PST 05104 PHARMACOLOGY AND

THERAPEUTICS.

Session 5: Drug Receptor Interaction.

Learning Tasks .

• By the end of this session students are expected to be able to:

• Describe of drug-receptor interaction
• Describe the types of receptors
• Explain the concept of receptor regulation
Drug-Receptor Interaction .
• A drug receptor is a specialized target macromolecule, present on the
cell surface or intracellularly, that binds a drug and mediates its
pharmacologic actions.
• It describes protein molecules whose function is to recognize and
respond to endogenous chemical signals.
• The term is most often used to describe the target molecules through
which soluble physiological mediators-hormones, neurotransmitters,
inflammatory mediators, etc.-produce their effects.
Drug-Receptor Interaction
cont…
• Examples are acetylcholine receptors, cytokine receptors, steroid
receptors, and growth hormone receptors
• Pharmacological effects, therefore, require, in general, that drug
molecules must be 'bound' to particular constituents of cells and
tissues in order to produce an effect.
Drug-Receptor Interaction
cont…
• Four main kinds of regulatory protein are commonly involved as primary
drug targets, namely:
• receptors
• enzymes
• carrier molecules (transporters)
• ion channels

• The function of a cell alters when a drug interacts with a receptor cell.
• At its most fundamental level, the interaction of drug and receptor follows
the law of mass action.
Drug-Receptor Interaction
cont…
• The law of mass action dictates that:
• The combination of drug (also called ligand) and receptor depends on the concentrations
of each
• The amount of drug-receptor complex formed determines the magnitude of the response
• A minimum number of drug receptor complexes must be formed for a response to be
initiated (threshold)
• As drug concentration increases, the number of drug-receptor complexes increases and
drug effect increases
• A point will be reached at which all receptors are bound to drug, and therefore no further
drug-receptor complexes can be formed and the response does not increase any further
(saturation)
• Law of Mass Action Applied to Drugs:
Drug-Receptor Interaction
cont…
• Drug +Receptor ↔ Drug-Receptor Complex →Effect
• Occupation of a receptor by a drug molecule may or may not result in
activation of the receptor.
• By activation, we mean that the receptor is affected by the bound
molecule in such a way as to elicit a tissue response
• agonists, which 'activate' the receptors
• If a drug binds to the receptor without causing activation and thereby
prevents the agonist from binding, it is termed a receptor antagonist.
Drug-Receptor Interaction
cont…
• Selectivity of Drug Responses.
• Drug molecules exhibit preferential affinity for receptors as follows:
• The cell will respond only to the spectrum of drugs that exhibit affinity
for the receptors expressed by the cell.
• The greater the extent to which a drug molecule exhibits high affinity
for only one receptor, the more selective will be the drug’s actions,
with lower potential for side effects.
Drug-Receptor Interaction
cont…
• The higher the affinity and efficacy of a given drug, the smaller the
amount of drug necessary to activate a critical mass of drug receptors
to effect a tissue response, and the lower the potential for
nonselective actions.
• As the concentration of a drug increases, the drug will combine with
receptors for which it has lower affinity and may generate off-target
effects.
• Thus selectivity of a drug to a specific receptor is obtained at low to
moderate doses.
Types of Receptors.
• There are four receptor types or superfamilies namely:
• Type 1-Ligand-gated ion channels (ionotropic receptors)
• Type 2- G-protein-coupled receptors (GPCRs) [metabotropic receptors
or seven-transmembrane-spanning (heptahelical) receptors
• Type 3-Kinase (Enzyme) linked and related receptors
• Type 4-Nuclear receptorsIntranuclear/intracellular receptors (e.g.
gonadal and glucocorticosteroids hormones)
Type 1-Ligand-gated ion channels/Trans
membrane ion channel (ionotropic receptors).

• Conduct ions across membrane in response to ligand binding, voltage

gradient or second messenger; e.g., H+/K+-ATP’ase
• Transmembrane ion channels allow the passage of ions from one side
of a membrane to another.
• Channels can exist in the open, closed, or inactive state, which
represent different conformations of the channel protein.
Type 1-Ligand-gated ion channels/Trans
membrane ion channel (ionotropic receptors)
cont...
• Drugs may affect the function of these channels by directly opening or
closing the channel (ligand gated channels), by influencing the
voltage-dependent characteristics of the channels (voltage gated
channels) and the amount of time the channel spends in a given state,
or by generating second messengers that subsequently open or close
the channel (second messenger gated).
• Examples include the following:
• Cholinergic receptors located in skeletal muscle bind nicotine,
resulting in opening of sodium channels, initiation of an action
potential in the muscle, and finally muscle contraction.
Type 1-Ligand-gated ion channels/Trans
membrane ion channel (ionotropic receptors)
cont...
• Neuromuscular (paralyzing) drugs antagonize this nicotinic receptor,
thereby preventing muscle contraction.
• Drugs that stimulate GABAA receptors open chloride channels,
causing hyperpolarization (making the cell more negative) and
reducing the probability of an action potential being produced,
thereby turning off the target neuron.
• Drugs that treat anxiety and sleep disorders are clinical examples of
these types of drugs.
Type 1-Ligand-gated ion channels/Trans
membrane ion channel (ionotropic receptors)
cont...
• Voltage gated ion channels.
• These ion channels change conformation (open, closed, or inactive) in
response to changes in membrane voltage.
• Drug binding to the channel alters the response of the channel to changes
in membrane voltage such that the open, closed, or inactivate state may be
lengthened or shortened.
• An example is a local anesthetic agent that binds to sodium channels that
are responsive to the arrival of an action potential.
• Local anesthetics lock the channels in the inactive state, thereby rendering
them temporarily nonresponsive to future action potentials and thereby
block transmission of pain signals.
Type 2: Transmembrane linked to intracellular G protein/
G-Protein Coupled Receptor/ Metabotropic Receptors

