Basic Pharmacology

Drug Receptor
interaction Studies
Introduction
What is a drug and its mechanism of action

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 Introduction To Pharmacology -
Definitions
• Pharmacology is the study of the interaction of chemicals with
living systems.
• Medical pharmacology is the study of drugs used for the diagnosis,
prevention, and treatment of disease.
• Toxicology is the study of the untoward effects of chemical agents
on living systems. It is usually considered an area of pharmacology.
• Pharmacodynamic properties of a drug describe the action of the
drug on the body, including receptor interactions, dose-response
phenomena, and mechanisms of therapeutic and toxic action.
• Pharmacokinetic properties describe the action of the body on the
drug, including absorption, distribution, metabolism, and excretion.
Elimination of a drug may be achieved by metabolism or by
excretion.
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 What is a Drug?

A natural or synthetic substance which (when taken

into a living body) affects its functioning or
structure, and is used in the diagnosis, mitigation,
treatment, or prevention of a disease or relief of
discomfort.

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 Some Terms Relevant to Drugs
• Prophylactic refers to a drug or procedure aimed to prevent disease
• Palliative refers to a drug or procedure aimed to relieve symptoms
• Therapeutic refers to a drug or procedure aimed to cure disease
• Tolerance is the increased resistance to the usual effects of an established
dose of a particular drug
• Effective dose (ED50) is the concentration at which 50% of the subject show
a predefined response
• Efficacy refers to the inherent capability of a drug to produce a desired effect
• Potency compares the relative effectiveness of drugs to produce a desired
effect
e.g. Drug A requires fewer milligrams than Drug B to achieve the same pharmacological
response
--> Drug A has the higher potency, yet, both drugs have the same efficacy.

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 History of Pharmacology
• Initially most medicines were of botanical or
zoological origin
• Early agents were naturally occurring inorganic salts and plant alkaloids
– Opium
– Foxglove
– Mercury, arsenic or lead compounds
• Most ineffective or actually dangerous
• Standardization of dose very difficult
– Narrow therapeutic index with foxglove
• Since 1950’s, large increase in synthetic organic
chemicals

• Recent introduction of recombinant DNA

technology has extended synthesis to
molecules of human origin
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 History of Pharmacology
• Major advance in safe use of naturally derived agents
was the isolation, purification and chemical
characterization of the active compound:
– Allowed administration of a controlled dose
– Allowed administration of the active component of
herbal mixtures to be given alone
– Identification and characterization of active
component allowed definition of mechanism of
action, leading to synthesis of improved agents with
greater selectivity, potency, altered duration of
action, etc.
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 History of Pharmacology
• Aspirin® - first synthetic drug
– Hippocrates: pain relief treatments with powder made from the bark and
leaves of the willow tree (Salix sp.)
– Johann Buchner (1829): isolated Salicin as the active ingredient in
Meadowsweet (Spiraea ulmaria)
(hydrolyzed into glucose and Salicyl-aldehyde ->oxidyzed to Salicylic Acid)
Salicylic Acid is very tough on the stomach->

– Felix Hoffman (1898-9): Chemist at Bayer synthezised

Acetyl-Salicylic Acid, (process discovered originally by Charles Gerhardt in 1853) and
tested it on his arthritis-suffering father!
– March 6, 1899: Bayer receives patent for Aspirin®
– Sales today exceed 50 billion pills per year

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 History of Pharmacology
• 20th Century: Dramatic change in antimicrobial
therapy
– Survival of patients with severe infections with
historically high mortalityare
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– Introduction of sulfonamides (Gelmo 1908:

Sulfanilamide) and arsenic compounds (Ehrlich
1908/10: arsephenamine= Salvarsan) and subsequently
penicillins (Fleming 1928/29)

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 Current Status: New Drugs Being
Identified Through Drug Discovery
• Drug discovery is the process through which potential new medicines are identified.
– Involves a wide range of scientific disciplines, including biology, chemistry & pharmacology.

• A drug discovery program initiates because there is a disease or clinical condition

without suitable medical products available and it is this unmet clinical need which is
the underlying driving motivation for the project.

• The new drugs can be:

• Analogues to existing drugs
– Usually shows only minor changes in potency, absorption, duration of action
• New applications for existing drugs
– Occasionally unexpected additional properties may become evident when the compounds are
tested in humans
• Sulfanilamide --> thiazide diuretics
• Sulfanilamide --> sulfonylurea hypoglycemics
• Aspirin® --> Anti-aggregatory --> Cardioprotective

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 THE NATURE OF DRUGS
• A. Size. The great majority of drugs lie in the range from molecular
weight 100 to 1,000. Drugs in this range are large enough to allow
selectivity of action and small enough to allow adequate movement
within the various compartments in the body.

