What would you think if I gave you a drug and said this is going to help you but I want you to know ahead of time that 50% of the dose is not affected, in fact the drug is 50% not pure. The idea of that would make you feel you want another drug. The reality of that is that a large # of drugs we give are 50% impure and the reason is b/c so many drugs we give are racemic mixtures, a 50:50 mixture of enantiomers. Most drugs that demonstrate optical activity only one isomer is pharmalogically active, so what that means is that we are giving a product where 50% of it is inactive. There are some important considerations you have to take into account when you have drugs that are optically active and what we would like to do today is take the things we have gone thru this semester where we have really ignored stereochemistry thru that whole process and talk about the times in which you need to consider aspects of stereochemistry. This has become a big issue now the FDA has pushed for drug companies to be able to characterize both isomers when giving a racemic mixture, also to force manufactures to only market the active isomer and not going with the standard practice of giving a drug which is only 50% pure.
There are also some drugs on the market as racemic mixtures that now compounds are being introduced as enantiomers and therefore this results in different doses because now you are giving a drug which is 100% active. Stereochemistry has long been recognized, Louis Pasteur was probably the 1st to state the significance of it , he said most natural organic products, the essential products of life are asymmetric? This established perhaps the only well marketed line of demarcation that can at present be drawn between the chemistry of dead matter and the chemistry of living matter. What he was trying to say is that basically the chemistry of life is highly dependent on geometric form and as a consequence stereochemistry is essential. If you look at the drugs on the market over 60% are optically active. In 1980, at least 398 drugs that were marketed as racemic mixtures. We now want to review some of the nomenclature that you never thought you would see again since organic chemistry. Remember when you talk about stereochemistry you are talking about a carbon atom which has 4 different ligands. In this case when you have four different ligands this is asymmetric and often referred to as a chiral carbon. This results in 2 mirror images that can not be superimposed. On pg.152 what is shown is an example of L(+) alanine and D(-) alanine and no matter how many times you try to twist and turn that molecule you can never superimpose the left hand side on top of the right hand side. You cannot superimpose optically active isomers, you recall from organic chemistry that when you have this type of situation that such a compound will rotate plane polarized light and one isomer will rotate in one direction and the other isomer in the other. A compound that rotates it to the right is dextrorotatory and that is signified using the term d or (+).
The Business plan on Technical Analysis & Efficient Market Hypothesis
In finance, technical analysis is a security analysis discipline used for forecasting the direction of prices through the study of past market data, primarily price and volume. Behavioral economics and quantitative analysis use many of the same tools of technical analysis, which, being an aspect of active management, stands in contradiction to much of modern portfolio theory. The efficacy of both ...
A substance that turns it to the left is levoratatory and is signified as L or (-).
You also remember when you have a pair of nonsuperimposable images like this there are different words used to describe them. Sometimes they are called optical isomers, optical antipodes, most commonly in the drug literature they are referred to as enantiomers. What is extremely important to recognize is that enantiomers are chemically identical., they have the same melting point, kp, same solubility, same lipophilicity. From a chemical point of view they are identical the only difference is there geometric configuration, that is the only place they are not identical. The other thing you will recognize is that the rotation of plane polarized light does not indicate the configuration. The absolute configuration is generally determined by X-ray crystallography and you recall that the designations for this based on the actual geometric configurations is You also recall that if you have a pure enantiomer its thermodynamically unstable and will tend to break down to give you a 50:50 mixture of 2 enantiomers. When you have such a mixture its referred to as a racemic mixture and you generally designate it as d,L or (+),(-).
The Essay on Melting Point Compound Solvent Test
Determination of Melting Points of Benzoic Acid and Benzamide and Composition Diagram of Their Mixtures PURPOSE: The purpose of this experiment is to determine the melting point of benzoic acid and benzamide and make a composition diagram for the mixtures of benzoic acid and benzamide to determine the eutectic point of the mixtures. The melting point of the given unknown will be determined using ...
