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Ser S4 Lec 1: Anesthesia by Frederick C. Loyola, M.D. January 26, 2011
yi
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na Inhaled anesthetics: Can be a volatile liquid-
Ya halogenated hydrocarbons (isoflurane, desflurane,
sevoflurane) – aerosolized in a specialized vaporizer
delivery system, or gas (PONV).
ay
Jep I. General anesthesia Several different classes of intravenous drugs , alone
vis A. Inhalational agents or in combination with other anesthetic and analgesic drugs,
Ma B. Intravenous anesthesia to achieve the desired anesthetic state.
s
Rev II. Local anesthesia

III. Neuromuscular blockers

i
Ma
n
Re
y GENERAL ANESTHESIA
Ico  Induces a physiologic state of analgesia, amnesia, loss of
ulfi Pre-test: consciousness, inhibition of sensory & autonomic reflexes,
Pa skeletal muscle relaxation
s Matching Type:  Extent depends on specific drug, dosage, and clinical situation
 Ideal: smooth and rapid induction
Viv

o prompt recovery
ene
Arl 1. Severe depression of CNS
a 2. Inhaled anesthetics with antiemetic effects o wide margin of safety
Niň 3. Malignant Hyperthermia o devoid of adverse effects
ng 4. Dissociative Anesthesia  Balanced anesthesia (combination)
5. An Ester
da
6. An Amide Modern anesthesia involves a combination of IV
Da
7. Preop sedation (induction) & inhaled (maintenance of anesthesia)
Sevoflurane can be used to induce as well
8. Neurolept Anesthesia
r
IV propofol can be used for maintenance
che 9. Anesthetic potency Muscle relaxant – commonly used to facilitate
Tea 10. Toxins from frog tracheal intubation & optimize surgical conditions during
o operation
Ric
kie A. D-tubocurarine
Nic B. prilocaine STAGES OF ANESTHESIA: (Guedel’s Sign)
d C. cocaine Stage Comments
D. midazolam From analgesia w/o amnesia to
Gla I Stage of Analgesia:
Je E. batrachotoxin analgesia with amnesia
nz F. propofol From irregular respiration up to
G. ketamine resumption of regular breathing,
H. fentanyl II Stage of Excitement: (delirious, vocalize, retching,
Ay

I. stage 4 vomiting), aims to shorten or limit

h
Kat J. stage 3 duration.
Jho K. MAC value From recurrence of regular
h respiration to complete cessation
III Stage of Surgical anesthesia:
na of spontaneous breathing
Gie (apnea), 4 planes
o Severe depression of the CNS,
Stage of Medullary Affection of vasomotor center in
Ed IV
elle Depression: the medulla, respiratory center in
Joc the brainstem
e
Job A. Inhaled Anesthetics
Ivz  MAC value
rk o Measure of anesthetic potency, is the minimal alveolar
Ma anesthetic concentration (% of inspired anesthetic in
l air) at which 50% of patients do not respond to a
che surgical stimulus
Ra o Additive
o Lower in elderly
“G”
n
Joh
Ian
a

