Four Basic GI Processes

• motility-pass food stuff/chyme along tract, mix
• secretion-enzymes, biological detergents/ions provide optimized env. for digestion/absorption
• digestion-physical/chemical modifications of food so absorption can occur
• absorption-nutrients/H₂O/ions 

Salivary Glands

• secrete saliva/mucous vital to initial breakdown of food
• parotid-serous secretion(amylase)
• sublingual/submandibular-serous/mucous (provides lubrication for esophagus) 

GI Submucosal

• contains a lot of glands
• function to secrete fluid(bicarbonate, enzymes mucus material) -which protects GI from self digestion
• plexus of nerves btw border of muscle and submucosal layer(meissners plexus), coordinates activity and function of GI system 

Myenteric(Aubach) Plexus

• resides in muscular layer of GI tract
• controls circular and longitudinal muscles that help propogate peristalic contraction

Mucosa Layer of GI

• epithelium
• enterocytes (absorption)
• enteroendocrine cells (secretory granules)
• lamina propria
• muscularis mucosae

GI Smooth Muscle

Slow Waves

• not action potentions but occur rhytmically
• determined by frequency of muscle E_m (5-15 mV)  
• 3-12 cycles per min dpenending on area of GI tract-3 stomach, 12 small intestine
• slow wave initiation not completely known but involves the ICCs
• dont usually cause muscle contraction in GI, except in stomach
• slow wave frequency and height modulated by body temp and metabolic activity(intrinsic and extrinsic nerves)

Auebach's Plexus

• GI movements
• increase tone of gut wall
• increase intensity of rhythmical contractions
• increased rate of contraction
• increase velocity of conduction of excitatory wave
• can have inhibitory function to regulate sphincters(pyloric, ileocecal) - by release of VIP

Meissner's Plexus

• GI secretion and local blood flow
• local absoprtion
• local contraction of submucosal muscle

Vagus Nerve

(GI function)

• major regulator of motor and secretory activity of the gastrointestinal system and is frequently excitatory
• facilitates peristalsis, acid secretion and GI movement
• also works with sacral plexus for parasymp inervation

Swallowing reflex

• medulla and lower pons control the swallowing reflex and are called the deglutittion or swallowing center
• motor impulses from swallowing center to pharynx and esophagus are transmitted by the 5, 9, 10 and 12 cranial nerves
• pharyngeal stage of swallowing is a reflex act

Dysphagia

• difficulty in swallowing
• Achalasia-lower esophageal sphincter fails to relax following a swallow
• muscle degenerative diseases

Esophageal Reflux

(esophagitis)

• lower sphincter fails to block reflux of stomach contents
• heartburn sensation, GERD

Functions of Stomach

• storage site for food
• acidification of env to kill microorganisms
• secretion of intrinsic factor
• secretion of mucus and HCO3
• solubilize/mix food to form chyme mixture
• decrease particle size
• empty food into the duodenum at an optimal rate

Gastric Motility

• fundus through body have icc pacemakers and peristaltic waves that move over thin muscles slowly moving food to antrum
• Antrum has strong peristaltic contractions that mix food with gastric secretions to form chyme.
• intense peristaltic contractions drive chyme through pyloric sphincter(6x normal peristaltic waves)

Control of stomach Emptying

• food volume(stomach stretching)
• peptides and amino acids cause release of gastrin from pyloric antrum G-cells
• gastrin increases gastric contraction
• duodenum also inhibits stomach emptying by monitoring for duodenum distention, degree of irritation of duodenal mucosa, acidity and osmolality of chyme, breakdown products(protein needs more time to be digested)

Gastric Inhibitory Peptide

• weakly inhibits gastric movements, thought to stimulate insulin release 

Duel Effects of Gastrin

• closes pyloric sphincter to decrease emptying
• stimulates gastric contractions to increase emptying
• so, initially decreases, but eventually increases
• allows for better mixing 

Motilin

• upper duodenum
• stimulus is fasting
• increases gastrointestinal motility

Small Intestine Motility Control

• gastroenteric reflex-wall distention conducted through myenteric plexus from stomach down to SI
• increase-CCK, insulin, motilin, gastrin, serotonin
• decrease-secretin and glucagon

Ileocecal Sphincter

• prevents reflux of colon contents into small intestine
• gastrin relaxes ileocecal sphincter-secretion occurs after a meal

Large Intestine Motility

• promotes absorption and allows storage
• segmenting contractions(haustrations of low frequency)-large circular contrictions
• new haustral contractions occur in other areas nearby, thefore the fecal material is slowly dug into and rolled over
• all fecal materal gradually exposed to the mucosal surface of large intestine
• only about 80 to 200 mi

Defication Reflex

• initiated by distension of rectum
• mediated by internal and external nerves
• causes contraction of smooth muscle of rectum and relaxation of internal anal sphincter
• volunatry control can over ride defecation reflux until next mas movement

Constipation

• produces abdominal discomfort, headache, nausea and lack of appetite due to large intestine distention
• caused by suppression of urge to defecate, decreased colon muscular activity due to emotional states, decreased dietary roughage, aging, fecal obstruction and nerve injury
• treated with cathartic(MgSO4 or Mg(OH)2 or laxatives

Diarrhea

• increased stool fluidity results from excessive water secretion and hypermotility of small intestine

Hirshsprung's Disease

• known as megacolon-enteric neurons are absent from distal part of the colon-dont have reflex relaxation of distal rectum and internal anal sphincter

Gastric Secretion

• about 3 liters per day
• secreted by exocrine glands in the mucosa of the body and fundus
• four types of secretory cells-oxyntic, pyloric, peptic and mucous neck

HCl

• secreted from parietal cells
• aids in breakdown of tough tissue
• activates pepsin-proteolytic enzyme(provides low pH needed for pepsin activity)
• kills bacteria(except certain types)
• can cause ulcers
• change of canaliculi trigger HCl release

Parietal Cell Acid Secretion

• extrusion of H+ into lumen for k+ (H-k pump)
• passive movement of Cl- 
• CO2 and H2O were taken into cell and converted to HCO3- and H+
• HCO3- is extruded for Cl-
• secretion stimulated by ACh, gastrin and histamine(eterochromaffin-like(ECL) cells) 
• gastrin binds to CCK_B receptors at a lower km

Somatostatin

• regulates acid secretion at two different points
• somatostatin is released from D cells and is stimulated by ACh
• can inhibit ECL cells from releasing histamine(histamine stimulates parietal cells)
• can inhibit parietal cells from releasing HCl
• also inhibits dgested protein amino acids that are released from G-cell

Histamine and HCl secretion

• secreted from ECL cells and stimulate secretion of HCl in parietal cells
• histamine released in response to acetylcholine and gastrin
• causes HCl secretion
• acts on H2 receptor
• H2 antagonists are anti ulcer drugs

Intrinsic Factor

• allows vitamin b12 to be absorbed(forms complex that has receptor in ileum
• B12 is needed in erythrocyte production and deficiency leads to pernicious anemia
•  Cobalamin(CBL and is originally attached to food) and is considered is originally bound to heptochlorin after
• heptochlorin gets degraded and Intrinsic factor can bind

Phases of Acid Secretion Triggering

• cephalic phase
• Gastric phase
• intestinal phase

Cephalic Phase

• first phase of meal triggering of acid secretion
• due to sight, smell, thought, taste of food
• neurogenic signals originate in cerebral cortex and appetite center
• signals transported via the vagus nerve to stomach
• account for 20% of gastric secretion

Gastric Phase

• second phase of meal triggering of acid secretion
• as bolus of food comes into stomach
• vagovagal reflex, enteric reflexes and gastrin mechanism excited
• leads to secretion of gastric juices
• account for 70% of gastric secretion

Intestinal Phase

• third phase of meal triggering of acid secretion
• digested protein in the lumen of the small intestine stimulates gastrin release

Pepsin Release

• inactive molecule pepsinogen is released by chief cells and is stored as zymogen granules
• gastric lumen HCl converts pepsinogen to active pepsin
• pepsin splits peptide bonds to release small peptides, also autoactivates itself
• ACh is most effective stimulus of pepsinogen release
• pH must be lower then 3.5 to prevent inactivation of pepsin

Ulcer Protective Measures

• gastric mucosal barrier
• food, salivary secretions dilute and neutralize acidic secretions 
• pancreatic secretions neutralize gastric acid as it enters the deodenum
• cells lining stomach regenerate rapidly

