INTRODUCTION TO GI & HEPATIC PHYSIOLOGY

MARK P. OKAMOTO, PHARMD
DEAN & PROFESSOR PCOM SCHOOL OF PHARMACY

Objectives
  At

the end of this series of lectures, students should be able to:

• List organs involved in the digestion and absorption of foodstuffs • Describe the digestion and absorption of:
• Carbohydrates • Proteins • Fats

• Describe the absorption of water and ions in the GIT • Describe the function of the large intestine

Objectives
  At

the end of this series of lectures, students should be able to:

• Describe the endocrine and exocrine functions of the pancreas • Describe the function of the small and large intestine • Describe colonic movements and the processes associated with defecation • Describe the constituents and function of bile • Describe the creation and transport of bile from the liver to the GIT

Objectives
  At

the end of this series of lectures, students should be able to:

• Describe the physiology associated with the gall bladder • List the functions of the liver • Describe the different biotransformation processes in the liver • Describe the cytochrome p450 system and how various isoenzymes affect drug metabolism • Describe how hepatic blood flow affects drug clearance and define the concept of extraction ratios

Digestion   Dietary carbohydrates • The major sources of carbohydrates in the human diet are: • Sucrose (disaccharide) • Lactose (disaccharide) • Starches (polysaccharides) • Cellulose (non-digestable) .

Digestion   Carbohydrate digestion • Saliva contains ptyalin (alpha-amylase) hydrolyzes carbohydrates in foods • Digestion continues in the stomach due to gastric secretions • Pancreatic amylase is a powerful enzyme aiding in carbohydrate digestion in the duodenum • Enterocytes in the small intestine contain carbohydrate enzymes .

Digestion   Protein digestion •  Consumption of polypeptides stimulates the activation of pepsin (when pH is low) •  Pepsin can digest protein collagens found in many meats •  Most protein digestion occurs in the duodenum and jejunum as a result of pancreation enzymes • Trypsin / chymotrypsin • Carboxypeptidase • Proelastase •  Enterocytes in the small intestine release peptidases to further break down proteins .

Digestion   Fat digestion • Most dietary fats are triglycerides • Triglyceride digestion begins in the mouth and stomach by lingual lipases • Bile acids and lecithin (from bile) emulsify dietary fats so that water soluble enzymes can act on the fat globules • Pancreatic lipase is the most important enzyme involved in fat digestion .

but not much foodstuffs .Absorption   Absorption of foodstuffs •  The stomach does not routinely absorb foodstuffs •  Lacks villi •  Presence of tight epithelial intercellular junctions •  Intestinal microvilli greatly increase the surface are available for absorption •  Carbohydrates •  Fats •  Amino acids •  Water / electrolytes •  Large intestine absorbs additional water and electrolytes.

Absorption   Absorption of carbohydrates •  Glucose • Co-transported with the active transport of Na •  Monosaccharides   Absorption of proteins •  Absorbed through luminal membranes of intestinal epithelial cells • Dipeptides • Tripeptides • Amino acids •  Binds with a specific transport protein that requires Na binding .

Absorption   Absorption of fats •  Triglycerides are digested to form monoglycerides and free fatty acids •  These products are dissolved in lipid portions of bile micelles •  Bile micelles are soluble in chyme. diffuse out of the micelles into epithelial cells •  Micelles are recycled performing the same action repeatedly •  Fatty acids and monoglycerides in the epithelial cells are taken up by smooth ER and form chylomicrons •  Some fatty acids are absorbed directly into portal blood .

Absorption   Water   Ion absorption • Passive diffusion absorption • Active transport • Sodium • Calcium • Iron • Potassion • Magnesium • Phosphate • Diffusion to maintain electrical neutrality .

Absorption   Large intestine • Most of the water & electrolytes in chyme are absorbed in the colon (5-8 L/day) • < 100 mL of fluid is excreted in the feces • Ions are mostly absorbed with little lost in feces • Colonic mucosa has a high capacity for active sodium absorption (followed by passive Cl absorption) • Bicarbonate ions are secreted in the colon while Cl is absorbed .

Absorption   Large intestine • Numerous bacteria are present in the colon • Bacteria are involved in the activation of: • Vit K • Vit B12 • Thiamine • Riboflavin • Bacteria also form various gases (flatus) • CO2 • Hydrogen • Methane .

