June 18, 2025 • 36 mins
Continue your journey to mastering anaesthesia—one chapter at a time.
In this episode, Dr. J.R. Decker reads and discusses Chapter 7 (Part 1) of Morgan & Mikhail’s Clinical Anesthesiology (7th Edition).
Follow as you read along to strengthen your foundations in anaesthesia, one clear and engaging session at a time.
Perfect for trainees, revision, or daily listening.
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:01):
Morgan and Michael's Clinical Anesthesiology, 7th Edition,
Chapter 7. Pharmacological principles Key
concepts 1. Drug molecules obey the law of
(00:24):
mass action. When the plasma concentration
exceeds the tissue concentration, the drug moves
from the plasma into the tissue.When the plasma concentration is
less than the tissue concentration, the drug moves
from the tissue back to plasma to most drugs that readily cross
(00:54):
the blood brain barrier. For example, lipophilic drugs
like hypnotics and opioids are avidly taken up in body fat. 3
Biotransformation is the chemical process by which the
(01:15):
drug molecule is altered in the body.
The liver is the primary organ of metabolism for drugs. 4 Small
unbound molecules freely pass from plasma into the glomerular
(01:36):
filtrate. The non ionised that is
uncharged fraction of drug is reabsorbed in the renal tubules
whereas the ionised that is charged portion is excreted in
urine. 5 Elimination half life is the time required for the
(02:06):
drug concentration to fall by 50%.
For drugs described by multi compartment pharmatical
kinetics, for example all drugs used in anaesthesia, there are
multiple elimination half lives.6 The offset of a drug's effect
(02:32):
cannot be predicted from half lives.
The context sensitive half time is a clinically useful concept
to describe the rate of decreasein drug concentration and should
be used instead of half lives tocompare the pharmacokinetic
properties of intravenous drugs used in anaesthesia.
(03:01):
The clinical practise of anesthesiology is directly
connected to the science of clinical pharmacology.
One would think, therefore, thatthe study of pharmacokinetics
and pharmacodynamics would receive attention comparable to
with that given to airway assessment, choice of inhalation
(03:24):
and aesthetic neuromuscular blockade, or treatment of sepsis
in anesthesiologic curricula andexaminations.
Sadly, the frequent misidentification or misuse of
pharmacokinetic principles and measurements suggests that this
(03:46):
is not yet the case. Pharmacokinetics
Pharmacokinetics defines the relationships among drug dosing,
drug concentration in body fluids and tissues, and time.
(04:09):
It consists of four linked processes, absorption,
distribution, biotransformation and excretion.
Absorption. Absorption defines the processes
(04:33):
by which a drug moves from the site of administration to the
bloodstream. There are many possible routes
of Drug Administration. Inhalational, oral, sublingual,
transtracheal, rectal, transdermal, transmucosal,
(05:01):
subcutaneous, intramuscular, intravenous, perineural,
peridural and intrathico absorption is influenced by the
physical characteristics of the drug, that is, solubility, PKA,
(05:28):
diluence, binders, formulation, dose, the site of absorption,
for example, gut, lung, skin, muscle, and in some cases, for
example, perineural or subcutaneous administration of
(05:49):
local anaesthetics by additives such as epinephrine.
Bioavailability defines the fraction of the administered
dose that reaches the systemic circulation.
For example, nitroglycerin is well absorbed by the
(06:13):
gastrointestinal tract but has low bioavailability when
administered orally. The reason is that nitroglycerin
undergoes extensive first pass hepatic metabolism before
reaching the systemic circulation.
(06:38):
Oral Drug Administration is convenient, inexpensive, and
relatively tolerant of dosing errors.
However, it requires the cooperation of the patient,
exposes the drug to 1st pass hepatic metabolism and permits
(07:01):
gastric pH, digestive enzymes, motility, food and order drugs
to potentially reduce the predictability of systemic drug
delivery. Non ionised, that is uncharged
drugs are more readily absorbed than ionised that is charged
(07:27):
forms. Therefore, an acidic
environment, that is stomach favours the absorption of acidic
drugs, that is, A + H gives you AH, whereas a more alkaline
(07:49):
environment, that is intestine favours basic drugs, that is, BH
gives you H + B. Nevertheless, in most cases, the
(08:09):
greater aggregate amount of drugs is absorbed from the
intestine rather than the stomach because of the greater
surface area of the small intestine and longer transit
duration. All venous drainage from the
stomach and small intestine flows to the liver.
