Principles of Drug Action PDF

Principles of Drug Action Physiochemical Properties of Drug Absorption and Membrane Transport Lecture #21  Medicinal Chemistry Drug Drug...

Principles of Drug Action Physiochemical Properties of Drug Absorption and Membrane Transport Lecture #21  Medicinal Chemistry Drug Drug Distribution; Absorption: Physicochemical Physiochemical properties Discovery Properties of Drugs-1 of Drug Absorption and Optimization membrane transport Functional Group (FG) & Acidity and Basicity of FG Development (Drug Target) Physicochemical Properties Enzymes of Drugs-2 and 3 Receptors - Forces Involved in Drug-Receptor Remaining Key Questions: Interactions - Chirality How Drugs Are Absorbed? - Salts, Solubility How new drugs can be designed for better absorption? Chemical strategies for getting drugs to the target  Learning Objectives Primary processes involved in the absorption of a drug into the body. What barriers does the drug need to pass through? – Have to adjust the chemistry of the drug to overcome the barriers. Calculate the acid form or base form of the ionized drug at different pH. Explain the physicochemical properties of drugs that influence their movement through biological membranes and barriers. Understand and apply Lipinski’s rule of five and Veber’s theory to the analysis of drug molecules for potential effectiveness in orally administered drugs. Explain the role of membrane transporters in drug absorption 1. Movement of the drug through the GI tract Systemic circulation---to site of action Systemic circulation Pre-systemic metabolism— “First pass” elimination  1. GI tract/Oral Absorption 1. Oral Drug Absorption: GI tract Orally taken drugs must cross the gut wall to reach the blood supply Most orally active drugs pass through the cells lining the gut wall Thus, drugs are required to cross two fatty cell membranes Balance of hydrophilic/hydrophobic character is required Polar acidic drugs can be targeted vs gut infections Processes occur along with drug absorption when drug molecules travel down the gastrointestinal tract and the factors that affect drug absorption. (Textbook)  1. GI tract/Oral Absorption 2. Biological Membrane 2. Biological Membrane is made of phospholipid bilayer. The sequence of events in drug absorption from formulations of solid dosage forms (Textbook). The cytoplasm of a cell is surrounded by a non-aqueous phase, the membrane. Integral proteins are embedded in a lipid bilayer. Drugs need to be both aqueous-soluble (hydrophilic) and lipid-soluble (lipophilic).  2. Biological Membrane The basic structure of an animal cell membrane (from the textbook) https://www.youtube.com/watch?v=Pfu1DE9PK2w  2. Biological Membrane The structure of the membrane is primarily determined by the structure of the lipids of which it is comprised The principal classes of lipids found in membranes are neutral cholesterol and the ionic phospholipids, e.g. phosphatidylcholine. All of these lipids are amphipathic, which means that one end of the molecule is hydrophilic (water soluble): the hydroxyl group in cholesterol; the ammonium groups in the phospholipids, and the other end is hydrophobic: the steroid and hydrocarbon moieties. Agents interacting with cell membrane lipids Exterior High [Na+] Phospholipid Bilayer Interior High [K+] Pharmacist Alert Agents interacting with cell membrane lipids Drugs acting on cell membrane lipids - Anaesthetics and some antibiotics Action of amphotericin B (antifungal agent) - builds tunnels through membrane and drains cell Hydrophilic OH Hydrophilic HO O Me OH O OH OH OH OH O OH HOOC Me H Hydrophilic Me Me O O Hydrophobic region NH2 HO HO Pharmacist Alert Agents interacting with cell membrane lipids TUNNEL HO2C OH OH CO2H Sugar Sugar OH HO OH HO OH HO OH HO OH HO OH HO OH HO Polar tunnel formed CELL MEMBRANE Escape route for ions OH HO OH HO OH HO OH HO OH HO OH HO OH HO Sugar Sugar HO2C OH CO2H OH  3. Mechanisms of Drug Absorption Membrane Transport Mechanisms of membrane transport. Transport mechanisms most commonly used by therapeutic agents include passive diffusion and facilitated transport.  3. Drug Absorption 3.1. Transcellular absorption 3.1. Transcellular (Through the membrane) 3.1.1. Down the concentration gradient (passive) Diffusion: drug molecules penetrate the membrane by virtue of their solubility in the lipid bilayer; usually directly proportional to the magnitude of the lipid:water partition coefficient of the drug. (Non-specific, anything appropriately lipophilic) Channel transport (specific for certain molecules, binding recognition) Carrier-mediated (passive) transport (specific for certain molecules, binding recognition)  3. Drug Absorption 3.1.1. Simple Diffusion and Membrane Channels There are a number of useful routes of drug administration, but almost all require that the drug cross one or more biological membranes to reach its site of action. A B (A) Simple diffusion. (B) Membrane channels.  