Comparative pharmacology for anesthetics PDF

Comparative Pharmacology
for Anaesthetist

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
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First Edition : 2008
ISBN 978-81-8448-406-9
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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

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

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.

2 Comparative 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.

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.

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

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.

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

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.

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.

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
Et Et Typical 70 – 80 Normal
Et Ea Atypical heterozygous 50 – 60 Slightly prolonged (15–20 minutes)
Ea Ea 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 pressure Sustained 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...

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

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

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.
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.

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

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.

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 H1 and H2 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.

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 NM type NN 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 ED95
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 NM 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.

Contd...
COMPARATIVESTUDYOFCOMMONLYUSEDMUSCLERELAXANTS
PancuroniumAtracuriumVecuroniumRocuronium
ChemicalBis-quaternaryItisaStructuresameasAminosteroid
Structureaminosteroid.benzylisoquinoliniumesterpancuroniumbut
withoutquaternary
methylgroup.
(monoquaternary
aminosteroid)
MetabolismPancuroniumAtracuriumVecuroniumRocuronium
3,desacetylpancuroniumquaternaryalcoholLaudanosine+→→→→→Modestprolongation
++quaternary3,desacetylvecuroniumofdurationofactionseen
17,desacetylpancuroniumquaternaryacidmonoacrylate+17,desacetylvecuroniumwithhepaticfailure.
++3,17desacetylvecuronium→→→→→Pharmacokineticsnot
3,17desacetylpancuroniumaffectedmuchin
→→→→→3desacetylderivative→→→→→3,desacetylderivativerenalfailure.
hasneuromuscularmetaboliteshaveinsignificanthas80percentactivity
blockingproperty.actiononNMJ.ofparentcompound
15–30%
proteininbond
10to40%
85%excreted
unchangedvia
urineLiver
deacetylation
Major
pathway
HYDROLYSIS
bynonspecific
esterasesin
blood
HOFFMANN
elimination
Metabolism
Minor
pathway
82%protein
bound
Major
pathway
30%
protein
bound
excreted
unchanged
byliver
Minor
pathway
excreted
unchanged
inurine
40%excreted
unchangedin
bile
60-90%
protein
bound
15%excreted
unchanged
inurine
30-40%
metabolized
byliver

→→→→→ActionprolongedinHoffmannelimination→→→→→Durationofaction
renalfailure.BothItisachemicalprocessresultingisprolongedafterrepeated
hepaticandrenalintononenzymaticdegradationofdosinginpatientofhepatic
atracuriumtoquaternarymonoacrylateandrenaldysfunction.
dysfunctionrequireandlaudanosine.Itisnotaffectedby
dosemodification.hepatic,renal,cholinesteraseactivitybut
increasedbyincreaseintempreature.
Thechemicalprocessisdecreased
inhypothermiaandacidosis.
Laudanosine
→→→→→Principalmetaboliteof
atracuriummetabolism.
→→→→→accumulatesafterprolonged
infusioninrenalfailurepatients.
→→→→→CausesCNSstimulationandseizures.
Itdoesnotpossesanyneuromuscular
blockingproperty.
Sideeffects•Thereisincreasein•Histaminereleasecanoccuriflarge•Itisdevoidofany•Itdoesnotcause
heartrate,bloodbolusesareusedleadingtoHypotension,significantcardio-histaminereleaseeven
pressureandtachycardiaandbronchospasm.vasculareffect.whengivenaslarge
cardiacoutputduetoHoweverthereareboluses.
vagolyticactionandreportsofbradycardiain•Possesssome
catecholaminerelease.patientsreceivingvagolyticproperty
•Whencombinedwithvecuronium,whennowhichcanbeuseful
halothaneandprioranticholinergicagainstbradycardia
tricyclicantidepressantsdrugisusedduringcausedbyvagal
lifethreatningarrhythmiaspremedication.stimulationduring
canoccur.•Lackshistaminesurgicalprocedures.
•Cautionisrequiredwhilereleasepotential.(peritoneumhandling,
useinpatientswithophthalmologic
borderlinecardiacreserve.surgeries).
Contd...
PancuroniumAtracuriumVecuroniumRocuronium

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

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 > N2O/O2/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.
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
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

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)
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

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
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.

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.

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.
• 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.
• 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.

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.

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 •Phenylpiperidinederivatives
• 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

Opioids 27
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
OP3 µ - mu 1, 2, 3
OP2 κ - Kappa 1, 2, 3
OP1 ∂ - delta 1, 2, 3

OP3 (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. µ1 mediate
supraspinal analgesia.
µ2 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 (µ1)
Spinal (µ2)
• Respiratory depression (µ2)
• Constipation (µ2)
• Sedation
• Euphoria
• Miosis
• Depression of cough reflex (µ2)
• Attenuation of baroreceptor reflex
OP2 (κκκκκ) Receptor
Agonist :- Ketocyclazocine and Dynorphin A.
Selective antagonist :- Norbinaltorphimine.
Action
κ3 receptors mediate supraspinal analgesia while κ1 receptors are important for spinal
analgesia.
Actions of K receptors
• Analgesia
supraspinal (κ3)
spinal (κ1)
• constipation
• sedation
• Dysphoria, hallucinations
• Miosis (lower ceiling)
• Increased diuresis

Opioids 29
OP1 (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

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.

