SAQ model answers Flashcards
Part A: Sandy has hypertension (high blood pressure) and is prescribed a non-selective beta-adrenoceptor blocker, propranolol. Although Sandy noticed a reduction in her symptoms and felt much calmer she was finding that at the doses prescribed, she was experiencing fatigue and respiratory problems during her gym workouts even though she used her inhaler.
A. Based on your knowledge of beta adrenoceptors explain the mechanism of action of the beta blocker propranolol with respect to it’s receptor targets, their location, and how it acts in order to reduce blood pressure. (4 marks)
Propranolol is a non-selective beta adrenoceptor antagonist, which means it binds to both beta1 and beta2 adrenoceptors.
Propranolol binds to the orthosteric binding site of the beta adrenoceptors to inhibit the action of noradrenaline and adrenaline in these tissues.
Receptor Targets and Locations:
Beta-1 receptors: Predominantly located in the heart. They increase heart rate and contractility when stimulated.
Beta-2 receptors: blood vessels, gastrointestinal tract (beta2), bronchial smooth muscle (beta2), skeletal muscle, blood vessel/vascular beds
Mechanism of Action:
Beta-1 Blockade: By blocking beta-1 receptors in the heart, propranolol reduces heart rate, myocardial contractility, and cardiac output, (rate and force of contraction) leading to a decrease in blood pressure. This action helps alleviate hypertension by reducing the workload on the heart.
propranolol reduces the sympathetic nervous system’s effects on the heart, leading to lower heart rate and cardiac output. This reduction in cardiac output decreases the overall blood pressure.
–> Blood Vessels: Activation of alpha-1 receptors causes vasoconstriction, increasing peripheral resistance. However, beta-2 receptor activation causes vasodilation in skeletal muscle vessels. so not blood vessels
== only targets the heart
Part A: Sandy has hypertension (high blood pressure) and is prescribed a non-selective beta-adrenoceptor blocker, propranolol. Although Sandy noticed a reduction in her symptoms and felt much calmer she was finding that at the doses prescribed, she was experiencing fatigue and respiratory problems during her gym workouts even though she used her inhaler.
B. Explain with respect to selectivity and specificity why the therapeutic dose of propranolol was causing the side effect of fatigue during Sandy’s gym workout. (3 marks)
Propranolol has specificity for both beta1 and beta2 adrenoceptors. At therapeutic doses it is also non-selective for both of these receptors, so it will bind to both.
heart (beta 1) : This means that it will bind to beta1 adrenoceptors in the heart to reduce rate and force of contraction.
==> With lower blood pressure during exercise, less oxygen can get to tissues.
Bronchiole smooth muscle vasodilation (beta 2) : At the same time it is binding to beta2 adrenoceptors in the bronchi, reducing adrenaline-induced bronchodilation, hence reducing oxygen intake.
skeletal muscle vasodilation (beta 2) : By blocking beta2 adrenoceptors in skeletal muscle vasculature, it is also preventing vasodilation and oxygen-carrying blood to get to the skeletal muscles for their effective functioning during exercise.
==> The reduced rate and force of contraction, reduced bronchodilation, and reduced vasodilation in regions requiring increased oxygen, Sandy will experience fatigue during exercise.
Part A: Sandy has hypertension (high blood pressure) and is prescribed a non-selective beta-adrenoceptor blocker, propranolol. Although Sandy noticed a reduction in her symptoms and felt much calmer she was finding that at the doses prescribed, she was experiencing fatigue and respiratory problems during her gym workouts even though she used her inhaler.
C. What sort of antagonism is occurring between propranolol and salbutamol and which receptors are involved? (2 marks)
Propranolol is a competitive antagonist of salbutamol, inhibiting its ability to bind to beta2 adrenoceptors in the bronchial smooth muscle, and preventing salbutamol-induced bronchodilation.
salbutamol = beta-2 adrenergic agonist —> binds to the beta 2 adrenoceptors
Part B Sandy visited her doctor, who decided to switch Sandy to a different beta blocker medication, atenolol, which binds only to beta1 adrenoceptors at therapeutic doses. Sandy noticed that the dose of atenolol she took (50 mg) was less than that of propranolol (100 mg).
D. Explain this difference in dose for the two drugs with respect to drug dissociation constants. (2 marks)
Dissociation constant is a measure of affinity. A lower dose is required for atenolol’s therapeutic effect compared with propranolol. This means atenolol has greater affinity for its receptors compared with propranolol.
lower Kd, higher affinity, requires lower dose /concentrations to occupy the receptors effectively
Atenolol:
Dose: 50 mg
Receptor Targets: Selective for beta-1 adrenoceptors at therapeutic doses.
Dissociation Constant: Atenolol has a lower K_d, indicating a higher affinity for beta-1 receptors. This higher affinity means that a lower dose of atenolol is needed to effectively block beta-1 receptors and produce the desired therapeutic effect.
