Biopharm

• The Digestive System


  • Emergence of teeth
  • Digestion starts in the mouth
  • Gland under the tongue pump out the saliva when the food is being chewed (amylase enzyme)
  • 13 foot journey in the gut
  • Wave of contracting muscles: peristalsis moves the food down the esophagus, allow us to eat upside down
  • Acids break the food down in the stomach
  • Pyloric sphincter - opens/ closes in the presence of food stomach to the small intestine
  • Small intestine is where the absorption of nutrients happen (villi and microvilli)
  • Pancreas secretes juice that neutralizes the stomach acid
  • Bile from the liver breaks down the fats for easy absorption
  • Small intestine to large intestine valve: Ileocecal sphincter
  • Waste and dead cells pass through the bacteria filled large inestine that produces enzymes for the breaking of carbohydrates. This is where the extraction of water occurs

  
• Absorption


  The process of uptake of the compound from the site of administration into the systemic circulation (circulatory system)
• Sites of absorption


  • Gastrointestinal tract (most commonly occurring)
  • Lungs
  • Skin

  
• Pharmacokinetics of oral absorption

  • Variability of systemic drug absorption at the site of administration
  • Possible drug degradation; can be inactivated and affect drug concentration
  • Inter and intra patient differences in the rate and extent of absorption
• For ALL routes of administration GI, lung, skin (EXCEPT s.c. i.m. or i.v. injection), drugs must cross (epithelial) cell membranes in order to reach the plasma
• Epithelial cells


  The cells in the stomach and the brain
• Except for injection, drugs must cross cell membranes. Thus, drug absorption is usually limited by the rate drugs can cross cell membranes by passive Diffusion, ion-pairing, endocytosis, facilitated transport or active transport
• All other routes - cross epithelial to reach the site of action
• The absorption of orally administered drugs are limited
• Absorption depends on how fast the drugs can pass through using different transport mechanisms
• Epithelial cells


  • Junctions tightly arranged, (i.e. drugs must move THROUGH cells (diffusion, ion pairing, filtration, endocytosis, facilitated or active transport)
  • Small intestine and brain cell structure, follow LUNA
• Endothelial cells


  • Junctions loosely arranged (i.e. drugs can move AROUND cells by bulk flow)
  • Transcellular/paracellular transport
  • These cells have similar internal but very dissimilar external organization, resulting in very different rates of drug transport across these cellular barriers
• GI Absorption


  • Many substances can be absorbed rapidly through the wall of the gastrointestinal tract
  • Passage into the blood only requires transport across an epithelial layer
  • Because of its villous structure, this epithelial layer has a very large surface area
  • The epithelial cells also have microvilli in the small intestin; these are responsible for even further enlargement of the surface area
• Small Intestine


  • MAJOR mechanism for drug absorption is PASSIVE DIFFUSION (LUNA drugs)
  • Even though the average pH if the small intestine is about 5 (to 6.5) , the extensive surface area and voluminous perfusion PREVENT the onset of equilibrium conditions that might otherwise limit the rate of absorption by diffusion
  • Duodenum (5) is more acidic than Jejunum (6) and Ileum (6.5)
• The large surface area and high rate of perfusion OVERCOME pH effects that would otherwise limit passive diffusion (absorption) of charged (ionized) drug molecules
• Comparison of the size of the absorptive surface of the various parts of the GIT (in m2)

  • Oral cavity: 0.02
  • Stomach: 0.1-0.2
  • Small intestine: 100
  • Large intestine: 0.5-10
  • Rectum: 0.04-0.07
• Factors affecting the Rate and Extent of Absorption for Oral Drugs

  • GI Motility
  • Gastric-Emptying Time
  • Surface Area of the GIT
  • Blood Flow to the Absorption Site
• GI Motility


  • Motility - (peristaltic) movement of SI
  • Involuntary muscle movement (continuous contraction)
  • Amount and rate are effected
• Absorption window in the GIT

  • Area where drugs are greatly soluble at particular pH
  • Absorbed through a specific mechanism at a specific segment (any transport system)
  • Absorbed in specific segments of the GI tract
  • Varies between drugs due to pKa (5.5-6)
• Transit time (how long does the drug stay in the body) of the drug in the GIT

  • Depends upon the Pharmacologic properties of the Drug
  • Depends upon the Types of Dosage Form
  • Depends upon Various Physiologic Factors

  
• Typical Motility Patterns


  • Phase 1 (30-60 mins) - Quiescence, greatly absorbed = no contraction
  • Phase 2 (20-40 mins) - Medium amplitude but can be as high as phase 3, irregular contractions
  • Phase 3 (5-15 mins) - Contractions ! (regular; 4-5 contrns/min), High amplitude
  • Phase 4 (0-5 mins) - Feces formation, Start is regular contraction from Phase 3 (slow movement) → mixed contents made into feces

  
• Digestive (fed) state


  • One phase only, as long as food is present in the stomach
  • Regular frequent contractions; Short amplitude lower than phase 3 (4-5 contractions/ min)

  
• Migrating motor complex


  The alternating cycles of activity which acts as a propulsive movement that empties the upper GIT to the cecum- during fasted state
• Anti-diarrheal drug has fast action - kasi site of action is the SI na mismo
• Pylorus/ Pyloric sphincter


  Prevents regurgitation or movement of food from the distal to the proximal direction

  
• Gastric Emptying Time


  • Duodenum has the greatest capacity for the absorption of drugs from the GIT, a delay in the gastric emptying time for the drug to reach the duodenum will slow the RATE and possibly the EXTENT of drug absorption, thereby prolong the onset time for the drug
• Penicillin - unstable in an acid and decomposes if stomach emptying is delayed


  Should be taken on an empty stomach; avoid taking with meals
• Aspirin taken with food

  Causes GI irritation, slower rate of digestion if taken with a fatty meal, onset of action will be delayed
• Delay in gastric emptying time affects the extent of drugs
• Different constituents of a meal will empty from the stomach at different times
• Comparison of the size of the absorptive surface of the various parts of the GIT

  • Buccal: Approx. 7, Small, Short
  • Esophagus: 5-6, Small, Short
  • Stomach: 1-3, Small, 30-40 mins
  • Duodenum: 6-6.5, Very large - 10-14 ft, About 3 hrs until the ileum
  • Ileum: 7-8
  • Colon: 5.5-7, Not very large- 4-5 ft, Long up to 24 hrs
• Bigger surface area


  Longer transit time, Higher absorption rate
• Ingestion of a solid dosage form with a glass cold water


  Accelerates gastric emptying, significantly increases absorption
• Ingestion with a fatty meal, acidic drink, or with another drug with anticholinergic properties

  Retards gastric emptying
• Sympathetic output (as in stress)

  Slows gastric emptying
• Stomach likes lukewarm consumptions
• Food properties


  • pH
  • Surface Area
  • Transit Time
• Buccal


  • Approx. pH 7
  • Small surface area
  • Short transit time unless controlled
• Esophagus


  • pH 5-6
  • Small surface area
  • Short transit time
• Stomach


  • pH 1-3
  • Small surface area
  • 30-40 mins transit time