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Anesthetics
Anesthetics
COURSE OUTCOMES:
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
Ms. Swati R. D.
Nav: Exists in Three States
Extracellular
Activation gate
Inactivation gate
Intracellular
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:
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]
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
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
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
Ms. Swati R. D.
General Anesthesia
Inhalational Anesthetics
•Gas
•Volatile liquids
Intravenous Anesthetics
•Inducing agents
Ms. Swati R. D.
Ms. Swati R. D.
Intravenous General Anesthetics
Inducing agents:
Ultrashort acting barbiturates: Thiopentone sodium
Methohexital sodium
Non barbiturates: Propofol
Etomidate
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
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
0.1 nA
Ms. Swati R. D. 1 min
Inhalational Anesthetic Potency
= ‘MAC’
‘Minimum
Alveolar
Concentration’
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
Ms. Swati R. D.
Lipid vs. Blood Solubility of
Inhalational Anesthetics
Lipid solubility = Potency = MAC
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
Diffusive hypoxia
• 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
• Abolishes bronchospasm
• 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.
Ms. Swati R. D.
Ultra-short-acting Barbiturates
• Intravenous administration produces very rapid
induction due to high lipid solubility.
Ms. Swati R. D.
Etomidate (a non-barbiturate sedative induction agent)