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Nin
 o Reduced by other drugs (eg. opioids and sedative-  Pulmonary Ventilation
Mechanism of action: interaction with neuronal  Pulmonary Blood Flow
membrane lipids leading to inhibition of ion flux.  Arteriovenous Concentration Gradient
 Primary molecular target: GABAA receptor chloride channel
(inhibitory transmission) Rates of Onset & Recovery of Inhaled Anesthetics
 Depends on blood:gas partition coefficients (blood solubility)
Properties of Inhaled Anesthetics  High blood solubility means it takes longer to achieve a partial
Blood:Gas Brain:Blood Minimal pressure that allows movement from the blood into the CNS
Anesthetic Partition Partition Alveolar Conc Metabolism Comments
Coefficient1 Coefficient1 (MAC) (%)2  High blood gas solubility ratio = slow onset
Incomplete  When anesthesia ends, agents with high blood solubility take
Nitrous anesthetic; rapid
oxide
0.47 1.1 > 100 None onset and longer to achieve a partial pressure that allows movement from
recovery the blood into the alveoli, thus their recovery rates are slower
Low volatility;
poor induction  This principle underlies the introduction of several newer agents
Desflurane 0.42 1.3 6–7 < 0.05% agent; rapid (deflurane & sevoflurane) which have low blood:gas solubility
recovery
Rapid onset and
ratios, affording both rapid onset of anesthesia & rapid recovery.
Sevo- 2–5% recovery;
0.69 1.7 2.0
flurane (fluoride) unstable in soda-
lime
Medium rate of
Isoflurane 1.40 2.6 1.40 < 2% onset and The onset of gas anesthetics action and recovery
recovery
from gas anesthetics. There is a phramacokinetic principle
Medium rate of
Enflurane 1.80 1.4 1.7 8% onset and here called blood:gas partition coefficient. (blood solubility).
recovery High blood:gas partition coefficient coincides with high
Medium rate of blood solubility….it takes longer for the anesthetic to work
Halothane 2.30 2.9 0.75 > 40% onset and since it has to saturate the blood first before it can come out
recovery of the blood to enter the tissues like the cns.
Methoxy- > 70% Very slow onset When anesthesia ends and you turn off the gas…
12 2.0 0.16 and recovery
flurane (fluoride)
Note the MAC values: halothane (0.75 %), Isoflurane (1.4 %), evoflurane (2%), desflurane (6-7
%), & Nitrous Oxide (>100%)

Why do we use NITROUS OXIDE?

Because MAC values are Additive. Nitrous oxide is being used
so as to lessen the amount of other anesthetic with more dangerous
side effects…like cardiac suppressant
In the dental arena, they usually use nitrous oxide alone but
with the use of local anesthetic. Nitrous oxide is not a very strong
anesthetic. Usually attains a low level of analgesia. Vary with
patients… elderly, reduced by other drugs like opioids and other
sedative hypnotics. *Why induction of anesthesia is slower with more soluble anesthetic
Highly lipid soluble. Their potency as a compound depends on gases.
their lipid solubility. The more lipid soluble, the less u need. Their
activity is in the lipids of neuronal membrane to influence ionic flux.  Solubility in blood is represented by the relative size of the
(inhibition of ionic flux) specifically for synapse membranes. blood compartment (the more soluble, the larger the
compartment).
 Relative partial pressures of the agents in the compartments
are indicated by the degree of filling of each compartment.
PHARMACOKINETICS
 For a given concentration or partial pressure of the two
anesthetic gases in the inspired air, it will take much longer
Uptake and Distribution of Inhaled Anesthetics for the blood partial pressure of the more soluble gas
 Solubility (halothane) to rise to the same partial pressure as in the
 Anesthetic Concentration in the inspired air alveoli.

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  Since the concentration of the anesthetic agent in the brain (↑ intracranial pressure) & relax uterine smooth muscle
can rise no faster than the concentration in the blood, the  Hypotension (vasodilation & some cardiodepression) – halothane
onset of anesthesia will be slower with halothane than with may sensitize myocardium to catecholamines
nitrous oxide.
 Malignant hyperthermia (rare) with halogenated agents in
Comparison of arterial tensions of combination with NM blockers.
Inhalational anesthetics as a function of time
(less soluble vs more soluble) Do we really need another inhaled anesthetic?
 Halothane associated hepatitis (rare)
 Euphoric & disinhibitory effects of inhaled nitrous oxide (laughing
gas) abused – sometimes OD toxicity
 Desflurane- low volatility (specialized heated vaporizer),
pungency (coughing & symphathetic SE)
 Sevoflurane- chemically unstable, reacts with CO2 absorbents-
Olefinic Comp (Compound A) – nephrotoxic
 Xenon (high cost)

