Unit-3.pdf

PHARM 134: Biopharmaceutics and Pharmacokinetics 1st Semester of A.Y. 2024-2025 Title Unit 3: DRUG ABSORPTION Introduction This chapter focuses on the anatomic...

PHARM 134: Biopharmaceutics and Pharmacokinetics 1st Semester of A.Y. 2024-2025 Title Unit 3: DRUG ABSORPTION Introduction This chapter focuses on the anatomic and physiologic considerations for the systemic absorption of a drug. Since the major route of drug administration is the oral route, major emphasis in the chapter will be on gastrointestinal drug absorption. Learning At the end of the chapter, you must have: Outcomes 1. Determined the different factors affecting drug absorption. 2. Described the various drug passages across the cell membrane. 3. Described the influence of the different physiologic factors on drug absorption. Warm-Up Which of the following affect/s drug absorption? Activity a. Route of administration b. Physicochemical properties of the drug c. Physiological factors d. All e. None Learning Inputs Drug Absorption is the transfer of drug from its administration site to the blood. Many drugs administered by extravascular routes are intended for local effect. Other drugs are designed to be absorbed from the site of administration into the systemic circulation. For systemic drug absorption, the drug may cross cellular membranes. After oral administration, drug molecules must cross the intestinal epithelium by going either through or between the epithelial cells to reach the systemic circulation. The systemic absorption of a drug is dependent on (1) the physicochemical properties of the drug, (2) the nature of the drug product, and (3) the anatomy and physiology of the drug absorption site. Lesson 1: Physiologic Factors Related to Drug Absorption A. Route of Administration (discussed in Unit 1) B. Membrane Physiology Page 1 of 13  Figure 1. Fluid-Mosaic Model by Singer and Nicolson in 1972 Nature of Cell Membrane Membranes are major structures in cells, surrounding the entire cell (plasma membrane) and acting as a boundary between the cell and the interstitial fluid. Membranes enclose most of the cell organelles (eg, the mitochondrion membrane). Cell membranes are semipermeable partitions that act as selective barriers to the passage of molecules. Water, some selected small molecules, and lipid-soluble molecules pass through such membranes, whereas highly charged molecules and large molecules, such as proteins and protein-bound drugs, do not. Cell membranes are generally thin, approximately 70–100 Å in thickness. The lipid bilayer or unit membrane theory, originally proposed by Davson and Danielli (1952), considers the plasma membrane to be composed of two layers of phospholipid between two surface layers of proteins, with the hydrophilic “head” groups of the phospholipids facing the protein layers and the hydrophobic “tail” groups of the phospholipidsaligned in the interior. The lipid bilayer theory explains the observation that lipid-soluble drugs tend to penetrate cell membranes more easily than polar molecules. However, the bilayer cell membrane structure does not account for the diffusion of water, small- molecular-weight molecules such as urea, and certain charged ions. The fluid mosaic model, proposed by Singer and Nicolson (1972), explains the transcellular diffusion of polar molecules (Lodish, 1979). According to this model, the cell membrane consists of globular proteins embedded in a dynamic fluid, lipid bilayer matrix. These proteins provide a pathway for the selective transfer of certain polar molecules and charged ions through the lipid barrier. Page 2 of 13  Transmembrane proteins are inter-dispersed throughout the membrane. Two types of pores of about 10 nm and 50–70 nm was inferred to be present in membranes based on capillary membrane transport studies (Pratt and Taylor, 1990). These small pores provide a channel through which water, ions, and dissolved solutes such as urea may move across the membrane. Membrane proteins embedded in the bilayer serve special purposes. These membrane proteins function as structural anchors, receptors, ion channels, or transporters to transduce electrical or chemical signaling