Comparative pharmacology for anesthetics PDF

Comparative pharmacology for anesthetics PDF

2. Comparative Pharmacology
for Anaesthetist

4. Comparative Pharmacology
for Anaesthetist
Armeen Ahmed
Consultant
Intensive Care Unit
Nishat Hospital
Lucknow (UP), India
Vipin Dhama
Lecturer
Department of Anaesthesiology
LLRM Medical College
Meerut (UP), India
Nitin Garg
Attending Consultant
Department of Critical Care Medicine
Escorts Heart Center and Research Institute
New Delhi, India
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Comparative Pharmacology for Anaesthetist
© 2008, Armeen Ahmed, Vipin Dhama, Nitin Garg
All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any
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6. Preface
During our days as PG students of anaesthesiology, we were busy in OTs and ICU
most of the time. Due to hectic schedule, it was difficult to spend long hours in
library and read in details about the subject. It was even more difficult to remember
the properties of various anaesthetic drugs. Later, when we reached in our final year
of postgraduation, we found that the best way to memorize about drugs was to
‘COMPARE’ them. We started making comparative charts of various drugs of similar
nature. After completion of our postgraduation, we realised that these notes can be
condensed into a book. That is how this book came into existence. We have used
comparative charts, line diagrams and points of clinical relevance for easy
understanding of anaesthetic drugs. We do hope that the book will be used as an
adjuvant to the reference books of anaesthesiology by the students.
We wish to express our gratitude to Mr Devendra and Mr Arvind who spent long
hours in typing the manuscript.
The authors wish to thank and acknowledge the invaluable support of Jaypee
Brothers Medical Publishers (P) Ltd.
Armeen Ahmed
Vipin Dhama
Nitin Garg

8. Contents
1. Neuromuscular Blocking Agents Neuromuscular Junction
(Structure and Function) ----------------------------------------------------------------1
2. Opioids------------------------------------------------------------------------------------- 26
3. Volatile Anaesthetics------------------------------------------------------------------ 54
4. Intravenous Induction Agents------------------------------------------------------ 76
5. Inotropes----------------------------------------------------------------------------------- 92
6. Anticholinergic Drugs--------------------------------------------------------------- 102
7. Anticholinesterases------------------------------------------------------------------ 107
8. Local Anaesthetics-------------------------------------------------------------------- 115
9. Miscellaneous Drugs---------------------------------------------------------------- 140
Index--------------------------------------------------------------------------------------- 153

9. Neuromuscular Blocking Agents
Neuromuscular Junction
(Structure and Function)
1
Neuromuscular junction consists of two components:
a. nerve terminal which forms the presynaptic structure
b. muscle terminal which forms the postsynaptic region. In between the two lies the
synaptic cleft.
Presynaptic Structure and Events in Impulse Transmission
As the nerve terminal reaches a neuromuscular junction
it looses its myelin sheath and gets insulated from the
surrounding fluid by one or more Schwann cells.

10. 2Comparative Pharmacology for Anaesthetist
The presynaptic membrane (the membrane of nerve terminal lying just opposite to
muscle terminal) is thickened in patches to form active zones. Vesicles containing
acetylcholine are clustered against these active zones. These active zones also contain
voltage gated calcium channels arranged along their sides.
When action potential reaches nerve terminal, voltage gated calcium channels open
up causing heavy influx of calcium ions. Calcium ions exert an attractive force on the
vesicles clustered in zone 1 thus causing them to fuse with neural membrane, with
simultaneous release of acetylcholine molecules in the synaptic cleft.
The acetylcholine molecules are released in uniformly sized packets called as quanta.
The number of these quanta (packets of acetylcholine) can be increased by increasing
the intracellular calcium. Clinically this is seen during post-tetanic stimulation. When
a muscle is stimulated at very high frequency, calcium enters the presynaptic terminal
during each cycle but there is no time for excretion back into ECF.

11. Neuromuscular Blocking Agents Neuromuscular Junction (Structure and Function)3
This high concentration of calcium causes strong muscle contraction which can be
documented during neuromuscular monitoring.
Zone 2 is the area where large sized vesicles are present as reserve pool. When the
nerve is repeatedly stimulated these vesicles are mobilized from zone 2 to zone 1 and
more acetylcholine becomes available for impulse transmission.
Synthesis of Acetylcholine
Acetylcholine is synthesized inside the nerve terminal by the enzyme choline acetyl-
transferase.
ECF Mitochondria
Choline + Acetyl CoA
Enzyme acetyltransferase
Acetylcholine
Packed in vesicles which are
strategically positioned for release
Presynaptic Ach receptors:- There are acetylcholine receptors present on the nerve terminal
also. They are possibly involved in mobilization of vesicles from their storage sites to
active sites.
Synaptic Cleft
It is the area between presynaptic and postsynaptic membranes. It is also called as
junctional cleft and is 20 – 30 nm in size. It is composed of thin layer of spongy reticular
fibres with ECF filled in between. Muscle and nerve terminals are held tightly together
by these fibres.

12. 4Comparative Pharmacology for Anaesthetist
Enzyme acetylcholinesterase is synthesized in the muscle terminal and secreted
into the junctional cleft. However, even after secretion it remains attached to the post-
synaptic membrane via thin stalk of protein filaments. Enzyme acetylcholinesterase is
responsible for destruction of Ach after its action at Ach receptor. Why it does not
destroy acetylcholine molecule before reaching Ach receptor is not clear.
Postsynaptic Structure and Events in Impulse Transmission
The postsynaptic region is formed by muscle terminal. It consists of two areas
i. junctional area
ii. perijunctional area
The membrane of the junctional area is invaginated to form multiple folds. This
increases the surface area many number of times.
Shoulders of the invaginations are rich in Ach receptors while deep areas have both
Na
+
channels and Ach receptors. The perijunctional area is rich in Na
+
channels.
Ach Receptors
Ach receptors are synthesized inside the muscle fiber. They are composed of 5 subunits
(a, b, g, d and e). On the basis of these subunits they are classified as:
a. Adult/mature/junctional
b. Fetal/extra junctional
Muscle terminal
Postsynaptic membrane

13. Neuromuscular Blocking Agents Neuromuscular Junction (Structure and Function)5
Adult/Mature Ach Receptor
It is composed of 2α, 1β, 1ε and 1δ subunits. These subunits form a cylinder which
protrudes on both the sides of cell membrane.
When two molecules of Ach attach on each α subunit, the channel opens allowing
passage partially hydrated Na
+
, K
+
, Ca
++
ions depending upon the ion selectivity of
the channel.
Fetal/extrajunctional Ach Receptor
During prolonged immobilization, neuromuscular diseases extrajunctional Ach
receptors are synthesized by muscle. They are composed of 2α, 1β, 1γ, 1δ subunits.
These receptors have different properties. They are more sensitive to Ach and remain
open for more prolonged duration after its use. They are spread over a large area of
muscle surface.
As a result patients with high density of fetal receptors become prone for
hyperkalemic response after succinylcholine. The rise in K
+
level can be life threatening
so succinylcholine should be avoided in such patients.

14. 6Comparative Pharmacology for Anaesthetist
Conditions predisposing for the development of fetal Ach receptors:
• Prolonged immobilization
• Burns
• Sepsis
• Neuromuscular disorder
• Upper/Lower motor neuron lesions.
SODIUM CHANNELS
They are found in deep invaginations of the postsynaptic plate and perijunctional area.
Each channel has two gates; activation (voltage) gate and inactivation (time) gate.
The channel exists in 3 forms:
Resting state
A – Activation gate closed
I – Inactivation/time gate open
Activated State
Both gates open
Inactive State
A – Activation gate open
I – Inactivation/time gate closed

15. Neuromuscular Blocking Agents Neuromuscular Junction (Structure and Function)7
For ion current to flow both the gates should open. During resting state inactivation
(time) gate remains open while activation gate is closed. Once the depolarization begins
their activation gate also opens and ionic current flows. Within a few milliseconds the
inactivation gate which is also called the time gate closes stopping ion flow.
Inactivation gate cannot open unless activation gate closes down while activation
gate cannot close down unless depolarization current is over. During use of
succinylcholine there is continuous depolarization of end plate as succinylcholine
attaches to Ach receptors, detaches and then reattaches to another Ach receptors. Thus
sodium channels in the perijunctional area get arrested in inactivation state.
SUCCINYLCHOLINE
It is a short acting depolarizing muscle relaxant. Its unique features are rapid onset of
action and excellent muscle relaxation required for intubation. Due to these properties
it is still the drug of choice for rapid sequence intubation. However, the drug should be
cautiously used as it produces a wide range of side effects.
Chemistry
It is a dicholine ester of succinic acid.
Pharmacokinetics
→ Note that there is no pseudocholinesterase present at NMJ. Termination of action
occurs by diffusion of the drug back into circulation.

16. 8Comparative Pharmacology for Anaesthetist
ENZYME PSEUDOCHOLINESTERASE
Pseudocholinesterase is a lipoprotein synthesized in liver. Duration of action of
succinylcholine is governed by its metabolism caused by enzyme pseudocholinesterase.
If its metabolism is slowed down more drug reaches NMJ leading to prolonged duration
of action.
Reduced rate of succinylcholine
metabolism
CAUSES
Low concentration Low activity of
of pseudocholinesterase pseudocholinesterase
in the blood
Conditions associated Genetically determined
• liver disease ATYPICAL ENZYME
• pregnancy
• renal failure
• heart failure
• hypoproteinemia Drugs that depress
• burns pseudocholinesterase
• thyrotoxicosis activity
• carcinomatosis • bambuterol
• OCPs
• lithium
• cytotoxic agents
• lignocaine
• Neostigmine
• metoclopramide
Atypical Pseudocholinesterase
Some individuals who are otherwise healthy show a prolonged duration of
neuromuscular blockade after usual dose of succinylcholine. They possess atypical
pseudocholinesterase enzyme which has reduced capacity to metabolize its substrate.
Pseudocholinesterase function is measured in terms of DIBUCAINE NUMBER.
Dibucaine is a local anesthetic which inhibits pseudocholinesterase. Normal enzyme
is inhibited more effectively by dibucaine (70 – 80%) as compared to atypical enzyme.
The percentage of inhibition of pseudocholinesterase is termed as dibucaine number.
It is directly proportional to pseudocholinesterase function. No correlation exists
between dibucaine number and concentration of the enzyme.

17. Neuromuscular Blocking Agents Neuromuscular Junction (Structure and Function)9
Clinically significant prolongation of neuromuscular blockade caused by reduced
concentration or function of pseudocholinesterase can be overcome by giving fresh
frozen plasma and continued mechanical ventilation till patient recovers.
Genotype Types of Dibucaine number Response to
pseudocholinesterases succinylcholine
E
t
E
t
Typical 70 – 80 Normal
E
t
E
a
Atypical heterozygous 50 – 60 Slightly prolonged (15–20 minutes)
E
a
E
a
Atypical homozygous 20 – 30 Greatly prolonged (many hours)
DOSES OF SUCCINYLCHOLINE
I/V – 0.5 – 2 mg/kg
onset – 30 to 90 sec
Duration 5 to 10 minutes
t ½ - 2 to 4 minutes
I/M – 2.5 mg/kg
Infants require higher dose (2 mg/kg) due to their greater body water.
Side Effects
ORGAN AFFECTED Signs/ symptoms Pathophysiology
It causes increase in intracranial Increased cerebral activity due to
pressure. This effect can be stimulation of muscle stretch
overcome by pretreatment receptors.
with nondepolarizer.
Increase in intraocular pressureSustained contraction of extraocular
occurs 2–4 minutes after muscles as they have multiple
administration of succinylcholine neuronal innervation. Cycloplegic
and lasts for 5 to 10 minutes. action and choroidal plexus
Pretreatment with nondepolarizer dilatation due to Sch may also
(sub paralyzing dose) can be play a role.
used to overcome this problem.
Sch can cause sinus bradycardia, Sch stimulates cholinergic system
junctional rhythms and due to its structural similarity with
ventricular arrhythmias. It is acetylcholine. Cardiac affects of Sch
more common after 2nd dose are due to direct action on heart as
of Sch due to sensitization well as muscarinic and ganglionic
of the heart by hydrolysis stimulation.
products (Succinylmonocholine
and choline). SA node
suppression causes AV node to
act as pacemaker. If both SA
Contd...

18. 10Comparative Pharmacology for Anaesthetist
and AV node are suppressed,
ventricular escape beats occur.
In extreme cases patient may
develop ventricular fibrillation.
In contrast to the above
action increase in heart rate and
blood pressure via ganglionic
stimulation occur with large
doses of Sch.
Masseter spasm is mostly seen in Exaggerated response to
children. It may interfere in succinylcholine at NMJ.
ventilating the patient. It is not
a predictor of malignant
hyperthermia.
Increased IGP: Increase in Abdominal wall muscle contraction
intragastric pressure following and vagomimetic action of
use of Sch is seen. The increase succinylcholine. Prior
in IGP is variable and not of administraion of vagolytic drugs
much concern in normal may partly overcome this effect
individuals. However in patients of Sch. Pretreatment with
with hiatal hernia, intestinal nondepolarizer inhibit
obstruction etc. caution is fasiculations and subsequent
needed to prevent aspiration of increase in IGP.
gastric contents.
Muscle pain: Muscle pain, Unsynchronized skeletal muscle
myoglobinuria and increased contractions due to generalized
CPK levels are seen after depolarization. Myoglobinuria
use of Sch in postoperative results due to muscle damage
period. following fasiculations.
HYPERKALEMIA–K
+
levels rise Sustained opening of receptor ion
by 0.5 meq/L following channels due to generalized
Sch injection. However under depolarization. (for further details
certain conditions this rise see mechanism of action of Sch).
can be significant, enough to
cause life threatening arrhythmias.
They include prolonged
immobilization, renal failure,
neuromuscular disease,
metabolic acidosis, trauma,
closed head injury. intraabdominal
infections, spinal cord injury,
burns. Pretreatment with
nondepolarizer doesn’t reduce
or alter the amount of potassium
release following Sch.
Contd...
ORGAN AFFECTED Signs/ symptoms Pathophysiology

19. Neuromuscular Blocking Agents Neuromuscular Junction (Structure and Function)11
FASCICULATIONS (PRESYNAPTIC EVENT)
Many adverse effects of Sch are due to fasciculations. Fasciculations are uncoordinated
muscle twitchings that occur due to action of succinylcholine on presynaptic Ach
receptors. These receptors are present on presynaptic nerve terminal and their activation
cause nerve terminal depolarization.
Fasciculations can be inhibited by using a subparalysing dose of nondepolariser
(atracurium 0.03 mg/kg, vecuronium 0.007 mg/kg, pancuronium 0.01 mg/kg) given
3 minutes before succinylcholine
Mechanism of Action
Phase I Block
a.End plate depolarization: Succinylcholine mimics action of acetylcholine at NMJ, the
only difference being relatively slow metabolism of Sch. Acetylcholine undergoes
hydrolysis immediately (within a few milliseconds) after its release, by
acetylcholinesterases present in the synaptic cleft while succinylcholine has to go
all the way back to circulation where it can be metabolized by plasma cholinesterases.
As a result agonist (succinylcholine) is available at NMJ for prolonged duration.
Sch molecule attaches to one Ach receptor, detaches and immediately attaches to
another Ach receptor. This keeps the end plate in depolarized state.
Presynaptic acetylcholine receptors (NICOTINIC)
Action of Sch on presynaptic receptors
Depolarization of nerve terminal
Muscle pain in postoperative period Backward propagation of action potential to all
branches of that motor unit
Increased ICP Uncoordinated muscle twitching
Increased intragastric pressure

20. 12Comparative Pharmacology for Anaesthetist
As already discussed muscle terminal of the neuromuscular junction consists of
two areas; junctional and perijunctional. The voltage gated sodium channels present
in the perijunctional area get arrested in inactivation state due to continuous
depolarization of junctional area. The final result is blockade of impulse transmission
after initial stimulation of the muscle fiber.
b.Desensitization: It is a phenomenon seen with prolonged exposure of the receptor to
the agonist. The number of receptors and their affinity for agonist remain in dynamic
state. Overstimulation of the receptor by agonist enhance refractoriness while
understimulation results into increased sensitivity.
In simpler terms acetylcholine receptor exists in two states, sensitized and
desensitized. Increased availability of acetylcholine or any other agonist (Sch) increase
the number of Desensitized receptors and vice versa.
Overstimulation
Sensitized Desensitized
state state
Understimulation
Two states of acetylcholine receptor
A desensitized receptor means that agonist binds to the receptor but ionic conduction
through receptor channel doesn’t take place.
Clinical Significance
Clinical significance of the above described phenomenon is that total number of channels
available for impulse transmission is reduced if more receptors remain desensitized.
Patient becomes more sensitive to nondepolarizing muscle relaxants after Sch use.
Phase II Block
After repeated dosing, infusion or single large bolus (5-7 mg/kg) of succinylcholine
characterstics of neuromuscular blockade change. Duration of blockade is prolonged
and now it resembles nondepolarizer blockade on neuromuscular monitoring. It is
called as Phase II block.
Mechanism
Mechanism behind phase II block is polyfactorial.
a. Repeated end plate depolarization causing ionic imbalance of NMJ and altered
membrane function.
b. Desensitization due to continuous presence of agonist at the site of action.
Patients with atypical plasma cholinesterase may develop phase II block even with
usual doses of succinylcholine.
Clinical Significance
If features of phase II block appear after Sch use, one must ventilate the patient till
spontaneous recovery occurs. Reversal with anticholinesterases is not recommended.

21. Neuromuscular Blocking Agents Neuromuscular Junction (Structure and Function)13
NON-DEPOLARISING MUSCLE RELAXANT
Drug that compete with Ach for binding with a subunit of nicotinic receptors present
at NMJ are called as non depolarising muscle relaxants. One must remember that two
molecules of Ach are required for transmission of impulse while only one molecule of
non depolariser is required for blockade of impulse transmission.
Ach Ach Two molecules of agonist required for transmission.
NMD Only one molecule of antagonist is required for blockade.
Thus reaction is biased towards antagonist.
Classification
• On the basis of chemical structure.
• On the basis of action.
On the Basis of Action
Non-depolarising muscle relaxants
Long acting Intermediate acting Short acting
• Doxacurium • Atracurium • Mivacurium
• Pancuronium • Cisatracurium
• dTC • Vecuronium
• Gallamine • Rocuronium
On the Basis of Chemical Structure
Non-depolarising muscle relaxants
Steroidal compounds Phenolic ether Strychnos alkaloid
(high potency, lack histamine release, • Gallamine (long acting, •Alcuronium (long
vagolytic, excreted by Kidneys) strongly vagolytic, excreted acting, weakly vagolytic,
• Pancuronium unchanged via kidneys) lacks histamine release)
• Pipecuronium
• Vecuronium
• Rocuronium Benzylisoquinolium Compounds
(high potency, tendency to cause histamine release except
doxacurium and cisatracurium, lack of vagolytic property)
• dTC
• Metocurine
• Doxacurium
• Cisatracurium
• Atracurium
• Mivacurium

22. 14Comparative Pharmacology for Anaesthetist
STRUCTURE–ACTIVITY RELATIONSHIP
Neuromuscular blocking drugs are quaternary ammonium compounds. They possess
two positive charges separated by a bridging structure which is lipophilic.
++
Lipophilic bridge
Due to their positive charge NMBs are attracted towards nicotinic receptors. The
lipophilic bridge determines the potency and varies in size in different drugs.
• In vecuronium, rocuronium, dTC one positive charge is tertiary amine and other is
quaternary ammonium.
• Bridging structure is an ester in many drugs (e.g. succinylcholine, atracurium,
vecuronium, rocuronium, mivacurium)
PHARMACOKINETICS
Pharmacokinetics of non depolarising muscle relaxants can be read under following
heads.
a.Absorption: All neuromuscular blockers are not absorbed orally. They are given only
via intravenous route.
b.Distribution: NMBs are large molecules. They are poorly lipid soluble compounds
unable to cross blood brain barrier, placenta, renal tubular epithelium. Due to their
highly ionized nature they are water soluble and volume of distribution resembles
ECF volume. Degree of protein binding is low and changes in plasma protein levels
do not produce much change in pharmacokinetics.
c. Metabolism and excretion
Long acting muscle relaxants Short acting
Mivacurium undergoes hydrolysis
Pancuronium, doxacurium by plasma pseudocholinesterases
Intermediate acting relaxants
Excreted mainly unchanged
via kidneys. Action Atracuruim and cisatracurium
significantly prolonged undergo Hoffmann elimination
in renal failure while vecuronium is partially
metabolized in liver and
partially excreted unchanged via
kidneys. Rocuronium is not
metabolized. It is primarily
excreted unchanged via liver.
Metabolites of vecuronium, atracurium
and Mivacurium are excreted in urine
and bile.

23. Neuromuscular Blocking Agents Neuromuscular Junction (Structure and Function)15
Side Effects
Histamine release: Histamine is a chemical mediator stored in granules of mast cells.
Mast cell degranulation can occur in response to a variety of stimuli, e.g.
a. Trauma
b. Antigen-antibody reaction
c. Complement fixation
d. Chemical stimulus.
Muscle relaxants can cause histamine release via immune mediated reactions (an
aphylactic reactions) as well as via direct displacement of contents of mast cell granules
(chemical stimulus). This occurs due to bulky cationic nature of muscle relaxant
molecule.
Mast cell granulation
Immune mediated histamine release due to muscle relaxants is rare and results into
more serious effects (severe Hypotension, bronchospasm cardiac arrest etc).
Chemically mediated histamine release is dose dependent response seen mainly
with benzylisoquinolinium compounds (dTC, atracurium, pancuronium, mivacurium,
metocurine).
It causes following features:
a. Tachycardia with slight fall in blood pressure
b. Facial flushing
c. Bronchospasm (rare).
Factors Modulating Histamine Release
Chemically mediated histamine release is a DOSE DEPENDENT phenomenon. The
threshold dose to release histamine are as following
atracurium 0.5 mg/kg
mivacurium 0.2 mg/kg
As we go on increasing the dose, chances of histamine release are increased.
•Rate of injection:- If muscle relaxants are given slowly (over 60 sec), histamine release
can be prevented or reduced.
•Pretreatment with Histamine blockers:- Physiological effects produced by histamine
release can be attenuated by pretreatment with H
1
and H
2
blockers.
•Tachyphylaxis:- Subsequent doses of neuromuscular blocking drugs cause decreased
amount of histamine release. This is because available histamine has previously
been released from mast cells and has been metabolised.

24. 16Comparative Pharmacology for Anaesthetist
Autonomic Effect
Acetylcholine is the neurotransmitter found in autonomic nervous system and some
somatic sites. A quick look on the different types of Ach receptors and their location is
shown in the diagram below.
Ach receptors
Muscarinic
Site:- heart, blood vessels, eye, autonomic
ganglia, exocrine glands, visceral
smooth muscle.
Nicotinic N
M
type N
N
type
Site: muscle end plate Site: ganglionic cells, adrenal
of skeletal muscles. medulla, spinal cord, centers in brain.
Drug Dose required Dose required Intubating dose Dose required ED
95
to produce to produced to produce
vagal blockade sympathetic histamine release
ganglia blockade
Pancuronium .2 mg/kg >17.5 mg/kg .08–0.1 mg/kg none 0.07 mg/kg
Vecuronium 1 mg/kg >12 mg/kg 0.1–0.2 mg/kg none 0.5 mg/kg
Rocuronium 1.2 mg/kg >3 mg/kg 0.6 – 1.0 mg/kg none 0.3 mg/kg
Atracurium 3.6 mg/kg 9.2 mg/kg 0.5 – 0.6 mg/kg .5 mg/kg 0.23 mg/kg
Nondepolarising muscle relaxants act as antagonist at N
M
type receptors. However
when used in higher concentrations they can produce antagonist action at Ach receptors
located at other sites also.
Ganglion blockade:- Ach receptors present in autonomic ganglia are commonly
blocked by d – tubocurarine. Other muscle relaxants show this effect only at higher
dose range.
Muscarinic Blockade:- Muscarinic receptors are found in SA node of the heart.
Blockade of these receptors cause tachycardia.
Vagal block or muscarinic blockade is seen with
pancuronium and gallamine. Gallamine is a
potent vagolytic drug while pancuronium
shows partial vagal blockade. Rocuronium also
shows some increase in heart rate via same
mechanism at high doses. Vecuronium and
atracurium are devoid of such action in clinical
dose range.
Muscarinic blockade is seen only at SA node receptors in heart. Blockade of other
muscarinic sites eg bowel, bladder, bronchi, pupils is not seen.

25. Neuromuscular Blocking Agents Neuromuscular Junction (Structure and Function)17
Contd...
COMPARATIVE STUDY OF COMMONLY USED MUSCLE RELAXANTS
Pancuronium Atracurium Vecuronium Rocuronium
Chemical Bis-quaternaryIt is aStructure same asAminosteroid
Structure aminosteroid.benzylisoquinolinium esterpancuronium but
without quaternary
methyl group.
(mono quaternary
aminosteroid)
Metabolism PancuroniumAtracuriumVecuroniumRocuronium
3, desacetylpancuronium quaternary alcohol Laudanosine +→→→→→ Modest prolongation
++quaternary3, desacetyl vecuronium of duration of action seen
17, desacetylpancuronium quaternary acid monoacrylate+17, desacetyl vecuronium with hepatic failure.
++3,17desacetyl vecuronium→→ →→→ Pharmacokinetics not
3,17 desacetylpancuroniumaffected much in
→→ →→→ 3 desacetyl derivative→→ →→→ 3, desacetyl derivative renal failure.
has neuromuscular metabolites have insignificanthas 80 percent activity
blocking property.action on NMJ.of parent compound
15 – 30%
protein in bond
10 to 40%
85% excreted
unchanged via
urine
Liver
deacetylation
Major
pathway
HYDROLYSIS
by non specific
esterases in
blood
HOFFMANN
elimination
Metabolism
Minor
pathway
82% protein
bound
Major pathway
30%
protein
bound
excreted unchanged
by liver
Minor
pathway
excreted
unchanged
in urine
40% excreted
unchanged in
bile
60-90%
protein
bound
15% excreted
unchanged
in urine
30-40%
metabolized
by liver

26. 18Comparative Pharmacology for Anaesthetist
→→→→→ Action prolonged in
Hoffmann elimination→→ →→→ Duration of action
renal failure. Both It is a chemical process resulting is prolonged after repeated
hepatic and renal into nonenzymatic degradation of dosing in patient of hepatic
atracurium to quaternary monoacrylate and renal dysfunction.
dysfunction require and laudanosine. It is not affected by
dose modification. hepatic, renal, cholinesterase activity but
increased by increase in tempreature.
The chemical process is decreased
in hypothermia and acidosis.
Laudanosine
→→→→→ Principal metabolite of
atracurium metabolism.
→→ →→→ accumulates after prolonged
infusion in renal failure patients.
→→ →→→ Causes CNS stimulation and seizures.
It does not posses any neuromuscular
blocking property.
Side effects • There is increase in • Histamine release can occur if large • It is devoid of any • It does not cause
heart rate, blood boluses are used leading to Hypotension, significant cardio- histamine release even
pressure and tachycardia and bronchospasm. vascular effect. when given as large
cardiac output due to However there are boluses.
vagolytic action and reports of bradycardia in • Possess some
catecholamine release. patients receiving vagolytic property
• When combined with vecuronium, when no which can be useful
halothane and prior anticholinergic against bradycardia
tricyclic antidepressants drug is used during caused by vagal
life threatning arrhythmias premedication. stimulation during
can occur. • Lacks histamine surgical procedures.
• Caution is required while release potential. (peritoneum handling,
use in patients with ophthalmologic
borderline cardiac reserve. surgeries).
Contd...
Pancuronium Atracurium Vecuronium Rocuronium

27. Neuromuscular Blocking Agents Neuromuscular Junction (Structure and Function)19
Clinical Significance
Tachycardia due to pancuronium might be beneficial in patients undergoing high opioid
anesthesia while it becomes troublesome when used along with halothane and tricyclic
antidepressant, as in this setting arrhythmias can be precipitated. Selection of the drug
should be done according to the patients pathophysiological state and other drugs
being simultaneously used. Atracurium and vecuronium themselves do not cause any
change in heart rate but they do not counteract the vagal stimulation induced
bradycardia during handling of peritoneum and abdominal viscera.
CLINICALLY IMPORTANT DRUG INTERACTIONS
OF MUSCLE RELAXANTS
Volatile Anaesthetics

28. 20Comparative Pharmacology for Anaesthetist
Potentiation of neuromuscular blockade by volatile anaesthetics depends upon the
following factors
a. Type of Volatile agent used: desflurane > Sevo flurane < Isoflurane and enflurane >
Halothane > N
2
O/O
2
/opioid
b. Type of muscle relaxant used: Tubocurarine, Pancuronium > Vecuronium,
Atracurium
c. Dose of Volatile anesthetic used: Higher concentration of volatile anesthetic will
cause more augmentation of blockade.
Clinical Significance
When volatile agents and non depolarising muscle relaxants are used simultaneously,
one must reduce the dose of muscle relaxant by 15 – 20 percent in order to avoid
difficulty in extubation.
Local Anaesthetics
Clinical Significance
This action of local anesthetics is clinically significant mainly when used intravenously
(e.g. as antiarrhythmic agent).
Note: Other antiarrhythmic agents (e.g. quinidine) also interfere with neuromuscular
function and can potentiate residual blockade in recovery room.
Magnesium
Magnesium
1. decreases Ach release from nerve terminal
2. makes the muscle fibre less excitable
Potentiation of Neuromuscular blockade

29. Neuromuscular Blocking Agents Neuromuscular Junction (Structure and Function)21
Clinical Significance
Muscle relaxants should be used with caution in pre-eclamptic or eclamptic patients
on magsulph therapy. Magnesium augments both nondepolarisers as well as
depolarising agent (succinylcholine).
Antibiotics
Drugs that can potentiate neuromuscular blockade are
• Aminoglycosides
a. streptomycin
b. gentamicin
c. kanamycin
d. tobramycin
Mechanism:- decrease in Ach release from nerve terminal.
• Polymixins (mainly postjunctional action)
• clindamycin (has both prejunctional and postjunctional action)
Clinical Significance
If one suspects antibiotic induced augmentation of neuromuscular blockade,
neostigmine in higher doses (maximum 5 mg/70 kg) can be tried. Generally such
problems are polyfactorial and continued mechanical ventilation should be executed
till spontaneous respiration returns.
Other Drugs Potentiating Neuromuscular Blockade
•Calcium Channel blockers
– Verapamil
– Nifedipine
•Furosemide
•lithium
•Dantrolene
Drugs That Cause Antagonism/faster Recovery
from Neuromuscular Blockade
•Calcium
•Anticonvulsants
(chronic therapy) — Carbamazepine and phenytoin
•Theophylline
•Aminophylline

30. 22Comparative Pharmacology for Anaesthetist
FACTORS AFFECTING NON DEPOLARIZING BLOCKADE
1. RENAL DYSFUNCTION / FAILURE
Pathological changes in renal dysfunction/failure
GFR is reduced
Drugs partially or completely
dependent on kidney for
excretion show increased
duration of action
e.g:- pancuronium Pipercuronium
Total body water is Decreased plasma
increased leading to cholinesterase activity
increased volume of
distribution of water
soluble drugs
(all muscle relaxants).
Prolonged action of drug
dependent on the enzyme for
metabolism e.g:- mivacurium
loading dose of muscle relaxant is increased
Clinical Significance
For the purpose of easy understanding muscle relaxants can be divided into three groups
on their basis of excretion
A. Muscle relaxants majorily dependent on kidneys for excretion
• gallamine
• metocurine
B. Muscle relaxants partially dependent on kidneys for excretion
• Pancuronium (60 - 80%) · Rocuronium (5 - 15%)
• Vecuronium (15% - 25%)
C. Muscle relaxants not dependent on kidneys for excretion
• atracurium
• cis atracurium
It is clear that group A drugs should not be used in patients with renal dysfunction;
group B drugs should be used only with careful titration (i.e. though loading dose
might remain same or increase depending upon the total body water, subsequent
maintenance doses are given at larger time interval and smaller in amount). Group C
drugs can be used conveniently in renal dysfunction.
Atracurium produces a metabolite named laudanosine. This compound has potential
to cause seizures and it accumulates in renal failure. However this becomes clinically
significant only when prolonged infusions of atracurium are used in renal failure
patients in ICU settings.

