Drug Receptor Interaction
Session 5: Drug Receptor Interaction
Total Session Time: 120 minutes
Prerequisites
None
Learning Tasks
By the end of this session students are expected to be able to:
Describe the drug-receptor interaction
Describe the types of receptors
Explain the concept of receptor regulation
Resources Needed:
Flip charts, marker pens, and masking tape
Black/white board and chalk/whiteboard markers
Computer and LCD Projector
SESSION OVERVIEW
Step
Time
Activity/
Content
Step
Time
Activity/
Content
Step
Time
Method
Content
Method
Method
1
1
05 minutes
05 minutes
Presentation
Introduction, Learning tasks
Introduction, Learning tasks
2
2
30 minutes
30 minutes
Presentation/
Drug-Receptor Interaction
Drug-Receptor Interaction
2
2
30 minutes
30 minutes
Buzzing
Drug-Receptor Interaction
Drug-Receptor Interaction
Buzzing
3
3
45 minutes
45 minutes
Presentation/
Types of Receptor
Types of Receptor
3
3
45 minutes
45 minutes
brainstorming
Types of Receptor
Types of Receptor
brainstorming
4
4
30 minutes
30 minutes
Presentation
Concept of Receptor Regulation
Concept of Receptor Regulation
5
5
05 minutes
05 minutes
Presentation
Key Points
Key Points
6
6
05 minutes
05 minutes
Presentation
Evaluation
Evaluation
PST 05104 Pharmacology & Therapeutics 33 NTA Level 5 Semester 1 Facilitator Guide
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing.
STEP 2: Drug-Receptor Interaction (30 minutes)
Activity: Buzzing (5 minutes)
ASK students to pair up and buzz on the following question for 2 minutes
How does drug interact with receptors?
ALLOW few pairs to respond and let other pairs add on points not mentioned
WRITE their response on the flip chart/board
CLARIFY and SUMMARIZE by using the content below
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 recognise 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.
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.
Four main kinds of regulatory protein are commonly involved as primary drug targets, namely:
o receptors o enzymes
o carrier molecules (transporters) o 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.
PST 05104 Pharmacology & Therapeutics 34 NTA Level 5 Semester 1 Facilitator Guide
The law of mass action dictates that:
o The combination of drug (also called ligand) and receptor depends on the concentrations of each
o The amount of drug-receptor complex formed determines the magnitude of the response
o A minimum number of drug receptor complexes must be formed for a response to be initiated (threshold)
o As drug concentration increases, the number of drug-receptor complexes increases and drug effect increases
o 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 ↔ 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.
•
The tendency of a drug to bind to the receptors is governed by its affinity, whereas the tendency for it, once bound, to activate the receptor is denoted by its efficacy.
PST 05104 Pharmacology & Therapeutics 35 NTA Level 5 Semester 1 Facilitator Guide
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.
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.
STEP 3: Types of Receptor 45Minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are the types of receptors?
ALLOW few students to respond
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
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
PST 05104 Pharmacology & Therapeutics 36 NTA Level 5 Semester 1 Facilitator Guide
Type 1-Ligand-gated ion channels/Trans membrane ion channel (ionotropic receptors)
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.
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:
o 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.
PST 05104 Pharmacology & Therapeutics 37 NTA Level 5 Semester 1 Facilitator Guide
o Neuromuscular (paralyzing) drugs antagonize this nicotinic receptor, thereby preventing muscle contraction.
o 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.
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, catalysing the conversion of GTP to GDP.
β and γ subunits remain together as a βγ complex.
PST 05104 Pharmacology & Therapeutics 38 NTA Level 5 Semester 1 Facilitator Guide
G-proteins appear to be freely diffusible in the plane of the membranThe e, 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
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 as shown in the following figure below;
PST 05104 Pharmacology & Therapeutics 39 NTA Level 5 Semester 1 Facilitator Guide
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;
o Adenylate cyclase which catalyses the conversion of ATP to cyclic AMP;
o Guanylate cyclase which catalyses the conversion of GMP to cyclic GMP (cyclic AMP and cyclic GMP are known collectively as cyclic nucleotides)
o 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.
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
PST 05104 Pharmacology & Therapeutics 40 NTA Level 5 Semester 1 Facilitator Guide
STEP 4: Concept of Receptor Regulation (30minutes)
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 internalised 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.
PST 05104 Pharmacology & Therapeutics 41 NTA Level 5 Semester 1 Facilitator Guide
Summary
STEP 5: Key Points (5 minutes)
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
STEP 6: Evaluation (5 minutes)
What are receptors?
What are the four types of receptors?
What is desentization of receptors?
PST 05104 Pharmacology & Therapeutics 42 NTA Level 5 Semester 1 Facilitator Guide
References
Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.
Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.
Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:
Jaypee Brothers Medical P.
Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.
Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.
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.
PST 05104 Pharmacology & Therapeutics 43 NTA Level 5 Semester 1 Facilitator Guide
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