A good example of that would be propranolol which is designated using as d,L-propranolol, therefore when you see that you know that this drug is a racemic mixture, that is the form in which it is marketed. If it is marketed as a pure isomer then it would only have d,propranolol or l, propranolol. Now there are some compounds that have more than one chiral center and when that happens and you rotate only one of these chiral centers you will end up with a compound that is not a mirror image of the non-inverted compound and this process is referred to as epimerization and results in the formation of diastereomers. What is impt to recognize is that diastereomers are different than enantiomers they are not only geometrically different but also chemically distinguishable. In the middle of pg.132 it just shows you 4 cinchona alkaloids that are diastereomers and 2 of which are marketed as drugs quinidine and quinine. Quinidine is widely used in the treatment of arrythimias and quinine is used in the treatment of malaria. Therefore here you have compounds that display different activity and have different physical chemical properties . This table below is just a review for you of nomenclature that you went thru in organic chemistry.
d-/l- is the rightward or leftward rotation of plane polarized light D-/L- is the rightward or leftward arrangement of molecule and has to come from x-ray crystallography data. Limited for amino acids R-/S- is the rightward/leftward rotation; so you can have a drug that is levorotatory in how it turns plane polarized light but actually has an absolute configuration that is right ward, therefore you would get this configuration R-/S- R-(-)- is levorotatory but with absolute configuration R Pharmacodynamic Significance of Stereoisomers What is shown on pg.133 is two enantiomers which have a significant different pharmacologic effect in terms of taste. This is d-carvone (caraway) and on the right is l-carvone (spearmint), The only difference here is the geometric configuration. Now how can you have compounds that are mirror images of one another and yet have such different taste? It relates to their ability to interact with receptors. For example if we have a chiral carbon and we have our 4 substituents and it interacts with the receptor designated here as 3 points on the receptor designated as B? C? D? and these are the points of interaction on the molecule. If now we look at the mirror image of that compound and try to rearrange this, we can never rearrange it in a way where we get more than 2 sites of interaction .
The Essay on Differences And Effects Of Natural And Synthetic Fertilizers
Differences and Effects of Natural and Synthetic Fertilizers At the core of the growth and germination of plants lie the nutrients they receive from the soil. The nutrients required for growth are classified into two groupings, and micronutrient's. Micronutrients are those that are needed in very large amounts, and whose absence can do a great harm to the development of the plant life. These ...
We are only going to be able to combine 2 sites at once. So now interaction with the receptor is significantly different because of this slight geometric change. That?s why geometry is important because in order to exert its effect most drugs have to interact with a macromolecule and so the geometry of the drug becomes very important in that interaction and a slight change may move from a 3 point interaction to a 2 point interaction which can have a big impact on the effect you exert. It may take a drug from being pharmalogically active to being inactive, an example of that can be seen with Ketamine. At the top of pg.134 ketamine is shown and its used widely in veterinary medicine as a local anesthetic. If you look at S-(+)-ketamine its far more potent than R-(-)-ketamine in terms of its anesthetic ability, one of the problems with R(-)- ketamine is in terms of its spontaneous motor activity and post-emergent distress. This graph gives you some measure, it shows the percent reduction in median frequency vs plasma concentration for these two isomers, the R and S isomer. You will notice that the EC50 for the S isomer is much lower than for the R isomer indicating its much more potent.
You will also notice that the Emax is substantially higher for the S ketamine than the R ketamine. So here just small different geometric configurations and you get significant differences in the pharmalogical effect. The table below just provides you with a number of examples of this, where you can see a wide range of differences. You can see drugs where there is a marked difference in the activity of different isomers. A good example of that would be terbutaline, if you look at the minus plus isomer in terms of its ability to act as a bronchodilator, you get trachea relaxation. The difference in activity of these two isomers is 3000:1, so in essence the plus(+) isomer is inactive at any given dose. Then you have a compound like propranolol if you look at the S to R in terms of its ability to block tachycardia, so its beta receptor blocking activity, you see the difference is about 100:1. Pindolol is something similar its isomers are 200:1. In contrast if you look at something like methadone and you look at ability to cause respiratory depression you see its isomers only have a difference of about 3:1. So you get a wide range of differences in isomers. You can have some isomers that display no difference in terms of one another in terms of pharmalogical activity, some which make the difference between active and inactive and all of these are the result of what is the impact of this geometric difference, can it still fit in the receptor pocket, can it still bind as tightly to the receptor.
The Essay on Difference between active and passive forms
Difference between active and passive forms Introduction Active forms Inactive forms of the sentence, the doer or the thing that is doing the action is the subject of the sentence while the one that is receiving the action is the subject of the sentence. Most of the sentences in the real world are in the active forms. It is always in the form; (Action Doer or the subject)+(Verb)+( The ...