31. Neuromuscular Blocking Agents Neuromuscular Junction (Structure and Function)23
2. HEPATIC DYSFUNCTION / FAILURE
Pathological changes affecting muscle in hepatic dysfunction patients
Total body water is increased
depending upon the type and extent
Drugs dependent on liver for of liver disease
metabolism or excretion show
prolonged duration of action
Initial loading dose of muscle relaxant
is increased while subsequent
maintenance doses are reduced and
given after longer time interval
Increased plasma concentration
of bile salts cause reduced uptake
of muscle relaxants by liver
severe liver disease
cause reduced plasma
Clearance of such drugs cholinesterase activity.
is reduced even further. As a result there is
prolonged action of
mivacurium
Drugs Largely Dependent on Liver for Metabolism or Excretion or Both
•Rocuronium:- Major route of excretion is via biliary tract. It should not be used in
patients with biliary obstruction (intra or extrahepatic) as well as severe hepatic
dysfunction.
Drugs Partially Dependent on Liver for Metabolism or Excretion or Both
•Pancuronium:- 10 to 40 percent of the drug is metabolized in liver. Its 3 desacetyl
metabolite is also active. It should be avoided in liver dysfunction.
•Vecuronium:- Depends on liver for metabolism as well as excretion. It should be
avoided in hepatic dysfunction patients especially if the surgery is prolonged and
repeated doses are required.
•dTC, Pipercuronium, Doxacurium:- These drugs should be avoided in hepatic
dysfunction.
Drugs Independent of Hepatic Metabolism or Excretion
Atracurium and cisatracurium are the drug of choice for patients with hepatic
dysfunction due to their organ-independent clearance.

32. 24Comparative Pharmacology for Anaesthetist
3. AGE
a. INFANTS (< 1 year age)
Physiological differences in infants that affect muscle relaxant pharmacodynamics and
pharmacokinetics:-
•infants have higher cardiac output as compared to adults, so onset of action of
muscle relaxants is faster.
•Infants are more sensitive to muscle relaxants owing to immature NMJ. However
on the other hand they have higher percentage of total body water (60 – 70%) as
compared to adults (TBW – 50 to 60%). Larger TBW means larger volume of
distribution. The two factors neutralize each other and clinically loading dose
remains same.
•Duration of action of muscle relaxants is prolonged due to immature clearance
mechanism (liver and kidneys) as well as large volume of distribution.
Large volume of distribution means that more drug is distributed to peripheral
compartment and is not available for metabolism and excretion via liver and kidneys.
Clinical Significance
•As a general rule loading dose of muscle relaxants remain same in infants but
subsequent doses should be given less frequently and in lower doses as compared
to adults.
•Atracurium and Cisatracurium do not show prolongation in duration of action in
infants due to organ independent metabolism.
b. ELDERLY
Pathophysiological changes seen in elderly are:
•Decreased total body water and increased body fat. This results in reduced volume
of distribution of water soluble drugs.
•Decreased renal and hepatic blood flow. Reduction in GFR and metabolising capacity
of liver cause prolonged duration of action for most muscle relaxants.
•NMJ show following changes
a. decreased release of Ach
b. flattening of postjunctional membrane
Despite these changes sensitivity for nondepolarising agents remain same in elderly.
•Plasma cholinesterase activity is reduced in elderly.
Clinical Significance
•Atracurium and cisatracurium are preferred in elderly due to organ independent
metabolism.
•Succinylcholine and mivacurium show relatively prolonged duration of action due
to reduced plasma cholinesterase activity.

33. Neuromuscular Blocking Agents Neuromuscular Junction (Structure and Function)25
4. TEMPERATURE
Hypothermia cause reduced metabolism of atracurium. Metabolism and excretion of
other muscle relaxants is also delayed. Normal body temperature should be maintained
in order to achieve adequate recovery from neuromuscular blockade.
5. OTHER FACTORS
•Hypokalemia, Hypocalcemia and Hypermagnesemia potentiate neuromuscular
blockade.
•Acidosis (respiratory and metabolic) cause increased duration of neuromuscular
blockade.

34. Opioids 2
DEFINITION
Opioids are the drugs that specifically bind to opioid receptors. These receptors are
present in the central nervous system as well as peripheral tissues.
CLASSIFICATION OF OPIOIDS
a. on the basis of origin
b. on the basis of structure
c. on the basis of action
On the basis of ORIGIN
Opioids
Natural Semi-synthetic Synthetic
(derived from poppy plant) • Heroine • Pentazocine.
• Morphine • Buprenorphine • Butorphanol
• Codiene • Phenylpiperidine derivatives
• Thebaine (e.g. fentanyl)
On the basis of STRUCTURE
Morphinan or Phenylpiperidines Morphinan Benzomorphan Methadone
Thebaine derivative derivatives derivatives derivatives
• Morphine • Pethidine • Butorphanol • Pentazocine • Methadone
• Nalorphine • Fentanyl
• Buprenorphine • Sufentanil
• Naloxone • Alfentanil
• Naltrexone • Remifentanil

35. Opioids27
On the basis of ACTION
Pure agonists Agonist-antagonist Partial/weak agonists Pure antagonists
• morphine • nalorphine • buprenorphine • naloxone
• fentanyl • pentazocine • butorphanol • naltrexone
• sufentanil • nalbuphine • nalmefene
OPIOID RECEPTORS
Location
Though opioid receptors are found scattered in CNS and peripheral tissues, their
high densities occur in five areas of CNS.
Classification
Opioid receptors are classified as following:
NEW (IUPHAR) (OLD) SUB TYPE
OP
3
µ - mu 1, 2, 3
OP
2
κ - Kappa 1, 2, 3
OP
1 ∂ - delta 1, 2, 3

36. 28Comparative Pharmacology for Anaesthetist
OP
3
(µ) Receptor
Agonist :- Morphine, endomorphins, 1 and 2.
Selective antagonist :- β- funaltrexamine
Receptor site :- Periaqueductal gray, thalamus, nucleus ambigus, nucleus tractus
solitarious.
Action
µ receptors have high affinity with morphine. They are of two types. µ
1
mediate
supraspinal analgesia.
µ
2
receptors are mainly located in spinal cord and peripheral tissues where they
mediate spinal analgesia, respiratory inhibition and constipation.
Actions of µ receptors
• Analgesia
Supraspinal (µ
1)
Spinal (µ
2
)
• Respiratory depression (µ
2
)
• Constipation (µ
2)
• Sedation
• Euphoria
• Miosis
• Depression of cough reflex (µ
2
)
• Attenuation of baroreceptor reflex
OP
2
(κκκκκ) Receptor
Agonist :- Ketocyclazocine and Dynorphin A.
Selective antagonist :- Norbinaltorphimine.
Action
κ
3
receptors mediate supraspinal analgesia while κ
1
receptors are important for spinal
analgesia.
Actions of K receptors
• Analgesia
supraspinal (κ
3)
spinal (κ
1
)
• constipation
• sedation
• Dysphoria, hallucinations
• Miosis (lower ceiling)
• Increased diuresis

37. Opioids29
OP
1
(δδδδδ) Receptor
Agonist :- Leu/Met Enkephalins.
Actions of δ receptors
• Analgesia
supraspinal (∂
1
∂
2
)
spinal (∂
1
)
• Respiratory depression
• Increased growth hormone release
• Inhibits dopamine release
• Affective behavior
• modulation of µ receptor activity
σσσσσ (SIGMA) Receptors
They are no longer considered as opioid receptors. They are neither activated by
morphine nor blocked by naloxone. They are activated by drugs like pentazocine,
butorphanol etc, their action includes mydriasis, tachycardia, dysphoria,
psychotomimetic actions.
Concept of Agonist, Partial Agonist and Antagonist
Agonists are the drugs that bind to receptor and produce maximal effect. Partial
agonists bind to receptor to produce submaximal effect. Antagonists bind to receptor
to produce no effect.
Dose response curve of a partial agonist show a ceiling effect, thus reflecting
lower maximal response. Partial agonist can precipitate withdrawl of an agonist in
dependent subjects.
MECHANISM OF ACTION
OPIOID RECEPTOR + OPIOID (Ionized State)
G Protein Mediated
Inhibition of calcium entry Facilitation of Inhibition of adenyl
into cell via N, P, Q, R, potassium efflux cyclase.
Calcium channels.
Decreased release of Hyperpolarization of cell, Reduced cAMP formation
Excitatory neurotransmitter thus making it less excitable
Reduced intracellular calcium
Decreased release of
neurotransmitter

38. 30Comparative Pharmacology for Anaesthetist
Analgesia (Pain Control) System of the Body
Another mechanism of action of opioids is activation of analgesia system of the body.
Analgesia system consists of periaqueductal gray, raphe magnus nucleus and pain
inhibitory complex located in the dorsal horns of spinal cord. Opioid receptors are
present in the periaqueductal gray as well as raphe nucleus; activation of which can
lead to complete suppression of very strong pain signals entering via dorsal spinal
roots.

39. Opioids31
PHARMACOKINETICS OF OPIOIDS—A COMPARATIVE STUDY
MorphineMeperidineFentanylAlfentanilSufentanil Remifentanil
PKa 8 – 8.4 6.5 8.0 7.07
Absorption Well absorbedBio-availabilityThese drugs are normally used via intravenous route.
after oral when given orally. after oral
administrationBecause of high administration
hepatic extraction is 45-75 percent
ratio, oral bio- due to
availability is significant first
20-30 percent. pass effect.
When morphine
is given orally
morphine-6-
glucuronide is
the primary
active compound.
Lipid solubility LowHigher thanHighly lipid Lipid solubility Twice as lipid Highly lipid soluble
morphinesoluble. less than soluble as
fentanyl but fentanyl
still highly
lipid soluble.
Protein binding 10-20 percent Highly protein 80 percent 90 percent 93 percent 70 percent protein
mostly with bound mostly protein binding, protein bound protein bound, bound, mainly with
albumin with α
1
acid mostly with α
1
with α
1
acid mainly with α
1
α
1
acid glycoprotein
glycoprotein acid glycoproteinglycoprotein acid glycoprotein
Unionized10-20 percent <10 percent <10 percent 90 percent 20 percent 60-70 percent
fraction at
Physiological pH
Note that alfentanil has remarkably high unionized fraction followed by remifentanil.
This leads to higher diffusible fraction available for brain penetration
Contd..

40. 32Comparative Pharmacology for Anaesthetist
Contd..
MorphineMeperidineFentanylAlfentanilSufentanil Remifentanil
PKa 8 – 8.4 6.5 8.0 7.07
Fate in the body The drug showsSignificant uptake Extensive Small volume of Same as fentanyl No significant
little uptake by by lungs during distribution in distribution andbut much more sequestration by
lungs. It has high first pass the body. First low intrinsicpotent and lipid lungs. Widespread
hepatic extractionpulmonary pass uptake by capacity of liver to soluble. extrahepatic
ratio andcirculationlungs is 75%. metabolise this metabolism by blood
metabolized via metabolized in Has high hepatic drug. Diffusible and tissue
hepatic and liver to active extraction ratio. fraction is highnonspecific
extrahepaticmetabolite.Metabolized in due to large esterases. Unstable
pathways. Metabolite liver tounionized in solution form for
Penetration innormeperidine pharmacologicallypercentagelong periods.
brain is slow.accumulates ininactive metabolite of the drug at Lyophilized powder
Metabolite M6G renal failure. Itnorfentanyl.physiological pH. is reconstituted
accumulates incauses seizures. This leads to faster before use. Very
renal failure. onset of action rapid onset and
as compared short duration
to fentanyl. of action.

41. Opioids33
PHARMACOKINETICS OF MORPHINE
Fate of Morphine
POINTS TO REMEMBER
• Low lipid solubility
• Biotransformation in liver into active metabolite (M6G)
• Slow onset and prolonged duration of action
• Only 10-20 percent drug remains unionized due to high pKa (8)
• 20-40 percent protein binding, mainly albumin

42. 34Comparative Pharmacology for Anaesthetist
PHARMACOKINETICS OF MEPERIDINE
POINTS TO REMEMBER
• More lipid soluble than morphine
• < 10 percent unionized fraction.
• 70 percent protein binding mainly with α
1
acid glycoprotein
Intravenous injection
Distribution in the body 65% uptake by lungs
Metabolized in liver
Meperidinic acid Norpethidine
PHARMACOKINETICS OF FENTANYL
POINTS TO REMEMBER
• Extensively distributed in the body due to high lipid solubility
• 80 percent plasma protein binding mainly with α
1
acid glycoprotein
• <10 percent unionized fraction
• duration of action is small for small doses while for large doses it is more. Reason being
“filling up” of tissue compartment
Small dose → Termination of action depends on distribution
Large dose → Termination of action depends on clearance via liver.
Pharmacokinetics of sufentanyl is same as fentanyl for its high
potency and lipid solubility. It exists 20% in unionized form

43. Opioids35
PHARMACOKINETICS OF ALFENTANIL
POINTS TO REMEMBER
• Small volume of distribution
• 90 percent unionized fraction
• Lipid soluble (but less than fentanyl)
• 90 percent protein bound mainly to α
1
acid glycoprotein
• Metabolism altered in
LIVER DYSFUNCTION
• Reduction in alfentanil plasma concentration depends more on metabolic clearance than
distribution because it has a small volume of distribution
• Diffusible fraction (unionized drug) is high at physiological pH leading to faster onset as
compared to fentanyl.
Liver has low intrinsic capacity to metabolite this drug
PHARMACOKINETICS OF REMIFENTANIL
POINTS TO REMEMBER
• Due to its ester linkages it is susceptible to hydrolysis by blood and tissue nonspecific
esterases resulting in rapid metabolism.
• Highly lipid soluble.
• Pharmacokinetics uninfluenced by liver and renal failure.
• It is not a substrate for hydrolysis by pseudocholinesterases
• Context sensitive half time is around 4 minutes and is independent of the duration of
infusion.
Intravenous injection
Distribution in the body
Widespread extrahepatic hydrolysis. (by nonspecific esterases)
Major metabolite though active, is very less potent
No significant contribution to the total effect

44. 36Comparative Pharmacology for Anaesthetist
ONSET TIME (INTRAVENOUS DRUG)
Ultrashort short long
1-2 mins 4-10 mins >15 mins
Alfentanil Fentanyl Morphine
Remifentanil Sufentanil Buprenorphine
DURATION OF ACTION
Long (> 2 hrs) Intermediate (30 minutes to 2 hrs) Short (< 30 minutes)
Morphine Fentanyl Alfentanil
Buprenorphine Sufentanil Remifentanil
Methadone Pethidine
Butorphanol
The time of onset and duration of action of opioids are related to its lipid solubility
and degree of ionization at physiological pH. A greater lipid solubility and greater
non-ionized fraction allow for quicker crossing of blood brain barrier, quicker access
to CNS and quicker redistribution.
PHARMACODYNAMICS
“Opioids form an important component of balanced anesthesia due to their remarkable
ability to provide analgesia and hemodynamic stability even in the presence of very
strong noxious stimulus such as laryngoscopy and intubation.”
Analgesia
• Analgesia due to opioids has two components.
Spinal → Action on substantia gelatinosa of dorsal horn.
Supraspinal → Action on medulla, mid-brain, limbic system and cerebral cortex.
• Perception of pain is supressed along with its associated reactions (fear, anxiety,
autonomic reaction).
• The degree of pain relief is related to the dose of opioid. On increasing the dose
analgesia increases.
• Poorly localized dull visceral pain carried by type C fibres is relieved more
effectively than sharply defined somatic pain carried by Aδ fibres.
• It was found that if an opioid is given before the exposure to noxious stimulus,
dose required was less than the dose of opioid required, when it was given after
the noxious stimulus.
This is called as pre – emptive analgesia. The theory behind pre – emptive analgesia
is interruption of repetitive firing of C – fibres and sensitization of dorsal horn cells.

45. Opioids37
Sustained
Noxiousstimulus
– blocked if opioid is given
before the noxious stimulus.
Repetitive C – fibre firing
Sensitization of dorsal horn cells
of spinal cord
Hyperexcitable state and hyperalgesia
More dose of analgesic is required to relieve pain
CARDIOVASCULAR SYSTEM
Heart Rate
• Meperidine, due to its structural similarity with atropine causes increase in heart
rate.
• Morphine, fentanyl, sufentanil, remifentanil and alfentanil cause vagus mediated
decrease in heart rate.
Cardiac Contractility
• Meperidine is a myocardial depressant and it should not be used in patients with
borderline cardiac function.
• When given alone opioids cause no, or minimal depression of cardiac contractility.
• When opioids are used along with other anesthetic drugs (N
2
O, benzodiazepines,
barbiturates etc.) significant myocardial depression occurs.
Blood Pressure
• Opioids cause fall in blood pressure via histamine release, vagal mediated
bradycardia, venodilation and decreased sympathetic tone.
Histamine release is seen with morphine, its semisynthetic derivatives, pethidine
and some of its analogues, these agents displace histamine from its binding sites
in basophils and mast cells. Effect of histamine release can be minimized by giving
the drug slowly and/or pre – treatment with H
1
and H
2
blockers.
POINTS OF CLINICAL SIGNIFICANCE
1. In patients who are adequately filled and lying supine, hypotension seldom occurs
with opioids (provided significant bradycardia is avoided). However if they are
allowed to stand, postural hypotension may develop due to loss of sympathetic
tone.

46. 38Comparative Pharmacology for Anaesthetist
2. Patients dependent on sympathetic tone for maintenance of their blood pressure
may undergo significant hypotension after intravenous opioid administration.
example-hemorrhagic shock patients, critically ill patients with severe sepsis.
3. There are reports of intraoperative hypertension during opioid anesthesia. It occurs
due to inadequate anesthetic depth and can be overcomed with addition of volatile
anesthetic agents.
RESPIRATORY SYSTEM
Ventilation
Opioids are potent respiratory depressants. Respiratory depression is dose dependent
and via direct action on respiratory center located in medulla. CO
2
responsiveness as
well as hypoxic ventilatory drive, both are depressed. This results into downward
and rightward shift of the CO
2
response curve and rise in resting PaCO
2
.
Respiratory Rate and Tidal Volume
Opioids cause decrease in respiratory rate more than decrease in tidal volume. High
dose opioids result into irregular respiration. Patient may become apneic without
loss of consciousness.
• Opioids depress cough reflex and trigger CTZ, thus making the patient prone for
aspiration. Inhibition of sighing and coughing promotes airway obstruction as
well as basal atelectasis; especially in patients who are on prolonged mechanical
ventilation
• Morphine and Meperidine cause histamine induced bronchospasm. Fentanyl and
its congeners do not release histamine. They are beneficial in asthmatics due to
inhibition of sympathetic reflexes.

47. Opioids39
Delayed Respiratory Depression
There are reports of delayed respiratory depression seen with drugs like fentanyl.
Fentanyl has a large volume of distribution. After an initial intravenous bolus dose,
75 percent of the drug is taken up by lungs. It is also distributed to skeletal muscles
and undergo ion trapping in stomach. Due to delayed release of this sequestered
dose secondary increase in plasma level occurs. This is the mechanism behind delayed
respiratory depression seen with fentanyl and its congeners.
Points of Clinical Relevance
All the staff members in recovery should be well aware of delayed respiratory
depression that occurs with fentanyl and its congeners.
Opioids facilitate intubation by blunting the response to laryngoscopy and airway
manipulation. In simple words “patient tolerates tube better.”
Opioids are respiratory depressants. Hypercarbia and hypoxemia frequently occur
if ventilation is not assisted or any other factor that stimulates respiration (eg pain) is
not there. Hypercarbia and hypoxemia both have two effects on peripheral blood
vessels. They cause vasodilation via direct action and vasoconstriction via sympathetic
stimulation (indirect action).
Opioids block this indirect action. Thus peripheral vasodilation results. Therefore
we conclude that if patients on opioids are allowed to hypoventilate they may develop
hypotension.
MUSCLE RIGIDITY
Many workers have reported skeletal muscle rigidity after large and bolus dose of
potent intravenous opioids namely fentanyl and its congeners.
It can also manifest as tonic posturing of the body as well as seizure like tonic
clonic movements of the hands and feet.

48. 40Comparative Pharmacology for Anaesthetist
EEG report classically show no abnormality thus suggesting it to be a subcortical
event. Striatonigral pathways are considered to be responsible for the opioid induced
muscle rigidity.
Clinically this is important because it can lead to difficulty in mask ventilation and
increase in intrathoracic pressure while attempting IPPV. Forceful mask ventilation
against a closed glottic opening may result in entry of air into the stomach and thus
make the patient prone for aspiration.
Clinical manifestation
Skeletal muscle Glottic Seizure like tonic
rigidity closure clonic movements of hands
Increased
thoraco-abdominal
muscle tone
Stiff chest syndrome
• Decreased
pulmonary compliance
decreased FRC
Impaired ventilation
increased PCWP, increased CVP
hypercarbia, hypoxia
Prophylaxis for the stiff chest syndrome.
• Priming with non-depolarizer.
• Slow, intermittent, small doses of opioids.
• Use of inhalational agent
Treatment for stiff chest syndrome
• Neuromuscular blocking agents.
• Naloxone.
Rigidity can appear during induction, emergence or many hours after the last
dose of opioid. Secondary peak in plasma levels due to reappearance of the
sequestered drug is responsible for delayed muscle rigidity seen in many patients.

49. Opioids41
CENTRAL NERVOUS SYSTEM
Stimulates 4 centres Depresses 4 centres
• Vagal Centre (decreased H.R) • Cough centre
• Edinger westphal nucleus (miosis) • Respiratory centre
• CTZ (vomiting) • Temperature regulating centre
• Scratch centre (Pruritis) • Vasomotor centre
Opioids are CNS depressants. CNS depression produced by opioids
characteristically has a ceiling which is subanesthetic. In simpler words they do not
produce complete CNS depression and anesthesia with opioids as sole agents is
associated with problems of recall, awareness, hypertension, tachycardia and rigidity.
Opioids fail to produce isoelectric EEG even at high doses. Sedation produced by
opioids is different from other hypnotics. They produce a state of detachment and
indifference to surrounding as well as to one’s own body. MAC of potent inhalational
agents is reduced by 50 percent.
Cerebral oxygen consumption, cerebral metabolic rate and cerebral blood flow
all are reduced, provided carbondioxide is not retained due to hypoventilation
produced by opioids. Opioids as we know are respiratory depressants and CO
2
retention is a common occurrence with their use if ventilation is not assisted.
Hypercarbia causes vasodilation and thus offset the beneficial affect achieved by
reduction of cerebral metabolic rate due to CNS depression.
Opioids have minimal affect on ICP. Rigidity produced by opioids can lead to
increase in ICP. They do not possess anticonvulsant action, on the contrary there are
reports of opioids causing neuroexcitatory phenomenon in the form of tonic – clonic
movements and seizure – like activity.
Effect on Mood and Subjective Behaviour
• Loss of apprehension
• Detachment
• Lethargy
• Mental clouding
• Inability to concentrate.
Pruritis
Pruritis is one of the common side- effect of opioids. It is believed to be centrally
mediated and reversed by very small doses of naloxone. Face and nose are the most
common sites. Pruritis is more common after neuraxial opioids.
Shivering
Some opioids show antishivering property. They include meperidine, butorphanol
and tramadol. Antishivering action is mediated through non - µ - opioid receptors.

50. 42Comparative Pharmacology for Anaesthetist
Gastrointestinal System
Gastric emptying time is slowed via central and peripheral mechanisms. Biliary colic
may be precipitated due to contraction of sphincter of oddi. Biliary spasm may mimic
the pain of angina pectoris. Increased tone and decreased propulsive action of both
small and large intestine results into constipation.
Increased gastric
emptying time
Central mechanism Peripheral mechanism
Vagal mediated
Increased pyloric Opioid receptors in
sphincter tone myentric plexus and cholinergic nerve
terminals inhibit
release of acetylcholine
Spasm of biliary Increased tone of
smooth muscles sphincter of oddi
Increased biliary duct pressure
Biliary colic
Vomiting is induced by following mechanisms
• CTZ stimulations.
• Decreased gastrointestinal motility.
• Prolonged gastric emptying time.
Tolerance does not develop to constipating action of opioids.
HORMONES AND ENDOCRINE SYSTEM
STRESS RESPONSE BLOCKED/ATTENUATED By OPIOIDS.
Release of catabolic hormones
(cortisol, catecholamines, glucagon and thyroxine)
• Increased cardiac risk
• Increased protein catabolism.
• Hyperglycemia

51. Opioids43
Inhibition of stress response is dose dependent. More potent opioids inhibit stress
response more effectively.
Immunity
Decreased by long-term use of opioids.
Allergy
• usually cause anaphylactoid reaction, (mostly morphine).
• Reaction to synthetic opioids are rare.
NEURAXIAL OPIOIDS
Opioids can be used in epidural space as well as intrathecally. Epidural dose of opioids
is 5 to 10 times the intrathecal dose.
Mechanism of action of neuraxial opioids: As we know pain is transmitted via A δ and C
fibres. A δ fibres of spinal nerves are responsible for transmission of “acute-sharp”
pain and C fibres transmit “slow –chronic” pain. A δ fibres terminate mainly in lamina
I (Lamina marginalis) of the dorsal horns and there excite the second order neurons
of the spinothalamic tract. C fibres terminate in laminas II and III of the dorsal horns,
which together are called the substantia gelatinosa. Where the type C fibres synapse
in the dorsal horns of the spinal cord they are believed to release substance P as the
synaptic transmitter. Substance P is a neuropeptide. It is slow to build up at the
synapse and also slow to be destroyed.
Analgesia produced by neuraxial opioids does not result into sympathetic
denervation, skeletal muscle weakness or loss of proprioception.
Opioid receptors are present in substantia gelatinosa. Neuraxial opioids act by
inhibiting release of substance P in this region.

52. 44Comparative Pharmacology for Anaesthetist
Fate of Neuraxial Opioids
Epidural administration of opioids
Systemic absorption Diffusion across the Uptake by epidural fat
via epidural venous plexus dura mater into CSF
Systemic blood level Gain access to µ opioids
receptors on the substantia
gelatinosa of spinal cord
Analgesia
Analgesia
• Highly lipid soluble agents like fentanyl, sufentanyl are absorbed significantly by
venous plexus present in epidural space. They offer no advantage over IV opioids.
• Morphine is poorly lipid soluble and so it remains in epidural space for longer
duration. Analgesia due to epidural morphine has slow onset and longer duration.
Intrathecal administration of opioids
Lipophilic opioids Lipophobic opioids
(fentanyl) (morphine)
Show limited cephalad migration in Remain in CSF for longer duration and
CSF due to uptake into the spinal cord show cephalad migration. The underlying cause
of this is bulk flow of CSF from lumbar region to
cephalad direction.
LIPOPHILIC VS HYDROPHILIC OPIOIDS
LIPOPHILIC (Fentanyl) HYDROPHILIC (Morphine)
• Rapid diffusion across duramater • Slow diffusion across duramater
• Quick onset and shorter duration of action • Delayed onset and long action
• Segmental effect (local action) • Potential to migrate cephalad in CSF
(Rostral spread).
• Can only be used when the catheter tip • Lower lumbar injection can provide analgesia
is close to incisional dermatome for thoracic and upper abdominal procedures.

