Pbl Exam 5 Case 5

Front 1

1. Five requirements for digestion

Back 1

1. Movement of food through the alimentary tract
2. Secretion of digestive juices and digestion of the food
3. Absorption of water
4. Circulation of blood through the GI organs to carry way the absorbed substances
5. Control of all these function by local, nervous and hormonal systems

Front 2

2. Layers of the intestinal wall from outer surface inward

Back 2

1. Serosa
2. Longitudinal muscle layer
3. Circular muscle layer
4. Submucosa
5. Mucosa

Front 3

3. GI smooth muscle

Back 3

Functions as a syncytium
Individual smooth muscle fibers in the GI tract are 200 to 500 um in length and 2 to 10 um in diameter.

In the longitudinal muscle layer, the bundles extend longitudinally down the intestinal tract; in the circular muscle layer, they extend around the gut.

A few connections exist btwn the two layers so that excitation of one often excites the other.

Front 4

4. Gap junctions

Back 4

Within each bundle, the muscle fibers are electrically connected w/one another thru large numbers of gap junctions that allow low-resistance movement of ions form one muscle cell to the next.

Front 5

5. Action potential travel

Back 5

Since each muscle layer functions as a syncytium, when an action potential is elicited anywhere w/in the muscle mass, it generally travels in all directions in the muscle.

Front 6

6. Electrical activity of GI smooth muscle

Back 6

The smooth muscle of the GI tract is excited by continual slow, intrinsic electrical activity along the membranes of the muscle fibers.

Has two basic types of electrical waves:
1. slow waves
2. spikes

Front 7

7. Slow waves

Back 7

Most GI contractions occur rhythmically, and this rhythm is determined mainly by the freq of slow waves of smooth muscle membrane potential.

*Are not action potentials. Instead, they are slow, undulating changes in the resting membrane potential. Varies 5-10 mV and freq are about 3-12 per minute.

Do not cause muscle contraction by themselves (except in the stomach)

Front 8

8. Cause of slow waves

Back 8

Appear to be cause by complex interactions among the smooth muscle cells and specialized cells, called the interstitial cells of Cajal, that are believed to act as electrical pacemakers for smooth muscle cells.

Front 9

9. Interstitial cells of Cajal

Back 9

These interstitial cells form a network with each other and are interposed between the smooth muscle layers, w/synaptic like contacts to smooth muscle cells.

Undergo cyclic changes in membrane potential due to unique ion channels that periodically open and produced inward currents that may generate slow wave activity.

Front 10

10. Spike potentials

Back 10

Are true action potentials.

Occur automatically when the resting membrane potential of the GI smooth muscle becomes more positive than about -40 mV.

(normal resting membrane potential in the smooth muscle fibers of the gut is between -50 and -60 mV)

Front 11

11. Relationship of slow waves to spike potentials

Back 11

The higher the slow wave potential rises, the greater the frequency of the spike potentials, usually ranging btwn 1 and 10 spikes per second.

Front 12

12. Differences between action potentials in the GI tract and skeletal muscle

Back 12

They last 10 to 40 times as long in GI muscle as the action potentials in large nerve fibers.

In nerve fibers, the action potentials are caused almost entirely by rapid entry of Na ions through Na channels to the interior of the fibers.

In GI smooth muscle fibers, the channels responsible for the action potentials allow especially large numbers of Ca ions to enter along w/smaller numbers of Na ions and therefore are called calcium-sodium channels.

Front 13

13. Calcium-sodium channel opening/closing

Back 13

These channels are much slower to open and close than are the rapid sodium channels of large nerve fibers.

The slowness of opening and closing accounts for the long duration of the action potentials.

Front 14

14. Four factors that depolarize the membrane (make it more excitable)

Back 14

1. Stretching of the muscle
2. Stimulation by acetylcholine
3. Stimulation by parasympathetic nerves that secrete acetylcholine at their endings
4. Stimulation by several specific GI hormones

Front 15

15. Factors that hyperpolarize the membrane

Back 15

1. The effect of norepinephrine or epinephrine on the fiber membrane
2. Stimulation of the sympathetic nerves that secrete mainly norepinephrine at their endings

Front 16

16. Tonic contraction

Back 16

Some smooth muscle of the GI tract exhibits tonic contraction as well as or instead of rhythmical contractions.

Tonic contraction is continuous, not associated w/the basic electrical rhythm of the slow waves but often lasting several minutes or even hours.

Front 17

17. Causes of tonic contraction

Back 17

1. Sometimes caused by continuous repetitive spike potentials - the greater the freq the greater the degree of contraction.
2. Hormones or other factors that bring about continuous partial depolarization of the membrane w/o causing action potentials
3. Continuous entry of calcium ions into the interior of the cell brought about in ways not associated w/changes in membrane potential.

Front 18

18. Enteric nervous system

Back 18

The GI system's own nervous system

Lies in the wall of the gut, beginning in the esophagus and extending all the way to the anus.

Highly developed and controls GI movements and secretions

Front 19

19. Composition of enteric nervous system

Back 19

1. An outer plexus lying between the longitudinal and circular muscle layers, called the myenteric plexus or Auerbach's plexus

2. An inner plexus, call the submucosal plexus or Meissner's plexus, that lies in the submucosa.

Front 20

20. Myenteric plexus and submucosal plexus

Back 20

Myenteric controls mainly the GI movements

Submucosal controls mainly GI secretion and local blood flow.

Front 21

21. Myenteric plexus in detail

Back 21

Consists mostly of a linear chain of many interconnecting neurons that extends the entire length of the GI tract.

When stimulated, its principal effects are:
1. increased tonic contraction or "tone" of the gut wall
2. increase intensity of the rhythmical contractions
3. slightly increased rate of the rhythm of contraction
4. increased velocity of conduction of excitatory waves along the gut wall, causing more rapid movement of the gut peristaltic waves.

Front 22

22. Myenteric plexus: inhibitory or excitatory?

Back 22

Should not be considered entirely excitatory b/c some of its neurons are inhibitory.

Inhibitory signals are especially useful for inhibiting some of the intestinal sphincter muscles that impede movements of food along successive segments of the GI tract.

Front 23

23. Submucosal plexus in detail

Back 23

Is mainly concerned w/controlling function w/in the inner wall fo each minute segment of the intestine.

Help control:
1. Local intestinal secretion
2. Local absorption
3. Local contraction o the submucosal muscle that causes various degrees of infolding of the GI mucosa.

Front 24

24. Types of neurotransmiters secreted by eneric neurons

Back 24

1. acetylcholine
2. norepinephrine
3. adeonsine triphosphate
4. serotonin
5. dopamine
6. cholecystokinin
7. substance P
8. vasoactive intestinal polypeptide
9. somatostatin
10. leu-enkephalin
11. metenkaphalin
12. bombesin

Front 25

25. Acetylcholine, norepinephrine

Back 25

Acetylcholine almost always excites GI activity;

Norepinephrine almost always inhibits GI activity.

Front 26

26. Parasympathetic innervation of the GI tract

Back 26

1. Cranial parasympathetic nerves (vagus)
2. Sacral parasympathetics
3. Pelvic nerves

Postganglionic parasympathetic neurons are located mainly in the myenteric and submucosal plexuses.

Mainly excitatory

Front 27

27. Sympathetic innervation of the GI tract

Back 27

Originate in the spinal cord between segments T5 and L2

Preganglionic sympathetic fibers located along sympathetic trunk and go to celiac ganglion and various mesenteric ganglia.

The postganglionic sympathetic neuron bodies are in their ganglia, and postganglionic fibers then spread through to all parts of the gut.

Generally inhibits activity of the GI tract

Front 28

28. Afferent sensory nerve fibers from the gut

Back 28

Can be stimulated by:
1. Irritation of the gut mucosa
2. Excessive distension of the gut
3. Presence of specific chemical substances in the gut

*80% of the nerve fibers in the vagus nerves are afferent rather than efferent.

Front 29

29. GI reflexes

Back 29

1. Reflexes that are integrated entirely within the gut wall enteric nervous system
2. Reflexes from the gut to the prevertebral sympathetic ganglia and then back to the GI tract
3. Reflexes from the gut to the spinal cord or brain stem and then back to the GI tract.

Front 30

30. Gastrin

Back 30

Secreted by the "G" cells of the antrum fo the stomach in response to stimuli associated w/ingestion of a meal, such as distention fo the stomach, the products of proteins, and gastrin releasing peptide which is released during vagal stimulation

Actions:
1. Stimulation of gastric acid secretion
2. Stimulation of growth by the gastric mucosa

Front 31

31. Cholecystokinin

Back 31

Secreted by the "I" cells in the mucosa of the duodenum and jejunum mainly in response to digestive products of fat, fatty acids, and monoglycerides in the intestinal contents.

Also interacts w/the gallbladder, expelling bile into the small intestine; also inhibits stomach contraction

Front 32

32. Secretin

Back 32

Secreted by "S" cells in the mucosa of the duodenum in response to acidic gastric juice emptying in to the duodenum from the pylorus of the stomach.

Has a mild effect on motility of the GI tract and acts to promote pancreatic secretion of bicarbonate

Front 33

33. Gastric inhibitory peptide

Back 33

Secreted by the mucosa of the upper small intestine mainly in response to fatty acids and amino acids.

It has a mild effect in decreasing motor activity of the stomach as therefore slows emptying of gastric contents into the duodenum when the upper small intestine is already overloaded w/food.

Front 34

34. Motilin

Back 34

Secreted by the upper duodenum during fasting, and the only known function of this hormone is to increase GI motility

Front 35

35. Two types of movements that occur in the GI tract

Back 35

1. Propulsive movements, which cause food to move forward along the tract at an appropriate rate to accommodate digestion and absorption

2. Mixing movements, which keep the intestinal contents thoroughly mixed at all times

Front 36

36. Peristalsis

Back 36

A contractile ring appears around the gut and then moves forward;

It is an inherent property of many syncytial smooth muscle tubes; stimulation at any point in the gut can cause a contractile ring to appear in the circular muscle.

The usual stimulus for peristalsis is distention of the gut which stimulates the myenteric nervous system

Front 37

37. Function of the myenteric plexus in peristalsis?

Back 37

The myenteric plexus is required for effectual peristalsis;

Can inhibit peristalsis by depressing the activity of the myenteric plexus, i.e. congenital absence or atropine administration that paralyzes the cholinergic nerve endings in the plexus.

Front 38

38. Directional movement of peristaltic waves towards the anus

Back 38

Peristalsis can occur in either direction from stimulated point, but it normally continues for a considerable distance towards the anus.

Due to probable polarization in the anal direction

Front 39

39. Law of the gut

Back 39

AKA "Myenteric reflex" or "Peristaltic reflex"

When a segment of the intestinal tract is excited by distention and initiates peristalsis, the contractile ring begins on the orad side of the distended segment and moves toward the distended segment, pushing the intestinal contents downstream.

At the same time the gut sometimes relaxes several cm downstream toward the anus which is call "receptive relaxation" thus allowing the food to be propelled more easily downstream.

Front 40

40. Splanchnic circulation

Back 40

The blood vessels fo the GI system are part of the splanchnic circulation, which includes the blood flow thru the gut itself plus blood flow thru the spleen, pancreas and liver.

This system is designed so all the blood flows through these organs and then immediately to the liver by way of the portal system.

Front 41

41. Flow of blood through the liver

Back 41

1. Portal vein

2. Liver sinusoids
-lined with reticuloendothelial cells which remove bacteria and harmful agents

3. Hepatic veins

4. Vena cava

Front 42

42. Nonfat, water soluble nutrients

Back 42

Absorbed from the gut and are transported in the portal venous blood to the liver sinusoids.

Here, the reticuloendothelial cells and the hepatic cells absorb and store temporarily 1/2 to 3/4 of the nutrients

Front 43

43. Fats, non-soluble nutrients

Back 43

NOT carried in the portal blood but are instead absorbed in the intestinal lymphatics and then conducted to the systemic circulation by way of the thoracic duct.

Fat bypasses the liver.

Front 44

44. Causes of increased blood flow during GI activity

Back 44

Several vasodilator substances are released from the mucosa; include peptide hormones: CCK, Gastrin, Secretin, etc..

Some of the GI glands also release two kinins, kallidin and bradykinin which are also powerful vasodilators

Decreased O2 concentration in the gut wall can increase intestinal blood flow at least 50 to 100%
-decreased O2 can also lead to a release of adenosine which is also a vasodilator

Front 45

45. Countercurrent blood flow in the GI tract

Back 45

The arterial and venous flow into and out of the villus are in opposite directions and they lie close to one another.

B/c of this, much of the blood O2 diffuses out of the arterioles directly into the adjacent venules w/o ever being carried in the blood to the tips of the villi.

As much as 80% of the O2 takes this shortcut.

Under normal conditions, this shunting is not harmful to the villi, but in diseased conditions blood flow to the gut becomes greatly reduced.

Front 46

46. Stimulation of the parasympathetics/sympathetics going to the stomach and lower colon leads to...

Back 46

Parasympathetic: Increased blood flow and glandular secretion

*Sympathetic: Intense vasoconstriction of the arterioles and greatly decreased blood flow.
-regulated by "autoregulatory escape", in which the flow returns to normal

*Important for heavy exercise or times in which blood is needed elsewhere as intestinal and mesenteric veins can provide as much as 200 to 400 mL of extra blood to sustain the circulation.

Front 47

47. What areas of the brain control chewing?

Back 47

Most of the muscles of chewing are innervated by the motor branch of the fifth cranial nerve, and the chewing process is controlled by nuclei in the brain stem.

Stimulation of specific reticular areas in the brain stem taste centers will cause rhythmical chewing movements.

Also, stimulation of areas in the hypothalamus, amygdala, and even the cerebral cortex near the sensory areas for taste and smell can often cause chewing.

Front 48

48. What is the chewing reflex?

Back 48

The presence of a bolus of food in the mouth at first initiates reflex inhibition of the muscles of mastication, which allows the lower jaw to drop.

The drop in turn initiates a stretch reflex of the jaw muscles that leads to rebound contraction. This automatically raises the jaw to cause closure of the teeth, but it also compresses the bolus again against the linings of the mouth, which inhibits the jaw muscles once again, allowing the jaw to drop and rebound another time.

Front 49

49. What is the importance of chewing?

Back 49

Chewing is important for digestion of all foods, but especially important for most fruits and raw veggies b/c these have indigestible cellulose membranes around their nutrient portions that must be broken before the food can be digested.

Also, digestive enzymes act only on the surfaces of food particles; therefore, the rate of digestion is absolutely dependent on the surface area exposed to the digestive secretions.

In addition, grinding the food to a very fine particulate consistency prevents excoriation fo the GI tract and increases the ease with which food is emptied from the stomach into the small intestine, then into all succeeding segments of the gut.

Front 50

50. What are the three stages of swallowing?

Back 50

1. A voluntary stage, which initates the swallowing process

2. A pharyngeal stage, which is involuntary and constitutes passage of food through the pharynx into the esophagus

3. An esophageal stage, another involuntary phase that transports food from the pharynx to the stomach

Front 51

51. What occurs during the pharyngeal stage of swallowing?

Back 51

As the bolus of food enters the posterior mouth and pharynx, it stimulates epithelial swallowing receptor areas all around the opening of the pharynx, especially on the tonsillar pillars, and impulses from these pass to the brain stem to initiate a series of automatic pharyngeal muscle contractions.

Front 52

52. What are some important automatic pharyngeal muscle contractions that take place during the pharyngeal stage?

Back 52

1. Soft palate is pulled upward to close posterior nares
2. The palatopharyngeal folds are pulled medially to form a sagittal slit thru which the food must pass
3. Vocal cords are strongly approximated, and the larynx is pulled upward and anteriorly
4. Upper esophageal sphincter relaxes
5. Entire muscular wall of the pharynx contracts.

