July 11, 2025 • 31 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 2) 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.
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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, Part 2 Compartment Models Multi compartment models
provide a mathematical frameworkthat can be used to relate drug
(00:24):
duels to changes in drug concentrations over time.
Conceptually, the compartments in these models are tissues with
a similar distribution time calls.
(00:44):
For example, the plasma and lungs are components of the
central compartments. The organs and muscles,
sometimes called the vessel richgroup, could be the second or
rapidly equilibrating compartment.
(01:09):
Fat and skin have the capacity to bind large quantities of
lipophilic drug but are poorly perfused.
These could represent the third or slowly equilibrating
compartments. This is an intuitive definition
(01:32):
of compartments, but it is important to recognise that the
compartments of a pharmacokinetic model are
mathematical abstractions that relate those to observed
concentration. A1 to one relationship does not
exist between any mathematicallyidentified compartment and any
(01:58):
organ or tissue in the body. Many drugs used in anaesthesia
are well described by two compartment models.
This is generally the case if the studies used to characterise
(02:19):
the pharmacokinetics do not include rapid arterial sampling
over the first few minutes. Without rapid arterial sampling,
the ultra rapid initial drop in plasma concentration immediately
after a bolus injection is missed and the central
(02:43):
compartment volume is blended into the rapidly equilibrating
compartment. When rapid arterial sampling is
used in pharmacokinetic experiments, the results
generally support the use of a three compartment model.
(03:06):
Thus, the number of identifiablecompartments reported in a
pharmacokinetic study may be more a function of the
experimental design than a characteristic of the drug.
Next, we get to Figure 7-1, explaining that two compartment
(03:30):
model demonstrates the changes in drug concentrations in the
distribution phase and the elimination phase.
Kindly pause this recording and go through Figure 7-1.
(03:51):
As previously noted, in compartmental models the
instantaneous concentration at the time of a bolus injection is
assumed to be the amount of the bolus divided by the central
compartment volume. This is not correct.
(04:15):
If the bolus is giving over a few seconds, the instantaneous
concentration is 0 because the drug is all in the vein, still
flowing to the heart. It takes a minute or two for the
drug to mix in the central compartment volume.
(04:37):
This MIS specification is commonto conventional pharmacokinetic
models. More physiologically based
models, sometimes called front end kinetic models, can
characterise the initial delay in concentration.
(05:01):
The additional complexity that these models introduce is useful
only if the concentrations over the first few minutes are
clinically important. After the first few minutes,
front end models resemble conventional compartmental
(05:23):
models. In the first few minutes
following initial Bolo's administration of a drug, the
concentration drops very rapidlyas the drug quickly diffuses
into peripheral compartments. Concentrations often decline by
(05:45):
an order of magnitude over 10 minutes.
For drugs with very rapid hepatic clearance, for example
propofol, or those that are metabolised in the blood, for
example, remifentanyl metabolismcontributes significantly to the
(06:07):
rapid initial drop in concentration.
Following this very rapid drop, a period of slower decrease in
plasma concentration occurs. During this period, the rapidly
equilibrating compartments is nolonger removing drug from the
(06:29):
plasma. Instead, drug returns to the
plasma from the rapidly equilibrating compartments.
The reversed role of the rapidlyequilibrating tissues from
extracting drug to returning drug accounts for the slower
(06:53):
rate of decline in plasma concentration in this
intermediate phase. Eventually there is an even
slower rate of decrease in plasma concentration, which is
which is log linear until the drug is no longer detectable.
(07:17):
This term terminal log linear phase occurs after the slowly
equilibrating compartment shiftsfrom net removal of drug from
the plasma to net return of the drug to the plasma.
During this terminal phase, the organ of elimination, which is
(07:41):
typically the liver, is exposed to the body's entire body drug
load, which accounts for the very slow rate of decrease in
plasma drug concentration. During this final phase, the
mathematical models used to describe a drug with two or
(08:04):
three compartments are respectively CP of T is equals
to AE to the minus alpha t + b Eto the minus beta T, and CP of T
(08:29):
is equals to AE to the minus alpha t + b E to the minus beta
T plus CE to the minus gamma T, where CP of T equals plasma
concentration at time T and alpha.