(08:33):
As a result, the bioavailabilityof highly metabolised drugs may
be significantly reduced by first pass hepatic metabolism.
Because the venous drainage fromthe mouth and oesophagus flows
into the superior venal cover rather than into the portal
(08:55):
system, sublingual or bucal drugabsorption bypasses the liver
and 1st pass metabolism. Rectal administration partly
bypasses the portal system and represents an alternative route
(09:17):
in small children or patients who are unable to tolerate oral
ingestion. However, rectal absorption can
be erratic and many drugs irritate the rectal mucosa.
Transdermal Drug Administration can provide prolonged continuous
(09:42):
administration for some drugs. However, the stratum corneum is
an effective barrier to all but small lipid soluble drugs, for
example, Clonidine, nitroglycerin, scopolamine,
(10:02):
fentanyl, freebase local anaesthetics, that is, EMLA.
EMLA. Parenteral roots of Drug
Administration include subcutaneous, intramuscular and
intravenous injection. Subcutaneous and intramuscular
(10:27):
absorption depend on drug diffusion from the site of
injection to the bloodstream. The rate at which a drug enters
the bloodstream depends on both blood flow to the injected
tissue and the injected formulation.
(10:50):
Drugs dissolved in solution are absorbed faster than those
present in suspensions. Irritating preparations can
cause pain and tissue necrosis, for example intramuscular
diazepam. Intravenous injections bypass
(11:14):
the process of absorption distribution.
Once absorbed, a drug is distributed by the bloodstream
throughout the body. Highly perfused organs, that is,
(11:36):
the so-called vessel rich group receive a disproportionate
fraction of the cardiac output. Therefore, these tissues receive
a disproportionate amount of drugs of drug in the first
minute following Drug Administration.
(11:58):
These tissues approach equilibration with the plasma
concentration more rapidly than less well perfused tissues
because of the differences in blood flow.
However, less well perfused tissues such as fat and skin may
(12:19):
have an enormous capacity to absorb lipophilic drugs,
resulting in a large reservoir of drug following lung infusions
or larger doses. Next we get to Table 7-1 talking
(12:40):
about tissue group composition, relative body mass and
percentage of cardiac output. Kindly pause this recording to
go through Table 7-1. 1 Drug molecules obey the law of mass
(13:08):
action. When plasma concentration
exceeds the concentration in tissue, the drug moves from the
plasma into tissue. When the plasma concentration is
less than the tissue concentration, the drug moves
from the tissue back to plasma. The rate of rise in drug
(13:37):
concentration in an organ is determined by that organs
perfusion and the relative drug solubility in the organ compared
with blood. The equilibrium concentration in
an organ relative to blood depends only on the relative
solubility of the drug in the organ relative to blood, unless
(14:02):
the organ is capable of metabolising the drug.
Molecules in blood are either free or bound to blood
constituents such as plasma proteins and lipids.
The free concentration equilibrates between organs and
(14:26):
tissues. The equilibration between bound
and unbound molecules is instantaneous.
As unbound molecules of of drug diffuse into tissue, they are
instantly replaced by previouslybound molecules.
(14:48):
Plasma protein binding does not affect the rates of transfer
directly, but it does affect therelative solubility of the drug
in blood and tissue. When a drug is highly bound in
blood, a much larger dose will be required to achieve the same
(15:11):
systemic effect. If the drug is highly bound in
tissues and unbound in plasma, the relative solubility favours
drug transfer into tissue. Put another way, a drug that is
highly bound in tissue but not in blood will have a very large
(15:35):
free drug concentration gradientdriving drug into the tissue.
Conversely, if the drug is highly protein bound in plasma
and has few binding sites in thetissue, transfer of a small
amount of drug may be enough to bring the free drug
(15:57):
concentration into equilibrium between blood and tissue.
Thus, high levels of binding in blood relative to tissues will
increase the rate of onset of drug effects because fewer
molecules will need to transfer into the tissue to produce an
(16:19):
effective free drug concentration.
Albumin has two main binding sites with an affinity for many
acidic and neutral drugs, including diazepam.
(16:40):
Highly bound drugs, for example warfarin, can be displaced by
other drugs competing for the same binding site, for example
indocyamine green or etheroscreinic acid, with
dangerous consequences. A1 acid glycoprotein, that is,
(17:06):
AAG binds basic drugs, that is, local anaesthetics, tricyclic
antidepressants. If the concentrations of these
proteins are diminished, the relative solubility of the drugs
in blood is decreased, increasing tissue.
