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LAA 9.18.2022 PHYSIOLOGICAL PROPERTIES OF DRUG MOLECULES CONDENSED NOTES How many targets does each drug Each drug encounters 10 to the 4th power or targets! encounter in the body? Pharmacodynamics: What the drug does to the body...

LAA 9.18.2022 PHYSIOLOGICAL PROPERTIES OF DRUG MOLECULES CONDENSED NOTES How many targets does each drug Each drug encounters 10 to the 4th power or targets! encounter in the body? Pharmacodynamics: What the drug does to the body Pharmacokinetics (ADME) What the body does to the drug - Absorption - Distribution - Metabolism - Excretion Remember that a drug cannot be effective unless it is able to attain a relevant concentration at its site of action. Where does absorption occur The largest site of absorption is the small intestine because it is the primarily and why? organ with large surface area to be able to maximize the absorption of drug molecules. - Some absorption occurs in the mouth, and some in the large intestine but the MOST is in the small intestine. - The stomach may potentially break down a drug because it is very acidic with pH of 2. Describe the first pass effect: Oral drugs need to pass through the liver before it can be distributed through the body. Because of the 1st pass effect, you must consider that some of the drug will be lost by metabolism carried out by the liver. How does a hydrophilic drug leave It passes through a capillary pore or is transported by a plasma protein. the blood stream? (it cannot pass easily without a capillary pore)*small molecules can pass, but large proteins cannot - There are NO capillary pores at the blood brain barrier What intermolecular force do Van der Waals forces hydrophobic tails of phospholipids interact with? Elaborate on the cell membrane Polar heads of phospholipids face and interact with watery aqueous environment located on the outer surfaces of the membrane. - this provides a hydrophobic barrier around the cell! Free passage of water and polar molecules into the interior of the cell is prevented by the phospholipid bilayer. What is the term for the action of the pharmacodynamics drug on the body?  LAA 9.18.2022 What is the action of cytochrome They increase the polarity of the drug (most of the time) P450 enzymes? - Cytochrome p450 enzymes degrade and/or modify the drug. *The products of a reaction involving cytochrome P450 enzymes are metabolites Why should we be careful about Sometimes, even when cytochrome P450 acts on a drug it is not polar metabolites? enough to be excreted from the body. We need to ensure that any metabolites that are formed do not cause harm to the body Remember, metabolites are NOT a target for drug molecules. They are the products of a reaction involving cytochrome P450 enzymes. Is the barrier created by the Hydrophobic. It prevents the passage of water and polar molecules phospholipid bilayer hydrophobic or even though the heads of phospholipids are water loving. hydrophilic? List the drug targets that have been Lipids, proteins, nucleic acids, carbohydrates. presented to us in class They are macromolecules, meaning that the drugs that are to act on a target are generally smaller than the target. Elaborate on drug targets: Drugs interact with their targets by binding to a binding site Binding sites are usually hydrophobic hollows or clefts on the surface of large molecules Interactions between drug-target involve intermolecular interactions. The functional groups on drugs are involved in binding interactions Drugs are mostly in equilibrium between being bound and unbound What is “Induced fit” This describes what happens to a binding site when it interacts with a drug. The binding interactions result in a conformational change of shape of the binding site to accommodate the shape of the drug. - Induced fit is important for the pharmacological effect of the drug What are the physiochemical Stereochemistry, acid/base properties including acid strength (pKa properties? and degrees of ionization; unionized drugs are absorbed), and water solubility including hydrogen bonds and ionization What is the normal MW for effective 200-500 for synthetic drugs drugs? - C, H, N. O. P, S, Br, Cl, I, and sometimes B. Describe the decorated scaffold A way of drawing a drug molecule model Use this model to project functional groups in proper 3D relationships to bind their targets. Convenient when diagramming alterations to functional groups. Many drugs do not have a central scaffold. What 2 important factors control the 1. The static (fixed) arrangement of groups around a stereo genic 3D structure of a drug molecule? center (think of the wedges and dashes we drew in organic chemistry) 2. Conformation of the molecule, which often changes because conformation is dynamic Hybridization This is a way to describe the different states that carbon atoms can be in terms of # of s and p orbitals 2  LAA 9.18.2022 - There are 3 hybridization states for carbon. 