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Last edited: 9/2/2022

PHARMACODYNAMICS
Pharmacodynamics Medical Editors: Aldrich, Jona & Jude

OUTLINE
I) INTRODUCTION V) TACHYPHYLAXIS AND TOLERANCE VIII) INTRINSIC ACTIVITY (AGONISTS AND
II) TYPES OF DRUG-RECEPTOR INTERACTIONS (A) TACHYPHYLAXIS ANTAGONISTS)
(A) LIGAND-GATED ION CHANNELS (B) TOLERANCE (A) FULL AGONISTS
(B) G-PROTEIN COUPLED RECEPTORS VI) DOSE-RESPONSE RELATIONSHIP (B) PARTIAL AGONIST
QUICK RECAP OF EXTRACELLULAR (A) PHASES IN DOSE-RESPONSE CURVES (C) INVERSE AGONIST
RECEPTOR INTERACTION (B) POTENCY (A) COMPETITIVE ANTAGONIST
III) EXTRACELLULAR RECEPTORS (C) EFFICACY (B) NONCOMPETITIVE ANTAGONIST
(A) TYROSINE KINASE RECEPTORS (D) CASE: BUMETANIDE AND FUROSEMIDE SUMMARY OF ANTAGONIST
IV) INTRACELLULAR RECEPTORS VII) THERAPEUTIC INDEX IX) REVIEW QUESTIONS
(A) NARROW THERAPEUTIC INDEX X) REFERENCES
(B) LARGE THERAPEUTIC INDEX

I) INTRODUCTION

(1) Absorption (4) Elimination

After a drug is done performing its particular function or
Drug moves through the gastrointestinal tract has to be it’s moving through the circulation
absorbed, crossing cell membrane o It can be taken to these organs
When it moves cross the cell membrane to get into the  Kidneys
blood • Where it can be excreted
o It goes into the hepatic portal system  Liver
o Hepatic portal system will then take this medication to • Where it can be metabolized and also
the liver excreted
o These are the primary organs of clearance of drugs
(2) Metabolism (First-pass effect)
If the drug goes via the oral route, the liver will get some Pharmacokinetics & pharmacodynamics
piece of that drug
Pharmacodynamic
o Where it can activate or break down some of the
actual drugs → first-pass effect/metabolism Now whenever the drug gets to the actual tissues
o What we can see is what the drug does to the actual
What it will do is some of that drug may be metabolized
body
o And then the other remaining portions are put into the
systemic circulation Pharmacokinetics
(3) Distribution Whereas pharmacokinetics is like what the body is
From there we know once the drug goes actually doing to the drug
It will actually distribute throughout the actual vasculature
and into the tissues
o Where it can go and exert its effect
o This is where we’re going to see the
pharmacodynamic effect

Remember pharmacokinetics
ADME
o Absorption of the drug
o Distribution of the drug
o Metabolism of the drug
o Excretion of the drug

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 II) TYPES OF DRUG-RECEPTOR INTERACTIONS

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Now we have to see what this drug actually does to the body particularly the cellular component of our tissues or organs
Zoom in at this drug interaction
We’re going to look at one of these particular cells
o We have our drug
In order for drug to be able to bind to a cell and produces a particular cellular response
o It needs to be able to act on a receptor
Once it binds to that receptor
o It will then produce a particular cascade of events intracellularly
o That activates or inhibit the cells
In order for the drug to do that, it has to bind either
o Extracellular receptor
 Via second messenger systems work to be able to stimulate second messages to produce the cellular response
o Intracellular receptor
 The drug has to be able to move into the cell and bind onto a intracellular receptor
 Where it produce a cellular response via specific cascade of events
What we have to understand now
We take this drug and have it bind onto extracellular receptors
o What are the different types of extracellular receptors and why are they different?
o What are some examples of drugs that act with different types of receptors?
And then we talk about the intracellular receptors
o What kind of drugs particularly interact that way?
We’ll talk about desensitization/tachyphylaxis and tolerance with respect to drug-receptor interactions