(17:28):
Optic kidney disease, liver disease, chronic heart failure,
and some malignancies decrease albumin production.
Major bones of more than 20% of body surface area lead to
(17:51):
albumin loss. Trauma, including surgery,
infection, myocardial infarction, and chronic pain
increase AAG levels. Pregnancy is associated with
(18:12):
reduced AAG concentrations. None of these factors has much
relevance to propofol, which is administered with its own
binding molecules, That is, the lipid in the emotion 2
(18:36):
lipophilic molecules can readilytransform between the blood and
organs. Charged molecules are able to
pass in small quantities in mostorgans.
However, the blood brain barrieris a special case.
(18:59):
Permeation of the central nervous system by ionised drugs
is limited by pericapillary glial cells and endothelial cell
tight junctions. Most drugs that readily cross
the blood brain barrier, for example lipophilic drugs like
(19:20):
hypnotics and opioids, are avidly taken up in body fat.
The time calls of the distribution of drugs into
peripheral tissues is complex and is best described using
computer models and simulation following intravenous bolus
(19:44):
administration. Rapid distribution of drug from
the plasma into tissues accountsfor the profound decrease in
plasma concentration observed inthe first few minutes.
For each tissue, there is a point in time at which the
apparent concentration in the tissue is the same as the
(20:08):
concentration in the plasma. The redistribution phase that is
from each tissue follows this moment of equilibration.
During redistribution, drug returns from tissues back into
(20:31):
plasma. This return of drug back to the
plasma slows the rate of declinein plasma drug concentration
following administration of a bolus of an induction agent.
(20:53):
Distribution generally contributes to rapid emergence
by removing drug from the plasmafor many minutes following
prolonged infusions of lipophilic anaesthetic drugs.
Redistribution generally delays emergence as drug returns from
(21:15):
tissue reservoirs to the plasma for many hours.
The complex process of drug distribution into and out of
tissues is one reason that half lives provide almost no guidance
for predicting emergence times. The offset of a drug's clinical
(21:41):
actions is best predicted by computer models using the
context sensitive half time or decrement time.
The context sensitive half time is the time required for a 50%
decrease in plasma drug concentration to occur following
(22:05):
a pseudo steady state infusion. In other words, an infusion that
has continued long enough to yield nearly steady state
concentrations. Here the context is the duration
of the infusion, which defines the total mass of drug remaining
(22:28):
within the subject. The context sensitive decrement
time is a more generalised concept referring to any
clinically relevant decreased concentration in any tissue,
particularly the brain or effectsite.
(22:52):
The volume of distribution VD isthe apparent volume into which a
drug has distributed that is mixed.
This volume is calculated by dividing a bolus dose of drug by
the plasma concentration at time0.
(23:19):
In practise, the concentration used to define the VD is often
often obtained by extrapolating subsequent concentrations back
to zero time when the drug was injected.
This assumes immediate and complete mixing as follows.
(23:45):
VD is equals to bolus dose over concentration at time 0.
The concept of a single VD does not apply to any intravenous
drugs used in anaesthesia. All in intravenous anaesthetic
(24:11):
drugs are better modelled with at least 2 compartments, a
central component and a peripheral component.
The behaviour of many of these drugs is more precisely
described using 3 compartments, a central compartment, A rapidly
(24:38):
equilibrating peripheral compartment and a slowly
equilibrating peripheral compartment.
The central compartment may be thought of as including the
blood and any ultra rapidly equilibrating tissues such as
(24:59):
the lungs. The peripheral compartment is
composed of the other body tissues.
For drugs with two peripheral compartments, the rapidly
equilibrating compartment comprises the organs and
muscles, while the slowly equilibrating compartment
(25:23):
roughly represents the distribution of the drug into
fat and skin. These compartments are
designated V1 that is central, V2 that is rapid distribution,
and V3 that is slow distribution.
(25:51):
The volume of distribution at steady state VDSS is the
algebraic sum of these compartment volumes.
V1 is calculated by the above equation showing the
relationship between volume, dose and concentration.
(26:17):
The other volumes are calculatedthrough pharmacokinetic
modelling. A small VDSS implies that the
drug has high aqueous solubilityand will remain largely within
the intravascular space. For example, the VDSS of
(26:45):
vercoronium is about 200 mils per kilogramme in adult men and
about 160 mils per kilogramme inadult women, indicating that
vercoronium is mostly present inbody water with little
distribution into fat. However, the typical general
(27:10):
anaesthetics is lipophilic, resulting in a VDSS that exceeds
total body water that is approximately 600 mils per
kilogramme in adult meals. For example, the VDSS of
(27:31):
fentanyl is about 350 litres in adults and the VDSS of propofol
may exceed 500 litre. 5000 litres VDSS does not represent a
real volume, but rather reflectsthe volume into which the
(27:55):
administered drug. Those would need to distribute
to account for the observed plasma concentration.