Fecal composition   Feces • 75% water • 25% solid matter • Dead bacteria • Fat • Inorganic matter • Undigested roughage • Brown color is caused by stercobilin and urobilin (products of bilirubin) .

Large intestine .

Large intestine blood flow .

Pancreas   Organ attached to the duodenum that has both endocrine and exocrine functions: • Endocrine • Secretes insulin and glucagon into blood • Exocrine • Secretes enzymes that digest carbohydrates. fats and proteins • Secretes bicarbonate that neutralizes the HCl entering the duodenum .

Pancreas   Pancreatic enzymes: • Trypsin / chymotrypsin (forms peptide fragments) • Carboxypeptidase (forms amino acids) • Lipase (forms free fatty acids) • Amylase (splits polysaccharides) • Deoxy and ribonucleases (splits nucleic acids) .

Pancreas .

fatty acids and amino acids) .Gastrointestinal reflexes   GI reflexes are initiated by intestinal stimuli: • Wall distention by food contents • Osmolarity of the chyme (partially digested food) • Acidity of the chyme • Presence of digested particles (monosaccharides.

Biliary functions   Overall function of bile: • Aids in fat digestion and absorption • Means for excretion of waste products • Bilirubin • Excess cholesterol • Emulsify fats into smaller particles • Aid in absorption of digested fat products through the intestinal mucosal membranes • Bile contains bicarbonate which also neutralizes stomach acid .

Bile   Bile pigments are formed by the breakdown of hemoglobin • Bilirubin is extracted from the systemic circulation by the liver and secreted into the bile • Bile pigments are yellow and give bile a golden color • The pigments are digested in the GIT and give feces their brown color • Reabsorbed pigments go to the systemic circulation and are excreted in the urine .

Bile   Bile salts • Cholesterol is the precursor to bile salts • Converted to cholic acid and chenodeoxycholic acid • Forms bile acids • Emulsifying effect on fat particles • Binds with: −  Fatty acids −  Monoglycerides −  Cholesterol −  Other lipids • The bound complex (micelle) is then absorbed .

Bile   Bile passage • Formed by the hepatocytes in the liver • Flows from bile canaliculi to smaller bile ducts in the liver • Hepatic duct forms common bile duct • Flows to cystic duct for storage in gall bladder or is dumped into the duodenum • Enterohepatic recirculation is possible .

Gall bladder   Between meals. but becomes concentrated as fluids are reabsorbed (30-60 ml) • Presence of fatty foods in the duodenum stimulates GB contraction & bile release • Release of CCK • Gall bladder contraction • Relaxation of the sphincter of Oddi . the liver produces bile and it is stored in the gall bladder • Large amount of bile is stored in the gall bladder.

toxins and other substances .Introduction to liver function   The liver is one of the most important organs in the body and performs a variety of functions • Nutritional / metabolic balance • Maintenance of fluid / electrolyte status • Coagulation control • Metabolism of drugs.

drugs normally metabolized by the liver may require dose alterations because the liver has lost its capacity to metabolize or eliminate the drug .Introduction to liver function   Liver function can significantly affect the pharmacokinetics of drug •  Main mechanisms for drug elimination by the liver • Biliary excretion • Biotransformation •  In hepatic disease.

Liver .

Liver lobule .

.

Biotransformation   The process of biotransformation induces • More polar metabolites (water soluble and filtered/secreted by the kidney) • Less active metabolites (with some exceptions) • Prednisone into prednisolone   Biotransformation can be divided into several types of reactions: • Phase 1 reactions (alteration) • Phase 2 reactions (conjugation) .

Biotransformation   Phase 1 reactions • Oxidation • Reduction • Demethylation   Phase 2 reactions • Glucuronidation • Sulfation • Acetylation .

Cytochrome p450   An enzyme system which catalyzes oxidative drug metabolism (mostly in liver and gut)   Numerous isoenzymes of the p450 family exist (up to 200 specific enzymes have been isolated)   The 3 main groups of cytochrome p450 enzymes are: • CYP1 • CYP2 • CYP3 (most common) .

some types of liver diseases only affects one isoenzyme while others affect many isoenzymes   .Cytochrome p450 There are MANY cyp isoenzymes that affect drug metabolism (a few are listed here) •  CYP1A2 •  CYP3A4 •  CYP2E1 •  CYP2C   Some drugs are affected by only one isoenzyme. while other drugs may be metabolized by multiple isoenzymes   In addition.

