid of disadvantages and adverse effects. Therefore,
different anesthetics are given in a balanced formulation to
maximize favorable effects and minimize disadvantages
of each anesthetic. Nitrous oxide (60-70%) can be used a
"carrier" gas to minimize requirement of other inhaled or
intravenous anesthetics.

Given:
Nitrous oxide (40% formulation) – rapid onset, low potency
Halothane (60% formulation) – slow onset, high potency

Multiply the MAC of each to the % in the formulation and

add the products to get the MAC value of the formulation.

Nitrous oxide – MAC of 100 X 40% = 40

Halothane – MAC of .75 X 60% = 0.45

40.00 + 0.45 = 40.45% (MAC value of the formulation,

which has a higher potency than nitrous oxide with a faster
onset than halothane)

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 CNS Pharmacology II: General Anesthesia

PHARMACOKINETICS
 Taken up through gas exchange in alveoli
 Determinants of kinetics of inhaled anesthetics:
o Uptake from alveoli into blood
o Distribution and partitioning into compartments

UPTAKE AND DISTRIBUTION

 Concentration of inhaled anesthetic in mixture of gases
is proportional to its partial pressure or tension
 Achieving a brain concentration of inhaled anesthetic to
provide adequate anesthesia requires transfer of
anesthetic from the blood to the brain

FACTORS AND RELATIONSHIP TO UPTAKE

Solubility properties of anesthetic Inverse "PING-PONG AND SAND" ANALOGY TO SOLUBILITY
Concentration in inspired air Direct
Volume of pulmonary ventilation Direct  Ping-pong – desflurane or nitrous oxide (low solubility)
Pulmonary blood flow Inverse  Sand – halothane or isoflurane (high solubility)
Arteriovenous concentration gradient Inverse  Pail or container – blood

It takes less ping-pong balls than sand grains to fill up

TRANSMASTER'S NOTE
a pail or container. Simple, isn't it?
The aforementioned factors are exactly the same as
those found in the 10th edition of Katzung.
Based on the previous figure, an anesthetic with low
Some of the factors have been rephrased in the 12 th solubility or blood:gas partition coefficient such as
edition of Katzung. nitrous oxide (top panel) rapidly equilibrates with the blood,
rapidly increases its partial pressure, and passes more rapidly
into the brain, resulting in faster induction of anesthesia
1. SOLUBILITY
compared to an anesthetic with high solubility or blood:gas
 Very important factor influencing transfer of anesthetic
partition coefficient (bottom panel) such as halothane.
from the lungs to the arterial blood
 Blood:gas partition coefficient
o Relative affinity of anesthetic for the blood
compared with that of inspired gas
o Useful index of solubility
 Low-solubility
o Less molecules required to raise partial
pressure  rapid  in arterial tension
o Desflurane and nitrous oxide
 Relatively insoluble in blood
 Extremely low blood:gas partition coefficient
 Rapid equilibration  fast onset of action
 Moderate-to-high solubility
o More molecules required to raise partial
pressure  slow  in partial tension
o Halothane and isoflurane
Alveolar anesthetic concentration (FA) approaches inspired
anesthetic concentration (FI) fastest for least soluble agents,
nitrous oxide (coefficient of 0.47) and desflurane (0.42)