Biotransformation 3. Biotransformation includes the
(28:20):
chemical processes by which the drug molecule is altered in the
body. The liver is the primary organ
of metabolism for most drugs. An exception is the esters,
which undergo hydrolysis in the plasma or tissues.
(28:43):
The end products of biotransformation are often, but
not always, inactive and water soluble.
Water solubility allows excretion by the kidneys.
Metabolic biotransformation is frequently divided into phase
(29:06):
one and phase two reactions. Phase one reactions convert a
parent compound into more polar metabolites through oxidation,
reduction or hydrolysis. Phase two reactions couple, that
(29:31):
is conjugate a parent drug or a phase one metabolite with an
endogenous substrate, for example glucoronic acid, to form
water soluble metabolites that can be eliminated in the urine
or stool. Although this is usually a
(29:54):
sequential process, phase one metabolites may be excreted
without undergoing phase two biotransformation, and a phase
one phase two reaction can precede or occur without a phase
one reaction. Hepatic clearance is the volume
(30:17):
of blood or plasma, whichever was measured in the assay,
cleared of drug per unit of time.
The units of clearance are unitsof flow, that is, volume per
unit. Time clearance may be expressed
(30:40):
in millilitres per minute, litres per hour, or any other
convenient units of flow. If every molecule of drug that
enters the liver is metabolised,hepatic clearance will equal
liver blood flow. This is true for every for very
(31:07):
few drugs, though it is very nearly the case for propofol.
For most drugs, only a fraction of the drug that enters the
liver is removed. The fraction removed is called
the extraction ratio. The hepatic clearance can
(31:31):
therefore be expressed as the liver blood flow times the
extraction ratio. If the extraction ratio is 50%,
hepatic clearance is 50% of liver blood flow.
The clearance of drugs efficiently removed by the liver
(31:54):
that is having a high hepatic extraction ratio is proportional
to hepatic blood flow. For example, because the liver
removes almost all of the propofol that passes through it
when the hepatic blood flow double S, the clearance of
(32:15):
propofol double S induction of liver enzymes has no effect on
propofol clearance because the liver so efficiently removes all
of the propofol that passes through it.
Even severe loss of liver tissueas occurs in cirrhosis has
(32:39):
little effect on propofol clearance.
Drugs such as propofol, Propranolol, lidocaine, morphine
and nitroglycerin have flow dependent clearance.
(33:01):
Many drugs have low hepatic extraction ratios and are slowly
cleared by the liver. For these drugs, the rate
limiting step is not the flow ofblood to the liver but rather
the metabolic capacity of the liver itself.
(33:24):
Changes in liver blood flow havelittle effect on the clearance
of such drugs. However, if liver enzymes are
induced, clearance will be will increase because the liver has
more capacity to metabolise the drug.
(33:45):
Conversely, if the liver is damaged, less capacity is
available for metabolism and clearance is reduced.
Drugs with low hepatic extraction ratios thus have
capacity dependent clearance. The extraction ratios of
(34:09):
methadone and alfentanil are 10%and 15%, respectively, making
these capacity dependent drugs excretion 4.
(34:35):
Some drugs and many drug metabolites are excreted by the
kidneys. Renal clearance is the rate of
elimination of a drug from the body by kidney excretion.
This concept is analogous to hepatic clearance and similarly
(34:59):
renal clearance can be expressedas the renal blood flow times
the renal extraction ratio. Small unbound drugs freely pass
from plasma into the glomerular filtrate.
(35:19):
The non ionised, that is uncharged fraction of a drug is
reabsorbed into the renal tubules whereas the ionised that
is charged portion remains and is secreted in urine.
The fraction of drug ionised depends on the pH.
(35:45):
Thus renal elimination of drugs that exist in ionised and non
ionised forms depends in part onurinary pH.
The kidney actively secrets somedrugs into the renal tubules.
(36:06):
Many drugs and drug metabolites pass from the liver into the
intestine via the biliary system.
Some drugs excreted into the bile are then reabsorbed in the
intestine, a process called enterohepatic recirculation.
(36:31):
Occasionally, metabolites excreted in bile are
subsequently converted back to the parent drug.