Common Causes of Ulcers

• stress: increased HCl production
• injury-increased HCl permeability
• increased HCl secretion-inc HCl in duodenum
• ectopic gastrin production(zollinger-ellison syndrom) or from a tumor
• bacterial infection-increased HCl permeability

Helicobacter pylori

• bacterial infection
• increased HCl permeability(leads to ulcers)
• discovered twice
• 2x prevalance in type O blood types
• weaken the gastric mucosal barrier by causing persistent inflamation

Types of GI Glands

• mucous glands
• pits-crypts of lieberkuhn
• tubular glands(stomach and upper duodenum)
• salivary, pancreas and liver-specialized secretory responsible for digestion and emulsification

Exocrine Pancreas Secretions

• digestive enzymes: secreted by the acinar cells
• aqueous alkaline fluid: screted by the duct cells(sodium bicarbonate)
• pancreatic exocrine secretion is regulated by secretin and Cholecystokinin(CCK) that secreted by the small intestine
• secretin stimulates the secretion of sodium bicarbonate from the pancreas
• CCK stimulates(regulates) the secretion of prancreas digestive enzymes

S Cells

• secrete secretin
• stimulus is the acidity of the chyme reaching the duodenum
• effects of secretin is to increase secretion from pancreatic ducts(alkaline watery fluid contains large amounts of HCO3) to neutralize acid

I cells

• secretes cholecystokinin
• stimulus for CCK secretion is presence of fat/lipids(mainly) and protein in the chyme reaching duodenum
• effect of CCK is to stimulate acinar cells to produce digestive enzymes through a CCKA receptor
• indirectly stimulate enzyme secretion by parasympathetic pathway

Pancreatic Digestive Enzymes

• trypsin(inactive till in duodenum) degrades proteins into peptides of various sizes
• carboxypolypeptidase-degrades peptides into ind. AA
• trypsin inhibitor 
• pancreatic amylase breaks down polysaccharides and disaccharides
• pancreatic lipase breaks down triglycerides into monoglycerides and fatty acids
• cholesterol esterase-hydrolysis of esters
• phospholipase-splits FA from phospholipids
• lipase and amylase are secreted in active form  

Enterokinase

• converts trypsinogen to trypsin in the lumen of the small intestine
• trypsin then converts chymotrypsinogen to chymotrypsin and procarboxypeptidase to carboxypeptidase
• these are all pancreatic proteolytic enzymes

Pancreatic Secretion Phases

• cephalic phase: only 10-15% of total secretion activation of vagal efferents stimulates enzymes
• Gastric phase-only present in some species(not significant in humans
• intestinal phase-majority of secretion(combination of hormones CCK and secretin results in maximal enzymes and bicarbonate release)

Acute Pancreatitis

• nonbacterial inflammatory disease caused by activation, interstitial liberation and autodigestion of the pancreas by its own enzymes
• enzymes autodigest and cause fibrosis, leads to thrombi and necrosis of tissue
• gallstones and alcohol account for 90%(other causes are tumor, hperlipidemia and hyperalcemia)
• treatments include reduction of pancreatic secretory stimuli, correction of fluid and electrolyte derangements and protease inhibitor use

Functions of Saliva

• digestion of carbohydrates by salivary amylase(ptylalin): degrades complex carbs, same specificity as pancreatic amylase(different pH optimization of 7), 75% of starch can be digested
• lubrication(mucus-contains mucin): swallowing bolus of food, normal speech
• cleansing action, excretion from body(heavy metals, virus:rabies), water balance(dry mouth causes thirst sensation), buffering action, and lipase(need acidic pH optimum)

Types of aciner cells in salivary glands

• serous cells-secrete water, inorganic salts and amylase(watery saliva)
• mucous cells-secrete glycoprotein mucins(viscous saliva)

Salivary Glands

• parotids-serous secretion containing amylase(25% of secreted volume
• submandibular-serous pls mucous secretion(70% secreted volume)
• sublingual-primarily mucus secretion(5% secreted volume)
• buccal-small, numerous glands-secrete mucus
• stimulation is largely dependent on cholinergic and a-adrenergic stimulation

Autonomic Control of Salivary Secretion

• both parasympathetic(cholinergic) and symp (noradrenergic) stimulation are excitatory to salivary secretion
• parasymp: superior and inferior salivatory nuclei-increases serous secretions
• sympathetic: superior cervical ganglia-increases mucous secretions

Xerostomia

• dry mouth due to poor saliva secretion
• results in difficulty in swallowing and chewing, poor speech, and poor dental health(lots of cavities)
• does not result in poor digestion or absorption

Folds of Kerckring

• found in small intestine
• work to increase surface area and thus absorption by 1000 fold

Large intestine Anatomy

• lack of villi-limited amplification of surface area
• semilunar folds
• crypts

Fluid Balance in GI tract

• Fluid load in Small intestine is about 9L/day, despite fluid intake of about 2L/day
• difference is accounted for by salivary, gastric, pancreatic and biliary secretions
• Small intestine absorbs a large portion of this
• large intestine absorbs most of what is left

Segmental Heterogeneity

• Na+ absorption stimulated by HCO3 in proximal portion of small intestine
• electrogenic Na absorption(potential differences) in rectosigmoid segment of colon
• absorptive function located in villus cells of SI, and secretory function located in crypts
• specific transport mech restricted to different cells
• SI: abs water, Na, Cl, and K; Secretes: HCO3-
• Colon: abs: water, Na, Cl; Secretes: K, HCO3-

Nutrient Coupled Na Absorption

• electrogenic (sodium gradient)
• glucose and amino acid-coupled Na absorption (cotransporter)
• SGLT1
• GLUT2 or GLUT5
• found in jejunum and a little in ileum

Electroneutral Exchange

• establisment of sodium electrical gradient
• stimulated by luminal alkalinity
• H/Na exchanger
• leads to Na uptake across apical membrane
• proton extrusion into lumen
• not dependent on HCO3-
• fount in jejunum and some duodenum

Parallel Exchange Coupled to pH change

• parallel apical Na-H, Cl-HCO3 exchangers
• linked to small changes in pH interdigestive Na absorption
• electroneutral
• regulated by cAMP, cGMP, Ca2+
• decrease Ca2+, decrease NaClabsorbtion 
• found in ileum and proximal colon

ENaC Channel

• epithelial Na Channel
• regulated by the diuretic amiloride
• mineralocorticoids-regulate Na uptake rapidly, gradually, slowly
• mostly in Distal Colon

Intestine Cl Absorption

• passive (driving force derives from Na absorption) found in Jejunum and distal Colon
• Electroneutral Cl-HCO3 exchange: DRA antiporter abs Cl in exchange for HCO3 in mostly proximal colon and then ileum and distal colon
• Parallel exchange: electriacal NaCl absorption also mediates Cl absorption in ileum and proximal clolon(mediated by parallel Na-H exchange and Cl-HCO3- exchange

Cl- Secretion in Crypts

• Na/K/Cl cotransporter brings Cl into cells
• apical Cl channels (CFTR) extrude Cl
• allows Na to follow
• effects of secretagogues (increased Ca2+ and cAMP) typically leading to increase in Cl secretion
• increased amounts of Cl secretion can lead to diarrhea

Bacterial Gastroenteritis: Cholera

• pathogen and virulence factors (caused by vibrio cholerae, most imporant virulence factor is production of cholera toxin)
• pathogenesis and epidemiology
• endotoxin E. Coli increases cAMP leading to increased Cl secretion (cholerea toxin does same thing), na follows Cl back out
• diagnosis based on presence of ricewater stool
• treat with care and tetracycline
• proper hygine is important preventative, vaccines only short lived

Pottassium Absorption and secretion

• passive absorption (jejunum and ileum)
• passive secretion (proximal colon, and mostly distal colon) (distal colon has greatest transmembrane difference)
• active K+ secretion (proximal colon and some distal)
• active absorption(distal colon) (apical H-K pump)

Active K+ secretion

• found in proximal colon and some distal colon
• Na/K pump and Na/k/Cl cotransporter
• K is then secreted out apical or basolateral membrane dependent on state of cell
• cAMP: increases apical K channel activity
• aldosterone: increases passive secretion of Na-K pump and activates apical K channels

