Thomas M Guenthner Ph D Department of Pharmacology UIC College of Medicine E 418 MSB 996 2558 tmg uic edu GENERAL PRINCIPLES OF DRUG DISPOSITION AND PHARMACOKINETICS I Routes of Administration Enteral Special Utility Limitations Risks Easy Usually safe Economical Relatively slow Less predictable First pass effect Patient compliance Sublingual Rapid response No first pass effect Bypasses gi acids and enzymes Many molecules do not penetrate oral mucosa Not used for irritating substances Rectal Unconscious patients Vomiting patients Small children Minimal first pass effect Bypasses gi acids and enzymes Irregular and incomplete absorption Not used for irritating substances Solutions must be isotonic Special Utility Limitations Risks Most rapid response emergencies Permits titration of dosage Most suitable for irritating substances and large volumes Lowest intra individual variability Greatest risks overdose anaphylaxis infection embolism vascular injury extravasion Moderate volumes Faster absorption than s c Not used for irritating substances Sterile abscesses May interfere with diagnostic tests Precluded during anticoagulant therapy Subcutaneous s c Slower absorption than i m Absorption slowed by vasoconstriction Not used for irritating substances Large volumes are painful Intraperitoneal i p Provides large absorbing surface Primarily used on lab animals First pass effect Risks adhesions infection injury Useful for local effects Poisons and toxins Least effective for systemic absorption Intrathecal i t Local anesthetics antibiotics Bypasses BBB and blood CSF barrier Risks infection headaches Pulmonary Useful for gases vapors aerosols Very rapid absorption Not used for irritating substances Difficult to control dose Oral p o Parenteral Intravenous i v Intramuscular i m Topical First Pass Effect When a drug is administered orally the drug is absorbed by the mesenteric veins These veins drain into the portal vein which flows into the hepatic sinusoids For some drugs a substantial portion of the dose is removed and metabolized by the hepatocytes in its first pass through the liver before the drug enters the systemic circulation Also evidence that significant first pass metabolism can occur in gi epithelial cells The intraperitoneal route of administration may also demonstrate a significant first pass effect The rectal route of administration demonstrates a minimal first pass effect because the inferior rectal veins drain primarily into the inferior vena cava and bypass the liver If equieffective doses are administered the following rank order describes the speed of effect IV IM SC Oral and the following rank order describes the duration of the effect Oral SC IM IV II Absorption A Definition Movement of a drug from its site of administration to the systemic arterial circulation B Movement of Drugs Across Membranes Active Transport i energy dependent ii saturable iii against an electrochemical gradient iv selective carrier mediated Facilitated Diffusion i requires NO energy ii saturable iii NEVER against an electrochemical gradient iv selective carrier mediated Pinocytosis Drugs of large molecular weight MW 900 may enter cells by pinocytosis or phagocytosis Passive Diffusion This is the MOST COMMON mechanism for drug transport Lipid soluble drugs permeate across the cell membrane by passive diffusion between the lipid molecules of the cell membrane C Absorption of Drugs by the Gastrointestinal Tract Epithelial Barriers to Drugs Epithelial cells in the GI are joined to one another by occluding zonulae tight junctions Drugs must pass THROUGH the cells and can not pass around the cells Surface Area Larger surface areas absorb drugs faster than smaller ones The gastric mucosa has villi the small intestines have microvilli Therefore the intestines have a much greater surface area than the stomach Most drugs can be absorbed by the intestines As a generalization the presence of food will slow 2 gastric emptying time and will slow the absorption of an orally administered drug Also many drugs slow gastric emptying and may slow the absorption of a second drug D Chemical Factors That Affect NON IONIC PASSIVE DIFFUSION Molecular size of the drug Solubility in water Concentration of the drug Oil Water partition coefficient Kp of the drug Kp Coil Cwater Where Coil is the concentration of drug in the oil or organic phase and Cwater is the concentration of the drug in the water or aqueous phase The extent of ionization the pH of the environment and the pKa of the drug pH pKa log UNPROTONATED FORM R PROTONATED FORM RH Gastric absorption The pH of gastric juice is low 1 to 3 Weak bases will be ionized and will be poorly absorbed Weak acids will be unionized and will be absorbed well Furthermore weak bases even if they are administered IV may cross the capillaries and the gastric mucosa and enter the gastric juice where they become ionized and trapped They may be absorbed later when they reach the intestines Intestinal absorption The pH of intestinal juice is more basic than gastric juice 5 to 6 Here most weak bases will be unionized and will be readily absorbed In contrast most weak acids will be ionized and will be poorly absorbed 3 4 FORMULAS FOR CALCULATING THE RATIO OF DRUG CONCENTRATIONS IN TWO SEPARATE COMPARTMENTS FOR AN ACID FOR A BASE C1 1 10 pKa pH1 C2 1 10 pKa pH2 C1 1 10 pH1 pKa C2 1 10 pH2 pKa Effect of pH on Gastric Absorption pKa Absorbed in 1 hour pH 1 Absorbed in 1 hour pH 8 5 sulfosalicylic acid 1 0 0 salicylic acid 3 0 61 13 thiopental 7 6 46 34 aniline 4 6 6 56 quinine 8 4 0 18 Drug Acids bases Effect of Partition Coefficient on Drug Absorption Barbiturate Barbital Secobarbital Thiopental pKa 7 8 7 9 7 6 Kp Hept H2O 0 001 0 1 3 3 5 Absorbed in 1 hour 4 30 46 Bioavailability The Bioavailable Fraction usually written F is the percentile fraction of the total dose that enters the systemic circulation With the IV route of administration 100 of the drug enters the systemic circulation and F is equal to 1 With the oral route only a fraction of the total dose enters the systemic circulation and the Bioavailable Fraction F is equal to that fraction One can compare the Bioavailable Fractions of two preparations or of a single preparation under different conditions by comparing the areas under the curve of plots of plasma drug concentration versus time F is not the only important parameter of bioavailability maximal plasma levels or concentrations Cmax can also vary for different pharmaceutical
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