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2. ANESTHETIC CONCENTRATION IN INSPIRED AIR
 Concentration of inhaled anesthetic in inspired gas
mixture  direct effects on both maximum tension that
can be achieved in the alveoli and rate of
 More true in anesthetic with low MAC or more blood-
soluble anesthetics**
  inspired anesthetic concentration   rate of
induction of anesthesia by increasing rate of transfer
into the blood according to Fick's law
 High partial pressure of inhaled anesthetic in the lungs
 rapid achievement of anesthetic levels in the blood**
 Taken advantage of by initial administration of gas
concentrations higher than what is required for
maintenance of anesthesia**
3. PULMONARY VENTILATION
 Rate of rise of anesthetic agents in arterial blood
directly dependent on:
o Ventilatory rate
o Depth of ventilation
 Magnitude of effect varies according to blood:gas
partition coefficient
 Effect of  pulmonary ventilation
o Slight  in arterial tension of anesthetics with
low blood solubility or low coefficient
o Can significantly increase tension of anesthetics
with moderate to high solubility
 Fourfold increase in ventilation
o Twofold increase in arterial tension of halothane
(high coefficient) but increases that of nitrous
oxide (low coefficient) by only 15%
 Hyperventilation
o Faster induction of anesthesia with inhaled
anesthetics, especially those with slow onset
 Opioid analgesics
o Respiratory depression   ventilation  slows
onset of anesthesia with inhaled anesthetics
Effect of ventilation on FA/FI – increased ventilation (8 versus
2 L/min) has a much greater effect on equilibration of
halothane than nitrous oxide
4. PULMONARY BLOOD FLOW
 Changes in blood flow to and from the lungs influence
transfer processes of anesthetic gases
  pulmonary blood flow
Martin
CNS Pharmacology II: General Anesthesia
o Exposes larger volume of blood to anesthetic 
slow  in tension of anesthetic, especially those
with moderate to high solubility
  pulmonary blood flow
o  rate of rise of arterial tension of inhaled
anesthetics
 Circulatory shock
o  cardiac output and  ventilation  accelerated
induction of anesthesia with halothane and
isoflurane (highly-soluble, slow-onset agents)
5. ARTERIOVENOUS CONCENTRATION GRADIENT
 Dependent mainly on uptake of anesthetic by tissues,
including nonneural tissues
 Venous blood returning to the lungs may contain
significantly less anesthetic than arterial blood
  gradient
o Longer time to equilibrate with brain tissue
 Influencing factors in anesthetic entry into tissues:
o Tissue:blood partition coefficients
o Rates of blood flow to tissues
o Concentration gradients
 Induction phase of anesthesia
o Highly perfused tissues (brain, heart, liver,
kidneys, splanchnic bed)
 Exert the greatest influence on AV gradient
 Maintenance phase of anesthesia
o Drug transferred between various tissues at rates
dependent on solubility and blood flow
o Muscle and skin
 Less perfused  drug accumulates slowly
o Adipose tissues
 Very low perfusion  equilibrium unlikely
ELIMINATION
 Time of recovery from inhalation anesthesia depends on
rate of elimination of anesthetics from the brain
 Processes of anesthetic transfer during recovery –
opposite of those in induction (again, the five factors)
 Factors governing rate of recovery:
o Blood:gas partition coefficient of anesthetic – very
important factor
o Pulmonary blood flow
o Magnitude of ventilation
o Tissue solubility of anesthetic
RECOVERY INDUCTION
Reverse transfer cannot Increased anesthetic
be enhanced because concentration in inspired air
concentration in lungs cannot enhances transfer
be reduced below zero
Anesthetic tension varies Zero initial anesthetic
in different tissues tension in all tissues
 Blood:gas partition coefficient
o Anesthetics with low solubility or coefficient
 Rapid washout rate of nitrous oxide, desflurane,
and sevoflurane  rapid recovery
o Halothane
 2X soluble in brain and 5X more soluble in
blood than nitrous oxide and desflurane
 Slowly eliminated  slow recovery
 Duration of exposure to anesthetic
o Marked effect on recovery time, especially in the case
of more soluble anesthetics
o Prolonged inhalation
 Accumulation in tissues  gradual elimination 
slow decline in tension during recovery
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 CNS Pharmacology II: General Anesthesia