3. Drug Absorption 3.1. Transcellular absorption 3.1.Transcellular 3.1.2. Active transport (Through the membrane) 3.1.2. Up the concentration gradient (active, requires energy) Carrier mediated-active transport: occurs against a concentration gradient or an electrochemical gradient; can become saturated at high concentration Specific for certain molecules, binding recognition  3. Drug Absorption 3.1. Transcellular 3.1.2. Active transport 3.1.2. Active Transport Active transport through transporter proteins (specific, saturable; Fe in gut; L-DOPA at blood-brain barrier; anion/cation transport in kidney)  3. Drug Absorption 3.1.2. Active transport 3.1. Transcellular 3.1.2. Active Transport The drug must have affinity for the carrier. Membrane passage via transport mechanisms is subject to competitive inhibition by another substance possessing similar affinity for the same carrier.  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Cell Cell Membrane Transport RECEPTOR Membrane Protein Cell  Pharmacist Alert Agents blocking Transport Proteins Examples Me CO2Me N Cocaine H H O CO2Me H C NH O Reuptake inhibitor for serotonin in Methylphenidate central nervous system (Ritalin) Causes euphoric effects Reuptake inhibitor for Reuptake inhibitor of noradrenaline noradrenaline and dopamine in the peripheral system Used to treat attention deficit Suppresses hunger hyperactivity disorder Agents binding to transport proteins prevent re-uptake of neurotransmitters (e.g. dopamine, serotonin, noradrenaline) Results in increased levels of affected neurotransmitters Results in a similar effect as using an agonist for neurotransmitters  Pharmacist Alert Agents blocking Transport Proteins N Examples H N Desipramine Me Me H O N H Example of a tricyclic F3C Fluoxetine antidepressant (Prozac) Non-selective reuptake inhibitor for noradrenaline Selective serotonin reuptake Principle treatment for inhibitor (SSRI) depression from 1960-1980 Used as an antidepressant MeO Reboxetine Me OH N Venlafaxine O Me OMe Selective noradrenaline N reuptake inhibitor Dual noradrenaline and H (SNRI) serotonin reuptake Used as an inhibitor antidepressant since Used as an antidepressant  Pharmacist Alert Agents blocking Transport Proteins Examples Me Reuptake inhibitor for noradrenaline and dopamine Cl N Used as an antidepressant and H O to aid smoking cessation Bupropion (Zyban) NMe2 Reuptake inhibitor of serotonin, Me noradrenaline and dopamine Cl Used as an anti-obesity agent Me Sibutramine 3.1. Transcellular absorption 3. Drug Absorption 3.1. Transcellular (Through the membrane) Also passive Active transport can move UP the concentration gradient. Passive diffusion and passive transport only move DOWN the concentration gradient.  3. Drug Absorption 3.1. Transcellular Active vs. Passive Transport Saturable Requires protein receptor: carrier, or channel  3. Drug Absorption 3.2. Paracellular 3.2. Paracellular Absorption (Pass in the space between cells) Dependent on size of drug (Mwt less than 200) vs. size of pore (Non-specific, anything appropriately sized) Passive: down the concentration gradient, or electrochemical gradient NOT move through lipid Nanoparticle Characteristics o Smaller in size o Solubility o Different physical and chemical properties compared to small- molecule drugs Pharmacist Alert Enhanced Permeability and Retention (EPR) o This effect is the driving force of nanocarrier in the tumor tissues o Utilizing the passive mechanisms of EPR is a critical design parameter of nanocarrier delivery to tumors o The pore size in endothelial https://www.researchgate.net/figure/A-schematic-representation-of-the- Enhanced-Permeability-and-Retention-EPR-effect-The_fig1_347232197 walls determined the entry of NPs into the tissues. Disorganized, leaky Pharmacist Alert DOXIL o Using nanoparticles (NPs) to improve the solubility and stability of poorly water-soluble drugs o Using NPs to deliver the drugs to specific cells or organs https://www.fiercepharma.com/m-a/updated-j-j-releases-more-doxil-its-popular-can cer-med-has-been-dogged-by-supply-issues https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/overview- COVID-19-vaccines.html harmacist Alert Mechanisms of Resistance to the Effects of Anti-cancer Drugs Mechanisms of resistance can include the following: -Upregulation of the MDR efflux pumps -Decreased cellular uptake (if the anticancer drug requires a transporter for cellular uptake) by downregulation of uptake transporters. -Increased concentration of cellular target (enzyme, structural protein) or a mutated Pharmacodynamic target (reducing binding affinity) Mechanisms of Resistance -Detoxification of the reactive species of the drug by glutathione  4. Partition Coefficient 4. Partition Coefficient (P) A reasonable model for passive transport to the site of action would be the ability to partition between a lipid membrane and water, expresses as P (or log P).  