B. INTRAVENOUS ANESTHETICS
Drug Comments

• Rapid-onset & short-acting barbiturates used mainly for

Thiopental induction
• ↓ Respiratory and cardiac function, but no ↑ cerebral blood
flow
*Tensions of three anesthetic gases in arterial blood as a function of time after • Rapid recovery via redistribution from CNS to peripheral
beginning inhalation. Nitrous oxide is relatively insoluble (blood:gas partition tissues, but liver metabolism required for elimination
coefficient = 0.47); methoxyflurane is much more soluble (coefficient = 12); and
halothane is intermediate (2.3). • IV benzodiazepine for preop sedation & in anesthesia protocols
Midazolam
(conscious sedation)
• Anterograde amnesia, ↓ respiratory function
• Reversed by flumazenil

• Rapid onset & short duration, “dissociative anesthesia” with

amnesia, catatonia & analgesia
Ketamine • CV stimulation (stimulates central SNS) and inhibits reuptake
of norepinephrine at sympathetic nerve terminals
• Emergence reaction (dreams, hallucinations) offset by BZs or
propofol

Propofol • Very rapid onset & recovery, plus antiemetic effects

• Induction & maintenance, especially outpatient surgery
• Intravenous Anesthetics

• Sufentanil, remifentanil
Fentanyl
• Opioid analgesic (others related) – short duration IV, oral &
patch forms also used. Chest wall rigidity with IV use
• Neurolept anesthesia = fentanyl + droperidol + nitrous oxide

• Carboxylated imidazole
Etomidate • Used in patients with limited cardiovascular reserve
*The rate of rise of anesthetic gas tension in arterial blood is directly • Can attain adequate sedation with no analgesic property
dependent on both the rate and depth of ventilation (ie, minute • Ideal for combination with opioids
ventilation). The magnitude of the effect varies according to the
blood:gas partition coefficient. An increase in pulmonary ventilation is LOCAL ANESTHETICS
accompanied by only a slight increase in arterial tension of an
anesthetic with low blood solubility or low coefficient but can  Weak bases (pKa=8) for regional anesthesia via infiltration near
significantly increase tension of agents with moderate-to-high blood nerve bundles, or by epidural & subarachnoid injection
solubility (Figure 25-5). For example, a fourfold increase in ventilation  Ionized (protonated) & non-ionized (non protonated) forms
rate almost doubles the arterial tension of halothane during the first 10  Esters (procaine, cocaine,tetracaine, benzocaine) metabolized by
minutes of anesthesia but increases the arterial tension of nitrous
plasma & tissue esterases;
oxide by only 15%. Therefore, hyperventilation increases the speed of
induction of anesthesia with inhaled anesthetics that would normally  Amides (lidocaine, mepivacaine,ropivacaine, articaine,prilocaine,
have a slow onset. Depression of respiration by opioid analgesics bupivacaine) metabolized by liver
slows the onset of anesthesia of inhaled anesthetics if ventilation is not  Local Anesthetics
manually or mechanically assisted  Ionized forms (RNH3+) binds to a component of the Na+ ion
channel located inside nerve membrane
Actions of Inhaled Anesthetics
 Lower response to increased pCO2, ↑ cerebral blood flow

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  For access to its target, the local anesthetic must first cross the  Alpha adrenoceptor agonists (eg. Epinephrine)
lipid bilayer & it does so in its non-ionized form (RNH2)  LA absorption into the blood, prolonging effects. Cocaine causes
vasoconstriction.

Adverse Effects of Local Anesthetics

 Neurotoxicity – dizziness, nystagmus, sensory impairment,
seizures
 ↓ CV parameters, except cocaine (↑HR & BP)
 Allergies – esters via PABA formation

SODIUM CHANNEL TOXINS

Tetrodotoxins & Saxitoxins

 Tetrodotoxin (puffer fish) & saxitoxin (dinoflagellate “red tide”)
bind externally to the “ready state” of Na+ channels in both cardiac
& nerve cell membrane - ↓ conduction
Ciguatoxin & Batrachotoxin
 Ciguatoxin (exotic fish Moray eel) & batrachotoxin (frogs) bind in
the Na+ channel – prevent inactivation, persistent depolarization &
channel inactivation]

NEUROMUSCULAR BLOCKING DRUGS

Uses
• Surgical relaxation
• Tracheal Intubation
• Control of Ventilation
• Treatment of convulsions