(08:52):
Beta and gamma are the exponentsthat characterise the very
rapid, that is very steep, intermediate and low, that is a
log. Linear portions of the plasma
concentration over time respectively.
(09:13):
Drugs described by two compartments and three
compartment models will have twoor three half lives each.
Half life is calculated as the natural log of two, that is,
0.693 divided by the exponents. The coefficients AB and C
(09:42):
represent the contribution of each of the exponents to the
overall decrease in concentration over time.
The two compartment model is described by a curve with two
exponents and two coefficients, whereas the three compartment
(10:06):
model is described by a curve with three exponents and three
coefficients. The mathematical relationships
among compartments, clearances, coefficients, and exponents are
complex. Every coefficient and every
(10:28):
exponent is a function of every volume and every clearance. 5 6
Elimination halftime is the timerequired for the drug
concentration to fall by 50%. For drugs described by multi
(10:56):
compartment pharmacokinetics, for example fentanyl,
sulfentanyl, there are multiple elimination half lives.
In other words, the elimination half time is context dependent.
The offset of a drug's effect cannot be predicted from half
(11:19):
lives alone. Moreover, one cannot easily
determine how rapidly a drug effect will disappear simply by
looking at coefficients, exponents, and half lives.
For example, the terminal half life of sulfentanil is about 10
(11:44):
hours, whereas that of alphentanil is 2 hours.
This does not mean that recoveryfrom alfentanil will be faster,
because clinical recovery from one, I mean from clinical dosing
will be influenced by all half lives, not just the terminal 1.
(12:10):
Computer models readily demonstrate that recovery from
an infusion lasting several hours will be faster when the
drug administered is sulfentanilthan it will be when the infused
drug is alphentanil. The time required for a 50%
(12:32):
decrease in concentration depends on the duration or
context of the infusion. The context sensitive half time
mentioned earlier captures this concept and should be used
instead of half lives. To compare the pharmacokinetic
(12:57):
properties of intravenous drugs used in anaesthesia.
Pharmaco dynamics Pharmacodynamics, The study of
how drugs affect the body, involves the concepts of
(13:21):
potency, efficacy, and therapeutic window.
The fundamental pharmacodynamic concepts are captured in the
relationship between exposure toa drug and physiological
response to the drug, often called the dose response or
(13:46):
concentration response relationship.
Exposure Response relationships As the body is exposed to an
increasing amount of a drug, theresponse to the drug similarly
(14:09):
increases, typically up to a maximal value.
This fundamental fundamental concept in the exposure versus
response relationship is captured graphically by plotting
exposure, that is usually dose of concentration on the X axis
(14:34):
as the independent variable and the body's response on the Y
axis as the dependent variable. Depending on the circumstances,
the duals or concentration may be plotted on a linear scale or
(14:57):
a logarithmic scale, while the response is typically plotted
either as the actual measured response or as a fraction of the
baseline or maximum physiological measurements.
For our purposes here, basic pharmacodynamic properties are
(15:21):
described in terms of concentration, but any metric of
drug exposure, for example thosearea under the curve, could be
used. Next we get to Figure 7-2,
talking about the shape of the dose or concentration response
(15:44):
curve, depending on whether the dose or plasma concentration is
plotted on a linear or logarithmic scale.
Kindly pause this recording to go through Figure 7.
Hyphen 2. The shape of the relationship is
(16:06):
typically sigmoidal, as shown inFigure 7 iPhone, iPhone 2.
The sigmoidal shape reflects theobservation that often a certain
minimal amount of drug must be present before there is any
measurable physiological response.
(16:35):
Thus, the left side of the curveis flat until the drug
concentration reaches a threshold.
The right side is also flat, reflecting the maximum
physiological response of the body, beyond which the body
(16:57):
simply cannot respond to additional drug.
Thus the curve is flat on both the left and right sides.
A sigmoidal curve is required toconnect the baseline to the
(17:20):
asymptote, which is why sigmodalcurves are ubiquitous.
When modelling pharmacodynamics.The sigmodal relationship
between exposure and response isdefined by one of two
interchangeable reflect relationships.