Front 53

53. What areas are the most sensitive for initiating the pharyngeal stage of swallowing?

Back 53

The areas lie in a ring around the pharyngeal opening, with greatest sensitivity on the tonsillar pillars.

Impulses are transmitted from these areas through the sensory portions of the trigeminal and glossopharyngeal nerves into the medulla oblongata, either into or closely associated with the tractus solitarius, which receives essentially all sensory impulses form the mouth.

Front 54

54. What areas in the brain control swallowing?

Back 54

The areas in the medulla and lower pons

Front 55

55. What happens to respiration during the pharyngeal stage of swallowing?

Back 55

It interrupts respiration for only a fraction of a usual respiratory cycle.

The swallowing center specifically inhibits the respiratory center of the medulla during this time, halting respiration at any point in its cycle to allow swallowing to proceed.

Front 56

56. What are the two types of peristaltic movements that occur in the esophagus?

Back 56

1. Primary peristalsis
2. Secondary peristalsis

Front 57

57. What is primary peristalsis?

Back 57

Primary peristalsis is simply continuation of the peristaltic wave that begins in the pharynx and spreads into the esophagus during the pharyngeal stage of swallowing.

This wave passes all the way from the pharynx to the stomach in about 8-10 seconds.

Front 58

58. What happens if the primary peristaltic wave fails to move all the food into the stomach?

Back 58

The secondary peristaltic wave occurs. This wave results from distention of the esophagus itself by the retained food; it continues until all the food has emptied into the stomach.

The secondary peristaltic waves are initiated partly by intrinsic neural circuits int he myenteric nervous system and partly by reflexes that begin in the pharynx and are then transmitted upward through vagal afferent fibers to the medulla and back again to the esophagus through glossopharyngeal and vagal efferent nerve fibers.

Front 59

59. What are the two types of muscular of the pharyngeal wall?

Back 59

The upper third is striated muscle, and it is innervated by skeletal nerve impulses from the glossopharyngeal and vagal nerves.

The lower two thirds is smooth muscle, but this portion of the esophagus is also strongly controlled by the vagus nerves acting through connections with the esophageal myenteric nervous system. When the vagus nerves are cut, the myenteric nerve plexus of the esophagus becomes excitable enough after a few days to cause secondary peristaltic waves even without support from the vagal reflexes.

Front 60

60. What happens to the stomach when an esophageal peristaltic wave approaches?

Back 60

A wave of relaxation, transmitted through myenteric inhibitory neurons, preceded the peristalsis.

Furthermore, the entire stomach and, to a lesser extent, even the duodenum become relaxed as this wave reaches the lower end of the esophagus and thus are prepared ahead of time to receive the food propelled into the esophagus during swallowing.

Front 61

61. What is the lower esophageal spincter?

Back 61

AKA gastroesophageal sphincter.

This sphincter normally remains tonically constricted with an intraluminal pressure at this point in the esophagus of about 30 mm Hg, in contrast to the midportion of the esophagus, which normally remains relaxed.

When a peristaltic swallowing wave passes down the esophagus, there is "receptive relaxation" of the lower esophageal sphincter ahead of the peristaltic wave, which allows easy propulsion of the swallowed food into the stomach.

The tonic constriction of the lower esophageal sphincter helps to prevent significant reflux of stomach contents into the esophagus.

Front 62

62. What is achalasia?

Back 62

The lower esophageal sphincter does not relax satisfactorily, resulting in achalasia.

Front 63

63. What is another factor that helps to prevent reflux?

Back 63

A valve like mechanism of a short portion of the esophagus that extends slightly into the stomach. Increased intrabdominal pressure caves the esophagus inward at this point.

Thus, this valvelike closure of the lower esophagus helps to prevent high intra-abdominal pressure from forcing stomach contents backward into the esophagus.

Front 64

64. What are the three motor functions of the stomach?

Back 64

1. Storage of large quantities of food until it can be processed
2. Mixing of this food w/gastric secretions until it forms a semifluid mixture called chyme
3. Slow emptying of the chyme from the stomach into the small intestine at a rate suitable for proper digestion and absorption by the small intestine.

Front 65

65. Anatomy of the stomach

Back 65

Divided into two major parts, the body and the antrum.

Physiologically, it is more appropriately divided into the orad portion, comprising the first 2/3's of the body, and the caudad portion, comprising the remainder of the body plus the antrum.

Front 66

66. What are the storage functions of the stomach?

Back 66

As food enters the stomach, ti forms concentric circles of the food in the orad portion, the newest food lying closest to the esophageal opening and the oldest lying nearest the outer wall of the stomach.

When food stretches the stomach, a "vasovagal reflex" form the stomach reduces the tone in the muscular wall of the body of the stomach so that the wall bulges progressively outward, accommodating greater and greater quantities of food up to a limit in the completely relaxed stomach of .8 to 1.5 L.

Front 67

67. Gastric glands and digestive juices

Back 67

The digestive juices of the stomach are secreted by gastric glands, which are present in almost the entire stomach except along a narrow strip on the lesser curvature of the stomach.

These secretions come immediately into contact w/that portion of the stored food lying against the mucosal surface of the stomach.

Front 68

68. What initiates the constrictor waves or mixing waves of the stomach?

Back 68

These waves are weak and peristaltic waves that move from the mid to upper portions of the stomach wall and move toward the antrum about every 15-20 second.

These waves are initiated by the gut wall basic electrical rhythm, which consists of electrical slow waves.

As the constrictor waves progress from the body into the antrum, they become more intense, becoming extremely intense and providing power peristaltic action potential driven constrictor rings that force the antral contents under higher and higher pressure toward the pylorus.

Front 69

69. What is the importance of these constrictor rings?

Back 69

They mix the stomach contents.

As each peristaltic wave approaches the pylorus, the pyloric muscle itself often contracts, which further impedes emptying through the pylorus.

Therefore, most of the antral contents are squeezed upstream through the peristaltic ring toward the body of the stomach, not through the pylorus. This "retropulsion" is a very important mixing mechanism.

Front 70

70. What is chyme?

Back 70

After food in the stomach has become thoroughly mixed with stomach secretion, the resulting mixture that passes down the gut is called chyme.

The appearance is that of a murky semifluid or paste.

Front 71

71. What are hunger contractions?

Back 71

AKA hunger pangs. Another type of intense contraction called, hunger contractions, often occurs when the stomach has been empty for several hours or more. They are rhythmical peristaltic contractions of the BODY of the stomach.

These contractions are most intense in young, healthy people who have high degrees of GI tonus; they are also greatly increased by the person's having lower than normal levels of blood sugar.

Hunger pangs do not begin until 12-24 hours after the last ingestion of food. They reach their greatest intensity in 3-4 days and gradually weaken in succeeding days.

Front 72

72. What is the pyloric pump?

Back 72

About 20% of the time while foo dis in the stomach, the contractions become intense, beginning mid stomach and spreading through the caudad stomach no longer as weak mixing contractions but as strong peristaltic, very tight ringlike constrictions that can cause stomach emptying.

These intense contractions forces up to several mL's of chyme into the duodenum, providing a pumping action.

Front 73

73. How does the pylorus control stomach emptying?

Back 73

The thickness in the distal opening of the stomach is 50-100% greater than in the earlier portions of the stomach antrum, and it remains slightly tonically contracted almost all the time.

The pylorus is usually open enough for water and other fluid to empty from the stomach into the duodenum with ease. Conversely, the constriction usually prevents passage of food particles until they have become mixed into a fluid like chyme.

The degree of constriction of the pylorus is increased or decreased under the influence of nervous and humoral reflex signals.

Front 74

74. What regulates the rate at which the stomach empties?

Back 74

Signals form both the stomach and the duodenum.

However, the duodenum provides by far the more potent of the signals, controlling the emptying of chyme into the duodenum at a rate no greater than the rate at which the chyme can be digested and absorbed in the small intestine.

Front 75

75. What is the effect of gastric food volume on emptying?

How?

Back 75

Increased food volume in the stomach promotes increased emptying.

It is not caused by increased storage pressure of food in the stomach; however, stretching of the stomach wall does elicit local myenteric reflexes in the wall that greatly accentuate activity of the pyloric pump and at the same time inhibit the pylorus.

Front 76

76. How does gastrin effect stomach emptying?

Back 76

Gastrin has the potent effect to cause secretion of highly acidic gastric juice by the stomach glands.

Gastrin also has mild to moderate stimulatory effects on motor functions in the body of the stomach. Most important, it seems to enhance the activity of the pyloric pump.

Front 77

77. How do the enterogastric nervous reflexes from the duodenum affect stomach emptying?

Back 77

When food enters the duodenum, multiple nervous reflexes are sent to the stomach to slow or even stop stomach emptying if the volume of chyme in the duodenum becomes too much.

Front 78

78. What are the three routes by which these enterogastric reflexes are mediated?

Back 78

1. Directly from the duodenum to the stomach through the entiric nervous system in the gut wall
2. Through extrinsic nerves that go to the prevertebral sympathetic ganglia and then back through inhibitor sympathetic nerve fibers to the stomach
3. Probably to a slight extent through the vagus nerves all the way to the brain stem, where they inhibit the normal excitatory signals transmitted to the stomach through the vagi.

Front 79

79. What are the two effects these entergastric reflexes have?

Back 79

1. They strongly inhibit the "pyloric pump" propulsive contractions
2. They increase the tone of the pyloric sphincter

Front 80

80. What are the five factors that are continually monitored in the duodenum and that can initiate enterogastric inhibitory reflexes?

Back 80

1. The degree of distention of the duodenum
2. The presence of any degree of irritation of the duodenal mucosa
3. The degree of acidity of the duodenal chyme
4. The degree of osmolality of the chyme
5. The presence of certain breakdown products in the chyme, especially breakdown products of proteins some fats

Front 81

81. How do irritants and acids in the duodenal chyme effect enterogastric reflexes?

Back 81

The enterogastric inhibitory reflexes are especially sensitive to the presence of irritants and acids in the duodenal chyme, and they become strongly activated within as little as 30 seconds.

These reflexes block further release of acidic stomach contents into the duodenum until the duodenal chyme can be neutralized.

Front 82

82. How do breakdown products of protein digestion effect enterogastric reflexes?

Back 82

Breakdown products of protein digestion elicit inhibitory enterogastric reflexes, by slowing the rate of stomach emptying, sufficient time is ensured for adequate protein digestion in the duodenum and small intestine.

Front 83

83. How do hypertonic or hypertonic fluids effect enterogastric reflexes?

Back 83

Either hypotonic or hypertonic fluids (especially hypertonic) elicit the inhibitor reflexes.

Front 84

84. How do fats affect gastric emptying?

Back 84

When fats enter the duodenum, they extract several different hormones from the duodenal and jejunal epithelium, by binding or the epithelial cell receptors. In turn, the hormones are carried by way of the blood to the stomach, where the inhibit the pyloric pump and at the same time increase the strength of contraction of the pyloric sphincter.

They cause the release of CCK; this hormone acts as an inhibitor to block increased stomach motility caused by gastrin.

Front 85

85. What other hormones are inhibitors or stomach emptying?

Back 85

Secretin and gastric inhibitory peptide (GIP).

Secretin is released mainly from the duodenal mucosa in response to gastric acid passed from the stomach thru the pylorus.

GIP is released from the upper small intestine in response mainly to fat in the chyme, but to a lesser extent to carbs as well.

Front 86

86. In sum, what are the more important factors in the control of emptying stomach contents?

Back 86

The inhibitory feedback signals from the duodenum, including both enterogastric inhibitory nervous feedback reflexes and hormonal feedback by CCK.

Front 87

87. What are the two movements of the small intestine?

Back 87

1. Mixing contractions
2. Propulsive contractions?

Front 88

88. What are mixing contractions?

Back 88

AKA segmentation contractions.

When a portion of the small intestine becomes distended w/chyme, stretching of the intestinal wall elicits localized concentric contractions spaced at intervals along the intestine and lasting a fraction of a minute. These contractions cause segmentation of the small intestines (sausage links).

As one set of segmentation contractions relaxes, a new set often begins, but the contractions this time occur mainly at new points between the previous contractions.

Front 89

89. What determines the max freq of the segmentation contractions?

Back 89

The frequency of electrical slow waves in the intestinal wall determines the max freq of the segmentation contractions.

B/c this feq normally is not over 12 per minute in the duodenum and proximal jejunum, the amx freq of the segmentation in these areas is also about 12 per minute.

In the terminal ileum, the max freq is usually 8-9 per minute.

Front 90

90. How does atropine affect these segmentation contractions?

Back 90

They become exceedingly weak when the excitatory activity of the enteric nervous system is block by the drug atropine.

Front 91

91. Waves in the small intestine

Back 91

Chyme is propelled thru the small intestine by peristaltic waves. These waves are 0.5 -2.0 cm/sec and are faster in the proximal intestine and slower in the terminal intestine.

They normally are very weak and usually die out after traveling only 3-5 cm, very rarely farther than 10 cm, so that forward movement of the chyme is very slow.

This means that 3-5 hours are required for passage of chyme from the pylorus to the ileocecal valve.

Front 92

92. When does peristaltic activity of the small intestine increase/decrease?

Back 92

Greatly increased after a meal; caused by stretch of the duodenal wall, but also by a gastroenteric reflex that is initiated by distention of the stomach and conducted principally through the myenteric plexus from the stomach down along the wall of the small intestine.

Also, gastrin, CCK, insulin motilin, and serotonin, all of which enhance intestinal motility and are secreted during various phases of food processing.

Conversely, secretin and glucagon inhibit small intestinal motility.

Front 93

93. What is the function of the peristaltic wave sin the small intestine?

Back 93

They function not only to cause progression of chyme toward the ileocecal valve but also to spread out the chyme along the intestinal mucosa.

As the chyme enters the intestines and elicits peristalsis, this immediately spreads the chyme along the intestine. On reaching the ileocecal valve, the chyme is sometimes blocked for several hours until the person eats another meal. At that time, a gastroileal reflex intensifies peristalsis in the ileum and forces the remaining chyme through the ileocecal valve into the cecum of the large intestine.

Front 94

94. What is the peristaltic rush?

Back 94

Although peristalsis in the small intestine is normally weak, intense irritation of the intestinal mucosa, such as in infectious diarrhea, can cause both powerful and rapid peristalsis, called the peristaltic rush.

This is initiated partly by nervous reflex that involve the autonomic nervous system and brain stem and partly by intrinsic enhancement of the myenteric plexus reflexes within the gut wall itself. The powerful peristaltic contractions travel long distances in the small intestine within minutes, sweeping the contents of the intestine into the colon and thereby relieving the small intestine irritative chyme and excessive distention.

Front 95

95. What are the movements caused by the muscularis mucosae and muscle fibers of the villi?

Back 95

The muscularis mucoase can cause short folds to appear in the intestinal mucosa. In addition, individual fibers from this muscle extend into the intestinal villi and cause them to contract intermittently. The mucosal folds increase the surface area exposed to the chyme, thereby increasing absorption.

These mucosal and villous contractions are initiated mainly by local nervous reflexes int he submucosal nerve plexus that occur in response to chyme in the small intestine.

Front 96

96. What is the function of the ileocecal valve?

Back 96

To prevent backflow of fecal contents from the colon into the small intestine.

The valve itself protrudes into the lumen of the cecum and therefore is forcefully closed when excess pressure builds up in the cecum and tries to push cecal contents backward against the valve lips.

The valve usually can resist reverse pressure of at least 50-60 cm of water.

Front 97

97. What, then, is the purpose of the iliocecal sphincters?

Back 97

The wall of the ileum several cm immediately upstream from the ileocecal valve has a thickened circular muscle called the ileocecal sphincter. This sphincter normally remains mildly constricted and slows emptying of ileal contents into the cecum.

However, immediately after a meal, a gastroileal reflex intensifies peristalsis in the ileum and emptying of the ileal contents into the cecum proceeds.