4. Partition Coefficient 1-Octanol/Water The model would be the solubility of the compound in 1-octanol, which simulates a lipid membrane, relative to that in water (the model for the cytoplasm). 1-Octanol has a long saturated alkyl chain and a hydroxyl group for hydrogen bonding. This combination of lipophilic chains, hydrophilic groups, and water molecules gives 1-octanol properties very close to those of natural membranes.  Lipophilicity and Partition 4. Partition Coefficient Coefficient The movement of molecules from one phase to another is called partitioning. The greater the value of P, the higher is the lipid solubility of the solute. The partition coefficient is a measure of the relative affinities of the solute for an aqueous or non-aqueous or oil phase. Drug pairs in which chemical modification enhances lipophilicity.  From a practical viewpoint, drugs must exhibit a balance between hydrophilicity and lipophilicity.  5. Blood-brain barrier (BBB) 5. Blood-Brain Barrier (BBB) One of the most important membranes is known as the blood-brain barrier. Membrane that surrounds the capillaries of the circulatory system in the brain and protects it from passive diffusion of undesirable polar chemicals from the bloodstream. It also can block the delivery of the central nervous system drugs to their site of action. harmacist Alert Prodrugs to improve BBB membrane permeability Trojan Horse Strategy Prodrug designed to mimic biosynthetic building block Transported across cell membranes by carrier proteins Example -Levodopa for dopamine HO CH2 HO CH2 CO2H CH2 C H NH2 NH2 HO HO Dopamine Levodopa Useful in treating Parkinson’s Disease More polar amino acid Too polar to cross cell membranes and BBB Carried across cell membranes by carrier proteins for amino acids Decarboxylated in cell to dopamine 50 harmacist Alert Prodrugs to improve BBB membrane permeability Blood Brain supply cells H2N COOH H2N COOH L-Dopa Enzyme H2N Dopamine BLOOD BRAIN BARRIER 51  6. Lipinski’s Rule 6. Lipinski’s Rule of Five for oral bioavailability The rule derives its name from the fact that the relevant cutoffs are multiples of 5. The rule of five states that orally absorbed drugs tend to obey the following characteristics – Molecular weight less than 500. (But may be higher if other characteristics are met) – Calculated log P less than 5. (Most drugs with good oral bioavailability have Log P values less than 5.) – No more than 5 H-bond donors (expressed as the sum of OH and NH groups). – No more than 10 H-bond acceptors (expressed as the sum of N and O atoms). The rule was developed by a scientist from Pfizer after analyzing compounds from the World Drug Index. Not foolproof - several exceptions Lipinski’s ‘rules’ are really guidelines  6. Lipinski’s Rule Known exceptions to Lipinski’s rule of 5 Antibiotics, antifungals, vitamins, amino acids, and cardiac glycosides are an exception because they often have active transporters to carry them across membranes, so lipophilicity is not relevant. – Example: Lisinopril (an antihypertensive), via dipeptide transporters To get a drug across the blood-brain barrier, the upper limits really should be 3 H-bond donors and 6 H-bond acceptors. Very small molecules (MW < 200) that pass through paracellular junctions. http://faculty.missouri.edu/~gatesk/LipinskisRule.pdf  7. Veber Rule 7. Variation on Lipinski: Veber Rule (2002) Molecular flexibility is important to drug absorption – Too many rotatable bonds are bad for absorption – Less than or equal to 10 rotatable bonds The polar surface area of the molecule plays a role – Replace the number of H-bonding groups Molecular weight is not a factor in Veber’s analysis Rotatable bonds were Total no. of HBDs and HBAs ≤ 12 defined as any single bond, Number of rotatable bonds ≤ 10 not in a ring, bound to a nonterminal heavy (i.e., non- or hydrogen) atom. Excluded from the count were amide C- Polar surface area < 140 Angstroms N bonds because of their Number of rotatable bonds ≤ 10 high rotational energy barrier.  7. Veber Rule Do you predict that the compound below (MW = 663 g/mole) will have good oral bioavailability (membrane permeability to systemic circulation)? Why or why not? (Give three reasons) O H2N NHCH3 OH HN OCH3 O O N N H N N H O M. Wt = 663 Lipinski MW: No Veber H-donors: >5, Not Rotatable bonds: >>>10, Not H-acceptors: >10,Not H-donors + H-acceptors: >12,No  8. pH-partition theory 8. Diffusion of acidic and basic drugs through cell membrane lipid Membrane permeability of a drug depends on the lipophilicity of the molecule – Lipophilic compounds are non-polar and un-ionized. (In contrast, polar or ionized compounds are hydrophilic) – If a drug contains acidic or basic functional groups, only the un-ionized form will cross the