Some drugs will go into the pocket ok but wont bind as tightly and that?s where you see small differences between isomers. Some the geometric configuration is enough that it cant even get into the receptor and that?s where you see large differences in pharmalogic effect. So there is a couple of situations that can be observed. 1) You can have enanitiomers that have identical efficacy and toxicity. 2) You can have enantiomers that have the same therapeutic and toxic effects, but differ in the magnitude, so in the first case they are qualitatively and quantitatively the same and in the second case they are qualitatively the same but quantitatively different, they have the same pharmalogic effect but different magnitude. 3) You may have a situation where one enantiomer may posses all of the pharmacologic activity while the other is essentially inactive. 4) You may also have a situation where both are pharmacologically active but they have qualitatively different effects. For example if you look at Ibuprofen, a very commonly used over the counter nonsteroidal anti-inflammatory drug, it is optically active, present as R and S. S-Ibuprofen inhibits platelet thromboxane production twice as effectively as does the racemate.
The Essay on Drug Abuse on High School Students
The hypothesis for this report is that as an individual increases drug use, their success within their education decreases. To prove this is true, there were many investigations involved in the process. Firstly, there was secondary research provided in order to see the drug use of all teenagers in Ontario, as well as dropout rates in Ontario as a whole. As well as definitions, general drug ...
The R form rcemizes to the S-form and does not cause G.I. lesions, that seems to be related to the S-Ibuprofen. One of the things that seems to be unique about the non-steroidal anti-inflammatory agents is that you can get racemetic conversions in vivo. Therefore even if you give the pure isomer you could end up with the alternative and that occurs thru the below means on pg 135. If you give R-Ibuprofen it can undergo metabolism to form an acyl CoA conjugate which then several things can happen. One it can undergo hydrolysis to give you back R-IBU or in the presence of racemase you can end up with the conversion of S-IBU as a CoA conjugate and then in the presence of hydrolase you can give rise to S-IBU. So if you give somebody R-IBU as a pure enantomer you will find that they will exhibit concentrations of S-IBU because of this conversion that takes place. This is not a reaction that commonly occurs but what this does do is wart efforts to try to give a drug that might avoid some of the toxicities. The way this was discovered is there was some early data that suggested that the gastric lesions were actually coming from the S-IBU and that R-IBU did not cause it, so when studies were done it was a surprise to find even though you gave R you ended up with S and its because of this conversion and this complicates matters when you give a pure enantiomer, even though you give a pure enantiomer it does not mean you are not going to expose the patient to the other enantiomer, there are these unusual reactions that take place.
The other type of reaction you may see is a mixed agonist activity and a good example of that is labetalol, which is a combined alpha beta blocker and there are different levels of activity in terms of the alpha or beta receptors with the different isomers. If we look at pg. 136 at the top we can see what is being compared here is the RR, SS, RS, SR isomers. What you will notice is that if you look at the alpha 1 activity the SR isomer is the most potent. If you look at the beta 1 activity you can see that the RR isomer is the most potent and if we look at beta 2 activity the RR isomer is also the most potent there. So here we have multiple activities of the drug with different potencies with different isomers.
The Essay on Drug Trafficking in the United States 2
Drug trafficking has become an even bigger problem than ever before in the world today. Now days, more people are buying, selling and using drugs. To people who do it, it is just a fast and easy way to get money, not knowing all the risks. Some drug dealers are even aware of the risk that comes with the action and they still do it anyways. There are many risks when dealing drugs and the risks are ...
Bibliography:
Stereochemistry Considerations What would you think if I gave you a drug and said this is going to help you but I want you to know ahead of time that 50% of the dose is not affected, in fact the drug is 50% not pure. The idea of that would make you feel you want another drug. The reality of that is that a large # of drugs we give are 50% impure and the reason is b/c so many drugs we give are racemic mixtures, a 50:50 mixture of enantiomers. Most drugs that demonstrate optical activity only one isomer is pharmalogically active, so what that means is that we are giving a product where 50% of it is inactive. There are some important considerations you have to take into account when you have drugs that are optically active and what we would like to do today is take the things we have gone thru this semester where we have really ignored stereochemistry thru that whole process and talk about the times in which you need to consider aspects of stereochemistry. This has become a big issue now the FDA has pushed for drug companies to be able to characterize both isomers when giving a racemic mixture, also to force manufactures to only market the active isomer and not going with the standard practice of giving a drug which is only 50% pure.