Molecular weights of several endogenous molecules and drugs.

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 NATURE OF DRUGS (contd.)
• B. Chemistry and reactivity. Drugs may be small, simple molecules (amino
acids, simple amines, organic acids, alcohols, esters, ions, etc.),
carbohydrates, lipids, or even proteins.
• Binding of drugs to their receptors, the specific molecules in a biologic
system that mediate drug effects, is usually by noncovalent bonds
(hydrogen bonds, van de Waals attractions, and ionic bonds), and less
commonly by covalent bonds.
– Weaker, noncovalent bonds require a better fit of the drug to the receptor
binding site and, usually, a reversible type of action.
– Very strong bonding, eg, covalent bonds, usually involves less selectivity and
an irreversible interaction.

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 NATURE OF DRUGS (contd.)
• C. Shape. The overall shape of a drug molecule is important for the fit of the drug to
its receptor.

• Between a quarter and a half of all drugs in use exist as stereoisomers. In most cases
the stereoisomers are chiral enantiomers.
– Enantiomers are mirrored image twin molecules that result from the presence of an
asymmetric carbon, or in a few cases, other asymmetric atoms in their structures.

– Chiral enantiomers often differ in their ability to bind to and alter the function of receptors.
They also can differ in their rates of elimination and in their toxicity.

– Most chiral drugs are still provided as racemic mixtures (mixtures of isomers) because it is
expensive to separate the stereoisomers.

• In the past, little was known about the relative activity of stereoisomers.

• Presently, Food and Drug Administration (FDA) requires information about the
structure and activity of each isomer present in a racemic mixture of a new
medication.
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 More about enantiomers…

The two hands represent the enantiomers of Drug H. The shape of the
Levo enantiomer allows it to bind tightly to the drug-binding site in the
receptor. This binding is reversible.

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 HOW DO DRUGS WORK?

Most drugs work by interacting with

endogenous proteins:

• Some drugs antagonize, block or inhibit endogenous proteins

• Some drugs activate endogenous proteins

• A few drugs have unconventional mechanisms of action

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 HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT
ENDOGENOUS PROTEINS?

• Antagonists of Cell Surface Receptors

• Antagonists of Nuclear Receptors

• Enzyme Inhibitors

• Ion Channel Blockers

• Transport Inhibitors

• Inhibitors of Signal Transduction Proteins

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 Definition of RECEPTOR:

A macromolecular component of the organism that

binds the drug and initiates the drug’s effect.

Most receptors are proteins that have undergone various

post-translational modifications such as covalent
attachments of carbohydrate, lipid and phosphate.

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 HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?

Definition of CELL SURFACE RECEPTOR:

A receptor that is embedded in the cell membrane and

functions to receive chemical information from the
extracellular compartment and to transmit that
information to the intracellular compartment.

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 HOW DO DRUGS WORK BY ANTAGONIZING CELL
SURFACE RECEPTORS?

Extracellular Unbound Endogenous Activator (Agonist) of

Receptor
Compartment

Cell Membrane
Inactive Cell Surface Receptor

Intracellular
Compartment

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HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?

Bound Endogenous Activator (Agonist) of Receptor

Extracellular
Compartment

Cell Membrane
Active Cell Surface Receptor

Intracellular
Compartment

Cellular Response
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HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?

Displaced Endogenous Activator (Agonist) of Receptor

Extracellular
Compartment Bound Antagonist of Receptor (Drug)

Cell Membrane
Inactive Cell Surface Receptor
Intracellular
Compartment
Some important examples:
• Angiotensin Receptor Blockers (ARBs) for high blood pressure, heart failure, chronic renal
insufficiency (losartan [Cozaar®]; valsartan [Diovan®])
• Beta-Adrenoceptor Blockers for angina, myocardial infarction, heart failure, high blood
pressure, performance anxiety (propranolol [Inderal®]; atenolol [Tenormin®])
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HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS? KEY CONCEPTS:
• Cell surface receptors exist to transmit chemical signals from the
outside to the inside of the cell.
• Some drugs bind to cell surface receptors, yet do not activate
the receptors to trigger a response.
• When cell surface receptors bind the drug molecule, the
endogenous chemical cannot bind to the receptor and cannot
trigger a response.
• The drug is said to “antagonize” or “block” the receptor and is
referred to as a receptor antagonist.
Footnote:
• Most antagonists attach to binding site on receptor for endogenous agonist and sterically
prevent endogenous agonist from binding.
• However, antagonists may bind to remote site on receptor and cause allosteric effects that
displace endogenous agonist or prevent endogenous agonist from activating receptor.
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HOW DO DRUGS WORK BY ANTAGONIZING
NUCLEAR RECEPTORS?