o Short exposure
 Rapid recovery regardless of anesthetic solubility 4. RENAL EFFECTS
 Routes of elimination   glomerular filtration rate and renal blood flow
o Clearance via lungs (major route)   filtration fraction
o Hepatic metabolism  Impaired autoregulation of renal blood flow
 Halothane
‒ Oxidative metabolism  trifluoroacetic 5. HEPATIC EFFECTS
acid formation and release of bromide and  Concentration-dependent  in hepatic blood flow
chloride ions  Transient intraoperative changes in liver function sites
‒  oxygen tension  halothane metabolism 
chlorotrifluoroethyl free radical (reacts 6. UTERINE SMOOTH MUSCLE
with hepatic membrane components)  Dose-dependent uterine muscle relaxation caused
 Isoflurane and desflurane by halogenated anesthetics
‒ Least metabolized among the fluranes
‒ Only traces of trifluoroacetic acid appear in CLINICAL USES
urine even with prolonged administration  Commonly combined with intravenous anesthetics in
 Enflurane and sevoflurane balanced anesthesia technique
‒ Formation of fluoride ions (which do not  Most commonly used in US:
usually reach toxic levels) o Nitrous oxide
 Methoxyflurane o Desflurane
‒ Mostly metabolized by liver (70%) o Sevoflurane
‒ Methoxyflurane metabolism  fluoride ions o Isoflurane
 readily produce nephrotoxicity
o Nitrous oxide
TOXICITY
 Not metabolized by human tissues
 Broken down by intestinal bacteria 1. HEPATOTOXICITY
 Halothane-associated hepatic dysfunction (refer to
metabolism of halothane)
PHARMACODYNAMICS

MECHANISM OF ACTION 2. NEPHROTOXICITY

 Caused by fluoride ions formed from metabolism of
 Depression of spontaneous and evoked activity of neurons
methoxyflurane, enflurane, and sevoflurane (refer
in many regions of the brain
to metabolism of these drugs)
 Meyer-Overton principle
 Renal β-lyase – implicated in intrarenal generation
o Nonspecific interactions with the lipid matrix of
of fluoride ions
neuronal membranes  secondary changes in ion flux
 Sevoflurane
 Direct interactions with specific nerve membrane
o Chemically unstable
components  modification of ion currents
o Degrades to an olefinic compound A (potentially
 Facilitate GABA-mediated inhibition at GABAA receptor
nephrotoxic) upon exposure to carbon dioxide
site (major mediator of inhibitory synaptic transmission)
absorbents in anesthesia machines

ORGAN LEVEL EFFECTS 3. MALIGNANT HYPERTHERMIA

1. CARDIOVASCULAR SYSTEM  Caused by volatile agents (halothane) with muscle
 Depression of cardiac contractility relaxants (succinylcholine)
  mean arterial pressure  Consists of:
 Change heart rate: o Rapid onset of tachycardia and hypotension
o Directly by altering rate of SAN depolarization o Severe muscle rigidity
o Indirectly by shifting balance of ANS activity o Hyperthermia
 Dose-dependent  in right atrial pressure o Hyperkalemia
 Myocardial depression o Acidosis
 Dantrolene (antidote) –  Ca2+ release from SER
2. RESPIRATORY SYSTEM
 Dose-dependent  in tidal volume INTRAVENOUS ANESTHETICS
  respiratory rate insufficient to compensate for  in
 Widely used in rapid induction of general anesthesia
tidal volume
o Lipophilic properties
  minute ventilation due to  tidal volume and 
o Preferentially partitoin into highly perfused tissues
respiratory rate
 Provide sedation in ICU and monitored anesthesia care
 Respiratory depression
 Maintenance of anesthesia
  response to  levels of carbon dioxide
  apneic threshold (PaCO2 level below which apnea
occurs by lack of CO2-driven respiratory stimulation) BARBITURATES
  ventilatory response to hypoxia
THIOPENTAL (PENTOTHAL) AND
 Depression of mucociliary function in airways
METHOHEXITAL (BREVITAL)
 Mucus pooling and atelectasis
 Some degree of bronchodilation PHARMACODYNAMICS
 Presumably involves enhancement of inhibitory and
3. CEREBRAL EFFECTS
inhibition of excitatory neurotransmission
  metabolic activity
  cerebral blood flow and intracranial pressure
 EEG suppression

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 CNS Pharmacology II: General Anesthesia