For example, lorazepam is converted by the liver to
lorazepam glucoronide. In the intestine, Beta
(36:53):
glucoronidase breaks the Ester linkage, converting lorazepam
glucoronide back to lorazepam.
Morgan and Michael's Clinical Anesthesiology, 7th Edition,
Chapter 7. Pharmacological principles Key
concepts 1. Drug molecules obey the law of
(00:24):
mass action. When the plasma concentration
exceeds the tissue concentration, the drug moves
from the plasma into the tissue.When the plasma concentration is
less than the tissue concentration, the drug moves
from the tissue back to plasma to most drugs that readily cross
(00:54):
the blood brain barrier. For example, lipophilic drugs
like hypnotics and opioids are avidly taken up in body fat. 3
Biotransformation is the chemical process by which the
(01:15):
drug molecule is altered in the body.
The liver is the primary organ of metabolism for drugs. 4 Small
unbound molecules freely pass from plasma into the glomerular
(01:36):
filtrate. The non ionised that is
uncharged fraction of drug is reabsorbed in the renal tubules
whereas the ionised that is charged portion is excreted in
urine. 5 Elimination half life is the time required for the
(02:06):
drug concentration to fall by 50%.
For drugs described by multi compartment pharmatical
kinetics, for example all drugs used in anaesthesia, there are
multiple elimination half lives.6 The offset of a drug's effect
(02:32):
cannot be predicted from half lives.
The context sensitive half time is a clinically useful concept
to describe the rate of decreasein drug concentration and should
be used instead of half lives tocompare the pharmacokinetic
properties of intravenous drugs used in anaesthesia.
(03:01):
The clinical practise of anesthesiology is directly
connected to the science of clinical pharmacology.
One would think, therefore, thatthe study of pharmacokinetics
and pharmacodynamics would receive attention comparable to
with that given to airway assessment, choice of inhalation
(03:24):
and aesthetic neuromuscular blockade, or treatment of sepsis
in anesthesiologic curricula andexaminations.
Sadly, the frequent misidentification or misuse of
pharmacokinetic principles and measurements suggests that this
(03:46):
is not yet the case. Pharmacokinetics
Pharmacokinetics defines the relationships among drug dosing,
drug concentration in body fluids and tissues, and time.
(04:09):
It consists of four linked processes, absorption,
distribution, biotransformation and excretion.
Absorption. Absorption defines the processes
(04:33):
by which a drug moves from the site of administration to the
bloodstream. There are many possible routes
of Drug Administration. Inhalational, oral, sublingual,
transtracheal, rectal, transdermal, transmucosal,
(05:01):
subcutaneous, intramuscular, intravenous, perineural,
peridural and intrathico absorption is influenced by the
physical characteristics of the drug, that is, solubility, PKA,
(05:28):
diluence, binders, formulation, dose, the site of absorption,
for example, gut, lung, skin, muscle, and in some cases, for
example, perineural or subcutaneous administration of
(05:49):
local anaesthetics by additives such as epinephrine.
Bioavailability defines the fraction of the administered
dose that reaches the systemic circulation.
For example, nitroglycerin is well absorbed by the
(06:13):
gastrointestinal tract but has low bioavailability when
administered orally. The reason is that nitroglycerin
undergoes extensive first pass hepatic metabolism before
reaching the systemic circulation.
(06:38):
Oral Drug Administration is convenient, inexpensive, and
relatively tolerant of dosing errors.
However, it requires the cooperation of the patient,
exposes the drug to 1st pass hepatic metabolism and permits
(07:01):
gastric pH, digestive enzymes, motility, food and order drugs
to potentially reduce the predictability of systemic drug
delivery. Non ionised, that is uncharged
drugs are more readily absorbed than ionised that is charged
(07:27):
forms. Therefore, an acidic
environment, that is stomach favours the absorption of acidic
drugs, that is, A + H gives you AH, whereas a more alkaline
(07:49):
environment, that is intestine favours basic drugs, that is, BH
gives you H + B. Nevertheless, in most cases, the
(08:09):
greater aggregate amount of drugs is absorbed from the
intestine rather than the stomach because of the greater
surface area of the small intestine and longer transit
duration. All venous drainage from the
stomach and small intestine flows to the liver.
(08:33):
As a result, the bioavailabilityof highly metabolised drugs may
be significantly reduced by first pass hepatic metabolism.