53. Opioids45
SIDE EFFECTS OF NEURAXIAL OPIOIDS
Side effects due to neuraxial opioids
Side – effects due to systemic absorption Side- effects due to presence of drug in CSF
• Sedation • Pruritis
• Nausea, vomiting • urinary retention
• Respiratory depression • respiratory depression
Systemic absorption occur more with epidural route than with intrathecal route.
Sedation
Dose related sedation occurs with all neuraxial opioids. Most commonly it is associated
with sufentanil.
Respiratory Depression
It is the most serious side – effect of the epidural or intrathecal opioids. It is of two
types, early and late.
Respiratory depression
Early Late
• occurs within first 2 hrs • occurs between 6 to 12 hrs after
after administration of administration of neuraxial opioids.
neuraxial opioid
• Reason is systemic uptake • It is due to diffusion of opioids into CSF
of opioids via spinal cord vessels and migration into medullary respiratory centre
Risk Factors for Respiratory Depression
• High dose
• Administration of opioid with low lipid solubility (eg. morphine)
• Concurrent use of I.V. opioid/sedation
• Advance age
• Intrathecal use of opioids.
Points of Clinical Relevance
• Arterial hypoxemia and hypercarbia may develop despite a normal breathing
rate. Pulse oximeter should be used to assess oxygen saturation
• Delayed respiratory depression is more common with morphine.
• Sensorium of the patient is a good clinical guide to assess significant respiratory
depression
• Coughing increases the likelihood of cephalad migration of the drug in CSF.

54. 46Comparative Pharmacology for Anaesthetist
Pruritis
It is one of the most common problem faced after use of neuraxial opioids.
• It occurs due to cephalad migration of the drug in CSF and action on opioid
receptors located in trigeminal nucleus.
• Pruritis is more common over the face, neck or upper thorax. It is effectively
relieved by opioid antagonist, i.e. naloxone.
Urinary Retention
• Urinary retention is common in young males after neuraxial administration of
opioids. Mechanism is via inhibition of sacral parasympathetic nervous system by
neuraxial opioids. It results in relaxation of bladder muscles and urinary retention.
SIGNIFICANT DRUG INTERACTIONS
i. Opioids are most commonly used along with intravenous induction agents, muscle
relaxants and inhalational agents.
ii. Besides the drug interaction there are other factors influencing the combined
effect of two groups on various systems. They include
a. Hydration status
b. Presence of noxious stimulus
c. CO
2
retention
d. Chronic drug therapy
e. Disease pathophysiology
f. Use of other drugs.
1. Sedative – Hypnotics
A. Benzodiazepines + opioids → SUPRA-ADDITIVE affects (synergistic interaction)
CNS affects : Dose requirement is lowered for the groups in terms of inducing
anesthesia.
RS affects :Incidence of hypoventilation and hypoxemia are increased
manifold.
CVS affects : Significant cardiovascular depression (fall in BP, heart rate, SVR,
cardiac index).
B. Barbiturates + opioids:- Hypotension due to venodilation and reduced preload.
C. Propofol + opioids:- Decrease in mean arterial pressure, heart rate and systemic
vascular resistance.
D. Ketamine + opioids:- Little loss of cardiovascular stability.
2. Inhalational Anaesthetics
a. N
2
O + opioids:- Not a good combination; because both are associated with nausea
and vomiting. Decrease in cardiac output, heart rate, and arterial pressure can
occur. There is an increase in pulmonary vascular resistance. Nitrous oxide is a
weak amnesic agent.

55. Opioids47
b. Volatile Agents + opioids:- They are frequently combined as volatile agents provide
good amnesia and promote immobility. Newer volatile anesthetics and opioids
when combined together demonstrate well preserved cardiac output and mean
blood pressure.
Note:
• Desflurane can increase heart rate and mean arterial pressure during induction of
anesthesia due to increased sympathetic activity. To attenuate this effect fentanyl
1.5 µgm/kg is used.
3. Muscle Relaxants
a. Pancuronium :- Vagolytic action of Pancuronium attenuate opioid induced
bradycardia and support blood pressure.
b. Vecuronium :- It potentiate decrease in heart rate and cardiac index when used
with opioids.
4. MAO Inhibitors
Meperidine + MAOI → Excitatory or Depressive (Both interactions possible).
Excitatory:- We know that meperidine blocks neuronal uptake of serotonin. When
combined with MAO inhibitors there can be excess central serotoninergic activity
leading to agitation, headache, hemodynamic instability, fever, rigidity, convulsions,
coma.
Depressive Form:- MAO inhibitors block hepatic microsomal enzymes and can lead to
accumulation of meperidine. Net effect is respiratory depression, hypotension and
coma.
5. Calcium-channel Blockers
Opioids + CCBs → Depressed cardiac function, Bradycardia and heart block.
6. Erythromycin
Alfentanil action is prolonged as a result of impaired metabolism due to reduction in
oxidizing activity of Cyt P-450.
7. Cimetidine and Ranitidine
These drugs reduce hepatic blood flow and its metabolizing capacity, as a result
opioid effects are prolonged.
COMPLEX ACTION OPIOIDS
Complex action opioids form a group of drugs that possess partial agonist or
antagonist action at µ receptors besides being kappa (κ) agonist.

56. 48Comparative Pharmacology for Anaesthetist
They classically show ceiling of analgesic and respiratory depressant action.
(analgesia and respiratory depression does not increase after a certain point even on
increasing the dose). Some of them have CVS stimulating properties (i.e. pentazocine)
while others cause marked sedation (eg. Butorphanol). Clinically they are important
because some of these drugs have been successfully used as a part of balanced
anesthesia as well as postoperative analgesia.
Pentazocine (20-60 mg pentazocine = 10 mg morphine)
Chemistry: - Benzomorphan derivative.
• Weak antagonistic and more marked agonistic action.
• Analgesia and respiratory depression show a ceiling effect after 60 mg dose. They
do not increase much after this dose.
• Many of its actions are kappa and sigma mediated. Analgesia is characteristically
different from that due to morphine. It is mediated via K
1
receptors located in
spinal cord.
• Increase in blood pressure, heart rate and cardiac work occurs via sympathetic
stimulation. Should be avoided in cardiac patients. Plasma catecholamine
concentration is increased.
• Propensity to cause nausea, vomiting and biliary spasm are less severe than pure
µ agonists.
• It produces sedation and psychomimetic effects.
Pharmacokinetics:-
Oral bioavailability is 20 percent due to significant first pass metabolism in liver.
Elimination half life is 2 hrs. metabolites are excreted mainly via kidneys. Duration
of action of single dose is around 4 hrs.
Oral dose 50-100 mg
Parenteral dose:- 30–60 mg
Onset of action after I.V. injection:- 2–3 minutes
After I.M. injection:- 20 minutes
The drug possess irritant property. Local fibrosis can occur after repeated I.M. or
subcutaneous use.
Dependence:- The drug has low abuse potential when compared with pure agonists,
however chronic use can lead to physical dependence. It precipitates withdrawl in
morphine dependent subjects.
Buprenorphine (Thebaine Derivative)
Introduction
The most important character of this drug is its very slow onset and prolong duration
of action. It possess high affinity for opioid receptors with which it binds tightly. Its
actions are only partially reversed by naloxone due to tight binding. Doxapram is
used to reverse respiratory depression due to buprenorphine.

57. Opioids49
Key Points
• 33 times more potent than morphine
• Partial µ agonist. Binding with (κ) Kappa and (δ ) delta receptors is insignificant.
• Respiratory depression shows a ceiling effect after 0.15 to 1.2 mg dose in adults.
On further increasing the dose antagonistic action appears leading to increase in
respiration.
• It possess a BELL shaped dose – response curve. Recall that pure agonists (fentanyl
and morphine) have sigmoid shaped dose response curve.
• It is metabolized in liver. Excretion is via biliary tract into faeces. Metabolites are
unlikely to exert significant activity in renal failure.
• Substitutes for morphine at low level of dependence. Precipitates abstinence
syndromes in highly dependent subjects.
Routes of Administration
• Oral
•IM
•IV
• Sublingual
• Epidural.
Dose
• 0.3-0.6 mg IM. S/C, Slow I.V.
• 0.2-0.4 mg sublingual 6-8 hourly.
Interaction:- Severe respiratory depression occurs when this drug is co-administered
with benzodiazepines.
BUTORPHANOL
Introduction
It is a potent analgesic with actions mediated via κ (Kappa) receptors. It is kappa
agonist. Action at µ receptors is partial agonist or antagonist. It is used for providing
analgesia as a component of balanced anesthesia. It causes significant sedation.
Key Points
• 5 to 8 times more potent than morphine.
• Respiratory depression has a ceiling effects.
• Cardiovascular effects are similar to pentazocine, i.e. increase in cardiac work,
pulmonary artery pressure and pulmonary vascular resistance.
• Interaction with µ receptor is minimal. Does not precipitate withdrawl in morphine
dependent subjects.
• Available only in parenteral form due to poor oral bioavailability. Onset of action
is rapid and lasts for around 2–3 hrs.
• Spray for transnasal application is available (1–2 mg).

58. 50Comparative Pharmacology for Anaesthetist
NALBUPHINE
Introduction
It is a Kappa agonist and µ antagonist. It precipitates withdrawl in morphine
dependent subjects. Psychomimetic action and dysphoria is not significant due to
weak action at σ receptors.
Key Points
• Minimal cardiovascular stimulation
• Metabolized in liver, excreted via faeces
OPIOID ANTAGONISTS
a.NALOXONE: It is a pure opioid antagonist.
Chemistry: N-alkyl derivative of oxymorphone. Active at µ, κ and δ receptors but
greatest affinity for µ receptor.
Pharmacokinetics
• Onset of action 1-2 mins.
• Duration of effect 30-60 mins.
• Glucuronide conjugation in liver.
Formulation and Administration
• It comes as clear solution of naloxone hydrochloride 0.02/ 0.04 mg/ml
• Naloxone is used for reversal of respiratory depression caused by opioid overdose
as well as treatment of opioid poisoning.
a.Reversal of respiratory depression:- The drug is given in small incremental doses
until a desired end point is reached (ie restoration of spontaneous ventilation).
Normally 0.5 to 1.0 µgm/kg boluses are given every 2 to 3 minutes. Around
0.1 to 0.2 mg drug will achieve this effect in adults. If the drug is carefully
titrated respiratory depression can be reversed without reversal of analgesia.
•Morphine poisoning:- larger dose of naloxone is required in poisoning cases (generally
upto 0.4 to 2.0 mg).
Renarcotization
Naloxone has a short half life with duration of action lasting for 30 – 60 minutes
reappearance of respiratory depression may occur if the opioid being antagonized
has a longer action (e.g. morphine).
Another reason for recurrence of respiratory depression is mobilization of opioid
from its peripheral storage sites into the central compartment (e.g. Fentanyl).

59. Opioids51
Disadvantage of Naloxone Use
Naloxone use has been found to be associated with increase in heart rate, blood
pressure and central sympathetic activity, neurogenic pulmonary edema can occur in
extreme cases. The drug should not be used in patients with borderline cardiovascular
function and pheochromocytoma or cromaffin tissue tumors. It should be carefully
used in neuroanesthesia, as significant increase in cerebral blood flow can occur.
Other Uses of Naloxone
1. Septic shock: For reversal of endogenous opioids and increase in blood pressure
via increase in central sympathetic activity.
2. Postanesthetic apnea in children
3. It is also used in treatment of clonidine overdose, heat stroke, thalamic pain
syndromes and schizophrenia.
Opioids not Reversed by Naloxone
•Buprenorphine: It binds very strongly with opioid receptor. Doxapram is used for
reversal of buprenorphine induced respiratory depression
•Pentazocine: Actions of pentazocine which are mediated via s (sigma) receptors
are incompletely reversed by naloxone. They include dysphoria, mydriasis
tachycardia, psychomimetic action.
Other Drugs Reversed by Naloxone
Benzodiazepines, barbiturates and other non opioid CNS depressants may be partially
reversed by high dose naloxone.
NALTREXONE
This drug has two advantages when compared with naloxone
a. it is longer acting. t
½
is 8-12 hrs.
b. it is orally active.
Dose: 5 – 10 mg orally.
NALMEFENE
It is orally active pure opioid antagonist. Oral bioavailability is 40 to 50 percent and
plasma half life ranges from 3 to 10 hours.
Conducting the Case of an Opioid Addict
Points of Clinical Significance
• Acute opioid intoxication decreases anesthetic requirement while chronic abuse
increases it.

60. 52Comparative Pharmacology for Anaesthetist
• Elective surgery should be postponed for acutely intoxicated and those with signs
of withdrawl.
• If surgery cannot be avoided or in chronic patients, give abuse substance.
Withdrawl should be prevented by giving pure agonist. Complex action opioids
(agonist-antagonists or partial agonists) should not be used.
• Adequate premedication is necessary. General anesthesia is better as psychological
problems can be prevented. Inhalational based technique is preferred.
• Deaddiction should not be attempted in perioperative period.
Pethidine
It is a phenylpiperidine derivative. Pethidine has structural similarity with atropine
and some of its effects (dry mouth, blurred vision) are attributed to it.
The most important feature of pethidine is ADVERSE CARDIOVASCULAR effects.
The drug should not be used in patients with borderline cardiac function due to its
tendency to cause tachycardia and decreased cardiac contractility.
Meperidine/Pethidine is metabolized into meperidinic acid and norpethidine.
Norpethidine has propensity to cause CNS sideffects ie tremors, myoclonus, seizures.
This metabolite accumulates in renal failure and so pethidine should not be used in
such patients.
It is one of the preferred opioid in obstetrics due to less marked neonatal
depression when compared with morphine.
Key Points
• 1/10th as potent as morphine.
• Causes increase in heart rate and decrease in contractility.
• Inhibits postop shivering
Pethidine/Meperidine
Hydrolysis Demethylation
Meperidinic Acid Nor pethidine
(major metabolite) (minor metabolite)
—accumulates in renal failure
—cause seizures
• This drug does not cause spasm of sphincter of oddi. Preferred analgesic in biliary
colic.
• It has significant and potentially fatal interaction with MAO inhibitors due to its
property of inhibiting neuronal uptake of noradrenaline and serotonin. (Discussed
in detail in the section of drug interaction).

61. Opioids53
• Does not suppress cough
• Less potential to cause histamine release.
• Local anesthetic action.
• mechanism of action like tramadol.
• Dose 1-2 mg/kg.
TRAMADOL
Chemistry: Synthetic phenylpiperidine analogue of codeine.
Action:a. Stimulates mainly µ receptors.
b. inhibit reuptake of noradrenaline and serotonin at nerve endings.
Key Points
• Analgesic action only partially reversed by naloxone.
• 1/5th – 1/10th potency of morphine.
• When compared with morphine it causes
— Less respiratory depression
— Less sedation
— Less constipation
— Less urinary retention
— Less increase in intrabiliary pressure.
— hemodynamic effects are minimal.
• Dose 50-100 mg IV.can be repeated 4 hrly – 6 hrly.
— Max dose is 400 mg/day.
— Side – effects:- nausea, dizziness, dry mouth.
DOSES OF COMMON OPIOIDS
Morphine Intravenous dose 0.05 to 0.1 mg/kg
Intramuscular dose 0.1 to 0.2 mg/kg
Epidural dose 3 to 5 mg
Meperidine Intravenous dose 0.5 to 2 mg/kg
Intramuscular dose 0.5 to 3 mg/kg
Epidural dose 10 mg
Fentanyl Intravenous dose 0.5 to 150 µg/kg
Epidural dose 50 to 150 µg
Sufentanil Intravenous dose 1.2 to 30 µg/kg
Epidural dose 10 to 30 µg
Alfentanil Intravenous dose
– loading 5 to 100 µg/kg
– maintenance .5 to 3 µg/kg/min
Remifentanil Intravenous dose
– loading 1 µg/kg
– maintenance 0.5 to 20 µg/kg/min

62. Volatile Anaesthetics3
Volatile anaesthetics are agents administered in vapour form to the patient via
pulmonary route.
PHARMACOKINETICS
It deals with inhaled anaesthetics in respect to their:
a. Absorption (i.e. uptake from alveoli into pulmonary capillary blood)
b. Distribution in the body
c. Metabolism
d. Elimination
In other words under pharmacokinetics of volatile anaesthetics we study the factors
which influence the administration of anaesthetic from vaporization to its deposition
in the brain and various other tissues and finally removal from the body.
The journey of inhaled anaesthetic from vaporizer to patient’s brain (i.e. the target
organ) is affected by multiple factors. For convenience these factors can be studied
under following headings.
a. Factors affecting inspiratory concentration
b. Factors affecting alveolar concentration
c. Factors affecting arterial concentration
FATE OF INHALED ANAESTHETIC
Vaporizer Anaesthetic circuit Airways Alveoli Arterial
blood
Set concentration Inspiratory Alveolar Arterial
concentration concentration concentration
BODY ORGANS
Vessel fat muscle Vessel
rich group poor group

63. Volatile Anaesthetics55
Inhaled anaesthetic move down a concentration gradient from the vaporizer to
the body organs. The movement of the molecules of inhaled anaesthetic depends
upon various factors, out of which relative solubility between two phases i.e.(partition
coefficient) is the most important factor. At first the alveolar concentration equilibrates
with the inspired concentration of inhaled anesthetic, then arterial concentration
equilibrates with alveolar concentration and finally the body organs equilibrate with
arterial concentration. How fast this equilibrium is established between the two phases
depend upon relative solubility of the inhaled drug in the respective medium (i.e.
alveolar gas and blood, blood and brain etc.). The unit measuring this relative solubility
is called as partition coefficient. Another point of emphasis is that all body organs do
not equilibrate at the same rate with arterial concentration. On this basis they are
divided into four groups as shown in the diagram (vessel rich group, fat, muscles,
vessel poor group). Out of these groups vessel rich group is the first to equilibrate
with arterial concentration. The target organ of inhaled anaesthetic i.e. brain, falls in
this group. Once equilibrium is established between all these three phases i.e. alveolar
gas, blood and brain, alveolar concentration becomes an indirect measure of
concentration in the brain. By controlling alveolar concentration one can control the
brain concentration of the anaesthetic.
FA Fa Fbr
FA = Alveolar concentration
Fa = Arterial concentration
Fbr = Brain concentration
A. Factors Affecting Inspiratory Concentration
We fill the vaporizer and initiate flow of gases. Gas mixture leaving the vaporizer
carries the concentration set on vaporizer but patient lung may receive a different
concentration. It is affected by
1. breathing circuit volumes
2. fresh gas flow rate (FGF)
3. absorption of the inhaled anaesthetics in the rubber or plastic components of the
breathing system
(High fresh gas flow, low circuit volume and low circuit absorption reduce
difference between concentration set on vaporizer and inspired concentration).

64. 56Comparative Pharmacology for Anaesthetist
Note that concentration set at point A is not the same as delivered at point B
(patient’s airways). It is affected by FGF, breathing circuit volume and absorption by
machine/breathing circuit. Note that concentration delivered at point B is called as
F
I
(Inspired concentration).
B. Factors Affecting Alveolar Concentration
Before knowing factors affecting alveolar concentration we must know what is partial
pressure and what is equilibrium.
Partial Pressure
When a gas mixture is kept in a container, the molecules of the gas mixture exert
pressure on the walls of the container. The part of the total pressure that results from
any one gas in the mixture is called the partial pressure of that gas. The total pressure
of the mixture is the sum of the product of the partial pressures of the constituent
gases.
Equilibrium
Equilibrium is defined as equal partial pressures in two phases.
Partition Coefficient
It is the ratio of the concentrations of the anesthetics in two phases at equilibrium. In
other words it measures relative solubilities of an anaesthetic in two phases. Blood/
gas coefficient of isoflurane is 1.4 at 37
o
C. This implies that each ml of blood holds 1.4
times isoflurane as does alveolar gas.
ALVEOLAR GAS BLOOD
10 molecules Equilibrium 14 molecules
of isoflurane of isoflurane
No net movement
of molecules
Note that after achieving equilibrium blood contains more isoflurane than alveolar
gas. High blood gas coefficient means that agent is more soluble in blood than gas.
Affinity of agent for blood
Blood/gas coefficient =
_________________________________________
Affinity of agent for gas

65. Volatile Anaesthetics57
Concentration of inhaled anesthetic at point B is the inspired concentration.
Concentration achieved at point C is the alveolar concentration. The concentration of
inhaled anaesthetic that a patient inspires need not be the same as that achieved in
the alveolus. The factors governing alveolar concentration are
i. Uptake (absorption from alveoli into blood)
ii. Ventilation
iii.Concentration and second gas effect.
i.Uptake: As soon as the inhaled anaesthetic reaches the alveolus it starts getting
absorbed into the blood. Thus absorption (uptake) depends upon the solubility of
the agent in the blood as compared to alveolar gas, cardiac output and partial
pressure difference between alveolar gas and venous blood.
Uptake = solubility × cardiac output × partial pressure difference between alveolar
gas and venous blood.
SOLUBILITY
Concept of uptake/absorption is very simple to understand. If a drug is highly soluble
in blood it will easily diffuse out of the alveolus into the pulmonary capillaries and
concentration of the drug at point C in the diagram (i.e. alveolus) will fall. Thus it
will take longer time for alveolar concentration (F
A
) to become equal to inspired
concentration. So we conclude that highly soluble drugs i.e. drugs with high blood/
gas coefficient takes longer time to achieve a given alveolar concentration. Now
delay in rise of alveolar concentration means delay in achieving a definite brain
tissue concentration and finally delay in induction of anaesthesia. Thus, highly soluble
drugs will take longer time for induction.
Blood : gas partition coefficients or in similar words solubility of drug in blood as
compared to alveolar gas is influenced by a number of factors.
A. Haematocrit
Higher the haematocrit higher will be the solubility. That is why anaemic patients
show a more rapid induction of anaesthesia. The decreased solubility in blood in
anemic patients reflects the decrease in lipid-dissolving sites normally present on
erythrocytes. As a result alveolar concentration rises faster in anaemic patients leading
to faster induction.

66. 58Comparative Pharmacology for Anaesthetist
B. Fat Contents of the Blood
Fat acts as a large reservoir for inhalational anaesthetics. Increasing the fat content of
the blood e.g. postprandial lipidemia result in increased solubility of the drug in
blood. Final impact is modest slowing of rate of induction.
CARDIAC OUTPUT
Increased cardiac output
Increased pulmonary blood flow
Increased anaesthetic uptake
Decrease in alveolar concentration
Delayed induction
Low cardiac output increases alveolar concentration leading to anaesthetic
overdosage. It is important to remember that change in cardiac output effects soluble
agents more than insoluble agents.
Volatile anaesthetics that depress cardiac output can exert a positive feedback
response in this regard.
Volatile anaesthetic
Decreased cardiac output due to myocardial depression
Alveolar concentration rises (F
A)
Increase in depth of anaesthesia
More myocardial depression
PARTIAL PRESSURE DIFFERENCE BETWEEN
ALVEOLAR GAS AND VENOUS BLOOD
Anesthetic agent goes to the body tissues from alveoli via blood. At the start of
induction, concentration of agent in body tissues is nil. After dissolving in blood,
agent diffuses into tissues. This transfer also depends on 3 factors.
a. Tissue solubility
b. Tissue blood flow
c. Partial pressure difference between arterial blood and tissues.
Positive
feedback
loop

67. Volatile Anaesthetics59
Tissues are divided into 4 groups depending on the blood flow.
1. Vessel rich group (brain, heart, kidney, endocrine organ)
2. Muscles
3. Fat
4. Vessel poor group (bone, ligament, teeth, cartilage).
Out of these four groups vessel rich group gets the largest share of cardiac output
(around 75%) and that is why large amount of anaesthetic is delivered to these tissues.
They achieve a rapid equilibrium with arterial blood (approx 8 min). Uptake by
vessel rich group is minimal so it does not influence the alveolar concentration. Muscle
group has lower perfusion in relation to tissue mass, so equilibrium takes place after
2-4 hours of induction depending upon tissue/blood partition coefficient. Once
equilibrium with muscle is complete, only fat continues to store anaesthetic agent.
Fat has higher affinity for anesthetic agent than muscles. It takes days to fill. Absence
of significant blood flow to vessel poor group means that these tissues do not take
part in uptake process.
VENTILATION
Increasing the ventilation means increasing the quantity of anaesthetic agent being
deposited in the alveoli.
The net effect is a more rapid rate of increase in F
A
(alveolar concentration) towards
the F
I
(inspired concentration). Thus faster induction of anaesthesia.
Volatile agents depress ventilation and thus set in a negative feedback loop in this
regard.
Volatile agent
Depression of ventilation
Negative Decreased delivery of anaesthetic to the alveolus
feedback
loop
F
A
falls (takes longer time for equilibrium with F
I
)
Delayed induction
Another point of concern is that increasing the minute ventilation will cause CO
2
washout and thus lead to hypocapnia. Hypocapnia, if significant, will lead to cerebral
vasoconstriction and decreased delivery of anesthetic to the brain.
Ventilation affects the alveolar concentration of soluble agents more than insoluble
agents.
CONCENTRATION EFFECT
It means that increasing the inspired concentration of an anaesthetic agent increases
its rate of rise of alveolar concentration i.e. F
A
/F
I

68. 60Comparative Pharmacology for Anaesthetist
In other words greater the inspired concentration (F
I
), more rapidly alveolar
concentration, (F
A
) approaches inspired concentration (F
I
). It is caused by two factors
A. Concentrating effect
B. Augmentation of tracheal inflow
A. Concentrating Effect
This effect is more significant with nitrous oxide as it can be used in much higher
concentration. Nitrous oxide is more soluble in blood than nitrogen. When a patient
is given an anesthetic mixture containing N
2
O; some part of nitrous oxide is absorbed
in the pulmonary vasculature. As a result total volume of gas in the alveolus diminishes
and fractional concentration of anaesthetic mixture increases.
B. Augmentation of Tracheal Inflow
Loss of alveolar total gas volume due to absorption (uptake) of nitrous oxide will
cause more anaesthetic mixture to be filled in from the airways into the alveolus.
This will cause further rise in alveolar concentration of anaesthetic mixture.
SECOND GAS EFFECT
Increasing the concentration of nitrous oxide augments not only its own uptake but
also of concurrently used volatile anesthetic. This is called second gas effect.
Nitrous oxide
Augments its own alveolar concentration
Concentrating effect
Augments the alveolar concentration
of another volatile anesthetic
simultaneously used (eg halothane)
Second gas effect
Example
Suppose the anaesthetic gas mixture contains 2 percent second gas (2 molecules), 18
percent oxygen (18 molecules), 80 percent N
2
O (80 molecules)
Alveolar concentration of anaesthetic mixture = 2 percent – second gas
18 percent – O
2
80 percent – N
2
O
As seen in the diagram below, concentration of second gas changes from 2 to 3.4
percent after absorption of N
2
O. This is called as second gas effect. After absorption

69. Volatile Anaesthetics61
of 40 molecules of N
2
O, its concentration does not decreases by 50 percent but comes
to 67 percent from 80 percent (concentrating effect). Due to tracheal flow, it again
increases to 72 percent.
C. Factors Affecting Arterial Concentration
Effects of Shunts
A right to left shunt causes venous blood to mix with arterial blood without being
exposed to anesthetic in the alveoli. This dilutional effect of right to left shunt causes
decrease in partial pressure of anaesthetic in arterial blood. So we conclude that rate
of induction of anaesthesia is slowed with right to left shunt.
A left to right shunt has exactly the opposite effect. It causes re-exposure of the
arterial blood to alveolar ventilation and anaesthetic agent. As a result partial pressure
of anesthetic in the blood rises. These shunts have little clinical impact.
Effect of Dead Space
Increase in dead space increases the difference between alveolar partial pressure of
anesthetic and the partial pressure of anesthetic in the arterial blood. [Note- That
dead space is the area which is ventilated but not perfused].
Rate of induction is not affected provided minute ventilation remains the same.
FACTORS AFFECTING RECOVERY FROM INHALATIONAL ANAESTHESIA
A. Solubility and Duration of Anaesthesia
In simple words, prolonged duration of anaesthesia will hinder recovery from
anaesthesia due to soluble agents (e.g. isoflurane, halothane).
Duration of anaesthesia will have little effect on recovery if less soluble agents
are used. (eg sevoflurane, desflurane). The reason being very obvious, soluble agents
show higher uptake by the body, thus filing the fat and muscle reservoirs.
More the amount of drug stored in the reservoir, longer the duration required to
empty them. Thus prolonged anaesthesia will prolong recovery from soluble agents.