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EXTRACELLULAR RECEPTOR

(A) LIGAND-GATED ION CHANNELS

We have a neuron
Example
o On this neuron we have these particular channels
o That are supposed to allow for particular ions (positive
or negative ions) to flow in
There’s a little gate that’s basically controlling the
entry of ions
o These gates are blocking these ions from moving into
the actual cell
o These channels are Integral membrane proteins that
contain a pore which allows the regulated flow of
selected ions through the plasma membrane
Katzung, 2018]
But we give a particular drug that wants to bind to the little
pocket that’s a part of the ligand-gated ion channel
o Once it binds onto that pocket, it lifts the gate
open
o Now this gate was completely closed is now open
 There’s an opportunity for the particular ions to
easily flow in or out of this neuron
Quick recap
Lorazepam acts on GABAA receptor
GABAA receptors are ligand-gated ion channels
o These channels are generally closed
o We don’t want to be open
When GABA binds onto these channels
o What it will do is it will open up the channel
 And allow for negatively charged (Cl- ions) to
easily flow into the actual neuron
As these Cl- ions flow into the neuron
o It makes the cell super negative
o It basically hyperpolarize and decrease action
potentials
We can give lorazepam in situations where we want to
decrease the activity of neurons
o Very important situation → seizures
o So, it may be work to inhibit or decrease seizure
activity
Drugs bind onto a ligand-gated ion channel
o Either open or close that channel
o Depending upon what kind of channel they bind onto
 Will determine which kind of ion flows in or out
o And then there’s associated cellular response

(B) G-PROTEIN COUPLED RECEPTORS

Also called as seven pass receptors or serpentine receptors

Basically, it has a little receptor domain
o Where a drug would actually bind into that pocket
See how it actually moves through the actual membrane seven times
o That’s why they call it a seven-pass transmembrane receptor
What happens is drugs can actually bind onto these particular receptor domains
o When it binds onto the receptor domain of each one of these little pockets
o It changes the shape of the actual receptor (intracellular domain)
This intracellular domain is connected to something called G-protein
o There are different types of G-proteins

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(1) Gq protein

(i) Gq protein activation Example

Let’s say we have a drug bind to this receptor domain We have a drug like norepinephrine
o Changes the shape of the receptor o We want norepinephrine to act on the heart muscle
What it does is it stimulates a particular G-protein cells
o G-proteins normally bound to something called GDP What norepinephrine will do is it will bind onto this
What we’re going to do is we want to activate this even receptor
more Activate the Gq protein
o What we do is we have them pop out GDP and have Activate phospholipase C enzyme
them bind to GTP Increase diacylglycerol → activate protein kinase
o This really stimulates this Gq protein Protein kinases will go phosphorylate particular
channels
(ii) Phospholipase C activation AfraTafreeh.com o To increase Ca2+ ion influx or Na+ ion influx
Inositol trisphosphate will activate smooth
Gq protein will move along the cell membrane
endoplasmic reticulum or sarcoplasmic reticulum
o And stimulates this enzyme that’s embedded into the
o To release Ca2+ into the actual muscle cell
cell membrane → phospholipase C
What phospholipase C will do is it will break down The whole concept is
components of the cell membrane We increase ions inside the muscle cell particularly
o A molecule called PIP2 Ca2+
o It will be broken down into 2 components o We’re going to increase the contraction of the
 Diacylglycerol heart muscle cell
 Inositol trisphosphate
So we see the clinical response
What these things do is this will activate something called o It this was norepinephrine working on the heart
protein kinase C muscle cell
o This will work to increase Ca2+ ions inside of the cell o It would increase the amount of ions rushing into the
cell
Significance
 Stimulating it’s ability to contract
Let’s say channels that are on the cell membrane that
Cellular (heart muscle cell) response would be increased
currently are inactivated
contraction
o But we have this drug bind to this receptor, activate
this Gq protein
It then activates phospholipase C which activates
these second messengers like
o Diacylglycerol
o Inositol trisphosphate
This will increase Ca2+ inside the cell
Protein kinase C can then go and phosphorylate all of
these channels
o If it adds a phosphate group to these channels
o It may activate or inactivate them
If it activates them, it opens them up
o So, allow for example positive ions to easily flow
into the cell
o Bringing positive ions into the cell could
potentially stimulate this cell