Intestinal Mast Cell Activation

• mast cell activation leads to histamine release
• histamine via direct and inderect mechanism leads to Cl excretion
• directly it binds to receptors on cell and inderectly it binds to an enteric neuron that propogates the signal

Insulin

• functions through tyrosine kinase receptor
• increases cellular glucose uptake in muscle and adipose, glycogen syn in liver and muscle, protein syn in liver and muscle, and FA and trigly in liver and adipose
• decreases gluconeogenesis in liver, glycogenolysis in liver and muscle, ketogenesis in liver, lipolysis in adipose, proteolysis in muscle
• IRS1 inudces SREBP induction of lipogensis while IRST phosphyr and inactivates FOXO 
• influences these pathways through  PIP/Protein Kinase B(AKT)

Glucagon

• activates glucagon receptor coupled to G_as increasing cAMP levels
• increases: glycogenolysis in liver(no glucagon receptors in muscle), gluconeogenesis in liver, ketogenesis in liver(only organ ketogenesis) and lipolysis in adipose 

Epinephrine(adrenaline)

• Beta adrenergic  coupled to G_as and alpha will stimulate G_aq 
• Beta causes increase of cAMP
• increases glycogenolysis in liver and muscle and lipolysis in adipose tissue

Cortisol

• activated glucocorticoid receptors to increase gene transcription
• increases gluconeogenesis in liver, glucogen synthesis in liver and proteolysis in muscle
• decreases tussue glucose utilization in liver, muscle and adipose

Growth Hormone 

• function through tyrosine kinase GH receptors coupled to JAK-STAT 
• increases glycogenolysis in liver, lipolysis in adipose and positive nitrogen balance in muscle
• many growth hormone indirect effects are mediated by the synthesis of Insulin like growth factor somatomedin(IGF-I)

GLUT4

• glucose receptor for muscle and adipose tissure
• sit in cytosol and need to be activated by insulin to move from cytosol to plasma membrane
• when not activated you have insulin resistance(type II diabetes)

Altered Blood Concetrations in Fed state

• increase in glucose, chylomicrons (gut to adipose, muscle), VLDL(liver to muscle, adipose), amino acids(gut to liver, musclem adipose and brain), and insulin (pancreas to liver, muscle and adipose)

Altered Blood Concetrations in Basal

or Post Absorptive State

• increase in free fatty acids(8-25 mg/dl
• increase in glycerol
• increase in lactate(5-15mg/dL)
• increase in Urea (7-18mg/dL)
• increase in Glucagon(50-200pg/ml)

Hyper Catabolic Disease State

• patients w/ bruns, trauma, hemorrhage or infection with critical illness of diabetes and succumb to organ failure
• patients present w/ hyperglycemia, hypertriglyceridemia and insulin resisstance
• caused by impaired insulin signaling in liver, muscle and adipose tissue
• insulin resistance caused by IRS2 being inactivated in liver whle IRS1 is active, increasing lipogenesis
• IRS2 is inactivated by fatty acids or reactive oxygen species JNK
• also inactivated by cytokines that activate inflammatory I kappa kinase (IKK)
• treatment is insulin therapy(30% mort. reduction)

General Mechanisms of 

Digestion and Absorption 

• passive diffusion(no digestion)
• luminal hydrolisis of polymers to monomers
• brushborder hydrolysis of oligomer to monomer
• intracellular hydrolysis 
• luminal hydrolysis followed by intracellular resynthesis

GI Digestion and Absorption

• mouth- digestion: salivary amylase; absorption-little to none
• stomach- digestion: HCl, Pepsin; absorption: no nutrients, only alcohol and aspirin
• virtually all absorption occurs in the small intestine)surface area increased 600 fold from villus

Carbohydrate Digestion

• initiated by salivary amylase and majority done by pancreatic amylase in small intestine
• pH optimum 7, activated by Cl- ions
•  α1,4 bonds give straight chains and  α1,6 give branched
• amylase hydrolyses only 1,4 bonds-does not cleave terminal 1,4 linkages, 1,6 linkages or 1,4 linkages adjacet to 1,6
• glucose is not a product of starch digestion(further digestion needed

Disaccharide Breakdown

• amylase breaks down carb. to mostly disacchardides
• these are then broken down to constituent monosaccharides by enzymes in microvilli brush border(not secreted)
• maltose(glucose-glucose)--maltase--> glucose
• sucrose(glucose-fructose) --sucrase->glu and fru
• lactose (glucose-galactose)--lactase-> glu and gal

SGLT1 Transporter

• used for absorbtion of monosacharides
• it is a cotransporter of 2Na+ and then either galactose or glucose (80% use this transporter)
• found on lumen side 
• fructose uses GLUT5

Absorbtion of Simple Sugars

• limiting step is the rate of absorption-large excess in small intestine
• majority absorbted in duodenum and jejunum
• glucose/galactose absorbed passively under anaerobic conditions and actively absorbed by same carrier when O2 available
• deficiencies of brush  border enzymes cause osmotic diarrhea
• human SI can absorb up to 10kg sucrose per day

Disruption of Carbohydrate Absorption

• deficiency in brush border enzymes: lactase dficiency is either congenital or acquired later in life-most common (maltase deficiency is not known
• GI infection/disease: celiac disease, bacterial infections, protozoan infections can all cause inflammation and interference with brush border absorption
• consequence is osmotic diarrhea

Pepsin

• inactive precursor is pepsinogen
• active @ pH 2-3m inactive @ph>5
• secretion stimulated by acetylcholine or acid
• only protease which can break down collagen
• action terminated by neutralization by bicarbonate in duodenum
• all proteases(stomach and pancreatic) secreted as inactive precursors
• most protein digestion occurs in the duodenum/jejunum

Endopeptidases vs Exopeptidases

• endo-trpsin, chymotrypsin, elastase
• peptidases with affinity for peptide bonds adjacent to amino acids
• yield oligopeptides of 2-6 AA
• Exo- carboxypeptidases A and B
• hydrolyze bonds adjacent to carboxyl terminus resulting in release of individual AA

Protein Absorption

• absorption in luminal membranes of intestinal epithelial cells in form of di, tri and free amino acids
• co transported similar to glucose via Na+ or H+ co-transport mechanism
• enterocyte can phagocytose whole proteins with 10% direct(intact) pathway and 90% degradative pathway
• M cells can also phagocytose whole proteins via those 2 pathways

Oligopeptide absorption

• uses a PepT1 cotransporter. transports the peptide and H+ into the cell where a peptidase breaks down the peptide
• the H+ gradient is created by a Na-H+ antitransporter using the Na gradient created by the Na/k ATPase pump

Initial Fat hydrolysis

• lingual lipase in mouth
• gastric lipase in stomach
• majority is performed in proximal small intestine by actions of pancreatic lipase
• key preliminary step in fat hydrolysis is emulsification

Stomach mechanical processes for 

Emulsification

• reduce lipid roplet size
• increasing surface area ratio to volume
• stabilize emulsion by preventing dispersed lipid from coalescing(coating droplets with MAGs, cholesterol, bile salts, lysolecithins,etc)

Digestion of Fats

• fat stimulates CCK release->causes gallbladder contraction
• bile salts emulsify fats-> large surface area for enzymatic action
• lecithin important for emulsification
• pancreatic lipase(water soluble, acid liable)
• colipase very important(increases PL activity)
• PLA₂ : hydrolyzes glycerophospholipids, effective at alkaline pH, requires bile salts for activity
• carboxyl ester hydrolase: active against wide range of esters

Colipase

• secreted as procolipase and is cleaved to active colipase
• a cofactor for pancreatic lipase
• binds to emulsified lipid droplet which increases binding efficiency of pancreatic lipase(interaction btw 2 cause a conformation change in pancreatic lipase)

Re-esterfication of digested lipids

• fat molecules go to SER where they are repackaged and transported to golgi where they become chylomicrons
• chylomicrons are exocytosed into circulation via the thoracic duct

Steatorrhea

• undigested fat in feces
• due to a lack of lipases or severe lack of bile for emulsification

Vitamin B12

• released from food in stomach HCl
• bound by R proteins in the stomach
• then bound by intrinsic factor in the small intestine: intrinsic factor produced by gastric parietal cells, resistant to protease digestion, required for B12 absorption
• absence of intrinsic factor or dietary intake of B12 is
• once inside cell IF is degraded in lysosome and Trans-cobalamin II(TBC) shuttles B12 out of enterocyte
• other mechanisms for other water soluble vitamins and fat soluble ones abs like lipids