1. Sp3 : fully saturated. Tetra valent. Tetrahedral arrangement of attached groups. When oxygen is the central atom, oxygen has this hybridization when it has 2 functional groups and 2 lone pairs (oxygen only forms 2 bonds). Nitrogen has this hybridization when it is bonded to 3 functional groups and one lone pair (nitrogen forms 3 bonds). 2. Sp2 : unsaturated, trivalent, trigonal planar arrangement of attached groups. Nitrogen atom’s Sp2 hybridization is trigonal planar 3. Sp: unsaturated, di-valent, and linear arrangement of attached groups Stereoisomerism at Sp2 centers (there A stereoisomer has the same molecular formula, but a different 3D are 2 substituents) orientation of atoms. Sp carbons have no stereoisomerism because *There must be a pi bond there is no different 3D way to orient the atoms Cis: substituents are located on the SAME SIDE of the pi bond Trans: substituents are located on opposite sides of the pi bond E/Z E = opposite sides of the pi bond. Entegegen= German for opposite. - Use E and z when there are Zusammen = German for together more than 2 substituents: Z= together (same side of the pi bond) typically, there’s 4 R/S R: clockwise Assign priority S: counterclockwise Put the lowest priority in the back Define enantiomer: Non-superimposable mirror images - The same chemical and physical properties such as melting point - Different biological properties such as binding affinity - The more active isomer is called the eutomer - The less active isomer is called the distomer - The ratio of the eutomer and the distomer is called the eudismic ratio Occasionally, different enantiomers have COMPLETELY different effects Pfieffer’s Rule As potency of the eutomer, increases, the greater the eudismic ratio becomes. Define diastereomers: Non-superimposable, non-mirror images. - Different chemical properties - Different physical properties - Different biological properties - Completely different compounds Interactions with racemic drugs These give rise to two separate interactions of different energies. What is a conformational isomer? Isomers of a single compound that are related by changes in rotations around single (freely rotating) bonds or interconversion of ring 3  LAA 9.18.2022 conformations Typically, there is a bioactive conformation, the conformation that properly presents the pharmacophore to the receptor What is a weak acid? An acid with a higher pKa. Examples of weak acids include acetic acid, citric acid, nitrous acid. What is equilibrium determined by for Equilibrium is determined by the strength of the acid or the base a bronstead acid. - Favors the side of the reaction where the the proton will be added to the stronger base. An example of a strong base is triethyl amine. pKa The affinity for hydrogen atoms. Once pH goes below pKa (meaning that the pKa is larger than the pH), we will be adding protons. When pH is greater than pKa, we will be losing protons because the affinity for hydrogen atoms is low at at lower pKa pKa is used for convenience, the -log of Ka. Ka is the acid dissociation constant which determines what a molecule will do at a specific pH. For a weak acid, a lower pKa means a stronger acid. Because this means that the pH will be greater than the pKa and we will be having a low affinity for hydrogen atoms which means that weak acid will be more likely to donate its protons. Proton donation is what makes something an acid. Ka Ka = [ionized]/[unionized], so pKa is the -log of that Ionization: An ionized drug will be more water soluble, however it will not absorb well through the cell membrane due to the phospholipid bilayer An unionized drug will be more lipid soluble, thus it will be able to absorb well through the cell membrane phospholipid bilayer. Remember, the phospholipid bilayer allows small nonpolar molecules in An acid will not ionize in an acidic solution A base will ionize in an acidic solution A base will not ionize in a basic solution An acid will ionize in a basic solution Describe the characteristics of Phenol is an acid. It is a proton donor, and its pKa is 9-11! This acid will phenol have almost no ionization the stomach, were the pH is 2. Because as we have learned, an acid will not ionize in an acidic solution. The conjugate base of phenol is phenolate. Describe the characteristics of Arylamine isa base. It is a proton acceptor with a pKa of 9-11. This base arylamine will have almost 100% ionization at the pH of the stomach, because bases ionize in acidic solutions. Arylamine will gain a proton, making it + charged. 