Thomas M. Guenthner, Ph.D.Department of PharmacologyUIC College of MedicineE-418 MSB; [email protected] PRINCIPLES OF DRUG DISPOSITION AND PHARMACOKINETICSI. Routes of Administration.Enteral Special Utility Limitations/RisksOral(p.o.)#Easy #Usually safe#Economical#Relatively slow #Less predictable#First pass effect#Patient complianceSublingual#Rapid response#No first pass effect#Bypasses gi acids and enzymes#Many molecules do not penetrate oral mucosa#Not used for irritating substancesRectal#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 isotonicParenteral Special Utility Limitations/RisksIntravenous(i.v.)#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, extravasionIntramuscular(i.m.)#Moderate volumes#Faster absorption than s.c.#Not used for irritating substances#Sterile abscesses#May interfere with diagnostic tests#Precluded during anticoagulant therapySubcutaneous(s.c.)#Slower absorption than i.m.#Absorption slowed by vasoconstriction #Not used for irritating substances#Large volumes are painfulIntraperitoneal(i.p.)#Provides large absorbing surface#Primarily used on lab animals#First pass effect#Risks: adhesions, infection, injuryTopical#Useful for local effects#Poisons and toxins#Least effective for systemic absorptionIntrathecal(i.t.)#Local anesthetics/antibiotics#Bypasses BBB and blood-CSF barrier#Risks: infection, headachesPulmonary#Useful for gases, vapors, aerosols#Very rapid absorption#Not used for irritating substances#Difficult to control dose2# 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 somedrugs, a substantial portion of the dose is removed and metabolized by thehepatocytes in its first pass through the liver before the drug enters the systemiccirculation. Also evidence that significant first pass metabolism can occur in gi epithelialcells. ! The intraperitoneal route of administration may also demonstrate a significant first passeffect.! The rectal route of administration demonstrates a minimal first pass effect, because theinferior 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 ofeffect:IV > IM > SC > Oraland the following rank order describes the duration of the effect:Oral > SC > IM > IVII. Absorption.A. Definition: Movement of a drug from its site of administration to the systemic arterialcirculation.B. Movement of Drugs Across Membranes:# Active Transport: i) energy dependent; ii) saturable; iii) against anelectrochemical gradient; iv) selective carrier-mediated.# Facilitated Diffusion: i) requires NO energy; ii)saturable; iii) NEVER against anelectrochemical gradient; iv) selective carrier-mediated.# Pinocytosis: Drugs of large molecular weight (MW > 900) may enter cells bypinocytosis or phagocytosis.# Passive Diffusion: This is the MOST COMMON mechanism for drug transport. Lipid-soluble drugs permeate across the cell membrane by passive diffusionbetween 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 byoccluding zonulae (tight junctions). Drugs must pass THROUGH the cells and cannot pass around the cells.# Surface Area: Larger surface areas absorb drugs faster than smaller ones. Thegastric mucosa has villi, the small intestines have microvilli. Therefore, theintestines have a much greater surface area than the stomach. Most drugs can beabsorbed by the intestines. As a generalization, the presence of food will slow3()()pH - pK = logUNPROTONATED FORM RPROTONATED FORM RHaK=CCpoilwatergastric 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 seconddrug.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.Where Coil is the concentration of drug in the oil or organic phase, and Cwater is theconcentration of the drug in the water or aqueous phase# The extent of ionization (the pH of the environment and the pKa of the drug). # Gastric absorption: The pH of gastric juice is low (1 to 3). Weak bases will beionized and will be poorly absorbed. Weak acids will be unionized and will beabsorbed well. Furthermore, weak bases--even if they are administered IV--maycross the capillaries and the gastric mucosa and enter the gastric juice where theybecome ionized and trapped. They may be absorbed later when they reach theintestines.# Intestinal absorption: The pH of intestinal juice is more basic than gastric juice (5to 6). Here most weak bases will be unionized and will be readily absorbed. Incontrast, most weak acids will be ionized and will be poorly absorbed.45CC=1+101+1012(pH -pK )(pH -pK )1a2aCC=1+101+1012(pK -pH )(pK -pH )a1a2FORMULAS FOR CALCULATING THE RATIO OF DRUG CONCENTRATIONSIN TWO SEPARATE COMPARTMENTSFOR AN ACID:FOR A BASE:Effect of pH on Gastric AbsorptionDrug pKa% Absorbed in 1 hour (pH = 1) % Absorbed in 1 hour (pH = 8)Acids5-sulfosalicylic acid < 1 0 0salicylic acid 3.0 61 13thiopental 7.6 46 34basesaniline 4.6 6 56quinine 8.4 0 18Effect of Partition Coefficient on Drug AbsorptionBarbiturateBarbitalSecobarbitalThiopentalpKa7.87.97.6Kp (Hept/H2O)0.0010.13.3% Absorbed in 1 hour430466# Bioavailability: # The Bioavailable Fraction (usually written F) is the percentile fraction of the totaldose 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 BioavailableFraction (F) is equal to that fraction.# One can compare the Bioavailable Fractions of two preparations, or of a singlepreparation under different conditions, by comparing the areas under the curve ofplots of plasma drug concentration
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