Definition of NUCLEAR RECEPTOR:

A receptor that exists in the intracellular compartment

and upon activation binds to regulator regions in the
DNA and modulates gene expression.

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HOW DO DRUGS WORK BY ANTAGONIZING
NUCLEAR RECEPTORS?

Unbound Endogenous Activator

(Agonist) of Nuclear Receptor

Inactive Nuclear Receptor

In Cytosolic Compartment
DNA

Nucleus

Intracellular
Compartment Inactive Nuclear Receptor
In Nuclear Compartment

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HOW DO DRUGS WORK BY ANTAGONIZING
NUCLEAR RECEPTORS?

Active Nuclear Receptor

Bound Endogenous Activator
(Agonist) of Nuclear Receptor
DNA

Nucleus
Modulation of
Transcription

Intracellular
Compartment

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HOW DO DRUGS WORK BY ANTAGONIZING
NUCLEAR RECEPTORS?
Displaced Endogenous Activator
(Agonist) of Nuclear Receptor
Bound Antagonist
of Receptor (Drug)

Inactive Nuclear Receptor

In Cytosolic Compartment
DNA

Nucleus

Intracellular Inactive Nuclear Receptor

Compartment In Nuclear Compartment

Some important examples:

• Mineralocorticoid receptor antagonists for edema due to Liver cirrhosis and for heart failure
(Spironolactone [aldactone®])
• Estrogen Receptor Antagonists for the prevention and treatment of breast cancer (tamoxifen
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[Nolvadex®]) 25
HOW DO DRUGS WORK BY ANTAGONIZING
NUCLEAR RECEPTORS? KEY CONCEPTS:
• Nuclear receptors exist to mediate the effects of intracellular,
endogenous chemicals on gene expression.
• Some drugs bind to nuclear receptors, yet do not activate the
receptors to translocate to the nucleus, bind DNA and alter gene
expression.
• When nuclear receptors bind the drug molecule, the endogenous
chemical cannot bind to the receptor & cannot alter gene
expression.
• The drug is said to “antagonize” or “block” the receptor and is
referred to as a receptor antagonist.
Footnote:
• Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent endogenous
agonist from binding.
• However, antagonists may bind to remote site on receptor and cause allosteric effects that displace endogenous
agonist or prevent endogenous agonist from activating receptor.
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HOW DO DRUGS WORK BY INHIBITING ENZYMES?

Active Enzyme

Substrate Product

Cellular Function

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HOW DO DRUGS WORK BY INHIBITING ENZYMES?

Inactive Enzyme

Substrate

Bound Enzyme
Inhibitor (Drug)

Some important examples:

•Cyclooxygenase Inhibitors for pain relief, particularly due to arthritis (aspirin; ibuprofen [Motrin®])
•HMG-CoA Reductase Inhibitors for hypercholesterolemia (atorvastatin [Lipitor®]; pravastatin
[Pravachol®])
• Angiotensin Converting Enzyme (ACE) Inhibitors for high blood pressure, heart failure, and
•chronic renal insufficiency (captopril [Capoten®]; ramipril [Altace®])
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HOW DO DRUGS WORK BY INHIBITING ENZYMES?
KEY CONCEPTS:

• Enzymes catalyze the biosynthesis of products from

substrates.

• Some drugs bind to enzymes and inhibit enzymatic

activity.

• Loss of product due to enzyme inhibition mediates the

effects of enzyme inhibitors.

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HOW DO DRUGS WORK BY BLOCKING ION CHANNELS?
Ions (e.g., Ca++, Na+, K+)

Open Ion Channel

Intracellular
Compartment

[Ions]

Cellular Response

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 HOW DO DRUGS WORK BY BLOCKING ION CHANNELS?
Ions (e.g., Ca++, Na+)

Blocked Ion Channel

Drug that Blocks Ion Channels

Ions (e.g., K+)

Intracellular
Compartment

Some important examples:

• Calcium Channel Blockers (CCBs) for angina and high blood pressure (amlodipine
[Norvasc®]; diltiazem [Cardizem®])
• Sodium Channel Blockers to suppress cardiac arrhythmias (lidocaine [Xylocaine®];
amiodarone [Cordarone®])
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HOW DO DRUGS WORK BY BLOCKING ION CHANNELS?
KEY CONCEPTS:

• Ion channels allow ions to transverse the cell

membrane through a pore and down an electrochemical
gradient.