Front 98

98. What is the feedback control of the ileocecal sphincter?

Back 98

The degree of contraction of the ileocecal sphincter and the intensity of peristalsis in the terminal ileum are controlled significantly by reflexes from the cecum.

When the cecum is distended, contraction of the ileocecal sphincter becomes intensified and ileal peristalsis is inhibited.

Also, any irritant in the cecum delays emptying.

The reflexes from the cecum to the ileocecal sphincter and ileum are mediated both by way of the myenteric plexus in the gut wall itself and of the extrinsic autonomic nerves, especially by way of the prevertebral sympathetic ganglia.

Front 99

99. What are the two principal functions of the colon?

In what part of the colon do they occur?

Back 99

1. Absorption of water and electrolytes from the chyme to form solid feces
2. Storage of fecal matter until it can be expelled

The proximal half of the colon is concerned principally w/absorption, and the distal half with storage.

Front 100

100. What are haustrations?

Back 100

Mixing movements. In the same manner that segmentation movements occur in the small intestine, large circular constrictions occur in the large intestine. At each of these constrictions, about 2.5 cm of the circular muscle contracts. At the same time, the longitudinal muscle of the colon, which is aggregated into three longitudinal strips called teniae coli, contracts.

These combined contractions of the circular and longitudinal strips of muscle cause the unstimulated portion of the large intestine to bugle outward into baglike sacs called haustrations.

Front 101

101. What are the characteristics of haustrations?

Back 101

They usually reach peak intensity in about 30 s and then disappear during the next 60 s. They also at times move slowly toward the anus during contraction, especially in the cecum and ascending colon, and thereby provide a minor amt of forward propulsion.

After another few minutes, new contractions occur in other areas nearby. Therefore, the fecal material is slowly dug into and rolled over.

In this way, all the fecal material is gradually exposed to the mucosal surfaces of the large intestine.

Front 102

102. What are mass movements?

Back 102

Haustrations move the chyme from the ileocecal valve thru the colon. From the cecum to the sigmoid, mass movements can take over the propulsive role. These movements usually occur only 1-3 times daily, and usually occur about 15 min during the first hour after eating breakfast.

Front 103

103. What occurs during a mass movement?

Back 103

First, a constrictive ring occurs in response to a distended or irritated point in the colon, usually in the transverse colon.

Then, rapidly, the 20 or more cm of colon distal to the constrictive ring lose their haustrations and instead contract as a unit, propelling the fecal material in this segment en mass further down the colon. When they have forced a mass of feces into the rectum, the desire for defecation is felt.

Front 104

104. What initiates mass movements?

Back 104

Appearance of mass movements after meals is facilitate by gastrocolic and duodenocolic reflexes. These reflexes result form the distention of the stomach and duodenum, and are transmitted by way of the autonomic nervous system.

Irritation in the colon can also initiate intense mass movements. For ex, a person w/ulcerative colitis freq has mass movements that persist almost all the time.

Front 105

105. Why is the rectum empty for most of the time?

Back 105

This results from a weak functional sphincter that exists about 20 cm from the anus at the juncture between the sigmoid and the rectum. There is also a sharp angulation here that also contributes additional resistance to filling of the rectum.

Front 106

106. What prevents continual dribble of fecal matter through the anus?

Back 106

Through constriction of (1) an internal anal sphincter composed of circular smooth muscle, and (2) an external anal sphincter composed of striated voluntary muscle.

The external sphincter is controlled by nerve fibers in the pudendal nerve, and therefore is consciously or voluntary in control.

Subconsciously, the external sphincter is usually kept continuously constricted unless conscious signals inhibit the constriction.

Front 107

107. What are the intrinsic defecation reflexes?

Back 107

The intrinsic reflex is mediated by the local enteric nervous system in the rectal wall.

When feces enter the rectum, distention of the rectal wall initiates afferent signals that spread through the myenteric plexus to initiate peristaltic waves in teh descending colon, sigmoid, and rectum, forcing feces toward the anus.

As the peristaltic wave approaches the anus, the internal anal sphincter is relaxed by inhibitory signals from the myenteric plexus.

This intrinsic reflex is weak.

Front 108

108. What are the parasympathetic defecation reflexes?

Back 108

A parasympathetic defecation reflex is needed to cause defecation. This reflex involves the sacral segments of the spinal cord. When the nerve endings int he rectum are stimulated, signals are transmitted first into the spinal cord and then reflexively back to the descending colon, sigmoid, rectum, and anus by way of parasympathetic nerve fibers in the pelvic nerves.

These parasympathetic signals greatly intensify the peristaltic waves as well as relax the internal anal sphincter, thus converting the intrinsic myenteric defecation reflex from a weak effort into a powerful process of defecation.

Front 109

109. What else can help move a bowel movement?

Back 109

Defecation signals entering the spinal cord initiate other effects, such as taking a deep breath, closure of the glottis, and contraction of the abdominal wall muscles to force the fecal contents of the colon downward and at the same time cause the pelvic floor to relax downward and pull outward on the anal ring to evaginate the feces.

Front 110

110. What other autonomic reflexes affect bowel activity?

Back 110

The peritoneointestinal reflex results from irritation of the peritoneum; it strongly inhibits the excitatory enteric nerves and thereby can cause intestinal paralysis, especially in patients w/peritonitis.

The renointestinal and vesicointestinal reflexes inhibit intestinal activity as a result of kidney or bladder irritation.

Front 111

111. What are the two primary functions of the secretory glands in the GI tract?

Back 111

1. Digestive enzymes are secreted in most areas of the tract, from the mouth to the distal end of the ileum

2. Mucous glands, from the mouth to the anus, provide mucus for lubrication and protection of all parts of the alimentary tract.

Front 112

112. What type of cells are on the surface of the epithelim in most parts of the GI tract?

Back 112

Single-cell mucous glands, or mucous cells, or goblet cells.

The function mainly in response to local irritation of the epithelium; they extrude mucus directly onto the epithelial surface to act as a lubricant that also protects the surfaces from excoriation and digestion.

Front 113

113. What are the pits that represent invaginations of the epithelium into the submucosa?

Back 113

In the small intestine, these pits, called crypts of Lieberkuhn, are deep and contain specialized secretory cells.

Front 114

114. What type of cells are in the stomach and upper duodenum?

Back 114

Large numbers of deep tubular glands.

Front 115

115. In addition to direct stimulation of contact w/the gland, what other type of stimulation activates the enteric nervous system of the gut wall?

Back 115

1. Tactile stimulation
2. Chemical irritation
3.. Distention of the gut wall

Front 116

116. What is the effect of parasympathetic stimulation on the gut?

Back 116

Stimulation via parasympathetics increase the rates of glandular secretion.

Front 117

117. What is the effect of sympathetic stimulation on the gut?

Back 117

Stimulation via sympathetics causes a slight to moderate increase in secretion by some of the local glands.

But sympathetic stimulation also resutls in constriction of the blood vessels that supply the glands.

Thus, sympathetic stimulation has dual effects:
1. Slightly increases secretion
2. Reduces secretion mainly b/c of vasoconstrictive reduction of the blood supply

Front 118

118. What is the mechanism of the secretion of organic substances?

Back 118

1. The nutrient material needed for formation of the secretion must first diffuse or be actively transported by the blood into the base of the glandular cell.
2. Many mitochondria located inside the cell near its base use oxidative energy to form ATP.
3. Energy from the ATP, along w/substrates from nutrients, is then used to synthesize the organic secretory substances
4. The secretory materials are transported thru the tubules of the ER, passing to the Golgi
5. In the Golgi, the materials are modified, and discharged into the cytoplasm in the form of secretory vesicles.
6. These vesicles remained stored until nervous or hormonal control signals cause the cells to extrude their contents.

Front 119

119. What causes the exocytosis?

Back 119

The control signal first increase the cell membrane permeability to calcium ions, and calcium enters the cell.

The calcium in turn causes many of the vesicles to fuse w/the apical cell membrane. Then the apical cell membrane breaks open and releases the contents via exocytosis.

Front 120

120. What else is needed for glandular secretion?

Why?

Back 120

Secretion of sufficient water and electrolytes to go along w/the organic substances.

Normal cell voltage is between 30 - 40 mV across the membrane with negativity on the interior and positivity on the exterior.

Parasympathetic stimulation increases this polarization to values some 10 - 20 mV more negative than normal.

This increase in polarization voltage lasts for 1 s or longer after the nerve signal has arrived, indicating that it is caused by movement of negative ions (presumably chloride ions) thru the membrane to the interior of the cell, thus leading to secretion.

Front 121

121. How does nervous stimulation cause water and salts to pass thru the glandular cells and wash out the organic substances thru the secretory border?

Back 121

1. Nerve stimulation has a specific effect on the basal portion of the cell membrane to cause active transport of chloride ions to the cell interior
2. The resulting increase in electronegativity inside the cell by excess negatively charged chloride ions then causes positive ions such as sodium ions also to move thru the cell membrane to the interior of the cell.
3. Now, the new excess of both negative and positive ions inside the cell creates an osmotic force that causes osmosis of water to the interior, thereby increasing cell volume and hydrostatic pressure inside the cell.
4. The pressure in the cell then initiates minute openings of the secretory border of the cell, causing flushing of water, electrolytes, and organic material out of the secretory end of the glandular cell.

Front 122

122. Why is mucus important?

Six reasons...

Back 122

1. It has adherent qualities that make it adhere tightly to the food or other particles and to spread as a thin film over the surfaces
2. It has sufficient body that it coats the wall of the gut and prevents actual contact of most food particles w/the mucosa
3. It has a low resistance for slippage, so that the particles can slide along the epithelium with ease
4. It causes fecal particles to adhere to one another to form the feces that are expelled during a bowel movement
5. It is strongly resistant to digestion by the GI enzymes
6. The glycoproteins of mucus have amphoteric properties, which means it can also act as a buffer; mucus often contains moderate quantities of bicarb ions

Front 123

123. What are the two major types of protein secretion from the salivary glands?

Back 123

1. A serous secretion that contains ptyalin (an alpha amylase) needed for digesting starches

2. Mucus secretion that contains mucin for lubricating and for surface protective purposes.

Front 124

124. What type(s) of secretion does the parotid gland have?

Back 124

Almost entirely the serous type of secretion.

Front 125

125. What type(s) of secretion do the submandibular and sublingual glands have?

Back 125

Both serous and mucus secretion

Front 126

126. What type(s) of secretion does the buccal gland have?

Back 126

The buccal glands secrete only mucus.

Front 127

127. What types of ions are in the saliva?

Back 127

Saliva contains especially large quantities of potassium and bicarb ions.

Conversely, the concentrations of both sodium and chloride ions are several times less in saliva than in plasma.

Front 128

128. What occurs during the first stage of salivary secretion?

Back 128

The acini secrete a primary secretion that contains ptyalin and/or mucin in a solution of ions in concentrations not greatly different from those of typical ECF.

As the primary secretion flows through the ducts, two major active transport processes take place that alter the ionic composition of the saliva.

Front 129

129. What two major active transport processes take place that markedly modify the ionic composition of the fluid in saliva?

Back 129

1. Sodium ions are actively reabsorbed from all the salivary ducts and potassium ions are actively secreted in exchange for teh sodium. Therefore the sodium ion concentration of the saliva becomes greatly reduced, whereas the potassium ion concentration becomes increased.

2. Bicarbonate ions are secreted by the ductal epithelium into the lumen of the duct. This is partly caused by passive exchange of bicarb for chloride ions, but it may also result from an active secretory process.

Front 130

130. What is the net result of these active transport processes in the saliva?

Back 130

Under resting conditions, the concentration of sodium and chloride ions in the saliva are only about 15 mEq/L each, about 1/7th their concentration in plasma.

Conversely, the concentration of potassium ions is about 30 mEq/L, 7x as great as in plasma;

The concentration of bicarbonate ions is 50 - 70 mEq/L, about 2-3x that of plasma.

Front 131

131. What occurs during maximal salivation?

Back 131

The salivary ionic concentrations change considerably b/c the rate of formation of primary secretion by the acini can increase as much as 20x.

This acinar secretion then flows thru the ducts so rapidly that the ductal reconditioning of the secretion is considerably reduced.

Therefore, when copious quantities of saliva are being secreted, the sodium chloride concentration rises only to 1/2x or 2/3x that of plasma, and the potassium concentration rises to only 4x that of plasma.

Front 132

132. What is the function of saliva in oral hygiene?

Three major functions...

Back 132

1. The flow of saliva itself helps wash away pathogenic bacteria as well as food particles that provide their metabolic support.
2. It contains several factors that destroy bacteria, such as thiocyanate ions and proteolytic enzymes e.g. lysozyme that attack the bacteria, aid the thiocyanate ions in entering the bacteria where these ions in turn become bactericidal, and digest food particles
3. Saliva often contains significant amts of protein antibodies that can destroy oral bacterial including some that cause dental caries.

Front 133

133. What types of stimulation causes increased salivation?

Back 133

Excited by both taste and tactile stimuli from the tongue and other areas of the mouth and pharynx.

Many taste stimuli, especially the sour taste elicit copious secretion of saliva.

Also, certain tactile stimuli, i.e. the presence of smooth objects in the mouth cause marked salivation, whereas rough objects can less salivation.

Front 134

134. What areas of the CNS can inhibit/stimulate salivation?

Back 134

Salivation can also be stimulated or inhibited by nervous signals arriving in the salivatory nuclei from higher centers of the CNS.

The appetite area of the brain is located in proximity to the parasympathetic centers of the anterior hypothalamus, and it functions to a great extent in response to signals from the taste and smell areas of the cerebral cortex.

Front 135

135. How does irritation affect salivation?

Back 135

When irritating food are swallowed or when a person is nauseated b/c of some GI abnromality, salivation occurs.

The saliva, when swallowed, helps to remove the irritating facotr in the GI tract by diluting or neutralizing the irritant substances.

Front 136

136. What effect does sympathetic stimulation have on salivation?

Back 136

Sympathetic stimulation can also increase salivation a slight amt, much less so than does parasympathetic stimulation.

The sympathetic nerves originate from the superior cervical ganglia and travel along the surfaces of the blood vessel walls to the salivary glands.

Front 137

137. What effect does the vascular supply have on salivation?

Back 137

The secretion of saliva always requires adequate nutrients from the blood.

The parasympathetic nerve signals that induce copious salivation also moderately dilate the blood vessels.

In addition, salivation itself directly dilates the blood vessels, thus providing increased salivatory gland nutrition as needed by the secreting cells.

Front 138

138. What two vasodilator substances are secreted by the salivary cells?

Back 138

1. Kallikein, which acts as an enzyme to split one of the blood proteins, known as bradykinin
2. Bradykinin

Front 139

139. What types of secretion occur in the esophagus?

Back 139

The esophageal secretions are entirely mucous in character and principally provide lubrication for swallowing.

The main body of the esophagus is lined w/many simple mucus glands.

At the gastric end, and to a lesser extent in the initial portion, there are also many compound mucous glands.

The mucus secreted by the compound glands in the upper esophagus prevents mucosal excoriation by newly entering food, whereas the compound glands located near the esophagogastric junction protect the esophageal wall from digestion by acidic gastric juices that often reflex from the stomach back into the lower esophagus.

Front 140

140. What are the two types of tubular glands that are important in the stomach?

Where are they located, and what do they secrete?

