General Anesthesia

1

General Anesthetics

P h a r m a c o l o g y 6 0 4

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 .

D e p t . P h a r m a c o l o g y / T o x i c o l o g y

k l n i c h o l @h s c . vcu . edu

History of Anesthes ia

General Anesthesia -

Characterist ics• D e f i n i t i o n ( G & G ) - “ R e v e r s i b l e d e p r e s s i o n o f C N S

func t i on r e su l t i ng i n l o s s o f r e sponse t o and pe r cep t i on o f

a l l ex te rna l s t imul i . ”

- P r o d u c e r e v e r s i b l e " s l e e p "

- P r o d u c e a n a l g e s i a

- S u p p r e s s r e f l e x e s

- P r o d u c e m u s c l e r e l a x a t i o n

- P r o d u c e A m n e s i a

- D o n o t s u p p r e s s r e s p i r a t o r y a n d c a r d i o v a s c u l a r

f u n c t i o n

- I n e x p e n s i v e a n d e a s y t o a d m i n i s t e r

Balanced Anesthesia

• I d e a l g e n e r a l a n e s t h e t i c d o e s n o t e x i s t .

• C o m b i n a t i o n s o f d r u g s t o a c c o m p l i s h w h a t o n e

a n e s t h e t i c c a n n o t d o a l o n e .

• A g e n t s u s e d f o r b a l a n c e d a n e s t h e s i a a r e -

– H y p n o t i c s

– N e u r o m u s c u l a r b l o c k i n g a g e n t s

– A n a l g e s i c s

C O M B I N A T I O N O F D R U G S C A N L O W E R D O S E S O F

E A C H D R U G T O P R O D U C E T H E S A M E O R G R E A T E R

E F F E C T O N P A T I E N T

Four Stages of Anesthesia

• Stage I - ana lges ia

• Stage II - del i r ium

• Stage III - surgical anesthesia

• Stage IV - respiratory paralysis

Types of General Anesthetics

Extremely diverse group of chemicals which

produce a similar endpoint

• Inhalant or volati le

• Injectable ( intravenous)

2

Inhalational Anesthetics

• Administered as vapors or gases

• Special set of physical principles govern

absorption, distr ibution and elimination

• Partial pressure - proportional to the

concentration of anesthetic in gas or tissue

at equilibrium

MAC: Minimum Alveolar

Concentration• Potency measure

• 1 MAC is the concentrat ion necessary to

prevent responding in 50% of populat ion

1.0

0.8

0.6

0.4

0.2

0.0

0.40.30.20.10.0

[Halothane] mM

1.51.00.50.0

[Halothane] % atm

MAC

Fraction of Anesthetized

Patients

Factors affecting MAC

F a c t o r s d e c r e a s i n g M A C :

• Hypotension

• Anemia ( PCV < 13%).

• Hypothermia

• Metabolic acidosis

• Extreme hypoxia (PaO2 < 38 mmHg )

• Age: old animal require less anesthetic

• Premedication (opioids, sedatives, tranquilizers)

• Local anesthetics

• Pregnancy

• Hypothyroidism

• Concurrent use of nitrous oxide

F a c t o r s i n c r e a s i n g M A C :

• Increasing body temperature

• Hyperthyroidism

• Hypernatremia

F a c t o r s N O T a f f e c t i n g M A C

• Type of stimulation

• Duration of anesthesia• Species

• Sex• PaCO2 between range of 14-95 mmHg• Metabolic alkalosis

• PaO2 between range of 38-500 mmHg• Hypertension• Potassium

Solubility & Pharmacokinetics

• S o l u b i l i t y e x p r e s s e d a s p a r t i t i o n c o e f f i c i e n t s

( a r a t io o f the concen t ra t ion o f the agen t in two phases a t

e q u i l i b r i u m )

• B l o o d : g a s p a r t i t i o n c o e f f i c i e n t

– S o l u b i l i t y i n b l o o d

– ma in f ac to r t ha t de t e rmines t he r a t e o f i nduc t i on and

r e c o v e r y

• O i l : g a s p a r t i t i o n c o e f f i c i e n t

– fa t so lub i l i ty

– d e t e r m i n e s t h e p o t e n c y o f a n a n e s t h e t i c ( a s w e l l a s k i n e t i c s )

