number 11 Done by Lojayn Salah Corrected by Doctor Alia Shatnawi
The last thing we talked about in the previous lecture was the effect of a drug at a particular dose, and we took this equation: E= Emax C C+EC50 Also we took some concepts related to Graded dose-responses curve which are Potency and Efficacy. ------------------------------------------------------------------------------------------------------ In this lecture we are going to talk about another explanation or model of how drugs interact with receptors. There is a new theory which better describes the drug receptor interaction, the theory is called Two state model of drug-receptor interaction. This model postulates that a receptor, regardless of the presence or absence of a ligand, exists in two distinct conformational states, in one state, the receptor is active (Ra), in the other conformation, it is inactive (Ri). The two conformations are at equilibrium. This model or theory was postulated because receptors can do effect with absence of binding to any agonist, in another way, certain receptors has a certain degree of constitutive activity; which means activity done by the receptor itself. The recognition of constitutive activity may depend on the receptor density, the concentration of coupling molecules (in the case of a coupled system), and the number of effectors in the system. Thermodynamic considerations indicate that even in the absence of any agonist, some of the receptor pool must exist in the Ra form some of the time and may produce the same physiologic effect as agonist induced activity. The receptor spends energy to stay in the Ra or in the Ri conformations, it keeps changing its structure between the two forms until it finds a more
suitable relaxed position. That means at certain time, part of the receptor will be in the active conformation activating the cellular response even without the presence of a ligand. However, the equilibrium will be shifted by ligands that preferentially bind to one or the other conformation. So what happens when a ligand (agonist or antagonist) binds to the receptor? Ligands behavior in the two-state model: Drugs are categorized according to their intrinsic activity and resulting Emax values into: (Full Agonist, Partial Agonists, Inverse Agonists and Antagonists) each one of them affects the equilibrium in a different way. Agonists effect: let s take the doctor s example to simplify the idea: Let us suppose that there is a researcher who writes a lot of papers, if she was standing behind the table and trying to write on the computer at the same time, it will be so hard for her to write, in the other hand, if she was setting without a chair (bending her knees), she will be able to write but she won t feel comfortable, now let s say she got a chair and she was writing while setting on the chair, now she will be more effective in writing papers because she feels comfortable. That s what the drug (the agonist) does, the drug presents the doctors chair, it makes it more easy for the receptor to stay in the active form conformation, meaning that the receptor will need less energy to reach the active conformation, so the receptor will stay in that conformation for a longer period of time and there would be more activation. Now, what did we mean when we said that there is a drug that is partial/full agonist? Back to the chair example.. Let s say I bought a very expensive chair, and it was so comfortable, for sure I will be relaxed and I would write probably 10-20 pages in one hour, in the other hand, If I bought a 10 dollars chair I will write maybe 5 pages then I will stop because I m not feeling comfortable.
That is the difference between the full agonist (the comfortable chair) which will give me 20 pages of writing (full response or maximum response) and partial agonist (the other chair) which will give me 3-5 pages (25-50% of the maximum response). So, Full Agonist: is a drug when it binds to a receptor it will produce a maximal biological response that mimics the response to the endogenous ligand, full agonists bind only to the active conformation (Ra) of the receptor and stabilizes it in that conformation, so it has and intrinsic activity (efficacy Emax) of one; because it produces complete activation of a receptor at high drug concentrations. Partial Agonist: Partial Agonist cannot produce the same Emax as full agonist even if all the receptors are occupied. Question: Can the partial Agonist act as antagonist of the full agonist? When a receptor is exposed to both a partial agonist and full agonist, the partial agonist may act as an antagonist of the full agonist, it will prevent the full agonist from binding to the receptor. Let s say my full agonist is Epinephrine, it gives me the maximum response to shift the equilibrium toward the active form, if I give the patient pindolol which is a partial agonist it will compete with epinephrine on the binding site, so the Emax ( the degree of response) will be less.
