History of Anesthesia

General Anesthetics
Pharmacology 604
K a t h e r i n e L . N i c h o l s o n , D . V . M . , P h. D .
Dept. Pharmacology/Toxicology
k l n i c h o l @h s c . vcu . edu

General Anesthesia Characteristics

Definition (G&G) - Reversible depression of CNS

function resulting in loss of response to and perception of

Balanced Anesthesia

Ideal general anesthetic does not exist.

Combinations of drugs to accomplish what one

anesthetic can not do alone.

all external stimuli.

- Produce reversible "sleep"

Agents used for balanced anesthesia are -

- Produce analgesia

Hypnotics

- Suppress reflexes

Neuromuscular blocking agents

- Produce muscle relaxation

- Produce Amnesia
- Do not suppress respiratory and cardiovascular
function

Analgesics
COMBINATION OF DRUGS CAN LOWER DOSES OF
EACH DRUG TO PRODUCE

THE SAME OR GREATER

EFFECT ON PATIENT

- Inexpensive and easy to administer

Four Stages of Anesthesia

Stage I - a n a l g e s i a
Stage II - d e l i r i u m
Stage III - surgical anesthesia

Types of General Anesthetics

Extremely diverse group of chemicals which
produce a similar endpoint
Inhalant or volatile

Stage IV - respiratory paralysis

Injectable (intravenous)

MAC: Minimum Alveolar

Concentration

Inhalational Anesthetics

Potency measure
Administered as vapors or gases

1 MAC is the concentration necessary to

prevent responding in 50% of population

Special set of physical principles govern

absorption, distribution and elimination

[Halothane] % atm
0.0

Partial pressure - proportional to the

concentration of anesthetic in gas or tissue
at equilibrium

Fraction of
Anesthetized
Patients

0.5

1.0

1.5

1.0

0.8

0.6

0.4

0.2

MAC

0.0
0.0

0.1

0.2

0.3

0.4

[Halothane] mM

Solubility & P h a r m a c o k i n e t i c s

Factors affecting MAC

Solubility expressed as partition coefficients

Factors decreasing MAC:

Factors increasing MAC:

Hypotension

Increasing body temperature

Anemia ( PCV < 13%).

Hyperthyroidism

Hypothermia

Hypernatremia

Metabolic acidosis

Factors NOT affecting MAC

Extreme hypoxia (PaO2 < 38 mmHg )

Solubility in blood

Age: old animal require less anesthetic

Type of stimulation

Premedication (opioids, sedatives,

tranquilizers)

Duration of anesthesia
Species

Local anesthetics

Pregnancy

Hypothyroidism

Sex
PaCO2 between range of 14-95 mmHg
Metabolic alkalosis

Concurrent use of nitrous oxide

PaO2 between range of 38-500 mmHg

Hypertension
Potassium

(a ratio of the concentration of the agent in two phases at

equilibrium)

Blood:gas partition coefficient

main factor that determines the rate of induction and
recovery

Oil:gas partition coefficient

fat solubility
determines the potency of an anesthetic (as well as kinetics)

Anesthetic Properties

Induction and Recovery

MAC

The lower the blood:gas partition coefficient the faster the

induction and recovery
The lower the solubility in blood, the faster the process of
equilibration
Less drug has to be transferred via the lungs to the blood in
order to achieve a given partial pressure
A s i n g l e l u n g f u l o f a i r c o n t a i n i n g a l o w-s o l u b i l i t y a g e n t w i l l
bring the partial pressure in the blood closer to that of the
inspired air

Recovery is the same

Low solubility in blood = fast induction and recovery

High solubility in blood = slower induction and recovery

Anesthetic

Partition Coefficients
Oil:Gas

Oil:Water

Methoxyflurane

0.16

0.26

4.2

850

200

Halothane

0.77

0.19

0.63

200

320

Isoflurane

1.2

0.24

0.54

91

170

Enflurane

1.7

0.52

0.78

97

120

Diethylether

1.9

8.22

Sevoflurane

2.0

0.29

0.37

47

130

Fluroxene

3.4

0.95

0.71

67

94

Desflurane

6.0

0.52

0.22

19

86

Cyclopropane

9.2

0.72

0.20

0.15

0.019

2.2

0.085

1.1

2.1

0.075

1.8

0.39

1.3

Butane
Ethylene
Xenon
Nitrous Oxide

(% atm)

