General Anesthetics

Surgery Before Anesthesia

Fun and Frolics led to Early

Anesthesia

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

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

Anesthetic techniques
General anesthesia
Regional anesthesia
Local anesthesia
Conscious Sedation (monitored
anesthesia care)

What is Anesthesia
No universally accepted definition
Usually thought to consist of:

Amnesia
Analgesia
Lack of Movement
Hemodynamic Stability

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

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)

Desired Effects Of General Anesthesia

(Balanced Anesthesia)
Rapid induction
Sleep
Analgesia
Secretion control
Muscle relaxation
Rapid reversal

PhasesOf
of General
General Anesthesia
Stages
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

Stages
PhasesOf
ofGeneral
GeneralAnesthesia
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.

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

Anesthetic Techniques
Inhalation anesthesia
Anesthetics in gaseous state are taken up by
inhalation

Total intravenous anesthesia

Inhalation plus intravenous (Balanced
Anesthesia)
Most common

nesthetic drugs have rapid onset and offs

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

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

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

MAC Minimal Alveolar

Concentration
of an inhaled anesthetic that
"The alveolar concentration
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.

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

Factors Affecting
MAC

Circadian rhythm
Body temperature
Age
Other drugs
Prior use
Recent use

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)

ow do Inhalational Anesthetics Work

Meyer-Overton observation: There is a strong
linear correlation between lipid solubility and
anesthetic potency (MAC)

ow 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
Anesthesia can be reduced by high pressure

ow 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
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 87:199-205,
1990.

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

Inhaled
Anesthetics
Gases

Nitrous oxide
Present in the gaseous state at room temperatu
Supplied as compressed gas

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

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

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

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

Chemistry
(CF3)2CH-O-CH3
10%, excellent anesthesia
CF3CHFCF2-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

Inhaled Anesthetics

Inhaled Anesthetics Historical

Ether Slow onset, recovery,
explosive
Chloroform Slow onset, very toxic
Cyclopropane Fast onset, but very explosive
Halothane (Fluothane) first halogenated ether (nonflammable)
50% metabolism by P450, induction of hepatic
microsomal enzymes; 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

Inhaled Anesthetics Currently

Enflurane (Ethrane) Rapid, smooth induction and maintenance
2-10% metabolized in liver
Introduced as replacement for halothane
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

Inhaled Anesthetics
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
Degrades to form CO in dessicated soda-lime (Ba2OH
/NaOH/KOH; not Ca2OH)
Fast recovery responsive within 5-10 minutes

Inhaled Anesthetics
Sevoflurane (Ultane) Low solubility and low pungency = excellent
induction agent
Significant metabolism (5%; 10x > isoflurane); forms inorganic
fluoride and hexafluoroisopropranolol
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

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?

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 CO 2
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 + ETCO 2 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

Intravenous
Anesthetics
Most exert their actions by potentiating GABA

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

Intravenous Anesthetics

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

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.

Intravenous Anesthetics Ideal: Rapid Onset, Barbiturates

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.
Effect 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.

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

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

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-ofbody") experience misperceptions,

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
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

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.

Depth of sedation

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).

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.

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.

MAC Reduction
Isoflurane C oncentration (% )

2.00
1.50
1.00
0.50
0.00
0

10

20

30

40

50

60

Target Remifentanil Concentration (ng/ml)

S=success (no response to skin incision) F=failure (response to skin incision)
Lang et al, Anesthesiology 85, 721-728, 1996

Bolus Dose Equivalents

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

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!

