Pharmacodynamics

Fundamentals of Medicine
Dr Maryam Malekigorji
m.malekigorji@qmul.ac.uk
Resources

1. Medical Pharmacology at a Glance (9th edition)

by Michael J. Neal (Chapter 2)

2. Rang & Dales Pharmacology (10th edition) by

James Ritter, Rod Flower et al

3. The Top 100 Drugs (3rd edition) by Andrew

Hitchings, Dagan Lonsdale et al

4. Lippincott Illustrated Reviews : Pharmacology

(8th edition) by Karen Whalen (Chapter 2)
(£66.71 paperback, £32.99 Kindle – Amazon UK)

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Learning Outcomes
1. Be aware of different types of receptors as targets for ligand biding
(Lipids, nucleic acids, proteins).
2. Appreciate major classes of protein receptors (enzymes, carrier
molecules, ion channels, transmembrane).
3. Distinguish between various quantitative drug-receptor interactions
(graded & quantal dose response curves).
4. Explain what is meant by therapeutic index.
5. Differentiate between efficacy and potency.
6. Describe the relationship between receptor occupancy and spare
receptors.

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Learning
Objective 1
Be aware of different types of
receptors as targets for ligand
biding (Lipids, nucleic acids,
proteins).

4
 Drug common targets (receptors)

• Most drugs combine with specific

molecular components – receptors
- Lipids
- DNA
- Proteins:
1. Ligand gated ion channels –-
milliseconds
2. G-protein-coupled receptors –-
seconds
3. Kinase-linked receptors –-
minutes
4. Nuclear receptors –- hours
5. Enzymes
6. Transporters

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Receptors as targets for ligand binding

Lipids – general anaesthetics may act by dissolving

the membrane lipid affecting the physical state of the
membrane, influence the electrostatic potential or
increase membrane fluidity resulting in membrane
disorder (halothane, nitrous oxide)

DNA – anti-tumour agents used in chemotherapy.

Mitomycin- covalently binds to the DNA bases,
preventing DNA replication & degrading DNA by free
radical formation.
Idoxuridine (thymidine nucleoside analogue) - Can be
phosphorylated & incorporated into DNA. Used to inhibit
viral replication (herpes simplex, shingles )

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Learning
Objective 2
Appreciate major classes of
protein receptors (enzymes,
carrier molecules, ion channels,
transmembrane).

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1. Ligand-gated Ion Channels
• Found at the cell surface
• Often referred to as ionotropic receptors
(enable specific ions to stream in an out) – they
change in response to a stimulus – the ligand
such as a neurotransmitter!
• They work very quickly – milliseconds
• This explains their function in the nervous
system!
• They are transmembrane protein, which allow These proteins form these “switchable” pores in membranes
which allow the flow of ions
the movement of particular ions into the cell
• They open in response to binding of a
neurotransmitter at the binding pocket such as
acetylcholine, 5-HT, glutamate, GABA, ATP →
action potentials and sending of messages (or
the opposite)!

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 Ligand-Gated Ion Channels - Function
• The ligands are known as neurotransmitters –
they’ll allow that signal to move from one nerve
cell to another, getting around the lack of a
continuous physical connection
• The channels can be grouped:
- Cation selective – Na+, Ca2+, K+, or all three at once -
EXCITATORY
- Anion selective – mainly Cl- - INHIBITORY

 Na+ influx- depolarises cell: Nicotinic AChR (neuronal excitation)

 Ca2+ influx- depolarises cell: Glutamate (NMDA) (neuronal excitation)
 Cl- influx- hyperpolarises cell: GABA (gamma aminobutyric acid) (neuronal inhibition)

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Work by blocking the channel pore – Amiloride: diuretic, increasing the flow of urine via acting on distal tubule of the nephron
and blocking sodium transport

Bind to various regions of channel modulating function – BZDs: positive allosteric modulators on the GABA-A receptor
(chloride-selective ion channel). BZDs are sedative and slow down the body and brain's functions in anxiety and insomnia

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 2. G-protein-coupled receptors (GPCRs)
• Involved in the control of every aspect of our behaviour and
physiology
• 400 different types of receptors (largest class of receptors)
• This quantity, and their roles, make them the most popular class of
receptors when it comes to drug targeting (more than half of all
drugs target GPCRs)
• β-adrenoceptors – make your heart beats faster and stronger
• Histamine receptors bring about the contraction of airway
smooth muscles
• Dopamine receptors have roles in the central nervous system
and in motor control

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Understanding
G-Protein
Function

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Enzyme linked receptors- review of cell
signalling
Enzyme-linked receptors function
• directly as enzymes or are
• directly associated with enzymes that they activate.

