hepatic physiology ho
TRANSCRIPT
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