Agonists, Antagonists and Dose Response Relationship
Session 6: Agonists, Antagonists and Dose Response Relationship
Total Session Time: 120 minutes
Prerequisites
None
Learning Tasks
By the end of this session students are expected to be able to:
Describe Agonist and antagonist effects
Describe dose response relationship
Explain on factors modifying drug response
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
Presentation/
Description Of Agonist and Antagonist
Description Of Agonist and Antagonist
2
2
30 minutes
30 minutes
Presentation/
Effects
Effects
2
2
30 minutes
30 minutes
Brainstorming
Effects
Effects
Brainstorming
Presentation
3
3
45 minutes
45 minutes
Small Group
Description of Dose Response Relationship
Description of Dose Response Relationship
Discussion
4
4
30 minutes
30 minutes
Presentation/
Explanation on Factors Modifying Drug
Explanation on Factors Modifying Drug
4
4
30 minutes
30 minutes
Brainstorming
Responses
Responses
Brainstorming
Responses
Responses
5
5
05 minutes
05 minutes
Presentation
Key Points
Key Points
6
6
05 minutes
05 minutes
Presentation
Evaluation
Evaluation
PST 05104 Pharmacology & Therapeutics 44 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: Effect of Agonist and Antagonist (30minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What is the meaning of agonist and antagonist?
ALLOW few students to respond
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Drugs are categorized based on their intrinsic activity at a given receptor:
Agonist :
o Agonists (sometimes called full agonists) produce maximum activation of the receptor and elicit a maximum response from the tissue.
o They are assigned an intrinsic activity of 1.
o Agonists activate receptors for endogenous mediators – example salbutamol is an agonist at β2-adrenoceptors, the consequent effect may be excitatory (e.g. increased heart rate) or inhibitory (e.g. relaxation of airway smooth muscle).
o Agonists at nicotinic acetylcholine receptors (e.g. suxamethonium) exert an inhibitory effect (neuromuscular blockade) by causing long-lasting depolarization at the neuromuscular junction, and hence inactivation of the voltage- dependent sodium channels that initiate the action potential.
Partial Agonist
o A partial agonist is a drug that displays efficacy that is intermediate between that of an agonist and an antagonist
o Partial agonist produces a lower response at full receptor occupancy than full agonists o Partial agonists also produce concentration –effect curves that resemble those
observed with full agonists
PST 05104 Pharmacology & Therapeutics 45 NTA Level 5 Semester 1 Facilitator Guide
Inverse Agonist :
o Inverse agonists inhibit rather than activate the receptor.
o This phenomenon is evident with receptors that exhibit baseline (ongoing or constitutive) activity in the absence of agonist binding.
o In these cases, binding of the inverse agonist reduces the baseline activity of the receptor, which in turn elicits an effect opposite that of binding of the agonist.
o Inverse agonists and antagonists will elicit similar effects because both types of drugs will reverse the effects of endogenous ligands.
Antagonist:
o Antagonists bind but produce no activation of the receptor and therefore block responses from the tissue.
o They are assigned an intrinsic activity of 0.
There are two types of antagonism;
Competitive antagonists
o When combined with the receptor, they prevent access of the endogenous mediator. o The complex between competitive antagonist and receptor is reversible.
o Provided that the dose of agonist is increased sufficiently, a maximal effect can still be obtained, i.e. the antagonism is surmountable.
o β-Adrenoceptor antagonists are examples of reversible competitive antagonists.
Non-competitive antagonist:
o Bind irreversibly to agonist binding site
o The effect is equivalent to removing receptors from the system
PST 05104 Pharmacology & Therapeutics 46 NTA Level 5 Semester 1 Facilitator Guide
The effect of one drug can be reduced in the presence of another in other ways:
Chemical antagonism
Pharmacokinetic antagonism
Block of receptor-effector linkage
Physiological antagonism
Chemical antagonism
It refers to the uncommon situation where the two substances combine in solution; as a result, the effect of the active drug is lost.
o Eg 1→ chelating agent dimercaprol that bind to heavy metals and thus reduce their toxicity
o Eg 2 → the neutralising antibody infliximab which has an anti-inflammatory action due to its ability to sequester the inflammatory cytokine, tumour necrosis factor
Pharmacokinetic antagonism
PK antagonism occurs when:
o The rate of elimination of the active drug is increased (e.g. the anticoagulant effect of warfarin is ↓ when given together with phenobarbital,
o The rate of absorption of the active drug from the Git is reduced, o The rate of renal excretion may be increased.