70. 62Comparative Pharmacology for Anaesthetist
B. Metabolism
Removal of anaesthetic agent from the body is via exhalation, biotransformation and
transcutaneous loss. Therefore, metabolism also contributes to removal of anaesthetic
agent from the body along with alveolar ventilation, and hastens recovery. However
this pathway of elimination plays important role with halothane and methoxyflurane
only.
Both these drugs undergo extensive metabolism in liver as discussed later. This is
in contrast to rate of induction of anaesthesia which is not influenced by metabolism
even for drugs like halothane and methoxyflurane.
The basic difference between induction and recovery is that we can increase the
speed of induction by increasing the inspired concentration of inhaled anesthetic and
thus overcome the effect of solubility, but rate of recovery cannot be increased as
inspired concentration cannot become less than zero. Once the drug is inside the
body it will take its own time to come out.
Another point of emphasis is that, at the beginning of induction, all the tissues
have same anaesthetic partial pressure i.e. zero; while during the recovery partial
pressure are variable in different tissues. At the beginning of recovery vessel rich
group has partial pressure in equilibrium with alveolar partial pressure. Anaesthetic
partial pressure of inhaled anesthetic in muscles equilibrates with alveolar partial
pressure only after 2-4 hours of anaesthesia. Fat continues to take up anaesthetic
unless the alveolar partial pressure falls below partial pressure in fat. Thus muscle
and fat act as reservoirs of anaesthetic agent. More the anaesthetic stored in them
more time will be required for elimination.
PHARMACODYNAMICS
Mechanism of Action of Inhalational Agents
Many theories have been proposed to explain the mechanism of action of inhalational
agents but exact site of action macroscopic as well as microscopic is still not clear.
1.Unitary hypothesis: According to this theory, all inhaled anesthetics have a common
mechanism of action which is probably by interaction with a specific molecular
structure in CNS.
The property that correlates most with anesthetic potency is lipid solubility.
Therefore binding site of inhaled anaesthetic should be HYDROPHOBIC.
This theory is supported by Meyeroverton rule which states that product of
anesthetizing partial pressure and lipid solubility as measured by oil gas partition
coefficient is constant for all inhaled anesthetics.
It has been proposed that anesthesia occurs when specific number of inhaled
anaesthetic molecules attach themselves to a specific hydrophobic site in brain. Note
that number of molecules is important not the type of molecule.
Exception to this theory
•Enflurane and Isoflurane are isomers with same lipid solubility but different
potencies.

71. Volatile Anaesthetics63
•Certain lipid soluble compounds are convulsants rather than being anaesthetic
agents.
•Certain volatile lipid soluble polyhalogenated agents lack anaesthetic property.
2.Volume Expansion hypothesis: It can be explained by following flow chart
Specific number of anesthetic molecules
Bind with hydrophobic site in brain
The hydrophobic site expands so that its
volume exceeds a critical volume
Anesthesia
Points in favour of the hypothesis
•Increasing the pressure reverses many anaesthetic effects
Points against the hypothesis
•Not all lipid soluble agents are anaesthetics
•Decreasing the temperature should increase the anaesthetic requirement while
exactly the reverse is true. MAC reduces in hypothermia.
3. Various theories have been put forward to explain the site of action of inhaled
anaesthetics. They can be summarized in a flow chart. There are studies in favour
and against of most pathways.
Flow chart showing various theories of mechanism of action of volatile anaesthetics

72. 64Comparative Pharmacology for Anaesthetist
Recent data suggest that most likely mechanism of action of volatile anaesthetics
is via interaction with membrane proteins leading to opening/closure of ligand gated
ion channel. These ligands are various inhibitory neurotransmitters found in brain
(e.g. Glycine, GABA etc.)
Minimum Alveolar Concentration (MAC)
The alveolar concentration of an inhaled anaesthetic that prevents movement in 50
percent patients in response to a standardized stimulus is minimum alveolar
concentration of that agent.
Standardized stimulus in human – initial surgical skin incision.
MAC concept describes a concentration versus response relationship.
MAC awake – MAC of anaesthetic that allows patient to open his/her eyes on
verbal command during emergence from anaesthesia.
• MAC intubation – MAC of anaesthetic that allows intubation without movement
or coughing by the patient.
• MAC BAR – MAC of anaesthetic that inhibits increase in concentration of
catecholamines levels in venous blood in response to skin incision.
MAC intubation > MAC skin incision > MAC laryngoscopy
Advantages of MAC Concept
• It is an indirect measure of brain tissue concentration of anesthetic.
• Potencies of different volatile anaesthetics can be compared.
• Produces a standard for experimental studies.
MAC is roughly additive e.g. 0.5 MAC Halothane + 0.5 MAC Enflurane = Same
CNS depression as 1.0 MAC Isoflurane.
However, effect on other organs is different e.g. 0.5 MAC halothane causes more
myocardial depression than 0.5 MAC isoflurane.
Roughly 1.3 MAC of any anaesthetic (e.g. for isoflurane 1.3 × 1.2 = 1.56 percent)
prevents movement in 95 percent of patients (approximation of ED
95
of other drugs).
Factors Affecting MAC in Humans
Effect of MAC Factors
Decrease • Hypo/hyperthermia
• Old age
• Acute alcohol intoxication
• Hypoxia (PaO
2 <40 mmHg)
• Hyponatremia (dilutes CSF sodium)
• Narcotics, benzodiazepines, barbiturates, ketamine, local anaesthetics
(intravenous) except cocaine
Increase • Chronic alcoholism
• Young age (MAC is maximum at 6 months of age)
No change • Duration of anaesthesia
• Sex,hypercarbia and hypocarbia

73. Volatile Anaesthetics65
MAC in pregnancy decreases progressively (at term by 35-40%). It returns to
normal by III day after delivery. Changes in progesterone and endogenous opiate
levels have been implicated.
MAC is reduced by 4 percent per decade of age over 40 years.
MAC Values
Agent Neonate Infant Small children Adult
Halothane 0.87 1.1-1.2 0.87 0.75
Sevoflurane 3.2 3.2 2.5 2.0
Isoflurane 1.6 1.8-1.9 1.3-1.6 1.2
Desflurane 8-9 9-10 7-8 6.0
Enflurane - - - 1.7
PHARMACODYNAMICS
CVS effectsHalothane Enflurane Isoflurane Desflurane Sevoflurane
1. Myocardial All agents depress contractility in normal ventricular myocardium in following contractilityorder Halothane = Enflurane > Isoflurane = Desflurane = Sevoflurane.
Normal heartThis is due to inhibition of Ca
+2
transit by affecting both L and T type Ca channel.
Other mechanisms include inhibition of Na
+
-Ca
+
exchange and reduction
of intracellular Ca
+2
concentration.
Diseased heart Volatile anesthetics produce beneficial decrease in preload and afterload in patients
with heart failure and coronary artery disease. Thus during moderate LV dysfunction despite concomitant reduction in contractility, there is simultaneous improvements
in LV loading condition and relative maintenance of cardiac output.
2. Systemic This drug is a SVR is All these three drugs cause fall in SVR due to
vascular cutaneous and decreased potent vasodilator action. Cutaneous and
resistance cerebral skeletal blood flow is increased
vasodilator but
calculated SVR
does not change
significantly
due to
vasodilation in
some beds and
vasoconstriction
in other beds
3. Heart Rate Heart rate is Increased due Increased in No or minimal
decreased due to baroreceptorresponse to increase in heart
to direct effect activation in vasodilation rate. Tachycardia
on SA node. response to similar to occurs only when
Normal vasodilation. Itisoflurane used in > 1.5 MAC
response to also has mild β concentration.
hypovolemia agonist Can prolong
Contd...Contd...

74. 66Comparative Pharmacology for Anaesthetist
i.e. tachycardia properties. QT interval
is absent due to When concentration of
baroreceptor isoflurane and desflurane
reflex blockade. is increased rapidly, marked
tachycardia and rise in
blood pressure occurs due to
rise in catecholamine levels.
This response is more with
desflurane than isoflurane.
Young adults are more prone.
It can be attenuated by
opioids, β blocker and clonidine
4. Blood Decreased due Decreased due Myocardial contractility is preserved but
pressure to decreased to decreased decrease in systemic vascular resistance due to
heart rate andcontractilityvasodilation causes fall in mean arterial pressure.
contractility. and Cardiac output is maintained due to reflex increase
There is doseconcomitant in heart rate with isoflurane and desflurane. There
dependent fallvasodilation is minimal or no reflex tachycardia with sevoflurane
in cardiac that is why cardiac output is not so well
output and maintained with it.
blood pressure
5. Cardiac Reduction in afterload as well as preload along with decreased contractility
Protection preferentially alter myocardial O
2
demand supply ratio. During reperfusion
injury there is less of myocardial damage.
6. Adrenaline Dose of epinephrine necessary to cause cardiac arrhythmias is decreased by
inducedvolatile anesthetics. This effect is maximum with halothane and minimal to nonexistent
arrhythmias with Isoflurane, desflurane and sevoflurane. Dose of adrenaline above 1.5 µg/kg
should be avoided with halothane. Mechanism is through slowing of SA node
discharge and prolongation of His-purkinje and ventricular conduction time. This
makes the heart prone for re-entry arrhythmias. Adrenaline upto 4.5 µg/kg can be
used with other agents.
7. CoronaryMild coronary vasodilation occurs with all drugs except sevoflurane. Halo > Iso >
artery Des. This is due to inhibition of Ca
+2
influx. Isoflurane preferentially dilates small
vasodilation coronary resistance vessels to greater extent than the larger conductance vessels as a
result maldistribution of blood from ischemic to nonischemic areas can occur. This is
called as coronary steal syndrome. Changes in systemic blood pressure and heart
rate is clinically more important for development of ischemia than specific agent
used.
RS effects
i. Broncho- Best broncho- Pungency and
dilation anddilator among airway irritation
airways all the available during desflurane
volatile agents induction manifests
as salivation,
Contd...
Halothane Enflurane Isoflurane Desflurane Sevoflurane
Contd...

75. Volatile Anaesthetics67
coughing
laryngospasm,
breathholding.
This makes it
unsuitable for
pediatric patients.
All volatile agents cause bronchodilation by directly depressing smooth muscle
contractility and inhibiting reflex neural pathways. Nitric oxide and prostaglandins
may mediate bronchodilation. Isoflurane is preferred in status asthmaticus as risk of
arrhythmias is less.
ii. MucociliaryVolatile anaesthetics decrease rate of mucus clearance by decreasing cilia beat frequency
clearance or altering the characteristics of mucus. So after prolonged exposure to these agents
intraoperatively, chest physiotherapy for enhancing clearance of secretions from
airways must be initiated in postoperative period.
iii. MinuteAll volatile agents cause decrease in tidal volume. Breathing becomes rapid and
ventilation shallow. The resultant decrease in minute ventilation is partially offset by a
concomitant increase in respiratory rate. The relative increase in PaCO
2
with
different volatile agents is as follows
(a) at MAC < 1.24
Enflurane > Desflurane = Isoflurane > Sevoflurane = Halothane
(b) at higher MAC ventilatory depression is similar among all agents
Note: Isoflurane does not increase Respiratory rate as much as other agents.
Mechanism of ventilatory depression:
Central Mechanism: Volatile agents cause dose dependant depression of ventilatory
drive due to medullary center depression.
Peripheral Mechanism: Halothane and possibly other agents interfere with intercostals
muscle function. This action destabilizes the chest wall during spontaneous breathing.
The chest wall collapses inward during inspiration leading to decrease in lung volumes.
Chest wall expansion in response to chemical stimulation is also hampered.
Effect of Duration of anesthesia on Minute Ventilation: During prolonged administration
of volatile anesthetic (ie > 5 hrs), the respiratory depressant affect is apparently
overcomed. This manifests clinically as return of PaCO
2
levels back towards normal
after a few hours of continuous use of volatile agent.
iv. Response All volatile agents cause dose dependant decrease in ventilatory response to
to hypoxiahypercarbia and hypoxemia. Response to hypoxia is depressed even at subanaesthetic
and concentrations (upto 0.1 MAC of inhalational agent). The only exception being
hypercarbia desflurane. At 1.1 MAC complete abolition of this response occurs. This effect is
mediated via action of inhalational agents on peripheral chemoreceptors and it
appears rapidly i.e. within 30 sec. of starting an inhalational agent. The importance
of this depressive phenomenon is more profound in patients who depend on a
hypoxic drive to maintain their ventilation (eg chronic respiratory failure). They
fail to maintain normal ventilation while spontaneously breathing volatile agent.
Contd...
Halothane Enflurane Isoflurane Desflurane Sevoflurane
Contd...

76. 68Comparative Pharmacology for Anaesthetist
Volatile agents depress ventilatory response to hypercarbia but this effect is not
seen at subanesthetic doses. This is mediated via central chemoreceptors. It is
important to note that N
2
O depresses ventilatory response to hypoxia but there is
no major change in PaCO
2 levels, suggesting that substitution of N
2O for a portion
of volatile anesthetic would result in less depression of ventilation as a lower dose
of volatile agent will be required.
CNS Effects
i. Cerebral There are two effects on CBF. Cerebral vasodilation causes increase in cerebral blood
blood flow flow while decrease in cerebral metabolic rate (CMR) causes decrease in cerebral
blood flow. Out of these two effects vasodilation predominates and there is global
increase in CBF with volatile agents. Halothane >> En > Iso > Sevo = Des
ii. CMR All agents cause reduction in CMR. The degree of CMRO
2
reduction is less with
(Cerebral halothane as compared to other agents. Remember that an active brain requires
metabolic more oxygen while a sleeping/anesthetized brain requires less oxygen. Halothane
rate) produces relatively homogenous suppression of CMR while Isoflurane causes greater
reduction of CMR in neocortex than subcortex.
iii. ICP (Intra- ICP is raisedIt causes Drug induced Same as Same as isoflurane
cranial due to increase invasodilation isoflurane but seizures have
Pressure)vasodilation CBF as well tends to raise been reported in
and increased as increased the ICP but the children during
cerebral blood CSF produc- effect can be induction when
flow. The effect tion. CSF offset by sevoflurane is
on ICP can be absorption is induction of used in high
offset by also hampered hypocapnia concentration.
inducing resulting intosimultaneously
hypocapnia a sustained rise with introduction
few minutes in ICP. of isoflurane.
before starting Moreover its [Remember that
the drug tendency to CO
2
reduction
produce sei- should be
zure like instituted
changes in before exposure
EEG pattern to halothane.]
when used in Epileptogenesis
1.5-2MAC dose is not a clinical
makes it unfit concern with
for use in isoflurane.
neurosurgery.
Epileptiform
activity is
increased in
the presence
of hypocapnia.
Contd...
Halothane Enflurane Isoflurane Desflurane Sevoflurane
Contd...

77. Volatile Anaesthetics69
Role of volatile agents in neurosurgery: They are used in sub-MAC concentrations as a
part of balanced anesthesia. Vasodilation induced increase in ICP can be offset to
some extent by institution of hypocapnia. In patients with large tumor mass, unstable
ICP, vomiting with papilledema it is safer to give total intravenous anesthesia.
iv. CO
2
CO
2
responsiveness of the cerebral circulation is well maintained during
responsive- anesthesia with all the volatile anesthetic. Cerebral autoregulation in response
ness and to blood pressure changes is well maintained with lower concentration (MAC)
cerebral isoflurane but not with halothane. At higher concentration autoregulation in
autoregu- response to blood pressure changes is hampered by all agents.
lation
Renal effectReduced renal blood flow, GFR, urinary output occurs with all volatile agents. This is
usually secondary to cardiovascular sympathetic and endocrine changes. Preoperative
hydration attenuates or abolishes many of these changes.
i. Fluoride Fluoride is liberated during metabolism of fluorinated anesthetics. Methoxyfluorane
induced is most notorious in this respect. Fluoride induced renal damage manifests as
nephro- vasopressin resistant polyuric renal insufficiency and clinical features include polyuria,
toxicity hypernatremia, hyperosmolality, increased BUN and serum creatinine.
Halothane isEnflurane It is not Extremely Undergoes
not nephrotoxicdefluorination associatedresistant tomoderate
because it does may occasio-with fluoride defluorination. defluorination
not undergo nally result induced No evidence (similar to
significantinto mild nephrotoxity of enflurane).
defluorination renal dysfunc- in most nephrotoxicity Enzyme
under normal tion. Rate ofclinical induction causes
conditions. enflurane situation. increase in
Under hypoxic metabolism isHowever when sevoflurane
conditions and almost similar isoflurane is metabolism and
in the presence to sevofluraneused for fluoride
of enzyme metabolism prolonged period production.
inducers but intra-renal and in patients
defluorination production with impaired
can occur but of fluoride renal function,
it is never is more with one must
significantenflurane, remain cautions.
enough to leading to
cause renal more renal
damage damage with
enflurane
possibly.
Contd...
Halothane Enflurane Isoflurane Desflurane Sevoflurane
Contd...

78. 70Comparative Pharmacology for Anaesthetist
Compound – Sevoflurane is
A induced degraded by CO
2
nephro- absorbent
toxicity (Sodalime/
Baralyme) into
compound A and
compound B. Out
of these
compound A is
the major
degradation
product and is
nephrotoxic.
Factors increasing
production of
compound A are
low flow, fresh
absorbent, high
absorbent
temperature, use
of baralyme and
high sevoflurane
concentration.
Fresh gas flow
less than 2L/min
should be
avoided.
Other effects -All volatile anaesthetics relax skeletal muscles and potentiate neuromuscular
blockade. Isoflurane increases skeletal muscle blood flow.
- Volatile anesthetics including the newer agents can trigger malignant hyperthermia
in genetically susceptible patients. Halothane is the most potent trigger.
- They rapidly cross the placenta to enter the fetus, but these drugs are exhaled by
new born rapidly
- They produce similar and dose dependant decrease in uterine muscle tone.
Contd...
Halothane Enflurane Isoflurane Desflurane Sevoflurane

79. Volatile Anaesthetics71
METABOLISM
Halothane Enflurane Isoflurane Desflurane Sevoflurane
20-40 percent 1-8 percent of 0.2 percent 0.02 percent 1 to 5 percent of
of the absorbed the dose is of the of the the absorbed
halothane is slowly administered administered sevoflurane
metabolized inmetabolized dose is slowly dose is undergo
liver. in liver to non metabolised metabolised tometabolism.
(i) halothanevolatile in liver. Trifluoroacetic Sevoflurane
oxidative fluorinated Isoflurane acid which is
cyt P450 compounds. Liver cyt p450 excreted via
metabolism Kidneys. Resthexafluoro-
is exhaled out isopro panol
via lungs.
Trifluoro Trifluoro under goes
acetyldehyde acetyldehyde conjugation
Trifluoro Trifluoro
acetylchloride acetylchloride
excretion
Trifluoroacetic Trifluoroacetic
acid [MAJOR acid
END PRODUCT]
(ii) halothane
Reductive hypoxic
metabolism conditions
Br
–
, F
–
CDE, DBE
COMPOUNDS
Commercial It is a clear, Clear color-Clear It boils at It is slightly more
Preparationcolorless less liquidcolorless room soluble in blood
liquid, that with sweet liquid temperaturethan desflurane. It
should be smell. with pungent at high is non pungent
protected fromCommercial smell non- altitudes and alveolar
light as itpreparationinflammable. that is why concentration
undergoes has no Commercial special rises rapidly. It is
spontaneousstabilizers orpreparationvaporiser is an excellent agent
decompositionpreservatives. has no designed for for induction of
on exposure to Should be stabilisers or desflurane.pediatric patients.
light. It is protected frompreservatives.Due to its low It is a colorless,
stored in sunlight. It is readilysolubility in clear liquid and
amber color readily soluble soluble in blood and commercial
bottles. in rubber. rubber
Contd...

80. 72Comparative Pharmacology for Anaesthetist
Thymol 0.01% body tissues preparation has
percent is used there is a rapid no additives.
as preservative wash in and
to retard wash out of
spontaneous the drug. That
(oxidative) is why there
decomposition. is fast
Non inflammable. induction and
Readily soluble fast recovery.
in rubber. Does It is a clear
not attack metals colorless liquid
in absence of and commer-
water vapor cial preparation
has no stabilizers
or preservatives.
PHYSICAL PROPERTIES
Molecular 197.4 184.5 184.5 168 200
weight
Boiling point 50.2
o
C 56.5
o
C 48.5
o
C 23.5
o
C 58.5
o
C
Blood/gas 2.4 1.9 1.4 0.42 0.65
Coefficient
Vapor 283 175 240 681 160
pressure
mm Hg
at 20
o
C
Chemical halogenated halogenated halogenated halogenated halogenated
nature hydrocarbon methyl ethyl methyl, ethylether ether
ether whichether
is a geometric
isomer of
isoflurane
NITROUS OXIDE
Manufacture
Ammonium nitrate
245-270
o
C
Nitrous oxide + various impurities
Contd...
Halothane Enflurane Isoflurane Desflurane Sevoflurane

81. Volatile Anaesthetics73
Storage/Commercial Preparation
Nitrous oxide cylinders contain the drug in liquid as well
as gaseous form. The cylinder shows a constant pressure
until all the liquid is evaporated to gaseous form. At this
time pressure change becomes directly proportional to rate
at which gas moves out of the cylinder. Therefore if we
want to know the quantity of nitrous oxide in a cylinder it
should be weighed. Nitrous oxide cylinders should be kept
vertical while in use so that liquid phase of the drug remains
at the bottom.
Properties
It is colourless, sweet smelling gas that is nonflammable
but supports combustion
Boiling Point - 88
o
C
Critical temperature 36.5
o
C
Critical pressure 71.7 atmos
MAC 105
Blood/gas solubility coefficient 0.47
Mechanism of Action
Modulation of enkephalins and endorphins within central nervous system.
Pharmacodynamics
CVS: N
2
O has two effect on cardiovascular system. Indirect action is via stimulation
of sympathetic nervous system, though it is a directly acting myocardial depressant.
The combined effect results into modest increase in cardiac output and heart rate
when N
2
O is used in 50 to 70 percent concentration. It also causes increase in
pulmonary vascular resistance and right atrial pressure.
When used with opioids and in patients with cardiac disease , reduction in cardiac
contractility occurs along with fall in blood pressure.
RS: Tachypnea with decrease in tidal volume occurs. It depresses ventilatory response
to hypoxia but minimal change in resting PaCO
2
and minute ventilation is seen.
CNS: It is a powerful analgesic when used in concentrations > 20 percent. It is a CNS
depressant and causes mild elevation of intracranial pressure due to increase in
cerebral blood flow and CMRO
2
.
Other Effects: Activates CTZ and vomiting centre in medulla. The gas does not cause
skeletal muscle relaxation. It does not trigger malignant hyperthermia and can be
safely used in susceptible individuals.

82. 74Comparative Pharmacology for Anaesthetist
N
2
O
Oxidation of cobalt atom in vitamin B
12
Inhibition of Vit B
12
dependent enzymes
(methionine synthetase, thymidylate synthetase)
Hampered DNA synthesis
Megalo blastic anemia, sub acute combined degeneration of cord
Bone marrow depression, agranulocytosis
Metabolism, Toxicity
It is not metabolized by enzymes in human tissue. Less than 0.01 percent undergoes
metabolism by anaerobic bacteria in GIT
Some reports indicate teratogenic affect of nitrous oxide.
NITROUS OXIDE AND CLOSED GAS SPACES
Body cavities contain air in them. Nitrogen is the main component of air (78 percent).
Blood gas partition coefficient of N
2
is 0.015.It means than at equilibrium, body cavity
will contain 1000 molecules while blood will contain 15 molecules of N
2
.
15 molecules 1000
of equilibrium molecules
N
2 N
2
Blood Body space
Blood gas partition coefficient of N
2
O is 0.47 ie at equilibrium, 1000 molecules will
be present in (air) body cavity and 470 in blood.
1000
470 molecules molecules
of N
2
ON
2
O
Blood Body space
When blood containing N
2
O comes in contact with our body cavity, movement of
N
2
O inside cavity is more rapid than movement of N
2
into blood. This difference is
due to differences in solubility of the two gases.

83. Volatile Anaesthetics75
Clinical Significance
Volume of gas Volume of
diffusing into cavity gas diffusing out
CAVITY
Compliant cavity Non compliant cavity show
enlarges increase in pressure
e.g. pleural or peritoneal cavity e.g. middle ear
bullae rupture and pneumothorax displacement of graft in middle ear surgery
Use of 50 percent N
2
O might double the cavity while a 75 percent N
2
O concentration
might increase the cavity size three to four times.
DIFFUSION HYPOXIA
At the end of general anesthesia, N
2
O is switched off so that; inspired gas mixture
change from N
2
O + O
2
to N
2
+ O
2.
As a result N
2
O starts diffusing out of blood into alveoli while N
2
diffuses into
blood.
Due to difference in solubilities of the two gases N
2
O diffuses out more rapidly.
This dilutes other gases present in alveoli and relative concentration of O
2
falls. It is
termed as diffusion hypoxia.
Clinical Significance
100 percent oxygen should be given for at least 5-10 minutes after switching off N
2
O
in order to overcome the relative fall of O
2
concentration in the alveoli during recovery
from general anaesthesia.

84. Intravenous Induction Agents4
COMMERCIAL PREPARATION
ThiopentonePropofolKetamineMidazolamEtomidate • Available as sodium salt
mixed with 6 percent by
weight anhydrous Na
2
CO
3
.-
It is reconstituted inWater or
NS to form a highly alkaline
solution with pH around
10.5.
•Na
2
CO
3
maintains alkalinity-
of barbiturate solutions in the
presence of atmospheric CO
2
• Highly alkaline nature of the
solution prevents bacterial
growth
• For intravenous injection
only 2.5 percent thiopentone
solutions are used. 5 percent
and 10 percent solutions can
be given rectally.
• In powder form the drug is
stable Indefinitely at room
temperature. Solutions are
stable for 1 week if
refrigerated.
• Propofol is
available as 10, 12,
20, 25 and 50 ml
vials and
ampoules with 1
and 2%
concentration.
Commercial
preparation
contains
propofol,soyabean
oil, glycerol and
lecithin
• SPIVA is the-
commercial
preparation
withless lipid
contents
compared to
others
10 ml vial and 1
ml ampoules
containing 50
mg/ml of.-
Ketamine
hydrochloride
are available
Benzethonium
chloride 0.01
percent w/v is
the
preservative-
used in vials
while ampoules
are preservation
free.
• 5 ml and 10
ml vials
containing 1
mg/ml of
midazolam
hydrochloride
are available.
Vials have
benzethonium
chloride 0.01
percent w/v
as
preservatives.
• 1 ml ampoule
with 5 mg/ml
of midazolam
hydrochloride
are also
available.
Ampoules are
preservative
free.
• Propylene
glycol is the
preservative
used with
etomidate. Its
commercial
preparation
contains 2 mg/
ml of etomidate
and 35 percent
propylene-
glycol with
water.
• Propylene
glycol causes
mild hemolysis.
On prolonged
infusion it
causes problem
with body
osmolality.-
(solution
osmolality =
4640 mosm/l)

85. Intravenous Induction Agents77
STRUCTURE – ACTIVITY RELATIONSHIP
ThiopentonePropofolKetamineMidazolamEtomidate Barbiturates are derived from
barbituric acid which itself is formed
from urea and malonic acid.
Urea + malonic acid
Barbituric acid
Barbiturates
Oxy B Thio B (Sulphur
(Oxygen at C
2
)
at C
2
)Thiopentone,
pentobarbital
(B = Barbiturates)
• Addition of sulphur at C
2
position
causes increase in lipid solubility,
rapid onset and short duration of
action as compared to oxy-
barbiturates
It is an alkyl phenol
derivative. Chemically it
is 2, 6, di, isopropyl
phenol.
As we know phenols are
oils at room tempera-
ture. Propofol is there-
fore insoluble in aqueous
solution but highly lipid
soluble.
It is a phencyclidine
derivative. It exists as
S +and R – optical
isomers. S+ isomer is
3-4 times more potent
than R – form. It is also
associated with less
side effects and has
faster clearance. Only
racemic mixturesare
commercially available
at present, however
research interest on
single S + form is
growing.
It is an imidazoline
benzodiazepine
derivative with
characterstic pH
dependent solubility.
The imidazoline ring
opens at pH < 4 andthe
drug becomeswater
soluble. At body pH
(pH > 4) the ring closes
making the drug more
lipid soluble.
It is a carboxylatedimidazole
derivative.
• Length of side chain at C
5
position
determines the potency and
duration of action. Longer and
branched chains give greater
hypnotic activity to the compound
• Addition of methyl group at
position 1 results into a drug (such
as methohexital) with rapid onset,
short duration of action along with
increased incidence of excitatory
phenomenon e.g. Myoclonus.

86. 78Comparative Pharmacology for Anaesthetist
MECHANISM OF ACTION
ThiopentonePropofolKetamineMidazolamEtomidate GABA facilitatory action
Barbiturates bind to GABA
receptors ( β subunit) and prolong
the duration of binding of GABA
with its receptor. This leads to
prolonged opening of Cl
-
channel
GABA mimetic action
At high concentration barbiturates
directly cause opening of Cl
-
channel and cell membrane
hyperpolarisation
Mechanism of action
is mediated via GABA
as well as NMDA
subtype of glutamate
receptor.
Depresses some
parts of thalamus
and neo Cortex
while stimulates
limbic system. This
leads to what is
called as dissociative
anesthesia. It
interacts with
NMDAand
probablyopioid
receptors.
Benzodiazepine
receptors are located-
on n
2
subunit of
GABA
A
receptor.
Activation of
Benzodiazepine
receptor leads to
enhanced chloride-
gating and membrane
hyperpolarization.
Not clearly known,
probably GABA
mediated.

