number 9 Done by Nazek Hyasat Corrected by Bahaa Najjar & mohammed AL-shrouf Doctor Alia Shatnawi
HOW DO DRUGS WORK??? You know that receptors are targeted by drugs, the question now is how do these drugs work on the receptor? Drugs either activate or inhibit these receptors; which means they are either agonists or antagonists. *Some receptors are localised on the surface of the cells, others are intracellular receptors. *Antagonist: This word means blocker or inhibitor, drugs can affect the receptor in a certain way to give an opposite effect, so it s going to inhibit or block the binding of the drug, neurotransmitter or hormone to these receptors. *Agonist: a drug that binds to a receptor and activates it, so it initiates the signalling. Example: epinephrine (adrenaline), which binds to β-adrenergic receptor on smooth muscles Of bronchi, causes dilation. so, we use as agonist for adrenaline a drug called Albuterol which works as adrenaline does and use it to treat asthmatic people to help them breath. * ex- ibuprofen works through inhibiting an enzyme called cyclooxygenase, so this is another drug whose target is an enzyme, through inhibiting the enzyme s action we achieve the therapeutic effect which is analgesia, anti-inflammatory and antipyretic. So, these are two ways of how drugs work; either activate or inhibit the endogenous protein, another way is that a few have unconventional mechanisms of action. As an example: the drug we know as Gaviscon (commercial name) which is an antacid, is used to treat the excessive acidity of the stomach, it is an alkali (calcium carbonate) and chemically interacts with HCl present in the stomach to reduce the acidity. So, it doesn t work by interacting with the enzyme or receptor, but by a different mechanism. HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS? Antagonists of Cell Surface Receptors A CELL SURFACE RECEPTOR is embedded in the cell membrane and functions to receive chemical information from the extracellular compartment and transmit that information to the intracellular compartment. There are receptors present on the cell surface because we have certain endogenous molecules in the body that need to interact with these receptors, but they are not created for drugs that are normally there, like acetylcholine, neurotransmitters, hormones and sometimes peptides like angiotensin. Once this endogenous molecule binds to the receptor it is going to transmit signals from outside to inside the cell. What happens? When a ligand (any molecule that can bind and interact with the receptor to either activate or inhibit it) is bound to its receptor, if it s an agonist it will activate it (activation means after binding it will cause conformational changes in the receptor that will lead to the transmission of the signal inside the cell) so it will cause activation of another kind of protein in the cell; G-protein coupled receptors. Remember G-protein consist of 3 subunits and it is bound to a GDP molecule, when it receives signals and is activated it will bind to a GTP molecule and the 3 subunits will divide to βϒ complex and active ᾳ subunit, which will activate something else in the cell. that means the activation
of these proteins will activate further signalling events in the cell, resulting finally in certain actions like relaxation of a smooth muscle for example. The antagonist binds to the binding site of the endogenous molecules on the receptor but it doesn t activate it, it blocks it. ex- it prevents adrenaline from activating the receptor, so the signal will stop and some of the muscles will not be contracted, this is the opposite effect but it does not do so by initiating an opposite mechanism in the cell rather it blocks the action. β blockers (ex-propranolol), which blocks β adrenergic receptors of adrenaline (β2 in the bronchi which causes relaxation of smooth muscles and bronchodilation & β1 in the heart which causes increasing of heart rate), they bind to β1 and 2 adrenergic receptors(not selective) and occupy the binding place of adrenaline and prevent it from binding and activating the receptor. So instead of having continuous signals of activation, these signals will stop, and part of the smooth muscle cells of bronchi will not relax and instead will be contracted, in addition, the heart rate will not increase too (opposite effect). However, that doesn t mean these blockers initiated opposite mechanisms of action in the cell, they don t cause something inside the cell that leads to decreasing the concentration of C-AMP, they just block the action of adrenaline by preventing it from binding to its receptor, so it won t be able to increase the C-AMP concentration which causes less contraction in the heart. so we use them in some cardiac conditions like heart failure, angina, heart tension to decrease the effort that the heart is doing. propranolol antagonist must fit in the binding pocket of the adrenergic receptor, so it must have compatibility in shape as well as having affinity. Most