Pernicious Anemia

• absence of intrinsic factor or dietary intake of B12
• B12 is needed for red blood cell maturation

Calcium Uptake in Duodenum

• either paracellular or shuttled through enterocyte
• once it enters the enterocyte it becomes bound to calbindin
• vitamin D allows for synthesis of calbindin, as well as Na/Ca antitransporter and H/Na antitransporter that brings calcium out of the cell 
• calbindin shuttles the Ca to these to antitransporters
• the H/Ca antitransporter uses ATP

Absorption of Iron

• if in Fe³⁺ (ferric iron, non heme iron) must be reduced by the membrane bound protein Dcytb to Fe²⁺
• Fe²⁺ (ferrous iron, heme iron) is transported into the enterocyte via a DMT cotransporter that uses the gradient of H+
• once inside ferrous iron binds to mobilferrin which shuttles it to the transporter FP1 that transports it out. It is then oxidized back to feric iron and tranported in circulation via plasma transferrin 
• heme is transported into cell and heme oxygenase breaks it down to ferrous iron and billverdin(goes to bilirubin)

Hepatic/Liver Functions

• formation and secretion of bile
• storage of glycogen, buffer for blood glucose
• synthesis of urea
• metabolism of cholesterol and fat
• synthesis and endocrine secretion of many plasma proteins, including clotting factors
• detoxification of many drugs and other poisons
• cleansing of bacteria from blood
• processing of several steroid hormones and vitamin D
• volume reservoir for blood 
• catabolism of hemoglobin from worn-out red blood cells

Hepatic Lobule

• hexagonal in shape
• hepatic vein branch at center
• portal triads at each corner
• hepatocytes form barrier between canaliculi and sinusoid
• endothelial cells form a fenestrated structure allowing limited access to Space of Disse
• kupffer cells act as macrophages to remove particulate matter from blood

Classic Hepatic Lobule

• drains blood from the portal vein and teh hepatic artery to the hepatic or central vein

Portal Lobule

• drains bile from the hepatocytes to the bile duct in the protal triad

Portal Acinus

• supplies oxygenated blood to hepatocytes
• zone 1 near triad is most oxygenated
• zone II is moving towards the central vein
• zone III is right next to the central vein and least oxygenated

Liver Metabolism: 4 mechanisms

****

• imported from blood across basolateral membrane
• hepatocyte transport within cell
• modification of intracellular compound
• excretion of product into bile
• uptake includes: bile acids(cholic and chenodeoxycholic), organic anions/cations(OATP/OCTPs), salts(deprotonated forms of bile acids)
• MRP2 and BSEP transport BA- into bile canaliculus

Liver Excretory Function

• removal of bilirub(bile pigment)
• phagocytized macrophages(phag red blood cells) release unconjugated bilirubin
• this is taken up by hepatocytes and conjugated with glucuronic acid (uses enzyme UGT in ER)
• soluble form is excreted into bile 
• goes to gallbladder and or small intestine
• in small intestine can be further converted and excreted in feces or processed in kidney in form of urobilin(urine color)

ABCG5/ABCG8

• pump that allows for movement of cholesterol from hepatocyte to bile caniculi
• uses ATP
• main mechanism responsible for cholesterol movement in hepatocyte

Hepatocyte Detoxification Mechanisms

• cytochromeP450s hydroxylate your cytotoxic molecule
• after that the molecule goes into hepatocyte and undergoes conjugation with glutothyione (GSH)
• shuttled into bile where it undergoes further modification via transpeptidase that removes a glu molecule
• the element can then either enter hepatic circulation or enter kidney
• in kidney it is further modified with peptidases and tpically involve a mercapturic acid derivitive that allows it to be excreted out in the urine

Bile Acid Synthesis

• cholesterol gets converted to primary bile acids(cholic acid or chenodeoxycholic acid)
• then converted to secondary bile acids (deoxycholic acid or lithocholic acid)
• then converted to bile salts with conjugation with glycine or taurine
• Chol-BA is 14 reaction processing

Cholanglocyte

• plays role in liver with bicarb secretion
• Cl- - bicarb(HCO3) exhanger on apical side generates alkaline basic environment in lumen
• CFTR Cl- channels stimulated by cAMP to shuttle Cl- out of cell to stimulate the above exchanger
• somatostatin inhibits this process (Gicoupled rec)
• secretin(released in acidic env), glucagon and VIP activate (raise cAMP)
• Na/HCO3 co transporter brings bicarb into cell

Circulation and Absorption of Bile Acids

• bile acid delivery from liver to SI is in primary conjugated form(bound to taurine or glycine(BA-Z)
• most get absorbed in terminal Ileum as  BA-Z via a Na coupled cotransporter called ASBT
• a basolateral transporter called OSTα-OSTβ then transport it out to circulation to go back up to gallbladder or liver
• bacterial modification(deconjugation) can occur causing bile acids to form which can be absorbed by passive diffusion(only thing that happens in large intestine)

Cholelithiasis

• presence of gallstones in gallbladder or bile duct
• cholesterol(insoluble by itself) is major component of gallstone
• cholesterol is usually rendered soluble by forming complex with bile salts and lecithin
• increase in calcium or bilirubin concentrations can also cause gallstones(pigment stones)
• causes of gallstones: too much absorption of water from bile or too much absorption of bile acids from bile or too much cholesterol in bile or inflamation of eptithelium

Amino Acid Metabolism

• metabolized to a number of things rather quickly once taken up by hepatocyte (can go to αketoacid that can go to acetyl CoA, pyruvate or other citric acid intermediates)
• occurs fast so that they can be changed to metabolites that can be readily used
• main excretory product of AA metabolism is Urea that is excreted in urine

LPL

• breaks down chylomicrons into smaller constituents
• releases free fatty acids and glycerol molecules
• small amount of remnant chylomicrons and are endocytosed into liver to be modified into bile acids
• VLDL's can also be formed and can be degraded by LPL into more fatty acids and LDL

Osmolality of Saline

• normal saline is 300mOsm/L
• half normal saline is 150mOsm/L
• so you multiply these numbers by the number of liters you are adding(also add the liters to the total liters and divide the total osm by that)

100kg male with plasma osm of 315mOsm/L

infuse 2 liters of .5 normal saline(150mOsm/L

• 60 percent of person is water so 60kg or 60L or water
• 60L x 315 mOsm/L =18900
• 150mOsm/L x 2 liters = 300 
• 60L + 2 L =62 liters
• 1890+300=19200 ÷ 62 =309.7mOsm/L

Arcuate Artery

• runs in between the medulla and the cortex in the kidney
• gives off interlobular arteries by the nephrons
• the nephrons then give off afferent and efferent arterioles
• afferent brings blood into glomerulus and effernt takes it away
• pressure is lesser downstream of a constriction 
• pressure drops drastically at afferent arteriole and then later at efferent arteriole
• hydrostatic prussure higher at this capillary bed then anywhere else in body

Nephron

• 65% of what is filtered is reabsorbed in proximal tubule
• wall is very thin in thin descending loop of henle so water is reabsorbed passively 
• thin ascending loop has thin layer of cells but all reabsorbtion there is electrolytes(passive, uses gradient
• thick ascending loop of henle(has extensive machinery) -25% of reabsorbed sodium happens at this point
• juxtamedullary nephrons(important for water reabsorption and corticol nephrons(90%)(shorter loops of henle)(waste more water and sodium) 

Vasa Recta

• blood vessels that go around the loops of henle on juxtamedullary nephrons
• are slow flowing
• allows the medulla to have the hyperosmotic concentration with out the solutes washing away
• peritubular surround corticol nephrons

Dependence of Filterability on 

Charge and Size

(glomerulus)

• for a neutral dextran, the smaller the size, the more that is filtered
• more material gets filtered if it is cationic(positive) and less gets filtered if it is anionic(negative)
• if you remove the negative charge of the glomerulus then anions flow through more (as a neutral)

Net Filtration Equation

(glomuruls

• NF= Kf[{hydrostatic pressure}-{osmotoic pressure}]
• Kf does not normally limit filtration in a healthy glomerulus 

