Anesthetics

COURSE OUTCOMES:

At the end of the course students shall be able to

Summarize drugs acting on central nervous system as

depressants, stimulants and anesthetics

Ms. Swati R. D.
Surgery Before Anesthesia
Anesthesia
Local Anesthetics- local injection/ topical
Block conduction (Reversible) of pain impulses in
the periphery i.e. prior to spinal cord
Consciousness maintained
General Anesthetics
Prevent perception of pain
• Largely through effects on brain
• Loss of consciousness
• Amnesia
Muscle relaxation
Blockade of reflexes: somatic, autonomic
Inhalational, intravenous agents; neuromuscular
blockers
Ms. Swati R. D.
Local Anesthetics

Ms. Swati R. D.
Local Anesthetics
Act directly on nerve cells to block
impulse transmission
Not specific to any class of neurons –
block all
Utility comes from the reversibility of
their effects

Ms. Swati R. D.
Molecular Site of Action of
Local Anesthetics
Blockade of Voltage gated Na+ channels (Nav)
Nav
Present in all neurons
Nav Also present in other depolarizing cell types
(muscle)
Nav Responsible for main depolarizing current of
action potentials
→ Block Nav, block all action potentials and all
neuronal conduction

Ms. Swati R. D.
Requirements for
Local Anesthetic/Nav Binding

Nav, LA must each be in a specific state

Nav must be in ‘open’ or ‘inactivated state’
LA – must be in ionized (+ charged) form
HYDROPHOBIC PATHWAY
HYDROPHILIC PATHWAY

Ms. Swati R. D.
 Nav: Exists in Three States
Extracellular

Activation gate

Inactivation gate

Intracellular

‘Resting State’ = deactivated/ closed to Na+, but responsive

‘Open State’ = open to Na+ in depolarizing cell

‘Inactivated State’ = closed, resistant to opening

Ms. Swati R. D.
 Local Anesthetics Bind Nav in
‘Open’ & ‘Inactivated’ States

LAs don’t bind Nav in resting state

LAs are much more active in blocking rapidly firing
neurons than neurons at rest
Important: Stimulated pain fibers are actively firing
Ms. Swati R. D.
Molecular Mechanism of
Action of Local Anesthetics
Nav is a membrane bound protein
intracellular and extracellular portions
Local anesthetics bind to a specific site on Nav
LA binding site is located intracellularly

Thus, two steps for local anesthetic action

1) Passive diffusion across cell membrane to inside
of cell
2) Binding of LA to specific binding site of Nav

Ms. Swati R. D.
Two Steps for
Local Anesthetic/Nav Binding
Local Anesthetics: Weak bases
Uncharged form: required to pass cell
membrane to enter cell
Charged form: required to bind Na+
channel

CH3 H+ CH3
R-N + H+ R-N
CH3 CH3
Ms. Swati R. D.
Anesthetics and Voltage Gated
Na+ Channels
1. Uncharged form enters cell
CH3 H+ CH3
R-N + H+ R-N
CH3 CH3

1 2 Sodium Channel
3 4

Outer
Cell Membrane
Inner

CH3 H+ CH3
R-N + H+ R-N
CH3 CH3
2. R.Charged
Ms. Swati D. form binds to inhibitory site
 Local Anesthetic Structure
1 - Hydrophobic Group - aromatic
2 - Hydrophilic Group - secondary or tertiary
amine
3 - Amide or ester linkage
Ester can be hydrolysed in liver, serum
Amide more stable in vivo
CH3
O O CH3
C N CH3
O O
C2H5 C2H5
H2N C OCH2CH2 N O NH C CH2 N
C2H5 C2H5
C O
CH3
Procaine Cocaine
Lidocaine
CH3
O CH3
Ms. Swati O
H9C4 C3 NH CR. D. C2H5
N C OCH2CH2 N NH C CH N
 Local Anesthetic Structure:
Determinants of Activity
1 - Hydrophobic Group - aromatic = Lipophilicity
Increases local tissue binding, partitioning to sites of
action
Increases potency
Increases duration of action
Decreases systemic absorption and some side effects
CH3
O O CH3
C N CH3
O O
C2H5 C2H5
H2N C OCH2CH2 N O NH C CH2 N
C2H5 C2H5
C O
CH3
Procaine Cocaine
Lidocaine
CH3
CH3
O
O C2H5
H9C4 C3 NH C
N C OCH2CH2 N NH C CH N
N
H C3 C2H5 C3H7
CH3
Tetracaine Ms. Swati R. D.CH3 CH3
Mepivacaine Etidocaine
 Local Anesthetic Structure:
Determinants of Activity
2 - Hydrophilic Group - amine
Site of action of local anesthetics is intracellular
Only uncharged form penetrates neuronal membrane
pKa affects speed of onset
Determines amount of charge at physiological pH
Lower pKa, less charge, more rapid cell entry
• Procaine pKa = 8.9 Slow onset
• Lidocaine pKa = 7.9 Fast onset
CH3 H+ CH3
R-N + H+ R-N
CH3 CH3
Can penetrate cell membrane Cannot penetrate cell membrane
Ms. Swati R. D.
Local Anesthetic Structure:
Determinants of Activity
3 - Amide or ester linkage
Ester - hydrolysed by plasma & liver esterases
shorter acting - less systemic distribution
Cocaine, Procaine, Benzocaine, Tetracaine,
Chloroprocaine
Amide - stable - longer acting - more systemic
distribution
Lidocaine, Mepivacaine, Etidocaine,
Bupivacaine, Prilocaine