20
67
71
101

Potency

(mM)

15

Water:Gas

11

Blood
Solubility

57

9.7
15

5.2

49
790
13
24
3.3

Brain
Solubility

Nitrous Oxide

Nitrous Oxide - Disadvantages

Cannot produce anesthesia without h y p o x i a

Relatively safe

Poor muscle relaxation

Minimal effects on heart rate and blood

Diffuses into closed spaces

pressure
Little effect on respiration

Inhibits vitamin B-1 2 m e t a b o l i s m

Low blood solubility (quick recovery)

M A C v a l u e i s 1 0 5 % - Needs other agents
for surgical anesthesia

Inhibits m e t h i o n i n e s y n t h e t a s e (precursor to
DNA synthesis)
Abuse liability

Weak anesthetic, powerful analgesic

H a l o t h a n e ( Fluothane )

Anesthetics - H a l o g e n a t e d e t h e r s
7

Most potent inhalational anesthetic

MAC of 0.75%
4

MW

74

H CH 3 H

Fluroxene

126

H =CH

Methoxyflurane

165

Cl

Cl

Desflurane

168

Isoflurane
Enflurane

184
184

H
F

F
F

H
H

F
F

Cl
F

F
Cl

F
H

F
F

Sevoflurane

200

CF 3

Diethyl ether

Very soluble in blood and adipose tissue

Prolonged emergence

Inhibits sympathetic response to painful

stimuli

Enflurane ( E t h r a n e )

Halothane - Disadvantages
Decreases respiratory drive

Stable, nonflammable liquid with pungent odor

Depresses cardiovascular function

MAC 1.68%

S e n s i t i z e s m y o c a r d i u m -can lead to
ventricular arrhythmias

Cardiac effects
depression and decreased systemic vascular resistance
inhibits sympathetic baroreflex response

H a l o t h a n e Hepatitis
Malignant H y p e r t h e r m i a

sensitizes myocardium

Decreases respiratory drive

Metabolism one-tenth that of halothane

Epileptiform EEG patterns

r e l e a s e s f l u o r i d e i o n -- r e n a l t o x i c i t y

Isoflurane ( Forane)

Isoflurane Toxic Side Effects

Less soluble than halothane

MAC of 1.30 %

Excellent muscle relaxant

Depresses respiratory drive and ventilatory

Little metabolism (0.2%) -- low potential of

organotoxic metabolites

r e s p o n s e s- - (less than enthrane)

No EEG activity like enflurane

Depresses cardiovascular system

Bronchoirritating, laryngospasm

M y o c a r d i a l d e p r e s s a n t (less than enthrane)

I n h i b i t s s y m p a t h e t i c b a r o r e f l e x r e s p o n s e (less than
enthrane)
Produces most significant reduction in systemic
vascular resistance

S e n s i t i z e s m y o c a r d i u m - less than enthrane

Sevoflurane ( Ultane, Sevorane)

and Desflurane (Suprane)

Meyer Overton Correlation

HAL

Halothane

ISO

Isoflurane

ENF
SEV

Enflurane
Sevoflurane

FLU
DES

Fluroxene
Desflurane

CYC
MOF

Cyclopropane
Methoxyflurane

DEE
CHL

Diethylether
Chloroform

DDM

Dichlorodiflurormethane

PFE
CTF

Perfluoroethane
Carbon tetrafluroide

SHF
CYC

Sulfur hexafluoride
Cyclopropane

ETH
NO2

Ethylene
Nitrous oxide

XEN
NIT

Xenon
Nitrogen

KRY
ARG

Krypton
Argon

100
NIT

Expensive

PFE

SHF
KRY

NO2
ETH
XEN
HYD

1
Mouse MAC (atm)

Few side effects

ARG

DDM

Minimal systemic effects-- mild respiratory

and cardiac suppression

CTF

10

Potency

Low solubility in blood-- produces rapid

induction and emergence

CYC

0.1
FLU

DEE
ENF
ISO

0.01

CHL

HAL

MOF

0.001
0.01

0.1

10

100

1000

Olive Oil : Gas Partition Coefficient

Lipid- Based Theories of

Anesthetic Action

.however..
Volume expansion by nonanesthetic c o m p o u n d s
Correlation between fluidity and anesthetic levels only
occurred at high concentrations.
Small changes in temperature did produce significant
fluidity changes without causing anesthesia while large
changes in anesthetic concentration produced small
changes in fluidity.
Cut- off effect - M- O rule only holds up to a certain size
Inhalant anesthetics show stereoselectivity in effects

Hypothesized anesthetic effect was due to

disruption of lipid b i l a y e r of plasma
membranes.