Physiological antagonism
Physiological antagonism occurs when two drugs whose opposing actions in the body tend to cancel each other.
For example, histamine acts on receptors of the parietal cells of the gastric mucosa to stimulate acid secretion, while omeprazole blocks this effect by inhibiting the proton pump;
STEP 3: Dose – Response Relationship (45minutes)
There are two types of Dose –response relationships, which are best, represented in curves:
Graded dose-response curve
Quantal dose-response curve (all or none).
Graded dose-response curve
In this type, response is gradual
There is Gradual increase in response by increasing the dose (continuous response).
Lowering of blood pressure, heart rate, blood glucose level, cholesterol
Curve is usually sigmoid in shape
PST 05104 Pharmacology & Therapeutics 47 NTA Level 5 Semester 1 Facilitator Guide
Graded response Curves
Dose -response curves- Graded are used to determine
Maximum Efficacy (Emax): is the maximal biological response produced by a drug.
Median Effective concentration (EC50): is the concentration of the drug that gives 50% of the maximal response (Emax).
Quantal dose-response curve
Relate drug concentration to % percentage of patients responding (all or none response).
The response may be therapeutic response, adverse effect or lethal effect.
e.g. prevention of convulsion, arrhythmias or death.
Quanta dose-response curve are Used to determine
ED50
TD50
LD50
Therapeutic index
PST 05104 Pharmacology & Therapeutics 48 NTA Level 5 Semester 1 Facilitator Guide
A. 50% of individuals exhibit the specified therapeutic response
B. 50% of individuals exhibit the specified toxic effects
STEP 4: Factors Modifying Drug Responses (30minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are the factors modifying drug response?
ALLOW few students to respond
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Interindividual variability in responsiveness to drugs may be contributed by the following;
Pharmacodynamic factors
Pharmacogenetics factors
Pharmacokinetic factors
Pharmacodynamic factors
Variation in the response to equivalent drug concentrations arises because of various factors, such as differences in
receptor number and structure,
receptor-coupling mechanisms
Physiological changes in target organs resulted from differences in genetics, age and health.
PST 05104 Pharmacology & Therapeutics 49 NTA Level 5 Semester 1 Facilitator Guide
Pharmacogenetics factors
Some of the variation above may be influenced by genetic polymorphisms, which can result in altered responsiveness in drug targets (e.g. receptor function) or altered drug handling (e.g. enzyme activity).
Polymorphisms in drug absorption, distribution, or metabolism are major causes of interindividual variability
Pharmacokinetic factors
It is well recognised that the clinical response to drug administration varies widely between individuals and that most of this variability is pharmacokinetic in origin.
In general, variability arises because of inter-individual differences in rates of drug absorption, drug distribution and elimination, either by metabolism or excretion.
Variability of drug response is also a consequence of a variety of drug interactions which may influence pharmacokinetic parameters.
Among the many factors which are responsible for the variation in human drug response, age is relatively important.
As a consequence of impaired metabolism and excretion the inter-individual variation in the kinetic of many drugs is much greater in the elderly.
Also the degree of plasma-protein binding, in turn, influences the distribution, action, metabolism and renal excretion of drugs.
Thus changes in plasma protein binding of drugs, e.g. in diseased states, may give rise to altered pharmacokinetic and possibly altered drug response.
STEP 5: Key Points (5 minutes)
Drugs can act as agonist, partial agonist, inverse agonist or antagonist at receptors.
Drug response is represented as graded and quanta responses.
Interindividual variation in drug response may be contributed by pharmacodynamics, pharmacokinetics and pharmacogenetics factors.
STEP 6: Evaluation (5 minutes)
What is partial agonist?
What is physiological antagonism?
What are the factors, which affect drug responses among individuals?
PST 05104 Pharmacology & Therapeutics 50 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 51 NTA Level 5 Semester 1 Facilitator Guide
Unataka kutumiwa notes hizi kupitia WhatsApp?Kwa notes zilizopangiliwa vizuri kwa kusoma offline au PDF, bonyeza kitufe hapa chini. Ujumbe wenye Level, Semester, Module na Topic utaandaliwa moja kwa moja.TUMIWA NOTES WHATSAPP