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(2) Gs (G-stimulatory protein)

(iii) Adenylate cyclase function

(i) Gs protein activation
This drug binds onto this receptor and when it does
o The receptor changes its shape
o Then it activates the G-stimulatory protein
 In order for this protein to be truly protein
• Need to get rid of GDP
• And bind onto GTP
(ii) Adenylate cyclase stimulation
When it’s super activated
o It then will go move along the cell membrane
 And stimulate this particular enzyme embedded in
the cell membrane → adenylate cyclase
(3) Gi (G-inhibitory protein)
Once it’s activated, it takes ATP and converts it into
cAMP (cyclic AMP)
o cAMP will activate protein kinase A
o Protein kinase A phosphorylates things
There are particular channels that are on this particular
cell membrane
o Protein kinase A may go and phosphorylate this
If it phosphorylates these proteins on the cell membrane
o It can either open or close the ion channel
o Either way ions will move in or out of the cell
 It will potentially cause some cellular response
This could be norepinephrine as well
o It can do both of these concepts (Gq and Gs
protein cascade)

(i) Gi protein activation (ii) Gi protein effect

We have a drug, it binds to this G-protein coupled In this situation with Gi protein
receptor o We inhibit adenylate cyclase
 Changes its shape, activates Gi protein  We inhibit the ability to convert ATP into cAMP
o Gi protein will then release GDP and bind GTP o We decrease protein kinase A
 Gi protein will inhibit adenylate cyclase o We decrease the phosphorylation of these
particular proteins
Remember that  Depending upon what we’re looking for
Adenylate cyclase is supposed to convert ATP into  This could produce a particular cellular
cAMP response
cAMP is supposed to activate protein kinase A
Protein kinase A is supposed to go and phosphorylate
specific types of proteins
o Could be structural proteins, enzymatic proteins, or
functional proteins
o Which could either inactivate or activate the particular
protein or enzyme

QUICK RECAP OF EXTRACELLULAR RECEPTOR INTERACTION

So, when a drug interacts with a receptor to produce a cellular response
o It either can act on a ligand-gated ion channel
 Binding to a spot opening or closing the channel
 One of the two which produces a cellular response
o It can bind onto a protein that is connected on the outside of it (G-protein coupled receptor)
 Changes the shape of the protein
 That activates second messenger system to produce a cellular response

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 III) EXTRACELLULAR RECEPTORS

(A) TYROSINE KINASE RECEPTORS

(1) STRUCTURE (2) DOWNSTREAM MECHANISM
Has two main parts (Figure 1) The downstream mechanism starts with a signal-binding
o Extracellular ligand binding domain molecule or a ligand coming close to the receptor for
o Cytosolic domain with tyrosine kinase activity binding (Figure 1).
It can be insulin, growth factors, drugs, etc.

INSULIN binds to the tyrosine kinase receptors

Receptor tyrosine kinases start out as INACTIVE
MONOMERS . Note each has a ligand binding site.
Monomers combine to make dimers when signal
molecules bond with receptor signs
D IMERIZATION activates phosphorylation of the tyrosines
dangling in the cytoplasm
• Tyrosines CROSS-PHOSPHORYLATE each other
Fully phosphorylated, the active receptor has changed
its structure and is now recognized by multiple relay
proteins
Each can trigger a separate cellular response

Remember
Ligand-gated ion channels, GPCR, and tyrosine-kinase
receptors are FOR HYDROPHILIC , LARGE, POLAR , CHARGED
Figure 1. Tyrosine Kinase Receptor. drugs.

IV) INTRACELLULAR RECEPTORS

These are receptors FOR HYDROPHOBIC , SMALL , NONPOLAR , UNCHARGED drugs
o Examples: steroids, nitric oxide
(1) DOWNSTREAM MECHANISM
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The hydrophilic drug passes through the cell membrane.
It binds to an intracellular receptor.
The BOUND INTRACELLULAR RECEPTOR can now translocate to the nucleus and binds to a transcription factor
• Transcription Factors: regulate the degree of transcription of DNA to mRNA.
The transcription factor becomes stimulated and starts to regulate the cellular response by increasing the transcription process.