4  LAA 9.18.2022 At a pH of 10, the arylamine will be 50% ionized, and 50% unionized. This is because when pH= pKa, there is a 50/50 split of unionized to ionized The conjugate acid of arylamine is arylammonium, (the + charged molecule that is formed when the arylamine is put into the acidic conditions of the stomach). Which amino acids are – charged Cysteine and tyrosine and acidic with high pKa s? Which amino acids are charged and Aspartic acid, glutamic acid acidic with low pKa’s Which amino acids are basic Arginine (pKa =12.5), lysine (pKa =10.5), histidine (pKa =6) pKa and pH are equal when? When [A-]=[HA], when the concentration of ionized drug is equal to the concentration of unionized drug Which amino acids would be fully The basic ones. This is because bases will ionize at acidic pH ionized at stomach pH of 2? Fill in the blank: A_____ will ionize at Base, acidic an acidic pH Fill in the blank: ______ will ionize at a An acid basic pH Describe Bulk Flow Transfer This is the method in which drugs move around the body. - This is independent of drug structure. This happens when the drug has just been absorbed into the circulatory system, it is not yet time to move into cells. Describe Diffusional Transfer This is how drugs move into cells. Diffusional transfer is the transfer of molecules across non-aqueous barriers such as the cell membrane. - Dependent on the structure of the drug molecule! - Sometimes transporters are needed for diffusional transfer Log P A window that allows for both: 1. hydrophilicity to be able to distribute into the aqueous environment of the blood and cytosol 2. lipophilicity to be able to diffuse across the plasma membrane and into a cell. There is a rule of thumb for solubility. - If less than 0.5, then the molecule is water soluble - If greater than 0.5, then the molecule is water insoluble. Because a large P value indicated hydrophobicity so a large log P value is going to indicated water insolubility. Describe the partition coefficient P. It describes the hydrophobicity of a molecule. If you increase the concentration of drug in octanol (fat) you will increase P value. P indicates high hydrophobicity 5  LAA 9.18.2022 Equation: partition coefficient = [drug in organic material:octanol, olive oil, or benzene]/[drug in water or phosphate buffer at pH 7.4] Ideal P value is greater than negative 3 and less than positive 5. - In between -3 and +5 π Π is the hydrophobic substituent coefficient. It measures the contribution that a functional group makes to the partition coefficient, P. π is important because it identifies specific regions of a drug molecule that might interact with hydrophobic regions in its binding site Calculate π using this equation: π = logP of x, the monosubstituted derivative − logP of H, the standard compound What does a (+) π value indicate The substituent makes a greater contribution to the hydrophobicity, it is more hydrophobic than H, the standard compound Examples: carbons, both aliphatic and alkene -phenyl, chlorine, S What does a (-) π value indicate The substituent is limiting the hydrophobicity because it is less hydrophobic than H, the standard compound Examples: O2N both aromatic and aliphatic, N (amine), O (phenol, ether, hydroxyl) A water-soluble compound typically Less than 0.5 has a log P value of ______ than 0.5? Why do drugs need to be So they can be distributed throughout the body hydrophilic? Why do drugs need to be So they can diffuse across the cell membrane hydrophobic? What is log D used for? Log D is used to describe the compounds with ionizable groups. It is more accurate than Log P What 2 factors determine Clearance and absorption %. Bioavailability tells us how much to dose bioavailability? so that we can achieve an effective amount of unbound drug to do pharmacodynamic work on the body. Clearance (CL) Rate of removal of the drug from the body. Clearance determines the maintenance dose rate in PK class. Given as a rate, (Liters/hour) Volume of distribution: Theoretical volume into which a drug is disseminated (given as L). Remember to multiply by the weight of the patient if given as L/Kg. Lipinski’s Rule of 5: if the drug meets 2 or more of these criteria, then it is 1. If it has more than 5 hydrogen bond donors such as OH or NH bad. It would be very unlikely to be groups an orally active drug molecule. 6  LAA 9.18.2022 2. If it has more than 10 hydrogen bond acceptors such as N or O atoms 3. If it has a molecular weight greater than 500 g/mol 4. If it has a Log P greater than 5. Log P is the partition coefficient. Determined by log [oil phase]/[aqueous phase] What factors are related to drug Log P, Protein binding, clearance, and bioavailability are all related to structure? drug structure How many targets does each Each drug encounters 10 to the 4th power of targets! drug encounter in the body? This is STUDENT GENERATED material. Please refer to the professors' original content for clarification on any topics. These materials cannot be used as an excuse for getting a question wrong on any exam, quiz, or other assignments. 7