Protein-based theories of
Anesthetic Action

Ok, so which receptors

matter.
G A B AA
Glutamate (AMPA and NMDA)
Glycine ( s t r y c h n i n e-sensitive, in spinal cord
and brainstem)

Anesthetics bind to hydrophobic/ lipophilic

sites on proteins.

Nicotinic A C h

induce/prevent conformational change

alter kinetics of conformational changes
compete with ligands

Injectable anesthetics

Advantages
minimal equipment
direct CNS access
wide variety of agents, techniques

Disadvantages
recovery dependent on uncontrollable
factors
individual variation in drug response

Barbiturates
Phenobarbital
Pentobarbital Sodium
Thiopental Sodium
Thiamylal Sodium
Methohexital

potential for drug accumulation

Barbiturates - General
Very alkaline - very irritating to tissues
Depress p o l y s y n a p t i c responses in the CNS
Effect on GABA receptors
Depress Reticular Activating System
Depress sympathetic nervous system

Poor analgesics

Cardiopulmonary Effects
A r r h y t h m o g e n i c! ! !
Transient VPCs & ventricular bigeminy

Transient, moderate decrease in blood

pressure
Decrease cardiac contractility

Excitement at low doses

Vascular effects variable, but in general

cause mild vasodilatation

Low therapeutic index!

Respiratory depressants

Propofol

Disadvantages

G A B AA positive modulator
Solubilized in an emulsion

Expensive

Rapid onset, short duration of

Moderate hypotension, possible

bradyarrhythmias , respiratory depression
(apnea not uncommon)

action, rapid smooth recoveries w/o hangover

Useful for induction &/or maintenance (by
constant infusion)
Mild to moderate h y p o t e n s i o n , may produce
bradyarrhythmias

Poor analgesia (need high doses)

Drug vehicle supports bacterial growth

Respiratory depressant, may produce apnea

Etomidate
G A B AA positive modulator
non-barbiturate ultrashort sedative/hypnotic
minimal cardiovascular effects

Dissociative Anesthetics
Ketamine
Tiletamine
N M D A r e c e p t o r c h a n n e l blockers

rapid onset/recovery

Produces amnesia, superficial analgesia, and

catalepsy

wide safety margin

Dissociates the cortex from lower centers

Both excitatory & depressant effects on EEG
Actually has positive effects on CV measures
and minimal respiratory depression

Problems...

Neuroleptanalgesia

Seizures

combination of opioid + tranquilizer/sedative

Muscle rigidity

produces state of light anesthesia

P o o r visceral a n a l g e s i a

useful for debilitated or geriatric patients

Increased secretions

eg fentanyl/diazepam; d r o p e r i d o l / fentanyl;
o x y m o r p h o n e /midazolam; etc...

Poor recoveries - delirium

Increased myocardial work load

Overview of mechanisms
of action for general
anesthetic..

Ion Channels and Anesthesia

G A B A A - primary anesthetic target

Act as modulators, not direct agonists
Increase current induced by low level
GABA by >50%
Work by prolonging channel open time
Inhalants, barbs, b e n z o s , steroids,
propofol

G l y c i n e - important for spinal cord and

lower brainstem

G A B AA Rc a c t i v a t i o n

Ion Channels and Anesthesia

Glutamate - N M D A, A M P A & Kainate

Potential Receptor Targets

Dissociative anesthetics
Relatively insensitive to inhalants (?) and
barbiturates

n A C h - most simple anesthetics can stabilize

desensitized form

An esthetic

nACH

+++

+++

---

- --

-/0

N2 O

+++

+/0

-/0

- -- --

Definitely involved in many inhalant effects

Xenon

Increasing interest for role with other anesthetics

Barbiturates

Voltage gated ion channels N a + , K + , C a ++

GABAA Glycin e Neuronal AMP A NMDA

Halothane

+++

+/0

---

- --

Ketam ine

---

- --

Propofol

+++

+++

-/0

-/0

-/0

N eur oste roids

+++

-/0

Do not appear to play a role in anesthesia