Remember
The intracellular receptor pathway takes time to be able to
produce a clinical effect
In comparison to extracellular receptor pathway, which is
faster and more amplified

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V) TACHYPHYLAXIS AND TOLERANCE

(A) TACHYPHYLAXIS (B) TOLERANCE
When a patient is exposed to a large dose of a particular C HRONIC RESPONSE (hours, days, to weeks)
drug, the drug tends to bind to many different receptors Repeated exposure to a particular drug, unlike
producing a massive cellular response (Figure 2). tachyphylaxis (Figure 3)
Because of the intense response, the cell will employ It also causes the cell to employ protective mechanisms
protective mechanisms to produce a less significant against successive stimulation
cellular response. Occurs in [Katzung, 2018]
R APID RESPONSE TO A LARGE, INITIAL DOSE OF A DRUG o Opioids
Occurs in [Katzumg, 2018] o Benzodiazepines
o Amphetamine o Barbiturates
o Tyramine o Alcohol

Figure 2. Tachyphylaxis.
(1) MECHANISMS

(i) Decrease the synthesis of receptors Figure 3. Tolerance.

• There are less receptors the drug molecules
can bind to
(1) MECHANISMS
(ii) Kinases will add phosphate residues
(i) Decrease synthesis of receptors
• The phosphorylation of receptors tags these
receptors.
• A protein called ARRESTIN binds to tagged
(iii) Increase in metabolic enzymes
receptors leading to their inactivation. • There is an increase in the number of enzymes
• Even though there are drugs ready for binding, that break down the drug → reducing its
the receptors are arrested hence they will still actual efficacy
not be able to bind. • When patient is chronically exposed to a drug,
he/she will have an increase in the number
(iii) Endocytosis metabolic enzymes.
• Bringing the receptors back into the cell o Metabolic enzymes keep on breaking down
the drug reducing the response/effect.
• The activity of the metabolic enzyme is
overcome by increasing the dose of the drug to
produce the actual clinical effect

Pharmacodynamics PHARMACOLOGY: NOTE #7. 7 of 15

 VI) DOSE-RESPONSE RELATIONSHIP

Figure 4. Dose-response curves showing differences in potency (left) and efficacy (right).

X-axis: Concentration of the drug in log scale (log [drug Y-axis: Response of the drug
dose]) Shows a sigmoidal curve
o S-shaped curve

(A) PHASES IN DOSE-RESPONSE CURVES (C) EFFICACY

Phase 1: When you start with a low dosage of drug, only
a small amount of drug binding on the receptors leading
to a minimum clinical response
o Can be seen as a flat response
Phase 2: More drugs binding to more receptors leading to
an increase in response
o Shows a steep curve
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Phase 3: Eventually, the receptors are saturated by the
Figure 6. Efficacy of the drug.

drug to produce a cellular response leading to a plateau Dependent upon:

o Emax is maximum amount of drug to produce o Drug-receptor interaction
maximum amount of response
o Intrinsic activity of the drug
(B) POTENCY  How much clinical response the drug produces:
100%, 70%, etc.
 Some drugs are called full agonist (bind to the
receptors, effect is 100%) or partial agonist
(binding the effect will never going to be 100%)
Determined by the point where all the receptors are
stimulated
Figure 5. Potency of the drug. o 100% receptors are occupied
Correlational with affinity (1) Emax
o As affinity is increased, potency is increased
Point where all the receptors are occupied no matter if the
Strength of the drug-receptor interaction concentration of drug is increased
o The stronger the bond is, the more affinity, the A drug with decreased efficacy would shift the Emax
more potent the drug is downwards (Figure 1)
Higher potency does not necessarily produce the same Difference in efficacy is the difference in Emax (Figure 1)
efficacy
(1) EC50 (D) CASE: BUMETANIDE AND FUROSEMIDE

Concentration of the drug that will reach 50% of max

response
Measure of potency or affinity
EC50 and potency are inversely proportional
o As EC50 increases (curve shifts to the right = more
drug is given), the potency decreases
If potency decreases, the curve shifts to the right (Figure 1)
If potency increases, the curve shifts to the left (Figure 1)
Difference in potency is the difference in EC50 (Figure 1)
Figure 7. Difference and similarity of bumetanide and
furosemide in potency (left) and efficacy (right).
Bumetanide can be given in a very low dose to produce
50% of max effect = high potency
However, bumetanide and furosemide are similarly
efficacious
Just because the potency is different does not mean the
efficacy is different as well

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VII) THERAPEUTIC INDEX

Figure 8. Therapeutic index.