membrane by passive diffusion, the ionized form will not diffuse into the lipid. – However, the pH of the aqueous solution on either side of the membrane also plays a role (pH-partition hypothesis) Acidity and Basicity of Drugs pH-Partition Theory pKa can have a profound effect on the pharmacokinetic of the drug  8. pH-partition theory Lipid solubility: weak acids and weak bases pH-partition theory pH-partition theory: extent of absorption depends on a. acid dissociation constant (pKa), b. lipid solubility (log P, partition coefficient), and c. pH of fluid at the absorption site. Uses Henderson-Hasselbach equation-- Ionized form is water soluble, un-ionized form lipid soluble. The purpose of these equations (in pharmacy) is to calculate how much is ionized vs un-ionized/% ionization.  8. pH-partition theory Importance of Ionization of Drugs Most drugs are weak acids or bases and exist in solution as both the nonionized and ionized species. The nonionized molecules are usually lipid soluble and can diffuse across the cell membrane. In contrast, the ionized molecules are usually unable to penetrate the lipid membrane because of their low lipid solubility. % ionization curve for Acid % ionization curve for Base 100 100 % Un-ionized % Un-ionized 75 75 50 50 25 25 0 0 pH pH  Pharmacist Alert 8. pH-partition theory Example 1: Absorption (diffusion) of aspirin 0.001% un-ionized 99.99% ionized Aspirin, pKa ~3.4, (weak acid) is absorbed from stomach Stomach, 99% un-ionized 1% un-ionized  Pharmacist Alert 8. pH-partition theory Example 2: Absorption (diffusion) of codeine 90% Plasma, pH 7.4 10% Codeine, pKa = 8.2, H3CO H3CO (weak base) is not absorbed until pKa = 8.2 O H H (pH-pKa) ~1 O H reach duodenum. NCH3 90%, 10% NCH3 HO HO In stomach, only ~0.00001% Lipid Mucosal Membrane un-ionized H3CO H3CO pKa = 8.2 O H H (pH-pKa) ~2 O H NCH3 99%, 1% NCH3 HO HO 99% Duodenum, pH ~6 1%  8. pH-partition theory There is an easier/faster way…. Estimation of % ionization (in your head, no calculator) Absolute Difference in pKa, pH % one form % other form 0 50% 50% 1 90% 10% 2 99% 1% 3 99.9% 0.1% 4 99.99% 0.01% How do I determine which form is which percentage??? See the plots of % ionization…..  9. Strategies 9. Strategies for Optimizing Structure for Access to Target Improve solubility and membrane permeability – optimize hydrophilic/hydrophobic balance  Functional groups are very important in solubilizing organic compounds–especially ones that can hydrogen bond with solvents.  If compounds have functional groups that are capable of intermolecular bonding or intramolecular hydrogen bonding, then the potential for water solubility is increased.  9. Strategies 9.1 structural changes 9.1. Structural changes that will increase the lipophilicity of a drug molecule These changes cause a decrease in the water solubility (polarity) – Modify the ionizable groups to the unionizable (neutral) forms  Phenols to esters or ethers  Carboxylic acids to esters or amides  Amines to amides  Reduce double bonds  9. Strategies. 9.1. structural changes 9.2. Adjust solubility 9.2. Adjust Solubility and membrane permeability 9.2.1. Adding polar groups increases polarity and decreases hydrophobic character Useful for targeting drugs vs. gut infections Useful for reducing CNS side effects Cl N N N N N S OH N H N N C O C Cl F Cl F Tioconazole Fluconazole Antifungal agent with poor Systemic antifungal agent solubility - skin infections only improved blood solubility Disadvantage of adding polar groups: May introduce unwanted side effects  9. Strategies. 9.1. structural changes 9.2. Adjust solubility 9.2. Adjust Solubility and membrane permeability 9.2.2. Varying pKa alters the percentage of the drug which is ionized Alter pKa to obtain the required ratio of ionized to unionized drug Method Vary alkyl substituents on amine nitrogens Vary aryl substituents to influence aromatic amines or aromatic carboxylic acids Disadvantage May affect binding interactions  9. Strategies. 9.1. structural changes 9.2. Adjust solubility 9.2.2. Change in pKa (outside pKa 6-9 range) N N O N O N N N N N H H O O H2N NH (I) PRO3112 N NH2 amidine Decreased basicity Antithrombotic Nitrogen locked into heterocyclic ri Too basic (not effective in absorption) tionale Varying pKa alters the percentage of drug that is ionized Alter pKa to obtain the required ratio of ionized to unionized dru  Key Facts Processes involved in the absorption of a drug into the body. Predict the ionization site of the drug in the body. Understand Log P values and interpret associated lipophilicity. Calculate the acid form or base form of the ionized drug at different pH. Understand and apply Lipinski’s rule of five and Veber theory to the analysis of a drug molecule for potential effectiveness in orally administered drugs/ oral bioavailability. Strategies to adjust water solubility and membrane permeability