Biopharmaceutics 4th year

Factors affecting GI absorption of drug Dosage Form Factors

1) Disintegration time and Dissolution time Disintegration time (DT) is important in case of solid dosage form like tablets and capsules. DT depends on binder present, compression force (hardness). Drug dissolution is very important factors in drug absorption.

1) Disintegration time and Dissolution time Factors influencing dissolution of drugs are: Method of granulation, compression force, excipients such as binder, lubricant and Disintegrants

2)Pharmaceutic ingredients (excipients) Solvent: aqueous (water , syrup), non aqueous water miscible (PG, glycerol,sorbitol), non aqueous water immiscible (vegetable oil). aqueous (water , syrup) are miscible with body fluid and drug from them is rapidly absorbed

2)Pharmaceutic ingredients (excipients) non aqueous water miscible(PG, glycerol,sorbitol) are miscible with body fluid and show better bioavailability non aqueous water immiscible (vegetable oil) drug absorption depend on its partitioning from oil phase to body fluid

2)Pharmaceutic ingredients (excipients) Diluents: Are added to tablet or capsule formulation when the drug dose is inadequate to produce necessary bulk. Example/ starch, lactose, microcrystalline cellulose, and dicalcium phosphate (DCP) Tetracycline and DCP produce a complex that is unabsorbable.

2)Pharmaceutic ingredients (excipients) Binder Are materials used to hold powders together for granulation or produce cohesive form for direct compressible materials and to ensure intact tablet after compression

2)Pharmaceutic ingredients (excipients) Example/ starch, cellulose derivatives , pvp, gelatin….) Large amount of binder increase hardness and decrease disintegration/dissolution of tablet It is found Ethyle cellulose retard drug dissolution.

2)Pharmaceutic ingredients (excipients) Disintegrant: These agents are used to overcome the cohesive strength of tablet and break up them when they come in contact with water. Most of them are hydrophilic, a decrease in their amount may lower bioavailability.

2)Pharmaceutic ingredients (excipients) Lubricants: These agent are added to tablet formulation to decrease adhesion or friction of the materials to tablet machine Example/ zinc stearate or magnesium stearate If Disintegrant get coated by lubricant it affect disintegration so lubricant are added at final stage before compression.

2)Pharmaceutic ingredients (excipients) Coating: The effect of coating materials on dissolution time of drug is in the following order Enteric coated > sugar coated> non enteric film coated

3) Type of dosage form The bioavailability of a drug is from various dosage forms decrease in the following order Solution>emulsion>suspension> capsule> tablet> coated tablet > enteric coated tablet>sustained release product

4) Product age and storage conditions A number of changes especially on physicochemical properties of drug or dosage form can affect bioavailability. In the case of solution, precipitation of drug or conversion of metastable to poorly stable, stable polymorph may occur In solid dosage form (tablet , capsule), disintegration and dissolution are affected due to aging and storage condition.

Factors affecting GI absorption of drug Patient Related Factors

1) Age In infant gastric pH is high, intestine surface area and blood flow is low compared to adult In elderly persons, Altered gastric emptying Decrease surface area Incident of achlorhydria Bacterial overgrowth Causes impaired absorption

2) Gastric Emptying -Is the passage from the stomach to intestine. Rapid gastric emptying increase drug bioavailability??

Factors affecting gastric emptying Volume of meal -Larger bulk of meal, longer gastric emptying Composition of meal Gastric emptying is in the following order carbohydrate> protein>fat fatty meal delay gastric emptying

Factors affecting gastric emptying Physical state of meal Liquid materials take 1 hr to empty while solid materials take 6 hr to empty Gastrointestinal pH Gastric emptying is retarded at low pH and promoted at alkaline pH

Factors affecting gastric emptying Electrolyte Water, isotonic solution , solution of low salt concentration empty the stomach rapidly whereas higher electrolyte concentration decrease gastric emptying rate

Factors affecting gastric emptying Body Posture Gastric emptying is favored during standing and lying on right side whereas lying on left side or supine position delay gastric emptying Emotional state Stress, anxiety promote gastric motility while depression retard it

Factors affecting gastric emptying Exercise Vigorous physical training may retard gastric emptying Disease state -Gastroenteritis, ulcer, pyloric stenosis, diabetes hypothyrodism retard gastric emptying - hyperthyrodism, gastrectomy duodenal ulcer promote gastric emptying

Factors affecting gastric emptying Drugs Retard gastric emptying poorly soluble antacids, anticholinergic,tricyclic antidepressant Metochlorpromide, domperidone stimulate gastric emptying

3)Intestinal Transit Long intestinal transit is desirable for complete drug absorption