(17:45):
Effects is equals to E Max multiplied by C gamma over C50
gamma plus C gamma. Or effect is equals to E0 plus E
(18:08):
Max minus E0IN bracket multiplied by C gamma over C50
gamma plus C gamma. In both cases, C is drug
concentration, C50 is the concentration associated with a
(18:33):
half maximal effect, and gamma describes the steepness of the
concentration versus response relationship, and it's also
known as the heal coefficient. In the first equation, E Max is
the maximum physiological measurement, not the maximum
(18:57):
change from baseline. For the second equation, E Max
is the maximum change from the baseline effect, that is E0.
Once defined in this fashion, each parameter of the
pharmacodynamic model speaks to the specific concepts mentioned
(19:21):
earlier. E Max is related to the
intrinsic efficacy of a drug. Highly efficacious drugs have a
large maximum physiological effect, characterised by a large
E Max. For drugs that lack efficacy, E
(19:47):
Max will equal E 0. C50 is a measure of drug
potency. Highly potent drugs have a low
C50, thus small amounts produce the drug effect.
(20:11):
Drugs lacking potency have a high C50, indicating that a
large amount of drug is requiredto achieve the drug effects.
The parameter gamma indicates the steepness of the
relationship between concentration and effect.
(20:36):
A gamma value less than one indicates a very gradual
increase in drug effects with increasing concentration.
A gamma value greater than 4 suggests that once drug effect
is observed, small increases in drug concentration produce large
(21:00):
increases in drug effects until the maximum effect is reached.
The curve described above represents the relationship of
drug concentration to a continuous physiological
response. The same relationship can be
(21:23):
used to characterise the probability of a binary that is
yes, no response to a drug. Dose probability is equals to P0
plus P Max minus P0IN bracket multiplied by C gamma over C50
(21:52):
gamma plus C gamma. In this case, the probability P
ranges from zero, that is no chance, to one that is
certainty. P0 is the probability of a yes
(22:14):
response in the absence of drug P.
Max is the maximum probability necessarily less than or equal
to 1. As before, C is the
(22:34):
concentration, C50 is the concentration associated with
half maximal effect, and gamma describes the stiffness of the
concentration versus response relationship.
Half maximal effect is the same as 50% probability of a response
(22:59):
when P0 is 0 and P Max is 1. The therapeutic window of a drug
is the range between the concentration associated with
the desired therapeutic effects and the concentration associated
(23:19):
with a toxic drug response. This range can be measured as
either the difference between 2 points on the same concentration
versus response curve, that is, when the toxicity represents an
exaggerated form of the desired drug response, or the distance
(23:43):
between 2 distinct curves, that is, when the toxicity represents
a different response or process from the desired drug response.
For a drug such as sodium nitropruside, a single
concentration versus response curve defines the relationship
(24:07):
between concentration and decrease in blood pressure.
The therapeutic window might be the difference in the
concentration producing a desired 20% decrease in blood
pressure and a toxic concentration that produces a
catastrophic 60% decrease in blood pressure.
(24:33):
However, for a drug such as lidocaine, the therapeutic
window might be the difference between the C50 for suppression
of ventricular arrhythmias and the C50 for lidocaine induced
seizures, the two drug effects being described by separate
(24:57):
concentration versus response relationships.
The therapeutic index is the C50for toxicity divided by the C50
for the desired therapeutic effect.
Because of the risk of ventilatory and cardiovascular
(25:19):
depression that is even at concentrations only slightly
greater than those producing anaesthesia, most inhaled and
intravenous hypnotics are considered to have very low
therapeutic indices relative to other drugs.
(25:44):
Drug Receptors Drug receptors are macromolecules, typically
proteins that buying the drug that is agonist and mediate the
drug response. Pharmacological antagonists
(26:08):
reverse the effects of the egonist, but do not otherwise
exert an effect on their own. Competitive antagonism occurs
when the antagonist competes with the egonist for the same
binding site, each potentially displacing the other.
(26:31):
Non competitive antagonism occurs when the antagonist,
through covalent binding or another process, primarily
impairs the drug's access to thereceptor.
The drug effect is governed by the fraction of receptors that
(26:52):
are occupied by an egonist. That fraction is based on the
concentration of the drug, the concentration of the receptor,
and the strength of binding between the drug and the
receptor. This binding is described by the
(27:13):
law of mass action, which statesthat the reaction rate is
proportional to the concentrations of the reactants.