Back 140

1. Oxyntic glands (AKA gastric glands) located on the inside surfaces of the body and fundus of the stomach, constituting the proximal 80% of the stomach
-secretes HCl, pepsinogen, intrinsic factor, and mucus

2. Pyloric glands located in the antral portion of the stomach, the distal 20% of the stomach
-secretes mainly mucus for protection of the pyloric mucosa from the stomach acid, and also secretes gastrin

Front 141

141. Oxyntic glands

Back 141

A typical oxyntic gland is composed of three cell types:
1. Mucous neck cells, which secrete mainly mucus
2. Peptic (or chief) cells, which secrete large quantities of pepsinogen
3. Parietal (or oxyntic) cells, which secrete HCl and intrinsic factor

Front 142

142. Where is the HCl formed in the parietal cells?

Back 142

The structure of the parietal cell contains large branching intracellular canaliculi. The HCl is formed at the villus-like projections inside these canaliculi and is then conducted thru the canaliculi to the secretory end of the cell.

Front 143

143. What is step 1/4 in the mechanism for secretion of HCl by the parietal cells?

Back 143

1. Chloride ion is actively transported from the cytoplasm of the parietal cell into the lumen of the canaliculus, and sodium ions are actively transported out of the canaliculus into the cytoplasm of the parietal cell. These two effects together create a negative potential of -40 to -70 millivolts in the canaliculus, which in turn causes diffusion of positively charged potassium ions and a small number of sodium ions from the cell cytoplasm into the canaliculus. Thus, in effect, mainly potassium chloride and much smaller amounts of sodium chloride enter the canaliculus.

Front 144

144. What is step 2/4 in the mechanism for secretion of HCl by the parietal cells?

Back 144

2. Water becomes dissociated into hydrogen ions and hydroxyl ions in the cell cytoplasm. The hydrogen ions are then actively secreted into the canaliculus in exchange for potassium ions: this active exchange process is catalyzed by H+,K+- ATPase. In addition, the sodium ions are actively reabsorbed by a separate sodium pump. Thus, most of the potassium and sodium ions that had diffused into the canaliculus are reabsorbed into the cell cytoplasm, and hydrogen ions take their place in the canaliculus, giving a strong solution of hydrochloric acid in the canaliculus. The hydrochloric acid is then secreted outward through the open end of the canaliculus into the lumen of the gland.

Front 145

145. What is step 3/4 in the mechanism for secretion of HCl by the parietal cells?

Back 145

3. Water passes into the canaliculus by osmosis because of extra ions secreted into the canaliculus. Thus, the final secretion from the canaliculus contains water, hydrochloric acid at a concentration of about 150 to 160 mEq/L, potassium chloride at a concentration of 15 mEq/L, and a small amount of sodium chloride.

Front 146

146. What is step 4/4 in the mechanism for secretion of HCl by the parietal cells?

Back 146

4. Finally, carbon dioxide, either formed during metabolism in the cell or entering the cell from the blood, combines under the influence of carbonic anhydrase with the hydroxyl ions (from step 2) to form bicarbonate ions. These then diffuse out of the cell cytoplasm into the extracellular fluid in exchange for chloride ions that enter the cell from the extracellular fluid and are later secreted into the canaliculus.

Front 147

147. Were is pepsinogen secreted?

What happens when it is secreted?

Back 147

Several slightly different types of pepsinogen are secreted by the peptic and mucous cells of the gastric glands.

When it comes into contact w/HCl, it is activated to form pepsin.

Front 148

148. What is the function of pepsin?

Back 148

Pepsin functions as an active proteolytic enzyme in a highly acid medium (pH 1.8-3.5) but above a pH of 5 it is not active.

Front 149

149. Intrinsic factor is secreted by what and where?

Why is it important?

Back 149

The substance intrinsic factor, essential for absorption of vitamin B12 in the ileum, is secreted by the parietal cells along with the secretion of hydrochloric acid.

When the acid-producing parietal cells of the stomach are destroyed, which frequently occurs in chronic gastritis, the person develops not only achlorhydria (lack of stomach acid secretion) but often also pernicious anemia because of failure of maturation of the red blood cells in the absence of vitamin B12 stimulation of the bone marrow.

Front 150

150. What are the pyloric glands and what are they composed of?

Back 150

They pyloric glands are structurally similar to the oxyntic glands but contain few peptic cells and almost no parietal cells.

Instead, they contain mostly mucous cells that secrete a small amt of pepsinogen, and an especially large amt of thin mucus that helps to lubricate food movement, as well as to protect the stomach wall from digestion.

They pyloric glands also secrete gastrin.

Front 151

151. What type of cells are on the entire surface of the stomach mucosa?

What is a special characteristic of these cells?

Back 151

The enire surface of the stomach mucosa between glands has a continuous layer of a special type of mucous cells called "surface mucous cells".

They secrete large quanitities of a very viscid mucus that coats the stomach mucosa w/a gel layer of mucus, thus providing a major shell of protection and lubrication.

*Another characteristic of this mucus is that it is alkaline.

Front 152

152. What are the only cells that secrete HCl?

Back 152

The parietal cells, located deep in the oxyntic glands of the main body of the stomach are the only cells that secrete HCl.

However, secretion of this acid is under continuous control by both endocrine and nervous signals. Also, the parietal cells operate in close association with another type of cell called enterochromaffin-like cells (ECL cells), the primary function of which is to secrete histamine.

Front 153

153. Where are the ECL cells located?

Back 153

The ECL cells lie in the deep recesses of the oxyntic glands and therefore release histamine in direct contact w/the parietal cells of the gland.

The rate of formation and secretion of HCl by the parietal cells is related to the amt of histamine secreted by the ECL cells.

Front 154

154. What are two different ways ECL cells can be stimulated?

Back 154

1. Probably the most potent mechanism is by the hormonal substance gastrin, which is formed almost entirely in the antral portion of the stomach mucosa in response to proteins in the food being digested

2. In addition, the ECL cells can be stimulated by (a) ACh released from stomach vagal nerve endings and (b) probably also by hormonal substances secreted by the enteric nervous system of the stomach

Front 155

155. What does gastrin do and where is it formed?

How does it interact with histamine?

Back 155

Gastrin is itself a hormone secreted by gastrin cells. These cells are located in the pyloric glands in the distal end of the stomach.

When meats or other protein containing foods reach the antral end of the stomach, some of the proteins from these foods have a special stimulatory effect on the gastrin cells in the pyloric glands to cause release of gastrin into the digestive juices of the stomach.

The vigorous mixing of the gastric juices transports the gastrin rapidly to the ECL cells in the body of the stomach, causing release of histamine directly into the deep oxyntic glands. The histamine then acts quickly to stimulate gastric hydrochloric acid secretion.

Front 156

156. Pepsinogen secretion occurs in response to which two types of signals?

Back 156

1. Stimulation of the peptic cells by ACh released from the vagus nerves or from the gastric enteric nervous plexus

2. Stimulation of peptic cell secretion in response to acid in the stomach.

The acid in the stomach probably does not stimulate the peptic cells directly but instead elicits additional enteric nervous reflexes that support the original nervous signals to the peptic cells. Therefore, the rate of secretion of pepsinogen is strongly influenced by the amt of acid the stomach.

Front 157

157. What are the three phases of gastric secretion?

Back 157

1. Cephalic phase
2. Gastric phase
3. Intestinal phase

Front 158

158. What occurs in the cephalic phase?

Back 158

The cephalic phase of gastric secretion occurs even before food enters the stomach, especially while it is being eaten.

It results from the sight, smell, thought, or taste of food, and the greater the appetite, the more intense is the stimulation. Neurogenic signals that cause the cephalic phase of gastric secretion originate in the cerebral cortex and in the appetite centers of the amygdala and hypothalamus. They are transmitted through the dorsal motor nuclei of the vagi and thence through the vagus nerves to the stomach.

This phase of secretion normally accounts for about 20 per cent of the gastric secretion associated with eating a meal.

Front 159

159. What occurs in the gastric phase?

Back 159

Once food enters the stomach, it excites (1) long vagovagal reflexes from the stomach to the brain and back to the stomach, (2) local enteric reflexes, and (3) the gastrin mechanism, all of which in turn cause secretion of gastric juice during several hours while food remains in the stomach.

The gastric phase of secretion accounts for about 70 per cent of the total gastric secretion associated with eating a meal and therefore accounts for most of the total daily gastric secretion of about 1500 milliliters.

Front 160

160. What occurs in the intestinal phase?

Back 160

The presence of food in the upper portion of the small intestine, particularly in the duodenum, will continue to cause stomach secretion of small amounts of gastric juice, probably partly because of small amounts of gastrin released by the duodenal mucosa.

Front 161

161. How does intestinal chyme affect gastric secretion?

Back 161

Although intestinal chyme slightly stimulates gastric secretion during the early intestinal phase of stomach secretion, it paradoxically inhibits gastric secretion at other times.

Front 162

162. What two types of influences cause this inhibition?

Back 162

1. The presence of food in the small intestine initiates a reverse enterogastric reflex, transmitted thru the myenteric nervous system as well as thru the extrinsic sympathetic and vagi nerves, that inhibits stomach secretion. This reflex can be initiated by distending the small bowel, by the presence of acid in the upper intestine, by the presence of protein breakdown products, or by irritation of the mucosa.

2. The presence of acid, fat, protein breakdown products, hyperosmotic or hypoosomotic fluids, or any irritating factor in the upper small intestine causes release of several intestinal hormones. One of these is secretin, which is especially important for control of pancreatic secretion.

Front 163

163. Is there secretion during the interdigestive period?

Back 163

The stomach secretes a few mLs of gastric juice each hour during the interdigestive period when little or no digestion is occurring anywhere in the gut.

The secretion that does occur usually is almost entirely of the nonoxyntic type, composed mainly of mucus but little pepsin and almost no acid.

Front 164

164. Chemical composition fo gastrin, CCK, and secretin?

Back 164

They are all large polypeptides. The terminal five AAs in the gastrin and CCK molecular chains are the same. The functional activity of gastrin resides in the terminal four AAs, and the activity for CCK resides in the terminal eight AAs.

Front 165

165. What is pentagastrin?

Back 165

A synthetic gastrin that is composed of the terminal four AAs of natural gastrin plus the AA alanine, and has all the same physiologic properties as the natural gastrin.

Front 166

166. Pancreatic secretion

Back 166

The pancreas, which lies parallel to and beneath the stomach, is a large compound gland with most of its internal structure similar to that of the salivary glands.

The pancreatic digestive enzymes are secreted by pancreatic acini, and large volumes of sodium bicarbonate solution are secreted by the small ductules and larger ducts leading from the acini. The combined product of enzymes and sodium bicarbonate then flows through a long pancreatic duct that normally joins the hepatic duct immediately before it empties into the duodenum through the papilla of Vater, surrounded by the sphincter of Oddi.

Front 167

167. What stimulates pancreatic secretions?

How are these pancreatic secretions different than insulin secretion?

Back 167

Pancreatic juice is secreted most abundantly in response to the presence of chyme in the upper portions of the small intestine, and the characteristics of the pancreatic juice are determined to some extent by the types of food in the chyme.

Insulin is secreted directly into the blood, not into the intestines.

Front 168

168. What is in pancreatic secretions?

Back 168

Contains multiple enzymes and large quantities of bicarb ions. The most important of the pancreatic enzymes for digesting proteins are trypsin, chymotrypsin, and carboxypolypeptidase.

By far the most abundant of these is trypsin.

Front 169

169. What does trypsin, chymotrypsin and carboxypolypeptidase do?

Back 169

Trypsin and chymotrypsin split whole and partially digested proteins into peptides of various sizes but do not cause release of individual AAs.

However, carboxypolypeptidase does split some peptides into individual AAs, thus completing digestion of some proteins all the way to the AA state.

Front 170

170. Pancreatic amylase

Back 170

This pancreatic enzyme is important for digesting carbohydrates. It hydrolyzes starches, glycogen, and most other carbohydrates, except cellulose to form mostly disaccharides and a few trisaccharides.

Front 171

171. What are the 3 main enzymes for fat digestion?

Back 171

1. Pancreatic lipase, which is capable of hydrolyzing neutral fat into fatty acids and monoglycerides
2. Cholesterol esterase, which causes hydrolysis of cholesterol esters
3. Phospholipase, which splits fatty acids from phospholipids

Front 172

172. How is trysinogen activated?

Back 172

Via an enzyme called enterokinase, which is secreted by the intestinal mucosa when chyme comes in contact w/the mucosa.

Also, trypsinogen can be autocatalytically activated by trypsin that has already been formed from previously secreted trypsinogen.

Front 173

173. What is the importance of trypsin inhibitor, and where is it formed?

Back 173

The same cells that secrete proteolytic enzymes into the acini of the pancreas also secrete another substance called trypsin inhibitor.

This substance is formed in the cytoplasm of the glandular cells, and it prevents activation of trypsin both inside the secretory cells and in the acini and ducts of the pancreas.

And, b/c it is tryspin that activates the other pancreatic proteolytic enzymes, this inhibitor prevents activation of the others as well.

Front 174

174. Acute pancreatitis and trypsin inhibitor

Back 174

The effect of trypsin inhibitor is often overwhelmed when the pancreas becomes severely damaged or when a duct become blocked.

In this case, the pancreatic secretion rapidly become activated and can literally digest the entire pancreas within a few hours.

Front 175

175. Secretion of bicarb ions by the pancreas

Back 175

Bicarb ions and water are secreted mainly by the epithelial cells of the ductules and ducts that lead from the acini.

This provides a large quantity of alkali in the pancreatic juice that serves to neutralize the HCl emptied into the duodenum from the stomach.

Front 176

176. What are the three basic steps int he cellular mechanism for secreting sodium bicarb solution into the pancreatic ductules and ducts?

Back 176

1. Carbon dioxide diffuses to the interior of the cell from the blood and, under the influence of carbonic anhydrase, combines with water to form carbonic acid (H2CO3). The carbonic acid in turn dissociates into bicarbonate ions and hydrogenions (HCO3- and H+). Then the bicarbonate ions are actively transported in association with sodium ions (Na+) through the luminal border of the cell into the lumen of the duct.
2. The hydrogen ions formed by dissociation of carbonic acid inside the cell are exchanged for sodium ions through the blood border of the cell by a secondary active transport process. This supplies the sodium ions (Na+) that are transported through the luminal border into the pancreatic duct lumen to provide electrical neutrality for the secreted bicarbonate ions.
3. The overall movement of sodium and bicarbonate ions from the blood into the duct lumen creates an osmotic pressure gradient that causes osmosis of water also into the pancreatic duct, thus forming an almost completely isosmotic bicarbonate solution.

Front 177

177. What are the three stimuli that are important in causing pancreatic secretion?

Back 177

1. ACh, which is released from the parasympathetic vagi nerve endings and from other cholinergic nerves in the enteric nervous system

2. CCK, which is secreted by the duodenal and upper jejunal mucosa when food enters the small intestine

3. Secretin, which is also secreted by the duodenal and jejunal mucosa when highly acid food enters the small intestine

Front 178

178. How do these three stimuli interact?

Back 178

ACh and CCK stimulate the acinar cells of the pancreas, causing production of large quantities of pancreatic digestive enzymes but relatively small quantities of water and electrolytes to go with the enzymes.

Without the water, most of the enzymes remain temporarily stored in the acini and ducts until more fluid secretion comes along to wash them into the duodenum.

Secretin, in contrast to the others, stimulates secretion of large quantities of water solution of sodium bicarb by the pancreatic ductal epithelium.

Front 179

179. What are the multiplicative effects of different stimuli?

Back 179

When all the different stimuli of pancreatic secretion occur at once, the total secretion is far greater than the sum fo the secretions caused by each one separately.

Therefore, the various stimuli are said to "multiply" or "potentiate" one another.

Front 180

180. In the pancreas this time, what are the three phases of pancreatic secretion?

Back 180

1. Cephalic
2. Gastric
3. Intestinal

Front 181

181. Cephalic phase of pancreatic secretion

Back 181

During the cephalic phase of pancreatic secretion, the same nervous signals from the brain that cause secretion in the stomach also cause acetylcholine release by the vagal nerve endings in the pancreas.