Similarly, the curve shows log [dose] on the x-axis but with %patients on the y-axis.
ED50: concentration of the drug to produce the clinically desired effect of the drug in 50% of patient’s population
TD50: concentration of the drug to produce a toxic effect in 50% of the patient’s population
Therapeutic index is the difference between ED50 and TD50
𝑇𝑇𝐷𝐷
o 𝑇𝑇ℎ𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑖𝑖𝑖𝑖 𝑖𝑖 = ( 50 )
𝐸𝐸𝐷𝐷50
𝑖𝑖
𝑖𝑖
(A) NARROW THERAPEUTIC INDEX (B) LARGE THERAPEUTIC INDEX
Decreased TD50 = narrow therapeutic index High TD50 = large therapeutic index
High risk of side effects Less risk of side effects
Margin of error is very tiny Example of drugs: Penicillin G, steroids
Example of drugs with narrow therapeutic index:
GWTDAL (Guy, warning, these drugs are lethal)
o Gentamicin
o Warfarin (INR)
o Theophylline
o Digoxin
o AEDs
o Lithium
Important that these drugs are monitored!

Table 1. Comparison of narrow and large therapeutic indices.

Narrow TI Large TI

Side effects High Low

Gentamicin Penicillin G
Warfarin Steroids
Theophylline
Examples Digoxin
AEDs
Lithium

Pharmacodynamics PHARMACOLOGY: NOTE #7. 9 of 15

 VIII) INTRINSIC ACTIVITY (AGONISTS AND ANTAGONISTS)

Whenever we have a drug that binds to a particular receptor

o We want to compare it to our endogenous system
Example
We have a blood vessel
o And on that blood vessel we have a receptor called 𝛼𝛼1 -receptor
What we know is that norepinephrine and epinephrine are basically molecules that will bind onto this receptor
o Stimulate it and trigger vasoconstriction
o That’s the response / effect of the drug binding onto that receptor

AGONISTS
Let’s assume that there are 100% receptor binding by norepinephrine
o We know that it’s effect is vasoconstriction
(1) If we give drug A that also can act like norepinephrine
Whenever it binds onto 100% of the receptors are completely saturated with this drug
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o And it produces the same, max intensity or maximal effect (100% effect) of vasoconstriction just like norepinephrine
o It is a full agonist
(2) If we give drug B and bind onto 100% of the receptors are saturated by this other type of agonist
But it doesn’t produce the same maximal effect or efficacy as drug A did
We call this partial agonist
(3) When we have drug C binds onto 𝜶𝜶𝟏𝟏 -receptor and all it does is it keeps the actual receptor completely inactivated
Then we significantly reduce the actual efficacy and maximal effect of that drug to below the basal activity of the receptor
o Because normally receptors have some degree of basal activity
o Degree of basal activity is about 12%

(A) FULL AGONISTS

Graph

Log concentration of drug (log([𝐷𝐷 𝐷𝐷]) on the x-axis

𝐷𝐷𝐷𝐷
Response on the y-axis
o Just like dose-response curve
What we’re going to see is that there’s 12% basal activity
o We’re going to increase it from that point
We can give a drug just like norepinephrine
o We can just give it exogenously That would be the curve at 100% max efficacy if we give
a full agonist
Example of drugs o Remember full agonist will mimic the basic
Levofed norepinephrine endogenous system
Phenylephrine
Epinephrine
o They can bind onto the 𝛼𝛼1 -receptors and produce the
same type of maximal effect
Drug effect
These will all produce the same type of clinical
response
When they bind to 100% of the receptors are bound by a drug
o They produce the max clinical response/effect (Emax)