Opioids 31PHARMACOKINETICSOFOPIOIDS—ACOMPARATIVESTUDY
MorphineMeperidineFentanylAlfentanilSufentanilRemifentanil
PKa8–8.46.58.07.07
AbsorptionWellabsorbedBio-availabilityThesedrugsarenormallyusedviaintravenousroute.
afteroralwhengivenorally.afteroral
administrationBecauseofhighadministration
hepaticextractionis45-75percent
ratio,oralbio-dueto
availabilityissignificantfirst
20-30percent.passeffect.
Whenmorphine
isgivenorally
morphine-6-
glucuronideis
theprimary
activecompound.
LipidsolubilityLowHigherthanHighlylipidLipidsolubilityTwiceaslipidHighlylipidsoluble
morphinesoluble.lessthansolubleas
fentanylbutfentanyl
stillhighly
lipidsoluble.
Proteinbinding10-20percentHighlyprotein80percent90percent93percent70percentprotein
mostlywithboundmostlyproteinbinding,proteinboundproteinbound,bound,mainlywith
albuminwithα1acidmostlywithα1withα1acidmainlywithα1α1acidglycoprotein
glycoproteinacidglycoproteinglycoproteinacidglycoprotein
Unionized10-20percent<10percent<10percent90percent20percent60-70percent
fractionat
PhysiologicalpH
Notethatalfentanilhasremarkablyhighunionizedfractionfollowedbyremifentanil.
Thisleadstohigherdiffusiblefractionavailableforbrainpenetration
Contd..

Contd..
MorphineMeperidineFentanylAlfentanilSufentanilRemifentanil
PKa8–8.46.58.07.07
FateinthebodyThedrugshowsSignificantuptakeExtensiveSmallvolumeofSameasfentanylNosignificant
littleuptakebybylungsduringdistributionindistributionandbutmuchmoresequestrationby
lungs.Ithashighfirstpassthebody.Firstlowintrinsicpotentandlipidlungs.Widespread
hepaticextractionpulmonarypassuptakebycapacityoflivertosoluble.extrahepatic
ratioandcirculationlungsis75%.metabolisethismetabolismbyblood
metabolizedviametabolizedinHashighhepaticdrug.Diffusibleandtissue
hepaticandlivertoactiveextractionratio.fractionishighnonspecific
extrahepaticmetabolite.Metabolizedinduetolargeesterases.Unstable
pathways.Metabolitelivertounionizedinsolutionformfor
Penetrationinnormeperidinepharmacologicallypercentagelongperiods.
brainisslow.accumulatesininactivemetaboliteofthedrugatLyophilizedpowder
MetaboliteM6Grenalfailure.Itnorfentanyl.physiologicalpH.isreconstituted
accumulatesincausesseizures.Thisleadstofasterbeforeuse.Very
renalfailure.onsetofactionrapidonsetand
ascomparedshortduration
tofentanyl.ofaction.

Opioids 33
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

PHARMACOKINETICS OF MEPERIDINE
POINTS TO REMEMBER
• More lipid soluble than morphine
• < 10 percent unionized fraction.
• 70 percent protein binding mainly with α1 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 α1 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

Opioids 35
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 α1 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

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.

Opioids 37
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 (N2O, 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 H1 and H2 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.

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. CO2 responsiveness as
well as hypoxic ventilatory drive, both are depressed. This results into downward
and rightward shift of the CO2 response curve and rise in resting PaCO2.
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.

Opioids 39
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.

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.

Opioids 41
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 CO2
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.

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

Opioids 43
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.

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.

Opioids 45
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.

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. CO2 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. N2O + 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.

Opioids 47
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.

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 K1 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.

Opioids 49
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).

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).

Opioids 51
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. t½ 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.

• 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).

Opioids 53
• 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

Volatile Anaesthetics 3
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

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).

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
FI (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 37o
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

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 (FA) 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.

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 (FA)
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

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 FA (alveolar concentration) towards
the FI (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
FA falls (takes longer time for equilibrium with FI)
Delayed induction
Another point of concern is that increasing the minute ventilation will cause CO2
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. FA/FI

In other words greater the inspired concentration (FI), more rapidly alveolar
concentration, (FA) approaches inspired concentration (FI). 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 N2O; 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 N2O (80 molecules)
Alveolar concentration of anaesthetic mixture = 2 percent – second gas
18 percent – O2
80 percent – N2O
As seen in the diagram below, concentration of second gas changes from 2 to 3.4
percent after absorption of N2O. This is called as second gas effect. After absorption

of 40 molecules of N2O, 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.

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.

• 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

Comparative pharmacology for anesthetics PDF

Comparative pharmacology for anesthetics PDF

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