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

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 1.5-2stomach acid secretion ِ:gastrin and histamineStomach emptying

• Doudenum: pH 6-6.5, optimum pH for enzymatic digestion of proteins and peptidespancreatic juice: enzymes: trypsin, chymotrypsin, carboxypeptidases, amylase, pancreatic lipaseHigh absorption capacity

• Jejunum• Ilium

• Colonlacks villi, limited drug absorptionmore viscous and semisolid nature of lumen contentslined with mucin: lubricant and protectantpH: 5.5-7Aerobic and anaerobic m.o.: drug metabolismResidual area for drug absorption

RectumSmall amount of fluid (2 ml) with pH of 7Perfused 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 motilitySufficient residency is needed for optimum absorptionResidency is 3-4 hours, could be prolonged in fed status (8-

12 hours)Intersubject variability is lowerInfluenced by disease situationColon: 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

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 secretionsBile and pancreatic secretionsBile: 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 formsPromote 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, smokingInhibition: 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