This causes moderate amounts of enzymes to be secreted into the pancreatic acini, accounting for about 20 per cent of the total secretion of pancreatic enzymes after a meal.

But little of the secretion flows immediately through the pancreatic ducts into the intestine because only small amounts of water and electrolytes are secreted along with the enzymes.

Front 182

182. Gastric phase of pancreatic secretion

Back 182

During the gastric phase, the nervous stimulation of enzyme secretion continues, accounting for another 5 to 10 per cent of pancreatic enzymes secreted after a meal.

But, again, only small amounts reach the duodenum because of continued lack of significant fluid secretion.

Front 183

183. Intestinal phase of pancreatic secretion

Back 183

After the chyme leaves the stomach and enters the small intestine, pancreatic secretion becomes copious, mainly in response to the hormone secretin.

Front 184

184. What does secretin stimulate?

What is the one truly potent constituent of chyme that causes this secretin release?

Back 184

Secretin stimulate secretion of copious quantities of bicarb ions to neutralize the chyme.

The one truly potent constituent of chyme that causes this secretin release is the HCl from the stomach.

Front 185

185. What does secretin do to pancreas?

Why is the secretin mechanism important ?

Back 185

It causes the pancreas to secrete large quantities of fluid containing high concentrations of bicarb ions, but low concentration of chloride ions.

Secretin begins to be released from the mucosa of the small intestine when the pH of the duodenal contents falls below 4.5 - 5.0, and its release increase greatly as the pH falls to 3.0. B/c the mucosa of the small intestine cannot withstand the digestive action of gastric acid juice, this is essential in protecting from the development of duodenal ulcers.

Front 186

186. What causes secretion of CCK?

Back 186

The presence of food in the upper small intestine also causes CCK to be released from the I cells in the mucosa of the duodenum and upper jejunum.

This release of CCK results especially from the presence of proteoses and peptones (products of partial protein digestion) and long-chain fatty acids in the chyme coming from the stomach.

Front 187

187. Where does the CCK go after it's secreted?

Back 187

CCK, like secretin, passes by way of the blood to the pancreas but instead of causing sodium bicarb secretion it causes mainly secretion of still much more pancreatic digestive enzymes by the acinal cells.

This effect is similar to that caused by vagal stimulation but even more pronounced, accounting for 70-80% of the total secretion of the pancreatic digestive enzymes after a meal.

Front 188

188. What are three differences between the pancreatic stimulatory effects of secretin and CCK?

Back 188

1. Intense sodium bicarb secretion in response to acid in the duodenum, stimulated by secretin
2. A dual effect in response to soap (a fat)
3. Intense digestive enzyme secretion (when peptones enter the duodenum) stimulated by CCK

Front 189

189. What are the two major functions of bile secreted by the liver?

Back 189

1. Plays an important role in fat digestion and absorption because of bile acids in the bile do two things: (1) they help to emulsify the large fat particles of the food into many minute particles, (2) they aid in absorption of the digested fat end products through the intestinal mucosal membrane

2. Bile serves as a means for excretion of several important waste products from the blood. These include especially bilirubin, an end product of hemoglobin destruction, and excesses of cholesterol.

Front 190

190. What are the two stages of bile secretion by the liver?

Back 190

(1) The initial portion is secreted by the principal functional cells of the liver, the hepatocytes; this initial secretion contains large amounts of bile acids, cholesterol, and other organic constituents. It is secreted into minute bile canaliculi that originate between the hepatic cells.

(2) Next, the bile flows in the canaliculi toward the interlobular septa, where the canaliculi empty into terminal bile ducts and then into progressively larger ducts, finally reaching the hepatic duct and common bile duct. From these the bile either empties directly into the duodenum or is diverted for minutes up to several hours through the cystic duct into the gallbladder.

Front 191

191. What second secretion is added to the liver bile?

Back 191

In its course through the bile ducts, a second portion of liver secretion is added to the initial bile. This additional secretion is a watery solution of sodium and bicarbonate ions secreted by secretory epithelial cells that line the ductules and ducts.

This second secretion sometimes increases the total quantity of bile by as much as an additional 100 per cent.

Front 192

192. What stimulates this second secretion?

Back 192

The second secretion is stimulated especially by secretin, which causes release of additional quantities of bicarbonate ions to supplement the bicarbonate ions in pancreatic secretion (for neutralizing acid that empties into the duodenum from the stomach).

Front 193

193. Where is bile stored and concentrated?

Back 193

Bile is secreted continually by the liver cells, but most of it is normally stored int the gallbladder until needed in the duodenum.

As much as 12 hours of bile secretion can be stored in the gallbladder b/c water, sodium, chloride, and most other small electrolytes are continually absorbed thru the gallbladder mucosa, concentrating the remaining bile constituents that contain the bile salts, cholesterol, lecithin, and bilirubin.

Front 194

194. What causes most of the gallbladder absorption?

Back 194

Caused by active transport of sodium through the gallbladder epithelium, and this is followed by secondary absorption of chloride ions, and most other diffusible constituents.

Bile is normally concentrated int his way about 5-fold, but it can be concentrated up to a max of 20-fold.

Front 195

195. What is in bile?

Back 195

The most abundant substances are bile salts. Also secreted or excreted in large concentrations are bilirubin, cholesterol, lecithin, and the usual electrolytes of plasma.

Front 196

196. What causes the emptying of the gallbladder?

Back 196

The most potent stimulus for cause the gallbladder contractions is CCK. This is released in response to fatty food in the duodenum.

Also, the gallbladder is stimulated less strongly by ACh-secreting nerve fibers from both the vagi and the intestinal enteric nervous system.

Front 197

197. What is the mechanism for gallbladder emptying?

Back 197

When food begins to be digested in the upper gastrointestinal tract, the gallbladder begins to empty, especially when fatty foods reach the duodenum about 30 minutes after a meal.

The mechanism of gallbladder emptying is rhythmical contractions of the wall of the gallbladder, but effective emptying also requires simultaneous relaxation of the sphincter of Oddi, which guards the exit of the common bile duct into the duodenum.

Front 198

198. What are bile salts?

Back 198

The liver cells synthesize about 6 grams of bile salts daily. The precursor of the bile salts is cholesterol, which is either present in the diet or synthesized in the liver cells during the course of fat metabolism.

The cholesterol is first converted to cholic acid or chenodeoxycholic acid in about equal quantities. These acids in turn combine principally with glycine and to a lesser extent with taurine to form glyco- and tauro conjugated bile acids.

The salts of these acids, mainly sodium salts, are then secreted in the bile.

Front 199

199. What are the two important actions bile salts have on the intestinal tract?

Back 199

First, they have a detergent action on the fat particles in the food. This decreases the surface tension of the particles and allows agitation in the intestinal tract to break the fat globules into minute sizes. This is called the emulsifying or detergent function of bile salts.

Second, and even more important than the emulsifying function, bile salts help in the absorption of (1) fatty acids, (2) monoglycerides, (3) cholesterol, and (4) other lipids from the intestinal tract. They do this by forming very small physical complexes with these lipids; the complexes are called micelles, and they are semi-soluble in the chyme because of the electrical charges of the bile salts.

The intestinal lipids are “ferried” in this form to the intestinal mucosa, where they are then absorbed into the blood.

Without the presence of bile salts in the intestinal tract, up to 40 per cent of the ingested fats are lost into the feces, and the person often develops a metabolic deficit because of this nutrient loss.

Front 200

200. What is the enterohepatic circulation of bile salts?

Back 200

About 94 per cent of the bile salts are reabsorbed into the blood from the small intestine, about one half of this by diffusion through the mucosa in the early portions of the small intestine and the remainder by an active transport process through the intestinal mucosa in the distal ileum.

They then enter the portal blood and pass back to the liver. On reaching the liver, on first passage through the venous sinusoids these salts are absorbed almost entirely back into the hepatic cells and then are resecreted into the bile.

Front 201

201. What is the importance of the enterohepatic circulation?

Back 201

In this way, about 94 per cent of all the bile salts are recirculated into the bile, so that on the average these salts make the entire circuit some 17 times before being carried out in the feces.

The small quantities of bile salts lost into the feces are replaced by new amounts formed continually by the liver cells.

Front 202

202. The quantity of bile secreted by the liver each day is dependent upon...?

Back 202

The availability of bile salts. The greater the quantity of bile salts in the enterohepatic circulation, the greater the rate of bile secretion.

Ingestion of supplemental bile salts can increase bile secretion.

Front 203

203. What happens if a bile fistula occurs?

Back 203

If a bile fistula empties the bile salts to the exterior for several days to several weeks so that they cannot be reabsorbed from the ileum, the liver increases its production of bile salts 6- to 10-fold, which increases the rate of bile secretion most of the way back to normal.

This demonstrates that the daily rate of liver bile salt secretion is actively controlled by the availability (or lack of availability) of bile salts in the enterohepatic circulation.

Front 204

204. What is the role of secretin in bile secretion?

Back 204

The secretin that also stimulates pancreatic secretion increases bile secretion, sometimes more than doubling its secretion for several hours after a meal.

This increase is almost entirely secretion of a sodium bicarb rich watery solution by the epithelial cells of the bile ductules and cuts, and not increased secretion by the liver parenchymal cells themselves.

The bicarb in turn passes into the small intestine and joins the bicarb from the pancreas in neutralizing the HCl.

Thus, the secretin feedback mechanism for neutralizing duodenal acid operates not only thru its effects on pancreatic secretion but also to a lesser extent thru its effect on secretion by the liver ductules and ducts.

Front 205

205. Liver secretion of cholesterol

Back 205

Bile salts are formed in the hepatic cells from cholesterol in the blood plasma. In the process of secreting the bile salts, about 1 to 2 grams of cholesterol are removed from the blood plasma and secreted into the bile each day.

Cholesterol is almost completely insoluble in pure water, but the bile salts and lecithin in bile combine physically with the cholesterol to form ultramicroscopic micelles in the form of a colloidal solution.

When the bile becomes concentrated in the gallbladder, the bile salts and lecithin become concentrated along with the cholesterol, which keeps the cholesterol in solution.

Front 206

206. What are gallstones?

Who are most likely to form gallstones?

Back 206

Under abnormal conditions, the cholesterol may precipitate in the gallbladder, resulting in the formation of cholesterol gallstones.

The amount of cholesterol in the bile is determined partly by the quantity of fat that the person eats, because liver cells synthesize cholesterol as one of the products of fat metabolism in the body.

For this reason, people on a high-fat diet over a period of years are prone to the development of gallstones.

Front 207

207. What secretes mucus in the duodenum?

Where are they located?

Back 207

Brunner's glands in the duodenum.

An extensive array of compound mucous glands, called Brunner’s glands, is located in the wall of the first few centimeters of the duodenum, mainly between the pylorus of the stomach and the papilla of Vater where pancreatic secretion and bile empty into the duodenum.

Front 208

208. Brunner's glands secrete large amounts of alkaline mucus in response to what three stimuli?

Back 208

1. Tactile or irritating stimuli on the duodenal mucosa
2. Vagal stimulation, which cases increased Brunner's glands secretion concurrently w/increase in stomach secretion
3. GI hormones, especially secretin

Front 209

209. What is the function of Brunner's glands?

Back 209

To secret mucus to protect the duodenal wall from digestion and to neutral the chyme.

Front 210

210. What inhibits Brunner's gland secretion?

Back 210

Sympathetic stimulation

Front 211

211. What secretes mucus int he small intestine?

Where are they located?

Back 211

Crypts of Lieberkuhn. These crypts lie between the intestinal villi.

Front 212

212. What two types of cells compose the epithelium that covers the crypts and villi of the small intestine?

Back 212

1. A moderate number of goblet cells, which secrete mucus that lubricates and protects the intestinal surfaces

2. A large number of enterocytes, which in the crypts secrete large quantities of water and electrolytes and over the surfaces of adjacent villi reabsorb the water and electrolytes along with end products of digestion.

Front 213

213. What is the importance of the watery fluid/mucus in the small intestine?

Back 213

The flow of fluid from the crypts into the villi supplies a watery vehicle for absorption of substances from the chyme when it comes into contact w/the villi.

Front 214

214. What is the mechanism of secretion of the watery fluid?

Back 214

The exact mechanism that controls the marked secretion of watery fluid by the crypts of Lieberkühn is not known.

It is believed to involve at least two active secretory processes: (1) active secretion of chloride ions into the crypts and (2) active secretion of bicarbonate ions.

The secretion of both of these ions causes electrical drag as well of positively charged sodium ions through the membrane and into the secreted fluid.

Finally, all these ions together cause osmotic movement of water.

Front 215

215. What digestive enzymes are active in the small intestine?

Back 215

When secretions of the small intestine are collected without cellular debris, they have almost no enzymes. The enterocytes of the mucosa, especially those that cover the villi, do contain digestive enzymes that digest specific food substances while they are being absorbed through the epithelium.

These enzymes are the following: (1) several peptidases for splitting small peptides into amino acids, (2) four enzymes - sucrase, maltase, isomaltase, and lactase - for splitting disaccharides into monosaccharides, and (3) small amounts of intestinal lipase for splitting neutral fats into glycerol and fatty acids.

Front 216

216. What regulates the secretions in the small intestine?

Back 216

Local stimuli;

By far the most important means for regulating small intestine secretion are local enteric nervous reflexes, especially reflexes initiated by tactile or irritative stimuli from the chyme in the intestines.

Front 217

217. What secretes mucus in the large intestine?

Back 217

The mucosa of the large intestine, like that of the small intestine, has many crypts of Lieberkühn; however, unlike the small intestine, there are no villi.

The epithelial cells contain almost no enzymes. Instead, they consist mainly of mucous cells that secrete only mucus.

The great preponderance of secretion in the large intestine is mucus. This mucus contains moderate amounts of bicarbonate ions secreted by a few non–mucus secreting epithelial cells. The rate of secretion of mucus is regulated principally by direct, tactile stimulation of the epithelial cells lining the large intestine and by local nervous reflexes to the mucous cells in the crypts of Lieberkühn.

Front 218

218. What stimulates mucus secretion in the large intestine?

Back 218

Stimulation of the pelvic nerves from the spinal cord, which carry parasympathetic innervation to the distal one half to two thirds of the large intestine, also can cause marked increase in mucus secretion.

This occurs along with increase in peristaltic motility of the colon.

During extreme parasympathetic stimulation, often caused by emotional disturbances, so much mucus can occasionally be secreted into the large intestine that the person has a bowel movement of ropy mucus as often as every 30 minutes; this mucus often contains little or no fecal material.

Front 219

219. What is the role of the mucus in the large intestine?

Back 219

Mucus in the large intestine protects the intestinal wall against excoriation, but in addition, it provides an adherent medium for holding fecal matter together.

Furthermore, it protects the intestinal wall from the great amount of bacterial activity that takes place inside the feces, and, finally, the mucus plus the alkalinity of the secretion (pH of 8.0 caused by large amounts of sodium bicarbonate) provides a barrier to keep acids formed in the feces from attacking the intestinal wall.

Front 220

220. What is enteritis, and what is the result?

Back 220

Whenever a segment of the large intestine becomes intensely irritated, as occurs when bacterial infection becomes rampant during enteritis, the mucosa secretes extra large quantities of water and electrolytes in addition to the normal viscid alkaline mucus.

This acts to dilute the irritating factors and to cause rapid movement of the feces toward the anus.

The result is diarrhea, with loss of large quantities of water and electrolytes. But the diarrhea also washes away irritant factors, which promotes earlier recovery from the disease than might otherwise occur.

Front 221

221. Where does the esophagus develop from?

What is the normal size and position?

Back 221

The esophagus develops from the cranial portion of the foregut and is recognizable by the third week of gestation.

The normal esophagus is a hollow, highly distensible muscular tube that extends from the epiglottis in the pharynx, at about C6, to the gastroesophageal junction at the level of T11 or T12.

It is 10-11 cm long in newborns and it is 25 cm in adults.