D multiplied by RU gives Dr Moving forward, it's K on moving
(27:42):
backwards, it's K off. Where D is the concentration of
the drug, RU is the concentration of unbound
receptor, and Dr is the concentration of bound receptor.
(28:02):
The rate constant K on defines the rate of ligand binding to
the receptor. The rate constant K off defines
the rate of ligand on binding from the receptor.
Steady state occurs almost instantly because the rate of
(28:26):
formation at steady state is 0. It follows that D multiplied by
ruk on minus DRK off. In this equation, KD is the
dissociation rate constant defined as K on divided by K
(28:52):
off. If we define F fractional
receptor occupancy as Dr over Drplus RU, we can solve for
receptor occupancy as F is equals to D over KD plus D.
(29:18):
The receptors are half occupied when D is equals to KD.
Thus, KD is the concentration ofdrug associated with 50%
receptor occupancy. Receptor occupancy is only the
(29:42):
first step in mediating drug effect.
Binding of the drug to the receptor can trigger myriad
subsequent steps, including opening, closing, or inhibition
of an ion channel, activation ofthe G protein, activation of an
(30:07):
intracellular kinase, direct interaction with the cellular
structure, or direct binding to DNA.
Like the concentration versus response curve, the shape of the
curve relating fractional receptor occupancy to drug
(30:30):
concentration is intrinsically sigmoidal.
However, the concentration associated with 50% receptor
occupancy and the concentration associated with 50% of maximal
drug effects are not necessarilythe same.
(30:54):
Maximal drug effects could occurat very low receptor occupancy
or for partial lagoonies at greater than 100% receptor
occupancy. Prolong the binding and
activation of a receptor by an egonist may lead to
(31:18):
desensitisation or tolerance. If the binding of an endogenous
ligand is chronically blocked orchronically reduced, receptors
may proliferate, resulting in hyper reactivity and increased
(31:40):
sensitivity. For example, after spinal cord
injury, nicotinic acetylcholine receptors are not stimulated by
impulses in motor nerves and proliferate in denervated
(32:00):
muscle. This can lead to exaggerated
responses, including hypercalemia to Socina choline.
This is the end of Chapter 7.
Morgan and Michael's Clinical Anesthesiology 7th Edition,
Chapter 7, Part 2 Compartment Models Multi compartment models
provide a mathematical frameworkthat can be used to relate drug
(00:24):
duels to changes in drug concentrations over time.
Conceptually, the compartments in these models are tissues with
a similar distribution time calls.
(00:44):
For example, the plasma and lungs are components of the
central compartments. The organs and muscles,
sometimes called the vessel richgroup, could be the second or
rapidly equilibrating compartment.
(01:09):
Fat and skin have the capacity to bind large quantities of
lipophilic drug but are poorly perfused.
These could represent the third or slowly equilibrating
compartments. This is an intuitive definition
(01:32):
of compartments, but it is important to recognise that the
compartments of a pharmacokinetic model are
mathematical abstractions that relate those to observed
concentration. A1 to one relationship does not
exist between any mathematicallyidentified compartment and any
(01:58):
organ or tissue in the body. Many drugs used in anaesthesia
are well described by two compartment models.
This is generally the case if the studies used to characterise
(02:19):
the pharmacokinetics do not include rapid arterial sampling
over the first few minutes. Without rapid arterial sampling,
the ultra rapid initial drop in plasma concentration immediately
after a bolus injection is missed and the central
(02:43):
compartment volume is blended into the rapidly equilibrating
compartment. When rapid arterial sampling is
used in pharmacokinetic experiments, the results
generally support the use of a three compartment model.
(03:06):
Thus, the number of identifiablecompartments reported in a
pharmacokinetic study may be more a function of the
experimental design than a characteristic of the drug.
Next, we get to Figure 7-1, explaining that two compartment
(03:30):
model demonstrates the changes in drug concentrations in the
distribution phase and the elimination phase.
Kindly pause this recording and go through Figure 7-1.
(03:51):
As previously noted, in compartmental models the
instantaneous concentration at the time of a bolus injection is
assumed to be the amount of the bolus divided by the central
compartment volume. This is not correct.
(04:15):
If the bolus is giving over a few seconds, the instantaneous
concentration is 0 because the drug is all in the vein, still
flowing to the heart. It takes a minute or two for the
drug to mix in the central compartment volume.