Part B Sandy visited her doctor, who decided to switch Sandy to a different beta blocker medication, atenolol, which binds only to beta1 adrenoceptors at therapeutic doses. Sandy noticed that the dose of atenolol she took (50 mg) was less than that of propranolol (100 mg).
E. Do the different dissociation constants for atenolol and propranolol have any effect on their respective intrinsic efficacies? Why? (2 marks)
K_d and intrinsic efficacy are independent properties.
dissocation constant : Drugs with lower K_d values (higher affinity) require lower concentrations to occupy the receptors effectively.
intrinsic efficacy : Intrinsic efficacy is the ability of a drug to activate the receptor and elicit a maximal response once bound.
—> A drug can have a high affinity (low K_d) but low intrinsic efficacy (partial agonist), or low affinity (high K_d) but high intrinsic efficacy (full agonist). Thus, K_d and intrinsic efficacy are independent properties.
The difference in affinity between atenolol and propranolol has no effect on their intrinsic efficacies because they are both antagonists with an intrinsic efficacy of zero.
–> Antagonists are drugs that bind to receptors but do not activate them. Instead, they block or dampen the action of agonists (substances that do activate the receptor).
Intrinsic efficacy is a measure of a drug’s ability to produce a response after binding. For antagonists, this value is zero because they do not produce a response themselves. Since antagonists do not activate the receptors, they have an intrinsic efficacy of zero.
Part B Sandy visited her doctor, who decided to switch Sandy to a different beta blocker medication, atenolol, which binds only to beta1 adrenoceptors at therapeutic doses. Sandy noticed that the dose of atenolol she took (50 mg) was less than that of propranolol (100 mg).
F. By definition the magnitude of the effect for an antagonist, at a particular concentration, is independent of the dissociation constant for agonists that act on the same receptor. Explain what is meant by this? (2 marks)
salbutamol mechanism
When salbutamol binds to beta-2 adrenergic receptors in the airways, it leads to a series of cellular events:
- Activation of Adenylate Cyclase:
—>Binding of salbutamol to the beta-2 receptor activates the enzyme adenylate cyclase/ (or adenylyl cyclase).
2 . Increase in cAMP:
–> adenylyl cyclase converts ATP to cyclic AMP (cAMP).
- cAMP leads toRelaxation of Smooth Muscle cells in the airways, resulting in bronchodilation (widening of the airways).
whats kB
K_B (Binding Constant): K_B is a measure of the concentration of an antagonist that causes a specific shift (typically a twofold shift) in the potency of an agonist.
Functional Assay: Because antagonists do not have intrinsic efficacy (they do not activate the receptor), their K_B can be determined by observing how much they shift the concentration-response curve of an agonist.
Twofold Shift: The K_B is the concentration of the antagonist that causes the agonist’s EC50 (the concentration at which the agonist produces 50% of its maximum effect) to double. This means you need twice the amount of agonist to achieve the same effect in the presence of this concentration of antagonist.
== need to double dose to restore EC50 response
Pharmacodynamics vs pharmacokinetics
Pharmacodynamics: the eects of the drug on the body
Pharmacokinetics: the way the body affects the drug with time
affinity
- Refers to the drugs ability to bind to the receptor
- Drugs with higher affinity only need a very small concentration to bind to the target
- This higher affinity means that a lower dose is needed
Intrinsic effcacy
- A measure of the ability of a drug to elicit a response
- the maximal response it can elicit when fully occupies receptor
- Full agonists: intrinsic efficacy = 1
- Antagonists: intrinsic efficacy = 0 (does not activate receptor and blocks agonist)
- Partial agonists: intrinsic efficacy = between 0 and
independent of drug concentration/ dependent on drug’s ability to activate receptor
Potency
Refers to the concentration of a drug that causes a specied eect
amount of drug needed to produce a specific effect
- A drug that causes a specied eect at smaller concentration is more potent
- EC50- concentration of drug required to give half-maximal response
- more potent drug has a lower EC50 value
- dependent on drugs affinity for receptor and intrinsic efficacy
Specicity and selectivity
Specicity = the ability of a drug to bind preferentially to one site over another
- Selectivity = the ability of a drug concentration to produce one eect over another
types of receptors
Receptors
In Pharmacology, a receptor is a specic type of drug target
- G protein-coupled receptors (metabotropic)
- Ligand-gated ion channels (ionotropic)
- Kinase-linked
- Nuclear – within the nucleus
Allosteric Modulators:
Binding Site: Allosteric modulators bind to a site on the macromolecule (such as a receptor or enzyme) that is different from the active site (also known as the orthosteric site).
Effect on Agonists: They do not have an effect on their own but can enhance or reduce the response of the receptor to an agonist that binds to the orthosteric site.
Alteration of Function: Allosteric modulators can alter the affinity (how well the agonist binds) or the intrinsic efficacy (how effectively the agonist activates the receptor) of the agonist.