Because the venous drainage fromthe mouth and oesophagus flows
into the superior venal cover rather than into the portal
(08:55):
system, sublingual or bucal drugabsorption bypasses the liver
and 1st pass metabolism. Rectal administration partly
bypasses the portal system and represents an alternative route
(09:17):
in small children or patients who are unable to tolerate oral
ingestion. However, rectal absorption can
be erratic and many drugs irritate the rectal mucosa.
Transdermal Drug Administration can provide prolonged continuous
(09:42):
administration for some drugs. However, the stratum corneum is
an effective barrier to all but small lipid soluble drugs, for
example, Clonidine, nitroglycerin, scopolamine,
(10:02):
fentanyl, freebase local anaesthetics, that is, EMLA.
EMLA. Parenteral roots of Drug
Administration include subcutaneous, intramuscular and
intravenous injection. Subcutaneous and intramuscular
(10:27):
absorption depend on drug diffusion from the site of
injection to the bloodstream. The rate at which a drug enters
the bloodstream depends on both blood flow to the injected
tissue and the injected formulation.
(10:50):
Drugs dissolved in solution are absorbed faster than those
present in suspensions. Irritating preparations can
cause pain and tissue necrosis, for example intramuscular
diazepam. Intravenous injections bypass
(11:14):
the process of absorption distribution.
Once absorbed, a drug is distributed by the bloodstream
throughout the body. Highly perfused organs, that is,
(11:36):
the so-called vessel rich group receive a disproportionate
fraction of the cardiac output. Therefore, these tissues receive
a disproportionate amount of drugs of drug in the first
minute following Drug Administration.
(11:58):
These tissues approach equilibration with the plasma
concentration more rapidly than less well perfused tissues
because of the differences in blood flow.
However, less well perfused tissues such as fat and skin may
(12:19):
have an enormous capacity to absorb lipophilic drugs,
resulting in a large reservoir of drug following lung infusions
or larger doses. Next we get to Table 7-1 talking
(12:40):
about tissue group composition, relative body mass and
percentage of cardiac output. Kindly pause this recording to
go through Table 7-1. 1 Drug molecules obey the law of mass
(13:08):
action. When plasma concentration
exceeds the concentration in tissue, the drug moves from the
plasma into tissue. When the plasma concentration is
less than the tissue concentration, the drug moves
from the tissue back to plasma. The rate of rise in drug
(13:37):
concentration in an organ is determined by that organs
perfusion and the relative drug solubility in the organ compared
with blood. The equilibrium concentration in
an organ relative to blood depends only on the relative
solubility of the drug in the organ relative to blood, unless
(14:02):
the organ is capable of metabolising the drug.
Molecules in blood are either free or bound to blood
constituents such as plasma proteins and lipids.
The free concentration equilibrates between organs and
(14:26):
tissues. The equilibration between bound
and unbound molecules is instantaneous.
As unbound molecules of of drug diffuse into tissue, they are
instantly replaced by previouslybound molecules.
(14:48):
Plasma protein binding does not affect the rates of transfer
directly, but it does affect therelative solubility of the drug
in blood and tissue. When a drug is highly bound in
blood, a much larger dose will be required to achieve the same
(15:11):
systemic effect. If the drug is highly bound in
tissues and unbound in plasma, the relative solubility favours
drug transfer into tissue. Put another way, a drug that is
highly bound in tissue but not in blood will have a very large
(15:35):
free drug concentration gradientdriving drug into the tissue.
Conversely, if the drug is highly protein bound in plasma
and has few binding sites in thetissue, transfer of a small
amount of drug may be enough to bring the free drug
(15:57):
concentration into equilibrium between blood and tissue.
Thus, high levels of binding in blood relative to tissues will
increase the rate of onset of drug effects because fewer
molecules will need to transfer into the tissue to produce an
(16:19):
effective free drug concentration.
Albumin has two main binding sites with an affinity for many
acidic and neutral drugs, including diazepam.
(16:40):
Highly bound drugs, for example warfarin, can be displaced by
other drugs competing for the same binding site, for example
indocyamine green or etheroscreinic acid, with
dangerous consequences. A1 acid glycoprotein, that is,
(17:06):
AAG binds basic drugs, that is, local anaesthetics, tricyclic
antidepressants. If the concentrations of these
proteins are diminished, the relative solubility of the drugs
in blood is decreased, increasing tissue.
(17:28):
Optic kidney disease, liver disease, chronic heart failure,
and some malignancies decrease albumin production.