(04:37):
This MIS specification is commonto conventional pharmacokinetic
models. More physiologically based
models, sometimes called front end kinetic models, can
characterise the initial delay in concentration.
(05:01):
The additional complexity that these models introduce is useful
only if the concentrations over the first few minutes are
clinically important. After the first few minutes,
front end models resemble conventional compartmental
(05:23):
models. In the first few minutes
following initial Bolo's administration of a drug, the
concentration drops very rapidlyas the drug quickly diffuses
into peripheral compartments. Concentrations often decline by
(05:45):
an order of magnitude over 10 minutes.
For drugs with very rapid hepatic clearance, for example
propofol, or those that are metabolised in the blood, for
example, remifentanyl metabolismcontributes significantly to the
(06:07):
rapid initial drop in concentration.
Following this very rapid drop, a period of slower decrease in
plasma concentration occurs. During this period, the rapidly
equilibrating compartments is nolonger removing drug from the
(06:29):
plasma. Instead, drug returns to the
plasma from the rapidly equilibrating compartments.
The reversed role of the rapidlyequilibrating tissues from
extracting drug to returning drug accounts for the slower
(06:53):
rate of decline in plasma concentration in this
intermediate phase. Eventually there is an even
slower rate of decrease in plasma concentration, which is
which is log linear until the drug is no longer detectable.
(07:17):
This term terminal log linear phase occurs after the slowly
equilibrating compartment shiftsfrom net removal of drug from
the plasma to net return of the drug to the plasma.
During this terminal phase, the organ of elimination, which is
(07:41):
typically the liver, is exposed to the body's entire body drug
load, which accounts for the very slow rate of decrease in
plasma drug concentration. During this final phase, the
mathematical models used to describe a drug with two or
(08:04):
three compartments are respectively CP of T is equals
to AE to the minus alpha t + b Eto the minus beta T, and CP of T
(08:29):
is equals to AE to the minus alpha t + b E to the minus beta
T plus CE to the minus gamma T, where CP of T equals plasma
concentration at time T and alpha.
(08:52):
Beta and gamma are the exponentsthat characterise the very
rapid, that is very steep, intermediate and low, that is a
log. Linear portions of the plasma
concentration over time respectively.
(09:13):
Drugs described by two compartments and three
compartment models will have twoor three half lives each.
Half life is calculated as the natural log of two, that is,
0.693 divided by the exponents. The coefficients AB and C
(09:42):
represent the contribution of each of the exponents to the
overall decrease in concentration over time.
The two compartment model is described by a curve with two
exponents and two coefficients, whereas the three compartment
(10:06):
model is described by a curve with three exponents and three
coefficients. The mathematical relationships
among compartments, clearances, coefficients, and exponents are
complex. Every coefficient and every
(10:28):
exponent is a function of every volume and every clearance. 5 6
Elimination halftime is the timerequired for the drug
concentration to fall by 50%. For drugs described by multi
(10:56):
compartment pharmacokinetics, for example fentanyl,
sulfentanyl, there are multiple elimination half lives.
In other words, the elimination half time is context dependent.
The offset of a drug's effect cannot be predicted from half
(11:19):
lives alone. Moreover, one cannot easily
determine how rapidly a drug effect will disappear simply by
looking at coefficients, exponents, and half lives.
For example, the terminal half life of sulfentanil is about 10
(11:44):
hours, whereas that of alphentanil is 2 hours.
This does not mean that recoveryfrom alfentanil will be faster,
because clinical recovery from one, I mean from clinical dosing
will be influenced by all half lives, not just the terminal 1.
(12:10):
Computer models readily demonstrate that recovery from
an infusion lasting several hours will be faster when the
drug administered is sulfentanilthan it will be when the infused
drug is alphentanil. The time required for a 50%
(12:32):
decrease in concentration depends on the duration or
context of the infusion. The context sensitive half time
mentioned earlier captures this concept and should be used
instead of half lives. To compare the pharmacokinetic
(12:57):
properties of intravenous drugs used in anaesthesia.
Pharmaco dynamics Pharmacodynamics, The study of
how drugs affect the body, involves the concepts of
(13:21):
potency, efficacy, and therapeutic window.