Ms. Swati R. D.
 Local Anesthetic Structure
1 - Hydrophobic Group:
Lipid solubility ➔ Potency
2 - Hydrophilic Group:
pKa ➔ Speed of Onset
3 - Amide vs. ester linkage:
Esterase Resistance ➔Duration of Action
CH3
O O CH3
C N CH3
O O
C2H5 C2H5
H2N C OCH2CH2 N O NH C CH2 N
C2H5 C2H5
C O
CH3
Procaine Cocaine
Lidocaine
CH3
O CH3
Ms. Swati O
H9C4 C3 NH CR. D. C2H5
N C OCH2CH2 N NH C CH N
Lipophilicity, pKa, and Protein
binding
Drug Tissue Onset of Plasma duration Main unwanted effects
penetration action t half
Esters
Low Potency - Short Duration
Procaine Poor Medium <1 Short CNS & CVS,
Chloroprocaine Moderate Medium 1 Short As Procaine
High Potency - Long Duration
Tetracaine Moderate Very slow 1 Long CVS

Amides
Medium Potency - Medium Duration
Mepivacaine Good Rapid 2 Medium As Procaine
Prilocaine Moderate Medium 2 Medium Methaemoglobinemia,
CNS & CVS ( No vasodilation)
Lidocaine Good Rapid 2 Medium As tetracaine
Articaine Good Rapid 0.5 Short As tetracaine
High Potency - Long Duration
Etidocaine Moderate Slow Long CNS & CVS
Bupivicaine Moderate Slow 2 Long S isomer:CVS & CNS, R isomer
safe
Ropivacaine Moderate Slow 2 Long CNS & Less CVS
CNS: Restlessness, Shivering, anxiety, rare convulsions followed by respiratory depression
CVS: Bradycardia,Myocardial depression, conduction block, vasodilation (decreased B.P.)

Ms. Swati R. D.
Local Anesthetics: Potency on
Different Nerve Fibers
In most patients given an LA:

Pain is blocked first, followed with

increasing time or dose by:
1 - Sensation of Temperature
2 - Sensation of Touch
3 - Sensation of Deep Pressure
4 - Motor function

Ms. Swati R. D.
Local Anesthetics: Effects on
Different Nerve Fibers
Pain carried by:
A fibers (small, myelinated)
C-fibers (small, unmyelinated)
Blocked at lower dose [anesthetic]

Motor and proprioception (position) carried

by:
A, A fibers (larger, myelinated)
Blocked at higher dose [anesthetic]
Ms. Swati R. D.
Peripheral Nerve Fibers:
Types

Ms. Swati R. D.
Reasons for Differential Blockade
Rate: Sensory vs. Motor
Sensory (A, C) fibers fire at higher rate than motor
fibers (A)
More access to channel site = More voltage-dependent
binding of the local anesthetic
Sensory action potential duration is longer:
More access to channel site = More voltage-dependent
binding of the local anesthetic
Sensory fibers have poorer passive propagation
(cable properties) to overcome partial block

Ms. Swati R. D.
Addition of Vasoconstrictor to
Local Anesthetics
Cocaine itself is a vasoconstrictor
Lengthens anesthesia by slowing local
removal
Slows blood loss
Synthetic local anesthetics do not have
intrinsic vasoconstrictor activity
Often include epinephrine 1:200,000 or
norepinephrine 1:100,000
Additional beneficial action - lowers
systemic concentrations
Ms. Swati R. D.
Problems with Addition of
Vasoconstrictor to Local
Anesthetics