87. Intravenous Induction Agents79
PHARMACOKINETICS
ThiopentonePropofolKetamineMidazolamEtomidate • IV administration of
thiopental
Distribution to vessel rich
group (e.g. brain)
Induction of anesthesia
Redistribution to less
well perfused tissue
(muscle)
Termination of induction
– Awakening
Redistribution to poorly
perfused tissue (fat)
Elimination by
metabolism in liver
Metabolites excreted via
kidneys.
• Highly lipid soluble
drug which is
distributed rapidly to
the vessel rich group.
Action terminates due
to redistribution.
• 98 percent plasma-
protein bound.
• Metabolised in liver to
inactive glucuronide
and sulphate
conjugates and
corresponding quinol.
Extrahepatic
metabolism also
present. Liver and renal
impairment do not
affect the metabolism
significantly.
• Metabolites are inactive
and its rapid clearance
from the plasma allows
the drug to be
administered as
continuous infusion
without excessive
cumulative effect.
• Clearance 18 – 40 ml/
kg/min
•t
1/2
α = 2.5 minutes
β = 55 minutes
• It is highly lipid soluble
drug with distribution
pattern similar to
thiopentone.
• Oral bioavailability is
around 20 percent
• Metabolized in liver to
hydroxynorketamine
(metabolite II) and
Norketamine
(metabolite I). Nor is 20
– 30 percent active as
compared to parent
compound
• Clearance 12–17 ml/
kg/min
• Alteration in hepatic
blood flow effect clea-
rance e.g. halothane
decreases clearance.
• Causes acceleration of
its own metabolism by
enzyme induction. This
is probably the
mechanism behind
tolerance to its
analgesic effect after
repeated doses. (e.g.
burn patients)
• The drug first distri-
buted to vessel rich
group and then to fat.
• Oral bioavailability is 44
percent and bio-
availability via IM route
is 80 to 100%.
• It is 96% plasma protein
bound. Patients with
low albumin may show
enhanced response.
• Metabolized in liver to
hydroxy midazolams.
1-hydroxy midazolam
possess 20–30% activity
of the parent com-
pound. It is normally
cleared faster than
parent compound but
can cause increased
sedation in patients
with renal impairment.
• Clearance 6–11 ml/
kg/min (most rapid
among all
benzodiazepines)
• Hepatic clearance of
midazolam may be
decreased with drugs-
like erythromycin and
calcium channel
blockers.
• Awakening after single
bolus dose of etomidate
is more rapid than
thiopentone.
• Prompt awakening after
an induction dose is due
to redistribution. Rapid
metabolism may also
play role.
• The drug is 76 percent
protein bound
• Metabolised inliver via
ester hydrolysis into
inactive metabolites
which are excreted in
urine. 2 percent of the
drug is excreted
unchanged in urine.
• Non-cumulative with
repeated administration.
• Clearance 18 – 25 ml/kg/
min
• Drugs decreasing hepatic
blood flow may prolong
elimination half life.
Contd...

88. 80Comparative Pharmacology for Anaesthetist
Contd... ThiopentonePropofolKetamineMidazolamEtomidate • Metabolites are not
active
• Clearance is 2.5 to 4
ml/kg/min.
• It is 65–80 percent
protein bound.
(mainly albumin).
Conditions associated
with decreased
albumin e.g. cirrhosis,
result in increased free
drug level. Thus dose
requirement is
reduced.
• It remains 61 percent
unionized at physio-
logical pH. Increasing
the pH byhyperventi-
lation increases the
unionized (diffusible)
fraction and will
therefore enhance the
effects of a given dose.
• Dose should be
reduced in elderly
because of a lower
cardiac output and
capacity to
compensate for
circulatory changes
produced by the
durg.Same as is for
hypovolemic patients.
• Occasional appearance
of green urine in
patients receiving
propofol is due to
quinol metabolite.
• Context sensitive half
life is around 25 minutes
after 3 hrs of infusion.
Propofol
98% plasma protein bound
Metabolism
HepaticExtra hepatic
Inactive metabolites
Excreted via kidneys.
• Repeated bolus doses
and infusions cause
accumulation
t
1/2
α = 10 minutes
β = 2 - 3 hours.
Ketamine
20 – 50% plasma
protein binding
N- demethylation and
hydroxylation
Hydroxy nor ketamine
nor ketamine
Excreted via kidneys
after glucuronide
conjugation.
• Clearance is also-
reduced in elderly
patients and critically
ill.
• elimination half life
t
½
β = 1.5 to 3.5 hrs.
44% Oral
IV
100% 80% IM
Bioavailability
Protein binding
(very high)
1 hydroxy midazolam
(20 – 30% activity)
Excreted
via kidneys
Prolongs sedation in
renal impairment
T ½
α1 (initial distribution half
life)
= 2.6 minutes
α2 (redistribution half life)
= 29 minutes
β (elimination half life)
= 75 minutes

89. Intravenous Induction Agents81
PHARMACODYNAMICS
Neurotransmitters in the Brain
Neurotransmitters in human brain can be classified broadly into two groups
i. small molecule, rapidly acting transmitters
e.g. norepinephrine, glycine, dopamine, acetylcholine, GABA, serotonin
ii. neuropeptides
e.g.Substance P
enkephalin
Thyrotropin releasing hormone
ACTH
Small molecule rapidly acting transmitters are involved in acute responses of the
nervous system. They are either inhibitory or excitatory.
i. acetylcholine – mainly excitatory
– some actions inhibitory
ii. Dopamine: - usually inhibitory
iii.Norepinephrine: - mainly excitatory
Some inhibitory effects
iv. GABA: - inhibitory
v. Glutamate: - excitatory
vi. Glycine: - inhibitory
vii. Serotonin: - inhibitor of pain pathways
Anesthetic agents act via potentiation or activation of these inhibitory or excitatory
pathways.
GABA (γγγγγ-AMINOBUTYRIC ACID)
GABA is the principal inhibitory neurotransmitter in human brain. GABA receptors
are of two types; GABA
A
and GABA
B
. Out of these two GABA
A
receptors are made
up of 5 subunits namely α, β, γ, δ and ρ. these subunits are proteins. They form a
complex to produce a chloride ion channel when they are inserted into cell membrane.
Activation of GABA
A
receptor leads to increased chloride conductance (Cl
–
) and
thus hyperpolarize the cell membrane. This reduces the excitability of neurons. Many
anesthetic agents act via GABA
A
receptors. There are specific binding sites present
on these receptors for various drugs eg. barbiturates, benzodiazepines etc.

90. 82Comparative Pharmacology for Anaesthetist
CENTRAL NERVOUS SYSTEM
ThiopentonePropofolKetamineMidazolamEtomidate 1. Produces unconscious-
ness with induction doses.
Subhypnotic doses may
cause increase in sensitivity
to pain (hyperalgesia). It
causes progressive suppres-
sion of cortical activity and
can finally lead to flat EEG
at high doses.
1. Unconsciousness occurs
with induction doses while
subhypnotic doses produce
amnesia and sedation. Does
not possess analgesic
properties.
1. Produces a dissociative
state along with amnesia
and profound analgesia. A
cataleptic state with eyes
open, nystagmus, saliva-
tion, lacrimation and main-
tenance of airway reflexes
which are non protective is
seen. Possess analgesic pro-
perties even at subanes-
thetic doses.
1. They possess anticon-
vulsant, hypnotic, anxiolytic
and sedative action on CNS.
Analgesia is not signi-
ficant. Produce anterograde
amnesia. Flat EEG is not
achieved.
1. Produces unconscious-
ness with reduction in CMR,
CBF, CMRO
2
and ICP.
No analgesic activity.
2. May activate seizure foci
in patients with epilepsy.
This feature is used for
mapping of foci in
neurosurgery before ablation.
3. Myoclonus is common
during etomidate induction.
2. Produces dose depen-
dent decrease in cerebral
metabolism, cerebral blood
flow and cerebral oxygen
requirement.
2. Produces decrease in
cerebral blood flow and
oxygen requirement.
2. Causes increase in CBF,
ICP and CMRO
2
2. Decrease CBF and
CMRO
2
3. Reduction in ICP is more
than MAP. Thus CPP
(cerebral perfusion pres-
sure) is well maintained.
[CPP = MAP – ICP]
4. IOP (introcular pres-
sure) is reduced by 40%
5. Produces retrograde
amnesia
6. Seizures refractory to
other anticonvulsants
respond to barbiturates.
7. Cerebroprotective action
against regional cerebral
ischemia but not global
ischemia.
8. It has greater sensitivity
for cerebral cortex and
reticular activating system.
3. In patients with raised
ICP, decrease in ICP is
associated with decrease in
CPP, therefore may not be
beneficial.
4. Decreases IOP more than
thiopentone
5. occasional involuntary
movements can occur
following induction.
6. Proconvulsant properties
are controversial. It has been
successfully used in control
of refractory seizures.
7. Its greatest advantage
over other agents is rapid and
complete awakening after
induction.
8. Possess antiemetic
action.
3. Causes increase in IOP.
Contraindicated in patients
with glaucoma.
4. Undesirable emergence
reactions are seen with keta-
mine. They occur at the time
of awakening and manifest
as unpleasant dreams,
aggressiveness, violence,
sense of floating. These
reactions are associated with
misinterpretation of visual
and auditory stimuli. They
occur mostly in 1st hour of
awakening and more com-
mon with large dose, fe-
males, increasing age. Mana-
gement includes benzodia-
zepines and droperidol.
5. Though return of con-
sciousness after ketamine
anesthesia may occur in 10
– 15 minutes but complete
recovery is often delayed.
3. Seizure threshold is
raised. Used for treatment
of seizures due to alcohol
withdrawl, LA toxicity and
epilepsy.
4. Possess centrally acting
muscle relaxant action.

91. Intravenous Induction Agents83
CARDIOVASCULAR EFFECTS
Cardiovascular effects of intravenous agents are studied with reference to:
a. effect on preload (venodilation)
b. effect on afterload (systemic vascular resistance)
c. effect on heart rate
d. effect on cardiac contractility
e. effect on central sympathetic outflow
f. effect on myocardial oxygen demand/supply ratio.
As a general rule volume depleted patients are more likely to show profound
Hypotension. Concomitant use of other drugs and their effect on cardiovascular
system should always be kept in mind while anticipating hemodynamic effects in a
particular patient, (e.g. opioids + benzodiazepine cause marked CVS depression;
while single use of each group does not produce major hemodynamic changes).

92. 84Comparative Pharmacology for Anaesthetist
CARDIOVASCULAR EFFECTS
ThiopentonesodiumPropofolKetamineMidazolamEtomidate 1. In induction doses it
causes transient fall in
blood pressure.
Mechanism
a. venodilation and peri-
pheral pooling of blood
b. decreased cardiac
contractility (minor
mechanism)
c. decreased central
sympathetic outflow.
2. Heart rate is increased via
baroreceptor activation
3. cardiac output falls
inspite of compensatory
tachycardia
4. fall in BP is more marked
in hypertensives because
they are chronically
volume depleted
1. Dose dependent fall in
blood pressure usually to
a greater extent than
comparable dose of
thiopentone
Mechanism
a. Venodilation and
peripheral pooling
b. fall in systemic vascular
resistance
c. decreased cardiac
contractility
2. Reflex tachycardia does
not occur due to
attenuation of
baroreceptor reflex
mechanism
3. cardiac output falls by
20%
1. It causes increase in heart
rate, blood pressure and
cardiacoutput via
stimulation of
sympathetic system.
There is resultant increase
in circulating
norepinephrine
2. Cardiovascular effects are
not dose dependent
3. Ketamine itself is a
direct myocardial
depressant. Under
normal conditions
Indirect action-
(sympathetic
stimulation)
predominates and
patient show increase in
blood pressure and heart
rate. If, however central
sympathetic outflow
isblunted due to other
factors (drugs like
opioids) or body-
catecholamine levels are
exhausted fall in bp and
cardiac output occurs.
1. In induction doses, causes
fall in blood pressure due
to fall in systemic vascular
resistance.
2. Heart rate, cardiacoutput
are well preserved.
3. Relatively stable
hemodynamics due to-
slower onset of action.
4. Hemodynamic changes
are pronounced, if a large
bolus is given in a volume
depleted patient or
administered with an-
opioid.
1. Most cardiostable
intravenous inducing
agent.
2. Heart rate, blood
pressure, cardiac output
and cardiac contractility
show minimal change
3. No effect on sympathetic
system
4. Myocardial oxygen-
demand supply ratio is
well preserved.
5. Should be cautiously
used in patients who are-
dependent on preload for
maintenance of cardiac
output. eg. compensated
shock, pericardial
tamponade.
Note:- It decreases
myocardial contractility
more than propofol,
ketamine, etomidate and
midazolam.
6
. No tendency to cause-
arrhythmias
4. Fall in blood pressure is
more marked in
hypertensives, elderly,
hypovolemics andwhen
drug is injected rapidly
5. myocardial oxygen
demand supply ratio is
well preserved if
dangerous fall in blood
pressure is avoided.4. Myocardial oxygen-
demand is increased.
Contraindicated in
ischaemic heart disease.

93. Intravenous Induction Agents85
EFFECT ON RESPIRATORY SYSTEM
Respiratory effects of intravenous agents are studied under following heads.
a. effect on respiration (rate, tidal volume)
b. effect on responsiveness to hypercarbia and hypoxemia
c. effect on laryngeal and pharyngeal reflexes.
d. Bronchodilation.
Most of the intravenous inducing agents (except ketamine) are centrally acting
respiratory depressants. Apnea follows large undiluted boluses. Airway assessment
should always be done before giving any of these drugs. Simultaneously administered
opioids accentuate respiratory depression.

94. 86Comparative Pharmacology for Anaesthetist
RESPIRATORY SYSTEM
ThiopentonePropofolKetamineMidazolamEtomidate 1. It causes marked de-
pression of respiration.
Both rate and depth of
respiration are affected.
Apnea can occur.
2. Response to hypercarbia
and hypoxemia are
depressed.
3.Factors affecting:-
• rate of injection
• dose and concentration
of the drug
• co-administered drugs.
4. Laryngeal reflexes are
not depressed and
laryngospasm can occur
under light thiopentone
anesthesia.
5. Mucociliary action of
respiratory mucosa is
depressed (similar to
volatile agents)
6. Does not cause
bronchodilation
1. It is a potent respiratory
depressant. Apnea
might be prolonged for
more than 30 seconds.
Incidence and duration
of apnea is greater with
propofol than
thiopentone.
2. Response to hypercarbia
and hypoxemia are
depressed.
3.Factors affecting
respiratory depression
are same as thiopentone.
4. Depression of laryngeal
and pharyngeal reflexes
is better than
thiopentone. This
facilitates insertion of
LMA.
5. Causes bronchodilation
but not as potent as
halothane. Mechanism
is via direct smooth
muscle relaxation.
1. Respiration is rarely
depressed after usual
doses of ketamine but
occasionally it may occur
if the drug is given very
rapidly or along with
other CNS depressants.
2. Response to hypercarbia
is not altered.
3.Factors affecting:- Drug
may act as respiratory
depressant in children
especially in large
boluses.
4. Although coughing, gag-
reflex, swallowing are
relatively intact after
ketamine but they are not
completely protective
and silent aspiration can
occur.
5. Bronchodilation due to
direct smooth muscle
relaxant effect as well as
sympathomimetic action
Bronchodilation is as
potent as halothane.
1. Dose related transient
respiratory depression.
Apnea can occur if large
bolus is given especially
with opioid premedi-
cation.
2. Response to hypercarbia
is transiently depressed
and usually not
significant.
3.Factors affecting:
respiratory depression
due to midazolam is
more marked in elderly
and COPD patients.
1. Action on ventilation is
minimal
2. Apnea rarely occurs after
induction doses.
3. Hiccups or coughing
may occur during
etomidate induction.
6
. Increased salivation can
produce upper airway
obstruction.

95. Intravenous Induction Agents87
SIDE EFFECTS AND COMPLICATIONS
ThiopentonePropofol KetamineMidazolamEtomidate • garlic taste in mouth
• mild involuntary
muscular movements
(myoclonus)
• If inadequate induction
dose is used, coughing
and hiccups can occur.
Mechanism is depres-
sion of inhibitory areas
first.
• The drug crosses
placenta and is also
secreted into milk.
• Allergic reactions inthe
form of anaphylactic
and anaphylactoid
reactions occur rarely.
• Pain at injection site
decreased by using a
large vein and adding
lidocaine (0.5 mg / kg)
• myoclonus
• greater incidence and
duration of apnea as
compared to
thiopentone.
• Propofol emulsion sup-
ports bacterial growth.
The drug should be
prepared under sterile
conditions. Unused
propofol should be-
discarded after 6 hours
to prevent bacterial
contamination.
• fall in B/P is more than
thiopentone
• sympathetic system-
activation
Increased heart rate,
B/P, cardiac output,
myocardial oxygen
demand.
• stimulates oral
secretions.
Administration of an
antisialogogue
(eg.glycopyrolate) is
helpful.
• Increased ICP
• increased (IOP)
intraocular pressure.
• nystagmus, diplopia
blepharospasm can
occur
• Flat dose response-
curve gives high
margin of safety as
compared with
barbiturates
• crosses placenta and
may depress neonate
• Nausea and vomiting
• Myoclonus during
induction
• Pain at injection site
• Corticosteroid and
mineralocorticoid
synthesis suppression
• Thrombophlebitis
• overdose can result
into severe
cardiorespiratory
depression
• Laryngospasm can
occur if patients
airway is handled
under thiopentone
alone or when plane
of anesthesia is
inadequate
• Thrombophlebitis can
occur due to chemical
irritation especially
with 5% thiopentone.
• Rapidly crosses
placenta. Effect on
foetus is not greater
than thiopentone
• Propofol is a lipid emul-
sion and its infusion
should be cautiously
used in patients with
disorders of lipid meta-
bolism (pancreatitis)
• Rarely causes throm-
oophlebitis
• Common signs of
anesthetic depth are
less reliable when
ketamine is used.
• Increased muscletone
• Potentiation of
neuromuscular
blockers
• Allergy rare

96. 88Comparative Pharmacology for Anaesthetist
Intra-arterial Injection of Thiopentone
Signs and Symptoms
• Intense burning pain
• Blanching of skin
• Severe vasoconstriction and disappearance of radial pulse
Pathophysiology
Mixing of thiopentone with arterial blood
crystals precipitate due to change in pH
blockade of arterioles and capillaries
endothelial damage
arterial thrombosis Gangrene
Damage is more with 5 percent thiopentone.
Treatment: LEAVE IV CANNULA IN ARTERY
• Dilute the drug by injecting saline.
• Relieve vascular spasm by
i. inj papaverine 40-80 mg/10-20 ml NaCl 0.9 percent
ii. 5 to 10 ml of 1 percent xylocaine
iii. brachial plexus/stellate ganglion block (sympathectomy)

97. Intravenous Induction Agents89
CONTRAINDICATIONS
ThiopentonePropofolKetamineMidazolamEtomidate • Porphyria-
Barbiturates induce
the enzyme
aminolaevulinic acid
synthetase (ALA
synthetase)It causes
increase in levels of
Porphyrin and can
precipitate an acute
attack
• Cardiovascular
collapse
• Impending coma
(hepatic failure, renal
failure, diabetes)
• Adrenocortical failure
• Myxedema
• severe anemia
• care must be taken in
hypovolemic patients
• should be avoided in
epilepsy
• Raised ICP
• Raised IOP and
penetrating eye
injuries
• Psychiatric disorders
• As sole anesthetic
agent in
hypertensives, IHD
and CVA patients.
• first trimester of
pregnancy (birth
defects may occur →
cleft lip and cleft
palate)
• epilepsy
• adrenocortical
insufficiency
ONSET OF ACTION ThiopentonePropofolKetamineMidazolamEtomidate Within one arm brain
circulation time (10-20 sec)
Within one arm brain
circulation time (about 30
sec)
Generally more than one
arm brain circulation time
(30-60 sec)
Generally more than one
arm brain circulation time
Within one arm brain
circulation time (10-65
sec)

98. 90Comparative Pharmacology for Anaesthetist
DURATION OF HYPNOSIS
ThiopentonePropofolKetamineMidazolamEtomidate 5-15 minutes1-8 minutes10-15 minutes>15 minutes5-8 minutes CLINICAL USES ThiopentonePropofolKetamineMidazolamEtomidate 1. Induction of
anaesthesia
2. Treatment of
increased ICP,
especially in patients
who do not respond
to hyperventilation
and drug induced
diuresis.
3. Cerebral protection. It
can improve survival
following focal brain
ischemia.
4. Refractory seizures.
1. Induction of
anaesthesia
2. Maintenance of general
anaesthesia
3. Sedation following
regional anaesthesia
4. Sedation in ICU
5. Monitored anesthesia
care (MAC)
6. In subhypnotic doses
• used for treatment of
chemotherapy induce
vomiting
• refractory post-
operative nausea
vomiting.
• T/t of pruritis
associated with
neuraxial opioids
1. Induction of anesthesia
in
a. hypovolemic patients
b. bronchospastic and
reactive airway disease
c. IM induction in
children with difficult
IV access.
2. maintenance of general
anesthesia
3. for analgesia and
sedation during burn
dressing changes,
debridement proce-
dures
4. supplementation of
regional anaesthesia.
1. Pre-operative
medication
2. Intravenous sedation
and amnesia during
a. regional anaesthesia
b. procedures like
endoscopy,
bronchoscopy
c. ICU
d. Postoperatively
3. Induction of general
anaesthesia. Mostly
used for co-induction
where two or more
inducing agents are
combined together to
produce anaesthesia
(e.g. opioids + Mida-
zolam or propofol +
Midazolam) Induction
with midazolam alone
has the disadvantage
of delayed induction,
delayed awakening
and lack of analgesia.
1. Induction of
anesthesia in patients
with cardiovascular
unstability. However
its use is limiteddue
to adrenocortical
suppression even
with a single dose.
Postoperative nausea
vomiting is another
limiting factor.
2. Maintenance of
anaesthesia.

99. Intravenous Induction Agents91
DOSES
Thiopentone SodPropofolKetamineMidazolamEtomidate Induction- 2.5-4.5 mg / kg
IV adults
5-6 mg / kg IV children
7-8 mg / kg IV infants
2-2.5 mg / kg IV reduced
with increasing age
0.5-2 mg / kg IV
4–6 mg / kg IM
0.05 - 0.15 mg / kg IV0.2-0.6 mg / kg IV
Maintenance: Not used
due to cumulative effect.
50-150 µg/kg/min/IV
with N
2
O or an opiate.
15-45 µg/kg/min IV with
N
2
O 50-70% in O
2
or
30-90 µg/kg/min IV
without N
2
O
1.0 µg/kg/min10 µg/kg/min with N
2
O
and an opiate.
Sedation: Not used due to
anti-analgesic properties.
25-75 µg/kg/min IV0.2-0.8 mg/kg IV
or
2-4 mg/kg IM
This is also the analgesic
dose for ketamine.
0.5-1 mg IV, repeated
or
0.06 mg / kg IM
5-8 µg/kg/min should
be used only for short
periods because of
inhibition of
corticosteroid synthesis.

100. Inotropes 5
Dopamine Dobutamine A drenaline Noradrenaline
Presentation As a clear,
colorless
solution for
injection
containing 40
mg/ml of
dopamine
hydrochloride
It comes in vials
containing 250 mg
of dobutamine
hydrochloride and
250 mg mannitol
in a lyophilised
form. It is also
available as 20 ml
vial containing 250
mg of dobutamine
hydrochloride
with 4-8 mg of
sodium bisulphite
dissolved in water.
It comes as a clear
solution for
injection containing
1 mg/ml of
adrenaline
hydrochloride. It
also comes as
aerosol spray
delivering 280 µg
metered dose of
adrenaline acid
tartrate.
As a clear colourless
solution for
injection containing
2 mg/ml of
noradrenaline acid
tartrate.
Chemical origin A catecholamine a synthetic
isoprenaline
derivative
a catecholamine a catecholamine
t
1/2
1 minute 2.4 minutes 2 minutes 3 minutes
Dose a. Renal dose 0.5
– 2 µg/kg/min
b. β
1
action 2 -
10 µg/kg/min
c. α and β
1
action (both) 10
– 20 µg/kg/min
d. endogenous
noradrenaline
release at dose >
5 µg/kg/min
Standard
intravenous dose
is 2.5 µg/kg/min
to 10 µg/kg/min ;
occasionally the
drug is used upto
40 µg/kg/min
(1) Dose regimen
for pressor support
(a)
1–2 µg/min
predominantly
activates β
2
receptors leading to
vascular and
bronchial smooth
muscle relaxation
(b) 2 – 10 µg/min
(25 –120 ng/kg/ min) β
1
and β
2
action. Heart rate,
contractility and
conduction through
AV node increased.
It is used for its
vasopressor action
in the dose of .01 to
.5 µg/kg/min.
Contd...

101. Inotropes93
Contd...
Dopamine Dobutamine A drenaline Noradrenaline
(c) > 10 µg/min (> 100
ng/kg/min) marked
α stimulation and
generalized vaso-
constrictions
(2) Dose for CPR1 mg
(ie 0.02 mg/kg) IV
adrenaline stat is
given for asystole,
VF, and EMD. In
situations where
intravenous access is
not available
adrenaline dose is
tripled and diluted in
10 ml saline, to be
given via endo-
tracheal tube or intra-
osseous route.
(3)
Dose for
bronchodilation:-
Due to its
vasoconstrictive
action adrenaline is
used to reduce
airway obstruction
caused by
oedematous mucosa
in patients of severe
croup, post
extubation and
traumatic airway
edema. Adrenaline
is used for
nebulization in such
patients. Effect of
each nebulization
lasts for around half
to one hour.
Subcutaneous
injection of
adrenaline is also
used for this
purpose. Dose is 300
µg (1/3rd ampoule)
Contd...

102. 94Comparative Pharmacology for Anaesthetist
Contd...
Dopamine Dobutamine A drenaline Noradrenaline
every 20 minutes.
Upto 3 such doses
can be given.
Mechanism of
action
Dopamine has 2
mechanisms of
action one is via
direct stimulation
of receptors and
second is via
indirect release
of noradrenaline
Direct Action:-
• Low doses:- It
stimulates dopa-
minergic recep-
tors D
1
and D
2
• D
1
causes
mesenteric and
renal bed
vasodilatation
• β action begins
at around 3 µg/
kg/min
• Beyond 10 µg/
kg/min α action
predominates
Indirect Action:-
Its indirect action
is via release of
noradrenaline.
This action begins
at a dose of 5 µg/
kg/min. Pro-
longed use of
dopamine causes
depletion of nor-
adrenaline stores
and decreased
response to the
drug.
Contd...
It is a
predominantly β
adrenergic
receptor
stimulating agent
(β
1 > β
2>α)
At lower doses it
causes β
stimulation. At
higher doses α
stimulation
predominates. The
drug causes β
mediated renin
release. This
indirectly
potentiates the
vasoconstrictor
action.
This drug exerts its
action
predominantly at α
- adrenergic
receptors, with a
minor action on
beta receptors.
Noradrenaline
when given
exogenously (ie. via
intravenous route)
can produce
bradycardia while
endogenous release
of the drug evokes
tachycardia.

103. Inotropes95
Contd...
Dopamine Dobutamine A drenaline Noradrenaline
Contd...
CVS effects
HEART:-
Produces
positive
inotropic effect
by stimulating
β
1
receptors.
Heart rate is
increased due to
positive
chronotropy
Force of cardiac
contraction
(positive
inotropism) is
increased via direct
β
1
action. Afterload
is decreased due to
β
2
mediated fallin
peripheral vascular
resistance. Increase
in cardiac
contractility along
with fall in
afterload causes
improvement in
CHF patients. Left
ventricular end
diastolic volume
reduces and organ
perfusion
improves.
It has both positive
inotropic and
positive
chronotropic effect
on heart. As a result
myocardial oxygen
demand is also
increased. It is the
drug of choice at the
end of
cardiopulmonary
bypass when
maximal inotropic
effect is required.
Conduction through
AV node improves
and AV block if
present is reduced.
It causes increase in
peripheral vascular
resistance leading to
rise in blood
pressure. Cardiac
output remains
unchanged or
decreases slightly as
heart has to work
against increased
afterload. This also
results into
increased
myocardial oxygen
demand.
Blood vesselsEndogenous
norepinephrine
release produced
by dopamine
causes conside-
rable vasocons-
triction. More-
over this drug
has no major
action on β
2
receptors and
therefore unop-
posed stimula-
tion of α
1
recep-
tors is responsi-
ble for over all
vasoconstriction.
At low doses D
1
mediated
splanchnic and
renal vasodila-
tion occurs.
Vasodilation occurs
due to β
2
action on
blood vessels.
At lower doses β
mediated
vasodilation occur
while at higher
doses
vasoconstriction
predominates
leading to increase in
SVR
It causes α
mediated increase
in peripheral
vascular resistance
leading to increase
in blood pressure.