• G-proteins consist of 3 subunits, alpha, beta and gamma. (α, β, γ)

• Guanine nucleotides bind to the α subunit, which has enzymic
activity, catalyzing the conversion of GTP to GDP.
• β and γ subunits remain together as a βγ complex.
• G-proteins appear to be freely diffusible in the plane of the
membrane, so a single pool of G-protein in a cell can interact with
several different receptors and effectors in an essentially promiscuous
fashion.
• In the 'resting' state, the G-protein exists as an unattached αβγ trimer,
with GDP occupying the site on the α subunit
Type 2: Transmembrane linked to intracellular
G protein/ G-Protein Coupled Receptor/
Metabotropic Receptors cont…
• When a GPCR is activated by an agonist molecule, a conformational
change occurs, involving the cytoplasmic domain of the receptor ,
causing it to acquire high affinity for αβγ.
• Association of αβγ with the receptor occurs within about 50 ms,
causing the bound GDP to dissociate and to be replaced with GTP
(GDP-GTP exchange), which in turn causes dissociation of the G-
protein trimer, releasing α-GTP and βγ subunits;
• These are the 'active' forms of the G-protein, which diffuse in the
membrane and can associate with various enzymes and ion channels,
causing activation of the target
Type 2: Transmembrane linked to intracellular
G protein/ G-Protein Coupled Receptor/
Metabotropic Receptors cont…
• Examples include adrenergic receptors:
• In many cases the transduction or coupling mechanism is linked to the
final effector system via an intermediate cell signalling (second
messenger) system which are;
• Adenylate cyclase which catalyses the conversion of ATP to cyclic AMP;
• Guanylate cyclase which catalyses the conversion of GMP to cyclic GMP
(cyclic AMP and cyclic GMP are known collectively as cyclic nucleotides)
• Calcium and calmodulin; phospholipase C which catalyses
phosphoinositide turnover producing inositol phosphates (IP3) and
diacyl glycerol(DAG).
Type 3-Kinase (Enzyme) linked and related
receptors.

• There is a large and heterogenous group of membrane receptors responding

to protein mediators.
• They comprise an extracellular ligand-binding domain linked to an
intracellular domain by a single transmembrane helix.
• In many cases the intracellular domain is enzymic in nature ( with protein
kinase or guanylate cyclase activity)

• Examples include receptor tyrosine kinases

• Ligand binding stimulates the kinase enzymatic activity, which then initiates
and amplifies intracellular signals and feedback responses by changing the
phosphorylation status of cellular proteins.
Type 4-Nuclear receptorsIntranuclear/intracellular
receptors (e.g. gonadal and glucocorticosteroids hormones)

• Ligands bind to their receptor in cytoplasm and the complex then

migrates to the nucleus and binds to specific DNA sites, producing
alterations in gene transcription and altered protein synthesis. Such
effects occur over a time-course of minutes to hours.
• Receptors using this coupling mechanism include: Sex hormones:
estrogen, androgens, Glucocorticoids, Mineralocorticoids, Thyroid or
retinoid receptor family and Vitamin D receptors
Concept of Receptor Regulation .
• Prolonged exposure of receptors to agonists, as frequently occurs in
therapeutic use, can cause
• Desensitization of receptors
• Translocation of receptors
Desensitization.

• Desensitization mostly occurs in receptors directly coupled to ion channels.

• It can occurs at the neuromuscular junction as the result of a conformational
change in the receptor, resulting in tight binding of the agonist molecule
without the opening of the ionic channel.
• Desensitization of ion channels can also be caused by phosphorylation of
intracellular regions of the receptor protein which is a second, slower
mechanism.
• Phosphorylation of the receptor interferes with its ability to activate second
messenger cascades, although it can still bind the agonist molecule.
• This type of desensitization usually takes a few minutes to develop, and
recovers at a similar rate when the agonist is removed.
Translocation of Receptors

• Prolonged exposure to agonists often results in a gradual decrease in the

number of receptors expressed on the cell surface, as a result of
internalisation of the receptors.
• This is shown for β-adrenoceptors whereby the number of β-adrenoceptors
can fall to about 10% of normal in 8 h in the presence of a low concentration
of isoprenaline, and recovery takes several days.
• The internalized receptors are taken into the cell by endocytosis of patches
of the membrane, a process that also depends on receptor phosphorylation.
• This type of adaptation is common for hormone receptors and has obvious
relevance to the effects produced when drugs are given for extended
periods.
 Key Points.

• There are four types of drug receptors

• Prolonged use of drugs can result into up or down regulation of
receptors
• Drug receptor- interaction exhibit specific properties
Evaluation.

• What are receptors?

• What are the four types of receptors?
• What is desentization of receptors?
References
• Ministry of Health and Social Welfare. (2013). Standard Treatment
Guidelines & National Essential Medicines List Tanzania Mainland (4th
ed.). Dar es salaam, Tanzania government printers.

• Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L.

Michael. (2014). Pharmacotherapy: A Pathophysiologic Approach (9th
ed.). New York, McGraw-Hill Education.

• Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th

ed) New York, Lippincott Williams and Wilkins.
References cont…
• School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical
Handbook (2nd ed.).
• Dar es Salaam, ARDHI University press.

• The Royal Pharmaceutical Society of Great Britain. (2007). Martindale,

the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.

• The Royal Pharmaceutical Society of Great Britain. 2009. British National

Formulary
• (59th ed). London, BMJ Group and RPS Publishing.