Snyder 2.

11 Diagram that talked about how a drug gets to its receptor, and in the course of getting there, places where it gets lost, go through that have nothing to do with activity of the drug All the various membranes, first has to get into the blood, then out of the blood organ, cell Now most drugs get where they have to go by process of passive diffusion Active transport specific in certain instances Slide 19 A drug must get from site of administration to receptor, a number of factors come into play How well a drug can pass a membrane Passive diffusion lipid solubility Generally speaking positive/negative charged cannot pass through membrane through passive diffusion PH difference across membrane play a key role Size of molecule, whether it has a charge or not In order for a drug to get to its site of action, has to pass through the bloodstream, there are many drugs that are not soluble very well but can be bound to proteins Physicochemical properties Extent to which a drug gets to an organ is influenced by how much blood in the organ indication of the blood flow through the organ as a function of the weight of the organ For example, if you look at the blood flow through the kidneys rather rapid, lot of blood flow, organ is pretty small Heart controls with pump, brain has fairly high blood flow, and large organ fairly, Skin and skeletal muscles In order for a drug to get any of these, depends on the blood flowing through the organ and then how well the drug can be extracted by passive/active diffusion Various way drugs can be bound Plasma proteins are very important for carrying drugs, abumin is the major protein involved in transporting drugs

Various sites on the surface where there can be reversible binding so that initially when the drug presents in the bloodstream, attaches itself to albumin, and then when it gets to the organ Can have binding to proteins in the RBC Binding to tissues There are 2 different kinds of binding Reversible gets on the protein and then off Covalent bonding endpoint dibenamine How it can inhibit a receptor site by covalent bonding to a site that would not be functional anymore as opposed to a competitive inhibitor which would be reversibly bound, would come off again Transporting to site has to be reversible Binding is a major function of plasma proteins transferring is essential, binds and transports iron iron in diet from GIT and has to get into bone marrow where you can make heme and hemoglobin Cerul plasma? similar job with copper Lipoproteins are able to transport various vitamins that are lipid soluble, A and B and steroid hormones Gammaglobulin antibodies, infection, not involved in binding drugs Albumin is the major drug transporter protein Plasma, and the drug bound to albumin, and there will always be some eq between amt bound and amt free Whats important to recognize is that the degree that this drug will be absorbed depends on the concentration on free drug Could be a lot bound to protein but the driving force that causes the free drug to move across the membrane and into the cell is the amount of free drug present and that sets the concentration gradient Free drug will go into the organ/cell, as long as the concentration is higher in the plasma than it is in the cell Once the drug gets in there will bind to various proteins in the cell as well as the receptor The drug will continue to enter the cell as long as there is a difference in concentration inside and outside When these equal no further net flow concentration

Take a pill, body will eventually excrete, when this starts to happen have very low levels in the blood but have it in the organ so at this point the free drug within the organ will be moving force to move it out into the blood again This drug will continue to leave the cell until such time as the concentrations are equal Never experience eq until your dead, always in kinetic mode As drug as being secreted from organ into the blood, the blood is flowing away never really have equal concentrations inside and outside get to point where theres little or no drug left Degree of binding is critical for many drugs Difumerol? Anticoagulant Aminothyrine European version of aspirin Dicumerol is 99% bound and 1% free, 1% responsible for anticoagulant activity Its possible for another drug to come along and displace one of these drugs from abumin, so there is more free drug in the blood 20 21 not a big difference Dicumarol 1-2 100% increase excessive bleeding Important to note interaction between drugs and how they displace them from plasma proteins because if you displace enough of the drug you may get an ADR because its present at a higher concentration than you want Cell membrane very complex Largely made up of proteins, but has a lot of lipids as well The main point is that charged chemicals cannot pass by diffusion a chemical must be uncharged because it relates to the lipid thats in the membrane Active transport Ions such as Na, K, glucose which is needed for cellular metabolism In order for these to enter the cell, must be coupled to ATP Passive transport concentration gradient Active against concentration gradient

Cant get glucose into cell without energy, wont passively diffuse Carrier Mediated Limited chemical that can react with a carrier within a membrane Carrier can be released into the cell and then can pick up more of the chemical Most drugs that we deal with are usually weak acid or weak base Weak acid is RCOOH, RNH2 weak base Natural property of acids and bases in water Acid can give a way a proton, base can be one that can acquire proton Everything on bottom is an acid, and everything on top is a base, and everything in between has a ratio of base/acid Start out with all acid - titrate with base, as we do this we begin to get more and more of the charged form as the Hydrogen ion is released always have a ratio until you get 100% form of basic and all are charged The pt where 50% is charged/ncharged numerically down to the x asis it is the pka! RNH3 is charged acid , as you add NaOH, titrate, midpoint where 50% is uncharged amino form, and 50% in c harged amino form pKA if titrated all of it it will be on the NH2 Once aniline hits the stomach, begins to acquire protons and have some NH3 unless equilibrium, The charged compounds cannot cross So the RNH2 compound will cross and drive it until equal concentrations Once the base gets into the blood begins to ionize and can have both rnh2 and rnh3+ Where will the aniline be?? Ratio not absolute amount What crosses the membrane is the uncharged form, and has to be equal Uncharged form is the numerator RNH2 want to make them equal to 1 Aniline low pH, aniline has charge, and very little of it can be absorbed from stomach to blood Whats interesting about the carboxy acid and the amine if you were to administer them by

IV m would get the same end result as if PO transported across the membrane until the equilibrium is reach and once thats reached its the pH on either side how much is transferred to the other side of the membrane The animals 1. theoretical applications to predict the actual ratios in the animal 2. go in the right direction but these animals arent at equilibrium, theyre not dead theyre alive, they hav eblood flowing, will never achieve eq, but can get a good idea of direction of flow 3. acids can be reasonably absorbed in the gastric juices to plasma, and bases cannot maybe theres something about the lining of the intestine, stomach wall thats different absorption at pH1 if you raise the ph up to 8 obviously you change the system completely because you change the degree of ionization if you decrease to the pH 8, the acids are not as well as absorbed, but bases are well absorbed. Through stomach wall a whole range of barbiturates are used for sedatives Thiopental rapidly acting Barbital slow acting These 2 drugs have the same pH, same pk? So why is barbital slower acting than thiopental Measure the time it takes to attain a ration in the CSF, that and plasma of 1 Whats the difference? look at the partition coefficient, chloroform (fat solvent) when you reach eq between the 2 layers in the separatory funnel theres 100 more times thiopental in the chloroform layer but barbital is only 5x as much 20 fold difference which you see in the time Going beyond pH and pK concerned with absolute lipid solubility key role of passamge into the brain

Kidney - metabolized to be more water soluble become increasingly charged cant be reabsorbed to reenter bloodstream like uncharged can