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

Simple Combinations
Fentanyl
75-150 on induction
25-50 g now and then during the case

Propofol
2-3 mg/kg on induction

N2O
70%

Sevoflurane
0.3-0.6%

Relaxant of choice

Local/Regional Anesthetics

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

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)

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

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)

Local anesthetics: Uses

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

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

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

PKa

% RN at
PH 7.4

Onset in
minutes

Mepivicai
ne

7.6

40

2 to 4

Etidocain
e

7.7

33

2 to 4

Articaine

7.8

29

2 to 4

Lidocaine

7.9

25

2 to 4

Prilocain
e

7.9

25

2 to 4

Bupivicai
ne

8.1

18

5 to 8

Procaine

9.1

14 to 18

H 2N

C 2H 5

COCH 2CH 2

Cationic acid

O
H 2N

COCH 2CH 2

+ H

C 2H 5

C 2H 5

Log Base = pH pKa

Acid

C 2H 5

Nonionized base

Lipoid barriers

[1.0]

(nerve sheath)

(Henderson-Hasselbalch equation)

For procaine (p
K a = 8.9)
at tissue pH (7.4)

Extracellular
fluid

Base

Nerve membrane
Base =
0.03
Acid

Axoplasm

Acid [1.0]

*
Base

[3.1]

Acid [2.5]

Structure

Structure

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

Mode of action

Mode of action

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 Afibers.

Choice of local anesthetics

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

Clinical use

Choice of local anesthetics

Technique
Topical
Infiltration

Peripheral nerve block

Spinal
Epidural

I.V. regional anesthesia

Appropriate drugs
Cocaine, tetracaine, lidocaine
Procaine, lidocaine, mepivacaine,
bupivacaine, ropivacaine,
etidocaine
Chloroprocaine, lidocaine,
mepivacaine, bupivacaine,
ropivacaine, etidocaine
Procaine, tetracaine, lidocaine,
bupivacaine
Chloroprocaine, lidocaine,
bupivacaine, ropivacaine,
etidocaine
Lidocaine

Factors
activity

influencing

anesthetic

Needle in appropriate location (most

important)
Dose of local anesthetic
Time since injection
Use of vasoconstrictors
pH adjustment
Nerve block enhanced in pregnancy

Redistribution and metabolism

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

Local anesthetic toxicity

Allergy
CNS toxicity
Cardiovascular toxicity

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.

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

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

Cardiovascular toxicity

Depressed myocardial contractility

Systemic vasodilation
Hypotension
Arrhythmias, including ventricular
fibrillation (bupivicaine)

Avoiding systemic toxicity

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

Maximum safe doses of local

anesthetics in adults
Anesthetic
Procaine
Chloroprocaine
Tetracaine
Lidocaine
Mepivicaine
Bupivacaine

Dose (mg)
500
600
100 (topical)
300
300
175

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

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

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

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

Neuromuscular Blocking Drugs

Neuromuscular blocking
drugs
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.

Neuromuscular blocking
drugs
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

Neuromuscular blocking
drugs

(CH3)3N+-(CH2)6-N+(CH3)3
Hexamethonium
(ganglionic)

(CH3)3N+-(CH2)10-N+(CH3)3
Decamethonium
(motor endplate)

Neuromuscular blocking drugs

Acetylcholine is released from motor
neurons
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

Non-depolarizing Neuromuscular
blocking drugs

Competetive antagonist of the

nicotinic 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

Nondepolarizing drugs:
Metabolism
Important in patients with impaired
organ clearance or
plasmacholinesterase deficiency
Hepatic metabolism and renal
excretion (most common)
Atracurium, cisatracurium:nonenzymatic (Hoffman
elimination)
Mivacurium: plasma cholinesterase

Depolarizing Neuromuscular blocking

drugs

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

Succinlycholine: Pharmacokinetics

Fast onset (1 min)

Short duration of action (2 to 3
min)
Rapidly hydrolyzed by plasma
cholinesterase

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

Succinylcholine: Side effects

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

Succinylcholine: Phase II block

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

Acetylcholinesterase
inhibitors
Acetylcholinesterase inhibitors have
muscarinic effects

Bronchospasm
Urination
Intestinal cramping
Bradycardia

Prevented by muscarinic blocking

agent

Selection of muscle relexant:

Onset and duration
Route of metabolism and elimination

Monitoring NM blockade

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