General Anesthetics

Michael H. Ossipov, Ph.D.

Department of Pharmacology

AnesthesiaSurgery Before

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 deemed
a failure because patient reacted.

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

Anesthesia

Allow surgical, obstetrical and diagnostic

procedures to be performed in a manner which
is painless to the patient
Allow control of factors such as physiologic
functions and patient movement

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:

Oblivion
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

PhasesStagesofOfGeneralGeneralAnesthesiaAnesthesia

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 Of General Anesthesia

Phases of General 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.
Stage IV: Too deep; essentially an overdose and represents anesthetic
crisis. This is the stage between respiratory arrest and death due to
circulatory collapse.

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

Anesthetic drugs have rapid onset and offset

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

"The alveolar concentration of an inhaled anesthetic that 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.
MAC values remain constant regardless of stimuli, weight, sex, and even
across species
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 with adjuvant i.v.
drugs

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)

How do Inhalational Anesthetics Work?

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

How 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
Supported by NMR and electron-spin resonance studies

 Anesthesia can be reduced by high pressure

How 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

Immobility is due to a spinal mechanism, but site is

unknown
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)

Sodium
channels

Nicotinic
acetylcholine

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 temperature and pressure
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 (non-flammable)
50% metabolism by P450, induction of hepatic microsomal
enzymes; TFA, 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
Renotoxic

Inhaled Anesthetics Currently

Enflurane (Ethrane) Rapid, smooth induction and maintenance
2-10% metabolized in liver
Introduced as replacement for halothane, canabilized to make
way for isoflurane
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
Most widely employed

Inhaled Anesthetics New Kids on the Block

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, No coronary steal

Degrades to form CO in dessicated soda-lime (Ba2OH /NaOH/ KOH;

not Ca2OH)
Fast recovery responsive within 5-10 minutes

Inhaled Anesthetics New Kids on the Block

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 CO2 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 + ETCO2 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 GABAA 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 - Barbiturates

Ideal: Rapid Onset, 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.
Build-up in adipose tissue = very long emergence from anesthesia (e.g.; one
case took 4 days to emerge)

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
Antiemetic effect
Feeling of well-being
Widely used for ambulatory surgery

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
Adverse effects: Pain, emesis, involuntary myoclonic movements,
inhibition of adrenal steroid synthesis

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-of-body") experience
misperceptions, misinterpretations, illusions
may be associated with euphoria, excitement, confusion, fear

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)
Rapid administration can cause transient apnea

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 degree minute
to minute control

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.

What is Balanced Anesthesia?

Garbage Anesthesia (everything but the
kitchen sink)
2

LOT (Little Of This, Little of That)

Mixed Technique

The Usual

MAC Reduction
Isoflurane Concentration (%)

2.00

1.50

1.00

0.00

0 10 20 30 40 50 60

0
.
5
Target Remifentanil
0
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

Michael H. Ossipov, Ph.D.

Department of Pharmacology

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,
EMLA)
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
(unprotonate

d N)
form
requi
red
to
trave
rse
tissu
e to
site
of
actio
n

pH of
formul
ation
is
irrelev
ant
since
drug
ends
up in
intersti
tial
fluid

Quaternary
analogs, low
pH bathing
medium
suggests
major form
active at site
is cationic,
but both
charged and
uncharged
species are
active
PKa

Etidoc
aine

8.1

7.7
Procain
e
Articai
ne

9.1

7.8
% RN
at PH
Lidoc
aine
7.9

Priloc
aine
7.9

Onset
in
7.4
minutes

40
2 to

Mepivicaine
7.6

Bupivi
caine

4
33

2 to

2 to

5 to

29

25

2 to

2 to

14 to

18

25

18

O
C
2

H
5

C H
2

H2N
COCH 2CH 2

H2N
COCH 2CH 2

C
2

C2H5

Cationic acid

Log

Base
Acid = pH p Ka

(Henderson-Hasselbalch equation)

For procaine (p Ka = 8.9) at tissue pH (7.4)

Base

Acid = 0.03

[1.0]

fluid
Nonionized base
[1.0]

Lipoid barriers

Extracellular

(nerve sheath)

Nerve membrane

Base
Acid

[3.1]

Acid

Axoplasm

[2.5]

Base

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

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 A-fibers.

Choice of local anesthetics

Onset
Duration
Regional anesthetic technique
Sensory vs. motor block

Potential for toxicity

Clinical use
Onset
Duration
Esters

Procaine
Slow
Short

Chloroprocaine
Fast
Short
Tetracaine
Slow
Long
Amides

Lidocaine
Fast
Moderate

Mepivacaine
Fast
Moderate
Bupivacaine
Moderate
Long
Ropivacaine
Moderate
Long
Etidocaine
Fast
Long

Choice of local anesthetics

Technique
Appropriate drugs
Topical
Cocaine, tetracaine, lidocaine
Infiltration

Procaine, lidocaine, mepivacaine,

bupivacaine, ropivacaine,
Peripheral nerve block
etidocaine

Chloroprocaine, lidocaine,

mepivacaine, bupivacaine,
Spinal
ropivacaine, etidocaine

Procaine, tetracaine, lidocaine,

Epidural
bupivacaine

Chloroprocaine, lidocaine,

bupivacaine, ropivacaine,
I.V. regional anesthesia

etidocaine

Lidocaine

Factors influencing anesthetic activity

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 Dose (mg)

Procaine

500

Chloroprocaine

600

Tetracaine 100 (topical)

Lidocaine 300
Mepivicaine

300

Bupivacaine

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 bodily functions
- use of epinephrine at end arteries (i.e.; fingers, toes) can cause
severe vasoconstriction leading to gangrene

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
used mainly for lower abdomen, legs, saddle
block

- Lidocaine (short procedures), bupivacaine (intermediate to long),

tetracaine (long procedures)

Neuromuscular Blocking Drugs

Michael H. Ossipov, Ph.D.

Department of Pharmacology

Neuromuscular blocking
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 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 Decamethonium
(ganglionic) (motor endplate)

(CH3)3N -(CH2)10-N (CH3)3

Neuromuscular blocking drugs

Acetylcholine is released from motor neurons in

discrete quanta
+

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 2

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 of

ACh, shifting equilibrium to favor displacing
the antagonist from motor

Nondepolarizing drugs: Metabolism

Important in patients with impaired organ

clearance or plasmacholinesterase
deficiency

Hepatic metabolism and renal excretion

(most common)
Atracurium, cis-atracurium: 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 respiratory
muscles

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