Nicotinic Receptor Antagonists

 Non-depolarizing (competitive) – reversed by AChE inhibitors
 ↓ frequency of Na+ channel opening at skeletal endplate causing
progressive muscle paralysis (Rx: use in anesthesia & ICU)

Drug Comments

• blocks ANS ganglia & releases histamine - ↓BP;

D-tubocurarine
implicated in malignant hyperthermia

Pancuronium • more rapid onset & recovery, ↑ BP

Atracurium • spontaneously inactivated – laudanosine

• Very short duration, metabolized by plasma
Mivacurium
pseudocholinesterase, histamine release

Succinylcholine
 Depolarization (noncompetitive) acting in 2 phases:
o Phase 1 – brief stimulation – fasciculation
o Phase 2 – depolarization – flaccid paralysis, not
reversed by AChE inhibitors
 Short duration since rapidly inactivated by pseudocholinesterases
Nerve Fiber Sensitivity to Local Anesthetics
– genotypic variants with low enzyme activity - ↑ duration
 Most sensitive – smaller diameter & high firing rates (state-
 Low doses - ↓ HR (vagal) ; high dose - ↑ (ganglionic stimulation)
dependency)
 Hyperkalemia, Increased intraocular pressure, muscle pain;
 Type B & C > type A delta > type A beta & gamma > type A alpha
 Implicated in malignant hyperthermia
Absorption

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  Increase IOP- tonic contraction of myofibrils, transient dilation of • During recovery from nondepolarizing block, the
ocular choroidal blood vessels. amount of fade decreases and the TOF ratio
 Fasciculation of abdominal muscles causes increase intragastric approaches 1.0.
pressure • Recovery to a TOF greater than 0.7 is typically
necessary for resumption of spontaneous ventilation.
TRAIN OF FOUR (TOF) • However, complete clinical recovery from a non-
depolarizing block is considered to require a TOF
greater than 0.9.
• Fade in the TOF response after administration of
succinylcholine signifies the development of a phase
II block.

Tetanic stimulation
• Consists of very rapid (30-100 Hz)
delivery of electrical stimuli for several
seconds.
• During a nondepolarizing block (and a
phase II block after succinylcholine), the
response is not sustained and fade is observed.
• Fade in response to tetanic stimulation is normally
considered a presynaptic event.
• However, the degree of fade depends primarily on the
degree of neuromuscular blockade.
• During a partial nondepolarizing blockade, tetanic
nerve stimulation is followed by an increase in the
posttetanic twitch response, so-called posttetanic
(*, first posttetanic contraction.) facilitation of neuromuscular transmission.
• During intense neuromuscular blockade, there is no
response to either tetanic or posttetanic stimulation.
*Muscle responses to different patterns of nerve stimulation used • As the intensity of the block diminishes, the response
in monitoring skeletal muscle relaxation. The alterations to posttetanic twitch stimulation reappears. The time to
produced by a nondepolarizing blocker and depolarizing and reappearance of the first response to TOF stimulation is related to
desensitizing blockade by succinylcholine are shown. the posttetanic count.
In the train of four (TOF) pattern, four stimuli are applied at 2 Hz.
The TOF ratio (TOF-R) is calculated from the strength of the Double-burst stimulation pattern
fourth contraction divided by that of the first. • Newer mode of electrical nerve stimulation developed
In the double burst pattern, three stimuli are applied at 50 Hz, with the goal of allowing for manual detection of
followed by a 700 ms rest period and then repeated. residual neuromuscular blockade when it is not
In the posttetanic potentiation pattern, several seconds of 50 Hz possible to record the responses to single-twitch,
stimulation are applied, followed by several seconds of rest
and then by single stimuli at a slow rate (eg, 0.5 Hz). The
number of detectable posttetanic twitches is the posttetanic “Action springs not from thought,
count (PTC).
but from a readiness for
The three most commonly used patterns include (1) single-twitch
stimulation, (2) train-of-four (TOF) stimulation, and (3) tetanic responsibility”
stimulation. Two newer modalities are also available to monitor
neuromuscular transmission: double-burst stimulation and
Special Thanks to our Guest Transer,
posttetanic count.
Paul Lawrence Filomeno.
TOF stimulation ‘til next time!
• Involves four successive supramaximal stimuli given
at intervals of 0.5 second (2 Hz). TOF, or tetanic stimulation.
• Each stimulus causes the muscle to contract, and the • Three nerve stimuli are delivered at 50 Hz followed by
relative magnitude of the response of the fourth twitch a 700 ms rest period and then, by two or three
compared with the first twitch is the TOF ratio. additional stimuli at 50 Hz.
• With a depolarizing block, all four twitches are • It is easier to detect fade in the responses to double-
reduced in a dose-related fashion. burst stimulation than to TOF stimulation. The
• With a nondepolarizing block, the TOF ratio absence of fade in response to double-burst
decreases ("fades") and is inversely proportional to stimulation implies that clinically significant residual
the degree of blockade. neuromuscular blockade does not exist.