Induction and Recovery

• T h e l o w e r t h e b l o o d : g a s p a r t i t i o n c o e f f i c i e n t t h e f a s t e r t h e

i n d u c t i o n a n d r e c o v e r y

– T h e l o w e r t h e s o l u b i l i t y i n b l o o d , t h e f a s t e r t h e p r o c e s s o f e q u i l i b r a t i o n

– L e s s d r u g h a s t o b e t r a n s f e r r e d v i a t h e l u n g s t o t h e b l o o d i n o rde r t o ach ieve a g iven pa r t i a l p re s su re

– 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-so lub i l i ty agen t wi l l b r i n g t h e p a r t i a l p r e s s u r e i n t h e b l o o d c l o s e r t o t h a t o f t h e insp i red a i r

• R e c o v e r y i s t h e s a m e

L o w s o l u b i l i t y i n b l o o d = f a s t i n d u c t i o n a n d r e c o v e r y

H i g h s o l u b i l i t y i n b l o o d = s l o w e r i n d u c t i o n a n d r e c o v e r y

MAC Partition Coefficients

Anesthetic (% atm) (mM) Water:Gas 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 11 57 5.2

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 9.7 49

Butane 20 0.15 0.019 15 790

Ethylene 67 2.2 0.085 1.1 13

Xenon 71 2.1 0.075 1.8 24

Nitrous Oxide 101 15 0.39 1.3 3.3

Anesthetic Properties

P o t e n c y BloodSolubility

BrainSolubility

3

Nitrous Oxide

• Relatively safe

– M i n i m a l e f f e c t s o n h e a r t r a t e a n d b l o o d

p r e s s u r e

– L i t t l e e f f e c t o n r e s p i r a t i o n

• Low blood solubil i ty (quick recovery)

• MAC value is 105% - Needs other agents

for surgical anesthesia

• Weak anesthet ic , powerful analgesic

Nitrous Oxide - Disadvantages

• Cannot produce anesthesia without hypoxia

• Poor muscle relaxation

• Diffuses into closed spaces

• Inhibits vitamin B-12 metabol i sm

• Inhibits methionine synthetase (precursor to

DNA synthes is )

• Abuse l iabi l i ty

Anesthetics - Halogenated ethers8 1 2

C C O C

6 5 4

37

MW 1 2 3 4 5 6 7 8

Diethyl ether 74 H H CH H H H H H

Fluroxene 126 H H =CH H F F F

Methoxyflurane 165 F H H H F Cl H Cl

Desflurane 168 H F H F F F F F

Isoflurane 184 H F H F Cl F F F

Enflurane 184 F F H F F Cl H F

Sevoflurane 200 H H F H CF F F F3

3

2

Halothane (Fluothane®)

• Most potent inhalat ional anesthet ic

– M A C o f 0 . 7 5 %

• Very soluble in blood and adipose tissue

– P r o l o n g e d e m e r g e n c e

• Inhibits sympathetic response to painful

s t imul i

Halothane - Disadvantages

• Decreases respiratory drive

• Depresses cardiovascular function

• Sensi t izes myocardium -can lead to

ventricular arrhythmias

• “ Halo thane Hepatitis”

• Malignant Hyper thermia

Enflurane ( Ethrane®)

• S t a b l e , n o n f l a m m a b l e l i q u i d w i t h p u n g e n t o d o r

• M A C 1 . 6 8 %

• C a r d i a c e f f e c t s

– d e p r e s s i o n a n d d e c r e a s e d s y s t e m i c v a s c u l a r r e s i s t a n c e

– 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

– s e n s i t i z e s m y o c a r d i u m

• D e c r e a s e s r e s p i r a t o r y d r i v e

• M e t a b o l i s m o n e - t e n t h t h a t o f h a l o t h a n e

– 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

• E p i l e p t i f o r m E E G p a t t e r n s

4

Isoflurane (Forane®)• Less soluble than ha lo thane

• M A C o f 1 . 3 0 %

• E x c e l l e n t m u s c l e r e l a x a n t

• D e p r e s s e s r e s p i r a t o r y d r i v e a n d v e n t i l a t o r y

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

• D e p r e s s e s c a r d i o v a s c u l a r s y s t e m

– 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 baroref lex r e s p o n s e (less than enthrane)