• Some drugs bind to ion channels and physically block

the pore or cause an allosteric change that closes the
pore.

• Changes in the intracellular concentration of ions

mediates the effects of inhibitors of ion channels.

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HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?
Membrane Impermeable Solute

Active Transporter

Membrane Impermeable Solute

Cellular Response Intracellular

Compartment

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 HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?
Membrane
Impermeable Solute
Inactive Transporter

Drug that Inhibits Transporters

Intracellular
Membrane
Compartment
Impermeable Solute

Some important examples:

• Selective Serotonin Reuptake Inhibitors (SSRIs) for the treatment of depression (fluoxetine [Prozac®];
fluvoxamine [Luvox®])
• Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) in renal epithelial cells to increase urine and
sodium output for the treatment of edema (furosemide [Lasix®]; bumetanide [Bumex®])
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HOW DO DRUGS WORK BY INHIBITING TRANSPROTERS?
KEY CONCEPTS:

• Transporters bind to and shuttle membrane

impermeable solutes across the cell membrane.

• Some drugs bind to transporters and cause allosteric

changes that prevent proper functioning of the
transporters.

• Changes in the intracellular concentration of specific

solutes mediates the effects of inhibitors of
transporters.

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 HOW DO DRUGS WORK BY INHIBITING SIGNAL
TRANSDUCTION PROTEINS?
(Some overlap with enzyme inhibitors)

Extracellular
Compartment Bound Endogenous Activator (Agonist) of Receptor

Cell Membrane Active Cell Surface Receptor

Multiple Signal Transduction Proteins

Intracellular (each is a potential drug target)
Compartment

Cellular Response
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 HOW DO DRUGS WORK BY INHIBITING
SIGNAL TRANSDUCTION PROTEINS?
Extracellular
Compartment Bound Endogenous Activator (Agonist) of Receptor

Cell Membrane Active Cell Surface Receptor

Intracellular Blockade or Augmentation

Compartment of Signal Transduction Pathway by Drug

Some important examples:

• Tyrosine Kinase Inhibitors for chronic myelocytic leukemia (imatinib [Gleevec®])

• Type 5 Phosphodiesterase Inhibitors for erectile dysfunction (sildenafil [Viagra®])

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HOW DO DRUGS WORK BY INHIBITING SIGNAL
TRANSDUCTION PROTEINS?
KEY CONCEPTS:

• Signal transduction proteins transmit a chemical signal

from a receptor to the final biological target.

• Some drugs bind to and inhibit key signal transduction

proteins.

• Inhibition of key signal transduction proteins may

block or augment the signal transduction pathway and
this mediates the effects of the drug.

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HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS
PROTEINS?

• Agonists of Cell Surface Receptors

• Agonists of Nuclear Receptors

• Enzyme Activators

• Ion Channel Openers

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HOW DO DRUGS WORK BY ACTIVATING CELL
SURFACE RECEPTORS?

Extracellular
Compartment

Cell Membrane Inactive Cell Surface Receptor

Intracellular
Compartment

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 HOW DO DRUGS WORK BY ACTIVATING CELL
SURFACE RECEPTORS?
Extracellular
Compartment Bound Exogenous Agonist of Receptor (Drug)

Cell Membrane Active Cell Surface Receptor

Intracellular
Compartment

Cellular Response
Some important examples:

• Alpha1-Adrenoceptor Agonists for nasal congestion (oxymetazoline [Afrin®]; phenylephrine

[Neosynephrine®])
• Opioid Receptor Agonists for analgesia (morphine; meperidine [Demerol®])
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HOW DO DRUGS WORK BY ACTIVATING CELL
SURFACE RECEPTORS? KEY CONCEPTS:
• Cell surface receptors exist to transmit chemical signals
from the outside to the inside of the cell.
• Some drugs bind to cell surface receptors and trigger a
response.
• Drugs in this group are called receptor agonists.
• Some drug agonists are actually the endogenous
chemical signal, whereas other drug agonists mimic
endogenous chemical signals.
Footnote:
• Most agonists attach to binding site on receptor for endogenous agonist and trigger a response.
• However, agonists may bind to remote site on receptor and cause allosteric effects that increase the
ability of an endogenous agonist to bind to or activate the receptor.
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HOW DO DRUGS WORK BY ACTIVATING NUCLEAR
RECEPTORS?

Inactive Nuclear Receptor

In Cytosolic Compartment
DNA

Nucleus

Intracellular Inactive Nuclear Receptor

Compartment In Nuclear Compartment

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 HOW DO DRUGS WORK BY ACTIVATING NUCLEAR
RECEPTORS?