pathways that facilitate or prevent selective actions. Transport Processes Across the Membranes a. Passive Diffusion no energy ü A lipophilic drug may pass through the cell or go around it. ü If the drug has a low molecular weight and is lipophilic, the lipid cell membrane is not a barrier to drug diffusion and absorption. ü Major transmembrane transport for most drugs. ü Molecules spontaneously diffuse from a region of higher concentration to a region of lower concentration. ü No external energy is expended. ü Fick’s first law Rate of Diffusion = dM = DAK (CGI - Cp) dt h Parameters D: Diffusion coefficient A: Surface area h: Membrane thickness (CGI-Cp): Concentration difference Diffusion Coefficient Related to – Size and lipid solubility of the drug – Viscosity of the diffusion medium Lipid solubility ↑ D ↑ dM/dt ↑ Molecular size ↑ D ↓ dM/dt ↓ Surface Area As surface area ↑ diffusion ↑ For example, intestinal lining surface area (villae and microvillae) are much larger than that of stomach. Thus, absorption from intestine is faster. Page 3 of 13  § Membrane Thickness Thinner membranes lead to faster diffusion e.g. membrane in the lung is quite thin. ü Factors Affecting the Rate of Passive Diffusion major transport downhill does not require energy Concentration Gradient along concetn gradient and against Degree of Lipid Solubility Surface Area of the Membrane pka of a substance ph outside and inside of the membrane Lipid/water partition coefficient Diffusion Coefficient b. Carrier-Mediated Transport Numerous specialized carrier-mediated transport systems are present in the body, especially in the intestine for the absorption of ions and nutrients required by the body. i. Active Transport low to high ü Active Transport is a carrier-mediated transmembrane process that plays an important role in the gastrointestinal absorption and in renal and biliary secretion of many drugs and metabolites. ü Requires a carrier that binds the drug to form a carrier– drug complex that shuttles the drug across the membrane and then dissociates the drug on the other side of the membrane ü An energy consuming system ü Can be saturated ü Can proceed against a concentration gradient ü Competitive inhibition possible ü Examples: Na+, K+, I-, Fe++, Ca++, hexoses, monosaccharides, amino acids, strong organic acids and bases, organic phosphates, cardiac glycosides, pyrimidine bases, B-vitamins, testosterone, estradiol, 5-FU ii. Facilitated Transport ü Requires a carrier (e.g. vitamin B12) ü Saturable ü Can’t go against a concentration gradient, just faster down-hill c. Vesicular Transport kahit solid particle ü Process of engulfing particles or dissolved materials by a cell ü Does not require a drug to be aqueous solution to be absorbed solid = phagocytosis liqui = pinocytosis endocystosis and exocytosis Page 4 of 13  ü An example of exocytosis is the transport of a protein such as insulin from insulin- producing cells of the pancreas into the extracellular space. ü The insulin molecules are first packaged into intracellular vesicles, which then fuse with the plasma membrane to release the insulin outside the cell. ü Exocytosis ü Endocytosis d. Pore (Convective) Transport ü Drug transport across tight (narrow) junctions between cells or trans- endothelial channels of cells is known as paracellular transport. It involves both diffusion and the convective (bulk) flow of water and accompanying water-soluble drug molecules through the paracellular channels. ü Drug molecules dissolved in the aqueous medium at the absorption site, move along with the solvent (solvent shift) through the pore. ü Ions as well as neutral molecules may pass through the pores ü Very small molecules (such as urea, water, and sugars) are able to cross cell membranes rapidly, as if the membrane contained channels or pores. ü Although such pores have never been directly observed by microscopy, the model of drug permeation through aqueous pores is used to explain renal excretion of drugs and the uptake of drugs into the liver. ü Examples: inorganic & organic electrolytes (MW 150- 400), ionized sulfonamides, ions of opposite charge of pore lining e. Ion-Pair Formation ü Drugs link up