What about the Antagonist? Antagonist: is a drug or a chemical that resembles the agonist in some way, but what it does, it binds to a receptor with high affinity without activating it or affecting the equilibrium, it just prevents the agonist-receptor binding. antagonist has no effect in the absence of an agonist, but can decrease the effect of an agonist when present. We can say it is a neutral antagonist; because it won t make any effect, but physiologically the effect may be reversed. Question: Why Neutral Antagonists doesn t change the conformation? Importat Because by definition it binds to the receptor, it takes the agonist place and prevents the agonist binding, so it has an inhibitory effect but it doesn t shift the equilibrium/ conformation. *** We have another Antagonist called Inverse Agonist which is a drug that binds to the receptor and directs or shifts it more toward the inactive conformation, it s not neutral antagonist. Why did we call it an agonist while its affect is antagonism, although it's not a neutral antagonist? Because we are talking about a drug that binds to a receptor and changes the equilibrium, but you should remember that it is an agonist that inverses the action and the effect, it brings it more toward the inactive conformation. When can we see an inverse agonist? We do not see a lot of inverse agonists, because they just bind with the high constitutive activity receptors (receptor that gives an effect without the presence of ligands), stabilize them and shift receptors equilibrium towards the inactive state and reducing the level of basal activity. While in drugs with low constitutive activity there wouldn t be any effect. An example about inverse agonists is the GABA (gamma-aminobutyric acid) neurotransmitter, which is an inhibitory neurotransmitter in the central nervous system, it binds to GABA receptors which are chloride channels and causes its activation, the activation of the channel will make it open for chloride ions. Activation of the GABA receptor by GABA neurotransmitter will cause suppression on the central nervous system that s why it s one of the
inhibitory NT. GABA receptors have high constitutive activity, even in the absence of the ligand it will give the inhibitory effect on the central nervous system which leads to drowsiness and depression, all of that effects are seen without the presence of GABA neurotransmitter, so I can use a drug that binds to the GABA receptors and shift it more to the inactive form (closed form). We said that GABA receptor might work without the neurotransmitter, in the same time GABA NT is always found in the brainm so GABA receptor can be activated for some period of time even in the absence of the ligand. NOTE: Most of the receptors don t have high constitutive activity, so their effect with the absence of a ligand will be almost zero. ---------------------------------------------------------------------------- Antagonism may occur in two ways: 1) Competitive Antagonists: both the antagonist and the agonist bind on the same site on the receptor in a reversible manner, the competitive antagonist prevents an agonist from binding to its receptor. 2) Irreversible Antagonists: They bind covalently to the active site of the receptor, thereby reducing the number of receptors available to the agonist. Have a quick revision of a previous concept so you can link it with the current one: There are two types of Dose-response curves: 1) Graded curve: - measured in a single biologic unit. - Continuous scale ( dose effect) - Relates dose to intensity of effect. 2) Quantal curve: we re going to talk about it later in this sheet. What would be the effect of Competitive & Irreversible Antagonists on the Dose-response curve? Competitive Antagonists will shift the agonist dose-response curve to the right (increasing EC50) without affecting Emax. - EC50 will increase and the potency will decrease, because in the presence of the competitive antagonist there will be another drug competing the agonist
on the receptor, so the chance for the agonist to bind will be less, in this case I will need to increase the concentration of the agonist to get 50% of the Emax. - There would be no effect on the Emax because when I increase the drugs concentration the chance to reach the same Emax will still be available for the receptors. **Potency is a description while EC50 is a value. Irreversible Antagonists will decrease the Emax without changing the EC50. - It will decrease the Emax because it will decrease the number of receptors available, it will bind irreversibly to the receptor and it won t get out even if the drug concentration increases, and as we said before Emax depends on the number of receptors. Example: the antihypertensive drug phenoxybenzamine which binds irreversibly to α1- adrenergic receptors (receptors needed for vasoconstriction) if there is inhibition or antagonism for that receptors, vasodilation will occur, so the effect of phenoxybenzamine on the dose-response curve of norepinephrine is shown as decrement in the Emax without changing the EC50. Quantal Dose-response curve: - Population studies. - All or none pharmacologic effect. - Relates dose to frequency of effect.
In the previous lecture when we talked about Acetyl choline we saw that when we increase the concentration there would be a graded response in the muscle contraction. In the other hand, in quantal dose-response the effect is either having contraction or not. How do we plot the curve? We compare the dose of the drug with the percentage of individuals who gave the response. For example: If I m doing a study on section 1 and I give each student Ibuprofen, then I calculated the number of students who responded to the drug and how many still feel the pain. Let s say if 30% said the pain has gone for one pill of ibuprofen (2.5 mg), I can increase the dose until I reach a dose which gives me a response in 100% of the population. ** I cannot do this for all drugs, because of toxicity, so usually in some drugs researchers try different doses on animals. - Quantal dose-response curve gives a measure for drug safety. Let s say I have a drug with toxicity and I need to determine the safest dose that can be administered by human beings without causing toxicity, I can go ahead and do quantal dose-response curve on an animal decide what is the safest dose. - Morphine (drug works on the central nervous system) has many side effects such as respiratory depression, researchers did studies on rats to see at which level (dose) Morphine will be toxic then they plotted the curve (Quantal doseresponse curve) that presents drug concentration (dose of the drug) versus number of rats who gave the therapeutic response (the response of death), so this curve made them decide what is the safest dose of Morphine drug.
There is measure called Therapeutic Index (TI) which is a measure for the safety of the drugs, it s defined as the ratio of the dose produces toxicity in half the population (TD50) to the dose that produces a clinically desired or effective response in half the population (ED50): TI = TD50 ED50 ** ED50 is an indication for number of patients that gave the response, which is the dose at which 50% of the individuals exhibit specific effect. The difference between EC50 and ED50 : - We see EC50 in graded dose-response curve while ED50 is in the Quantal dose-response curve. - In EC50, C indicates the concentration of drug seen in the plasma, while D in ED50 is the dose given to the patient. If you want to know if the curve is talking about population or response, you have to know what is your (Y axis) is individual percentage or response percentage. Question: which one of the following curves is better? The curve on the right is the more preferable because we need the therapeutic window to be large because it gives you the chance yo increase the concentration without reachin even 1% of toxicity. Don t forget to refer back to the slides Best of luckkkk Lojayn Salah