104. 96Comparative Pharmacology for Anaesthetist
Contd...
Dopamine Dobutamine A drenaline Noradrenaline
Contd...
RS effects Ventilatory
response to
hypercapnia
and hypoxia is
reduced by
dopamine due
to action on
dopaminergic
receptor located
in the carotid
bodies
(Peripheral
chemo
receptors).
— It is a respiratory
stimulant though
this action is not
very significant
clinically.It is a
potent
bronchodilator due
to β

action. It
reduces vocal cord
edema in patients
of croup (acute
laryngotracheo-
bronchitis) via α
1
mediated
vasoconstriction.
It causes slight
increase in minute
volume along with
some degree of
bronchodilatation
CNS effects Available data
suggest that it
probably causes
vasodilation of
normal cerebral
vasculature with
no effect on
CMR. Very high
dose may cause
cerebral
vasoconstriction.
Exogenous
dopamine does
not cross blood
brain barrier
except in its
levo-rotatory
form.
It also
stimulates
chemosensitive-
trigger zone
leading to
nausea.
Increases CMR
and cerebral blood
flow at high doses.
No or minimal
effect is seen in
low doses. Blood
brain barrier
defect exaggerates
the phenomenon.
It penetrates CNS
to a limited extent.
CMR (Cerebral
Metabolic rate) and
CBF (Cerebral
blood flow) are
increased especially
when blood brain
barrier is open.
Available data
suggests that it does
not have much
effect on cerebral
blood flow and
cerebral metabolic
rate when blood
brain barrier is
intact. Cerebral
vasodilation and
increase in CMR
occurs when blood
brain barrier is
open.

105. Inotropes97
Contd...
Dopamine Dobutamine A drenaline Noradrenaline
Contd...
Kidneys At low doses
causes marked
renal
vasodilatation
leading to
corresponding
increase in renal
blood flow.
Increase in urine
output is also
due to
interference
with renal
tubular function.
At higher doses
vasoconstriction
predominates
and the
advantage on
renal blood flow
is lost.
Increase in cardiac
output causes
increase in urine
output. Specific
action on renal
blood flow is
absent.
Renal blood flow is
reduced by 40%,
although GFR may
remain minimally
altered.
Increase in
sphincter tone and
decrease in bladder
tone may cause
difficulty in
micturition.
Causes decreased
renal blood flow.
Gastrointestinal
system
Splanchnic
blood flow is
increased due to
action on DA
1
receptors.
Total increase in
cardiac output
improves organ
perfusion. Direct
action on
gastrointestinal
vasculature is not
present.
• Intestinal tone
and secretions are
decreased.
• Splanchnic blood
flow is increased
when used in β
dose, vasoconstric-
tion predominates
at higher doses.
• Hepatic and
splanchnic blood
flow are decreased.
Pregnant uterus Inhibits contractions
of pregnant uterus.
Increases
contractility of the
pregnant uterus,
may cause fetal
bradycardia and
asphyxia.

106. 98Comparative Pharmacology for Anaesthetist
Contd...
Dopamine Dobutamine A drenaline Noradrenaline
Contd...
Metabolic/other
effects
Release of
prolactin,
growth
hormone and
aldosterone are
depressed.
• Decreases insulin
secretion. Glucagon
secretion is
increased resulting
into rapid
glycogenolysis and
raised blood sugar
levels.
• Rise in activity of
lipases causes
increased
concentration of
FFA (free fatty
acids) in blood.
• BMR increases by
20 – 30%
• Renin activity is
increased in plasma.
• Decreases insulin
secretion leading to
hyperglycemia.
• Plasma renin
activity rises.
• FFA concentration
is increased.
Pharmaco-
kinetics
• Dopamine
MAO
and
COMT
Homovanillic
acid
3,4 dihydroxy
phenyl acetic
acid
• One fourth of
the administered
dose is
converted to
noradrenaline
within
adrenergic
nerve endings.
• Metabolites
are excreted in
urine either as
such or after
glucuronide
conjugation.
• Dobutamine
COMT
3-Omethyl
dobutamine
(inactive)
glucuronide
conjugation
excreted in urine
mainly.
Adrenaline
COMT
and MAO
Metadrenaline and
normetadrenaline
3 methoxy 4
hydroxyphenyl
ethylene
+
3 methoxy 4
hydroxy mandelic
acid
excreted
predominantly in
urine
Noradrenaline
MAO and
COMT
Methylation and
oxidative
deamination of the
compound
VMA
Predominant
metabolite;
excreted in urine
[3 methoxy, 4
hydroxy mandelic
acid]

107. Inotropes99
INOTROPE/VASOPRESSOR
Therapy
Hypotension is one of the most commonly occuring problem faced by an anesthetist
in operation theatre and intensive care units. As we know, there are four major
determinants of cardiac performance, namely preload, afterload, contractility and
heart rate. Out of these four, reduction in preload due to surgical field loss or other
losses is a major cause of hypotension in most patients.
Knowing the physiological derangement in a patient’s body is as important as
knowing the pharmacology of the inotrope or vasopressor, one wants to use.
Frequently patients are underfilled (volume depleted) and inotropes are wrongly
chosen to raise the blood pressure. Hypotension due to decreased preload should be
corrected by giving volume resuscitation and not by inotropes/vasopressors. Raising
the blood pressure with inotropes in a volume depleted patient gives a false sense of
security to the anesthetist but in real sense cardiac output and organ perfusion might
still remain poor, inspite of normal blood pressure. This results into ongoing acidosis
and organ dysfunction . Therefore one must remember that normal blood pressure
does not always mean normal tissue perfusion.
Excluding the patients with raised intracranial pressure and grossly deranged
cardiac or renal function, all the patients with hypotension should be adequately
filled before starting an inotrope or vasopressor. Central venous pressure is a
dependable guide for assessing the volume status of the patient. Generally we target
a CVP of around 9 to 12 mm Hg in spontaneously breathing patients or when PEEP
valve is not used in bains circuit. For patients on ventilator, target CVP is calculated
by first changing PEEP value from cm of H
2
O into mm Hg and then adding it to 10.
The new generation ventilators accommodate for the compressible volume of the
circuit. However if this facility is not there in the ventilator, only PEEP above 5 cm of
H
2
O becomes significant for calculating the target CVP.
Other crude methods of assessing the volume status of the patient are (1) heart
rate (2) urine output (3) pulse volume (4) capillary refill time. Heart rate though a
very nonspecific parameter, still remains an important method of knowing the volume
status of the patient.
Once the patient has been adequately filled and blood pressure still remains low,
vasopressor/inotrope therapy is initiated.
For patients who are in septic shock noradrenaline is the drug of choice; though
dopamine is also an alternative. A major disadvantage of dopamine is its tendency to
cause tachycardia. Septic shock patients, most of the time show increase in heart rate
due to various reasons (fever, acidosis, toxemia). Adding dopamine will increase the
heart rate even further. Once tachycardia is more than 160 beats/min, cardiac filling
gets compromised and cardiac output falls. In all such septic shock patients
noradrenaline is preferred over dopamine.
Moreover septic shock is basically a type of distributive shock. There is extensive
vasodilatation due to release of endotoxins and various chemical mediators.
Noradrenaline due to its potent vasoconstrictive α action increases total peripheral

108. 100Comparative Pharmacology for Anaesthetist
resistance and raises the blood pressure. Septic shock patients characteristically show
diastolic hypotension before actual fall in blood pressure. A vigilant anesthetist will,
depend more on mean arterial pressure rather than the absolute value of systolic
blood pressure. (mean arterial pressure = d b p +1/3 pulse pressure).
Dobutamine along with noradrenaline is a good combination in septic shock
patients if patient doesn’t respond to single drug therapy. Dobutamine is used to
augment the cardiac output as the myocardium may be too depressed due to toxins
in these patients while noradrenaline raises the total peripheral resistance. Dobutamine
should be started cautiously because it is an inodilator. It causes increase in force of
cardiac contraction and decreases total peripheral resistance. Vasodilatation is the
basic defect in septic shock and dobutamine augments vasodilatation. So whenever
dobutamine is used in a patient of septic shock for raising the cardiac output of a
depressed myocardium, noradrenaline or dopamine (vasopressor dose) should be
combined. Dose of dobutamine should be gradually raised keeping a close watch on
the blood pressure, otherwise precipitous fall in blood pressure can occur.
Patients who are in cardiogenic shock require optimization of preload, afterload,
cardiac contractility and heart rate. Preload is optimized by adequately filling the
patient [preload is defined as the end – diastolic fiber length or end – diastolic volume
of the heart].
According to Starlings law, cardiac muscle fiber best performs when stretched to
its maximal length (within physiological limits). This translates into peak ventricular
output occurring at filling pressures of 10 to 12 mm Hg. Thus we see that it is extremely
important to fill the patient properly for best result.
A failing myocardium cannot work against increased resistance. Optimization of
afterload requires a vasodilator so that forward flow becomes unhindered.
Dobutamine is a great drug as it matches the pathophysiology of cardiogenic shock;
it causes increase in contractility as well as decrease in afterload due to vasodilator
effect.
The only drawback with dobutamine is its tendency to cause tachycardia and
thus increase in myocardial oxygen demand. Tachycardia is more likely to occur
when suddenly large dose of dobutamine is given to the patient. It is advised that
dobutamine dose should be gradually increased to avoid tachycardia and precipitous
fall in blood pressure due to excessive vasodilatation.
When Your Inotrope/Vasopressor Doesn’t Work?
There are situations in perioperative period when inspite of adequate volume
resuscitation and inotrope support, patient continues to remain hypotensive.
Frequently ongoing volume loss either into the extravascular space or from surgical
field is the cause. If volume resuscitation has been adequately done then one must
look for other causes of refractory hypotension ie metabolic acidosis, hypocalcemia,
tension pneumothorax, cardiac tamponade.
One of the most common cause of hypotension refractory to inotrope therapy is
acidosis. Inotropes do not work effectively in acidotic patients. In patients with
metabolic acidosis correction of the underlying pathology is important. Soda

109. Inotropes101
bicarbonate can be used to buy time if pH has become less than 7.2. Continuous veno
– venous dialysis should be considered in severe cases. Hyperventilating the patient
also helps in correcting the pH. In patients with respiratory acidosis mechanical
ventilation may be required for correcting the pH.
Steroid depleted patients also respond poorly to inotrope/vasopressor support.
A 100 to 500 mg bolus of hydrocortisone can be given to patients with refractory
hypotension.
Another important cause of refractory hypotension is hypocalcemia. Patients with
deranged liver function frequently require multiple transfusions during major surgery.
They are prone for hypocalcemia because the citrate used for storing blood and
blood products is metabolized in liver. Citrate is a chelating agent and massive
transfusion can result into hypocalcemia in such patients. Other causes of hypocalcemia
in perioperative period include diuretic therapy, gastrointestinal loss and prolonged
history of poor intake.
A common mistake while giving inotrope is use of peripheral vein for
administration of the drug. Circulation in peripheral veins in state of shock is poor
and so is the drug delivery to heart. It is best to give inotrope/vasopressor through
external jugular or internal jugular vein, as the drug delivery to heart is better. These
minute considerations become important in state of crisis especially when there is an
impending cardiac arrest due to hypotension.
Another common mistake is use of same intravenous cannula for administration
of soda bicarbonate as well as inotrope/vasopressor. The two drugs are incompatible
and should not be used via same route.
RECENT ADVANCES
Renal Dose Dopamine –Is it useful?
‘Renal dose’ dopamine is frequently used by many anesthetists to improve urine
output in patients with renal failure. Recently this concept has been challenged in
many multicenter trials.
Dopamine is a proximal tubular diuretic. It acts on dopamine receptors present in
proximal convoluted tubule and prevent absorption of Na
+
ions. As a result more
Na
+
ions reach the distal part of tubule. Enhanced Na
+
delivery to distal tubular cells
cause increase in their oxygen demands. Therefore even if low dose dopamine cause
renal vascular bed dilatation. Oxygen requirement of renal parenchyma is probably
increased. Moreover recent data fail to prove any improvement in renal function by
use of low dose dopamine in patients of renal failure.

110. Anticholinergic Drugs6
Understanding Anticholinergics
Anticholinergic drugs inhibit action of acetylcholine at muscarinic receptors. They
are basically antimuscarinic drugs.
By competitive antagonist is implied that these drugs compete with acetylcholine
for binding with muscarinic receptors. There are five types of muscarinic receptors
M
1
, M
2
, M
3
, M
4
, M
5.
Binding of anticholinergic drugs at various muscarinic receptors
is reversible and can be overcome by increasing the concentration of acetylcholine in
the area of muscarinic receptors. It is important to note that antagonists themselves
do not initiate any change in cell function. They only prevent the agonist acetylcholine
from acting at muscarinic sites. All the clinical effects are due to lack of acetylcholine
action at its specific sites.
M
1
receptors:- They are primarily neuronal receptors located on ganglion cells and
central neurons in cortex, hippocampus and corpus striatum. Role in CNS is not
precisely known.
These receptors are also present in stomach and mediate gastric secretion and
relaxation of lower oesophageal sphincter tone on vagal stimulation.
M
2
receptors :- They are predominantly cardiac muscarinic receptors and cause vagus
mediated bradycardia.

111. Anticholinergic Drugs103
M
3
receptors :- They are found in visceral smooth muscles, glands and vascular
endothelium. Activation of these receptors cause visceral smooth muscle contraction,
glandular secretions and vasodilation.
M
4
:-
Action not known.
M
5
:-
The individual muscarinic antagonists differ mainly in terms of their relative
potency, duration of action and ability to penetrate into CNS.
Atropine Glycopyrrolate Hyoscine
Commercial
preparation
As a clear, colourless
solution for injection
containing 0.6 mg/ml of
atropine sulphate
As a clear solution for injection
containing 0.2 mg/ml of
glycopyrrolate. It is also
available as a fixed dose
combination containing 0.5 mg
of glycopyrrolate and 2.5 mg
of neostigmine.
As clear solution for
injection containing 0.4 mg/
ml of hyoscine hydro-
bromide. Hyoscine butyl
bromide comes as 10 mg
tablet and 20 mg/ml
injection.
Chemical
structure
It is a tertiary amine
and an ester of tropic
acid and tropine. (it is
an alkaloid derived
from Atropa
belladona).
Commercial
preparations are
mixture of dextro and
levorotatory isomers,
but the anticholinergic
effects are mainly due
to the levorotatory
form.
It is a quaternary ammoniun
compound.It is a synthetic
anticholinergic drug and
mandelic acid is present in
place of tropic acid.
It is a tertiary amine which
is the ester of tropic acid and
scopine. Scopolamine is 1 –
hyoscine. (It is an alkaloid
derived from Scopolia
carniolica).
CVS :-
Tachycardia
+ + +
Paradoxical bradycardia
can occur at low doses.
Mechanism:- Paradoxical
bradycardia at low
doses suggest a partial
agonist action of these
drugs.
+ +
Paradoxical bradycardia can
occur at low doses
+
Paradoxical bradycardia can
occur at low doses.
Arrhythmo-
genic
Decreases AV conduc-
tion time, so it is an
arrhythmogenic drug.
Less arrhythmogenic than
atropine
Rarely arrhythmogenic.
Contd...

112. 104Comparative Pharmacology for Anaesthetist
RS.
Bronchodilation
Contd...
Atropine Glycopyrrolate Hyoscine
+ + + + +
Decreased
bronchial
secretions
(Antisialagog-
ue action)
++ + + + +
CNS:- Crosses blood brain
barrier and can cause
central anticholinergic
syndrome. Sedation is
less marked than
hyoscine.
Cycloplegia and
mydriasis occurs.
Increase in intraocular
pressure can occur.
Does not cross blood brain
barrier because of its
quaternary structure. Has no
effect on pupil size or
accommodation. This drug
does not cause sedation.
Markedly crosses Blood
brain barrier. CNS
depressant with properties
of sedation. It is an
antiemetic, antanalgesic
and antiparkinsonian
drug. Can cause central
anticholinergic syndrome.
Marked cycloplegia and
mydriasis. Glaucoma can
be precipitated in patients
prone for it.
Gastrointestinal
system
Reduces salivation and
volume of gastric secre-
tion. Mild antispasmodic
action on the biliary
tree. Tone and
peristalsis, through out
the gut is reduced.
Reduction in gastric acid
volume is similar to atropine.
Antispasmodic property
similar to atropine.
Almost similar action as
atropine and
glycopyrrolate.
Genitourinary
system
Tone and peristalsis in
urinary tract is
decreased due to
smooth muscle
relaxation effect.
Same as atropine Same as atropine though
less marked.
Sweating Inhibited leading to
increase in body
temperature.
Inhibited but less marked than
atropine. Body temperature is
not much affected.
Inhibited more than
atropine.
Kinetics
absorption
Rapidly absorbed
from the gut; oral
bioavailability is
10 – 25%
Oral bioavailability is 5%Oral bioavailability is 10
percent. Well absorbed
following subcutaneous or
IM administration
Contd...

113. Anticholinergic Drugs105
Contd...
Atropine Glycopyrrolate Hyoscine
Distribution 50 percent protein
bound in plasma.
Crosses placenta and
blood brain barrier.
Crosses placenta and may
cause fetal tachycardia but
blood brain barrier is not
crossed.
11 percent protein bound in
plasma. Crosses placenta
and blood brain barrier.
Metabolism Hydrolysed in liver and
94 percent dose excreted
unchanged in urine.
Hydroxylation and oxidation
in liver .85 percent is excreted
in urine unchanged.
Extensively metabolized
in liver, only 2 percent
excreted unchanged in
urine.
DOSE - 0.01 to 0.02 mg/ Kg
for premedication
- Vagolytic dose is 2 – 3
mg.
- 0.005 to 0.01 mg/Kg for
premedication
- 0.01 to 0.02 mg/Kg for
premedication
Points of Clinical Significance
1.Atropine is the drug of choice for prophylaxis and treatment of vagal mediated
bradycardia.
For example:
• bradycardia due to peritoneal stimulation during abdominal surgeries.
• oculocardiac reflex during squint surgeries.
The drug is given as 0.5 mg IV every 3 to 5 minutes to a maximum total dose of
3 mg till the desired affects are achieved. Atropine sulphate in doses less than
0.5 mg may paradoxically cause further slowing of heart rate. This is considered
to be due to partial agonist action on muscarinic receptors at low doses. Paradoxical
bradycardia is more likely to occur if the drug is given as slow diluted intravenous
injection or via IM/SC route.
2. When given in large doses, atropine causes dilatation of cutaneous blood vessels
which is called as atropine flush.
3. Atropine and scopolamine cause dangerous inhibition of sweating when used in
large doses. This may lead to hyperthermia if patient is undergoing surgery in
poorly air conditioned OTs. Hyperthermia is more common in children and may
also occur even with usual doses.
4. In modern anesthesia anticholinergics are not used routinely for premedication.
There are specific indications for the use of specific drug. Antisialogogue action is
required only when ketamine is being used as an inducing agent or when significant
airway handling is anticipated as in case of bronchoscopy and airway related
surgeries. Glycopyrrolate is the preferred antisialogogue.
In children, vagal tone is high and airway manipulation can lead to reflex
bradycardia. In all such cases atropine serves as antisialogogue as well as vagolytic
drug.

114. 106Comparative Pharmacology for Anaesthetist
5. Glycopyrrolate is devoid of CNS and ophthalmic effects. It causes tachycardia
only when given intravenously. Scopolamine due to its sedative properties is
often used as the premedication of choice by many cardiac anesthetists.
6. Transdermal patches of scopolamine are used for the treatment of motion sickness.
Mechanism of action is via blockade of impulses from vestibular apparatus to the
vomiting center in brain.
7. Anticholinergics may cause urinary retention in patients with bladder outflow
obstruction. This effect is due to decreased bladder tone as a result of smooth
muscle relaxation.
8. Central anticholinergic syndrome:- Scopolamine and atropine can cross blood brain
barrier. When used in high doses central anticholinergic syndrome can occur.
Symptoms range from restlessness to unconsiousness. Mechanism behind the
syndrome is blockade of muscarinic receptors in the brain.Antihistaminics,
antipsychotics, tricyclic antidepressants possess inherent anticholinergic (anti-
muscarinic) action. When combined with anticholinergics can precipitate central
anticholinergic syndrome.
Anticholinergics are competitive antagonist. Their action can be overcomed by
increasing the concentration of agonist (acetylcholine) at the receptor site. This is
achieved via anticholinesterases. Physostigmine is the drug of choice for central
anticholinergic syndrome. Unlike other anticholinesterases it is lipid soluble tertiary
amine capable of crossing blood brain barrier. Dose given is .01 - .03 mg/Kg and can
be repeated after 15 to 30 minutes.

115. Anticholinesterases 7
Anticholinesterases are agents which prevent hydrolysis of acetylcholine by inhibiting
the enzyme cholinesterase.
Acetylcholine
Hydrolysis Enzyme cholinesterase
Choline + Acetate
Classification
Anticholinesterases
Reversible enzyme inhibitor Irreversible enzyme inhibitor
Carbamates Acridine Organophosphates Carbamates
Physostigmine Tacrine Dyflos Carbaryl
Neostigmine Ecothiophate Propoxur
Pyridostigmine
Edrophonium Malathion

116. 108Comparative Pharmacology for Anaesthetist
As shown in the diagram Acetylcholine acts on acetylcholine receptors. These receptors
are of two types, muscarinic and nicotinic. Drugs that block muscarinic receptors are
called as anticholinergic drugs (e.g. atropine) though it is a misnomer. Ideally they
are just antimuscarinic drugs. Nicotinic receptors are basically of two types N
M
and
N
N
.N
M,
receptors are located on neuromuscular junction while N
N
receptors are
present on autonomic ganglia, CNS and adrenal medulla. Neuromuscular blockers
(muscle relaxants) act as competitive antagonist of N
M
receptors. However drugs
like tubocurarine have receptor blocking action on N
N
receptors as well.
How anticholinesterases help in reversal of neuromuscular blockade caused by
non depolarizers can be understood by following diagram.
Concept of competitive antagonist and role of anticholinesterases
in overcoming competitive blockage

117. Anticholinesterases109
Anticholinesterases are primarily used for reversal of nondepolarizing muscle
blockade. They are also important because of common occurrence of organo-
phosphorus poisoning.
There are a few basic issues, that one must understand before giving reversal.
They are:
a. When to give the reversal?
b. Which drug to give?
c. How much to give?
d. How to minimize the side effects?
e. Factors affecting reversal.

118. 110Comparative Pharmacology for Anaesthetist
REVERSAL OF NEUROMUSCULAR BLOCKADE
1. When to give reversal agent:-
Recovery of neuromuscular blockade is governed by two factors.
a. Spontaneous recovery.
b. Pharmacological reversal.
Spontaneous recovery occurs due to fall in concentration of neuromuscular blocking
drug at the site of action i.e. NMJ, following fall in plasma concentration of the drug
due to elimination.
Pharmacological reversal is achieved by anticholinesterases. These drugs block
acetylcholine hydrolysis and increase the concentration of agonist (i.e. Ach) at the
site of action (i.e. NMJ). As we know that muscle relaxants are competitive antagonists,
thus increasing the concentration of agoinst at the site of action overcomes the
blockade. As a general rule.
“PHARMACOLOGICAL REVERSAL SHOULD BE ATTEMPTED ONLY WHEN
SPONTANEOUS RECOVERY HAS STARTED”.
In other words antagonism of the block should not be attempted when the block
is deep and profound.
Wherever neuromuscular monitoring is available it can be used as a guide to
assess spontaneous recovery (i.e. 10% twitch height). When neuromuscular monitoring
is not available spontaneous recovery can also be judged clinically.
Deep and Profound blocks require more time for reversal. Maximum antagonism
of blockade by neostigmine occur in 10 minutes. If recovery does not occur within 10
minutes, then recovery time will depend upon the duration of action of neuromuscular
blocking drug.

119. Anticholinesterases111
WHICH ONE TO GIVE?
Neostigmine is one of the most commonly used cholinesterase inhibitor due to its
high potency. Pyridostigmine is one-fifth as potent as neostigmine and edrophonium
is one-tenth as potent as neostigmine. Physostigmine crosses blood brain barrier so
it is not used as a reversal agent.
Edrophonium is more effective than neostigmine in reversal of mivacurium
blockade. Neostigmine inhibits plasma cholinesterase enzyme responsible for
mivacurium metabolism and elimination. Edrophonium has little effect on this enzyme
and so spontaneous recovery from mivacurium is not hampered.
FACTORS AFFECTING REVERSAL OF NEUROMUSCULAR BLOCKADE
1. Inhaled anesthetics retard antagonism of neuromuscular blockade. Concentration
of inhaled anesthetic should be reduced to minimum to facilitate reversal at the
end of a case.
2. Hypokalemia, hypothermia, respiratory acidosis may prevent or inhibit antagonism
of neuromuscular blockade by anticholinesterases.
3. Drugs like aminoglycosides and calcium channel blocker (Verapamil) interfere in
recovery from neuromuscular blockade.
HOW MUCH TO GIVE?
Maximal doses of commonly used anticholinesterases are as following –
Edrophonium 1 mg/kg
Neostigmine 70 µg/kg
Pyridostigmine 350 µg/kg.
If maximum dose fails to antagonize the block, there is no point in further increasing
the dose of anticholinesterase. It is so because these doses inhibit cholinesterase
completely. If recovery is incomplete even after 30 to 60 minutes of reversal, then an
additional dose of anticholinesterase can be given, which should be around half of
original dose.
MINIMIZING THE SIDE-EFFECTS
As we know that acetylcholine acts upon nicotinic as well as muscarinic receptors. By
Inhibiting cholinesterase enzyme, concentration of acetylcholine is increased at
nicotinic and muscarinic receptors. Muscarinic effects of acetylcholine are undesirable
and that is why anticholinesterases are given along with antimuscarinic
(anticholinergic) drugs during antagonism of neuromuscular blockade.
While combining an anticholinesterase with an anticholinergic one must keep in
mind that onset of action of anticholinergic should be faster than that of
anticholinesterase to avoid bradycardia.
Edrophonium has fast onset of action so it should be combined with atropine.
Onset of action of neostigmine matches with glycopyrrolate and so they are used in
combination. If atropine is combined with neostigmine there are chances of initial

120. 112Comparative Pharmacology for Anaesthetist
tachycardia followed by late bradycardia. This is due to early onset and short duration
of action of atropine as compared to neostigmine. Initial tachycardia is due to atropine
and late bradycardia is due to neostigmine.
Pyridostigmine has very slow onset of action. Tachycardia may occur both with
atropine and glycopyrrolate.
COMPARATIVE STUDY OF ANTICHOLINESTERASES
Neostigmine Edrophonium Pyridostigmine
Chemistry It is a quaternary amine,
which is an ester of an
alkylcarbamic acid.
It is a synthetic quaternary
ammonium compound. It
is devoid of carbamate
group.
It is structurally similar to
neostigmine consists of
carbamate moiety and
quaternary ammonium
compound.
Presentation It is available as clear
colorless solution for injec-
tion containing 2.5 mg/ml
of neostigmine methyl-
sulphate. A fixed dose
combination containing
0.5 mg of glycopyrrolate
and 2.5 mg of neostigmine
methylsulphate per ml is also
available.
It is available as clear
colorless solution for
injection containing 10
mg/ml of edrophonium
chloride.
It is available as 5 mg/ml
solution for injection.
DOSE for
reversal of
competitive
neuromuscu-
larblockade
Intravenous dose for the
reversal of non-depolarising
neuromuscular blockade is
50 to 80 µg/kg. Some books
mention upto 70 µg/kg. As
upper limit.
0.5 mg/kg to 1 mg/kg 0.35 mg/kg.
Onset of
action
5 to 10 minutes 1 to 2 minutes 10 – 15 minutes
Duration of
action
> 1 hr. 10 minutes > 2 hours
Mechanism
of action
It forms covalent bond with
the enzyme cholinesterase
due to the presence of
carbamyl group. Carbamy-
lated enzyme has a half life
of around 15 – 30 min.
Enzyme inhibition is
reversible.
It lacks carbamyl group and
so it forms only electro-
static attachment and
hydrogen bond with the
enzyme cholinesterase.
These bonds are short
lived and reaction truly
reversible. It also causes
presynaptic release of
acetylcholine.
Same as neostigmine.
Contd...

121. Anticholinesterases113
Contd...
Neostigmine Edrophonium Pyridostigmine
Pharma-
cokinetics
It is poorly absorbed when
administered orally. Oral
bioavailability is 1 – 2 percent.
It is 6 – 10 percent protein
bound. Due to its highly
ionized nature it does not
cross blood brain barrier.
Renal clearance is responsible
for 50 - 60% elimination of
the drug. Rest of the
neostigmine is metabolized
in liver and by plasma
esterases. Its clearance is
reduced in renal failure.
Renal elimination is 75 per-
cent. Poor lipid solubility
and CNS penetration.
When used in larger doses
ie.0.5 – 1.0 mg/kg sustained
antagonism of neuro-
muscular blockade results.
Renal elimination is 75
percent. Poor lipid solubility
and CNS penetration.
Note that clearance of all the three drugs is reduced in renal failure. Action of
long acting muscle relaxants eg. Pancuronium is also prolonged in renal failure.
Action of muscle relaxants and anticholinesterases are almost equally prolonged
in renal failure.
Pharmacodynamics
CNS These drugs do not cross Blood brain barrier and are devoid of
central effects.
CVS They cause bradycardia, hypotension and increased conduction
time of the cardiac tissue. Bradyarrhythmias and sinus arrest can
occur.
RS Smooth muscle stimulation can cause bronchoconstriction. Airway
secretions are increased.
Skeletal muscleThey inhibit acetylcholine hydrolysis and so once released,
acetylcholine rebinds to the same receptor, acts on neighbouring
receptors after diffusion and activates prejunctional fibers. This
causes repetitive firing which manifests clinically as twitching and
fasiculations. Higher doses cause persistent depolarization of end
plates leading to weakness and paralysis.
GI They cause increased salivation and gastric acid output. Nausea
and vomiting can occur. Gastrointestinal motility is increased.
Genitourinary Ureteric peristalsis is increased. Bladder sphincter is relaxed and
Tract detrusor muscle contracts.
Other effects Sweating and lacrimation are increased. Miosis and inability to
focus for near vision occurs due to action on sphincter of the iris
and ciliary muscle.