with an oppositely charged ion forming a neutral molecule which diffuses easily across membranes ü Strong electrolyte drugs are highly ionized or charged molecules, such as quaternary nitrogen compounds with extreme pKa values. ü Strong electrolyte drugs maintain their charge at all physiologic pH values and penetrate membranes poorly. ü When the ionized drug is linked up with an oppositely charged ion, an ion pair is formed in which the overall charge of the pair is neutral. This neutral drug complex diffuses more easily across the membrane. ü For example, the formation of ion pairs to facilitate drug absorption has been demonstrated for propranolol, a basic drug that forms an ion pair with oleic acid, and quinine, which forms ion pair with hexylsalicylate2) Page 5 of 13 C. Gastrointestinal Physiology The Enteral System a. Secretion, which includes transport of fluid, electrolytes, peptides and proteins into the lumen of the alimentary canal. b. Digestion is the breakdown of food constituents into smaller structures in preparation for absorption. c. Absorption is the entry of constituents from the lumen of the gut into the body The Gastrointestinal Tract 1. Oral Cavity pH is about 7 main secretion: Saliva also secretes mucin 2. Esophagus pH between 5 and 6 has no true sphincter valve, but there is a sphincter action in its lower part which prevents acid reflux there is very little drug dissolution in the esophagus Page 6 of 13  ph is for stability of drug 3. Stomach diffusion of drug is affected by pH of drug pH (fasting = 2-6; presence of food = 1.5 - 2) the stomach wall is highly muscular and is innervated by the vagus nerve biggest nerve to supply blood the mucous membrane of the stomach is divided by a system of furrows (gastric pits), which are again divided by tiny grooves 3 Glands: Mucous glands - secrete mucous Chief cells (zygomatic cells)* - secrete pepsin and other enzymes Parietal cells* - secrete HCl 4. Small Intestines where most absorption takes place 3 parts: Duodenum o pH is 6-6.5 sphincter valve o the complex fluid medium of duodenum helps to dissolve many drugs with limited aqueous solubility o site of ester prodrugs hydrolysis o proteolytic enzyme Jejunum Ileum o pH is about 7.6 o bile secretion 5. Colon extended release drugs pH is 7.9 - 8 lined with mucin has a very limited drug absorption theophylline and metoprolol not extended release but is sbsorbed in colon 6. Rectum absorption is usually erratic, cannot pH is about 7.5 to 8 predict bioavailability of drug. 3 hemorrhoidal veins: local : laxative o inferior systemic: paracetamol o middle local: mas mataas artery: away o superior systemic: small form heart vein: back to heart D. Factors Affecting Drug Absorption in the GIT § Direct Route. Most drugs (along with CHONs, amino acid, most of drugs: direct route salts and water)enter thru villi → small blood capillaries → (polar drugs) conveyed by the superior and inferior mesenteric veins → hepatic portal vein → liver → inferior vena cava → heart → entire circulation part of lymphatic system lipid soluble § Indirect Route (via the lacteals). Most fat is taken by this route. Thoracic duct → left subclavian vein near the heart Page 7 of 13  how fast yung laman ng stomach ay ineempty niya a. Gastric Emptying Rate (GER) Factor Effect volume of meal ↑ ingested food = initially↑ GE rate then ↓ GE rate meal type fats =↓ GE rate hot foods = ↓ GE rate cold foods = ↑ GE rate osmotic pressure ↑ osmotic pressure = ↓ GE rate viscosity ↑ viscosity = ↓ GE rate drugs ↓ GE rate: anticholinergics, narcotics, analgesics, ethanol, bile salts, acidification ↑ GE rate: glycerol, NaHCO3 physiologic stressed = ↑ GE rate condition depressed = ↓ GE rate * Penicillin - unstable in acid and decompose if GE is delayed * Aspirin - may irritate the gastric mucosa during prolonged contact b. Intestinal Motility rate and time: inversely proportional Factor Effect transit time food viscosity solid food = ↓ TT low transit time = increase time ↑ viscosity = ↓ TT, ↓ rate of dissolution, ↓ rate of diffusion drugs ↓ TT: anticholinergics, anti-histamines, narcotics for dyspepsia ↑ TT: domperidone, metoclopramide physiologic stressed (anxiety) = ↓ TT (14 hrs.) condition depressed = ↑ TT (49 hrs.) regular contraction irregular mix the content movement no force s A pictorial representation of the typical motility patterns in the interdigestive (fasted) and digestive (fed) state. (From Rubinstein et al, 1988, with permission.) Fasted/Interdigestive State Page 8 of 13  § During this state, the Migrating Motor Comples (MMC) act as the propulsive movement that empties the upper GIT to the cecum. Initially, the alimentary canal is quiescent, then irregular contractions followed by regular contractions with high amplitude push any residual contents further down the alimentary canal. Small Intestine Transit Time (SITT) = 4-8 hrs. Digestive/Fed State § During this state, the MMC is replaced by irregular contractions which mixes the intestinal contents and advancing the intestinal stream toward the colon in short segments. SITT = 8-12 hrs. c. Perfusion of the Gastrointestinal Tract The blood flow to the GI tract is important in carrying absorbed drug to the systemic circulation. A large network of capillaries and lymphatic blood vessels perfuse the duodenal region and supply to git peritoneum. The splanchnic circulation receives about 28% of the cardiac output and is increased after meals. This high degree of perfusion helps to maintain a concentration gradient favoring absorption. Once the drug is absorbed from the small intestine, it enters via the mesenteric vessels to the hepatic- portal vein and goes to the liver prior to reaching the systemic circulation. Any decrease in mesenteric blood flow, as in the case of congestive heart failure, will decrease the rate of drug removal from the intestinal tract, thereby reducing the rate of drug bioavailability (Benet et al, 1976). Splanchnic Blood Flow Factor Effect Food food uptake ↑ blood flow in splanchnic area Physical hard physical work ↓ blood flow in splanchnic work area d. Absorption through the Lymphatic System Lipophilic drugs → Microvilli → lacteal or lymphatic vessels → vena cava § Absorption of drugs through the lymphatic system bypasses the liver and avoids the first-pass effect due to liver metabolism. § The lymphatics are important in the absorption of dietary lipids and may be partially responsible for the absorption of some lipophilic drugs. § Many poorly water-soluble drugs are soluble in oil and lipids, which may dissolve in chylomicrons and be absorbed systemically via the lymphatic system. Examples: Bleomycin Page 9 of 13  or aclarubicin, halofantrine, certain testosterone derivatives, temarotene, ontazolast, vitamin D-3, and the pesticide, DDT g g y e. Food on Gastrointestinal Drug Absorption extent Effects of Food on Absorption rate Decreased Delayed Increased Unchanged Atenolol Aclofenac Carbamazepine ASA Captopril Cefadrine Chlorthiazide Chlorpropamide Cefalexin Diclofenac Dicumarol Ethambutol Demeclocycline Metronidazole Griseofulvin Hydralazine Ketoconazole Piroxicam (w/ high fatty Antipyrine Levodopa Quinidine food) Tolbutamide Lincomycin Sulfadiazine Labetalol Nafcilin Sulfisoxasole Methosalem Penicillin Theophylline Nitrofurantoin Tetracycline Valproic acid Propanolol Warfarin f. GIT Microbial Flora Digoxin may be inactivated by normal flora. It may cause also pathological conditions that can affect absorption. g. Double-Peak Phenomenon Serum concentrations of dipyridamole in three groups of four volunteers each. (A) After taking 25 mg as tablet intact. (B) As crushed tablet. (C) As tablet intact 2 hours before lunch. (From Mellinger TJ, Bohorfoush JG: Blood Page 10 of 13  levels of dipyridamole (Persantin) in humans. Arch Int Pharmacodynam Ther 163:471–480, 1966, with permission.) § Some drugs, such as ranitidine, cimetidine, and dipyridamole, after oral administration produce a blood concentration curve consisting of two peaks. § This double-peak phenomenon is generally observed after the administration of a single dose to fasted patients. § Attributed to variability in stomach emptying, variable intestinal motility, presence of food, enterohepatic affected by gastric emptying recycling, or failure of a tablet dosage form. § Cimetidine may be due to variability in stomach emptying and