Front 222

222. Where are the points of luminal narrowing in the esophagus?

There are four of them...

Back 222

1. Proximally at the cricoid cartilage
2. Midway in its ourse alongside the aortic arch
3. At the anterior crossing of the left main bronchus and left atrium
4. Distally where it pierces the diaphragm

Front 223

223. Where are the esophageal sphincters?

Are they anatomic or physiologic sphincters?

Back 223

A 3-cm segment in the proximal esophagus at the level of the cricopharyngeus muscle is referred to as the upper esophageal sphincter (UES).

The 2 - 4 cm segment just proximal to the anatomic gastroesophageal junction, at the level of the diaphragm, is referred to as the lower esophageal sphincter (LES).

Both "sphincters" are physiologic, in that there are no anatomic landmarks that delineate these higher-pressure regions from the intervening esophageal musculature.

Front 224

224. What is the wall of the esophagus composed up?

Back 224

Mucosa, submucosa, muscularis propria, and adventitia.

Front 225

225. What are the three components of the mucosa?

What type of cells are in the epithelial layer?

Back 225

1. A nonkeratinizing stratified squamous epithelial layer
2. Lamina propria
3. Muscularis mucosa

The epithelial layer has mature squamous cells overlying basal cells. The basal cells are reserve cells with great proliferative potential.

Front 226

226. What is the nonepithelial portion of the mucosa called?

What does it consist of?

Back 226

The lamina propria is the nonepithelial portion of the mucosa, above the muscularis mucosae.

It consists of areolar tissue and contains vascular structures and scattered leukocytes.

Finger-like extensions of the lamina propria, called papillae, extend into the epithelial layer.

Front 227

226. What does the submucosa consist of?

Back 227

Consists of loose CT containing blood vessels, a rich network of lymphatics, a sprinkling of leukocytes w/occasional lymphoid follicles, nerve fibers (including ganglia of the Meissner plexus), and submucosal glands

Submucosal glands connected ot the lumen by squamous epithelium-lined ducts are scattered along the entire esophagus but are more concentrated in the upper and lower portions. Their mucin-containing fluid secretions help lubricate the esophagus.

Front 228

227. What makes up the muscularis propria?

Back 228

The muscularis propria consists of an inner circular and an outer longitudinal coat of smooth muscle w/an intervening, well developed myenteric plexus (Auerbach plexus).

The muscularis propria of the proximal 6-8 cm of the esophagus also contains striated muscle fibers from the circopharyngeus muscle.

Front 229

228. What are four common symptoms of esophageal disorders?

Back 229

1. Dysphagia
2. Heartburn
3. Hematemesis
4. Pain

Front 230

229. What are ectopic tissue rests?

Back 230

The most common is ectopic gastric mucosa in the upper third of the esophagus ("inlet patch"), occurring in up to 2% of individuals.

Sebaceous glands or ectopic pancreatic tissue are much less frequent.

The acid secretions of the ectopic gastric mucosa or pancreatic enzymatic secretions can produce localized inflammation and discomfort.

Front 231

231. What are congenital cysts in the esophagus?

Back 231

Embryologic formation of the foregut can also give rise to congenital cysts. These are usually duplication cysts, containing double smooth muscle layers and derived from the lower esophagus in 60% of cases.

Rarely, bronchial or parenchymal pulmonary tissue may arise from the upper gut and is denoted bronchogenic cyst or pulmonary sequestration, respectively.

Front 232

232. What are atresias or fistulas?

Back 232

Absence of the esophagus is extremely rare; much more common are atresia and fistula formation.

In atresia, a segment of the esophagus is represented by only a thin, noncanalized cord, w/a proximal blind pouch connected to the pharynx and a lower pouch leading to the stomach.

Atresia is most commonly located at or near the tracheal bifurcation. It rarely occurs alone, but it is usually associated w/a fistula connecting the lower or upper pouch w/a bronchus or the trachea.

Front 233

233. What are the anomalies associated w/atresia or fistula of the esophagus?

Back 233

Associated anomalies include congenital heart disease, neurologic disease, genitourinary disease, and other GI malformations.

Atresia sometimes is associated w/the presence of a single umbilical artery.

Front 234

234. What are esophageal mucosal webs?

Back 234

These webs are uncommon ledgelike protrusions of the mucosa into the esophageal lumen.

These are semicircumferential, eccentric, and most common in the upper esophagus.

Well developed webs rarely protrude more than 5 mm into the lumen. The webs consist of squamous mucosa and a vascularized submucosal core.

Front 235

235. Where do the webs come from?

Back 235

Webs can be congenital in origin, or they may arise in association w/long-standing reflux esophagitis, chronic graft vs. host disease, or blistering skin diseases.

Front 236

236. What is Paterson-Brown-Kelly or Plummer-Vinson syndrome?

Back 236

When an upper esophageal web is accompanied by an iron deficiency anemia, glossitis, and cheilosis, the condition is referred to as the Paterson-Brown-Kelly or Plummer-Vinson syndrome.

Front 237

237. What are esophageal rings?

What are A rings? B rings?

Back 237

Esophageal rings are concentric plates of tissue protruding into the lumen of the distal esophagus.

One occurring above the squamocolumnar junction fo the esophagus and stomach is referred to as an A ring.

One located at the squamocolumnar junction of the lower esophagus is designated a Schatzki ring or a B ring.

Histologically, these rings consist of mucosa, submucosa, and sometimes a hypertrophied muscularis propria. Schatzki rings may have columnar gastric epithelium on their undersurface.

Front 238

238. Who is most likely to develop esophageal webs and rings?

What is the main symptom?

Back 238

Esophageal webs and rings are encountered most freq in women over 40 and are of uncertain etiology.

Episodic dysphagia is the main symptom associated w/webs and rings, usually provoked when an individual bolts solid food. Pain is rare.

Front 239

239. What is esophageal stenosis?

When and how does it present?

Back 239

This type of stenosis consists of fibrous thickening of the esophageal wall, particularly the submucosa, with atrophy of the muscularis propria. The lining eptihelium is usually thin and sometimes ulcerated.

Although occasionally of congenital origin, stenosis is ore freq the result of severe esophageal injury, w/inflammatory scarring from GERD, radiation, scleroderma, or caustic injury.

Stenosis usually develops in adulthood and becomes manifest by progressive dysphagia, at first to solid foods only but eventually to all foods, which constitutes the major symptom.

Front 240

240..What is achalasia?

What are the three major abnormalities in achalasia?

Back 240

Achalasia means "failure to relax".

It is characterized by three major abnormalities:
1. Aperistalsis
2. Partial or incomplete relaxation fo the LES w/swallowing
3. Increased resting tone of the LES.

Front 241

241. What is the pathogenesis of achalasia?

Back 241

It is thought to involve dysfunction of inhibitor neurons containing NO and VIP in the distal esophagus.

Degenerative changes in neural innervation, either intrinsic to the esophagus or in the extroesophageal vagus nerves and the dorsal motor nucleus of the vagus, may also occur.

Front 242

242. In what disease does secondary achalasia develop?

Back 242

Secondary achalasia may arise in Chagas disease, in which Trypanosoma cruzi causes destruction of the myenteric plexus of the esophagus, duodenum, colon, and ureter, with resultant dilation of these viscera.

Front 243

243. What other disorders can cause an achalasia like illness?

Back 243

Disorders of the dorsal motor nuclei, particularly polio or surgical ablation, can cause an achalasia like illness, as can diabetic autonomic neuropathy and infiltrative disorders such as malignancy, amyloidosis, and sarcoidosis.

In most instances, however, achalasia occurs as a primary disorder of uncertain etiology.

Front 244

244. What is the morphology of primary achalasia?

Back 244

In primary achalasia there is progressive dilation of the esophagus above the level of the LES. The wall of the esophagus may be of normal thickness, thicker than normal owing to hypertrophy of the muscularis, or markedly thinned by dilation.

The myenteric ganglia are usually absent form the body of the esophagus, but may or may not be reduced in number in the region of the ELS.

The mucosal lining may be unaffected, but sometimes inflammation, ulceration, or fibrotic thickening may be evident just above the LES.

Front 245

245. What are the clinical features of achalasia?

Back 245

Achalasia usually becomes manifest in young adulthood, but may appear in infancy or childhood.

The classic clinical symptom is progressive dysphagia. Nocturnal regurgitation and aspiration of undigested food may occur. The most serious aspect of this condition is the hazard of developing esophageal squamous cell carcinoma, said to occur in about 5% of patients, typically at an earlier age than those w/o this disease.

Other complications include Candida esophagitis, lower esophageal diverticula, and aspiration w/pneumonia or airway obstruction.

Front 246

246. What is a hiatial hernia?

What are the two anatomic patterns? Which is more common?

Back 246

Hiatal hernia is characterized by separation of the diaphragmatic crura and esophageal wall.

Two anatomic patterns are recognized: the axial, or sliding hernia, and the nonaxial, or paraesophageal hiatal hernia.

The sliding hernia constitutes 95% of cases; protrusion of the stomach above the diaphragm creates a bell-shaped dilation, bounded below by the diaphragmatic narrowing.

In paraesophageal hernias, a separate portion of the stomach, usually along the greater curvature, enters the thorax thru the widened foramen.

Front 247

247. What is the prevalence of hiatal hernias?

Back 247

They are found in 1-20% of adult subjects, w/incidence increasing w/age.

However, hiatal hernias are well recognized in infants and children.

Only about 9% of adults w/a sliding hernia suffer from heartburn or regurgitation of gastric juices into the mouth.

These symptoms are attributed to incompetence of the LES and are accentuated by positions favoring reflux and obesity.

Front 248

248. What are complications of hiatal hernias?

Back 248

Both types may ulcerate, causing bleeding and perforation. Paraesophageal hernias can become strangulated or obstructed, and early surgical repair has been advocated.

Reflux esophagitis is freq seen in association w/sliding hernias, but compromise of the LES w/regurgitation of peptic juices into the esophagus is probably the result of, rather than the cause of, a sliding hernia.

The uncommon paraesophageal hernias may be caused by previous surgery, including operations for sliding hernia.

Front 249

249. What is a diverticulum?

Back 249

A diverticulum is an outpouching of the alimentary tract that contains all visceral layers; a false diverticulum denotes an outpouching of mucosa and submucosa only.

True diverticula are usually discovered in later life and may develop in three regions of the esophagus.

Front 250

250. What are the three regions of the esophagus where diverticula may develop?

Back 250

1. Zenker diverticulum (pharyngoesophageal diverticulum) immediately above the UES
2. Traction diverticulum near the midpoint of the esophagus
3. Epiphrenic diverticulum immediately above the LES

Front 251

251. What causes Zenker diverticulum?

Back 251

Disordered cricopharyngeal motor dysfunction with or w/o GERD and diminished luminal size of the EUS are implicated in the genesis of Zenker diverticulum.

Front 252

252. What gives rise to mid-esophageal (traction) diverticula?

Back 252

Scarring resulting from mediastinal lymphadenitis (as from tuberculosis) was presumed to be a cause of traction on the esophagus. However, arguments have been advanced in factor of traction diverticula actually arising form motor dysfunction or being a congenital lesion.

Front 253

253. What causes epiphrenic diverticulum?

Back 253

Dyscoordination of peristalsis and LES relaxation are the proposed cause of epiphrenic diverticula.

Front 254

254. What are the symptoms of esophageal diverticula?

Back 254

Zenker diverticula may reach several centimeters in size and can accumulate significant amts of food. Typical symptoms include dysphagia, food regurgitation, and a mass in the neck; aspiration w/resultant pneumonia is a significant risk.

While midesophageal diverticula are generally asymptomatic, epiphrenic diverticula can give rise to nocturnal regurgitation of massive amounts of fluid.

Front 255

255. What is Mallory-Weiss syndrome?

In whom is this most common?

Back 255

Longitudinal tears in the esophagus at the esophagogastric junction or gastric cardia are termed Mallory-Weiss tears and are believed to be the consequence of severe retching or vomiting.

They are encountered most commonly in alcoholics, in whom they are attributed to episodes of excessive vomiting when drunk.

Normally, a reflex relaxation of the musculature of the GI tract precedes the antiperistaltic wave of contraction. During episodes of prolonged vomiting, it is speculated that this reflex relaxation fails to occur. The refluxing gastric contents suddenly overwhelm the contraction of the musculature at the gastric inlet, and massive dilation w/tearing of the stretched wall ensues.

Front 256

256. What is the morphology of a Mallory-Weiss tear?

Back 256

The linear irregular lacerations are oriented in the axis of the esophageal lumen and are several mLs to several cm's in length.

*They are usually found astride the esophagastric junction or in the proximal gastric mucosa.

The tears may involve only the mucosa or may penetrate deeply enough to perforate the wall. The histology is not distinctive and reflects trauma accompanied by fresh hemorrhage and a nonspecific inflammatory response. Infection of the mucosal defect may lead to an inflammatory ulcer or to mediastinitis.

Front 257

257. What are the clinical features of Mallory-Weiss syndrome?

Back 257

Esophageal lacerations account for 5-10% of bleeding episodes in the upper GI tract. Most often, bleeding is not profuse and ceases w/o surgical intervention, although massive hematemesis may occur.

Supportive therapy such as vasoconstrictive medications and transfusions, and sometimes balloon tamponade, is usually all that is required. Healing tends to be prompt, with minimal to no residua.

Front 258

258. What is Boerhaave syndrome?

Back 258

The rare instance of esophageal rupture is known as Boerhaave syndrome and may be a catastrophic event.

Front 259

259. What are esophageal varices?

Back 259

Portal hypertension, when sufficiently prolonged or severe, induces the formation of collateral bypass channels wherever the portal and caval systems communicate.

The collaterals that develop in the region of the lower esophagus when portal blood flow is diverted thru the coronary veins of the stomach into the plexus of esophageal subepithelial and submucosal veins, thence into the azygos veins, and eventually into the systemic circulation.

The increased pressure in the esophageal plexus produces dilated tortuous vessels called varices. Varices develop in 90% of cirrhotic patients and are most often associated w/alcoholic cirrhosis.

Front 260

260. What is the morphology of esophageal varices?

Back 260

Varices appear as tortuous dilated veins lying primarily within the submucosa of the distal esophagus and proximal stomach; venous channels directly beneath the esophageal epithelium may also become massively dilated. The net effect is irregular protrusion of the overlying mucosa into the lumem.

When the varix is unruptured, the mucosa may be normal, but often it is eroded and inflamed b/c of its exposed position.

*Variceal rupture produces massive hemorrhage into the lumen, as well as suffusion of the esophageal wall w/blood.

Front 261

261. What are the clinical features of esophageal varices?

Back 261

Varices usually produce no symptoms until they rupture, causing massive hematemesis. AMong patients w/advanced cirrhosis, half the deaths result from rupture of a varix. Some patients die as a direct consequence of the hemorrhage and others of the hepatic coma triggered by the hemorrhage.

Front 262

262. What are the common causes of hematemesis?

What factors lead to rupture?

Back 262

Even when varices are present, they account for less than half of all episodes of hematemesis. Collectively, concomitant gastritis, esophageal laceration, or peptic ulcers are more common causes.

Factors leading to rupture of a varix are unclear; silent inflammatory erosion of overlying thinned mucosa, increased tension in progressively dilated veins, and vomiting likely play a role.

Front 263

263. What is the treatment and prognosis for those with esophageal varices?

Back 263

Once begun, the hemorrhage rarely subsides spontaneously, and endoscopic injection of thrombotic agents or balloon tamponade is usually required.

40-50% of patients die in the first bleeding episode. Among those who survive, rebleeding occurs in over half within 1 year, w/a similar rate of mortality for each episode.

Front 264

264. What is esophagitis?

What is the prevalence?

Back 264

Inflammation of the esophageal mucosa.