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Spasmolytics
 Reduce excessive muscle tone or spasm in acute muscle injury &
CNS dysfunction (eg. Cerebral palsy, MS, stroke)

Drug Comments

• fascilitate GABA at GABA receptor - ↓ tonic output of

Benzodiazepines
primary spinal motor neurons

Baclofen • direct agonist at GABAB receptors in spinal cord –

activation - ↑ efflux of K+ (via 2nd messenger)IV
Dantrolene • blocks release of Ca2+ from SR – direct action on skeletal
muscle – Rx use in malignant hyperthermia

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Drugs Used for Local Anesthesia
Subclass Mechanism of Action Effects
Amides 
  Lidocaine Blockade of sodium channels Slows, then blocks action
potential propagation
  Bupivacaine Same as lidocaine Same as lidocaine
  Prilocaine, ropivacaine, mepivacaine, levobupivacaine: Like bupivacaine 
Esters 
  Procaine Like lidocaine Like lidocaine

  Cocaine Same as above also has Same as above

sympathomimetic effects
  Tetracaine: Used for spinal, epidural anesthesia; duration 2–3 h 

Drugs Used as Neuromuscular Blockers

Subclass Mechanism of Action Effects
Depolarizing neuromuscular blocking agent 
  Succinylcholine Agonist at nicotinic acetylcholine (ACh) Initial depolarization causes transient
receptors, especially at neuromuscular junctions contractions, followed by prolonged flaccid
depolarizes may stimulate ganglionic nicotinic paralysis depolarization is then followed by
ACh and cardiac muscarinic ACh receptors repolarization that is also accompanied by
paralysis
Nondepolarizing neuromuscular blocking agents 
  d-Tubocurarine  Competitive antagonist at nACh receptors, Prevents depolarization by ACh, causes flaccid
especially at neuromuscular junctions paralysis can cause histamine release with
hypotension
ACh receptors
  Cisatracurium Similar to tubocurarine Like tubocurarine but lacks histamine release
and antimuscarinic effects

  Rocuronium Similar to cisatracurium Like cisatracurium but slight antimuscarinic

effect
  Mivacurium: Rapid onset, short duration (10–20 min); metabolized by plasma cholinesterase
  Vecuronium: Intermediate duration; metabolized in liver 
Centrally acting spasmolytic drugs 
  Baclofen GABAB agonist, facilitates spinal inhibition of Pre- and postsynaptic inhibition of motor output
motor neurons
  Cyclobenzaprine Poorly understood inhibition of muscle stretch Reduction in hyperactive muscle reflexes
reflex in spinal cord antimuscarinic effects
  Chlorphenesin, methocarbamol, orphenadrine, others: Like cyclobenzaprine with varying degrees of antimuscarinic effect
  Diazepam Facilitates GABAergic transmission in central Increases interneuron inhibition of primary
nervous system motor afferents in spinal cord

  Tizanidine alpha2-Adrenoceptor agonist in the spinal cord Presynaptic and postsynaptic inhibition of reflex
  motor output
Direct-acting muscle relaxants 
  Dantrolene Blocks RyR1 Ca2+-release channels in the Reduces actin-myosin interaction
sarcoplasmic reticulum of skeletal muscle skeletal muscle contraction