Major bones of more than 20% of body surface area lead to
(17:51):
albumin loss. Trauma, including surgery,
infection, myocardial infarction, and chronic pain
increase AAG levels. Pregnancy is associated with
(18:12):
reduced AAG concentrations. None of these factors has much
relevance to propofol, which is administered with its own
binding molecules, That is, the lipid in the emotion 2
(18:36):
lipophilic molecules can readilytransform between the blood and
organs. Charged molecules are able to
pass in small quantities in mostorgans.
However, the blood brain barrieris a special case.
(18:59):
Permeation of the central nervous system by ionised drugs
is limited by pericapillary glial cells and endothelial cell
tight junctions. Most drugs that readily cross
the blood brain barrier, for example lipophilic drugs like
(19:20):
hypnotics and opioids, are avidly taken up in body fat.
The time calls of the distribution of drugs into
peripheral tissues is complex and is best described using
computer models and simulation following intravenous bolus
(19:44):
administration. Rapid distribution of drug from
the plasma into tissues accountsfor the profound decrease in
plasma concentration observed inthe first few minutes.
For each tissue, there is a point in time at which the
apparent concentration in the tissue is the same as the
(20:08):
concentration in the plasma. The redistribution phase that is
from each tissue follows this moment of equilibration.
During redistribution, drug returns from tissues back into
(20:31):
plasma. This return of drug back to the
plasma slows the rate of declinein plasma drug concentration
following administration of a bolus of an induction agent.
(20:53):
Distribution generally contributes to rapid emergence
by removing drug from the plasmafor many minutes following
prolonged infusions of lipophilic anaesthetic drugs.
Redistribution generally delays emergence as drug returns from
(21:15):
tissue reservoirs to the plasma for many hours.
The complex process of drug distribution into and out of
tissues is one reason that half lives provide almost no guidance
for predicting emergence times. The offset of a drug's clinical
(21:41):
actions is best predicted by computer models using the
context sensitive half time or decrement time.
The context sensitive half time is the time required for a 50%
decrease in plasma drug concentration to occur following
(22:05):
a pseudo steady state infusion. In other words, an infusion that
has continued long enough to yield nearly steady state
concentrations. Here the context is the duration
of the infusion, which defines the total mass of drug remaining
(22:28):
within the subject. The context sensitive decrement
time is a more generalised concept referring to any
clinically relevant decreased concentration in any tissue,
particularly the brain or effectsite.
(22:52):
The volume of distribution VD isthe apparent volume into which a
drug has distributed that is mixed.
This volume is calculated by dividing a bolus dose of drug by
the plasma concentration at time0.
(23:19):
In practise, the concentration used to define the VD is often
often obtained by extrapolating subsequent concentrations back
to zero time when the drug was injected.
This assumes immediate and complete mixing as follows.
(23:45):
VD is equals to bolus dose over concentration at time 0.
The concept of a single VD does not apply to any intravenous
drugs used in anaesthesia. All in intravenous anaesthetic
(24:11):
drugs are better modelled with at least 2 compartments, a
central component and a peripheral component.
The behaviour of many of these drugs is more precisely
described using 3 compartments, a central compartment, A rapidly
(24:38):
equilibrating peripheral compartment and a slowly
equilibrating peripheral compartment.
The central compartment may be thought of as including the
blood and any ultra rapidly equilibrating tissues such as
(24:59):
the lungs. The peripheral compartment is
composed of the other body tissues.
For drugs with two peripheral compartments, the rapidly
equilibrating compartment comprises the organs and
muscles, while the slowly equilibrating compartment
(25:23):
roughly represents the distribution of the drug into
fat and skin. These compartments are
designated V1 that is central, V2 that is rapid distribution,
and V3 that is slow distribution.
(25:51):
The volume of distribution at steady state VDSS is the
algebraic sum of these compartment volumes.
V1 is calculated by the above equation showing the
relationship between volume, dose and concentration.
(26:17):
The other volumes are calculatedthrough pharmacokinetic
modelling. A small VDSS implies that the
drug has high aqueous solubilityand will remain largely within
the intravascular space. For example, the VDSS of
(26:45):
vercoronium is about 200 mils per kilogramme in adult men and
about 160 mils per kilogramme inadult women, indicating that
vercoronium is mostly present inbody water with little
distribution into fat. However, the typical general
(27:10):
anaesthetics is lipophilic, resulting in a VDSS that exceeds
total body water that is approximately 600 mils per
kilogramme in adult meals. For example, the VDSS of
(27:31):
fentanyl is about 350 litres in adults and the VDSS of propofol
may exceed 500 litre. 5000 litres VDSS does not represent a
real volume, but rather reflectsthe volume into which the
(27:55):
administered drug. Those would need to distribute
to account for the observed plasma concentration.