– P r o d u c e s m o s t s i g n i f i c a n t r e d u c t i o n i n s y s t e m i c

v a s c u l a r r e s i s t a n c e

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

Isof lurane Toxic Side Effects

• Lit t le metabolism (0.2%) -- low potential of

organotoxic metaboli tes

• No EEG act ivi ty l ike enflurane

• Bronchoir r i ta t ing , la ryngospasm

Sevoflurane (Ultane®, Sevorane®)and Desflurane(Suprane®)

• Low solubil i ty in blood-- produces rapid

induct ion and emergence

• Minimal systemic effects-- mild respiratory

and cardiac suppression

• Few side effects

• Expensive0.001

0.01

0.1

1

10

100

Mou

se M

AC (at

m)

0.01 0.1 1 10 100 1000

Olive Oil : Gas Partition Coefficient

HAL

ISO ENF

FLU

MOF

DEE

CHL

DDM

PFECTF

SHF

CYC

ETHNO2 XEN HYD

NIT

KRY

ARG

Potency k

Meyer Overton Correlation

H A L H a l o t h a n e

I S O I s o f l u r a n e

E N F E n f l u r a n eS E V S e v o f l u r a n e

F L U F l u r o x e n eD E S D e s f l u r a n e

C Y C C y c l o p r o p a n eM O F M e t h o x y f l u r a n e

D E E D i e t h y l e t h e rC H L C h l o r o f o r m

D D M D i c h l o r o d i f l u r o r m e t h a n e

P F E P e r f l u o r o e t h a n eC T F C a r b o n t e t r a f l u r o i d e

S H F S u l f u r h e x a f l u o r i d eC Y C C y c l o p r o p a n e

E T H E t h y l e n eN O 2 N i t r o u s o x i d e

X E N X e n o nNIT N i t r o g e n

K R Y K r y p t o nA R G A r g o n

Lipid- Based Theories of

Anesthetic Action

Hypothesized anesthetic effect was due to

disruption of l ipid bi layer of plasma

membranes .

… . h o w e v e r … . .

• V o l u m e e x p a n s i o n b y n o n a n e s t h e t i c c o m p o u n d s

• C o r r e l a t i o n b e t w e e n f l u i d i t y a n d a n e s t h e t i c l e v e l s o n l y

o c c u r r e d a t h i g h c o n c e n t r a t i o n s .

• S m a l l c h a n g e s i n t e m p e r a t u r e d i d p r o d u c e s i g n i f i c a n t

f l u i d i t y c h a n g e s w i t h o u t c a u s i n g a n e s t h e s i a w h i l e l a r g e

c h a n g e s i n a n e s t h e t i c c o n c e n t r a t i o n p r o d u c e d s m a l l

c h a n g e s i n f l u i d i t y .

• C u t - o f f e f f e c t - M- O r u l e o n l y h o l d s u p t o a c e r t a i n s i z e

• I n h a l a n t a n e s t h e t i c s s h o w s t e r e o s e l e c t i v i t y i n e f f e c t s

5

Protein-based theories of

Anesthetic Action

Anesthetics bind to hydrophobic/ lipophilic

sites on proteins.

– i n d u c e / p r e v e n t c o n f o r m a t i o n a l c h a n g e

– a l t e r k i n e t i c s o f c o n f o r m a t i o n a l c h a n g e s

– c o m p e t e w i t h l i g a n d s

Ok, so which receptors

mat ter….

• G A B AA

• Glu tamate (AMPA and NMDA)

• Glycine ( s t rychnine-sensitive, in spinal cord

and brainstem)

• Nicotinic A C h

Injectable anesthetics

• A d v a n t a g e s

– m i n i m a l e q u i p m e n t

– ‘ d i r e c t ’ C N S a c c e s s

– w i d e v a r i e t y o f a g e n t s , t e c h n i q u e s

• D i s a d v a n t a g e s

– r e c o v e r y d e p e n d e n t o n u n c o n t r o l l a b l e

factors

– i n d i v i d u a l v a r i a t i o n i n d r u g r e s p o n s e

– p o t e n t i a l f o r d r u g ‘ a c c u m u l a t i o n ’

Barbiturates

• Phenobarbital

• Pentobarbi tal Sodium

• Thiopental Sodium

• Thiamylal Sodium

• Methohexital

Barbiturates - General

• Very alkaline - very irritating to tissues

• Depress polysynapt ic responses in the CNS

• Effect on GABA receptors

– D e p r e s s R e t i c u l a r A c t i v a t i n g S y s t e m

– D e p r e s s s y m p a t h e t i c n e r v o u s s y s t e m

• Poor analgesics

• Excitement at low doses

• Low therapeutic index!