Excessive vasoconstriction - necrosis

Systemic absorption may lead to
restlessness, tachycardia, arrythmias

Ms. Swati R. D.
Local Anesthetics:
Side Effects
When absorbed systemically, local
anesthetics can affect all organs relying
on depolarization or impulse
conduction
Brain
PNS
Heart
All types of muscle fibers
Ms. Swati R. D.
Local Anesthetics:
CNS Effects
Seen with high systemic doses
Accidental intravascular injection
Major procedures e.g. liposuction
At high doses, all can cause CNS stimulation
Early : numb lips, tinnitus, vertigo
Restlessness, muscle fasciculations, seizures
Not usually pleasant, rarely abused (except cocaine)
In higher doses - CNS depression
Somnolence, Coma
Respiratory depression, death

Ms. Swati R. D.
Local Anesthetics:
Cardiovascular effects
Main site of action: myocardium itself
Decreased excitability, conduction rate,
contraction force
Also act locally as vasodilators
Speeds elimination

Ms. Swati R. D.
Local Anesthetics: Needed
Improvements

Better control of the duration of block

Enhance selectivity for pain vs. motor
and autonomic blockade.
Improve safety, especially cardiotoxicity

Ms. Swati R. D.
Local Anesthetics:
Pharmacokinetics
Soluble surface LA:
Rapid absorption – Mucous membrane &
Abraded skin
Poor absorption – Intact skin
Decreased effect – Inflammation or injury
Procaine: insignificant absorption - Mucous
membrane, Not PPB
Lipohilic – widely distributed throughout the
body
Lidocaine & Prilocaine : oral – high first pass
Ms. Swati R. D.
metabolism
Local Anesthetics:
Pharmacokinetics
LA: PPB (alpha-1- acid glycoprotein)
Rapid but temporary binding to tissues
Ester linked hydrolysed by plasma
psudocholinesterases & esterases in the liver
Amide linked degraded only in liver
microsomes (dealkylation & hydrolysis)
Lidocaine metabolism: hepatic blood flow
dependent

Ms. Swati R. D.
Local Anesthetics: Techniques of administration
Topical anesthesia
eg: lidocaine, tetracaine, benzocaine
Infiltration & Block anesthesia
eg: procaine, chlorprocaine, lidocaine
Field block (Scalp & Anterior abdominal wall)
Nerve block (Mixed nerve)
Spinal anesthesia (Subarachnoid space: Isobaric solution)
eg: procaine, tetracaine, mepivacaine, lidocaine
Saddle block: Hyperbaric solution:- Obstetrics
Epidural & Caudal anesthesia (Epidural space)
eg: procaine, mepivacaine, lidocaine

Ms. Swati R. D.
Techniques of administration

Ms. Swati R. D.
General Anesthesia
Inhalational Anesthetics
•Gas

•Volatile liquids

Intravenous Anesthetics
•Inducing agents

•Slower acting drugs

Ms. Swati R. D.
General Anesthesia
Inhalational Anesthetics
•Gas

•Volatile liquids

Intravenous Anesthetics
•Inducing agents

•Slower acting drugs

Ms. Swati R. D.
Ms. Swati R. D.
 Intravenous General Anesthetics
Inducing agents:
Ultrashort acting barbiturates: Thiopentone sodium
Methohexital sodium
Non barbiturates: Propofol
Etomidate

Benzodiazepines: Diazepam, Lorazepam, Midazolam

Dissociative anesthetics: Ketamine & Fentanyl- Droperidol

Opioid analgesia: Fentanyl

Ms. Swati R. D.
Inhalational General Anesthetics

Gases:
Nitrous oxide, Cyclopropane, Ethylene

Volatile liquids:
Ether, Halogenated anesthetics

Ms. Swati R. D.
Goals of Anesthesia
Desired effects:
Loss of Conciousness-
Amnesia
Muscle Relaxation
Supression of Reflexes - somatic,
autonomic, endocrine

Ms. Swati R. D.
Advantages of Volatile Anesthetics

Rapid induction of anesthesia

Continuous adjustment of depth
Continuous monitoring of anesthetic
concentration
Rapid emergence from anesthesia
independent of metabolism
Not reliant on intravenous access

Ms. Swati R. D.
Molecular Mechanisms
Overall: inhibit both spontaneous and
evoked neuronal activity
Anesthetic stereospecific: must interact
with stereospecific molecules
OCHF OCHF
8
2 2
C C S(+) Isoflur ane
CI CF CF CI
H 3 3 H
(Inactive)
S(+) Isoflur ane R(-)
4
CH H H CH
3 3
H C H
N O C N
C H R(-) Isoflu ra ne
O C H 3 7
3 7
N C H N (Active)
H O C H 2 5 H
2 5 0
-80 -60 -40 -20 0
S(-) P en toba rbit al R(+)
Ms. Swati R. D.
Membr ane potentia l (mV)
Molecular Sites of Action -
Inhalational Anesthetics
Multiple ion channels in multiple brain
regions
Different inhalational anesthetics have
different specificities