PHARMACOKINETICS CONTRAINDICATIONS
 Hepatic metabolism  Acute porphyria
o Oxidation o Barbiturates   porphyrin production by stimulating
o N-dealkylation aminolevulinic acid synthetase (ALAS)
o Desulfuration
o Destruction of barbituric acid ring structure PROPOFOL (DIPRIVAN)
 Thiopental  2,6-diisopropylphenol
o Crosses blood-brain barrier  Alkyl phenol with hypnotic properties
o Rapid redistribution from CNS to peripheral tissues  Chemically distinct from other groups of IV anesthetics
 Methohexital
o Shorter elimination half-life than thiopental
PHARMACODYNAMICS
o More complete recovery
 Presumably potentiation of Cl- current mediated through
GABAA receptor complex

PHARMACOKINETICS
 Pharmacokinetic profile
o Suitable for continuous infusions
 Rapidly metabolized in liver
o Inactive water-soluble metabolites
 More complete recovery (less "hangover") than thiopental
 Redistribution to other tissues  termination of effect

Redistribution of thiopental after IV bolus administration

ORGAN LEVEL EFFECTS

1. CENTRAL NERVOUS SYSTEM EFFECTS
 Dose-dependent CNS depression ranging from
sedation to general anesthesia
 No analgesic effects
Context-sensitive half-time of intravenous anesthetics
 May  pain threshold  hyperalgesia
 Cerebral vasoconstriction   cerebral blood flow and 
intracranial pressure TRANSMASTER'S NOTE
o Useful for patients with cerebral swelling PROPOFOL IN GENERAL ANESTHESIA
  CMRO2
o Useful in management of patients with space- Based on the previous figure, propofol (red line)
occupying lesions maintains a relatively short context half-time (results in
rapid recovery) compared to thiopental (black line) even
2. CARDIOVASCULAR EFFECTS with prolonged infusion of up to 8 hours, making it the
 Peripheral vasodilation   systemic blood pressure preferred choice for intravenous anesthesia.
 Negative inotropic effects
ORGAN LEVEL EFFECTS
 Baroreceptor reflex inhibition (less pronounced than
1. CENTRAL NERVOUS SYSTEM EFFECTS
with propofol)
 Hypnosis
 Hemodynamic effects
 No analgesic effects
 Occasional excitatory effects
3. RESPIRATORY EFFECTS
o Twitching
 Respiratory depression
o Spontaneous movement
 Transient apnea
  intracranial pressure and CMRO2
  tidal volume, respiratory rate, and minute ventilation
  response to hypercapnia and hypoxia  Burst EEG suppression at large doses
 Suppression of laryngeal and cough reflexes (less
2. CARDIOVASCULAR EFFECTS
pronounced than with propofol)
 Profound arterial and venous vasodilation
 Most pronounced  in systemic blood pressure
4. OTHER EFFECTS
  preload and afterload
 Excruciating pain and intense vasoconstriction if
injected intra-arterially  severe tissue injury
o TX – ganglionic blockade in affected extremity 3. RESPIRATORY EFFECTS
 Apnea after induction dose
  tidal volume, respiratory rate, and minute ventilation
CLINICAL USES   response to hypercapnia and hypoxia
 Induction of anesthesia (unconsciousness)   upper airway reflexes
 Neuroprotection o Suitable for airway intubation

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 CNS Pharmacology II: General Anesthesia

4. OTHER EFFECTS  Anxiolysis and anterograde amnesia

 Antiemetic activity o Suited for preoperative medication
 Pain on injection  Sedation during monitored anesthesia care

CLINICAL USES KETAMINE (KETALAR)