122. 114Comparative Pharmacology for Anaesthetist
PHYSOSTIGMINE
It is a tertiary amine which is lipid soluble and crosses blood brain barrier. It is
unsuitable for reversal of neuromuscular blockade due to CNS effects but it is the
drug of choice for central anticholinergic syndrome caused due to excessive doses of
scopolamine and atropine.
Other uses:
• Postoperative shivering
• Reverses CNS depression due to benzodiazepines and volatile agents.
The drug is metabolized by plasma esterases and renal excretion is not important.
Dose 0.01 to 0.03 mg/Kg.

123. Local Anaesthetics 8
COMMERCIAL PREPARATION
• Local anaesthetics are weak bases. They are poorly soluble in water; so for
commercial purpose they are prepared as water soluble salt of an acid (recall that
Acid + Base salt + water), which is stable in solution form. Usually, acid
used is hydrochloride. pH of hydrochloride salt solution is acidic (usually ≤ 6).
• An acidic pH of the local anaesthetic solution is important if epinephrine is used
as an adjuvant as this catecholamine is unstable at alkaline pH.
• Onset of action and efficacy of LA can be improved by reformulating them as
carbonated solutions. Carbonated solutions have a higher pH than hydrochloride
salt solutions. How pH changes can improve onset and efficacy, is discussed later
in the chapter.
STRUCTURE – ACTIVITY RELATIONSHIP
• Local anaesthetic consists of an aromatic part linked with tertiary amine via an
intermediate chain.
• The aromatic part is fat soluble (lipophilic) while amine group is water soluble
(hydrophilic).
• The intermediate chain contains either an ester (-CO-) or amide (NHC
-
) linkage,
on the basis of which local anaesthetics are classified as amides and esters.
• Branching the intermediate chain results into more fat soluble compound, e.g.
etidocaine.
• Bulkier the moiety in terminal amino group, more is the potency of the drug, e.g.
bupivacaine.
• The amine portion of LA can accept one proton (H
+
) and exist in charged form. In
solution, local anaesthetic therefore exists as cationic and base form, the amount
of each being determined by the pH

of the solution.

124. 116Comparative Pharmacology for Anaesthetist
Acidic
LA H
+
LA+H
+
Alkaline
Cation Base
(water soluble but (fat soluble
non-diffusible form) diffusible form)
Higher the concentration of H
+
ions more the equation moves from right to left
and more drug exists in nondiffusable cationic form. On the other hand alkaline pH
favours the equation to move towards right and more drug exists in base form. That
is why carbonated solutions of local anesthetics show faster onset and increased
efficacy as compared to hydrochloride solutions.
CLASSIFICATION
1. Classification Based on chemical linkage
• Local anaesthetics are classified into esters and amides depending upon the
nature of the chemical linkage between the aromatic portion and the
intermediate chain.
Ester Amide
1. Ester linkage Amide linkage
2. unstable in solution Stable in solution
3. Ester drugs have high Pka value. Therefore
significantly more drug remains in cationic
poorly diffusible form at body pH.
They diffuse through tissues more rapidly than
esters because their pKa values are lower. They
exist in diffusible base form at body pH.
4. They are metabolized by plasmacholinestrases.
PABA (Para aminobenzoic acid) is the common
product of their hydrolysis.
Exception:- Cocaine undergoes significant
hepatic metabolism.
Metabolized in liver via enzymatic degradation.
5. Patients with atypical plasmacholinesterases
may show prolonged action of these drugs.
Such patients are at increased risk for developing
excess systemic concentration. Pregnant females
may have decreased plasma cholinesterase
activity.
Metabolism prolonged in hepatic disease and
conditions associated with decreased hepatic
blood flow.
6. Allergies common. — rare —
7. Metabolism fast; so less chances of developing
toxicity
Metabolism slow; so chances of toxicity increases.
Contd...

125. Local Anaesthetics117
2. Classification based on duration of action.
Short acting(15 minutes to 30 minutes)
Procaine
chlorprocaine
Intermediately acting(1 to 3 hrs)
Lidocaine
Prilocaine
Mepivacaine
Long acting(2 to 4 hrs)
Bupivacaine
Ropivacaine
Dibucaine
MECHANISM OF ACTION
Local anesthetics are Na
+
channel blockers. On the inner portion of Na
+
channel
specific receptor for local anesthetics is present. Local anesthetics gain entry to their
site of action via two mechanisms. Unionized base form penetrate cell membrane of
the neuron easily due to its lipophilic character.
Ionized cationic form reach the Na
+
channel directly through external orifice. One
must remember that only cationic form binds with Na
+
channel. Therefore base form
should convert into cationic form before binding with Na
+
channel.
Contd...
Ester Amide
8. Pka
Cocaine 8.7
Benzocaine 2.9
Procaine 8.9
Chlorprocaine 9.1
Tetracaine 8.5
Pka
Lidocaine 7.7
Mepivacaine 7.6
Prilocaine 7.7
Cinchocaine 7.9
Etidocaine 7.7
Bupivacaine 8.1
Ropivacaine 8.1

126. 118Comparative Pharmacology for Anaesthetist
B = Unionized lipid soluble form of local anesthetic
BH
+
= Ionized lipid insoluble form of local anesthetic
LA (B + H
+
BH
+
)
Characteristics of Blockade
• No effect on resting membrane potential.
• Does not affect repolarization
• Concentration dependent
• Reversible blockade
• Frequency – dependent blockade
Diagram showing various states of Na
+
channel

127. Local Anaesthetics119
Penetrates lipid barrier Enter the channel directly
Through external orifice when
Na
+
channel is in activated
state during action potential.
Reestablishes equilibrium with
its counter part B + H
+
BH
+
depending on the pKa and
acidity of the medium.
BH
+
acts from inner side of Na
+
channel Therefore LA selectively
block nerves that fire more
frequently (i.e. Na channel opens
more number of times)
Local anesthetic binds to
Receptor in inner portion of Frequency – dependent blockade
sodium channel
Prevent inward flow of Na
+
ions
Reversible conduction blockade
THREE STATES OF NA
+
CHANNEL
• Sodium channel is present on the neuronal membrane. It has two gates. One is
present near its extracellular mouth and is called as activation gate (A).
Another is present at its intracellular mouth and is called as inactivation gate (I).
Sodium channel during its resting state has activation gate (A) closed and inactivation
gate (I) open.

128. 120Comparative Pharmacology for Anaesthetist
During depolarization, activation gate also opens and Na
+
ions flow in
Within a few milliseconds inactivation gate closes and inward current of Na
+
ceases.
• LA receptor is present on the inner portion of Na
+
channel. It binds with cationic
form of the drug which fixes it in inactivation state. This results into slowing of
rate of depolarization. Threshold potential is not reached and conduction blockade
occurs.
PROPERTIES OF LOCAL ANAESTHETICS
In vitro properties (Properties studied in isolated nerve preparation)
1. Lipid Solubility:- Determines – Potency
Boundary wall of a cell is called as cell membrane. It forms a barrier between
intracellular and extracellular environment. Structure of a cell membrane consists of
two layers of lipid (lipid bilayer) with large number of protein molecules embedded
in it. Lipid soluble agents are able to travel these barriers more easily as compared to
agents with poor lipid solubility.
That is why highly lipid soluble local anesthetics produce conduction blockade at
lower concentration than less soluble local anesthetics. [More molecules cross lipid
barrier to reach their site of action i.e. Na
+
channels].
Lipid solubility is measured in terms of partition coefficient between oil or octanol
and water. Partition coefficient in simpler words is relative solubility of the drug in
two medium. LA with high partition coefficient are more lipid soluble while LA with
low partition coefficient are poorly lipid soluble.

129. Local Anaesthetics121
Drug Lidocaine Bupivacaine
Partition coefficient 43 346
Relative potency 2 8
2. Dissociation Constant (Pka)
Determines – Onset of Action
Pka is defined as the pH at which half (50 percent) of the drug is in ionized form and
half (50 percent) is in unionized form.
BH
+
B + H
+
(At Pka)
(50%) (50%)
All the local anesthetics have Pka more than 7.4. Any medium having a pH less
than 7.4 will therefore be acidic for the drug. Acidic medium (medium with more
H
+
ions) will make the equation move towards left and more drug well exist in cationic
nondiffusible form
BH
+
B + H
+
(At pH less than Pka i.e. acidic medium)
Drugs with Pka close to physiological pH will have more unionized fraction.
The unionized form is lipid soluble and responsible for penetration of the drug
through lipid barrier i.e. neuronal cell membrane, myelin sheath and other membranes.
Therefore drugs with Pka close to physiological pH will have more rapid onset.
Drug Lidocaine Bupivacaine
Pka 7.9 8.1
Onset Fast Moderate
• Local inflammation (tissue acidosis) increases the cationic form of LA and thus
reduces efficacy.
3. Protein Binding
Determines – Duration of Action
Protein binding affects the duration of action in two ways. a. Sodium channel is a protein spanning the lipid bilayer cell membrane. Affinity of
LA for protein determines its affinity for sodium channel. Greater the protein binding characteristics, longer the drug binding with sodium channel and longer
will be its wash out time.
b. Local anaesthetics bind to plasma proteins also. Saturation or interference with
plasma protein binding may result into increased free drug level. Clinically this
manifests as appearance of CNS toxicity even with lower doses.

130. 122Comparative Pharmacology for Anaesthetist
4. Frequency Dependent Blockade
Determines – Sensory Motor Dissociation
A resting nerve is less prone to blockade by local anesthetic as compared to the
nerve which is being repetitively stimulated. This results into what is called as frequency
dependent block.
Frequency dependent blockade is especially seen with lidocaine, bupivacaine and
ropivacaine. Clinically it results into greater decrease in pain and sensory transmission
(i.e. high frequency transmission) than that of motor/low frequency transmission. It
is called as sensorimotor dissociation and is clinically desirable.
In Vivo Properties (Properties studied in human subjects)
1. Vasodilation
Diagram showing biphasic action of LA
Except cocaine, most local anaesthetics cause vasoconstriction at low concentration
and vasodilation at high concentration. Vasodilation results in greater uptake of the
drug into the circulation and reduced drug concentration at the site of deposition
For example: Duration of action and potency of lidocaine and mepivacaine are almost
similar, when studied on isolated nerve preparation (in vitro studies). However when
injected into tissues (in vivo studies) enhanced vasodilator action of lidocaine results
in greater systemic absorption and shorter duration of action than mepivacaine.
This effect can be overcomed to some extent by addition of vasoconstrictors to
LA. Epinephrine containing LA solutions that is why show apparently enhanced
potency.

131. Local Anaesthetics123
2. Tissue Penetrance
In order to reach its site of action local anaesthetic has to traverse through neuronal
and non neuronal barrier. Rate of diffusion through these barriers is different for
different drugs. Besides pKa, tissue penetrance plays a major role in deciding the
speed of onset of a local anaesthetic.
For example: Chlorprocaine has a high pKa i.e. 8.7. Its onset of action should be very
slow as predicted by its pKa. On the contrary, it has one of the fastest clinical onset
due to remarkable tissue penetrance characteristic.
3. Differential Conduction Blockade
Different types of nerve fibres are found in our body:
• Type A fibers (α, β, σ, δ)
• Type B fibers
• Type C fibers.
Out of all these, small type B and C fibers are most susceptible to blockade,
followed by A δ fibers and finally A α and β fibers. Clinically this manifests as
autonomic and pain fibers being most sensitive and motor fibers being least sensitive
to blockade.
Order of Sensitivity to Blockade Clinically
(Starting from most sensitive)
Preganglionic autonomic
Cold
Warm
Pinprick
Pain
Touch
Deep pressure
Motor
Vibration and proprioception
• Sensitivity to blockade depends on
— Type of fibre
— Myelination
— Critical length of the axon that must be exposed to LA for blockade
As a general rule thick (large diameter) fibres are less sensitive than small diameter
fibres. Nonmyelinated are more sensitive than myelinated fibers.

132. 124Comparative Pharmacology for Anaesthetist
4. Mantle Effect
Mantle effect occurs due to specific pattern of arrangement of nerve. Mostly, fibres
that innervate the proximal part of the body are present on the outer surface of the
nerve while distal body parts are innervated by nerve fibres near the core of the
nerve.
Outer surface of the nerve is exposed to highest concentration of LA. That is why
proximal limb is first to get anaesthetized after peripheral nerve block. This is followed
by anaesthesia of the distal part. Regression of the block occurs in opposite fashion
because concentration of the local anaesthetic, first decreases in the core and then in
the periphery of the nerve.
5. Concentration Effect
Increasing the concentration of LA may increase its speed of onset, this is called as
concentration effect. By increasing the concentration we increase the number of
molecules available to cross the lipid barrier and thus fasten the onset of action.
However, higher concentrations should be used cautiously as there is increased risk
of systemic toxicity.
PHARMACOKINETICS
As the name indicates ‘LOCAL ANAESTHETICS’ are deposited near the nerve whose
neural transmission is to be inhibited.

133. Local Anaesthetics125
FATE OF LOCAL ANAESTHETIC
Drug deposited in close proximity of a nerve/plexus
Diffusion through nonneural Tissue bindingVascular uptake (depends on
and neural tissue barrier site of injection)
Crosses neuronal cell membrane Systemic circulation
(axolemma)
Binds with Na
+
channel and fixes it in Distribution to tissues depending on
INACTIVATED state Vascular perfusion
Dissociates from Na
+
channel and diffuses Metabolism
out of the nerve to enter systemic circulation
(depending upon protein binding character and
rate of fall of plasma drug level) Esters Amides
Plasma Liver (enzymatic
Cholinesterase degradation)
Recovery from Blockade
Metabolites excreted via kidneys.
a. Absorption: The systemic absorption of local anaesthetics is determined by :
1.Site of injection: Absorption depends upon vascularity of the area. Intravenous >
Tracheal > Intercostal > Paracervical > Caudal > Lumbar epidural > Brachial plexus
> subarachnoid > Subcutaneous.
2.Presence or absence of Vasoconstrictor: Epinephrine by reducing local blood flow will
reduce absorption from the site of injection. Some drugs have an inherent
vasoconstrictor action.
3.Pharmacologic profile of the agent:
– The degree of protein binding in the tissues; as only free drug is available for
uptake by the vasculature.
– The fat solubility; as the amount of drug dissolved in fat is not available for
absorption.
– Vaso activity; drugs that cause vasoconstriction will delay absorption.
– PKa of the drug; It determines the degree of ionization at tissue pH and thus
proportion available to cross lipid bilayer.
b. Distribution:
• Initial rapid disappearance of the drug from systemic circulation occurs due to
distribution to highly perfused organs. (brain, lungs, liver, kidney, heart)

134. 126Comparative Pharmacology for Anaesthetist
Lungs play a major role in extraction of LAs once the drug passes through
pulmonary vasculature. Propranolol interferes with extraction of bupivacaine by
lungs.
• The ensuing slow disappearance of the drug occurs due to distribution to less
perfused tissues (skeletal muscles and gut).
Skeletal muscles act as the greatest reservoir for LA agents because of large mass.
• High lipid solubility facilitates tissue uptake of the drug while plasma protein
binding property tends to retain LA in blood.
c. Metabolism: The metabolism of local anaesthetic agent is a function of chemical
linkage present in its intermediate chain.
Note:- Clearance rate of amide LAs is reduced after prolonged infusion; especially in
children.
FACTORS AFFECTING PHARMACOKINETICS
1.Age: infants have decreased levels of α
1
acid glycoprotein which is the major local
anaesthetic binding protein. This results in higher free drug concentration for
equivalent mg/kg doses. Moreover children do not mount premonitory signs of
local anaesthetic toxicity. Special precaution is warranted while using prolonged
infusions of LAs in paediatric population.
2.Low cardiac output states: All the conditions associated (e.g. hypovolemic shock,
heart failure), with decreased cardiac output will lead to decreased hepatic blood
flow. Hepatic metabolism of amide drugs is hampered and their action prolonged.
Blood levels are higher than anticipated.

135. Local Anaesthetics127
3.Pregnancy: Pregnant patients show increased sensitivity for LAs probably due to
prolonged increase in progesterone levels.
4.Poor Nutrition: Cachexic patients have low α
1
acid glycoprotein levels and so more
free drug is available to cross blood brain barrier. Toxicity appears at lower mg/
kg doses.
ADJUVANTS
Vasoconstrictors
Drugs used for vasoconstriction:
a. Adrenaline (0.1 mg adrenaline is added to 20 ml LA to give a 5 µg/ml
concentration).
b. Phenylephrine (0.1 mg adrenaline = 1 mg phenylephrine)
c. Felypressin : It is Synthetic derivative of vasopressin and can be safely used with
inhalational agents as it has little effect on cardiac rhythm.
Adrenaline
Advantages
• Prolongs the duration of action of local anesthetic by reducing its systemic uptake;
as a result more drug is available to cross neuronal cell membrane and produce
blockade.
• Slow and reduced systemic absorption lowers the risk of toxicity as peak drug
levels occur slightly later and are lower.
• Marker of accidental intravenous injection of local anesthetic; one must always
use adrenaline in test dose.
• Improves depth of analgesia by direct stimulation of α
2
receptors located on the
dorsal horn of spinal cord.
• When used in epidural solutions, β adrenergic effects of a small dose are usually
beneficial in maintaining cardiac output and heart rate.
Disadvantages
• Large doses of adrenaline (>0.25 mg total dose) are associated with cardiac rhythm
disturbances. The possibility of cardiac irritation is increased in the presence of
inhalational agents.
Contraindications for the use of adrenaline as an adjuvant with local anesthetics are:
• block of digit, foot, penis
• local infiltration of skin flap.
• severe hypertension, hyperthyroidism and PIH.

136. 128Comparative Pharmacology for Anaesthetist
ALKALINIZATION
Local anaesthetic + NaHCO
3
Increases the pH of the solution
More drug exists in unionized diffusible form
Rapid onset of anaesthesia
Acidic
BH
+
B + H
+
Alkaline
LA Dose of bicarbonate
Lidocaine 1 cc for each 10 cc
Bupivacaine 0.1 cc for each 10 cc
Note:- Over enthusiastic alkalinization may result into precipitation of poorly soluble
bases (LA) in highly alkaline medium (NaHCO
3
), such preparation is clinically
ineffective.
CARBONATION
Carbonated salts of local anaesthetics have following advantages.
• Increased speed of onset
• Enhanced quality and duration of block.
Conflicting data exists regarding the benefits of carbonated salts of local
anaesthetics. However proposed mechanism of their action is as following.

137. Local Anaesthetics129
Carbonated salt of LA
Higher pH than hydrochloride salt of LA
More drug available as unionized diffusible form
Increased speed of onset
CO
2

is released and diffuses inside
the neuronal cell membrane
Intracellular pH falls (becomes more acidic)
Concentration of ionized cationic
form is increased inside the cell
Enhanced nerve blockade
Clonidine: Increases the duration and quality of block.
• Causes analgesia via action on α
2
receptors.
• It causes vasodilation and hypotension due to which its role is limited as an
adjuvant for LAs.
• Significant increase in peak plasma level of LA occurs due to vasodilator action of
clonidine.
• Dose is 1 mg/kg for caudal/epidural block.
• The high cost of clonidine is also major limiting factor for its widespread application.
Hyaluronidase: It is an enzyme which breaks down collagen bonds and thus cause the
spread of LA in various tissue planes. It is used in retrobulbar and peribulbar blocks
of the eye.
Dextran: Controversies exist regarding its benefit as an adjuvant. It appears to prolong
the duration of action of LA but reliable and consistent evidence does not exist.
Ketamine: Preservative free ketamine has been used in paediatric patients for caudal
blocks. It extends analgesia via action on NMDA receptors.
Compounding: Often a short acting drug is combined with long-acting drug (e.g.
lidocaine + bupivacaine) in order to get the advantage of both i.e. rapid onset and
long duration.
– While mixing two drugs the maximum recommended doses should not be
exceeded as toxicities are additive.
– Final concentration of each drug is diluted by the addition of other.

138. 130Comparative Pharmacology for Anaesthetist
SYSTEMIC TOXICITY OF LOCAL ANESTHETICS
As the name indicate ‘LOCAL ANESTHETICS’ are meant to act at the site of
deposition, their systemic absorption is clinically undesirable. Systemic toxicity appears
due to increased plasma concentration of local anesthetics. Plasma concentration rises
abnormally due to any of the following reasons.
a. Systemic absorption after overdosage during regional anesthesia.
b. Inadvertent intravenous administration of the drug.
CARDIOVASCULAR TOXICITY
Local anesthetics are Na
+
channel blockers. Their cardiotoxic effects are due to
blockade of Na
+
channels present in the heart. This causes decrease in rate of
depolarization of cardiac muscle fibre.
Studies have shown that local anesthetics inhibit inward current of Ca
++
ions and
its release from sarcoplasmic reticulum.
Cardiotoxicity of LA
Local anesthetic in toxic doses
Blockade of Na
+
channels
Direct relaxation Hindered calcium influx
of peripheral vasculature and its triggered release from
sarcoplasmic reticulum
Peripheral vasodilatation Increased conduction Negative inotropic
time of the heart effect
PR interval prolongation
QRS complex duration increased
and
Decreased automaticity of SA node
Hypotension Bradycardia and heart block Decreased cardiac
output
Cardiac arrest

139. Local Anaesthetics131
Clinically these changes manifest as decreased myocardial contractility, automacity
and conduction velocity. When used in high doses LA cause relaxation of peripheral
vasculature leading to hypotension. The combined affect of bradycardia, decreased
contractility and hypotension can result into cardiac arrest.
Why Bupivacaine is more cardiotoxic than lidocaine ?
Bupivacaine binds with Na
+
channel more strongly than lidocaine. This is due to its
high protein binding character. It dissociates from Na
+
channel very slowly that is
why it is called as fast in slow out drug while lidocaine shows fast in fast out features.
Studies have shown that myocardial uptake of bupivacaine is greater as compared to
lidocaine, as a result it has the potential to cause severe cardiac arrhythmias. It causes
re-entrant type of arrhythmias similar to torsa de pointes. Fatal ventricular fibrillation
is seen with bupivacaine but not with lidocaine or tetracaine.
FACTORS AFFECTING CARDIOTOXICITY OF LOCAL ANAESTHETICS
I.PREGNANCY: Pregnant patients are more susceptible to cardiotoxic effects of
local anesthetics due to prolonged rise in circulating progesterone levels. It has
been suggested that progesterone increases the tissue sensitivity for local
anesthetics.
Moreover free drug levels are raised in pregnancy due to reduced protein binding.
Thus more drug is available to bind with cardiac Na
+
channels.
Magnesium used in treatment of PIH has been shown to play some protective
role against generation of re-entrant arrhythmias by bupivacaine.
II.DRUGS: The threshold for cardiac toxicity produced by bupivacaine is decreased
by concomitant use of drugs prolonging cardiac conduction e.g. Beta blockers,
calcium channel blockers, digitalis.
III.ACIDOSIS AND HYPOXIA: Hypoxia, acidosis and hypercarbia all potentiate
cardiodepressant action of local anesthetics. Severe acid-base changes following a
seizure can very well decrease the threshold for cardiac toxicity of these drugs.

140. 132Comparative Pharmacology for Anaesthetist
IV.HEART RATE: Tachycardia enhances frequency-dependent blockade of cardiac
sodium channels by bupivacaine. This effect is not marked with lidocaine.
V.ISOMER: Commercial preparation of bupivacaine is a racemic mixture of R and S
enantiomers. Out of these two R form is more cardiotoxic and less lipid soluble.
Cardiac arrest due to local anesthetic toxicity is difficult to revive. Massive doses
of adrenaline and atropine are required. Some reports suggest role of phenytoin and
bretylium.
CC/CNS RATIO
Cardiovascular system is relatively resistant to toxic effects of local anesthetic as
compared to central nervous system. The ratio of dose required to produce irreversible
cardiotoxicity and the dose required to produce convulsions is expressed as CC/
CNS ratio. For bupivacaine it is 3.7
+ 0.5 and for lidocaine it is 7.1 + 1.
CENTRAL NERVOUS SYSTEM TOXICITY
Mechanism
CNS toxicity is caused by effect of local anesthetic on neuronal cell membrane. Initially
there is blockade of amygdaloid complex followed by blockade of inhibitory pathways
in cerebral cortex. This allows facilitatory neurons to discharge electrical impulses
unopposed. As a result CNS excitation and convulsions occur. Further increase in
doses of local anesthetics suppress facilitatory pathways leading to CNS depression
and respiratory arrest.
LA OVERDOSE
Blockade of amygdaloid complex
Blockade of inhibitory pathways
Blockade of facilitatory pathways
RESPIRATORY ARREST
Flow chart showing mechanism of CNS toxicity

141. Local Anaesthetics133
Symptoms
CNS symptoms occur in the following sequence
Light headedness, dizziness, circumoral and tongue numbness
Visual and auditory disturbances
Disorientation
Drowsiness
Shivering, twitching over distal extremities and face
Tonic clonic convulsions
Coma and respiratory arrest
Excitatory phase is absent if other CNS depressants have been used.
FACTORS AFFECTING CNS TOXICITY
a.Potency: More potent drug require less dose to produce CNS toxicity. Lidocaine
demonstrate CNS toxicity at plasma concentrations of 5 to 10 μg/ml while
bupivacaine is associated with seizures at much lower levels (approx 4.5 to 5.5
μg/ml) of plasma concentration.
b.Rate of drug administration: The rapidity with which a particular blood level of the
drug is achieved is important in determining the threshold for CNS toxicity. CNS
symptoms appear at lower drug levels if the serum concentration is achieved in a
very short time.
c.Respiratory and metabolic acidosis: Acidosis reduces threshold for CNS toxicity
Metabolic acidosis
Protein binding of the drug decreases
More free drug available
Enhanced toxicity
d.Plasma clearance: Plasma clearance of esterases is reduced in patients having
pseudocholinesterase deficiency while clearance of amides is reduced in liver
diseases and conditions associated with reduced hepatic blood flow.

142. 134Comparative Pharmacology for Anaesthetist
e. Toxicity of local anesthetics are additive whether amides or esters.
f. Seizure threshold is increased in presence of other CNS depressants (i.e.
thiopentone, midazolam).
RESPIRATORY ACIDOSIS
Increased PaCO
2
Increased cerebral blood flow Diffusion of CO
2 Fall in body pH
into neuronal cells
More local anesthetic is Intracellular De creased protein
delivered to the brain acidosis binding of local anesthetic
Increased toxicity Base form of the drug changes Increased free drug
to cationic form
Cationic form fails to diffuse out More drug diffuses into brain
of the neuronal cells
Increased toxicity
Ion trapping
Increased toxicity

143. Local Anaesthetics135
MANAGEMENT OF CNS TOXICITY
Management is mainly supportive. Endotracheal intubation is done and mechanical
ventilation started to prevent aspiration, hypoxemia and respiratory acidosis.
Hyperventilation induced reduction in PaCO
2
cause cerebral vasoconstriction and
reduced local anesthetic delivery to the brain. Thiopentone and benzodiazepines are
used to control seizure.
LOCAL TISSUE TOXICITY OF LOCAL ANESTHETICS
TRANSIENT RADICULAR IRRITATION
CLINICAL FEATURES
Pain and burning sensation in lower back, buttocks and posterior thigh. Symptoms
appear within 24 hrs of recovery from spinal anesthesia and last upto one week.
Pathophysiology
Pathophysiology behind transient radicular irritation is direct inflammation of
lumbosacral nerves caused by local anesthetic. Lidocaine is more commonly associated
with this complication as compared to bupivacaine or tetracaine.
Diagram showing ion trapping seen in respiratory acidosis

144. 136Comparative Pharmacology for Anaesthetist
Factors Affecting Neurotoxicity
a. Patient position: Injury is exaggerated when nerves are stretched in lithotomy
position.
b. Obesity and outpatient anaesthesia are considered to increase the risk of transient
radicular irritation.
c. The incidence of transient radicular irritation is unaffected by concentration of
lidocaine, needle type, gender and history of back pain.
d. Vasoconstrictors can theoretically increase the risk of irritation by increasing the
duration of exposure to local anaesthetic.
CAUDA-EQUINA SYNDROME
Clinical Features
Sensory deficit, bowel bladder dysfunction and paraplegia due to diffuse lumbo
sacral plexus injury.
Mechanism of Injury
Use of microcatheters for continuous spinal anaesthesia
Extremely slow rate of injection of 5 percent lidocaine
Pooling of local anaesthetic in most dependant portion of subarachnoid space
High concentration of local anaesthetic achieved, resulting
into sustained diffuse injury of lumbosacral plexus
Irreversible neurotoxicity
ALLERGIES DUE TO LOCAL ANAESTHETIC
Ester LAs have more tendency to cause allergic reactions than amide drugs, reason
being their common metabolite Para amino benzoic acid which is allergenic.
Hypersensitivity reactions occur in the form of anaphylaxis and atopy. Atopic
reaction are more common and they manifest as local edema with or without
lymphadenopathy. Other allergic manifestations include dermatitis, asthma, rashes
etc. Allergy to amide LA is rare but they contain methylparaben as preservative in
their commercial preparation. This compound has structural similarity with PABA
and can produce allergies.