Ms. Swati R. D.
Molecular Sites of Action -
Inhalational Anesthetics
GABA-A receptors (Cl-)
most volatile anesthetics
NMDA channels: antagonist
N2O > halogenated
(2PK) Two-pore domain K+ Channels
nAChR
others

Ms. Swati R. D.
Role of GABAA Receptor
Channel
Halothane  inhibitory (hyperpolarizing)
responses to GABA
Also:  Na+, Ca++ influx,  K-channels,
 Nicotinic Receptors

GABA 3x10 -6M

halothane halothane

0.1 nA
Ms. Swati R. D. 1 min
Inhalational Anesthetic Potency
= ‘MAC’

‘Minimum
Alveolar
Concentration’

= [Anesthetic] in alveoli that will prevent 50% of patients

from responding to a painful stimulus]
Low MAC = High Potency
MAC or potency does not specify speed of
induction/recovery
Ms. Swati R. D.
Minimum Alveolar Concentration
= ‘MAC’

Why talk about ‘Alveolar’ concentration?

Because MAC is easy to measure
= to “End Expiratory [anesthetic]”
Because MAC is relevant

Ms. Swati R. D.
 Inhalational Anesthetic
Structure/Activity
Relationships
Relation to specific structural features
unclear
Key features so far known
Lipid solubility
• High Lipid solubility = high potency
Blood Solubility
• Low Blood solubility = fast onset

Ms. Swati R. D.
Meyer Overton Rule
for Inhalational Anesthetics
Potency is proportional to its lipid solubility
(oil:gas partition coefficient)

Ms. Swati R. D.
 Lipid Solubility =  Potency
=  MAC
Mechanism: probably reflects higher
local concentrations at molecular
targets
ion channels = membrane (lipid) bound

GAS

OIL
Lipid Solubility: LESSMs. Swati
MORER. D.
Low Blood/Gas Partitions ()
= Speed of Induction
Mechanism: Anesthetics with high
blood solubility must fill a much larger
pool to reach saturation e.g. require
much more agent to enter bloodstream

 Blood gas partition =  induction

Ms. Swati R. D.
Lipid vs. Blood Solubility of
Inhalational Anesthetics
 Lipid solubility =  Potency =  MAC

 Blood solubility =  speed of action

Lipid solubility and blood solubility are

somewhat correlated, so low potency
anesthetics tend to be rapid onset/offset
Ms. Swati R. D.
Inhalation Anesthetics

Oldest Agents:
Ether (diethyl ether)
first use in 1846 - effective; slow on/off, vomiting
Chloroform 1840’s
Nitrous oxide (N2O, dinitrogen monoxide)
first use in 1844 by Coulton
Halogenated anesthetics (e.g. Halothane)
first use in 1956

Ms. Swati R. D.
Ms. Swati R. D.
Nitrous Oxide (N2O)
Not a historical curiosity
Non-flammable, non-irritating, and has rapid
induction and recovery characteristics
Not as potent as ether, modern agents---
combined with other agents
Loss of consciousness at 30 - 70%
70 - 80% required for loss of consciousness,
leaving only 20% for oxygen
Low muscle relaxant effect, a
disadvantage
Ms. Swati R. D.
Nitrous Oxide
More analgesia than any halogenated agent
Low toxicity
Minimal cardiovascular effects

Minimal respiratory effects

Inactivation of methionine synthase – Bone

marrow depression- anemia & leucopenia

Diffusive hypoxia

Value is as an adjunct in combination with other

anesthetics ‘Balanced anesthesia’

Allows use of lower concentrations of other agents

Ms. Swati R. D.
 Halogenated Anesthetic
Agents
F Br F F F Cl F H
F C C H H C C O C H H C C O C H
F Cl Cl F F Cl F H

Halothane Enflurane Methoxyflurane

1956 1973 1960-2002
F H F F H F F
F C C O C H F C C O C H F C F H
F Cl F F F F H C O C H
F C F F
Isoflurane Desflurane
F
1981 1993 Sevoflurane
Ms. Swati R. D. 1995
Halogenated Anesthetic Agents:
Common Features
Potent
Smooth, rapid induction, awakening, good
control of planes of anesthesia
Low level post-operative nausea & vomiting
Can be used with oxygen and nitrous oxide
Storage at atmospheric pressure

