D4 - Antagonism dynamics Flashcards
Antagonists
- Endogenous neurotransmitters can produce unwanted effects
- Eg. Histamine causing hay fever
- Histamine release from mast cells activates histamine receptors causing itch, secretions and nasal congestion - possible to inhibit these unwanted effects
Chemical antagonists
- Bind directly with soluble agonists
- Inhibit agonist induced effect
- Monoclonal antibodies, soluble receptors - ‘biologicals’
○ Bind to protein agonists
○ Prevents the agonist from binding to and acting on the receptor - Eg. Infliximab (monoclonal antibody) and etanercept (soluble receptor)
○ Both neutralise pro inflammatory TNF- alpha
○ Prevents binding and activation of TNF receptors
○ Treats rheumatoid arthritis
§ Inflammatory condition driven by TNF alpha
Infliximab
- Eg. Infliximab (monoclonal antibody) and etanercept (soluble receptor)
○ Both neutralise pro inflammatory TNF- alpha
○ Prevents binding and activation of TNF receptors
○ Treats rheumatoid arthritis
§ Inflammatory condition driven by TNF alpha
Monoclonal antibodies
○ Some work by binding to agonist eg. inflixamab
○ Others work by binding to the receptor to inhibit agonist binding
§ Dupilumab binds to IL-4 receptor, suppressing eczema and asthma
○ Binding involves weak ionic bonds, hydrogen bonds, van der walls forces
○ Large number of high affinity interactions makes binding irreversible
○ Majority of monoclonal antibodies used to treat cancer and inflammatory diseases eg. Eczema, asthma, rheumatoid arthritis
Competitive receptor antagonists
- Compete with agonists for the same binding site on the receptor
- Blocks effect induced by endogenous agonists
○ Neurotransmitters
§ Acetylcholine, noradrenaline
○ Hormones
§ adrenaline
○ Mediators
§ Histamine blocked by cetirizine - cetirizine competes with histamine for the same binding site - antihistamine drug
○ Relies on the fact that the agonist binding is reversible
○ Antagonist will occupy binding site
○ When the competitive antagonist leaves, the binding site is free again, the agonist can bind
Which one (competitive antagonist or endogenous agonist) will mainly bind the receptor depends on
○ Relative concentration
○ Relative affinity - Blocks effect induced by endogenous agonists
dose response curve for Competitive receptor antagonists
Dose response curve
○ Increasing concentration of the antagonist moves the graph to the right
○ Rightward shift is theoretically unlimited, and does not cause reduction in maximum response
○ In the presence of antagonist, you need more agonist to produce a response
increasing concentration of a competitive receptor antagonist
ncreasing concentration of the antagonist moves the graph to the right
○ Rightward shift is theoretically unlimited, and does not cause reduction in maximum response
○ In the presence of antagonist, you need more agonist to produce a response
Metoprolol and adrenaline in patients with angina
○ Competitive antagonism between adrenaline and metoprolol
○ angina
§ Coronary arteries can be clocked by atherosclerotic plaque
§ When exercising, adrenaline is released and causes increased heart rate
§ Heart requires more oxygen from the coronary arteries
§ If coronary arteries are blocked then the heart goes into oxygen debt - causes angina pain
○ Metoprolol (competitive antagonist for B1 receptor)
§ Metoprolol blocks binding of adrenaline
§ Occupies B1 receptor without activating it
§ Decreases chances of heart going into oxygen debt
§ Decreases anginal attack
§ Often referred to as a beta blocker medication
angina
§ Coronary arteries can be clocked by atherosclerotic plaque
§ When exercising, adrenaline is released and causes increased heart rate
§ Heart requires more oxygen from the coronary arteries
§ If coronary arteries are blocked then the heart goes into oxygen debt - causes angina pain
metoprolol
○ Metoprolol (competitive antagonist for B1 receptor)
§ Metoprolol blocks binding of adrenaline
§ Occupies B1 receptor without activating it
§ Decreases chances of heart going into oxygen debt
§ Decreases anginal attack
§ Often referred to as a beta blocker medication
Metoprolol ○ Same level of adrenaline does not cause the heart to work any harder ○ Full protection against an anginal episode ○ Moves dose response curve to the right without a decrease in maximum response ○ In a high level of exertion, more adrenaline is released § Can overcome some of the metoprolol block § Metoprolol will only give partial protection in high exertion § May have to increase the dose - but this has possibility of adverse effects
metoprolol dose response curve
○ Same level of adrenaline does not cause the heart to work any harder
○ Full protection against an anginal episode
○ Moves dose response curve to the right without a decrease in maximum response
○ In a high level of exertion, more adrenaline is released
§ Can overcome some of the metoprolol block
§ Metoprolol will only give partial protection in high exertion
§ May have to increase the dose - but this has possibility of adverse effects
Irreversible receptor antagonists
- Irreversible (or slowly reversible) bond with binding site
- Phenoxybenzamine (PBZ)
○ Forms a covalent bond with agonist binding site on the alpha adrenoceptor
○ Prevents adrenaline from binding it
○ When in an aqueous solution, phenoxybenzamine forms an aziridinium ion which is highly reactive
○ Ion binds to cysteine amino acid residue in binding site of alpha adrenoreceptor to form a covalent receptor adduct
○ Permanently bound - adrenaline can no longer activate the receptor
○ Forms covalent bond with the receptor
○ The receptor can no longer be activated
○ Irreversible antagonist causes a reduction in the number of receptors
○ Effectively Decreases receptor density
○ Reduction in the maximum response produced by an agonist
○ Reduction in maximum response on the graph - Phenoxybenzamine (PBZ)
iverversable receptor antagonists dose response curve effect
○ Irreversible antagonist causes a reduction in the number of receptors
○ Effectively Decreases receptor density
○ Reduction in the maximum response produced by an agonist
○ Reduction in maximum response on the graph
- Phenoxybenzamine (PBZ)
○ Forms a covalent bond with agonist binding site on the alpha adrenoceptor
○ Prevents adrenaline from binding it
○ When in an aqueous solution, phenoxybenzamine forms an aziridinium ion which is highly reactive
○ Ion binds to cysteine amino acid residue in binding site of alpha adrenoreceptor to form a covalent receptor adduct
○ Permanently bound - adrenaline can no longer activate the receptor
○ Lacks selectivity for alpha adrenoceptors - rarely used clinically
§ Also blocks muscarinic - adverse side effects
Allosteric antagonists
- Bind to different binding site and causes a conformational change
- Reduces affinity or efficacy of the agonist for the receptor
- Do not compete with the agonist for the binding site
- Interaction with agonist and antagonist happens through the receptor - not at the same binding site
- Also called negative allosteric modulators (NAMS)