Injury to the esophageal mucosa w/subsequent inflammation is common worldwide. In the US and other Western countries, it is present in about 5% of the adult population; much higher prevalence is encountered in northern Iran and China.

Front 265

265. What is reflux esophagitis?

Back 265

Gastroesophageal reflux disease (GERD)

Reflex of gastric contents into the lower esophagus is the most important cause of esophagitis.

Front 266

266. What are five causative factors in GERD?

Back 266

1. Decreased efficacy of esophageal antireflux mechanisms, particularly LES tone. CNS depressants, hypothyroidism, pregnancy, systemic sclerosing disorders, EtOH or tobacco exposure, or the presence of a nasogastric tube may be contributing causes
2. Presence of a sliding hiatal hernia
3. Inadequate or slowed esophageal clearance of refluxed material
4. Delayed gastric emptying and increased gastric volume, contributing to the volume of refluxed material
5. Reduction in the reparative capacity of the esophageal mucosa by protracted exposure to gastric juices

Front 267

267. What is critical to the development of esophageal mucosal injury?

Back 267

The action of gastric juices; in severe cases refluxed bile from the duodenum also may contribute to the mucosal disruption.

Front 268

268. What is the morphology of GERD?

Back 268

Simple hyperemia (redness) may be the only alteration. In uncomplicated reflux esophagitis, three histologic features are characteristic:
1. The presence of inflammatory cells, including eosinophils, neutrophils, and excessive numbers of lymphocytes, in the squamous epithelial layer
2. Basal zone hyperplasia exceeding 20% of the epithelial thickness
3. Elongation of lamina propria papillae w/capillary congestion, extending into the top third of the epithelial layer

Front 269

269. What is an early histologic abnormality in GERD?

Back 269

Infiltrates of intraepithelial eosinophils are believed to be an early histologic abnormality, since they occur even in the absence of the basal zone hyperplasia.

Intraepithelial neutrophils, on the other hand, are markers of more severe injury such as ulceration rather than reflux esophagitis.

Front 270

270. What are the clinical features of GERD?

Back 270

The clinical manifestations consist principally of dysphagia, heartburn, and sometimes regurgitation of a sour brash, hematemesis, or melena. The severity of symptoms is not closely related to the presence or degree of histologic esophagitis; most people experience reflux symptoms w/o damage to the distal esophageal mucosa, due to the short duration of the reflux.

Anatomic damage appears best correlated w/prolonged exposure of the lower esophagus to refluxed material. Rarely, chronic symptoms are punctuated by attacks of severe chest pain that may be mistaken for a heart attack.

The potential consequences of severe reflux esophagitis are bleeding, ulceration, development of stricture, and a tendency to develop Barrett esophagus.

Front 271

271. What is Barrett esophagus?

Back 271

Barrett esophagus is a complication of long-standing gastroesophageal reflux, occurring over time in up to 10% of patients w/GERD.

It is the single most important risk factor for esophageal adenocarcinoma.

In Barrett esophagus, the distal squamous mucosa is replaced by metaplastic columnar epithelium, as a response to prolonged injury.

Front 272

272. What are the two criteria need for Dx of Barrett's?

Back 272

1. Endoscopic evidence of columnar epithelial lining above the gastroesophageal junction

2. Histologic evidence of intestinal metaplasia in the biopsy specimens from the columnar epithelium.

Front 273

273. What is the pathogenesis of Barrett's?

Back 273

Appears to result from an alteration in the differentiation program of stem cells of the esophageal mucosa.

The concept of "intestinal metaplasia" in Barrett's may not be entirely correct, since true absorptive enterocytes are not observed. Rather, admixed w/intestinal mucin-secreting goblet cells are columnar cells exhibiting both secretory and absorptive ultrastructural features; this is a phenotype not observed elsewhere in the alimentary tract.

Front 274

274. What is the morphology of Barrets?

1 of 2

Back 274

Barrett's is recognized as red, velvety mucosa located between the smooth pal pink esophageal squamous mucosa and the lusher light brown gastric mucosa. It may exist as tongues or patches (islands) extending up from the gastroesophageal junction or as a broad irregular circumferential band displacing the squamocolumnar junction several cm's cephalad. A small zone a metaplastic mucosa may be present only at the esophagogastric junction (short-segment Barrett mucosa).

Microscopically, the esophageal squamous epithelium is replaced by metaplastic columnar epithelium, complete w/surface epithelium and mucosal glands. The metaplastic mucosa may contain only gastric surface and glandular mucus-secreting cells, making clinical distinction from a hiatal hernia difficult.

*Definitive Dx is made when the columnar mucosa contains intestinal goblet cells.

Front 275

275. What is the morphology of Barrets?

2 of 2

Back 275

Critical to the pathologic eval of patients w/Barrett's is the search for dysplasia, the presumed precursor of malignancy, in columnar epithelium w/intestinal metaplasia.

Dysplasia is recognized by the presence of cytologic and architectural abnormalities in the columnar epithelium, consisting of enlarged, crowded, and stratified hyperchromatic nuclei and loss of intervening stroma between adjacent glandular structures.

Dysplasia is classified as low or high grade w/the predominant distinction being a basal orientation of all nuclei in low grade vs. nuclei consistently reaching the apex of eptiehlial cells in high grade.

Approx 50% of patients w/high grade dysplasia may already have adjacent adenocarcinoma.

Front 276

276. What are the clinical features of Barretts?

Back 276

Most of the patients w/first Dx of Barretts are between 40 and 60, although children occasional develop this condition. The incidence is highest among white males.

In addition to the symptoms of reflux, Barrett's is clinically significant due to the secondary complications of local ulceration with bleeding and stricture. Of greatest important is the development of adenocarcinoma, which occurs an estimated 30-40x increased rate over the general population.

Front 277

277. What are the causes of infection and chemical esophagitis?

Back 277

1. Ingestion of mucosal irritants such as alcohol, corrosive acids or alkalis, excessively hot fluids, or heavy smoking
2. Cytotoxic anticancer therapy
3. Infection following bacteremia or viremia; herpes simplex and CMV are common offenders in immunosuppressed patients
4. Fungal infection in debilitated or immunosuppressed patients or during broad-spectrum antimicrobial therapy; candidiasis by far the most common; murcormycosis and aspergillosis may occur
5. Uremia in the setting of renal failure

Front 278

278. What is the morphology of the esophagus in candidiasis?

Back 278

In candidiasis, patches of the entire esophagus become covered by adherent, gray-white pseudomembranes teeming w/densely matted fungal hyphae.

Front 279

279. What is the morphology of the esophagus in herpes virus or CMV?

Back 279

Herpes typically cause punched out ulcers; the nuclear inclusion of herpes are found in a narrow rim of degenerating epithelial cells at the margin of the ulcer.

CMV causes linear ulceration of the esophageal mucosa; the histologic findings of CMV-associated change w/both intranuclear and cytoplasmic inclusions are found in capillary endothelium and stromal cells in the base of the ulcer.

In both forms of infection immunohistochemical staining for virus-specific antigens provides a sensitive and specific diagnostic tool.

Front 280

280. What is the morphology of the esophagus with pathogenic bacteria?

Back 280

Pathogenic bacteria account for 10-15% of case of infectious esophagitis and exhibit bacterial invasion of the lamina propria w/necrosis of the squamous eptihelium

Front 281

281. What is the morphology of the esophagus in chemical injury?

Back 281

Injury produced by chemical may produce only mild erythema and edema, sloughing of the mucosa, or outright necrosis of the entire esophageal wall.

Localized esophageal ulceration may result from pharmaceutical tablets or capsules "sticking" in the esophagus.

Front 282

282. What is the morphology of the esophagus following irradiation?

Back 282

Following irradiation, submucosal and mural blood vessels exhibit marked intimal proliferation with luminal narrowing.

The submucosa becomes severely fibrotic, and the mucosa exhibits atrophy, with flattening of the papillae and thinning of the epithelium.

Front 283

283. What is the morphology of the esophagus in graft vs. host disease?

Back 283

GVHD shares features w/the skin manifestations (e.g., apoptosis of basal epithelial cells, separation of epithelium and lamina propria, atrophy and fibrosis of the lamina propria w/minimal inflammation).

Front 284

284. What are leiomyomas?

Back 284

Most common are benign tumors of smooth muscle origin, called leiomyomas.

Front 285

285. What are fibrovascular polyps or penduculated lipomas?

Back 285

Mucosal polyps are usually composed of a combo of fibrous, vascular, or adipose tissue covered by an intact mucosa, known as fibrovascular polyps or penduculated lipomas

Front 286

286. What are squamous papillomas?

What is a condyloma?

Back 286

Squamous papillomas are sessile lesions w/a central core of connective tissue and a hyperplastic papilliform squamous mucosa.

When the papilloma is associated w/HPV infection, the term condyloma applies.

Front 287

287. What are inflammatory polyps or psuedotumors?

Back 287

In rare instances, a mesenchymal mass of inflamed granulation tissue, called an inflammatory polyp, may resemble a malignant lesion, hence its alternative name inflammatory pseudotumor.

Front 288

288. From where do malignant tumors in the esophagus arise?

Back 288

With rare exceptions, malignant esophageal tumors arise from the epithelial layers.

In the US, most cancers used to be of squamous cell origin, but the incidence of these tumors has declined with a steady increase of adenocarcinomas.

Front 289

289. What is squamous cell carcinoma in the esophagus?

What is the pathogenesis?

Back 289

Most common type of carcinoma in the esophagus. Most occur in adults over age 50.

The pathogenesis is multifactorial, with environment and diet contributing synergistically, modified by genetic factors.

Front 290

290. What genetic alterations are linked to squamous cell carcinoma in the esophagus?

Back 290

For example, methylating nitroso compounds in the diet and in tobacco smoke may be the reason for the broad spectrum of p53 point mutations present in over half of esophageal cancers.

Other genetic alterations, such as mutations in p16INK4, and amplification of CYCLIN D1, C-MYC, and epithelial growth factor receptor (EGFR), are prevalent in these cancers as well.

Notably rare in squamous cell carcinoma in the esophagus are K-RAS and APC mutations.

Front 291

291. What four genetic predispositions are linked to squamous cell carcinoma in the esophagus?

Back 291

1. Long standing celiac disease
2. Ectodermal dysplasia
3. Epidermolysis bullosa
4. Racial disposition

Front 292

292. What three esophageal disorders are linked to squamous cell carcinoma in the esophagus?

Back 292

1. Long standing esophagitis
2. Achalasia
3. Plummer-Vinson syndrome

Front 293

293. What is the morphology of squamous cell carcinoma in the esophagus?

Back 293

They begin as apparent in situ lesions (intraepithelial neoplasm or carcinoma in situ).

When they become overt, about 20% of these tumors are located in the upper third, 50% in the middle third, and 30% in the lower third of the esophagus.

Early lesions appear as small, gray-white, plaque like thickenings or elevations of the mucoca. In months to years, these lesions become tumorous masses and may eventually encircle the lumen.

Front 294

294. What are the three morphologic patterns of squamous cell carcinoma in the esophagus?

Back 294

1. Protruded (60%), a polypoid exophytic lesion that protrudes into the lumen.

2. Flat (15%), a diffuse, infiltrative form that tends to spread within the wall of the esophagus, causing thickening, rigidity, and narrowing of the lumen.

3. Excavated (ulcerated, 25%), a necrotic cancerous ulceration that excavates deeply into the surrounding structures and may erode into the respiratory tree (with resultant fistula and pneumonia) or aorta (w/catastraphic exsanguination) or may permeate the mediastinum or pericardium.

Front 295

295. What is the histological differentiation of squamous cell carcinoma in the esophagus?

Back 295

Most squamous cell carcinomas are moderately to well differentiated.

Several variants may be seen, such as verrucous squamous cell carcinoma, spindle cell carcinoma, and basaloid squamous cell carcinoma.

Regardless of their degree of differentiation, most symptomatic tumors are quite large by the time of Dx.

Front 296

296. Do squamous cell carcinomas in the esophagus metastasize?

If yes, to where?

Back 296

The rich lymphatic network in the submucosa promotes extensive circumferential and longitudinal spread, and intramural tumor cell clusters may often be seen several cm's away from the main mass.

Local extension into adjacent mediastinal structures occurs early and often in this disease. Tumors located in the upper third of the esophagus also metastasize to cervical lymph nodes; those in the middle third to the mediastinal, paratracheal, and tracheobronchial nodes; and those in the lower third most often spread to the gastric and celiac groups of nodes.

Front 297

297. What are the clinical features of squamous cell carcinoma in the esophagus?

Back 297

Onset is insidious; symptoms typically develop late and include dysphagia, obstruction, weight loss, hemorrhage, sepsis secondary to ulceration, or respiratory tree fistulas w/aspiration.

Resection is possible in 80% of cases; although 5-year survival rates for all esophageal cancers is 9%, superficial carcinomas have a 5-year survival rate of 75%.

Front 298

298. What is adenocarcinoma of the esophagus?

Back 298

Adenocarcinoma of the esophagus is a malignant epithelial tumor w/glandular differentiation.

This type of cancer now represents up to half of all esophageal cancers in the US.

The majority of cases arise from the Barrett mucosa.

Front 299

299. What is the etiology of adenocarcinoma of the esophagus?

Back 299

Tobacco exposure and obesity are risk factors, but there is no close association between alcohol ingestion and the development of adenocarcinoma.

H. pylori infection may be a contributing factor.

Front 300

300. What is the pathogenesis of adenocarcinoma of the esophagus?

Back 300

The pathogenesis of adenocarcinoma from Barrett esophagus is a multistep process w/a long latency period associated w/many genetic changes.

The development of dysplasia seems to be a critical step in this process.

Barrett epithelial cells have higher proliferative activity, and dysplastic epithelial cells have higher proliferative activity, and dysplastic epithelial cells have lost cell-cycle control.

Front 301

301. What genetic alterations are associated with adenocarcinoma of the esophagus?

Back 301

Overexpression of p53 and an increased portion of cycling cells are present in the dysplastic epithelium.

In high-grade dysplasia, chromosomal abnormalities such as chromosome 4 amplification, are generally present.

When the dysplastic epithelium develops into adenocarcinoma, additional genetic changes, including nuclear translocation of β-catenin and amplification of c-ERB-B2, are present.

p53 mutations, along w/tetraploidy and aneuploidy, seem to occur early.

Front 302

302. What is the morphology of adenocarcinoma of the esophagus?

Back 302

Adenocarcinomas arising in the setting of Barrett's are usually located in the distal esophagus and may invade the adjacent gastric cardia.

Initially appearing as flat or raised patches of an otherwise intact mucosa, they may develop into large nodular masses up to 5 cm in diameter or may exhibit diffusely infiltrative or deeply ulcerative features.

Microscopically, most tumors are mucin-producing glandular tumors exhibiting intestinal type features; less often they are made up of diffusely infiltrative signet-ring cells of a gastric type or even poorly differentiated small cell type tumor.

Multiple foci of dysplastic mucosa are frequently adjacent to the tumor.

Front 303

303. What are the clinical features of adenocarcinoma of the esophagus?

Back 303

Tumors typically arise in patients older than 40, men more often than women, with symptoms as for squamous cell carcinoma.

Interestingly, previous symptoms of GERD are present in fewer than 50%.

Overall 5-year survival rate is less than 2%; screening programs detect disease earlier.

Front 304

304. Isosorbide dinitrate

Back 304

MOA: Donate NO, which activates guanylyl cyclase and increases dephosphorylation of myosin light chain in vascular smooth muscle, causing vasodilation

PURPOSE: Short-acting (subligual): Prophylaxis and treatment of acute anginal attacks; Long acting (oral, extended release): prophylaxis of angina, treatment of chronic ischemic heart disease, diffuse esophageal spasm.

