General Principles of Pharmacology PPT PDF

General Principles of Pharmacology Gary O. Rankin, Ph.D.  Physicochemical Properties of Drugs Molecular Size – How big is the drug? Solubility - Degree of fat and water solubility. Overall polarity determines solubility. Charge (ionic character) – Determined by acidic,...

General Principles of Pharmacology Gary O. Rankin, Ph.D.  Physicochemical Properties of Drugs Molecular Size – How big is the drug? Solubility - Degree of fat and water solubility. Overall polarity determines solubility. Charge (ionic character) – Determined by acidic, basic or neutral character of drugs.  Molecular Size Determined by the number & type of atoms in the drug molecule Determined by how atoms are arranged in space (straight chains, branched chains). Stereochemistry. Important for passing through pores (e.g. channels) and spaces between cells.  Solubility Fat and water solubility Determined by overall polarity of drug which is a function of the chemical groups present in the molecule (-OH, -Cl, - COOH). Measured by determining the partition coefficient (P.C.)  Partition Coefficient P.C. measured experimentally using water and 1-octanol (represents fat or lipid) P.C. = [Drug]fat/[Drug]water P.C. > 1 ; lipophilic; hydrophobic P.C. < 1 ; hydrophilic  Weakly Acidic Drugs Weakly acidic drugs (HA) donate protons (H+) to a proton acceptor (e.g. the dissolving media) HA + H2O ↔ H3O+ + A- Acid Conjugate Base R-COOH R-COO-  Weakly Basic Drugs Weakly basic drugs (B:) accept a proton (H+) from an acid in the dissolving media. B: + H3O+ ↔ H2O + BH+ Base Conjugate Acid R-NH2 R-NH3+  Neutral Drugs Neutral drugs neither donate nor accept protons at physiological pHs. Can be neutral, uncharged drugs (e.g. C2H5OH). Can be neutral, charged drugs (R4N+ or quaternary ammonium salts).  Functional Groups in Drug Molecules Neutral uncharged – many including alcohols, aldehydes, amides, esters, ethers, ketones, halides and nitro. Neutral charged – quaternary ammonium Acidic groups – Carboxylic acid, sulfonamides, sulfonylureas, imides and ureides. Basic groups – Amines and guanidines Henderson-Hasselbach Equation HA ↔ H+ + A- Equilibrium with weak acids involve an equilibrium constant (Keq) and are pH dependent. Keq = [H+][A-]/[HA] or [H+] x [A-]/[HA] Log [H+] = log Keq - log [A-]/[HA] -log [H+] = -log Keq + log[A-]/[HA] ; Note –log X = pX pH = pK + log [A-]/[HA]  HH Equation (cont.) pH = pK + log [A-]/[HA] A- = the base form of a weakly acidic drug HA = the acid form of a weakly acidic drug pH = pK + log ([base form]/[acid form])  HH Equation (cont.) pH = pK + log [B:]/[BH+] B: = the base form of a weakly basic drug BH+ = the acid form of a weakly basic drug pH = pK + log ([base form]/[acid form])  Using the HH Equation How much furosemide (a weak acid, pK = 4.4) is ionized in plasma (pH = 7.4)? pH = pK + log ([base form]/[acid form]) 7.4 = 4.4 + log ([A-]/[HA]) 3.0 = log ([A-]/[HA]) 103/1 = [A-]/[HA] So for each 1001 molecules of drug, 1000 are ionized and 1 is unionized. > 99% ionized.  Using the HH Equation How much cocaine (a weak base, pK = 8.4) is ionized in plasma (pH = 7.4)? pH = pK + log ([base form]/[acid form]) 7.4 = 8.4 + log ([B:]/[BH+]) -1.0 = log ([B:]/[BH+]) 1/10 = [B:]/[BH+] So for each 11 molecules of drug, 10 are ionized and 1 is unionized. ~ 91% ionized.  How Drugs Cross Biological Membranes Filtration through pores Passive diffusion across lipid-like membranes (uncharged drug species) 1. Simple passive diffusion 2. Carrier facilitated diffusion Active transport across membranes (charged drug species) Minor - endocytosis  Zamek-Gliszczynski et al. Drug Metab. Dispos., 42:650-664, 2014 ABSORPTION  Routes of Administration Enteral – placing the drug into some portion of the gastrointestinal tract to be absorbed. Parenteral – placing the drug into some portion of the body other than the GI tract. Topical – placing the drug onto the surface of tissue. Enteral Administration of Drugs  Oral Administration (p.o.) Absorption occurs from the stomach and small intestine (primary site for all drugs). Absorption primarily by passive diffusion. Rate of absorption depends on many factors (dissolution rate, PC of drug, ionic nature of drug, other drugs/food).  Oral Administration (p.o.) SI has a larger surface area (>2400x) than stomach and drugs are in the SI longer than stomach (hours vs ~30 min). Drugs are carried to liver from GI tract by portal system. First pass elimination effect – extensive hepatic clearance via biotransformation  Sublingual Drug are administered under the tongue. Drugs enter the general circulation following absorption by passive diffusion. Drugs enter the general circulation before passing through the liver. Useful for drugs such as nitroglycerine that do not survive oral administration. Bad taste of many drugs limits usefulness.  Rectal Drugs are placed into the rectum where the suppository dissolves to release the drug. Drugs are absorbed by passive diffusion. Drugs enter general circulation before passing through the liver. Good for unconscious, vomiting or uncooperative patients. Parental Administration of Drugs  Subcutaneous (s.c.) Drugs are directly placed under the skin for absorption. Absorption is primarily by passive diffusion at capillary membranes. Small hydrophilic molecules can enter through capillary pores, and even large hydrophilic molecules can enter pores (slowly). (e.g. insulin) Rate of absorption depends on blood flow to the injection site; vasoconstrictors & local drug effect  Intramuscular (i.m.) Generally same characteristics as s.c. route. Can use larger volumes, more irritating drugs than with s.c. route Good route for orally labile drugs (penicillins) Depot preparations available for some drugs (e.g. contraceptives)  Intravenous (i.v.) No absorption involved as drugs are placed directly into the blood. Advantage – Rapid onset; known amount of drug delivered Disadvantage – Cannot redraw drug or retard absorption. Good for emergency situations and hospitalized patients.  