 Most frequently administered intravenous anesthetic for  Phencyclidine derivative
induction of general anesthesia  IV anesthetic with analgesic properties
 Used also in maintenance of anesthesia
 Conscious sedation and short-duration general anesthesia PHARMACODYNAMICS
outside OR (interventional radiology and emergencies)  Blockade of glutamate effects on NMDA receptor
 Sedation of mechanically-ventilated ICU patients
 Outpatient surgery
PHARMACOKINETICS
 Partially water-soluble and highly lipophilic
FOSPROPOFOL (LUSEDRA)*
 Rapid onset of action
 Water-soluble prodrug  Rapidly distributed to well-perfused organs
 2,6-diisopropylphenoxymethyl phosphate disodium salt  Hepatic metabolism
o Norketamine
PHARMACOKINETICS  N-demethylated metabolite
 Rapidly metabolized by alkaline phosphate into:  Primary active metabolite
o Propofol  1/3 to 1/5 less potent than ketamine
o Phosphate  Hydroxylated and conjugated into water-soluble
o Formaldehyde inactive metabolites
 IV anesthetic with low protein binding
CLINICAL USES  Urinary and biliary excretion
 Sedation during monitored anesthesia care
ORGAN LEVEL EFFECTS
ADVERSE EFFECTS 1. CENTRAL NERVOUS SYSTEM EFFECTS
 Airway compromise  Cerebral vasodilation
 Paresthesia, often in perianal region   cerebral blood flow and CMRO2
 Unpleasant emergence reactions – main factor
limiting ketamine use; less severe in children
BENZODIAZEPINES
o Vivid colorful dreams
MIDAZOLAM (VERSED, HYPNOVEL) o Hallucinations
o Out-of-body experiences
 Benzodiazepine of choice in preoperative sedation
 Euphoria
 Readily terminated by flumazenil
2. CARDIOVASCULAR EFFECTS
PHARMACOKINETICS  Transient and significant increase in:
 Highly lipid-soluble o Systemic blood pressure
 Rapid onset of action o Heart rate
 Short elimination t½ of 2-4 hours o Cardiac output
 Slower effect-site equilibration  Direct myocardial depression
 Shortest context-sensitive t½ among benzodiazepines
o Suitable for continuous infusions 3. RESPIRATORY EFFECTS
 Minimal respiratory depression
ORGAN LEVEL EFFECTS  Response to hypercapnia preserved
1. CENTRAL NERVOUS SYSTEM EFFECTS  Transient hypoventilation
  cerebral blood flow and CMRO2  Short period of apnea
 Anticonvulsant activity  Bronchial smooth muscle relaxation

2. CARDIOVASCULAR EFFECTS CLINICAL USES

 Peripheral vasodilation  Induction of anesthesia
  in systemic blood pressure o Produces "dissociative anesthesia"
 Eyes remain wide open with a slow nystagmic
3. RESPIRATORY EFFECTS gaze (cataleptic state)
 Minimal depression of ventilation  Candidate for maintenance of anesthesia
 Transient apnea and severe respiratory  Regional anesthesia requiring additional analgesia
depression (if combined with opioid premedications)   opioid tolerance and opioid-induced hyperalgesia
  ventilatory response to CO2
 Airway obstruction
ADVERSE EFFECTS
 Psychotomimetic effects
4. OTHER EFFECTS
 Pain on parenteral administration
FENTANYL (AMIDATE)
CLINICAL USES  Sufentanil, remifentanil
 Opioid analgesic
 Conscious sedation
 Short duration
 Induction of general anesthesia
 IV, oral, and patch forms

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 CNS Pharmacology II: General Anesthesia

 Chest wall rigidity with IV use o Dose-dependent inhibition of 11β-hydroxylase

 Used in neurolept anesthesia with droperidol and NO (converts cholesterol to cortisol) – lasts 4-8 hours

#PharMasaya CORNER CLINICAL USES

 Rapid intravenous induction of anesthesia
"Neuro-" means "nerve" and "-lept" means "to hold," so
"neurolept" means "to get hold of the nurse." I mean, nerves. DEXMEDETOMIDINE (PRECEDEX)*
(Loyola, 2013)
 Highly selective α2-adrenergic agonist
 Antagonized by α2 antagonists (You don't say.)
ETOMIDATE (AMIDATE)  Active S-enantiomer of medetomidine (imidazole derivative)
 Carboxylated imidazole derivative
 Attain adequate sedation with no analgesic property PHARMACOKINETICS
 Minimal hemodynamic effects  Rapid hepatic metabolism
 Ideal for combination with opioids o Conjugation  N-methylation  hydroxylation  back
to conjugation
PHARMACODYNAMICS  Short half-life of 2-3 hours
 GABA-like effects
 Potentiation of GABAA-mediated Cl- currents CLINICAL USES
1. CENTRAL NERVOUS SYSTEM EFFECTS
PHARMACOKINETICS  Stimulation of α2R in locus ceruleus  hypnosis
 Metabolized by ester hydrolysis to inactive metabolites  Analgesia
 Urinary and biliary excretion  Sedative effect resembling physiologic sleep
 Short context-sensitive half-time   cerebral blood flow