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(B) PARTIAL AGONIST

Full agonist + partial agonist → competitive inhibition

If we keep giving high concentration of a partial agonist

and we give it in combination with an agonist
o Let’s say what we did we would bind onto 𝜇𝜇-receptor
We give buprenorphine and morphine

If we give buprenorphine
Sub-par max effect What it will do is it will bind to all of these 𝝁𝝁-receptors
And basically, as we increase the concentration of it
There’s opioid receptor called 𝜇𝜇 receptor (mu receptor)
o It’s going to block the actual morphine from being
o It loves to bind onto something called morphine
able to bind into that receptor
What happens is if we give partial agonist o Because it binds to same active site as
o They’ll bind onto these 𝜇𝜇 receptors buprenorphine
 Example: Buprenorphine
When we give an agonist and a partial agonist
Buprenorphine will actually bind onto these receptors together
o If it saturates 100% of the 𝝁𝝁-receptors o What we see is competitive inhibition
 It will produce a clinical effect that is below the  Where this buprenorphine is going to compete
max effect (sub-par max effect) with morphine for the actual 𝜇𝜇-receptor, blocking it
o Let’s say if this is 100%, this is like 70% or 60%
The only way that we’re going to be able to see
 It’s below the max effect → partial agonist
morphine produce max effect
It will not produce the max effect o We keep trying to increase the concentration of
o But there’s something really interesting about partial morphine
agonist o To eventually displace the buprenorphine out of
that active site
Graph
Remember
We go beyond the basal activity of the receptor
Partial agonist can also act like antagonist
o We see that as we increase the concentration of the
o If we increase the concentration of them
drug but we’re going to drop off our efficacy
o Specifically competitive antagonist
Because no matter what, we’ll never reach max effect

(C) INVERSE AGONIST

Mechanism of action Receptor conformation

These drugs will bind to the receptor Receptors can exist in two forms
o They will significantly decrease the effect of this drug o Can go back and forth between active form (R) and
o E.g., less than 12% which is the basal activity of the inactive form (R’)
drug What we do here is that when an inverse agonist interacts
We’re going to see this particular drug reduce the actual o It tries to be able to push the reaction and keep it in
maximal effects significantly to the point where it’s this inactive form
less than basal activity No other agonist will be able to bind to it
How do we decrease the drug receptor interaction o So completely reduce the drug-receptor interaction
where we go below the basal activity? below the basal activity
o We inactivate the receptor
Example of drugs
Antihistamines
o Can act on H1 or H2 receptors

Pharmacodynamics PHARMACOLOGY: NOTE #7. 11 of 15

 ANTAGONIST

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Overview
They work to be able to oppose the agonist
What happens is they try to be able to act like a neutral component
o So, they basically kind of inhibit any type of agonist being able to bind to the receptor
o But at least allow for the receptor to maintain basal activity
We have blood vessel that has 𝛼𝛼1 -receptor
o Norepinephrine will bind onto it and cause vasoconstriction
o An antagonist to that drug would be an 𝜶𝜶𝟏𝟏 -blocker
 That will basically bind to the receptor site
• Inhibiting or preventing norepinephrine from being able to exert its effect
 Therefore, there would be no vasoconstriction
What an antagonist does is it opposes the action of the agonist (norepinephrine)

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(A) COMPETITIVE ANTAGONIST

Let’s say we have our cell and receptor

o What we’re going to do is giving norepinephrine which is going to bind onto these 𝛼𝛼1 -receptors
 We have 𝛼𝛼1 -blockers
Drug example
Phentolamine
Drug effect
Phentolamine will plug into these receptors and basically block norepinephrine from being able to bind here
o Remember norepinephrine is supposed to bind to these receptors
Graph
Let’s say we have normal dose-response curve
Quick recap
o When norepinephrine binds to these receptors
o We know that it produces a nice sigmoidal curve In order for us to be able to produce the same kind of
What we’re going to do is we’re going to give maximal effect
phentolamine o We have to increase the dosage of agonist
o It’s going to block these receptors

