numbe r 9 Done by Nazek Hyasat Corrected Bahaa Najjar & mohammed AL-shrouf Docto Alia Shatnawi
HOW DO DRUGS WORK??? You know that receptor targets by the drugs, the question now how these drugs work on the receptor? Drugs either can activate or inhibit these receptors, which means they are either agonist or antagonist. *Some receptors are localised on the surface of the cells,others are intracellular receptors. *Antagonist: These words mean blocker or inhibitors, drugs can affect the receptor in certain way to give an opposite effect, so it going to inhibited or block the binding of the drugs, neurotransmitter or hormones to these receptors. *Agonist: is a drug that binds to receptor and activate it, so it initiate the signals. As example ; epinephrine (adrenaline) which bind to β-adrenergic receptor on smooth muscles Of bronchi causes dilation, we use as agonist for adrenaline drug called Abeturole which work the It work as adrenaline and use to treat asthmatic people to help them to breath. * ex- ibuprofen works through inhibiting enzyme called cyclooxygenase enzyme, so this is another drug target which is an enzyme, through inhibiting enzyme action we achieve the therapeutic effect which is analgesia, anti-inflammatory and antipruritic So these are two ways of how do drugs work either activate or inhibit the endogenous protein, the last way is that a few have unconventional mechanism of action. As example on the last way the drug we know as Gaviscon(commercial name) which is antacid used to treat the excessive acidity of the stomach, it is an alkali (calcium carbonate) chemically interacts with HCl present in the stomach so it reduce the acidity. So its not by interacting with enzyme or receptor, its another way.. HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS? Antagonists of Cell Surface Receptors A CELL SURFACE RECEPTOR that is embedded in the cell membrane and functions to receive chemical information from the extracellular compartment and to transmit that information to the intracellular compartment. There are receptors are present on the cell surface because we have certain endogenous molecules in the body that need to interact with these receptors they are not created for drugs they 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 ligand(any molecule that can bind and interact with the receptor either activate or inhibit it ) is bound to its receptor, if its agonist it will activate it ( activation means after its bound it will cause conformational changes in the receptor which will lead to transmition 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 its bind to GDP molecule, when it receives signals and activated it will bind to GTP and the 3 subunits will divide to βϒ complex and active ᾳ subunit, which will activate something else in the cell,that means the activate of these proteins will
activate further signalling events in the cell, finally will cause certain action like relaxation of smooth muscle for example. The antagonist binds to binding site of the endogenous molecules in the receptor and it doesn t turn it on, it doesn t do anything just blocked it.ex- it prevent adrenaline from activating the receptor, so the signal will stop and some of the muscle will be contracted so this is the opposite affect but it does not do so by initiating opposite mechanise in the cell, it block the action. β blockers (ex-propranolol), which block 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 occupied 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, so part of the smooth muscle cells of bronchi will not be relaxed and they will be contracted, in addition to decrease the heart rate (opposite effects ), but that doesn t mean these blockers initiated opposite machenesim of action in the cell, they don t cause something inside the cell will lead to decrease the concentration of C-AMP,they just block the action of adrenaline by preventing it from binding to receptor,so it wont be able to increase the C-AMP concentration which cause less contraction in the heart. so we use them in some cardiac conditions heart failure, angina,heart tension to decrease the effort that the heart is doing. propranolol antagonist must fits in the binding bocket of the adrenergic receptor so it has compatibility, so we have to have compatibility in shape and charge and we have to have affinity. Most antagonists attach to binding site on 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 has to 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 time then it will get off and allow to adrenaline or other suitable drug to bind, competitive means that there is a competition between the adrenaline and propranolol, so the binding will affect by the concentrations,which mean 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 >> noncompetitive antagonist We have 2 situations of noncompetitive case : 1) ᾳ1 receptors of adrenaline in the vascular smooth muscle cells (activation of it will cause vascular constriction ), suppose we have drug that bind irreversibly to it,so no matter how the concentration of adrenaline is increased, it will not be able to break that bond between the irreversible antagonist and the receptor, which mean the drug will stay in the body for long time, we can get ride of the effect of the drug by recycling the receptors ( degrading them with the bound drug and then synthesise new receptors )and this is not the optimum situation. The reversible binding is the optimum situation, because the time of action will not be so 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 receptor, you don t want that you have to have balance.