145. Local Anaesthetics137
Cross sensitivity does not exist between classes of local anaesthetics (ester and
amide). A patient allergic to ester may have no allergy with amide local anesthetics.
COMPARATIVE STUDY OF LIGNOCAINE AND BUPIVACAINE
Lignocaine Bupivacaine
Chemical nature It is a tertiary amide which is an amide
derivative of diethylamino acetic acid
It is an amide which is a structural
analogue of mepivacaine
Routes of
administration
It is used for infiltration, topical,
intrathecal and epidural anesthesia.-
Drug is used for peripheral nerve
blocks and also via, intravenous route
for ventricular arrhythmias, TIVA.
It may be given by infiltration,
intrathecally or epidural route.Drug is
also used for peripheral nerve blocks.
Dose For intravenous route :-1 to 1.5 mg/
kg preservative free solution
Toxic dose
> 3 mg/kg without adrenaline
> 7 mg/kg with adrenaline
Toxic dose > 2 mg/kg with or without adrenaline
Pharmacokinetics(a) Drug is 64 percent protein bound (b) 70 percent of the dose is metabolized in the liver.
(c) Lignocaine
dealkylation Liver
and hydrolysis
Monoethylglycine
+ xylidide
(Excreted in urine after further
metabolism)
(d) monoethylglycine has 80 percent
antiarrythmic activity of parent
compound. While xylidide has
minimal antiarrythmic action.
(e) Hepatic disease and reduced
hepatic blood flow as seen in CHF,
decrease the rate of lignocaine meta-
bolism. Its clearance is prolonged in
pregnancy induced hypertension and
malnutrition also.
(a) The drug is 95 percent protein
bound, mainly with α
1
acid
glycoprotein. If plasma protein binding
sites are saturated or interfered with
other compounds such as bilirubin,
propanol etc, free drug levels are
increased leading to toxicity appearing
at lower doses.
(b) Bupivacaine
N-de
alkylation Liver
Pipcolylxylidine
Other compounds like N-desbutyl
bupivacaine and 4 hydroxy bupivacaine
are also formed.
Excretion of the metabolites is via urine.
Onset and duration
of action
Onset of action is within 2 to 20
minutes, depending on the route of
administration. Duration of action is
between 1 to 3 hours depending upon
the presence of vasoconstrictors and
concentration used.
The drug acts within 10-20 minutes and
has a duration of action of 2-8 hours.
Addition of adrenaline to bupivacaine
solution does not prolong the duration
of action significantly.

146. 138Comparative Pharmacology for Anaesthetist
ROPIVACAINE
Chemistry
Amide local anesthetic. Structure similar to bupivacaine except for substitution of a
propyl group for the butyl group on the piperidine ring. Commercial preparation is
pure s-isomer.
Salient Features
• Safer alternative to bupivacaine due to less cardiac and CNS toxicity.
• Onset, potency, duration of action similar to bupivacaine.
• Lipid solubility little less than bupivacaine so possess higher therapeutic index.
• Cardiotoxic profile appears to be same in pregnant as well as nonpregnant animal
studies.
PRILOCAINE
Chemistry
It is an amide local anaesthetic derived from toluidine.
Salient Features
• Many properties (potency, speed of onset, protein binding) are similar to lignocaine.
• CNS and cardiovascular toxicity is less than that of lignocaine.
• maximum dose should not be more than 6 mg/kg.
EMLA
Eutectic mixture of local anaesthetic.

147. Local Anaesthetics139
Chemistry
It contains 2.5 percent lidocaine with 2.5 percent prilocaine in an emulsion form.
The term eutectic refers to lowering of melting point of two solids when they are
mixed together.
Salient Features
• It is a white cream used for anesthesia of intact skin (topical anesthesia). It is not
recommended over mucous membranes or open wounds as the fast rate of
absorption can lead to systemic toxicity.
•Method of application:- Usually 1-2 gms of cream is applied over 10 cm
2
area under
an occlusive dressing. Dressing is opened after 1-2 hrs, anesthesia achieved lasts
for around 2-4 hrs.
Uses
• Topical anesthesia before venipuncture, arterial cannulation, lumbar puncture,
circumcision.
• IV cannulation in children.
• Split-skin grafting as anesthesia achieved is around 5 mm deep.
BENZOCAINE AND BUTYLAMINOBENZOATE
They are used for topical anesthesia. Due to their low water solubility, they are not
absorbed through mucous membranes and open wound. 5 percent Benzocaine is
used for anal fissures, painful piles and proctoscopy. It is also used as lozenges for
sore throat and stomatitis.
OXETHAZAINE
Used along with antacids for relief of reflux oesophagitis and gastritis.
DIBUCAINE (CINCHOCAINE)
• This is the most potent and toxic local anaesthetic.
• It is metabolized in liver and is the most slowly eliminated of all amide derivatives.
• It is used as 1 percent ointment/cream for topical anaesthesia.

148. Miscellaneous Drugs 9
FUROSEMIDE
•Chemistry:- anthranilic acid (sulphonamide) derivative.
•Commercial preparation:
Injectable:- 10 mg/ml drug as clear colourless solution for injection.
Tablets:- 40 mg tablets are available. This drug is also available as fixed dose
preparation with spironolactone, amiloride, potassium etc.
•Mechanism of action:
Diagram showing site of action of furosemide
Site of Action
a. Its main site of action is in thick ascending limb of loop of Henle where it acts by
blocking Na
+
K
+
2Cl
–
channel.
It reaches its site of action via secretion through anion transport pump present in
proximal convoluted tubule.

149. Miscellaneous Drugs141
Na
+
and Cl
–
absorption in thick ascending limb of loop of Henle occurs via Na
+
–
K
+
– 2Cl
–
carrier which is present on the luminal membrane of tubular epithelium.
Energy for this process is obtained from NaKATPase pump present on the basolateral
membrane of tubular epithelum. This pump maintains a low concentration of Na
+
in
intracellular compartment which favours Na
+
reabsorption from tubular lumen.
Diagram showing mechanism of action of Na
+
– K
+
– 2Cl
–
carrier
Furosemide binds with Cl
–
site on the carrier and reduce net Na
+
reabsorption.
Thus tubular lumen becomes rich in Na
+
concentration and a high Na
+
load is delivered
to distal convoluted tubule. Solute loss results in water loss as well. Thus diuresis
and natriuresis result.
Diagram showing secretion of furosemide

150. 142Comparative Pharmacology for Anaesthetist
Other Actions of Furosemide
Furosemide
Increased synthesis of renal Prostaglandins
Local vasodilation and enhanced renal blood flow.
Changes in pressure relationship between Redistribution of blood in inner
various compartments (vascular, interstitial, corticomedullary region.
tubular)
Corticomedullary gradient lost
Reabsorption in PCT is reduced
Concentrating ability of kidney is lost
Enhanced diuresis
a. Furosemide shifts fluid from pulmonary circulation to systemic circulation. This
action is prostaglandin mediated and helps in relief of symptoms in pulmonary
edema patients. This action appears even before diuretic action.
b. It is a diabetogenic drug.
Pharmacokinetics
• Onset of action
Route Onset
Oral 20 – 40 minutes
I.V. 2 – 5 minutes
I.M. 10 – 20 minutes
•Duration of action: 3 to 6 hrs. t
1/2
is 1–2 hrs but may be prolonged in renal and
hepatic disease patients.
•Protein binding: Highly protein - bound. (around 90 – 95%) Because this drug is so
highly protein bound it is not filtered through glomerulus. It reaches its site of
action via secretion through organic anion transport pump. The drug’s ability to
cause diuresis depends on this transport pump.
•Dose:
– Bolus dose ranges from 10 to 80 mg depending upon the creatinine clearance.
–Infusion:- 1 – 4 mg/kg/hr
– Patients with higher serum creatinine require larger bolus to produce a given
amount of diuresis.

151. Miscellaneous Drugs143
SIDE EFFECTS OF DIURETIC THERAPY
1.Volume depletion:- Drug dose should always be titrated with the amount of diuresis
one wants to achieve. Over enthusiastic use of diuretic therapy can lead to severe
volume depletion and Hypotension.
Volume depletion
Decreased preload
Fall in cardiac output
Decreased renal perfusion
Prerenal azotemia
2.Hypokalemia:- Furosemide cause increased Na
+
delivery in DCT and collecting
ducts. This results into more K
+
excretion in exchange for Na
+
reabsorption. On
the otherhand volume depletion promote aldosterone secretion which again cause
hypokalemia.
Mechanism of hypokalemia
Increased delivery of Na
+
Enhanced secretion of aldosterone
and H
2O to the DCT due to volume depletion
Na
+
is reabsorbed and K
+
secreted Aldosterone promotes K
+
loss
Enhanced K
+
loss in urine Hypokalemia
Hypokalemia

152. 144Comparative Pharmacology for Anaesthetist
3.Metabolic alkalosis:-
Mechanism
Furosemide cause volume Volume depletion hypokalemia itself is an
loss from the body important cause of metabolic
alkalosis. In order to conserve
enhanced aldosterone K
+
ions, body secretes H
+
ions
secretion in urine, to maintain electro
neutrality. H
+
ions loss cause
Contraction of extracellular metabolic alkalosis
volume around a constant H
+
ion loss in urine
amount of ECF HCO
3

results
in metabolic akalosis
metabolic alkalosis
the thick ascending limb of loop of henle possess two mechanisms for Na
+
reabsorption. One is Na
+
- K
+
- 2 Cl
–
cotransport and other is Na
+
- H
+
exchanger. Furosemide inhibits the Na
+
- K
+
- 2 Cl
–
cotransport

as a result Na
+
- H
+
exchanger becomes more active and H
+
ions loss results.
4.Hypocalcemia:- Reabsorption of Ca
+2
ions in thick ascending limb of loop of Henle
occurs passively along with Na
+
& Cl
–
absorption and hence a parallel reduction
in Ca
+2
reabsorption occurs.
5. Hypomagnesemia
6. Hyperuricemia
7. Being a sulphonamide derivative it can cause hypersensitivity, rashes and
hyposensitivity.
8. High doses can cause interstitial nephritis. Transient auditory nerve damage and
pancreatitis have also been reported.
DRUG INTERACTIONS
1. Furosemide + Aminoglycosides → Increased ototoxicity
2. NSAIDs inhibit prostaglandin synthesis and cause decrease in its efficacy.
3. Probenecid inhibit tubular secretion of furosemide.
4. Enhances neuromuscular blockade by reducing transmitter release at nerve
terminal. Moreover hypokalemia produced by the drug potentiates neuromuscular
blockade even further.
METOCLOPRAMIDE
Chemistry:- It is a procainamide derivative but does not possess antiarrhythmic
properties like it.
Presentation:- As 10 mg tablets, and colorless solution for injection containing 5 mg/
ml of metoclopramide hydrochloride for injection.

153. Miscellaneous Drugs145
Pharmacokinetics:-
1.Absorption:- Rapidly absorbed by oral route. Oral bioavailability is around 30 – 90
percent. Wide variation is seen due to high first pass metabolism.
2.Distribution:- 10 – 20 percent protein bound. It crosses placenta, blood brain barrier
and is secreted in milk.
3.Metabolism:- Partly conjugated in liver to form sulphate derivative.
4.Excretion:- It is excreted via kidneys within 24 hrs. Dose reduction is required in
renal disease.
Action
Onset:-after oral use – 30 minutes to 45 minutes
IM injection – 10 minutes
IV injection – 2 minutes
Duration of action:- 4 to 6 hrs
Dose:-Oral 10 mg 8 hrly in 50 kg adults.
• 0.2 to 0.5-mg/kg I.V. for prevention of nausea and vomiting and aspiration
prophylaxis.
• Upto 1 mg/kg I.V. for chemotherapy induced vomiting.
Side Effects
1. Most commonly occuring side – effects are abdominal cramps due to increased
peristalsis; drowsiness and dizziness due to central action.
2 Extrapyramidal side – effects are seen when drug is used in high doses, in patients
with renal failure and extremes of age. Extrapyramidal side – effect that is most
commonly seen with this drug is akathisia. It manifests as a generalized state of
restlessness, agitation and discomfort. Other extrapyramidal adverse effects include
muscle dystonias.
3. Long-term use lead to sustained hyperprolactinemia which manifests as
galactorrhea and gynaecomastia.
Used for
a.acid aspiration prophylaxis:- It helps in the following ways
i. Increased LES tone.
ii. Decreased gastric acid volume due to prokinetic action.
iii. Antiemetic action.
b.Chemotherapy induced vomiting.
c.postoperative nausea vomiting.

154. 146Comparative Pharmacology for Anaesthetist
PROKINETIC ——— Metoclopramide mechanism of action ——— ANTIEMETIC
Dopamine antagonistCholinomimetic action 5HT
3
antagonism
(through D
2
receptors)seen with high doses
Enhanced Ach release in GIT neurons
Peripheral action Central action— hasten gastric emptying (Prokinetic)
— hasten gastric emptying — D
2
blockade at CTZ has — increased lower oesophageal tone.
— increased lower oesophageal central antiemetic action
tone—hyperprolactinemia
— extrapyramidal symptoms
PeripheralCentral
— 5HT
3
receptors are — antiemetic
present on vagal action on CTZ
afferents. Their
antagonism cause
decrease input to
vomiting center in brain.

155. Miscellaneous Drugs147
ONDANSETRON
(5HT3 Antagonist)
Presentation:- As a clear colorless solution for injection containing 2 mg/ml of
ondansetron hydrochloride dihydrate. 2 ml and 4 ml ampoules are available, 4 and
8 mg tablets are also available.
Chemical nature:- synthetic carbazole.
Mode of Action:-
Dual mode
Peripheral action Central action
Blocks 5HT
3
Blocks 5HT
3
receptors present receptors
on vagal afferents in CTZ
in GIT
Thus it block afferent pathway as well as central processing of emetogenic impulses.
Dose:- 0.06 mg/kg via. i.v. route
0.1 mg/kg via oral route
Drug dose can be repeated every 4-6 hrly
Effects:-
CVS : none
RS : none
CNS : none
GIT : antiemetic; no effect on gastric motility but large bowel transit time is
increased.
Side-effects:
– Constipation
– Headache/flushing
– Elevation of liver enzymes.
PHARMACOKINETICS
Rapidly absorbed orally. Oral bioavailability is 60 - 70 percent. Drug is 76 percent
protein bound. It is extensively metabolized in liver by both phase I and phase II
reactions. Phase I reactions include hydroxylation and demethylation while phase II
reactions include glucuronide and sulphate conjugation .
Hepatic impairment significantly prolongs its half life. No dose alteration is needed
in renal impairment.

156. 148Comparative Pharmacology for Anaesthetist
Mephentermine Ephedrine
Commercial
preparation
- Clear, colorless solution for
injection containing 30 mg/ml of
mephentrimine.
- Tablet Preparations are also
available as 10 – 20 mg oral.
Clear colorless solution for injection
containing 30 mg/ml of ephedrine
sulphate.
15/30/60 mg tablets are availabe. 0.75
percent nasal drops are also available.
Chemical nature Sympathomimetic amine (non
catecholamine) [Note: -
catecholamines are the drugs that
require cAMP for their action]
Sympathomimetic amine (non
catecholamine)
Mechanism of actionDirect - α and β receptor
stimulation. This drug is relatively
α1 selective.
Indirect:- Causes release of
norepinephrine from its stores.
Due to its relative selectiveness
direct positive chronotropic effect
on heart is generally counter
balanced by vagal stimulation
due to rise in BP (both systolic
and diastolic). Bradycardia can
occur depending on the degree
of vagal tone.
Direct: α and β receptor stimulation. This
drug causes marked β stimulation.
Indirect:- Causes release of norepine- phrine from its stores.
Due to its marked β stimulation, it is useful
in hypotension associated with
bradycardia.
Clinical use The drug is used for hypotension
during spinal anesthesia. A dose
of 5-30 mg is titrated according
to the response. Due to its
marked α agonist action this
drug is inferior to ephedrine in
pregnant patients; α agonist
action causes decreased uterine
blood flow and fetal compro-
mise.
Clinical use is similar to mephentrimine
except for the fact that this drug restores
maternal blood pressure as well as uterine
blood flow due to its β action. Dose for
hypotension after neuraxial blockade is
from 3 to 30 mg depending upon the
response.
Ephedrine mimics all the actions of
adrenaline. The only difference is that, it
is 100 times less potent than adrenaline. It
causes increase in cardiac output, heart
rate, force of cardiac contraction as well
as myocardial oxygen consumption.
Myocardial irritability is also increased.
This drug is also a respiratory stimulant
and causes bronchodilation. Cerebral
blood flow is increased. Renal blood
vessels undergo vasoconstriction similar
to adrenaline. This causes fall in renal
blood flow and GFR.
Onset and duration of
action
On IV administration onset of
action is rapid and duration
around 1 hr.
When given intravenously the onset of
action is rapid, the duration lasts for about
1 hr.

157. Miscellaneous Drugs149
Common points about both the drugs
Mephentrimine and ephedrine are not a substrate for MAO and so they are active
orally and their duration of action is longer.
Both these drugs show phenomenon of tachyphylaxis. Noradrenaline stores are
depleted after repeated drug administration. This leads to tolerance to indirect action
of the drug. One should remember that all sympathomimetic amines are capable of
producing tolerance or tachyphylaxis.
CORTICOSTEROIDS
Adrenal glands are located on upper pole of kidneys.
The gland consists of two parts – outer cortex and an inner medulla.
Adrenal cortex secretes compounds having a cyclopentaperhydrophenanthrene
nucleus (corticosteroids).
Adrenal medulla secretes catecholamines.
secretes • Cortisol
CORTEX •Aldosterone
• DHEA (precursor of testosterone)
secretes
MEDULLA
• Catecholamines
ADRENAL
GLAND
The actions of steroid can be classified into two groups.
1. Mineralocorticoid actions – Increased reabsorption of Na
+
from urine, sweat, colon.
– Increased K
+
and H
+
excretion in urine. (via exchange of Na
+
)
2. Glucocorticoid actions- Increase blood glucose levels (↑ glucose release from liver,
↓ tissue utilization of glucose)
– Increased lipolysis (↑ breakdown of triglycerides)
– Increased protein catabolism
– Suppression of inflammation (Main effect for which steroids are used clinically.
They prevent recruitment of inflammatory cells, interfere with complement
system, decrease production of acute phase reactants. However, steroids don’t
influence the cause of inflammation).
– Decreased absorption of Ca
2+
from GIT, increased resorption of Ca
2+
from
bone (osteoporotic action).
– Stimulate secretion of gastric acid.
– Inhibit allergic/hypersensitivity reactions.
– Permissive actions – Corticosteroids themselves don’t cause a particular action
but a critical level of steroid should be present for optimum physiological
activity e.g. bronchodilation, hemodynamic response to catecholamines, lipolysis
by GH, and glucagon.

158. 150Comparative Pharmacology for Anaesthetist
– Maintenance of normal GFR, secretory activity of Renal tubules, vasomotor
tone requires corticosteroids. These functions makes Adrenal Cortex essential
for life.
Compound Glucocorticoid a ction Mineralocorticoid action
a. Glucocorticoids– Short acting – Hydrocortisone 1 + 1 +
(t
1/2
< 12 hr)
– Intermediate. Acting
– Methylprednisolone 5 + 0.5 +
(t
1/2
– 12 – 36 hr)
– Long acting – Dexamethasone 25 + –
(t
1/2
> 36 hr)
b. Mineralocorticoid – fludrocortisone 10 + 150 +
Hydrocortisone – This compound has equal gluco - and mineralocorticoid activity. If
given orally, it undergoes a high 1st pass metabolism. It is highly bound to plasma
proteins.
Dexamethasone – It’s a highly potent steroid and causes suppression of HPA axis.
Steroids are metabolized by hepatic microsomal enzymes.
ROLE OF STEROIDS IN ANESTHETIC PRACTICE
Under normal conditions, Adrenal glands secrete 10 mg Cortisol/day. In stress, this
level can increase upto 200 – 300 mg/day. A person may have normal basal output
but may not be able to increase cortisol secretion in times of stress. (during surgery,
trauma, pain).
In a surgical patient, it may be very difficult to ascertain whether cortical deficiency
is present or not.
H/O weakness/wt. loss/skin pigmentation is a sensitive indicator of corticosteroid
deficiency. In perioperative period if hypotension persists even after adequate
resuscitation with fluid and inotropes, one can consider adding steroids in such
patients.
Use pf exogenous steroids can cause functional suppression of adrenal cortex. If a
pt. has received more than 20 mg/day prednisolone (or its equivalent dose of other
steroid) for 3 weeks or more in 12 months preceding surgery, he/she can be considered
to have functional suppression of HPA axis.
For a pt. who is taking steroids and needs to undergo a surgery the
recommendations are –
Minor/Moderate surgery – Usual dose + 50 – 75 mg Hydrocortisone I/V on
operative day (taper over 1 – 2 days).
Major Surgery – Usual dose + 100–200 mg Hydrocortisone I/V (taper over 2–3
days)
Critically ill pt./Emergency extensive surgery usual dose + Hydrocortisone 100
mg I/V 8 hrly until pt. is hemodynamically stable.
Monitor Na
+
, K
+
, glucose levels and taper dose over 5–7 days.

159. Miscellaneous Drugs151
OTHER USES
• As replacement therapy (in Addison’s disease). Hydrocortisone is used as it has
both mineralocorticoid and glucocorticoid actions. Routine dose is 20–30 mg/d.
Major amount of dose is given in morning to mimic the natural secretion of cortisol.
• Raised Intracranial tension – Dexamethasone 4 mg I/V is given 6 hrly. It is preferred
as it has got only glucocorticoid actions. Raised ICT due to tumour/abscess is
better controlled with steroids. These drug aren’t so effective in raised ICT due
to trauma/bleeding.
• Asthma – Corticosteroids aren’t bronchodilators but they decrease airway
inflammation hence used during acute exacerbation of COPD, Asthma. For chronic
use inhalation route is preferred.
For acute attack 120 mg Methylprednisolone I/V can be given 6 hrly and after
termination of a cute episode, switch over to oral steroids.
• For allergic/hypersensitivity reaction – corticosteroids can minimize the clinical
symptoms.
• Joint diseases (Rheumatoid Arthritis, osteoarthritis etc) and collagen diseases –
In joint diseases, steroids are used along with NSAIDs. Intraarticular injection of
corticosteroids can also be given in selected cases.
For collagen diseases (SLE, Dermatomyosits, Nephrotic Syndrome), Steroids are
preferred drugs. They can induce remission of disease.
• Pain management – steroids can be given via systemic/epidural route or used
topically.
Epidural injection is given to pt. of low back pain (d/t disc herniation, lumbosacral
joint sprain). Steroids decrease nerve root edema and provide relief from pain.
Upto 2 – 3 injection can be given at an interval of 1-2 weeks.Majority of pt. get
relief with use of 3 injection max. However TB of spine is a contraindication to
their use.

160. Index
A
Allergies due to local
anaesthetic 136
Anticholinergic drugs 102
clinical significance 105
Anticholinesterases 107
classification 107
comparative study 112
factors affecting reversal of
neuromuscular
blockade 111
minimizing the side
effects 111
pharmacodynamics 113
physostigmine 114
reversal of neuromuscular
blockade 110
B
Butorphanol 49
C
Cardiac output 58
Cardiovascular system 37
blood pressure 37
cardiac contractility 37
heart rate 37
Cauda-Equina syndrome 136
clinical features 136
mechanism of injury 136
Central nervous system 41
effect on mood and
subjective
behaviour 41
pruritis 41
shivering 41
Central nervous system
toxicity 132
factors affecting CNS
toxicity 133
plasma clearance 133
potency 133
rate of drug administ-
ration 133
respiratory and meta-
bolic acidosis 133
management of CNS
toxicity 135
mechanism 132
symptoms 133
Comparative study of
lignocaine and
bupivacaine 137
Complex action opioids 47
buprenorphine 48
routes of administration
49
pentazocine 48
chemistry 48
dependence 48
pharmacokinetics 48
Concentration effect 59
augmentation of tracheal
inflow 60
concentrating effect 60
D
Diffusion hypoxia 75
clinical significance 75
Doses of common opioids 53
Doses of succinylcholine 9
side effects 9
Drug interactions of muscle
relaxants 19
antibiotics 21
clinical significance 21
local anaesthetics 20
clinical significance 20
magnesium 20
clinical significance 21
volatile anaesthetics 19
clinical significance 20
E
Enzyme pseudocholinesterase 8
atypical pseudocho-
linesterase 8
F
Factors affecting arterial
concentration 61
effect of dead space 61
effects of shunts 61
Factors affecting cardiotoxicity
of local anaesthetics
131
acidosis and hypoxia 131
drugs 131
pregnancy 131
Factors affecting inspiratory
concentration 55
factors affecting alveolar
concentration 56
equilibrium 56
partial pressure 56
partition coefficient 56
Factors affecting non-depola-
rizing blockade 22
age 24
elderly 24
infants 24

161. 154Comparative Pharmacology for Anaesthetist
hepatic dysfunction/
failure 23
drug partially dependent
on liver for meta-
bolism or excretion
or both 23
drugs independent of
hepatic metabolism
or excretion 23
drugs largely dependent
on liver for meta-
bolism or excretion
or both 23
renal dysfunction/failure 22
clinical significance 22
temperature 25
Factors affecting recovery
from inhalational
anaesthesia 61
metabolism 62
solubility and duration of
anaesthesia 61
Fasciculations (presynaptic
event) 11
phase I block 11
clinical significance 12
phase II block 12
clinical significance 12
mechanism 12
Fate of inhaled anaesthetic 54
G
Gastrointestinal system 42
H
Hormones and endocrine
system 42
allergy 43
immunity 43
I
Inotrope/vasopressor 99
recent advances 101
renal dose dopamine 101
Intravenous induction
agents 76
cardiovascular effects 83
effect on respiratory
system 85
side effects and
complications 87
central nervous system 82
commercial preparation 76
contraindications 89
mechanism of action 78
pharmacodynamics 81
neurotransmitters in the
brain 81
pharmacokinetics 79
structure – activity
relationship 77
L
Lipophilic vs hydrophilic
opioids 44
Local anaesthetics 115
characteristics of blockade
118
classification 116
based on chemical
linkage 116
based on duration of
action 117
commercial preparation 115
factors affecting pharmaco-
kinetics 126
fate of local anaesthetic 125
in vivo properties 122
concentration effect 124
differential conduction
blockade 123
mantle effect 124
tissue penetrance 123
vasodilation 122
mechanism of action 117
pharmacokinetics 124
properties 120
dissociation constant
(Pka) 121
frequency dependent
blockade 122
lipid solubility 120
protein binding 121
structure – activity relation-
ship 115
Local tissue toxicity of local
anesthetics transient
radicular irritation
135
clinical features 135
factors affecting neuro-
toxicity 136
pathophysiology 135
M
Minimum alveolar concent-
ration (MAC) 64
advantages 64
factors affecting MAC in
humans 64
MAC values 65
pharmacodynamics 65
Miscellaneous drugs 140
corticosteroids 149
role of steroids in
anesthetic practice
150
furosemide 140
commercial preparation
140
mechanism of action 140
pharmacokinetics 142
site of action 140
metoclopramide 144
action 145
side effects 145
ondansetron 147
chemical nature 147
mode of action 147
Muscle rigidity 39
N
Nalbuphine 50
Nalmefene 51
Naltrexone 51
Neuraxial opioids 43
fate 44
mechanism 43
side effects 45
clinical relevance 45
pruritis 46
respiratory depression 45

162. Index155
risk factors for
respiratory
depression 45
sedation 45
urinary retention 46
Neuromuscular junction 1
muscle terminal 1
nerve terminal 1
Nitrous oxide 72
manufacture 72
mechanism of action 73
metabolism, toxicity 74
pharmacodynamics 73
properties 73
storage/commercial
preparation 73
Nitrous oxide and closed gas
spaces 74
clinical significance 75
Non-depolarising muscle
relaxant 13
classification 13
on the basis of action 13
on the basis of chemical
structure 13
O
Opioid antagonists 50
formulation and adminis-
tration 50
pharmacokinetics 50
renarcotization 50
Opioid receptors 27
analgesia (pain control)
system of the body
30
location 27
classification 27
mechanism of action 29
OP
1
(d) receptor 28
OP
2 (k) receptor 28
OP
3
(ì) receptor 28
s (SIGMA) receptors 29
Opioids 26
classification 26
on the basis of action 27
on the basis of origin 26
on the basis of structure
26
P
Partial pressure difference
between alveolar
gas and venous
blood 58
Pethidine 52
Pharmacodynamics 36
analgesia 36
Pharmacokinetics of 33
alfentanil 35
fentanyl 34
meperidine 34
morphine 33
remifentanil 35
Postsynaptic structure and
events in impulse
transmission 4
Ach receptors 4
adult/mature Ach
receptor 5
fetal/extrajunctional Ach
receptor 5
Presynaptic structure and
events in impulse
transmission 1
synaptic cleft 3
synthesis of acetylcholine 3
presynaptic Ach
receptors 3
R
Respiratory system 38
clinical relevance 39
delayed respiratory
depression 39
respiratory rate and tidal
volume 38
ventilation 38
S
Schwann cells 1
Second gas effect 60
Sodium channels 6
activated state 6
inactive state 6
resting state 6
Succinylcholine 7
chemistry 7
pharmacokinetics 7
Systemic toxicity of local
anesthetics 130
cardiovascular toxicity 130
cardiotoxicity of LA 130
T
Tramadol 53
V
Ventilation 59
Volatile anaesthetics 54