Active Nuclear Receptor

Bound Exogenous Agonist
of Receptor (Drug)
DNA

Intracellular Nucleus
Compartment Modulation of
Transcription

Some important examples:

• Estrogen Receptor Agonists for hormone replacement therapy in postmenopausal women (conjugated equine
estrogens [Premarin®])
• Glucocorticoid Receptor Agonist for inflammation (hydrocortisone[Cortef®]; dexamethasone [Decadron®])
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 HOW DO DRUGS WORK BY ACTIVATING NUCLEAR
RECEPTORS? KEY CONCEPTS:
• Nuclear receptors exist to mediate the effects of
intracellular, endogenous chemicals on gene
expression.
• Some drugs bind to nuclear receptors and trigger a
response.
• Drugs in this group are called receptor agonists.
• Some drug agonists are actually an endogenous
chemical, whereas other drug agonists mimic an
endogenous chemical.
Footnote:
• Most agonists attach to binding site on receptor for endogenous agonist and trigger a response.
• However, agonists may bind to remote site on receptor and cause allosteric effects that increase the
ability of an endogenous agonist to bind to or activate the receptor.
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 HOW DO DRUGS WORK BY ACTIVATING ENZYMES?
Inactive Enzyme

Substrate
Active Enzyme

Substrate Product

Enzyme Activator
(Drug)

Some important examples: Cellular Function

• Activators of Guanylyl Cyclase for angina (nitroglycerin; isosorbide dinitrate
[Isordil®])
• Reactivators of Cholinesterase after poisoning with nerve gas or
organophosphate pesticide (pralidoxime [Protopam®])
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 HOW DO DRUGS WORK BY ACTIVATING ENZYMES?
KEY CONCEPTS:

• Enzymes catalyze the biosynthesis of products from

substrates.

• Some drugs bind to enzymes and increase their

enzymatic activity.

• Increased biosynthesis of product mediates the

effects of enzyme activators.

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HOW DO DRUGS WORK BY OPENING ION CHANNELS?
Ions (e.g., Ca++, Na+)

Closed Ion Channel

Binding Site on Ion Channel

Ions (e.g., K+)

Intracellular
Compartment

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HOW DO DRUGS WORK BY OPENING ION CHANNELS?
Ions (e.g., Ca++, Na+, K+)

Open Ion Channel

Drug That Opens Ion Channel

[Ions]

Intracellular
Cellular Response Compartment

Some important examples:

• Potassium Channel Openers for hair regrowth (minoxidil [Rogaine®])
• GABAAChloride Channel Openers for anxiety (alprazolam[Xanax®]; midazolam [Versed®])
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HOW DO DRUGS WORK BY OPENING ION CHANNELS?
KEY CONCEPTS:
• Ion channels allow ions to transverse the cell membrane
through a pore and down an electrochemical gradient.

• Some drugs bind to ion channels and allosterically open

the ion channel or allosterically render the channel
more readily opened by other endogenous chemicals.

• Changes in the intracellular concentration of ions

mediates the effects of drugs that open ion channels.

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 HOW DO DRUGS WORK BY UNCONVENTIONAL
MECHANISMS OF ACTION?

• Disrupters of Structural Proteins

•Vinca Alkaloids for cancer (vincristine [Oncovin®]; vinblastine [Velban®])

• Drugs that Are Enzymes

• Thrombolytic therapy for acute myocardial infarction (alteplase [Activase®])

• Drugs that Covalently Link to Macromolecules

• DNA alkylating agents for the treatment of cancer (cyclophosphamide [Cytoxan®])
• Drugs that React Chemically with Small Molecules
• Antacids that neutralize gastric acid (prep containing Al(OH)3, Mg(OH)2 or CaCO3)
• Drugs that Bind Free Molecules or Atoms
•Chelating Agents for heavy metal poisoning (dimercaprol; penicillamine)

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 HOW DO DRUGS WORK BY UNCONVENTIONAL
MECHANISMS OF ACTION (Contd…)?

• Drugs that Are Nutrients

•Vitamins, minerals, lipids, carbohydrates, aminoacids

• Drugs that Exert Actions Due to Physical Properties

•Bulk Laxatives for constipation (psyllium [Metamucil®]; polycarbophil [Fibercon®]

• Drugs that Work Via an Antisense Action

Antisense Deoxyoligonucleotides for cytomegalovirus retinitis in patients with AIDS
(fomivirsen [Vitravene®]

• Drugs that Are Antigens

•Vaccines

• Drugs with Unknown Mechanisms of Action

•Inhalation Anesthetics for general anesthesia (Isoflurane [Forane®]; Sevoflurane
[Ultane®]
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The Drug Discovery Process

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