The fundamental pharmacodynamic concepts are captured in the
relationship between exposure toa drug and physiological
response to the drug, often called the dose response or
(13:46):
concentration response relationship.
Exposure Response relationships As the body is exposed to an
increasing amount of a drug, theresponse to the drug similarly
(14:09):
increases, typically up to a maximal value.
This fundamental fundamental concept in the exposure versus
response relationship is captured graphically by plotting
exposure, that is usually dose of concentration on the X axis
(14:34):
as the independent variable and the body's response on the Y
axis as the dependent variable. Depending on the circumstances,
the duals or concentration may be plotted on a linear scale or
(14:57):
a logarithmic scale, while the response is typically plotted
either as the actual measured response or as a fraction of the
baseline or maximum physiological measurements.
For our purposes here, basic pharmacodynamic properties are
(15:21):
described in terms of concentration, but any metric of
drug exposure, for example thosearea under the curve, could be
used. Next we get to Figure 7-2,
talking about the shape of the dose or concentration response
(15:44):
curve, depending on whether the dose or plasma concentration is
plotted on a linear or logarithmic scale.
Kindly pause this recording to go through Figure 7.
Hyphen 2. The shape of the relationship is
(16:06):
typically sigmoidal, as shown inFigure 7 iPhone, iPhone 2.
The sigmoidal shape reflects theobservation that often a certain
minimal amount of drug must be present before there is any
measurable physiological response.
(16:35):
Thus, the left side of the curveis flat until the drug
concentration reaches a threshold.
The right side is also flat, reflecting the maximum
physiological response of the body, beyond which the body
(16:57):
simply cannot respond to additional drug.
Thus the curve is flat on both the left and right sides.
A sigmoidal curve is required toconnect the baseline to the
(17:20):
asymptote, which is why sigmodalcurves are ubiquitous.
When modelling pharmacodynamics.The sigmodal relationship
between exposure and response isdefined by one of two
interchangeable reflect relationships.
(17:45):
Effects is equals to E Max multiplied by C gamma over C50
gamma plus C gamma. Or effect is equals to E0 plus E
(18:08):
Max minus E0IN bracket multiplied by C gamma over C50
gamma plus C gamma. In both cases, C is drug
concentration, C50 is the concentration associated with a
(18:33):
half maximal effect, and gamma describes the steepness of the
concentration versus response relationship, and it's also
known as the heal coefficient. In the first equation, E Max is
the maximum physiological measurement, not the maximum
(18:57):
change from baseline. For the second equation, E Max
is the maximum change from the baseline effect, that is E0.
Once defined in this fashion, each parameter of the
pharmacodynamic model speaks to the specific concepts mentioned
(19:21):
earlier. E Max is related to the
intrinsic efficacy of a drug. Highly efficacious drugs have a
large maximum physiological effect, characterised by a large
E Max. For drugs that lack efficacy, E
(19:47):
Max will equal E 0. C50 is a measure of drug
potency. Highly potent drugs have a low
C50, thus small amounts produce the drug effect.
(20:11):
Drugs lacking potency have a high C50, indicating that a
large amount of drug is requiredto achieve the drug effects.
The parameter gamma indicates the steepness of the
relationship between concentration and effect.
(20:36):
A gamma value less than one indicates a very gradual
increase in drug effects with increasing concentration.
A gamma value greater than 4 suggests that once drug effect
is observed, small increases in drug concentration produce large
(21:00):
increases in drug effects until the maximum effect is reached.
The curve described above represents the relationship of
drug concentration to a continuous physiological
response. The same relationship can be
(21:23):
used to characterise the probability of a binary that is
yes, no response to a drug. Dose probability is equals to P0
plus P Max minus P0IN bracket multiplied by C gamma over C50
(21:52):
gamma plus C gamma. In this case, the probability P
ranges from zero, that is no chance, to one that is
certainty. P0 is the probability of a yes
(22:14):
response in the absence of drug P.
Max is the maximum probability necessarily less than or equal
to 1. As before, C is the
(22:34):
concentration, C50 is the concentration associated with
half maximal effect, and gamma describes the stiffness of the
concentration versus response relationship.