(i) If there are any receptors that are available Curve shift to the right
Norepinephrine will still bind and produce some type of Remember
response o We have Emax
 Maximal effect that this actual drug-receptor
(ii) But if we still want to be able to produce the interaction can perform
maximum response o At 50% effect, we have 𝐸𝐸𝐶𝐶50
What we need to do is we need to increase the What is happening if we increase or shift the actual curve
concentration of our norepinephrine (agonist) to the right?
o To overcome and displace the antagonist out of o We increase the 𝑬𝑬𝑪𝑪𝟓𝟓𝟓𝟓
the active site o What does that do to the potency? It decreases the
potency
We want to pop those out of the active site so that we
have the ability to beat the antagonist out So, competitive antagonist decreases the potency
o And bind onto these receptors and produce the What do they do to the Emax? Nothing
same type of clinical response that we want Quick recap
No change in Emax
Increase 𝐸𝐸𝐶𝐶50
o Decrease potency
Increase the agonist concentration o Because these are inversely proportional

What we have to do if we need to be able to produce the
same clinical effect/response as an agonist would by
itself in the presence of antagonist
o We’re going to increase the concentration of the
agonist significantly to be able to produce the same
type of clinical response
We’re shifting the curve to the right, increasing our 𝐸𝐸𝐶𝐶50
o Which means we have to give more of the drug to be
able to have the same type of potent effect
o More drugs to displace the competitive inhibitor out of
the spot

Pharmacodynamics PHARMACOLOGY: NOTE #7. 13 of 15

 (B) NONCOMPETITIVE ANTAGONIST

We have 𝛼𝛼1 -receptor

o Norepinephrine is supposed to bind
So, we’re going to give 𝛼𝛼1 -blocker
o That’s going to work basically block/prevent work against the activity of the agonist
Example of drug
There is another 𝛼𝛼1 -blocker that act as non-competitive antagonist called phenoxybenzamine
Mechanism of action
Remember These non-competitive antagonist bind to the
Phentolamine bound to the actual active site allosteric site
o Same site where the actual agonist binds to o Changing its shape that no matter what even if we
Phenoxybenzamine does not bind to the active site try to increase the concentration of norepinephrine
So, when we have a non-competitive inhibitor like  It’s not going to matter
phenoxybenzamine  It’s going to have tons of active sites available
o It binds to another site besides the active site
called allosteric site (i) If we increase the concentration
o It’s a site on the actual protein or receptor other than
It will still have a difficult time being able to bind to
the active site AfraTafreeh.com
the active sites
When phenoxybenzamine binds to this It’s not going to be able to produce any improvement in
o It changes the shape of the actual receptor to the overall response or cellular effect
where now it’s not even the same shape o Response is going to plummet
 It’s going to be harder for that to be able to bind to o It’s going to plummet even if we increase the
the agonist (norepinephrine) concentration of the agonist

So, because of that, norepinephrine wants to be able to

bind here but it can’t
o Even though that there’s a site available
Quick recap
It’s not going to matter because this is non-competitive inhibitor
o Phenoxybenzamine is binding to the allosteric site
o Changing its shape to no matter what it’s not going to be able to bind properly to the agonist

Graph
If with respect to the concentration or potency that’s not But what we’re going to see is that the response/effect
going to change that’s going to decrease significantly
o It’s going to stay the same o Because the agonist can’t bind to the active site
Remember and produce response it wants to
o We have Emax (100% response/effect)  Because the non-competitive inhibitor changed its
o We have 50% effect and we have 𝐸𝐸𝐶𝐶50 shape by binding to the allosteric site
So, what we’ll see is the curve drop off before reaching
𝑬𝑬𝑪𝑪𝟓𝟓𝟓𝟓 is about exactly the same because even if we
maximum response/effect
increase the concentration of our agonist
o We see the decrease in Emax
o It’s not going to make any difference in the response
o There’s no effect on potency with respect to non- If we decrease in Emax
competitive inhibitors o We know that non-competitive inhibitors decrease the
efficacy of the drugs
No change in 𝐸𝐸𝐶𝐶50
Decrease the Emax with respect to non-competitive inhibitors
o So, the only way we can actually prevent this and
improve the efficacy is getting rid of the non-
competitive inhibitors
o We increase the drug concentration is not going to
affect it
14 of 15 PHARMACOLOGY: NOTE #7. Pharmacodynamics
 AfraTafreeh.com

