Absorption Across the Epithelium PDF

3 Absorption Across the Epithelium ILOs By the end of this lecture, students will be able to 1. Outline the model of Victorian transport across varied epithelial tissue 2. Interpret how properties of substances affect the transfer pattern 3. Appraise the relevance of its manipulati...

3 Absorption Across the Epithelium ILOs By the end of this lecture, students will be able to 1. Outline the model of Victorian transport across varied epithelial tissue 2. Interpret how properties of substances affect the transfer pattern 3. Appraise the relevance of its manipulation to achievement of therapeutic merits TRANSPORT of SUBSTANCES ACROSS the PHOSPHOLIPID BILAYER of a CELL MEMBRANE was reviewed in the previous block VICTORIAN TRANSPORT ACROSS THE EPITHELIUM At many body sites, any substance must be transported all the way through the whole cellular sheet instead of simply through the cell membrane. Transport of this type is termed Victorian Transport. It exists through the (1) intestinal epithelium, (2) epithelium of the renal tubules, (3) epithelium of all exocrine glands, (4) epithelium of the gallbladder, and (5) membrane of the choroid plexus of the brain (6) the placenta and other membranes. The basic mechanism for such Victorian Transport is that (1) active transport through the cell membrane occurs on one side of the transporting cells / then (2) either simple diffusion or facilitated diffusion occur through the membrane on the opposite side of transporting cell. This means that the UNIDIRECTIONAL TRANSPORT of substances TRANSCELLULAR is accomplished by presence of non-uniform distribution of transporters on opposing face of a cell. In (Figure 1); Solute carrier (SLC) superfamily; are mostly influx transporters involved in secondary active or facilitated transport. ATP-binding cassette (ABC) superfamily; are efflux transporters involved in active transport. Figure 1: Illustrate different examples of Victorian Transport. SLC; Solute carrier – ABC; ATP-binding cassette Thus, entry of any substance (or drug) into a cell by secondary active transport is achieved by the SLCs and its exit out of the cell is by facilitated diffusion. Both forces are driven by energy from Na+ gradient that keeps and maintains intracellular concentration of Na+ low by the pumping action + of the ABCs. VARIABLE FACTORS THAT INFLUENCE ABSORPTION ACROSS THE EPITHELIUM  In Link to the Absorption Site: ➔ Physiological versus pathological considerations: a. Temperature: The higher the temperature, the faster the rate of diffusion. Thus, the absorption process can occur more rapidly in a person with a fever. b. Surface area: The larger the membrane surface area available for diffusion, the faster is the absorption. For example, lung air sacs have a large surface area for diffusion of oxygen from air to blood. In emphysema, there is a reduction in that surface area that slows the rate of oxygen diffusion and makes breathing more difficult. c. Diffusion distance: The greater the distance that must be crossed the longer time it takes for absorption. For example, it takes only a fraction of a second for absorption of O across 2 alveolar epithelium but in pneumonia, fluid collects and increases the diffusion distance. This prolongs its absorption time as O must move through both the built-up fluid and the 2 membrane to reach the bloodstream. ➔ Pharmacological considerations: a. Stomach acidity can affect acid-labile drugs altering their property and impairing their absorption by intestine. So, these drugs must be given as enteric-coated tablets. b. GIT Motility changes: - A delay in gastric emptying time (as during food intake) will decrease the rate of intestinal absorption of some drugs, so are better taken on empty stomach. - An increase in intestinal motility (extensive diarrhea) can decrease contact time needed for proper absorption of some drugs by the intestine; to decrease their absorption. c. Presence of efflux transporters; as P-glycoprotein (P-Gp) that extrude back some drugs to the intestinal lumen; to decrease their absorption. This is taken in consideration during: - Dosage calculation when initially administering such drugs - Dosage readjustment, when concomitant inhibitors of P-Gp are used with them that will impair their back efflux, enhancing more absorption with liability to develop toxicity. d. Presence of variable food or other drugs in intestinal absorption milieu; for instant; caffeine and Vitamin C can accelerate absorption of acetaminophen & iron, respectively. In Link to The Absorbed Substance Itself: a. Its size and molecular weight; the smaller is the size and mass of a diffusing substance the more it is readily absorbed while if larger, it will be slower and less absorbed. b. Its degree of ionization; if that substance is a DRUG, then it can exist either in an ionized (polarized) water soluble or a non-ionized (non-polarized) lipid soluble form. When in a non-ionized form (uncharged / lipophilic); the drug will pass and diffuse readily across cell membranes. When in an ionized form (weak acid or base / hydrophilic) as most drugs are, then their degree of ionization will be dependent on their pKa (i.e., the pH at which their molecule is 50% ionized and 50% nonionized state) and the pH of the site it exists and is dissolved in (whether gastric secretion, intestinal secretion, urine, bile, …. etc.). Thus, drugs can pass, get absorbed and transported when they become poorly ionized. On the contrary, they tend to accumulate in the fluid compartment they exist in, when they are most highly ionized. This simply means that: Weak acids are more absorbed in fluid with lower pH and tend to accumulate in that with higher pH, as acetyl salicylic acid, …etc. Weak bases are more absorbed in fluid with higher pH and tend to accumulate in that with lower pH as atropine, …etc. IMPACT of MANIPULATION of VICTORIAN TRANSPORT by DRUGS  REGARDING THERAPEUTIC USES The use of Ezetimibe to inhibit the selective-cholesterol transporter in enterocyte. This anti- dyslipidemic agent will block exogenous cholesterol intake to help in treatment of hypercholesterolemia, Figure 2. Figure 2: Cholesterol transporter as a target of action for ezetimibe. The use of the Gliflozins; the Sodium-Glucose Co-transporter-2 Inhibitors to block glucose reabsorption in proximal convoluted tubules back to the plasma i.e., lowering blood glucose level. This antidiabetic drugs are used in treatment of diabetes and control of heart failure manifestations, Figure 3. Figure 3: Sodium-Glucose transporter-2 (SGLT-2) as a target of action for Dapagliflozin  REGARDING DRUG INTERACTIONS [CAUSING ADVERSE EFFECTS]: The cardiac glycoside: digoxin that is of limited use to control advanced manifestations of heart failure; can develop some adverse effects when other drugs are used with it at the same time during its intake. This is due to development of interaction occurring at the level of P-glycoprotein (P-Gp) superfamily of efflux transporters. Normally Digoxin is partially extruded after absorption back to intestinal lumen and after reabsorption back to be eliminated through renal tubules. But the concomitant use of ➔ Macrolide antibiotics; as erythromycin, that inhibits the P-Gp efflux transporters will: - Increase digoxin absorption from intestine. - Suppress its elimination in urine. Yield digoxin toxicity ➔ Some anti-epileptics; as carbamazepine, that activates the P-Gp efflux transporters will: - Suppress digoxin absorption from intestine. - Enhance its elimination in urine. Decrease digoxin efficacy. __________