PCOA - Pharmaceutical Sciences Questions and Answers Graded A+

PCOA - Pharmaceutical Sciences Questions and Answers Graded A+ What effects does change in structure and as a result biodistribution have on a drug? (Physico-Chemical Properties of Drugs) Changes the solubility, metabolism, and excretion properties of the drug within the limits of the biological target. Electrolytes Ionic/ weak acid or base Hydrogen Bonds Hydrogen bonds form between polar groups Interaction between an electronegative atom (O, N, S) and a polarized hydrogen. Polarized H is one that is bound to an electronegative atom. Water can accept and donate H-bonds. Competition between H-bonding between water molecules v. H-bonding between drug and water molecules Halogenated hydrocarbon contain C, H, and halides (CL, F, I) Alcohols Contain a hydrogen bond donor and acceptor R-OH aldehyde O=C-H pKa value Definition: a measure of the tendency to give up a proton indicates the acid or base properties of a particular functional group As pKa decreases, the better the acid, the easier it is to give up a proton. pKa of Carboxylic Acids pKa = 3-5 pKa of beta-Dicarbonyl compounds pKa = 3-5 Imide pKa = 4-5 N-arylsulfonimide pKa = 5-6 Sulfonimide pKa = 5-6 Acylurea pKa = 7-8 PKa of Phenols pKa = 8-10 Sulfonamide pKa = 9-10 Amino (base) pKa = 9-11 Contains nitrogen . Guanidino (base) pKa 12.0 Phosphoryl used in signal transduction in biochemistry Hydrogen closest to the double bonded oxygen pKa = 2-3 (resonance + electronegative atom) Hydrogen furthest from double bonded oxygen pKa = 6-7 Thiol pKa = 10 Aromatic Groups π-cloud: resonance forms - equal C-C bond lengths The π-electrons must be continuous. Follow Huckel's Rule Hückel's Rule If the # of π-electrons in the ring can be expressed as 4n+2, where n is 0,1,2,3..., then the compound is aromatic. e.g. benzene has 3 double bonds (6 π-electrons), which can be expressed as (4*1)+2 = 6, therefore benzene is aromatic. The π-electrons must be continuous. AMPHIPATHIC Compounds which have a mixture of hydrophobic and hydrophilic groups crystal packing how well molecule interacts with other identical molecules affects solubility Ionization State Water has a very high dielectric constant - it can effectively interact with ions, both positive and negative. Partition Coefficient (LogP) an experimental property of drugs, determined by partitioning the drug between two immiscible solvents: water and n-octanol. The Log of the ratio of the concentration of the drug in the organic layer versus the water layer is the partition coefficient (LogP). Representative of a compound's ability to partition into and out of biological lipids. logP = Log (conc. organic/conc. water) LogP = 0 -- equally soluble in water and organic matter LogP = +1 -- 10 x more soluble in organic matter LogP = -1 -- 10 x more soluble in water Weak Acids and Bases A proton donor and its corresponding proton acceptor make up a CONJUGATE ACID-BASE PAIR. HA = H+ + A- Remember: pKa is a measure of the tendency to give up a proton. As pKa decreases, the better the acid, the easier it is to give up a proton Henderson-Hasselbalch Equation pH = pKa + log (congugate acid conc./acid) Used to determine percent ionization of a given acid-base pair at a specific pH. Effect of Resonance on Acid-Base Properties The more Resonance = the more Stabilized spare Electrons = can handle giving up proton better = stronger acidic activity Effects of Electronegativity on Acid/Base Properties Placement of electronegative atoms next to acidic sites increase the acidity of the group (i.e lower pKa value). This effect is inductive, meaning through the sigma bond. More electronegative atoms, lower pKa. Farther the electronegative atoms from acidic site, higher pKa. How is solubility affected by the pH of a solution? Solubility Can be Enhanced or Diminished Depending Upon the pH of the Solution Based on the pKa of a compound it may be protonated or unprotonated at a given pH = more or less soluable. Will more aspirin be absorbed in the stomach, where the pH is 1.5 or the small intestines where the pH is 6.0 ? Aspirin has a pKa value of 3.5. When aspirin is in the protonated state, it is more fat soluble then when it is in the deprotonated state. Since most membranes in the body are made up of lipids and fats, most of the aspirin is absorbed in the stomach. STEREOISOMERS Organic molecules which have the same molecular connectivity but have different spatial arrangements May be 1. CONFIGURATIONAL isomers are created either by double bonds or chiral centers. They can only be changed by breaking a bond. 2. CONFORMATIONAL isomers are created by different geometerical arrangements around a bond which is free to rotate. They can be changed without breaking a bond. STEREOCHEMISTRY The study and description of stereoisomers dictates how drugs interact with their targets E/Z Isomers Different items bonded to the double bond Designation of Absolute Stereochemistry - R and S Counterclockwise (S) Clockwise (R) Enantiomers Can have different activities/ different potencies at the same target Newman projections Frequently used to determine the conformation of groups around a central bond. Drug Metabolism: Phase I Introduction of polar groups to increase water solubility Oxidation (add oxygen) Reduction (add hydrogen) Hydrolysis (breakdown) Drug Metabolism: Phase II Conjugation Reactions - Attachment of small, polar, and/or ionizable groups to Phase I metabolites to enhance excretion Protects against chemically reactive compounds or metabolites Glucuronides Mercapturic acid Sulfates (sulfanation pathway) Acetylation Amino Acids Methylation Glutathione (like electrophilic centers) Oxidation The most common phase I reaction. Catalyzed by mixed-function oxidases, monooxygenases or cytochrome P450 enzymes. Common reactions: Aromatic hydroxylation (Arenol) Benzylic hydroxylation Aliphatic hydroxylation Epoxidation of aromatic and alkenes Dealkylation of secondary and tertiary amines, ethers and thioethers Oxidation of primary amines Oxidative dehalogenation **Caution: may create electrophiles -- carcinogenic Hydrolysis Often done to of Esters and Amides Non-Specific Esterases (Liver, Kidney, Intestine) Specific Esterases (Acetylcholinesterase) Pseudocholinesterases (Plasma) Amidases (Liver Microsomes) Glucuronidation Most common conjugative pathway Glucuronyl transferases Liver, kidney, intestine, skin, lung, brain Also important in excretion of some endogenous substances, e.g., bilirubin, estrogens Pathway not well developed in neonates and children Occurs to: Carboxylic Acids, Nitrogens,