Oral Drug Absorption

Most common route of administration Anatomic and Physiologic consideration Major processes in GI: secretion, digestion and absorption

Oral cavity: saliva, pH around 7, ptyalin (salivary amylase), mucin Esophagus: pH of fluids 5-6, little drug dissolution, tablet lodging and irritation Stomach: innervated by the vagus nerve, local nerve plexus, hormones, mechanoreceptors, chemoreceptors control gastric secretions and emptying. Fasting pH 2-6, reduced in fed to 1.5-2 stomach acid secretionِ:gastrin and histamine Stomach emptying

Doudenum: pH 6-6.5, optimum pH for enzymatic digestion of proteins and peptides pancreatic juice: enzymes: trypsin, chymotrypsin, carboxypeptidases, amylase, pancreatic lipase High absorption capacity Jejunum Ilium

Colon lacks villi, limited drug absorption more viscous and semisolid nature of lumen contents lined with mucin: lubricant and protectant pH: 5.5-7 Aerobic and anaerobic m.o.: drug metabolism Residual area for drug absorption Rectum Small amount of fluid (2 ml) with pH of 7 Perfused by superior, middle and inferior hemorrhoidal veins

Drug absorption in the GIT Passive diffusion is the main mechanism Optimum site of absorption is the doudenum large SA, high perfusion, availability of carrier mediated absorption mechanisms

Physiological Factors that Influence Drug Absorption from GIT GI motility: Gastric emptying time and intestinal motility GI perfusion GI secretions Presence of food

Gastrointestinal motility Gastric emptying time Rapid emptying into the stomach Delay in gastric emptying would delay drug absorption (usually rate, possibly extent) Very high intersubject variability Factors that influence gastric emptying (table)

Liquids and small particles: rapid emptying Large particles: delay is usually seen (3-6 hours due to food) Non digestible solids: very slow emptying Intestinal motility Sufficient residency is needed for optimum absorption Residency is 3-4 hours, could be prolonged in fed status (8-12 hours) Intersubject variability is lower Influenced by disease situation Colon: 35 hours, influenced by diet

Drugs may influence intestinal transit: propanthelin Metoclopromide Laxatives Disease states: Diarrhea (brief residency)

Effect of food and diet on bioavailability Alteration in the rate of gastric emptying:delay in rate of absorption, Nitrofurantoin Stimulation of gastric secretions Competition between food components and drugs for specialised absorption mechanisms Complexion of drugs with components in the diet Increased viscosity of GI content and reduction in dissolution rate and diffusion to reach cell membranes Timing of drug administration in relation to food is important

Intersubject variations General health of the individual Gastrointestinal pH Intersubject variations General health of the individual Localized disease situations (gastric and duodenal ulcers) Types and amounts of food ingested Drug therapy Gastric pH may influence drug absorption in different ways: Ionisation and solubility of acids and bases Chemical stability of drugs in low gastric pH

Other gastrointestinal secretions Bile and pancreatic secretions Bile: pH 7.8-8.6 Bile salts, : bile salts, bilirubin, end products of haemoglobin break down, electrolytes, small amounts of cholesterol, phospholipids Promote dissolution of lipophilic drugs and dosage forms Promote membrane permeability (micelle formation) Insoluble complexes (neomycin, kanamycin, vancomycin) Pancreatic secretions Enzymes: proteolytic activity

Drug stability in GIT Chemical degradation. Gut lumen metabolism Gut wall metabolism Bacterial metabolism Hepatic metabolism

Factors influencing first pass metabolism Age Liver disease Enzyme induction and inhibition Induction: refampicin, smoking Inhibition: cimetidine Other miscellaneous factors that influence gastrointestinal absorption Local disease states Gastric surgery Malabsorption Chronic alcoholism Chemotherapy

EFFECT OF DISEASE STATES ON DRUG ABSORPTION Parkinson’s disease Achlorhydric patients: weak-base drugs, dapsone, itraconazole, and ketoconazole   Congestive heart failure: reduced splanchnic blood flow, edema in the bowel wall

Inflammatory bowel diseases Crohn’s disease: inflammatory disease of the distal small intestine and colon. Acccompanied by regions of thickening of the bowel wall, overgrowth of anaerobic bacteria, and sometimes obstruction and deterioration of the bowel. Effect on drug absorption is unpredictable (impaired absorption may occur) Higher plasma propranolol concentration Celiac disease: inflammatory disease affecting mostly the proximal small intestine Increased rate of stomach emptying and increased permeability

Intestinal Infections: Frequently cause diarrhea Ampicillin and nalidixic acid, oral contraceptives

Gastric surgeries Involve removal of part of the GIT: reduction in the epithelial surface area or changes in the motility or secretory patterns Partial gastrectomy: reduced abs of some drugs Resection of the small intestine Colonic resection and loss of salfasalazine activity

Drugs that Affect Absorption of Other Drugs Anticholinergics: Propantheline bromide: slow stomach emptying and motility of the small intestine. Tricyclic antidepressants and phenothiazines: have anticholinergic side effects Metoclopramide: stimulates stomach contraction, relaxes the pyloric sphincter, may reduce the effective time for the absorption, digoxin Antacids Cholestyramine