antagonists attach to the binding site on the receptor for endogenous agonist and sterically (just by occupying) prevent endogenous agonist from binding. There are 2 types of binding between the antagonist and the receptor: 1) Reversible binding >> the antagonist in this case must be competitive (WHAT does that mean? Propranolol for example, reversible means it will not block the β adrenergic receptors all the time, it will block them for certain period then it will get off and allow the adrenaline or other suitable drug to bind. Competitive means that there is a competition between the adrenaline and propranolol, so the binding will be affected by the concentrations, which means if we increase the concentration of one of them more, more of it will be able to bind and occupy more receptors than the other. 2) Irreversible binding >> non-competitive antagonist We have 2 situations of non-competitive antagonists: 1) ᾳ1 receptors of adrenaline in the vascular smooth muscle cells (activation of it will cause vascular constriction). Suppose we have a drug that binds irreversibly to it, then no matter how the concentration of adrenaline increases, it will not be able to break the bond between the irreversible antagonist and the receptor, which means the drug will remain in the body for a long time. We can get rid of the effect of the drug by recycling the receptors (degrading them with the bound drug and then synthesising new receptors) but this is not the optimum situation. The reversible binding is the optimum situation, because the time of action will not be very long. if you take a lot of the irreversible binding drug it will occupy all the receptors so you will completely stop the effect of adrenaline on those receptors, you don t want that, you need to have balance.
2) In this situation the drug binds to the receptor but it doesn t bind on the binding site of adrenaline (the receptor has a certain site for it that differs from the binding site), this binding will cause conformational changes in the receptor that will prevent the endogenous agonist from binding to it. NO matter how much the concentration of adrenaline increases, the antagonist changes the structure of the receptor so it will not be able to bind to the agonist. We call this antagonist>>allosteric antagonist Allosteric antagonists either prevent the agonist from binding to the receptor by changing its structure or bind to it and inhibit the agonist s effect. Note: not all receptors consist of more than one subunit. If a patient suffers from asthma and angina, would you give him propranolol? This drug as mentioned previously is β adrenergic blocker and affects both β1 and β2 receptors, which means it will cause the heart rate to decrease which is useful in the case of angina, but it also will cause bronchoconstriction and that is very dangerous because the patient is suffering from asthma as well, so we must keep that in mind and give the patient a drug with selective effect. If we used a subtype of adrenergic receptor that only targets β1 receptors without β2 receptors (more selectivity) we will not worry about the side effect. β1 agonist is used to treat heart failure and β2 agonist to treat asthma. *Another important example on useful antagonists is ARB. Angiotensin 2 > peptide hormone> has 2 mechanisms of working > - It increases the absorption of Na from renal tubules >> increases the absorption of water to the blood circulation (increases the volume)>> increases the blood pressure -it has receptors (angiotensin receptor) on vascular smooth muscle cells >> it binds to its receptors and causes signaling mechanism which will increase the Ca concentration in the cell >> muscle contraction>> cause the constriction of blood vessels >>direct increasing of the pressure. Drug ARB is an important drug to treat the hypertension (elevated blood pressure more than 140/100) >>>it is a angiotensin receptor blocker>>it is a competitive antagonist for angiotensin 2 receptors so it will bind to the receptor and inhibit its action whether it is reabsorption of Na or constriction of blood vessels, which will cause a decrease in the blood pressure. Drug ARB is used to treat high blood pressure(hypertension), heart failure and cardiovascular conditions. EXTRA note: A blood pressure less than 120/80 mmhg is normal, meaning that systolic pressure ( the maximum arterial pressure during contraction of the left ventricle of the heart) is less than 120 mmhg & diastolic (the minimum arterial pressure during relaxation and dilatation of the ventricles of the heart when the ventricles are filled with blood) is less than 80mmHg. Antagonists of Nuclear Receptors **There are other receptors that are present intracellularly. Sometimes there are nuclear transcription factors, some drugs bind to them and antagonise them. For example: Steroid hormones >> they bind to these transcription factors >> cause activation of these transcription factors to bind to DNA and initiate transcription. Steroid hormones are mineral corticoids.