Hepatic blood flow   Clearance of drugs that have a high extraction ratio are limited by hepatic blood flow • “Flow sensitive” or “perfusion limited”   Clearance of drugs that have a low extraction ratio are limited by intrinsic liver clearance • “Flow insensitive” or “capacity limited” .

bacterial.Hepatic disease   There are many etiologies associated with hepatic disease • Infections (viral. parasitic. fungal) • Alcoholism • Cirrhosis • Portal hypertension • Circulatory disorders • Autoimmune disease • Drug / chemical exposure .

Liver function tests   Despite the lack of clinical signs/ symptoms. laboratory tests can be very useful in the Dx and Tx of alcoholic liver disease • Serum albumin • Serum bilirubin • Transaminases • Gamma-glutamyltranspeptidase (GGT) • Alkaline phosphatase (AlkPhos) .

4 .Albumin   Normal •  3.4.7 gm/dL   Albumin is a protein produced by the liver   One of its main properties is maintaining oncotic pressure   Albumin concentrations are often used to evaluate liver function   Albumin concentrations are often monitored by pharmacists because many drugs are protein-bound values .

46 .17 .55 U/L (males) 7 .92 uKat/L (M) 0.0.12 .30 U/L (females) •  0.Transaminases   Normal •  •  Aspartate aminotransferase (AST) Previously known as serum glutamic oxaloacetic transaminase = SGOT values 10 .30 U/L •  0.23 uKat/L •  •  Alanine aminotransferase (ALT) •  Previously known as serum glutamic pyruvic transaminase (SGPT) 10 .0.2.5 uKat/L (F) •  .

Transaminases   Both transaminases are found in high quantities in heart and liver tissue • After acute injuries to these tissues. these enzymes are released in high quantities from the damaged cells • AST levels are commonly monitored • After acute MI to evaluate myocardial injury • After acute liver injury (viral hepatitis) to evaluate liver damage .

Transaminases   Serum transaminases • Levels of the serum transaminases can be deceiving • Depends on amount of liver function left after cirrhosis • Initially. serum transaminases rise significantly as hepatocytes are injured and AST and ALT are released into the blood • As liver disease progresses. AST and ALT levels may fall because of a reduced number of functioning hepatocytes .

2 .0 .1 .0.0 umol/L •  •  .20 umol/L values •  Direct bilirubin Indirect bilirubin 0.2 mg/dL •  2.1.1 to 0.4 .Bilirubin   Normal •  •  Total bilirubin 0.7 mg/dL •  3.12 umol/L •  0.0 .5.3 mg/dL •  2.

bilirubin is released into the blood •  Most bilirubin is quickly bound to serum albumin .Bilirubin   Bilirubin •  is created in the RE system (reticuloendothelial) Bilirubin is the breakdown product of hemoglobin from red blood cells •  After formation from the RE system.

unbound) is taken up by liver cells Gets converted to bilirubin diglucuronide Excreted in the bile after conjugation Is converted to urobilinogen by bacteria in the GI tract The urobilinogen is either degraded or excreted in the feces. or may be reabsorbed A portion may go back to the liver •  The remainder is excreted in the urine •  •  .e..Bilirubin   Free •  •  •  bilirubin (i.

Bilirubin   Conjugated •  bilirubin = Direct bilirubin = Indirect Bilirubin diglucuronide Bilirubin/albumin complex   Unconjugated •  .

Bilirubin   Hepatocellular damage •    Cholestasis •  When liver cells are damaged. and the liver is unable to conjugate bilirubin. the liver is still able to conjugate the bilirubin. the total bilirubin levels increase disproportionately compared to direct bilirubin When bile flow is blocked. but the obstruction prevents the flow of conjugated bilirubin to the GI tract There is an increase in direct (conjugated) bilirubin •  .

Bilirubin   Hemolysis •  •  •  When RBCs are degraded by the RE system at a faster rate than normal. the liver may not be able to conjugate all of this excessive bilirubin The excessive bilirubin will bind to available albumin (indirect bilirubin) When the indirect bilirubin levels rise disproportionately compared to total bilirubin levels. hemolysis should be suspected .

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