2) In this situation the drug bind to receptor but it doesn t bind to the binding site of adrenaline (the receptor has certain site for it differ from the binding site), this binding will cause conformational changes in the receptor will prevent the endogenous agonist from binding to receptor. NO matter how much the concentration of adrenaline is increased, the antagonist change the structure of the receptor so it will not be able to bind to the agonist We called this antagonist>>allosteric antagonist Allosteric antagonist either prevent the agonist from binding to receptor by changing its structure or it can bind but it will inhibit the agonist effect. Note : not all receptors consist of more than one subunit If a Patient suffer from asthma and angina, would you give him propranolol??? This drug as mentioned previously is β adrenergic blocker affect both β1 and β2 receptor, which mean it will cause decrease the heart rate which is useful in the case of angina, but it also will cause bronchoconstriction and that is very dangerous because the patient suffer from asthma also, so we must be aware and give the patient a drug with selective effect. If we used a subtype of adrenergic receptor only target β1 receptors without β2 receptor ( more selectivity) you will not worry about the side effect. β1 agonist to treat asthma and β2 agonist to treat heart faliar. *Other important example on useful antagonist is ARB. Angiotensin 2 > peptide hormone> has 2 mechanism of working > -increase the absorption of Na from renal tubules >> increase the absorption of water to the blood circulation (increase the volume )>> increase the blood pressure -it has receptors(angiotensin receptor) on vascular smooth muscle cells >> it bind to its receptor and cause 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 important drug to treat the hypertension (elevated blood pressure more than 140/100) >>>it is angiotensin receptor blocker>>it is competitive antagonist for angiotensin 2 receptors so it will bind to receptor and inhibits it s action whether it is reabsorption of Na or constriction of blood vessel so this will cause decrease in the blood pressure. It is used to treat high blood pressure, heart faliar and cardiovascular conditions. Antagonists of Nuclear Receptors **There is other receptors that present intracellurly.. Sometimes they are nuclear transcription factor, some drugs bind to them and antagonise them.. For example: Steroid hormones >> they will bind to these transcription factors >> cause activation of transcription factors to bind to DNA and initiate transcription Steroid hormones are mineral corticoid.. Aldosterone is mineral corticoid that works on certain transporter and causes reabsorption of Na and water and excretion of K >>>it increases water retention and causes edema.. To get red of the excessive water that accumulate around vital organs >>must use antagonist of aldosterone which is called spironolactone>>it binds to aldosterone receptor >> prevents this signals from happening >>prevent the complex(nuclear transcription factors) from binding to DNA and activation transcription of certain genes. What are the genes that aldosterone was transcripted it?? They are genes form transporters responsible for the reabsorption of Na
Spironolactone (antagonist )>>decrease these transports >> decrease Na reabsorption >> more Na will excrete with the urine and take with it water It works similar to competitive inhibitor but it affects intracellular process.. Enzyme Inhibitors *some drugs modulate things other than receptors like enzymes *30% of drugs targets are enzymes *cyclooxygenase enzyme for example which catalyse the formation of prostaglandin >>the drug used here is ibuprofen (aspirin) Ibuprofen binds to COX and block its action >> less product (prostaglandin )>>less of cellular effect which is inflammation and pain *another example is angiotensin converting enzyme (ACE) which convert angiotensin 1 to angiotensin 2 Angiotensin 2 can cause some elevation in blood pressure if it is presented in the body in high concentration To get rid of this excessive effect of angiotensin 2 there are 2 ways : 1)block its receptors 2)inhibit the synthesise of angiotensin 2 (reduce its amount ) by inhibit ACE The question you might ask..why I have 2 options??? Because as we know these drugs have side effects and some people cant tolerate these side effects. For example >>ACE inhibitor >>> one important side effect of it that it causes cough 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 increase cough. Ion Channel Blockers Transport Inhibitors Inhibitors of Signal Transduction Proteins Now lets talk about agonist.. *some drugs are working by activating endogenous protein Ex ; Nitroglycerin (drug for angina patient )>> it releases NO which is a gas and its small molecule so it can diffuse quickly through the membrane to go inside the cell (vascular smooth muscle cell ) then it is going to bind to 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 organ of the blood. It is used to treat angina when the heart does not work will because the heart does not get a good amount of blood. We use this drug as sublingual tablet to increase the bioavailability
If the patient take this drug orally the bioavailability will be low, so it must give 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 systematic circulation, that will cause decreasing the bioavailability so Nitroglycride takes sublingually > because the area under the tongue is highly vascularised so NO will go to the heart quickly, IF it takes through GI system it will be degraded and interact with other proteins causes modification of them and we will lose the purpose of the drug. some drugs are deactivated or degrade by lever or intestine, others by enzymes. Some hormones like insulin so they are degraded but the enzymes that is present in the stomach so we give it subcutaneously to avoid first pass metabolism NOTE: all drugs examples that are mentioned in the sheet are just for make the mechanism more clear and I mentioned them as doctor said them. Sorry for any mistake "Love your self and be proud of everything that you do, even your mistakes. Because even mistakes mean you're TRYING" The End