PHARMACODYNAMICS
UNIT 1
General and molecular aspects of Drug relation with receptors and ion channels
It is important that pharmacologist involved in medicines management are aware of the
sites of action for many commonly used drugs.
Drugs exert their effects at molecular (chemical) targets, of which there are many.
Below are some of the commonest.
Receptors:
The plasma membrane of a human cell is selectively permeable in that it helps control
what moves in and out of the cell.
The cell membrane consists of a thin structured bilayer of phospholipids and protein
molecules.
The surfaces of plasma membranes are generally studded with proteins that perform
different functions, like the reception of nutrients. In biochemistry these protein molecules
are referred to as receptors.
Molecules which bind to these receptors are called ligands. Examples of ligands are
neurotransmitters, hormones or drugs.
A large number of drugs, which are clinically effective, exert their action by interaction with
receptors.
Examples include:
ionotropic receptors- ligand-gated ion channels- such as the GABAA receptor, which binds
benzodiazepines.
G-protein coupled receptors such as adrenoceptors
kinase-linked receptors such as the insulin receptor
Nuclear receptors such as the thyroid receptor
Interaction of drug with receptor
Ion channels or ionotropic receptors
Ion channels provide receptors which drugs can interact with.
Drug actions at ion channels can take two forms.
The first form are known as channel blockers, whereby the drug blocks permeation of
the channel, and the second are channel modulators whereby the drug binds to a
receptor site within the ion channel and modulates permeation of the channel.
This can happen by the drug altering the channel’s response to its normal mediator.
Enzymes
Enzymes are biological catalysts that increase the rate of chemical reactions in the
body.
They are integral to many normal physiological functions.
Many drugs target enzymes to prevent them from carrying out their normal function –
for example, Enalopril acts on angiotensin converting enzymes, thereby preventing an
increase in blood pressure.
Enalopril
Transport systems
These are also known as carrier molecule
interactions.
In some transmitter systems, there is normal
physiological recycling of the transmitters,
such as serotonin.
After the release of serotonin from a neuron,
it is taken back up by that same neuron using
a serotonin-selective reuptake system.
The drug fluoxetine blocks the uptake
transporter for serotonin as its mode of
action.
This results in an increased level of serotonin
in the neuronal synapse. This mechanism has
an onward effect which facilitates an increase SSRI- Selective serotonin
receptor inhibitor=fluoxetine
in mood and makes fluoxetine and drugs
similar to it good antidepressants.
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of
membrane receptors in eukaryotes.
GPCRs consist of a single polypeptide that is folded into a globular shape and embedded
in a cell's plasma membrane
GPCRs interact with G proteins in the plasma membrane. When an external signaling
molecule binds to a GPCR, it causes a conformational change in the GPCR. This change
then triggers the interaction between the GPCR and a nearby G protein.
Between one-third and one-half of all marketed drugs act by binding to GPCRs.
Humans have nearly 1,000 different GPCRs, and each one is highly specific to a particular
signal.
G proteins are specialized proteins with the ability to bind the nucleotides guanosine
triphosphate (GTP) and guanosine diphosphate (GDP).
G proteins that associate with GPCRs are heterotrimeric, meaning they have three
different subunits: an alpha subunit, a beta subunit, and a gamma subunit. Two of these
subunits — alpha and gamma — are attached to the plasma membrane by lipid anchors
In unstimulated cells, the state of G alpha (orange circles) is defined by its interaction with GDP, G
beta-gamma (purple circles), and a G-protein-coupled receptor (GPCR; light green loops). Upon receptor
stimulation by a ligand called an agonist, the state of the receptor changes. G alpha dissociates from the
receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha
activation. G alpha then goes on to activate other molecules in the cell.
G protein-coupled
receptors (GPCRs), also known
as seven-(pass)-transmembrane
domain receptors
These are cell surface receptors that
detect molecules outside the cell and
activate cellular responses.
They are coupled with G proteins,
They pass through the cell
membrane seven times in form of six
loops - three extracellular loops
interacting with ligand molecules, three
intracellular loops interacting with G
proteins a N-terminal extracellular
region and a C-terminal intracellular
region
kinase-linked receptors
The insulin receptor is a member of the ligand-activated receptor and tyrosine
kinase family of transmembrane signaling proteins that collectively are
fundamentally important regulators of cell differentiation, growth, and
metabolism.
Dose response Curve
The concept of the dose response curve is one of the most important parts of
pharmacology. A dose response curve refers to the relationship between an effect of a
drug and the amount of drug given.
Dose response curves are essential to understand the drug's safe and hazardous levels, so
that the therapeutic index can be determined.
Dose response curves are charted on a simple x-/y-axis, with the drugs dosage typically
on the x axis and the response to the medication typically on the y-axis.
Most dose response curves are graphed on a logarithmic scale as opposed to a linear one
and often times, the y-axis is represented by percentages, to indicate the percentages of
individuals responding to the drug.
When evaluating a dose response curve, one of the main characteristics of the curve is
that it's a graded relationship. This means that as the amount of drug given is increased so
is the response to the drug.
Dose Response Curve Phases
There are three phases of a dose
response curve
First, the curve is flat as the amount of
drug given is not great enough to
initiate the response
In the second phases, the curves is
steadily rises, with each increase in the
drug dose there is also an increase in
desired response.
Finally the curve plateau at the top
indicating that any further increase in
drug dose will not increase a drug
response.
Agonistic and antagonistic drug action
Drugs can either be agonists or antagonists at their target sites.
When agonists or antagonists bind to receptors they are said to occupy the receptor
site.
The amount of drug occupying the receptor site relates to the magnitude of response
to the drug itself.
In simple terms the more of an agonist drug occupying a receptor, the greater the
response.
Agonists are drugs that bind to their targets and form a drug-receptor complex.
Agonists activate the receptors to produce a response (known as full agonists) and
have what is termed positive efficacy.
Antagonists are drugs that bind to their targets and form a drug receptor complex, but
without causing activation or response. They can block the receptor to its endogenous
activator, thereby blocking normal function.
Agonist: A ligand that binds to a
receptor and alters the receptor
state resulting in a biological
response."
Types of agonists
1. Full agonists
A full agonist is a drug which is
capable of producing a maximum
response that the target system is
capable of:
“When the receptor stimulus
induced by an agonist reaches the
maximal response capability of the
system (tissue), then it will produce
the system maximal response and
be a full agonist in that system.“
The agonist drug can exert a
maximal systemic response
2. Partial agonists
A partial agonist can never achieve
the maximal response that the system
is capable of, because its efficacy is
lower than that of a full agonist. A
partial agonist "in a given tissue,
under specified conditions, cannot
elicit as large an effect (even when
applied at high concentration, so that
all the receptors should be occupied)
as can another agonist acting through
the same receptors in the same
tissue"
3. Inverse agonists
An inverse agonist is a ligand which,
by binding to a receptor, produces
the opposite of the effect which
would be produced when an
agonist binds to the same receptor.
"A ligand that by binding to
receptors reduces the fraction of
them in an active conformation. if
some of the receptors are in the
active form in the absence of a
conventional agonist"