3)Intestinal Transit -The mixing movement of intestine due peristaltic contraction promote drug absorption by Firstly, increase drug intestinal membrane contact Secondly, by enhancing drug dissolution through agitation

3)Intestinal Transit Sometimes delay intestinal transit is desirable ,why? Factors affecting intestinal transit: Food Drug Disease pregnancy

4)Gastrointestinal pH GI pH affect drug absorption in different ways: Disintegration Dissolution Absorption stability

5)Disease state 3 major diseases can influence bioavailability of drug: Gastrointestinal diseases Cardiovascular diseases Hepatic diseases

Gastrointestinal Diseases Altered GI motility Gastrointestinal infection Gastrointestinal surgery

6)Blood flow to GI GIT supplied by blood capillary and lymphatic system Since blood flow to GIT is 500 to 1000 times more than lymph flow Most drugs reach systemic circulation through blood whereas few drugs taken by lymph

6)Blood flow to GI The high GI perfusion ensures that once the drug has crossed the membrane, it is rapidly removed from the absorption site

7)Gastrointestinal content A/ Food- Drug Interaction food interaction may be due to : Alteration of physiological functions GI emptying rate , fluid secretions, pH, blood flow

7)Gastrointestinal content A/ Food- Drug Interaction food interaction may be due to : Physicochemical interaction Alteration of drug dissolution , complexation and adsorption

7)Gastrointestinal content A/ Food- Drug Interaction As a general rules, drugs are better absorbed under fasting conditions and presence of food retards or prevent it. Foods doesn’t significantly affect a drug taken half an hour or more before meal and two hour or more after meal

7)Gastrointestinal content A/ Food- Drug Interaction Delay or decreased drug absorption by food may be due Delay gastric emptying Formation of poorly soluble, unabsorbable complex Increase viscosity thereby prevent drug dissolution

7)Gastrointestinal content A/ Food- Drug Interaction Increased drug absorption by food may be due Increase dissolution time for poorly drug Enhance solubility due to gastric secretion like bile Increase lymphatic secretion Enhance residence time and absorption site contact

7)Gastrointestinal content A/ Food- Drug Interaction

7)Gastrointestinal content B/ Fluid Volume Large fluid volume results in better dissolution, rapid gastric emptying, and enhanced absorption. C/ Drug- GI constituent interaction Drug may interact with mucin, bile, enzymes

7)Gastrointestinal content D) Drug – Drug interaction Physiological physicochemical

7)Gastrointestinal content 4) Drug – Drug interaction / Physiological Antibiotic inhibit bacterial metabolism of drug -Erythromycin enhance efficacy of digoxin - Antibiotic co administered with oral contraceptive decrease the efficacy of latter

7)Gastrointestinal content 4) Drug – Drug interaction / Physicochemical -antidiarrheal containing pectin- kaolin prevent absorption of number of drugs (adsorption) -Antacids or heavy metal retard absorption of some drugs (complexation) -basic drugs administered with antacids decrease dissolution rate ( change in pH)

8)Presystemic Metabolism/First –Pass Effects Before a drug reaches blood circulation, it pass through organs of elimination (GIT and liver) The loss of drug through biotransformation by such eliminating organs during its passage to systemic circulation is known as first pass effect or presystemic metabolism

8)Presystemic Metabolism/First –Pass Effects Systems which affect presystemic metabolism of drug are: Lumenal enzymes Gut wall enzymes/ mucosal Bacterial enzymes Hepatic enzymes

8)Presystemic Metabolism/First –Pass Effects

8)Presystemic Metabolism/First –Pass Effects Lumenal Enzymes Hydrolases and Peptidases are enzymes of intestinal and pancreatic secretion Hydrolases which hydrolyze ester drugs (chloramphenicol palmitate into active chloramphinicol )

8)Presystemic Metabolism/First –Pass Effects Lumenal Enzymes Peptidases split amide linkage and inactivate protein or polypeptide drugs. Approach to effect oral absorption is to deliver them to colon

8)Presystemic Metabolism/First –Pass Effects B) Gut Wall Enzymes Are enzymes present in stomach, intestine and colon Alcohol dehydrogenase (ADH) which is stomach enzyme inactivate ethanol

8)Presystemic Metabolism/First –Pass Effects C) Bacterial Enzymes Microflora is present in stomach, small intestine, and is rich in colon most of drugs remain unaffected by them But some drugs convert to active or toxic by colonic microbes

8)Presystemic Metabolism/First –Pass Effects C) Bacterial Enzymes Sulfasalazine is hydrolyzed to sulfapyridine and 5-amino salicylic acid by microbial enzymes

8)Presystemic Metabolism/First –Pass Effects D) Hepatic Enzymes Several drugs undergo hepatic metabolism e.g. propranolol

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