DRUG-RECEPTOR INTERACTIONS

AND
PHARMACODYNAMICS
RAMLA KASHIF
 OVERVIEW
Pharmacodynamics describes the actions of a drug on the body and the
influence of drug concentrations on the magnitude of the response.

Most drugs exert their effects, both beneficial and harmful, by

interacting with receptors present on the cell surface or within the cell.

The drug-receptor complex initiates alterations in biochemical and/or

molecular activity of a cell by a process called Signal Transduction.
 SIGNAL TRANSDUCTION
 Drugs act as signals, and their receptors act as signal
detectors.

Receptors transduce their recognition of a bound agonist

by initiating a series of reactions that ultimately result in a
specific intracellular response.
 AGONIST
•Agonist refers to a naturally occurring small
molecule or a drug that binds to a site on a
receptor protein and activates it.
 ANTAGONIST
•A receptor antagonist is a type of receptor ligand or
drug that blocks a biological response by binding to and
blocking a receptor rather than activating it like an
agonist. They are sometimes called blockers; examples
include alpha blockers, beta blockers, and calcium
channel blockers.
TARGETS FOR DRUG ACTION
The protein targets for drug action are
◦ Receptors

◦ Ion channels

◦ Enzymes

◦ Carrier molecules (transporters).

 RECEPTORS
Receptor is a protein molecule found on the cell
surface (cell-surface or membrane receptor) or
within a cell, usually in its nucleus (nuclear
receptor) that recognizes and binds with specific
molecules, producing some effect in the cell.
 LIGAND
A ligand is a substance that forms a complex with a
biomolecule to serve a biological purpose. In
protein-ligand binding, the ligand is usually a
molecule which produces a signal by binding to a
site on a target protein.
RECEPTOR
 MAJOR RECEPTOR
FAMILIES
 Ligand-gated ion channels

G protein- coupled receptors

Enzyme-linked receptors

Intracellular receptors (nuclear receptors)

 LIGAND-GATED ION CHANNELS

Ligand-gated ion channels (LICs, LGIC), also commonly referred to

as ionotropic receptors, are a group of transmembrane ion-channel
proteins which open to allow ions such as Na +, K+ , Ca2 , and/or Cl−
to pass through the membrane in response to the binding of a
chemical messenger (i.e. a ligand), such as a neurotransmitter.

The extracellular portion of LGIC usually contains the ligand-

binding sites. This site regulates the shape of the pore through
which ions can flow across cell membrane.
When a presynaptic neuron is excited, it releases a
neurotransmitter from vesicles into the synaptic cleft.

The neurotransmitter then binds to receptors located on the

postsynaptic neuron.

 If these receptors are ligand-gated ion channels, a resulting

conformational change opens the ion channels, which leads to a
flow of ions across the cell membrane.
This, in turn, results in either a depolarization, for an
excitatory receptor response, or a hyperpolarization, for
an inhibitory response.

Example: Stimulation of Nicotinic receptor by

acetylcholine results in sodium influx and potassium
outflux, generating an action potential in a neuron or
contraction in skeletal muscles.
G-PROTEIN COUPLED
RECEPTORS
 G PROTEIN-COUPLED
RECEPTORS (GPCRs)
 G protein-coupled receptors (GPCRs), also known as seven-(pass)-
transmembrane domain receptors, 7TM receptors, heptahelical
receptors, serpentine receptor, and G protein–linked receptors (GPLR)

GPCRs constitute a large protein family of receptors that detect molecules

outside the cell and activate internal signal transduction pathways and,
ultimately, cellular responses.

 Coupling with G proteins, they are called seven-transmembrane

receptors because they pass through the cell membrane seven times.
 The extracellular domain of this receptor contains the ligand-binding area
and the intracellular domain interacts (when activated) with a G protein or
effector molecule.

A diverse set of ligands bind to this type of receptor, including peptide

hormones, neurotransmitters, and odor molecules.

There are many kinds of G proteins for example, Gs, Gi and Gq, but they all
are composed of three protein subunits.

The alpha subunit binds guanosine triphosphate (GTP), and the beta and
gamma subunits anchor the G protein in the cell membrane.
Binding of an agonist to the receptor increases GTP binding to the alpha-
subunit, causing dissociation of the alpha-GTP complex.

These two complexes can then interact with other cellular effectors,
usually an enzyme, a protein or an ion channel, that are responsible for
further actions within the cell.

These reactions usually last several seconds to minutes.

Sometimes, the activated effectors produce second messengers that

further activate other effectors in the cell, causing a signal cascade effect.
 WHAT ARE SECOND
MESSENGERS?
Second messengers or effector molecules are molecules
that relay signals received at receptors on the cell surface
— such as the arrival of protein hormones, growth factors,
etc. — to target molecules in the cytosol and/or nucleus.

