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Biopharmaceutics & Pharmacokinetics-4 Journey of Oral Drugs through GIT • Drug travels through different region in GI tract Mouth Stomach Small Intestine Large Intestine • Tract is almost 4.5 m long • Each region is different in anatomy, pH, function • All these factors affect the drug absorption Mouth • Small surface area for drug absorption • Typical pH = 6.8 • Directly absorbed in to blood circulation • Drugs absorbed: • Neutral • Slightly basic • lipophilic Stomach • Bag like structure, smooth surface • Typical pH = 1.5- 3 (HCL secretion) • Acidic drugs: • Un-ionized so can be absorbed if it dissolves • Basic drugs: • Acidic environment helps in dissolution as the drugs are ionized • Ionised drug however limits absorption Why is Stomach NOT a major site for absorption ?? • Area: Total surface area for absorption is small • Nature of Epithelium: Most of the cells are secretion cells (mucus secreting) & not absorption • Gastric Residence Time: Drug stays in stomach for limited time affecting absorption Small Intestine • Major site of absorption for most of drugs • Very large surface area • Folds – Villi – Micro-villi lead to almost 600 times increase in surface area Why is Small Intestine a major site for drug absorption • Large Surface area: Structural arrangement of folds, villi & microvilli increase the surface area X 600 times • Long Length: long length results in increased total area compared to stomach • Greater Blood flow: almost 6 – 10 times greater than stomach • Favorable pH: Range is 5 – 7.5, most drugs Un-ionized in this range, increased absorption • Slow peristaltic movement & high permeability Large Intestine • Length, surface area (No Villi) very small compared to small intestine • pH : neutral or slightly alkaline • Long residence time (6-12 hr) might help in absorption of poorly soluble drugs/sustained release • Major role in absorption of water/electrolytes Physiological Factors affecting Drug Absorption • Gastric Emptying: • Passage of drugs from Stomach to Small Intestine • This movement can be rate limiting as major absorption of drugs in small intestine • Different parameters to measure gastric emptying: • Gastric empting rate • Gastric emptying time • Gastric emptying half life Factors affecting “Gastric Emptying” 1. Volume of Meal Larger meal , longer emptying time 2. Composition of Meal Carbohydrates > Proteins > Fats 3. Physical state/Viscosity of Meal Liquids > Solids 4. Temperature of Meal High or low temp of food slows gastric emptying 5. Gastrointestinal pH Slow at low pH, higher at alkaline Factor affecting “Gastric Emptying” 1. Electrolytes & Osmotic pressure Isotonic, water show rapid while high electrolyte conc slows gastric emptying 2. Body posture Standing, lying on right side promotes 3. Emotional state Stress/anxiety promotes gastric motility while depression slows movement Factor affecting “Gastric Emptying” 1. Exercise Vigorous training slows gastric emptying 2. Disease state Gasteroenteritis, gastric ulcer, pyloric stenosis, diabetes - slows gastric emptying Partial/total gastrectomy, duodenal ulcer, hyperthyroidism promotes gastric emptying Factors affecting “Gastric Emptying” Drugs That promote gastric movement: Metoclopramide, domperidone, cisapride That inhibit gastric movement: Antacids, anti-cholinergics, narcotic analgesics, tricyclic antidepressants Gastric emptying Rapid emptying advised where • Rapid onset desired • Dissolution in intestine (enteric) • Drugs unstable in stomach • Drugs best absorbed from distal small intestine Delay in gastric emptying advised where • Food promotes dissolution/absorption • Disintegration/dissolution promoted by gastric fluids • Drugs that dissolve slowly Time in Intestine (Intestinal Transit) • Since most absorption in small intestine, longer stay promotes absorption of drugs • Peristaltic movement promotes absorption by better membrane contact, agitation (promotes dissolution) • Longer stay is preferred for drugs • • • • • Dissolve slowly, release slowly Dissolve only in intestine Absorbed from specific sites Absorption through mucosa is slow Absorption from colon is minimal Intestinal Region Typical transit time Duodenum 5 min Jejunum 2 hrs Ileum 3 – 6 hrs Caecum 0.5 – 1 hrs Colon 6 – 12 hrs Gastrointestinal pH • Wide range on pH, affect absorption through various effects • Disintegration • Enteric coated formulations • Dissolution • pH affects dissolution of drugs • pH affects solubility of weak base/acids Gastrointestinal pH • Wide range on pH, affect absorption through various effects • Absorption • Drug pka, surrounding pH determine ionic state of drug • Non-ionized drug primarily absorbed • Stability • Acidic environment can affect stability of drugs • Ex penicillin, Erythromycin are enteric coated formulations Disease state affecting drug absorption • GI diseases & infections • Celiac disease leads to malabsorption due to • Increased gastric emptying rate • Altered intestinal metabolism, permeability • Impaired secretion of bile • Crohns disease leads to malabsorption due to • Altered intestinal metabolism • Decreased gut surface area • Decreased intestinal transit time • Gastric surgeries Disease state affecting drug absorption • Cardiovascular diseases • Cardiac failure affects bioavailability by • • • • • Oedema of intestine Altering pH Affecting peristaltic movement Gastric emptying Altering blood flow • Hepatic diseases • Conditions of hepatic failure (cirrhosis) affects drug bioavailability • Reduces overall first-pass effect Shariq AIKC/FinalYB/2014 Blood flow to GIT • GIT track extensively perfused by blood/lymphatic system • Almost 28 % of cardiac output to GIT (Splanchnic circulation) • High perfusion rate ensures “sink conditions’ • External conditions affect blood flow (drugs, food) Gastrointestinal Contents • Food-drug interactions: • Food can affect absorption • Can increase OR decrease absorption • In general drugs absorbed better under fasting conditions • Delay/Decrease in absorption • Delay in gastric emptying • Formation of poorly soluble complex • Increased viscosity • Increase in absorption • Increased time for dissolution • Enhanced solubility (bile secretion) • Prolonged residence time Gastrointestinal Contents • Fluid Volume: • Large volume facilitates dissolution, absorption • Drug-Drug interactions: • Can be either physico-chemical or physiological • Physico-chemical: • Adsorption • Complexation • pH change Gastrointestinal Contents • Drug-Drug interactions: • Physiological: • Decreased GI transit : Drugs slow GI movement & promote absorption • Increased gastric emptying: prokinetic drugs promote emptying improving absorption • Altered GI metabolism: Antibiotics affect GI microbial flora affecting overall bioavailability of drugs THANK YOU -PHARMA STREET