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

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, but not much foodstuffs

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 absorption • Passive diffusion

 Ion 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

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, fatty acids and amino acids)

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, the liver produces bile and it is stored in the gall bladder • Large amount of bile is stored in the gall

bladder, 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

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, toxins and other

substances

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, drugs normally metabolized by the liver may require dose alterations because the liver has lost its capacity to metabolize or eliminate the drug

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)

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, some types of liver diseases only affects one isoenzyme while others affect many isoenzymes

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”

Hepatic disease

 There are many etiologies associated with hepatic disease • Infections (viral, bacterial, 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)

Albumin  Normal values

•  3.4 - 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

Transaminases  Normal values

•  Aspartate aminotransferase (AST) •  Previously known as serum glutamic oxaloacetic

transaminase = SGOT •  10 - 30 U/L •  0.46 - 2.23 uKat/L

•  Alanine aminotransferase (ALT) •  Previously known as serum glutamic pyruvic

transaminase (SGPT) •  10 - 55 U/L (males) 7 - 30 U/L (females) •  0.17 - 0.92 uKat/L (M) 0.12 - 0.5 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

Bilirubin

 Normal values •  Total bilirubin

•  0.1 - 1.2 mg/dL •  2.0 - 20 umol/L

•  Direct bilirubin •  0.1 to 0.3 mg/dL •  2.0 - 5.0 umol/L

•  Indirect bilirubin •  0.2 - 0.7 mg/dL •  3.4 - 12 umol/L

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, bilirubin

is released into the blood •  Most bilirubin is quickly bound to serum

albumin

Bilirubin

 Free bilirubin (i.e., 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

Bilirubin

 Conjugated bilirubin = Direct •  Bilirubin diglucuronide

 Unconjugated bilirubin = Indirect •  Bilirubin/albumin complex

Bilirubin   Hepatocellular damage

•  When liver cells are damaged, and the liver is unable to conjugate bilirubin, the total bilirubin levels increase disproportionately compared to direct bilirubin

  Cholestasis •  When bile flow is blocked, the liver is still

able to conjugate the bilirubin, 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