Relaxing and Constricting Efferent Arteriole

• resistance here has a biphasic effect on GFR
• Relaxing the effernt arteriole increases flow through the glomerular capillary but decreases GFR because more blood is flowing out faster 
• constriction decreases renal blood flow, increases GFR because of build up in pressure in glomerular capillary
• once it gets to a certain resistance(constriction) though GFR starts to slope back down because there is so little renal blood flow(osmotic pressure so high that there is no driving force)
• in afferent relaxing increases GFR and constriction decreases

Units of Filtration

• GFR-120-125 ml/min
• Filtered fraction = GFR/RPF
• 0.2 =120ml/min/600ml/min

Intrinsic Regulation of 

Glomerular Filtration

• prevents extreme change in filtration rate(status quo)
• locally controlled by individual nephrons
• to maintain RBF, increases in resistance must match the increase in pressure
• constant GFR indicates that the icnreased resistance must cause Pgc to stay constant
• uses autoregulation
• can be over-rided when extracellular volume vary significantly from a normal range

Glomerular Autoregulation

• used for intrinsic regulation (uses afferent arteriole)
• myogenic response: reflex rsponse to pressure induced changes in arteriole stretch(increased art. pressure increases stretch which increases movemnt of EC calcium into muscle cell to induce vasoconstriction
• tubuloglomerular Feedback: increase GFR increases filtrate(Na, Cl, fluid) to macula dense which the Na/K/Cl cotransporters move into it. Increased Cl increases exchange of Cl for Ca through basolateral membrane. The increased Ca stimulates MD to release a pacrine agent (ATP, adenosine, thromboxane) that constricts afferent arteriole. decreases RBF and Pgc

Transcellular Pathway

• type of reabsorbtion in a nephron
• occurs in three steps
• crosses luminal wall
• crosses abluminal wall(baselateral membrane) into interstitium
• diffuses from interstitium into capillary (the diffusion distances btw the nephron epithelial cells and surrounding capillaries is very short

Nephron Symporters

• SGLT2 transports glucose and Na into cell at luminal early proximal T. (moves vast majority of glucose out)
• SGLT1 transports 2Na and glucose into cell at luminal late proximal t. (cleans up the rest)
• Na and phosphate symporter at luminal proximal tubule
• NBC transports Na and 3HCO3 into cell at abluminal proxmial T.
• Na Cl symporter at luminal distal tubule
• NKCC2 transports Na, K and 2 Cl out of the cell at the luminal thick ascending LOH

Nephron Antiporters

• NHE3 moves Na in and H out in luminal proximal t. and thick LOH
• NCX moves 3Na in and Ca out in abluminal proximal T, thick LOH and dist T
• Cl-HCO3 antiporter in abluminal collection duck 

Nephron Transport channels

• GLUT on abluminal proximal tubule
• Cl channel on abluminal proximal t., thick LOH and Distal T
• K channel on luminal and abluminal thick LOH and collecting duct
• Ca  channel on luminal proximal T, thick LOH and distal T.
• ENaC sodium channel on luminal collecting duct
• aquaporins at luminal and abluminal proxima t, thin descending LOH, late distal T, collecting duct

Nephron Glucose Titration Curve

• at about 200mg/dL the amount of reabsorbtion cannot completely keep up with the amount of filtered load
• when it reaches Tm(transport maximum), an increase in filtered load is a direct increase in excretion 
• Splay is the transition area from a slight amount of excretion to where the Transport maximum is, more of a curve then linear

Oligopeptide Reabsorbtion

• 99% are reabsorbed in the PCT with the rest being reabsorbed in remaining parts of nephron
• simple oligopeptides go through pores
• for larger ones they are hydrolyzed in brush border enzymes down to Amino acids

GFR Tracer

• concentration of filtered has to equal plasma concentration (freely filtered
• cannot be reabsorbed
• not secreted 
• each ml of filtrate contains the same number of tracer molecules as does each ml of plasma entering the efferent arteriole
• inulin(invasive but ideal)
• Ceatinine(endogenous or non-invasive, minor amount secreted in proximal tubule)

Renal Plasma Flow(RPF)

• all tracer delived to the kidney must be excreted
• Para-aminohippuric Acid(PAH): filtered + secreted in proxmial tubule(about 90% removed)
• problem is vasa recta of juxtamedullary nephrons does not come in contact with proximal tubule
• underestimation: can be corrected though by taking P of artery -Pvein (too invasive though)

Renal Blood Flow

• Renal plasma flow does not include the RBC
• Renal blood flow = RPF/(1-hematocrit) 

Sodium Reabsoprtion Locations

• 65% is in the proximal convoluted tubule 
• a little in thin ascending LOH depending on conc gradient(passive)
• 25% is uptaken in thick ascending limb of LOH
• some in distal convoluted tubule (5-7%) (Na-Cl symporter)
• 1-3% is taken up in collecting duct and where most of the regulation is

Sodium handling in Loop of Henle

• sodium is brought in along its concentration gradient 
• this symporter brings K against its concentration (K can leak back to filtrate and interstitium so you move essentially half a K) 
• Also symports 2 Cl
• makes lumen positive and interstitum negative, allows for electrochemical gradient for moving Na through tight junctions

Principle Cell

• found in connecting tubule or corticol collecting duct
• 2 priciple cells for each intercalated cells in corticol collecting duct(oposite in medullary colecting duct) 
• important for water and sodium reabs and K secretion
• ENaC(endothelial sodium channel)

Chloride Uptake in Nephron

• Early PCT(S1)-paracellular(solvent drag)(mostly HCO3 taken up here to counter Na)
• Late PCT(S3)-no paracellular, Na-H antiporter drives Hbase coming in that a antiporter for it drives Cl absorbtion(antiporter)
• Thick Ascend. LOH- Na-k-Cl symporter
• DCT - Na-Cl symporter
• Corticol collecting duct-only Cl taken up here(principle cells)
• Corticol collecting duct-HCO3-/Cl antiporter(pendrin)(intercalated cell)

Glomerulotubular Balance

• fraction(reabsorbed/filtered) of sodium reabsorbed in the Proximal Tubule is constant even when GFR changes
• If GFR is 50ml/min or 100ml/min, 2/3(65%) of filtered Na is still reabsorbed
• unused symporters are recruited when GFR goes up, until it reaches transport maxium
• distal tubule also contains unused symporters

Antidiuretic Hormone(ADH)

• increases water permeability in late distal tubule and collecting duct
• adds to medullary interstitial osmolality by increasing urea reabsorption
• attaches to V2 (hydrolyzes ATP to raise cAMP levels receptor that triggers the synthesis and insertion of luminal aquaporins(uses vessicles)
• theoreticall it would create an equal osmotic level in interstitium and filtrate
• happens in principle cells not intercallated cells
• also increases UT urea receptors in tubule(medullary collecting duct)
• Also increases Na reabs with NKCl symporter in thick asending LOH
• can cause vasoconstriction at high levels

Effect of increased Urea Permeability 

• noramlly urea is very slowly passivly reabsorbed in collecting ducts
• enhanced urea reabsorption can ultimately double the original(electrolyte-mediated) interstitial osmolality
• this leads to higher interstitial osmolarity as you go down the collecting duct
• remaining urea is recycled

Urea Reabsorption 

• PCT has some passive urea reabsorption from solvent drag and transcellular
• Thin Descending LOH: Urea moves back into lumen through UT channels
• Thin Ascending LOH: can be either but more likely secretion
• Inner medulary colelcting duct there is UT-A1 that is under control of ADH and UT-A3 that allows efflux to interstitium

Protection of Hyperosmotic interstitium

• low medullary blood flow
• countercurrent exchange mechanism (how vasa recta goes down to the bottom of the medullary then back up)

Mechanisms controlling sodium processing

in the nephron

• hemodynamics: proximal tubule-GT balance, distal tubule
• Control effective circulating volume: RAA, sympathetics, ADH(severe), ANP
• Humoral agents: Na pump inhibitor, prostaglandins and bradykinin, dopamine

R-A-A Axis overview

• Activation of JuxtaGlomerular Apparatus causes Renin secretion (three things must occur)
• JGA also activated by sympathetic stimulation and a decrease of NaCl to the JGA(flow decreases because GFR decreased)
• Renin release can also be activated by decrease in stretch of afferent arteriole(decreased Ca)
• Renin cleaves angiotensinogen to angiotensin I
• ACE in the lungs converts Angiotensin I to angiotensin II, which activates aldosterone