intestinal flow rates. h. Drug Interactions Physicochemical Drug Interactions. Drugs that can interact with one another and affect each other’s or both drugs’ absorption. Drug Combination Effect Caffeine + Phenothiazines caffeine will form an Butyrophenones insoluble compound that inhibits the absorption of the two drugs making them ineffective Doxycycline + Iron-containing drugs chelate formed decreases Calcium-containing the bioavailability of both std drugs drugs Sucralfate + Digoxin reduced absorption Ketoconazole protective lining Levothyroxine stomach Phenytoin Quinidine Ranitidine Tetracycline Theophylline Fluoroquinolones Cholestyramine ℬ-blockers malabsorption + Warfarin Cholestipol + Tetracycline Penicillin G Phenobarbital Thyroid drugs Estrogen Progesterone Orlistat + Drugs that require fat decreased absorption for absorption Kaopectate + Drug decreased absorbability and for absorption bioavailability Psyllium + Digoxin reduced biovailability promote laxtive effet;Nitrofurantoin to reduced weight Salicylates Physiological Drug Interaction. One drug can affect the physiological function of the body that can affect the absorption of the second drug. Page 11 of 13  Factor Effect Laxatives increases GIT motility resulting in lesser absorption Anticholinergic Drugs decreased GIT motility Locally acting antacids affect absorption by altering pH Histamine 2 blockers Proton pump inhibitors i. Disease States Drug absorption may be affected by any disease that causes changes in (1) intestinal blood flow, (2) gastrointestinal motility, (3) changes in stomach emptying time, (4) gastric pH that affects drug solubility, (5) intestinal pH that affects the extent of ionization, (6) the permeability of the gut wall, (7) bile secretion, (8) digestive enzyme secretion, or (9) alteration of normal GI flora. Disease State Effects on Drug Absorption Patients in an advanced delay drug absorption stage of Parkinson’s disease Patients on tricyclic reduced gastrointestinal motility or even antidepressants intestinal obstructions → delays in drug antipsychotic drugs with absorption, especially with slow-release anticholinergic side products effects Achlorhydric patients many weak-base drugs are unabsorbed dapsone, itraconazole, and ketoconazole may be less well absorbed low hcl secretion or release proton pump inhibitors render the stomach achlorhydric, which may also reduce drug absorption *co-administering orange juice, colas, or other acidic beverages can facilitate the absorption of some medications requiring an acidic environment HIV–AIDS patients are rapid gastric transit time and diarrhea can prone to a number of alter the absorption of orally administered gastrointestinal (GI) drug disturbances *Achlorhydria may or may not decrease absorption, depending on the acidity needed for absorption of a specific drug, Indinavir requires a normal acidic environment for absorption. Congestive heart failure reduced blood flow to the intestine and (CHF) patients with reduced intestinal motility results in a persistent edema decrease in drug absorption Crohn’s disease effect on drug absorption is unpredictable, large intestine impaired absorption of other drugs but increased absorption of orally administered propranolol Celiac disease increased rate of stomach emptying and affected: small intestine increased permeability of the small Page 12 of 13  *although it is not intestine. Cephalexin → increased possible to make general absorption predictions about these patient Patients with significant altered drug oral absorption blood loss, hypoxemia, or intestinal ischemia *may need to consider non-enteral routes of drug administration Central Activity 1: Structured Essay Activities Please answer the question in a paragraph form. You should write one paragraph for each response: 1. Describe how high fat meals increased the absorption of griseofulvin. 2. Describe how the absorption of Digoxin is influenced by the normal flora. Assessment Quiz and Long Exam (Post- The schedule for the examination will be announced. assessment) Course Ma. Danica Ines-Ramil Facilitator Associate Professor V Pharmacy Department 09272469018 [email protected] Page 13 of 13