There are also some drugs on the market as racemic mixtures that now compounds are being introduced as enantiomers and therefore this results in different doses because now you are giving a drug which is 100% active. Stereochemistry has long been recognized, Louis Pasteur was probably the 1st to state the significance of it , he said most natural organic products, the essential products of life are asymmetric? This established perhaps the only well marketed line of demarcation that can at present be drawn between the chemistry of dead matter and the chemistry of living matter. What he was trying to say is that basically the chemistry of life is highly dependent on geometric form and as a consequence stereochemistry is essential. If you look at the drugs on the market over 60% are optically active. In 1980, at least 398 drugs that were marketed as racemic mixtures. We now want to review some of the nomenclature that you never thought you would see again since organic chemistry. Nomenclature Remember when you talk about stereochemistry you are talking about a carbon atom which has 4 different ligands. In this case when you have four different ligands this is asymmetric and often referred to as a chiral carbon. This results in 2 mirror images that can not be superimposed. On pg.152 what is shown is an example of L(+) alanine and D(-) alanine and no matter how many times you try to twist and turn that molecule you can never superimpose the left hand side on top of the right hand side. You cannot superimpose optically active isomers, you recall from organic chemistry that when you have this type of situation that such a compound will rotate plane polarized light and one isomer will rotate in one direction and the other isomer in the other. A compound that rotates it to the right is dextrorotatory and that is signified using the term d or (+).
A substance that turns it to the left is levoratatory and is signified as L or (-).
You also remember when you have a pair of nonsuperimposable images like this there are different words used to describe them. Sometimes they are called optical isomers, optical antipodes, most commonly in the drug literature they are referred to as enantiomers. What is extremely important to recognize is that enantiomers are chemically identical., they have the same melting point, kp, same solubility, same lipophilicity. From a chemical point of view they are identical the only difference is there geometric configuration, that is the only place they are not identical. The other thing you will recognize is that the rotation of plane polarized light does not indicate the configuration. The absolute configuration is generally determined by X-ray crystallography and you recall that the designations for this based on the actual geometric configurations is R- rectus or D S-sinister or L You also recall that if you have a pure enantiomer its thermodynamically unstable and will tend to break down to give you a 50:50 mixture of 2 enantiomers. When you have such a mixture its referred to as a racemic mixture and you generally designate it as d,L or (+),(-).
A good example of that would be propranolol which is designated using as d,L-propranolol, therefore when you see that you know that this drug is a racemic mixture, that is the form in which it is marketed. If it is marketed as a pure isomer then it would only have d,propranolol or l, propranolol. Now there are some compounds that have more than one chiral center and when that happens and you rotate only one of these chiral centers you will end up with a compound that is not a mirror image of the non-inverted compound and this process is referred to as epimerization and results in the formation of diastereomers. What is impt to recognize is that diastereomers are different than enantiomers they are not only geometrically different but also chemically distinguishable. In the middle of pg.132 it just shows you 4 cinchona alkaloids that are diastereomers and 2 of which are marketed as drugs quinidine and quinine. Quinidine is widely used in the treatment of arrythimias and quinine is used in the treatment of malaria. Therefore here you have compounds that display different activity and have different physical chemical properties . This table below is just a review for you of nomenclature that you went thru in organic chemistry.
d-/l- is the rightward or leftward rotation of plane polarized light (+0-/(-)- is the same as d-/l- D-/L- is the rightward or leftward arrangement of molecule and has to come from x-ray crystallography data. Limited for amino acids R-/S- is the rightward/leftward rotation; so you can have a drug that is levorotatory in how it turns plane polarized light but actually has an absolute configuration that is right ward, therefore you would get this configuration R-/S- R-(-)- is levorotatory but with absolute configuration R Pharmacodynamic Significance of Stereoisomers What is shown on pg.133 is two enantiomers which have a significant different pharmacologic effect in terms of taste. This is d-carvone (caraway) and on the right is l-carvone (spearmint), The only difference here is the geometric configuration. Now how can you have compounds that are mirror images of one another and yet have such different taste? It relates to their ability to interact with receptors. For example if we have a chiral carbon and we have our 4 substituents and it interacts with the receptor designated here as 3 points on the receptor designated as B? C? D? and these are the points of interaction on the molecule.
If now we look at the mirror image of that compound and try to rearrange this, we can never rearrange it in a way where we get more than 2 sites of interaction . We are only going to be able to combine 2 sites at once. So now interaction with the receptor is significantly different because of this slight geometric change. That?s why geometry is important because in order to exert its effect most drugs have to interact with a macromolecule and so the geometry of the drug becomes very important in that interaction and a slight change may move from a 3 point interaction to a 2 point interaction which can have a big impact on the effect you exert. It may take a drug from being pharmalogically active to being inactive, an example of that can be seen with Ketamine. At the top of pg.134 ketamine is shown and its used widely in veterinary medicine as a local anesthetic. If you look at S-(+)-ketamine its far more potent than R-(-)-ketamine in terms of its anesthetic ability, one of the problems with R(-)- ketamine is in terms of its spontaneous motor activity and post-emergent distress. This graph gives you some measure, it shows the percent reduction in median frequency vs plasma concentration for these two isomers, the R and S isomer.