Intraarterial (i.a.) Drug is placed directly into an artery leading to a specific organ or tissue. No absorption. Achieves a high localized drug concentration in the target tissue. Used primarily in cancer chemotherapy.  Inhalation Used to administer gaseous anesthetics & analgesics. Used also for illegal drug use (e.g. cocaine). Drugs must dissolve in pulmonary fluids before absorption by a passive diffusion mechanism.  Intrathecal Drug is placed directly into the spinal subarachnoid space. Used for spinal anesthesia and in central nervous system (CNS) chemotherapy (cancer or antimicrobial).  Topical Adminstration of Drugs Patches – nitroglycerin, nicotine, clonidine, contraceptives, others Dermatological and ophthalmic applications Intravaginal – antimicrobials for a localized effect.  Drug Distribution There are many factors that influence drug distribution. Physicochemical properties of the drug Biological membranes encountered Protein binding/storage Blood perfusing a given tissue Disease states Capillary Endothelial Membrane The first barrier to drug distribution Drugs leave the blood by the same processes used to enter the blood (passive diffusion & movement through pores). Special capillary beds exist – Kidney – large pores in glomerulus – Liver – lacks a complete endothelial cell lining  Blood-Brain and Blood-CSF Barriers Drugs cross the BBB mainly via passive diffusion BBB – tight junctions between brain capillary endothelial cells. Astrocyte shealth. Drugs enter CSF via passive diffusion at ventricles or via active transport (choroid plexus). Movement mainly out of CSF and into blood.  Fetal Barrier The placenta is sometimes called a barrier to the fetus. Similar to a large capillary bed; exchange of fluids and nutrients with mother. Most drugs enter the fetus.  Prostate Gland Prostatic fluid pH = 6.4 (plasma pH = 7.4) Basic drugs enter by passive diffusion and become protonated (ionized). Ionic form of basic drug can’t diffuse out of prostate and “ion trapping” occurs. Blood supply is low relative to many other tissues.  Protein Binding Occurs in plasma and in tissues. Bonds between drugs and proteins are the same as between any two molecules. Bond types include covalent (strongest; may be irreversible), ionic, hydrogen, ion- dipole, dipole-dipole, Van der Waals and hydrophobic bonding.  Protein Binding Interactions Occur when a substance (another drug, non-drug xenobiotic, endogenous substance) competes with a drug for binding to a protein. The free concentration of the drug could be increased with or without significant consequences. Important for drugs with low therapeutic ratios.  Storage in Fat Lipid soluble drugs (e.g. thiopental) Environmental chemicals (polychlorinated biphenyls, dioxins, etc.) Poor blood supply – Accumulate slowly, efflux slowly. Passive diffusion is the mechanism of uptake and efflux.  Storage in Other Tissues Bone – Drugs that can complex calcium (e.g. tetracyclines) or replace calcium in bone (e.g. lead). Non-target tissue – Kidney (aminoglycosides; cephalosporins) and fat (e.g. anesthetics) can accumulate drugs that target other tissues.  Redistribution Redistribution can terminate the pharmacological action of many drugs, especially lipophilic drugs. Initial distribution depends on blood flow to a body region; but redistribution depends on other factors.  Biotransformation A change in chemical structure caused by a living system. Also called drug metabolism. The product of biotransformation is called a metabolite. Primarily occurs in liver, but can occur in kidney, lung, nervous tissue, plasma or the GI tract (epithelial cells, gastric pH, digestive enzymes, gut flora).  Results of Biotransformation Activate an inactive drug (prodrug) Inactivate an active drug (mainly) Convert active drug to active metabolite Convert active drug or metabolite to a toxic metabolite Metabolites are normally more polar, more water soluble, and excreted faster than the parent drug.  Classes of Biotransformation Reactions Phase I Oxidation Reduction Hydrolysis Phase II Conjugation or synthesis  Microsomal Enzymes Located in smooth endoplasmic reticulum of cells. Oxidative enzymes are known as mixed function oxidases (MFO) Cytochrome P450 (CYP) enzymes. CYP is the terminal oxidase. Substrates must have lipophilic character Activity is inducible (drugs, environmental chemicals, cigarette smoke, ethanol). Percentage Of Drugs Metabolized by Phase I and II Enzymes  Nonmicrosomal Enzymes Located in cytosol and mitochondria in cells. Also in blood (esterases). Activity is generally not inducible. Percentage of Drugs Metabolized by Phase I and II Enzymes  Factors that Affect the Rate of Biotransformation Enzyme activity inducers (e.g. drugs, smoking) Enzyme activity inhibitors (competing drugs) Age Liver function/disease Nutritional state Genetics (polymorphisms) Gender  Drug Excretion Primary routes of drug excretion are biliary (in bile) and renal (in urine). Other routes of excretion include sweat, saliva, breast milk and exhalation. Drug elimination and drug excretion are not equivalent. Elimination means the drug is no longer able to produce a pharmacological effect and can include excretion.