Angiotensin II

• enhances Na-H antiporter in PCT and thick ascending LOH
• causes vasoconstriction and diminishes GFR
• also enhancesENaC on the principle cell(pores become more permeable
• decreases flow in vasa recta(allows urea to accumulate in it)
• increases peritubular capillary osmotic pressure and decreases hydrostatic pressure
• increases filtration fraction by decreases renal blood flow
• increases resistance in both efferent and afferent arteriole

Aldosterone

• steroid that moves into principle cells and binds to transport protein(Mineralocorticoid receptor)
• goes to nucleus and increases cell transport channels(ENaC and potassium channels on luminal membrane)
• also increases Na/K pumps on abluminal membrane
• increases mitochondria to drive pumps 
• this all causes rapid movement of Na

ADH and Effective Circulating Volume

• increases activity of Na-k-Cl symporter in thick ascending LOH and ENaC activity in principle cell to enhance Na reabsorbtion
• only works during a significant decrease in Effective circulating volume

Sympathetic NS Direct Renal Effects

• activated by low Effective circulating volume
• vasoconstriction - decreased blood flow and GFR
• acts on Na-H antiporter and Na/K atpase in early PCT to increase uptake 

Atrial Natriuretic Peptide

• activated with High ECV
• increased stretch of heart bararecptors
• Atria(ANP) and some Ventricle (BNP) dilate afferent arteriole to maximize GFR, and inhibit ENaC on lumen of principle cells in medullary collecting duct
• ANP also increases renal blood flow, both to corticol and medullary regions to wash out electrolytes from interstium

Prostaglandins and Bradykinin

• acts on K channel on thick ascending limb LOH, causes less of a positive charge in filtrate that limits movement through tight junction of K and Na, causing decrease of Na uptake
• acts on ENaC on principle cell to slow down Na uptake

ADH sensitivity

• usually responds around 280mOsm
• if the volume in system is high(expanded) ADH  becomes less sensitive to an increase in Plasma osmolality
• if hypovolemia(low volume, volume contraction) its sensitivity increases signficantly(around 10%)

Processing of Large influx of potassium

• very low amount of potassium is in ECF, about 49 compared to the 140 in cells
• when a large load is taken up the body must find a way to get it out of ECF as to not mess with membrane potentials
• body does not excrete it very fast so instead it brings it into the cells and then over many hours excretes it in the kidneys

Potassium processing in nephron

• proximal tubule: minimal secretion with passive reabsorption to interstitium through solvent drag and tight jnx
• secretion in thin descending LOH and reapsorbtion in thin ascending LOH (involed with medullary trapping of K)
• thick ascending LOH: K-N-2Cl symporter, some diffusing into filtrate and some diffusion into interstitium, some reabsorb through tight jnx
• principal cells: Na/K pump brings K in and then potassium channels and a K-Cl symporter shuttles potassium into the filtrate, electical and conc gradient drive(also negative charge in lumen because Na from filtrate is taken up faster then Cl)
• αintercalated cells have K-H antiporter (ATP) to bring K in and shuttle H to filtrate

Aldosterone and Potassium 

• in the collecting duct it increases Na/K pumps on abluminal side of principal cells
• increases leaky potassium channels on luminal side
• and increases amount of ATP in principal cell
• potassium secretion effected by electrochemical gradient, concentration gradient and filtrate flow (increases flow, dec concentration, inc amount of potassium secreted

K diets effect on Secretion rate vs Distal Flow

• a high K diet causes a high secretion rate for not a significant increase in distal flow
• a low potassium diet requires a high distal flow for not a very significant increase in potassium secretion
• a normal potassium diet is somewhere in the middle

glucocorticoids and Potassium 

• they increase GFR and decrease water permeability in the neprhon
• this increases filtrate flow
• an increase in filtrate flow causes an increase in potassium secretion

Factors Altering electrochemical gradient

(affecting K+)

• negative charge in cytoplasm a result of potassium leak induced membrane potential
• negative charge in filtrate a result of the reabs of sodium greater then chloride(aldosterone enhances Na uptake too)
• note chloride is only anion reabs in the collecting duct so accumulation of other anions increases K secretion(example bicarb and betahydroxybutyrate in diabetes)

Potassium Acid-Base Effects

• acidosis: increase in intracellular H+ would cause an efflux of potassium out of the cell to maintain neutrality
• alkalosis: decrease in intracellular H+ would cause an influx of potassium into the cell
• alkolosis on principal cells leads to secretion and excretion of potassium because intracellular levels are so high(leads to changes in electrocardiogram)
• acidosis in principal cell leads to decrease in potassium secretion leads to elevation of plasma potassium, increasing filtration of potassium
• both acidosis and alkolosis cause loss of potassium

Sodium wasting conditions

• high salt diets, saline infusion, osmotic diuresis, proximal tubule diuretics
• cause increased flow in collecting ducts
• leads to increase of Potassium secretion

Parathyroid Hormone and Calcium

• a decrease in plasma concentration of calcium stimulates PTH secretion
• increasing plasma phosphate levels causes the phosphate to bind with plasma calcium: this increases PTH secretion via a backdoor mechanism that lowers plasma free calcium conc 
• PTH causes bone to release ionic Ca and HPO4--
• causes kindey to increase phosphate exc in proximal tubule and increase Ca reabs in TAL and distal tubule
• PTH also activates calciferol in proximal tubule

Parathyroid hormone and bone

• PTH and calciferol(levels increased from PTH) bind to receptors on osteoblasts to down regulate collagen syn and stimulate cytokine release
• cytokines cause proliferation of osteoclasts
• osteoclasts secrete acid and enzymes onto bone matrix to cause reabsorption of calcium and phosphate(enzymes and H+)

Parathyroid Hormone and nephron

• proximal tubule causes Na-PO4 symporter to leave the luminal membrane, decreasing PO4 reabs
• also activates enzyme to convert inactive Vit D to calciferol in proximal tubule
• distal tubule increases luminal permeability and increases abluminal Ca/3Na  antiporter and ATP dependent Ca transporter to get Ca to interstitium (where most fine control happens)(8% of reabs)

Calciferol Action

• bone:acts with PTH to increase number of osteoclasts
• kidney: increased calbindin-D in distal tubule epithelial cells to facilitate calcium transport from lumenal membrane to abluminal calcium pumps
• Intestines: increases lumenal calcium channels, increases calbindin D, increase abluminal calcium pumps(3Na/Caantiporter and Ca ATPase) and increase phosphate reabsorption(2Na/HPO4--) 
• calciferol has a negative feed back loop with its production

Calcium Reabsorption in Thich Ascending limb

• 25% of reabsoprtion here, not great deal of fine control
• PTH can increase number of Ca channels on luminal membrane
• Na-K-2Cl symporter causes a positive charge in lumen because of back flow of potassium to lumen
• this drives Ca to flow down an electrochemical gradient and some concentration gradient
• increased extracellular Ca binds to Ca sensing receptor on abluminal membrane, that leads to inhibatition of the Na-K-2Cl symporter and open characteristics of K backleak channel, decreasing electrochemical gradient

Daily Phosphate Processing

• 1500 g intake with 300mg excreted in feces
• kindey maintains balance by excreting excess
• 86% stored in bone, 13+% in ICF, 0.03% in ECF(10% of plasma phosphate is bound to protein and unavailable for filtration
• 80% reabs in PCT(3Na-HPO4 symporter)(2NA-H2PO4)
• acidosis inhibits binding to symporter and high filtrate phosphate stiumaltes decrease in # and activity of symporters

Magnesium distribution and reguation

• 67% is stored in the bone and 31% is stored in ICF
• the last 1-2% is in ECF and of that only 60% of it is in ionized form to be filtered(20 micrograms/ml)
• mg reabs is passive, with 15% in PCT(solvent drag or diffusion) and 70% in the Thick ascending limb of LOH 
• TAL: concentration and electrochemical(pos lumen) drives reabsorption paracellularly
•  paracellin-1 at junx acts as channel(changes Pmg alter amount)
• decreased plasma Mg stimulates PTH release

Urine Transport from kindney to bladder

and then out

• nephron output stretches calyx and stimulates the calyx pacemaker
• calyx pacemaker leads to peristaltic contraction of ureter
• this contraction can be enhanced by parasympathetic and inhibited by sympathetic
• trigone muscle in bladder prevents backflow into ureter
• bladder pressure does not increase much from 100 to 400ml and then drastically increases from 400 to 500