They are formed by transmembrane proteins

• ligand-binding site outside
• catalytic or enzyme-binding site inside the cell.

Enzyme-linked receptors are heterogeneous in structure

compared with the other two classes.
• The great majority are protein kinases - the largest class are
“receptor tyrosine kinases (RTK)” (majority are growth factor
receptors.)

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 3. Receptor Tyrosine Kinases (RTK)
• Protein receptors, containing up to 1000 amino
acids in their structure [epidermal growth factor/ insulin/cytokines]

• They possess three key parts:

- The extracellular binding domain
- The transmembrane helical region
- The intracellular domain

• The intracellular domain is enzymatic – which

then activates downstream signaling cascades
• The receptor binding area will bind with protein
mediators
• Most of their functions cause effect at a [signal transduction]
transcription level – thus, they have an important
role in cell division, growth, differentiation,
apoptosis, etc.

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Using RTK Function to Our Advantage - Pharmacology

• Being able to interact with these receptors in some

way has the potential to bring about significant effect
• Drugs can start, or stop these complex downstream
processes, which are massively important
• Herceptin:
- A monoclonal antibody which binds to the HER2 receptor
- Prevents receptor dimerization and thus stops the rest of the
signalling process involved in leukaemia

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4. Nuclear Receptors – Inside the Cell
• This family of around 48 receptors are
involved in the alteration of gene
transcription – they are transcription
factors
• Many of these structures are orphan
receptors – we don’t know what their
ligand(s) is/are
• They are activated by ligands such as lipids
and steroid hormones which are in the
cytoplasm of the cell
• Importantly, ligands for these receptors are
non-polar – this is what allows them to cross
the cell membrane
• Once bound, they’ll move into the cell
nucleus and cause their effects

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Nuclear Receptors – Function

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 Intracellular Receptor Proteins mechanism of
action
• Intracellular receptors all bind to specific DNA
sequences adjacent to the genes the ligand regulates

 Some (e.g., cortisol) are located the cytosol and enter the
nucleus after ligand binding.

 Some (e.g., thyroid and retinoid) are bound to DNA in the

nucleus.
CORTISOL THYROID

• The binding of ligand to the receptor causes the

ligand-binding domain of the receptor to clamp shut
around the ligand
• Coactivator proteins to bind to the receptor's
transcription-activating domain
• increasing gene transcription.

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5. Enzymes

Aspirin acting on cyclo-oxygenase (COX)

signalling pathway

----------------------------------------------------
dopamine β-hydroxylase.
DOPA → Noradrenaline
(normal substrate)
Methyl DOPA → Methylnoradrenaline
(false substrate)

----------------------------------------------------

Levodopa is a prodrug of dopamine that

is administered to patients with
Parkinson's due to its ability to cross the
blood-brain barrier

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6. Transporters

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Learning
Objective 3
Distinguish between various
quantitative drug receptor
interactions (graded & quantal
dose response curves).

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 Quantitative outcomes of drug-receptor interactions:
1. Direct measurement of a biological response.

A biological response is one that can be directly measured as a direct

consequence of drug action.

Examples include:
• rise in blood pressure;
• contraction or relaxation of smooth muscle in organ bath.

These are measured and plotted as concentration-effect or dose-effect curve.

However, theoretical concentration-occupancy curves should not be used to
measure affinity of drugs for their receptors. This is because:

1. Response is not always directly proportional to occupancy (integrated

response).

2. Ligand concentration at receptor is usually not known .

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 Quantitative outcomes of drug-receptor
interactions:
1. Direct measurement of a biological response -
graded dose response curves

Used when response of a particular system is measured

against
increasing concentrations of a drug. This measure is
continuous e.g.

• Smooth muscle contraction

• Change in blood pressure
• Change in rate of urine production
• Change in blood glucose concentration
Rectangular hyperbola Sigmoid

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 Quantitative outcomes of drug-receptor interactions:
2. Direct measurement of a biological response –
quantal (population) dose response curves

Response is all or nothing

Proportion of individuals responding varies according to dose

Gives a population (or normal) distribution

e.g.
• conscious vs unconscious
• seizure vs no seizure
• live vs dead

Can be used to work out lethal doses e.g. LD50

LD50 dose which kills 50% of the population.