Cardiopulmonary Effects

• Arrhy thmogenic!!!

– T r a n s i e n t V P C s & v e n t r i c u l a r b i g e m i n y

• Transient , moderate decrease in blood

pressure

• Decrease cardiac contracti l i ty

• Vascular effects variable, but in general

cause mild vasodilatat ion

• Respiratory depressants

6

Propofol

• G A B AA posit ive modulator

• Solubi l ized in an emulsion

• Rapid onset, short duration of

action, rapid smooth recoveries w/o ‘hangover’

• Useful for induction &/or maintenance (by

constant infusion)

• Mild to moderate hypotens ion , may produce

bradyarrhythmias

• Respiratory depressant , may produce apnea

Disadvantages

• Expensive

• Moderate hypotension, possible

bradyarrhythmias , respiratory depression

(apnea not uncommon)

• Poor analgesia (need high doses)

• Drug vehicle supports bacterial growth

Etomidate

• G A B AA posit ive modulator

• non-barbi turate ul t rashort sedat ive/hypnotic

• minimal cardiovascular effects

• rapid onset/recovery

• wide safety margin

Dissociative Anesthetics

• Ketamine

• Tiletamine

• NMDA receptor channel blockers

• Produces amnesia, superficial analgesia, and

catalepsy

• Dissociates the cortex from lower centers

• Both excitatory & depressant effects on EEG

• Actually has posit ive effects on CV measures

and minimal respiratory depression

Problems.. .

• Seizures

• Muscle r igidity

• Poor visceral analges ia

• Increased secretions

• Poor recoveries - delirium

• Increased myocardial work load

Neuroleptanalgesia

• combinat ion of opioid + tranquil izer/sedative

• produces state of l ight ‘anesthesia’

• useful for debilitated or geriatric patients

• eg fentanyl/diazepam; droper idol / fentanyl;

oxymorphone /midazolam; etc. . .

7

Overview of mechanisms

of action for general

anesthetic…..

Ion Channels and Anesthesia

• G A B A A - p r i m a r y a n e s t h e t i c t a r g e t

– A c t a s m o d u l a t o r s , n o t d i r e c t a g o n i s t s

– I n c r e a s e c u r r e n t i n d u c e d b y l o w l e v e l

G A B A b y > 5 0 %

– W o r k b y p r o l o n g i n g c h a n n e l o p e n -

t i m e

– Inha l an t s , ba rbs , b e n z o ’ s , s te ro ids ,

p ropo fo l

• G l y c i n e - i m p o r t a n t f o r s p i n a l c o r d a n d

l o w e r b r a i n s t e m

G A B A A R c a c t i v a t i o n

Ion Channels and Anesthesia

• G l u t a m a t e - N M D A , A M P A & K a i n a t e

– D i s s o c i a t i v e anes the t i c s

– R e l a t i v e l y i n s e n s i t i v e t o i n h a l a n t s ( ? ) a n d

b a r b i t u r a t e s

• n A C h - m o s t s i m p l e a n e s t h e t i c s c a n s t a b i l i z e

d e s e n s i t i z e d f o r m

– D e f i n i t e l y i n v o l v e d i n m a n y i n h a l a n t e f f e c t s

– Inc reas ing in t e re s t fo r ro l e wi th o the r anes the t i c s

• V o l t a g e g a t e d i o n c h a n n e l s -

– N a + , K+ , Ca ++

– D o n o t a p p e a r t o p l a y a r o l e i n a n e s t h e s i a

Potential Receptor Targets

Anesthetic GABAA Glycine Neuronal

nACHAMP A NMDA

Halothane +++ +++ - - - - - - -/0

N2 O +++ +/0 ? -/0 - - -

Xenon 0 ? ? 0 - - -

Barbiturates +++ +/0 - - - - - - 0

Ketamine 0 0 - - - 0 - - -

Propofol +++ +++ -/0 -/0 -/0

Neuroste roids +++ 0 -/0 0 0