Aldosterone is a mineral corticoid that works on certain transporters and causes reabsorption of Na and water and excretion of K >>>it increases water retention and causes edema. To get rid of the excessive water that accumulates around vital organs >> we must use an antagonist of aldosterone which is called spironolactone>>it binds to the aldosterone receptor >> prevents this signal from happening >>prevents the complex (Nuclear transcription factors) from binding to DNA and activating transcription of certain genes. What are the genes that aldosterone was transcribed from?? They are genes from transporters responsible for the reabsorption of Na Spironolactone (antagonist)>>decreases these transports >> decreases Na reabsorption >> more Na will excrete with the urine and take with it water It works similar to competitive inhibitors but it affects intracellular processes. Enzyme Inhibitors *some drugs modulate things other than receptors like enzymes. *30% of drugs targets are enzymes *cyclooxygenase(cox) enzyme for example which catalyses the formation of prostaglandin >>the drug used here is ibuprofen (aspirin) Ibuprofen binds to COX and blocks its action >> less product (prostaglandin)>>less of cellular effect which is inflammation and pain. *another example is angiotensin converting enzyme (ACE) which converts angiotensin 1 to angiotensin 2. Angiotensin 2 can cause some elevation in blood pressure if it is present in the body in high concentrations. To get rid of this excessive effect of angiotensin 2 there are 2 ways: 1)block its receptors. 2)inhibit the synthesis of angiotensin 2 (reduce its amount) by inhibiting ACE. The question you might ask is WHY do I have 2 options? Because as we know these drugs have side effects and some people cannot tolerate these side effects. For example>>ace inhibitor >>> one important side effect of it is that it causes coughing ACE causes degradation of peptide released in the case of allergic reactions (inflammatory mediator), so when ACE inhibitor is used the concentration of this peptide will increase and that will cause releasing of histamine and increases the coughing. Ion Channel Blockers Transport Inhibitors Inhibitors of Signal Transduction Proteins Now let s talk about agonists.. *some drugs work by activating endogenous proteins Ex ; Nitroglycerin (drug for angina patient )>> it releases NO which is a gas and a small molecule so it can diffuse quickly through the membrane to get inside the cell (vascular smooth muscle cell ) then it is going to bind to an enzyme called guanylate cyclase and activate it which will result in increasing the concentration of C-GMP which will cause activation of different channels and proteins and cause relaxation of smooth muscle cells,
vasodilation and more perfusion of blood to different organs of the body. It is used to treat angina when the heart isn t working well because it s not getting a good amount of blood. We use this drug as sublingual tablet to increase the bioavailability. If the patient takes this drug orally the bioavailability will be low, so it must be given sublingually to avoid the First Pass Effect Is a phenomenon of drug metabolism whereby the concentration of the drug is greatly reduced before it reaches the systemic circulation, which reduces the bioavailability. **Systemic circulation: carrying oxygenated blood away from the heart to the body, and returning deoxygenated blood back to the heart. so Nitroglycerin is taken sublingually > because the area under the tongue is highly vascularised so NO will go to the heart quickly, IF it is taken through GI system it will be degraded and will interact with other proteins causing modifications to them which will result in losing the purpose of the drug. some drugs are deactivated or degraded by liver or intestines, others by enzymes. Some hormones, like insulin, are degraded by first pass metabolism by enzymes present in the stomach if they reach it, so we give them subcutaneously to avoid that. **Insulin disrupts the stomach when present in it. NOTE: all drug examples that are mentioned in the sheet are just to make the mechanism clearer and I mentioned them as the doctor did. Sorry for any mistakes. "Love your self and be proud of everything that you do, even your mistakes. Because even mistakes mean you're TRYING" The End