Biotransformation 3. Biotransformation includes the
(28:20):
chemical processes by which the drug molecule is altered in the
body. The liver is the primary organ
of metabolism for most drugs. An exception is the esters,
which undergo hydrolysis in the plasma or tissues.
(28:43):
The end products of biotransformation are often, but
not always, inactive and water soluble.
Water solubility allows excretion by the kidneys.
Metabolic biotransformation is frequently divided into phase
(29:06):
one and phase two reactions. Phase one reactions convert a
parent compound into more polar metabolites through oxidation,
reduction or hydrolysis. Phase two reactions couple, that
(29:31):
is conjugate a parent drug or a phase one metabolite with an
endogenous substrate, for example glucoronic acid, to form
water soluble metabolites that can be eliminated in the urine
or stool. Although this is usually a
(29:54):
sequential process, phase one metabolites may be excreted
without undergoing phase two biotransformation, and a phase
one phase two reaction can precede or occur without a phase
one reaction. Hepatic clearance is the volume
(30:17):
of blood or plasma, whichever was measured in the assay,
cleared of drug per unit of time.
The units of clearance are unitsof flow, that is, volume per
unit. Time clearance may be expressed
(30:40):
in millilitres per minute, litres per hour, or any other
convenient units of flow. If every molecule of drug that
enters the liver is metabolised,hepatic clearance will equal
liver blood flow. This is true for every for very
(31:07):
few drugs, though it is very nearly the case for propofol.
For most drugs, only a fraction of the drug that enters the
liver is removed. The fraction removed is called
the extraction ratio. The hepatic clearance can
(31:31):
therefore be expressed as the liver blood flow times the
extraction ratio. If the extraction ratio is 50%,
hepatic clearance is 50% of liver blood flow.
The clearance of drugs efficiently removed by the liver
(31:54):
that is having a high hepatic extraction ratio is proportional
to hepatic blood flow. For example, because the liver
removes almost all of the propofol that passes through it
when the hepatic blood flow double S, the clearance of
(32:15):
propofol double S induction of liver enzymes has no effect on
propofol clearance because the liver so efficiently removes all
of the propofol that passes through it.
Even severe loss of liver tissueas occurs in cirrhosis has
(32:39):
little effect on propofol clearance.
Drugs such as propofol, Propranolol, lidocaine, morphine
and nitroglycerin have flow dependent clearance.
(33:01):
Many drugs have low hepatic extraction ratios and are slowly
cleared by the liver. For these drugs, the rate
limiting step is not the flow ofblood to the liver but rather
the metabolic capacity of the liver itself.
(33:24):
Changes in liver blood flow havelittle effect on the clearance
of such drugs. However, if liver enzymes are
induced, clearance will be will increase because the liver has
more capacity to metabolise the drug.
(33:45):
Conversely, if the liver is damaged, less capacity is
available for metabolism and clearance is reduced.
Drugs with low hepatic extraction ratios thus have
capacity dependent clearance. The extraction ratios of
(34:09):
methadone and alfentanil are 10%and 15%, respectively, making
these capacity dependent drugs excretion 4.
(34:35):
Some drugs and many drug metabolites are excreted by the
kidneys. Renal clearance is the rate of
elimination of a drug from the body by kidney excretion.
This concept is analogous to hepatic clearance and similarly
(34:59):
renal clearance can be expressedas the renal blood flow times
the renal extraction ratio. Small unbound drugs freely pass
from plasma into the glomerular filtrate.
(35:19):
The non ionised, that is uncharged fraction of a drug is
reabsorbed into the renal tubules whereas the ionised that
is charged portion remains and is secreted in urine.
The fraction of drug ionised depends on the pH.
(35:45):
Thus renal elimination of drugs that exist in ionised and non
ionised forms depends in part onurinary pH.
The kidney actively secrets somedrugs into the renal tubules.
(36:06):
Many drugs and drug metabolites pass from the liver into the
intestine via the biliary system.
Some drugs excreted into the bile are then reabsorbed in the
intestine, a process called enterohepatic recirculation.
(36:31):
Occasionally, metabolites excreted in bile are
subsequently converted back to the parent drug.
For example, lorazepam is converted by the liver to
lorazepam glucoronide. In the intestine, Beta
(36:53):
glucoronidase breaks the Ester linkage, converting lorazepam
glucoronide back to lorazepam.
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