Transcript Oral Drug 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 1.5-2
stomach acid secretion:ِ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
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