ORGAN LEVEL EFFECTS 2. CARDIOVASCULAR EFFECTS

1. CENTRAL NERVOUS SYSTEM EFFECTS  Infusion
 Cerebral vasoconstriction o Moderate  in heart rate, systemic vascular
  cerebral blood flow and intracranial pressure resistance, and systemic blood pressure
  CMRO2  IV bolus
  frequency in excitatory EEG spikes o Transient  in systemic blood pressure
 Heart block
2. CARDIOVASCULAR EFFECTS  Severe bradycardia
 Modest or absent  in systemic blood pressure  Asystole
 Minimal changes in heart rate and cardiac output
 Minimal myocardial depression 3. RESPIRATORY EFFECTS
 Small to moderate  in tidal volume
3. RESPIRATORY EFFECTS  Very little change in respiratory rate
 Less pronounced respiratory depression  No change in response to CO2

4. ENDOCRINE EFFECTS
 Adrenocortical suppression

PHARMACOKINETIC PROPERTIES OF INTRAVENOUS ANESTHETIC AGENTS

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REVIEW QUESTIONS 11. Preferred for induction and maintenance of anesthesia:

1. Anesthesiologists aim to shorten this stage of anesthesia: a. Diazepam
a. Stage I b. Midazolam
b. Stage II c. Propofol
c. Stage III d. Thiopental
d. Stage IV
12. Emergence reaction is an AE of this drug.
2. Reliable indicator in stage of surgical anesthesia: a. Etomidate
a. Hypnosis b. Fentanyl
b. Lack of response to surgical incision c. Ketamine
c. Medullary depression d. Methohexital
d. Resumption of regular respiration
13. IV anesthetic used in neurolept anesthesia:
3. MAC is the minimum % of anesthetic at which 50% of a. Fentanyl
patients do not respond to a/an/the: b. Ketamine
a. Elicitation of deep tendon reflex c. Propofol
b. Incision d. Thiopental
c. Trapezius muscle squeeze
d. Verbal command 14. Benzodiazepine used in conscious sedation:
a. Diazepam
4. All of the following have inverse relationships with uptake b. Lorazepam
of inhaled anesthetics except: c. Midazolam
a. Arteriovenous concentration gradient d. Triazolam
b. Pulmonary blood flow
c. Solubility 15. (Application) Which of the following conditions would
d. Ventilation entail the use of etomidate on as anesthetic of choice?
a. Cerebrovascular accident
5. All of the following pharmacokinetic properties of inhaled b. Heart failure
anesthetic are correct except: c. Both a and b
a. Anesthetic tension in each tissue varies in recovery d. Neither a nor b
b. Initial anesthetic tension in tissues pre-op = 0
c. Reverse transfer can be enhanced
d. None of the above

6. Equilibration time is prolonged in this condition.

a. Decreased gradient
b. High blood solubility
c. High blood:gas coefficient
d. Increased gradient

7. Inhaled anesthetic with a blood:gas partition coefficient

lower than that of nitrous oxide:
a. Desflurane
b. Halothane
c. Isoflurane
d. Sevoflurane

8. Chlorotrifluoroethyl free radical is a toxic metabolite of

this inhaled anesthetic and causes hepatic dysfunction.
a. Halothane
b. Isoflurane
c. Methoxyflurane
d. Nitrous oxide

9. Fluoride ion generation leading to nephrotoxicity is the

toxic mechanism of all of these drugs except:
a. Enflurane
b. Isoflurane
c. Methoxyflurane
d. Sevoflurane

10. IV anesthetic with the longest relative context half-time:

a. Methohexital
b. Midazolam
c. Propofol
d. Thiopental

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