Micturition Reflex

• micturition initiated with voluntary relaxation of external sphincter followed by reflex relaxation of internal sphincter
• afferents to cortex are stimulated as urine reaches posterior urethra
• removal of cortical inhibition so parasymp nerves can stimulate waves of contraction by detrusor muscle
• contraction of abbs can also increase bladder pressure

Diuretic Classes:sites of action

• carbonic anhydrase inhibitors: proximal tubule
• loop: loop of henle
• thiazide: distal convoluted tubule
• potassium-sparing: distal convoluted tubule and collecting duct
• osmotic: proximal tubule and loop of henle 
• diuretics tend to be secreted by ionic transport proteins(not freely filtered because usually bound to protein)

Carbonic Anhydrase inhibitor

• inhibit H secretion and HCO3- reabsorption, which reduces Na Reabsorption
• proximal tubules
• carbonic anhydrase normally causes formation of carbonic acid H2CO3 which can later break down to H and HCO3 or H2O and CO2 (both in lumen and in cytoplasm of nephron)
• the inhibitor does not allow the split of this inside the cell which does not allow free H for the H-Na antiporter

Loop Diuretics

• inhibit Na-K-2Cl co transport in luminal membrane
• mostly effects the thick ascending LOH
• are most effective diuretics because a significant fraction of Na reabsorption occurs in the LOH and downstream processes are limited

Thiazide diuretics

• inhibit Na-Cl co transport in luminal membrane
• effect early distal tubules

Aldosterone antogonists(Ksparring)

and

Na Channel Blockers

• inhibit action of aldosterone on tubular receptor, decrease Na reabsorption and decrease K secretion
• effects collecting ducts
• flow will increase
• called potassium sparring because you do not lose as much potassium

Osmotic Diuretics

• anything that is dumped into filtrate and cannot be removed
• inhibit water and solute reabsorption by increasing osmolarity of tubular filtrate
• proximal tubule and descending LOH
• glucose can function as osmotic diuretic

Proximal Tubule Disorders

• Renal Glycosuria: glucose reabsorption
• Aminoaciduria: amino acid reabsorption
• Renal Hypophosphatemia: phosphate reabsorption

Renal Tubular Acidosis

• elevated hydrogen ion throughout the body
• metabolic acidosis where not enough bicarb available
• effects bicarb reabsorption in proximal tubule
• effects hydrogen ion secretion in collecting duct

Collecting Duct disorders

• Nephrogenic Diabetes insipidus: unresponsive to ADH , effects principal cells of the collecting duct
• Liddles syndromeL hyperactivity of epithelial sodium channels, ENaC in cortical collecting duct

Barters and Gitelmans disorders

• barters syndrome affects sodium, potassium, and chloride by affecting the symporter in the loop of henle
• gitelmans syndrome affects sodium and chloride in the distal convoluted tubule

Dissociation Constant

• Keq= [H+][OH-]/[H2O]
• amount of H+ formed is defined by invidual acids Keq
• weak acids have low Keq, little dissociation (H2O)
• strong acids have high Keq, total dissociation(HCl)

pH of Body Fluid

• physiologic range is pH(6.8-7.8)
• arterial blood pH 7.4 (H+ of 40)
• venous blood pH 7.35 (more CO2, weak acid)
• interstitial fluid 7.35 
• intracellular fluid pH 6.0-7.4 (due to metabolism, more CO2 from TCA, and physiologic condition)
• urine pH 4.5-8.0 (normal is usually a little acidic)
• diabetes makes it more acidic
• Gastric HCl 0.8
• lower the pH the higher the H+ (6.8 = H+ of 160) 

Defenses against changes in pH

• 1st line: Buffer system in the body fluid (within seconds) (bicarbonate is quantitatively the most important in ECF)
• 2nd line: respiratory center (lung, acts within a few minutes)
• 3rd line: kidney (relatively slow, hours-day, but the most powerful of the acid-base regulatory systems)

Buffers

• a base that binds free hydrogen ions to form a weak acid
• phosphate buffer plays major role in buffering renal tubular fluid and intracellular fluild: HPO4-- 
• when calculating if you add 2mM of HCl and all of it dissociates you add 2 to the [HA] and subtract 2 from the [A-]: H=keq(HA/A-)
• ideal buffer system preven changes in pH when either acid or base is added and neutralize lot of added acid or base with minimal effect on pH
• systems buffering capacity is defined by buffer concentration and binding affinity for hydrogen ion

Bicarbonate/carbon dioxide 

buffer system

• H+ + HCO3- --> H2CO3 
• rx is slow unless carbonic anhydrase(CA) is present
• H2CO3 can dissociate to H2O and dissolved CO2
• the conjugate acid is H2CO3 + dissolved CO2
• at body temp there is 1k more dis CO2 then carbonic acid at equilibrium 
• Concentration of H2CO3 is negligible and dissolved CO2 = 0.03 x P_CO2
• acts on the system at a point where slow is low, thus does not effectively protect against the loss of H+ (pk= 6.1) 
• most powerful ECF buffer system due to that both are regulated by the kidney (HCO3) and lung(CO2), allowing them to be precisely controlled

Isohydric Principle 

• earch of the three buffer systems(bicarb, phosphate, protein) are in equilibrium with that pool of free hydrogen ion
• a change in the amount of hydrogen ion on any of the buffer systems willl impact all of the systesms (interdependence)
• buffer system buffers one another by shifting H back and forth btw them 
• H= K1 HA1/A1 = K2 HA2/A2= K3 HA3/A3

Sources of Hydrogen Ion

• oxidative metabolism creates a volatile acid
• protein and lipid catabolism yields non-volatile, fixed acid (sulfuric acid from protein and phosphoric acid from phospholipids) and normally produced at a rate of 40-60 mmoles/day
• other fixed acids may be overproduced in disease or be ingested such as ketoacids, lactic acid and salicyclic acid

Respiratory Acidosis

• inability of the lung to eliminate CO2 efficiently so the euilibrium shifts toward increased H+ and HCO3- and pH decreases
• CO2+H2O -> H + HCO3-
• normally 1.2 mmol/L CO2 is disolved corresponding to PCO2 of 40 mmHg
• opiates, anesthetics, sedatives, airway obstruction, COPD, ALS, Multiple sclerosis

Respiratory Alkalosis

• excessive loss of CO2 through ventilation driving equilibruim to the left away from H, increasing oH
• CO2 + H2O <--- H + HCO3-
• normally 1.2 mmol/L CO2 is disolved corresponding to PCO2 of 40 mmHg
• pneumonia, pulmonary embolus, high altitude, psychogenic, salicylate intoxication

Salicylate Intoxication

• can be caused by aspirin overdose
• respiratory alkalosis the the 1st disturbance to occur and starts soon after ingestion, due to direct stimulation of medullar respiratory center in brain and resulting in hyperventilation
• a few hours after ingestion, an anion gap metaolic acidosis begins to develop due to accumulation of organic acids in the blood. At higher conc, lipolysis increases, uncouple mitochondria and inhibit TCA, resulting in accumulation of lactate and pyruvate
• should decrease PCO2 and the hours later go into metabolic acidosis so decrease pH and bicarbonate 

Metabolic Alkalosis

• metabolic alkalosis is the abnormal loss of acid(as in vomiting) or addition of a weak base can lead to the condition of pH above 7.4
• examples are vomiting, hyperaldosteronisms and loop or thiazide diuretics
• causes increased H secretion in distal, greater anion gap from production of ketoacids(starvation)

Metabolic Acidosis

• metabolic acidosis is removal of HCO3 or another alkali or addition of acids other than CO2 or HCO3 (as can happen in renal failure), decreasing pH below 7.4
• lactic acidosis, ketoacidosis, salicylate intoxication, diarrhea, RTA, ect
• causes increased anion gap in some cases, GI and Renal loss of HCO3

Davenport Diagram

• combining chemical buffers with CO2/HCO3 such that: CO2+H2O -> HCO3- + H + Bⁿ -> HBⁿ⁺¹ 
• final pH depends on two buffering pathways with two different equilibrium equations 
• for a given Pco2, plotting HCO3 against pH yield a curve known as a CO2 isobar
• each of the isobars, HCO3- (y axis) increases exponentially with pH (X axis)
• slope of each isobar also rises exponentially with pH
• at a particular pH, an isobar representing a higher Pco2 has a steeper slope (pco2 occurs via altered resp function
• acidosis will shift the balance to the left and alkolosis to the right
• respiratory disturbances  will cause resp acidosis in the top left and resp alkalosis in the lower right corner of the nomogram (acute is same trend but closer to middle
• metabolic acidosis bottom left and alkalosis top right