Examples include cyclic AMP, cyclic GMP, inositol

trisphosphate, diacylglycerol, and calcium.
The second messengers relay the signals of hormones like
epinephrine, growth factors and others and cause some
kind of change in the activity of the cell.

Elevated concentration of second messengers leads to

rapid alteration in the activity of one or more cellular
enzymes.

Removal or degradation of second messenger terminate

the cellular response.
 TYPES OF SECONDARY
MESSENGER
MOLECULES
There are three basic types of secondary messenger
molecules:

Hydrophobic molecules: water-insoluble molecules such as

diacylglycerol, and phosphatidylinositols, which are
membrane-associated and diffuse from the plasma
membrane into the intermembrane space where they can
reach and regulate membrane-associated effector proteins.
Hydrophilic molecules: water-soluble molecules, such as
cAMP, cGMP, IP3, and Ca2+, that are located within the
cytosol.

Gases: Nitric oxide (NO), carbon monoxide (CO) and

hydrogen sulfide (H2S) which can diffuse both through
cytosol and across cellular membranes.
ENZYME-LINKED
RECEPTORS

Enzyme-linked receptors are cell-surface receptors, where

the binding of an extracellular ligand causes enzymatic
activity on the intracellular side.
They have two important domains:
• Extra-cellular ligand binding domain
•Intracellular domain
 The signaling molecule binds to the receptor outside of the
cell and causes a conformational change on the catalytic
function located on the receptor inside of the cell.
EXAMPLES OF
ENZYMATIC ACTION
Receptor tyrosine kinase, as an fibroblast growth factor
receptor. Most enzyme-linked receptors are of this type.

Guanylate cyclase, as in atrial natriuretic factor receptor.

4-NUCLEAR RECEPTOR
 INTRACELLULAR RECEPTORS
(NUCLEAR RECEPTORS)

Intracellular receptors are receptors located inside the cell rather than on
its cell membrane, therefore ligand must diffuse into the cell to interact
with the receptor.

In order to move across the target cell membrane, the ligand must have
sufficient lipid solubility.

The primary targets of these ligand- receptor complexes are transcription

factors in the cell nucleus.

The activated ligand-receptor complex then translocates to the nucleus.

The activation or inactivation of these factors causes the
transcription of DNA into RNA and translation of RNA into
proteins.

Examples are the class of nuclear receptors located in the

cell nucleus and the IP3 receptor located on the endoplasmic
reticulum.

The ligands that bind to them are usually intracellular second

messengers like (IP3) and extracellular lipophilic hormones
like steroids hormones.
 INTRACELLULAR
RECEPTORS:TYPES
Steroid hormone receptor:
•Sex hormones receptors (sex hormones)
Estrogen receptor
Androgen receptor
•Vitamin D receptor
•Glucocorticoid receptor
•Mineralocorticoid receptor
•Retinoic acid
 ION CHANNELS
Ion channels are pore-forming membrane proteins which allow the
passage of ions in and out of a cell through the plasma membrane.

Ion channels can be classified by different properties, including by the

gating mechanism or the ion selectivity of the pore.

Ion channels are essential for life and play a fundamental role in
physiological processes such as muscle contraction and nutrient
transport.
 CLASSIFICATION OF
ION CHANNELS
Classification by gating mechanism:

•Voltage-gated ion channels

•Ligand-gated ion channels (also known as ionotropic receptors)

•Light-gated ion channels

•Mechanosensitive ion channels

•Cyclic nucleotide-gated ion channels

•Calcium-gated ion channels

Classification by ion selectivity:
•Calcium
•Potassium
•Sodium
•Chloride
•Proton
•Non-selective (let any type of ion pass)
 ION CHANNELS
Vasodilator drugs of the dihydropyridine
type which inhibit the opening of L-type
calcium channels.

Sulfonylureas used in treating diabetes,

which act on ATP-sensitive potassium
channels of pancreatic β-cells and thereby
enhance insulin secretion.
 ENZYMES
An enzyme is a substance that acts as a catalyst in living
organisms, regulating the rate at which chemical reactions
proceed without itself being altered in the process.

 The biological processes that occur within all living

organisms are chemical reactions, and most are regulated
by enzymes.
 ENZYMES
Acetylcholinesterase inhibited by
neostigmine

Aspirin block COX enzyme

Levodopa (pro-drug) converted to

dopamine (drug)
 TRANSPORTERS
Transporters (membrane transport/carrier proteins) are
specialized membrane-spanning proteins that assist in the
movement of ions, peptides, small molecules, lipids and
macromolecules across a biological membrane.