Dose dependent cardiorespiratory depression

Require close monitoring
Cause uterine relaxation
Cause little analgesia, skeletal muscle relaxation
Ms. Swati R. D.
Halogenated Anesthetics: Differences
Halothane - most potent, slowest;
 cardiac sensitivity to catecholamines: arrhythmias;
hypersensitivity;
 intracranial pressure; hyperthermia

Enflurane - fast,  respiratory depression, seizures

Isoflurane -  respiratory depression, secretions; powerful

coronary vasodilation

Desflurane - fast, expensive, irritates airways

Sevoflurane - fast, expensive. Most widely used

Ms. Swati R. D.
Dissociative Anesthetics
• Class of drugs that dissociate consciousness from
perception of sensation

• Patient is awake & responsive but has catatonia,

amnesia, and selective analgesia

• Acts on limbic system and cortex rather than RAS

• Prototype = Ketamine
Related to phencyclidine (PCP)
May cause unpleasant sensations and dreams when
awakening

Ms. Swati R. D.
Ketamine – Beneficial Effects
• Produces good analgesia and amnesia

• Used in musculotendon, orthopedic and cutaneous

cases such as burn debridement

• Airway reflexes maintained

• No significant respiratory depression

• Abolishes bronchospasm

• Increases CO, HR & BP due to sympathetic

stimulation even though depresses myocardium
Ms. Swati R. D.
Ketamine – Adverse Effects

• “Emergence delirium” can be controlled with

barbiturates (thiopental), benzodiazepines
(diazepam), or psycho-sedatives (droperidol)

• Not used in thoracic or abdominal surgery

due to poor visceral analgesia

• Contraindicated in neurosurgical procedures

due to increased cerebral blood flow, O2
consumption, and intracranial pressure
Ms. Swati R. D.
 Neuroleptanalgesia
• Causes patient to become indifferent to surrounding
environment along with reduced motor activity

• Patient is sedated, sleepy, but remains responsive to

voice instructions.

• Prototype = Innovar®
Fixed-dose combination of 2 drugs
Fentanyl - a short acting (30-60 min), potent opioid analgesic
Droperidol – a long acting (3-6 hours) psycho-sedative
Sufentanil is sometimes substituted for fentanyl. It is 10X more
potent than fentanyl.
Both fentanyl and sufentanil have shorter time to peak analgesia
& shorter recovery times than morphine.
Ms. Swati R. D.
Intravenous Anesthetics
*Allows rapid induction because bypasses
pulmonary phase observed with inhalation GA.

*Disadvantage = loss of moment-to-moment

control.

*Must wait for circulatory, renal and metabolic

systems to lower blood levels

Ms. Swati R. D.
 Ultra-short-acting Barbiturates
• Intravenous administration produces very rapid
induction due to high lipid solubility.

• Short duration of action (5-10 min) due to redistribution

of drug from brain to other tissues.…….THIOPENTAL

• Subsequent doses have longer duration of action due to

saturation of peripheral tissues.

• Marked CNS depression →respiratory depression.

May cause apnea, cough, laryngeo- & broncho-spasm.

• Poor analgesia and muscle relaxation

Ms. Swati R. D.
 Barbiturates (continued)
• Minimal CV effects

• May decrease cerebral blood flow

Useful in patients with cerebral edema

Only a hypnotic if used alone (does not achieve objectives of

anesthesia)

• Causes vascular damage if extravasation occurs during iv injection

Ms. Swati R. D.
Etomidate (a non-barbiturate sedative induction agent)

• Induction and recovery similar to barbiturate

• Mild reflex tachycardia & transient apnea

• No analgesic or muscle relaxing effect

• May cause nausea, vomiting, injection pain and

myoclonus seizure

• May cause phlebitis & thrombophlebitis

• May cause adrenocortical suppression after a single

injection

• Contraindicated in children < 10 years, in pregnancy and

Ms. Swati R. D.
in delivery
 Propofol (a pre-anesthetic induction agent)

• Used for rapidly inducing anesthesia, for sedating during

regional anesthesia & in patients requiring controlled
ventilation. Causes less severe hangover & allows rapid
discharge from recovery room.
• Used for prolonged sedation in critical care unit.
Eliminated by rapid metabolism so can be used for
longer periods than can thiopental.
• Contraindicated to sedate children in ICU

• More negative inotropy than with etomidate or

thiopental

• May cause apnea if combined with iv narcotics

• May lower coronary blood flow

Ms. Swati R. D. (CBF) and CSF pressure
Ms. Swati R. D.