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Learning Objective
4
Explain what is meant by therapeutic
index.
 Therapeutic Index (TI)
• A ratio that expresses the relationship between the
dose expected to elicit some adverse effect (e.g.,
LD50, TD50, etc.) and the dose needed to elicit
therapeutic effects (e.g., ED50)
TI = Lethal dose(chosen %)/Effective dose(chosen %)

• Drugs with a narrow therapeutic window can be

difficult to use in clinical practice and often require
monitoring of plasma concentration to prevent toxicity

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 Drugs with a narrow therapeutic window
Drug Use Potential risk of plasma conc > MTC Potential risk of plasma
conc < MEC

Warfarin Anticoagulant Bleeding Blood clot

Gentamicin Antibiotic Nephrotoxicity and ototoxicity Infection recurrence /

resistance

Phenytoin Antiepileptic Nausea, CNS dysfunction Seizures

Lithium Antipsychotic Diarrhoea, vomiting, drowsiness, muscular Relapse of psychiatric

weakness and lack of coordination condition

Theophylline Bronchodilator Nausea, seizures Bronchoconstriction (asthma

attack)

Ciclosporin Immunosuppressant Nephrotoxicity Transplant rejection

Digoxin Atrial fibrillation Gastrointestinal upset, confusion, delirium, Arrhythmia

vision disturbance
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Effects produced by drugs – Risk-Benefit ratio

This is the adverse effects of a drug in relation to its beneficial

effects

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Learning
Objective 5
Differentiate between efficacy
and potency.

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Specificity of drug action is dependent on the following:

Efficacy : This describes the “ability or strength” of a single drug-receptor complex

in evoking a response in tissue. This applies only to those compounds that elicit a
response namely agonists.

For antagonists, efficacy is zero.

Potency : The “dose” of drug required to produce a given effect.

Affinity : The ability of a ligand to bind to a receptor. Applies to both agonists and
antagonists and is measured by the equilibrium dissociation constant Kd.
Kd: The concentration of a drug that results in binding to 50% of the receptors
The lower Kd value, the higher the receptor affinity
BUT – a Kd of 0 = not a drug at that receptor

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 Receptor Affinity and Efficacy – Related
to Chemical Reaction
• Affinity is the size of the attractive force between drug and receptor
– stronger bonds (such as covalent, ionic, and hydrogen bonds) lead
to greater affinity than interactions with weaker bonds (hydrophobic
and van der Waals)

• Efficacy – the size of the response at a receptor comes about from

the chemical interaction between drug and receptor

• This all leads to the drug response at a tissue level – the potency

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 The Binding Pocket
• The pocket, or ligand binding site, is an area of chemical specificity and affinity within a
receptor where bonds are formed with drug molecules or other ligands
• The bonding and release of substances at the pocket brings about that equilibrium noted
earlier
• It’s possible for several different molecules to bind to a pocket – this leads to competition
• Drugs with high affinity exhibit bonds with high intermolecular force with the pocket, and can
reside there longer, allowing receptors to change, bringing about efficacy

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 Potency vs Efficacy
• Efficacy (Emax) is the maximum effect
which can be expected from a drug (i.e.
when this magnitude of effect is reached,
increasing the dose will not produce a
greater magnitude of effect)

• Potency is defined as "the concentration

(EC50) or dose (ED50) of a drug required
to produce 50% of that drug’s maximal
effect.

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What are efficacy and potency?
Using oxycodone and nefopam as examples.

Oxycodone is more potent

than nefopam

Oxycodone is more
efficacious than nefopam

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This isn’t Just About Drugs!
• Remember that these actions are
happening in your body all the time,
even in the absence of drugs
• Ligands – naturally occurring molecules
within the body are being produced,
binding, and activating receptors all the
time
• They will bind at the binding pocket too
• Remember that these are often proteins,
much larger than a lot of drug molecules
– this can be important in terms of their
binding affinity

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 Learning
Objective 6
Describe the relationship between receptor
occupancy and spare receptors.

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 What is occupancy?

Occupancy :The proportion of

receptors occupied by ligand and is
denoted by the expression :

p = N
Ntot
N - occupied receptors
Ntot - total number of receptors
for an agonist in a tissue

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 Spare receptors
• Relationship between receptor occupancy
and response is not linear
• All receptors do not have to be occupied to
produce a full response
• A certain number of receptors are "spare“
• Receptors that do not bind drug for the
maximum biological effect to be produced
• They increase both sensitivity and speed of
a tissue's responsiveness to a ligand

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 Why is occupancy important?

Spare receptors

Spare receptors: Receptors that do not bind drug in order for

the maximum biological effect to be produced

ED50<Kd

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CONCENTRATION – RESPONSE RELATIONSHIPS

Full agonist: only few receptors occupied for maximal response

Partial agonist: all receptors occupied, maximal response not
reached

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To sum up:

• We understood the main classes of receptors

• We should have a better understanding about how drugs bring about
their effect, binding to receptors with a particular affinity, and bringing
about a response

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 Thank you!
m.malekigorji@qmul.ac.uk