You will notice that the EC50 for the S isomer is much lower than for the R isomer indicating its much more potent. You will also notice that the Emax is substantially higher for the S ketamine than the R ketamine. So here just small different geometric configurations and you get significant differences in the pharmalogical effect. The table below just provides you with a number of examples of this, where you can see a wide range of differences. You can see drugs where there is a marked difference in the activity of different isomers. A good example of that would be terbutaline, if you look at the minus plus isomer in terms of its ability to act as a bronchodilator, you get trachea relaxation. The difference in activity of these two isomers is 3000:1, so in essence the plus(+) isomer is inactive at any given dose. Then you have a compound like propranolol if you look at the S to R in terms of its ability to block tachycardia, so its beta receptor blocking activity, you see the difference is about 100:1. Pindolol is something similar its isomers are 200:1. In contrast if you look at something like methadone and you look at ability to cause respiratory depression you see its isomers only have a difference of about 3:1.
So you get a wide range of differences in isomers. You can have some isomers that display no difference in terms of one another in terms of pharmalogical activity, some which make the difference between active and inactive and all of these are the result of what is the impact of this geometric difference, can it still fit in the receptor pocket, can it still bind as tightly to the receptor. Some drugs will go into the pocket ok but wont bind as tightly and that?s where you see small differences between isomers. Some the geometric configuration is enough that it cant even get into the receptor and that?s where you see large differences in pharmalogic effect. So there is a couple of situations that can be observed. 1) You can have enanitiomers that have identical efficacy and toxicity. 2) You can have enantiomers that have the same therapeutic and toxic effects, but differ in the magnitude, so in the first case they are qualitatively and quantitatively the same and in the second case they are qualitatively the same but quantitatively different, they have the same pharmalogic effect but different magnitude. 3) You may have a situation where one enantiomer may posses all of the pharmacologic activity while the other is essentially inactive.
4) You may also have a situation where both are pharmacologically active but they have qualitatively different effects. For example if you look at Ibuprofen, a very commonly used over the counter nonsteroidal anti-inflammatory drug, it is optically active, present as R and S. S-Ibuprofen inhibits platelet thromboxane production twice as effectively as does the racemate. The R form rcemizes to the S-form and does not cause G.I. lesions, that seems to be related to the S-Ibuprofen. One of the things that seems to be unique about the non-steroidal anti-inflammatory agents is that you can get racemetic conversions in vivo. Therefore even if you give the pure isomer you could end up with the alternative and that occurs thru the below means on pg 135. If you give R-Ibuprofen it can undergo metabolism to form an acyl CoA conjugate which then several things can happen. One it can undergo hydrolysis to give you back R-IBU or in the presence of racemase you can end up with the conversion of S-IBU as a CoA conjugate and then in the presence of hydrolase you can give rise to S-IBU. So if you give somebody R-IBU as a pure enantomer you will find that they will exhibit concentrations of S-IBU because of this conversion that takes place.
This is not a reaction that commonly occurs but what this does do is wart efforts to try to give a drug that might avoid some of the toxicities. The way this was discovered is there was some early data that suggested that the gastric lesions were actually coming from the S-IBU and that R-IBU did not cause it, so when studies were done it was a surprise to find even though you gave R you ended up with S and its because of this conversion and this complicates matters when you give a pure enantiomer, even though you give a pure enantiomer it does not mean you are not going to expose the patient to the other enantiomer, there are these unusual reactions that take place. The other type of reaction you may see is a mixed agonist activity and a good example of that is labetalol, which is a combined alpha beta blocker and there are different levels of activity in terms of the alpha or beta receptors with the different isomers. If we look at pg. 136 at the top we can see what is being compared here is the RR, SS, RS, SR isomers. What you will notice is that if you look at the alpha 1 activity the SR isomer is the most potent. If you look at the beta 1 activity you can see that the RR isomer is the most potent and if we look at beta 2 activity the RR isomer is also the most potent there. So here we have multiple activities of the drug with different potencies with different isomers.