Half maximal effect is the same as 50% probability of a response
(22:59):
when P0 is 0 and P Max is 1. The therapeutic window of a drug
is the range between the concentration associated with
the desired therapeutic effects and the concentration associated
(23:19):
with a toxic drug response. This range can be measured as
either the difference between 2 points on the same concentration
versus response curve, that is, when the toxicity represents an
exaggerated form of the desired drug response, or the distance
(23:43):
between 2 distinct curves, that is, when the toxicity represents
a different response or process from the desired drug response.
For a drug such as sodium nitropruside, a single
concentration versus response curve defines the relationship
(24:07):
between concentration and decrease in blood pressure.
The therapeutic window might be the difference in the
concentration producing a desired 20% decrease in blood
pressure and a toxic concentration that produces a
catastrophic 60% decrease in blood pressure.
(24:33):
However, for a drug such as lidocaine, the therapeutic
window might be the difference between the C50 for suppression
of ventricular arrhythmias and the C50 for lidocaine induced
seizures, the two drug effects being described by separate
(24:57):
concentration versus response relationships.
The therapeutic index is the C50for toxicity divided by the C50
for the desired therapeutic effect.
Because of the risk of ventilatory and cardiovascular
(25:19):
depression that is even at concentrations only slightly
greater than those producing anaesthesia, most inhaled and
intravenous hypnotics are considered to have very low
therapeutic indices relative to other drugs.
(25:44):
Drug Receptors Drug receptors are macromolecules, typically
proteins that buying the drug that is agonist and mediate the
drug response. Pharmacological antagonists
(26:08):
reverse the effects of the egonist, but do not otherwise
exert an effect on their own. Competitive antagonism occurs
when the antagonist competes with the egonist for the same
binding site, each potentially displacing the other.
(26:31):
Non competitive antagonism occurs when the antagonist,
through covalent binding or another process, primarily
impairs the drug's access to thereceptor.
The drug effect is governed by the fraction of receptors that
(26:52):
are occupied by an egonist. That fraction is based on the
concentration of the drug, the concentration of the receptor,
and the strength of binding between the drug and the
receptor. This binding is described by the
(27:13):
law of mass action, which statesthat the reaction rate is
proportional to the concentrations of the reactants.
D multiplied by RU gives Dr Moving forward, it's K on moving
(27:42):
backwards, it's K off. Where D is the concentration of
the drug, RU is the concentration of unbound
receptor, and Dr is the concentration of bound receptor.
(28:02):
The rate constant K on defines the rate of ligand binding to
the receptor. The rate constant K off defines
the rate of ligand on binding from the receptor.
Steady state occurs almost instantly because the rate of
(28:26):
formation at steady state is 0. It follows that D multiplied by
ruk on minus DRK off. In this equation, KD is the
dissociation rate constant defined as K on divided by K
(28:52):
off. If we define F fractional
receptor occupancy as Dr over Drplus RU, we can solve for
receptor occupancy as F is equals to D over KD plus D.
(29:18):
The receptors are half occupied when D is equals to KD.
Thus, KD is the concentration ofdrug associated with 50%
receptor occupancy. Receptor occupancy is only the
(29:42):
first step in mediating drug effect.
Binding of the drug to the receptor can trigger myriad
subsequent steps, including opening, closing, or inhibition
of an ion channel, activation ofthe G protein, activation of an
(30:07):
intracellular kinase, direct interaction with the cellular
structure, or direct binding to DNA.
Like the concentration versus response curve, the shape of the
curve relating fractional receptor occupancy to drug
(30:30):
concentration is intrinsically sigmoidal.
However, the concentration associated with 50% receptor
occupancy and the concentration associated with 50% of maximal
drug effects are not necessarilythe same.
(30:54):
Maximal drug effects could occurat very low receptor occupancy
or for partial lagoonies at greater than 100% receptor
occupancy. Prolong the binding and
activation of a receptor by an egonist may lead to
(31:18):
desensitisation or tolerance. If the binding of an endogenous
ligand is chronically blocked orchronically reduced, receptors
may proliferate, resulting in hyper reactivity and increased
(31:40):
sensitivity. For example, after spinal cord
injury, nicotinic acetylcholine receptors are not stimulated by
impulses in motor nerves and proliferate in denervated
(32:00):
muscle. This can lead to exaggerated
responses, including hypercalemia to Socina choline.
This is the end of Chapter 7.
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