βnon-HCO3

• indicates buffering power of non-HCO3-
• varies with the hemoglobin content of blood, patients with anemia have a low
• patients with plycythemia(overprodoction of RBC) have a high 
• units are mM/pH unit
• with a high βnon-HCO3, a large amount of CO2 must flux through the combined equation before the free conc of HCO3 and H rise sufficiently to satisfy the CO2/HCO3 equilibrium

Renal Control of Acid-Base Balance

• kidneys control acid-base balance by excreting either an acidic or basic urine
• filters large volumes of bicarbonate and the extent to which they are either excreted or reabsorbed determines the removal of base from the blood
• secretes large numbers of H into the tubule lumen, thus removing H from the blood
• gain of the adjustment of pH by the kidney and the acid base balance it regulates is nerarly infinite, which means that tho it is slow it can completely correct for abnormalities in pH
• kidney secrets 4,400 mEq/day(to reabs bicarb and excrete nonvolitle acid) of H into tubular fluid that is buffered by the three types
• during acidosis the kidneys reabs all the bicarb and produce additional bicarb which is all added back to circ
• bicarb reab is facil/ by the enhanced conv of CO2 to H2CO3 via the enzyme carbonic anhydrase II 

Factors that Increas H secretion and

HCO3 Reabsorbtion 

• increas PCO2
• increased H and decreased HCO3
• decreased ECF volume(eq thiazide diuretics)
• 4: Increase Angiotensin II (proximal T)
• 5: Increased Aldosterone (CCT)
• Hypokalemia (proximal T)
• 4 and 5 increase Na reabs and excess H secrtion

Factors that decrease H secretion and 

HCO3 reabsorbtion 

• decrease in PCO2
• Decrease in H and increase in HCO3
• increase in ECF fluid volme
• decrease in angiotensin II and aldosterone
• hyperkalemia (high plasma potassium)
• CA inhibitor(acetazolamide)
• Ca inhibitor is a diuretic due to reducing Na, HCO3, water reabsorp, leading to excretion of alkaline urine

NH4 Excretion

• 60%(40mmol/day) of new HCO3 that the nephron generates the the product of net NH4 excretion
• 1: more then 50 mmol/day of NH4 is secreted by PCT
• 2: TAL reabs some NH4 and deposits it in the inerstitium
• 3: Some of this interstitial NH4 recycles back to PCT and thin descending limb or
• 4: some  enters the lumen of the collecting duct
• 5: some NH4 enters the vasa recta and leaves the kdiney
• net amount of new HCO3 generation from NH4 secretion is 1-2+3+4-V

Effect of Chronic Metabolic Acidosis

on Total NH4 excretion in urine

• increase in ECF H+
• leads to Increase in renal glutamine metabolism
• leads to increase in NH4 and HCO3
• glutamine is metabolized to αketoglutarate yeilding 2 NH4 and 2 HCO3
• NH4 is insoluble and thus trapped in filtrate
• chronic metabolic acidosis makes the NH4 production more sensitive to changes in filtrate H concentration(lower pH, higher NH4 production, slope steeper in chronic)

Renal Tubular Acidosis 

• due to defect in H secretion or HCO3 reabs or both
• Addisons disease and Fanconi's syndrome

Metabolic Acidosis diseases

• renal tubular acidosis
• chronic renal failure 
• diabetes melitus
• acid ingestion (increase anion gap)
• diarrhea (loss of bicarb in feces, normal anion gap) (most common cause )

Metabolic Alkalosis Causes

• diuretic therapy (except Ca inhib) 
• excess aldosterone (increaed Na reabs and stimulates H secretion)
• Vomiting (loss of HCl)
• ingestion of alkaline durgs such as bicarbonate used for upset stomachs or ulcers 

Anion Gap

• in metabolic acidsos, the serum HCO3 decreases as it is depleted in buffering fixed acid
• a normal anion gap happens if Cl- is increased to replace HCO3 (hyperchloremic metabolic acidosis)
• anion gap is increased when concentration of an unmeasured anion(phosphate, lactate, βhydroxybutyrate and formate) is increased to replace HCO3

Increased Anion Gap

• diabetes mellitus (ketoacidosis)
• lactic acidosis
• chronic renal failure
• aspirin poisoning
• methanol poisoning
• ethylene glycol poisoning
• starvation

Normal Anion Gap

• Diarrhea
• renal tubular acidosis
• carbonic anhydrase inhibitor
• addisons disease (insufficient aldosterone secretion)

Conditions that Alter Heat Production

• activity
• age (basal heat highest at like 6 and then drops dastically by 15 and then drops slowly from there)
• endocrine status(hormone)
• gender (BMR 10-15% lower)
• body size (body surface area) 
• shivering (up to 5 fold increase in heat production) (only mechanism for acute response)

Thyroxin and Catecholamines

• hormones that effect heat production
• no thryoxin lowers heat production from normal basal metabolic rate
• increased thyrodoxin increases heat production
• catecholamines are beta adrenergic agonists and have acute effect in raising heat production
• thyroxin effect prolonged changes

Body Surface Area and Heat

• Basal metabolic rate (BMR) is proportional to SA
• BMR = Calories/m²/hour
• surface area to weight ration decreases as weight increases (mouse BMR>>>horse BMR)

Thermoregulation sensors

• peripheral sensors in the skin and central thermoreceptor in the hypothalamus
• central sense core temperature, then provides input to control body temperature
• peripheral provide the brain with information about changes in environmental temperature
• effector: sympathetic or cholinergic activation to sweat glands, arteriole of the skin, adrenal medulla as well as motor neuron of skeletal muscle

Hypothalamic Theromoreceptors 

• preoptic anterior hypothalamus(poah, hot or heat center): firing rate increases when head temp increases
• posterior hypothalmus(cold): increased firing rate when head temp decreases(activated by cold and control shivering) 
• integrator of all temperature signals is in the posterior hypothalmus

Peripheral Thermoreceptors

• senseing changes in environmental temp
• most in skin: more cold sensitive(10X) than heat sensitive
• deep body temperature receptors: mainly in the spinal cord, abd cavity; detect mainly cold rather than warmth
• both wkin and deep body receptors are concerned with preventing hypothermia

Temperature Effectors for Hot

• effectors are temperature decreasing
• vasodilation of skin blood vessels
• sweating
• decreasing in heat production(inhibits thermogenesis and shivering) 

Temperature Effectors for Cold 

• temperature increasing
• skin vasoconstriction throughout body
• piloerection
• increase in thermogenesis(heat production)
• shivering-hypothalamic stimulation
• chemical thermogeneis(nonshivering thermogen) sympathetic stimulation
• increasing thyroxine output(by TRH)

Physical Mechanisms

responsible for heat transfer

• heat loss from skin or heat transfer to surroundings
• radiation (60%) (EMW)
• conduction to air (15%)
• conduction to objects (3%) 
• convection 
• evaporation (22%)
• If lower temperature the most heat is lost through conduction and radiation but if high temperature (40C) then all of heat is lost as evaporation and everything else causes heat gain

Countercurrent Heat Exchange

• cools blood delivered to skin surface
• cooled peripheral blood passes by warm coor blood
• venous blood returns recycled heat to the body core and this exchange causes lower thermal gradient at the skin

Pyrogens

• increases production of IL-1 in phagocytic cells
• IL-1 acts on the anterior hypothalamus to increase the production of prostaglandins
• prostaglandins increase the set-point temp, settin in motion the heat-generating mechanism that increase body temperature and produce fever

Aspirin and body temp

• reduces fever by inhibiting cyclooxygenase, thereby inhibiting the production of prostaglandins
• therefore, aspirin decreases the set point temp
• activates sweating, vasodilation to increase heat loss

Steroids and body temp

• reduce fever by blocking the release arachidonic acid from brain phospholipid thereby preventing the production of prostaglandins 

Heat Exhaustion and heat stroke

• heat exhaustion is caused by excessive sweating as a result, blood volume and arterial blood pressure decrease and fainting occurs
• heat stroke occurs when body temp increases to the point of tissue damage. the normal response to increased ambient temp(sweating) is impaired and core temperature increases further