SUMMARY OF ANTAGONIST
Antagonist
Competitive Noncompetitive
No change in Emax Decreased Emax
Increased 𝑬𝑬𝑪𝑪𝟓𝟓𝟓𝟓 No change in 𝑬𝑬𝑪𝑪𝟓𝟓𝟓𝟓
Decreased potency No effect on potency

IX) REVIEW QUESTIONS 11) Which of these drugs should be monitored

CLOSELY?
1) Which of the following is TRUE about
a) Amoxicillin
pharmacodynamics?
b) Bumetanide
a) What drug does to the body
c) Digoxin
b) What body does to the drug
d) All of the above
c) Involves ADME
d) Concerned in first pass effect 12) Partial agonists may act as antagonist
a) True
2) GABA-A receptors are examples of
b) False
a) Ligand-gated ion channel receptors
b) Intracellular receptors 13) Competitive agonist decreases Emax
c) GPCR a) True
d) None of the above b) False
3) Which G-protein is responsible for the breaking down 14) Which type of drugs that may cause the receptor
of PIP2 when activated? activity to be lower than basal activity?
a) Gq a) Full agonist
b) Gi b) Partial agonist
c) Gs c) Inverse agonist
d) Gd d) Competitive antagonist
e) Uncompetitive antagonist
4) Ligand-gated ion channel receptors are classified as
extracellular receptors that are related to influx and
efflux of ions X) REFERENCES
a) True
● Tao and Bhushan, Vikas. First Aid for the USMLE Step 1 2022,
b) False Thirty second edition. New York: McGraw-Hill Education, 2022.
5) G-stimulatory proteins work by activating adenylate ● Raffa, Robert B, Scott M. Rawls, Elena P. Beyzarov, and Frank
cyclase in order to activate protein kinase A H. Netter. Netter's Illustrated Pharmacology. 2013.
a) True
● Ritter, James. Rang and Dale's Pharmacology. Ninth edition.
b) False Edinburgh: Elsevier, 2020.
6) Which of the following ligands will not be able to utilize
the extracellular receptor pathway ● Brown, Morris J., Pankaj Sharma, Fraz A. Mir, and Peter N.
Bennett. Clinical Pharmacology. 12th ed. Philadelphia: Elsevier
a) Large [Imprint] Elsevier - Health Sciences Division, 2018.
b) Polar
c) Hydrophilic ● Goodman & Gilman's: The Pharmacological Basis of
d) Uncharged Therapeutics, 13e Brunton LL, Hilal-Dandan R, Knollmann BC.
Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.), Eds
7) Which of the following is TRUE about tolerance? (2018)
a) Due to chronic exposure to a drug ● Lippincott Illustrated Reviews: Pharmacology. 6th ed.
Philadelphia, PA: Wolters Kluwer, (2015)
b) Due to successive stimulation of the receptors ● Katzung BG. Katzung B.G.(Ed.), Ed Bertram G. Katzung: Basic
c) Employs the same mechanisms as tachyphylaxis & Clinical Pharmacology, 14e. McGraw Hill (2018)
except that it does not involve inactivation by arrestin
d) All the choices are correct
8) Which of the following is NOT true about tyrosine
kinase receptors
a) Its cytosolic domain has tyrosine kinase activity
b) Its extracellular domain is for ligand-binding
c) Tyrosines cross-phosphorylate each other
d) Tyrosine kinase receptors start out as inactive
dimers.
9) Which of the following is TRUE about drug potency?
a) The stronger the interaction, the higher the affinity,
the less potent the drug is
b) Higher potency usually produces higher efficacy
c) Potency can be measured with EC50 and this is
inversely proportional to each other
d) All of the above
10) Which of the following is FALSE about drug
efficacy?
a) Efficacy can be measured through Emax
b) A higher efficacious drug shifts the curve to the right
c) Efficacy is dependent upon the drug-receptor
interaction and intrinsic activity of the drug
d) All of the above

Pharmacodynamics PHARMACOLOGY: NOTE #7. 15 of 15