ADVERSE: Refractory hypotension, angina from reflex tachycardia, palpitations, syncope, flushing, headache

CONTRA: Severe hypotension, shock, or acute MI w/low left ventricular filling pressure; increased ICP, angle-closure glaucoma, anginal pain associated w/hypertrophic obstrutive cardiomyopathy, severe anemia; coadministration w/phosphodiesterase type V inhibitors (dildenafil, vardenafil, tadlafil)

Front 305

305. Isosorbide dinitrate therapeutic considerations

Back 305

Venous dilation > arteriolar dilation

Orally administered dinitrate has low bioavialability b/c organic nitrate reductases in the liver rapidly metabolize these drugs. To circumvent this, dinitrate can be administered sublingually.

Equivalent doses of isosorbide dinitrate can be more effective than NTG, b/c isosorbide dinitrate has a longer half life.

Continuous therapy leads to tolerance; tolerance can be avoided by providing nitrate-free interval.

Front 306

306. Isosorbide 5-mononitrate

Back 306

MOA: Donate NO, which activates guanylyl cyclase and increases dephosphorylation of myosin light chain in vascular smooth muscle, causing vasodilation

PURPOSE: Prophylaxis of angina, treatment of chornic ischemic heart disease

ADVERSE: Refractory hypotension, angina from reflex tachycardia, palpitations, syncope, flushing, headache

CONTRA: Severe hypotension, shock, or acute MI w/low left ventricular filling pressure; increased ICP, angle-closure glaucoma, anginal pain associated w/hypertrophic obstrutive cardiomyopathy, severe anemia; coadministration w/phosphodiesterase type V inhibitors (dildenafil, vardenafil, tadlafil)

Front 307

307. Isosorbide dinitrate therapeutic considerations

Back 307

Venous dilation > arteriolar dilation

Same as isosorbide dinitrate

Additionally, isosorbide 5-mononitrate is preferred over isosorbide dinitrate due to longer half-life, better absorption from the GI tract, non-susceptibility to extensive first-pass metabolism in the liver, less rebound angina, and greater efficacy at equivalent doses.

Front 308

308. Nitroglycerin

Back 308

MOA: Donate NO, which activates guanylyl cyclase and increases dephosphorylation of myosin light chain in vascular smooth muscle, causing vasodilation

PURPOSE: Short-acting (sublingual, spray): short-term treatment of acute anginal attacks; Long-acting (oral, buccal, transdermal patch): prophylaxis of angina, treatment of chronic ischemic heart disease; Intravenous: unstable angina, acute heart failure

ADVERSE: Refractory hypotension, angina from reflex tachycardia, palpitations, syncope, flushing, headache

CONTRA: Same as isosorbide dinitrate. Additionally, transdermal form is contraindicated in patients w/allergy to skin tape. IV form is contraindicated in patients w/cardiac tamponade, restrictive cardiomyopathy, or constrictive pericarditis.

Front 309

309. Therapeutic considerations for nitroglycerin

Back 309

Venous dilation > arteriolar dilation

Same as isosorbide dinitrate.

Additionally, equivalent doeses of nitroglycerin may be less effective than isosorbide dinitrate due to shorter half-life of nitroglycerin.

Ergotamine may oppose coronary vasodilation of nitrates

Front 310

310. Sodium nitroprusside

Back 310

MOA: This is a nitrate compound that consists of a nitroso group, five cyanide groups, and an iron atom. It causes vasodilation by release of NO. Unlike the organic nitrates, however, sodium nitroprusside appears to liberate NO primarily thru a nonenzymatic process. Thus, its actions does not appear to be targeted to specific types of vessels, and, consequently, the drug dilates both arteries and veins.

PURPOSE: Hypertensive emergencies, severe cardiac failure, ergot alkaloid toxicity

ADVERSE: Cyanide toxicity, cardiac arrhythmia, excessive bleeding, excessive hypotension, metabolic acidosis, bowel obstruction, methemoglobinemia, increase ICP, flushing, headache, renal azotemia

CONTRA: Preexisting hypotension, obstructive valvular disease, heart failure associated w/reduced peripheral vascular resistance, hepatic or renal failure, optic atrophy, surgery patients w/inadequate cerebral circulation, tobacco amblyopia

Front 311

311. Therapeutic considerations for sodium nitroprusside

Back 311

Venous dilation = arteriolar dilation

Thiocyanate toxicity becomes life-threatening at serum concentrations of 200 mg/L

Coadministration of sodium thiosulfate may reduce the risk of cyanide toxicity, but this interaction is not well studied.

Front 312

312. Why is the administration of doses of organic nitrates sufficient to vasodilate the epicardial arteries dangerous?

Back 312

Such doses can induce excessive peripheral arteriolar vasodilation and refractory hypotension.

B/c coronary perfusion depends on the pressure gradient between the aorta and the endocardium during diastole, a marked decrease in diastolic aortic pressure can lead to an insufficient supply of oxygen to the heart.

Moreover, systemic hypotension can lead to REFLEX TACHYCARDIA, which also decreases myocardial oxygen supply by shortening diastole and myocardial perfusion time.

Front 313

313. Why are nitrates used in patients w/heart failure?

Back 313

Nitrates can often by used to decrease pulmonary congestion in patients w/heart failure (by effecting venodilation and decreasing end-diastolic pressure), without eliciting significant reflex tachycardia.

Front 314

314. What is the first of the two hypotheses that attempt to explain organic nitrate tolerance?

Back 314

1. Tolerance results mainly from intracellular depletion of sulfhydryl-containing groups, such as glutathione and/or other forms of cysteine, that are involved in the formation of NO from organic nitrates.

Accordingly, tolerance could be attenuated or reversed by administering reduced thiol-containing compounds such as N-acetylcysteine.

Front 315

315. What is the second of the two hypotheses that attempt to explain organic nitrate tolerance?

Back 315

2. The free-radical (superoxide) hypothesis posits that cellular tolerance results from the formation of peroxynitrate, a highly reactive metabolite of NO that appears to inhibit guanylyl cyclase.

Accordingly, tolerance could be attenuated or reversed by administering agents that inhibit free-radical formation.

Front 316

316. The generation of NO from organic nitrates can cause relaxation of what types of smooth muscle?

Back 316

Esophageal, bronchial, biliary, intestinal, and genitourinary, in addition to vascular smooth muscle.

*The ability of NTG to relieve the angina-like chest pain of esophageal spasm can occasionally result in a misdiagnosis of coronary artery disease.

Front 317

317. How does NO generated from organic nitrates affect platelet formation?

Back 317

NO mediated increases in platelet cGMP inhibit platelet aggregation; together w/the vasodilatory effect of the nitrates, this antiplatelet effect may decrease the likelihood of coronary artery thrombosis.

Nitrate-induced inhibition of platelet aggregation may be especially important in the treatment of rest angina, b/c rest angina freq results from the formation of occlusive platelet aggregates at the site of atherosclerotic coronary artery lesions.

Front 318

318. What are the main contraindications of nitrates?

Back 318

Hypotension, elevated ICP, b/c NO-mediated vasodilation of cerebral arteries could further increase ICP.

Nitrates should be used w/caution in patients w/diastolic heart failure, who depend on an elevated ventricular preload for optimal cardiac output.

Front 319

319. What are the names of the phosphodiesterase inhibitors, and how doe they work?

Back 319

1. Sildenafil
2. Vardenafil
3. Tadalafil
4. Amrinone*
5. Milrinone*

Phosphodiesterase inhibitors prevent the hydrolysis of cyclic nucleotides (cAMP, cGMP) to their monophosphate forms (5'-AMP, 5'-GMP) by inhibiting PDE5. PDE5 is expressed mainly in the smooth muscle of the corpus cavernosum, but it is also expressed in the retina and in vascular smooth muscle cells.

*Not covered in this chapter

Front 320

320. Sildenafil, vardenafil, tadalafil

Back 320

MOA: Inhibits PDE5, and enzyme that converts cGMP to GMP, leading to cGMP accumulation in target tissues.

PURPOSE: Erectile dysfunction, Pulmonary hypertension (sildenafil)

ADVERSE: MI, non-arteritic ischemic optic neuropathy, priapism, headache, flushing, rash, diarrhea, dyspepsia.

CONTRA: Concomitant use of organic nitrate vasodilators

Front 321

321. Five therapeutic considerations for phosphodiesterase inhibitors...?

Back 321

1. PDE5 inhibits promote systemic vasodilation at doses much higher than those used to treat erectile dysfunction
2. High doses of sildenafil are efficacious in treatment of pulmonary hypertension
3. PDE5 inhibitors are contraindicated in patients taking organic nitrate vasodilators
4. Patients w/prior episodes of vision loss may be at incrased risk for non-arteritic ischemic optic neuropathy
5. Tadalefil has longer elimination half-life than sildenafil and vardenafil

Front 322

322. What are the three types of calcium channel blockers and how do they work?

Back 322

1. Dihydropyridines:
-Nifedipine
-Amlodipine
-Felodipine

2. Benzothiazepines
-Diltiazem

3. Phenylalkalmine
-Verapamil

In smooth muscle cells, decreased calcium entry through L-type channels keeps the intracellular calcium concentration low, thereby reducing calcium mediated activation of myosin light chain kinase, actin-myosin interaction, and smooth muscle contractility. Although calcium channel blockers can relax many types of smooth muscle, they appear to have the greatest effect on vascular smooth muscle.

Front 323

323. Why is skeletal muscle not significantly affect by calcium channel blockers?

Back 323

Skeletal muscle depends mainly on intracellular pools of calcium, (i.e. calcium from the sarcoplasmic reticulum) to support excitation-contraction coupling, and does not require as much transmembrane calcium influx thru the L-type channel.

Front 324

324. Dihydropyridines: nifedipine, amlodipine, felodipine

Back 324

MOA: Block voltage-gated L-type calcium channels and prevent the influx of calcium that promotes actin-myosin cross bridge formation

PURPOSE: Exertional angina, unstable angina, coronary spasm, hypertension, hypertrophic cardiomyopathy, Raynaud's phenomenon, pre-eclampsia

ADVERSE: Increase angina, rare MI, palpitations, peripheral edema, flushing, constipation, heartburn, dizziness

CONTRA: Preexisting hypotension

Front 325

325. Therapeutic considerations for the dihydropyridines: nifedipine, amlodipine, felodipine

Back 325

Arteriolar dilation > venous dilation

1. High vascular-to-cardiac selectivity; compared to diltiazem and verapamil, less depression of myocardial contractility and minimal effects on SA node automaticity and AV node conduction velocity.
2. Oral nifedipine has a rapid onset of action and can cause a brisk, precipitous fall in BP, which can trigger SEVERE REFLEX TACHYCARDIA
3. Coadministration w/nafcillin results in large decrease in plasma nifedipine level

Front 326

326. What is the main difference between amlodipine and nifedipine?

Back 326

Amlodipine (3rd gen) differs from nifedipine (1st gen) principally in its pharmacokinetic properties.

B/c amlodipine has a pKa of 8.7, it is predominantly in a positively charged form at physiologic pH.

This positive charge allows amlodipine to bind to cell membranes (which are typically negatively charged) w/high affinity, and contributes to the drug's late peak plasma concentration and slow hepatic metabolism.

Front 327

327. Benzothiazepines: Diltiazem

Back 327

MOA: Block voltage-gated L-type calcium channels and prevent the influx of calcium that promotes actin-myosin cross bridge formation

PURPOSE: Prinzmetal's or variant angina or chronic stable angina, hypertension, atrial fibrillation or flutter, paroxysmal supraventricular tachycardia

ADVERSE: Rare cardiac arrhythmia, atrioventricular block, bradyarrhythmia, exacerbation of heart failure, peripheral edema, syncope, gingival hyperplasia, dizziness

CONTRA: Sick sinus syndrome or 2nd or 3rd degree AV block; supraventricular tachycardia associated w/a bypass tract, left ventricular failure, hypotension (systolic BP < 90 mm HG), acute MI w/X-ray documented pulmonary congestion

Front 328

328. Therapeutic considerations for Diltiazem

Back 328

Low ratio of vascular-to-cardiac selectivity

1. Depresses both SA-node automaticity and AV-node conduction velocity (acts as a negative inotrope)
2. Raises serum carbamazepine levels, which may result in carbamazepine toxicity
3. *Avoid concomitant use of beta-adrenergic blockers

Front 329

329. Phenylalkylamine: verapamil

Back 329

MOA: Block voltage-gated L-type calcium channels and prevent the influx of calcium that promotes actin-myosin cross bridge formation
PURPOSE: Prinzmetal's or variant angina or chronic stable angina, hypertension, atrial fibrillation or flutter, paroxysmal supraventricular tachycardia

ADVERSE: Rare cardiac arrhythmia, atrioventricular block, bradyarrhythmia, exacerbation of heart failure, peripheral edema, syncope, gingival hyperplasia, dizziness

CONTRA: Same as diltiazem; Additionally, IV verapamil is contraindicated in patients w/ventricular tachycardia and patients receiving IV beta-blockers

Front 330

330. Therapeutic considerations for verapamil

Back 330

Same as diltiazem; Low ratio of vascular-to-cardiac selectivity

1. Additionally, verapamil has a greater suppressive effect on cardiac contractility than diltiazem
2. Alcohol consumption w/chronic verapamil therapy may result in higher serum alcohol concentrations
3. Coadministration with pimozide may result in higher pimozide concentrations and cardiac arrhythmias
4. Coadministration with simvastatin markedly increases simvastatin levels

Front 331

331. What are the potassium channel openers and how do they work?

Back 331

1. Minoxidil
2. Pinacidil
3. Nicorandil
4. Cromakalim

K+ channel openers cause direct arterial vasodilation by opening ATP-modulated K+ channels in the plasma membrane of vascular smooth muscle cells.

B/c these agents act by a mechanism that is entirely different from that of other vasodilators, K+ ATP channel openers represent a potent family of drugs that can be used to treat hypertension refractory to other antihypertensive therapeutics.

Front 332

332. Minoxidil, pinacidil, nicorandil, chromakalim

Back 332

MOA: Open ATP-modulated potassium channels and hyperpolarize plasma membrane, thereby inhibiting influx of calcium through voltage gated calcium channels

PURPOSE: Severe or refractory hypertension, male pattern alopecia (topical minoxidil)

ADVERSE: Angina, pericardial effusion, reflex tachycardia, Stevens-Johnson syndrome, leukopenia, thrombocytopenia, headache, flushing, hypotension, hirsutism, hypertrichosis, fluid retention, hypernatremia

CONTRA: Pheochromocytoma

Front 333

333. Therapeutic considerations for minoxidil, pinacidil, nicorandil, chromakalim

Back 333

Arteriolar dilation > venous dilation

1. Typically used in combination with a beta-blocker and a diuretic b/c beta-blockers can help to block the effects of reflex sympathetic activity.

2. Used with caution in patients w/impaired renal function or dissecting aortic aneurysm or after acute MI.

Front 334

334. What is the name of the lonesome endothelin receptor antagonist?

Back 334

Bosentan is a competitive antagonists at ETa and ETb receptors. It is approved for use in the treatment of pulmonary hypertension.

Front 335

335. Bosentan

Back 335

MOA: Blocks activation of endothelin receptors ETa and ETb by endogenous endothelin

PURPOSE: Severe pulmonary hypertension

ADVERSE: Hepatotoxicity, anemia, hypotension, fluid retention, headache, flushing

CONTRA: Pregnancy, concomitant use of cyclosporine A or glyburide

NOTES: Do not use in pregnant women! Monitor LFTs monthly. Generally avoid use in patients w/moderate to severe hepatic impairment. Use caution in patients w/hypovolemia, hypotension, heart failure, or anemia.

*Potential for interactions w/other drugs metabolized by P450 2C9 or P450 3A4 (e.g. hormonal contraceptives, simvastatin, warfarin, ketoconazole)

Front 336

336. What is hydralazine, and how does it work?

Back 336

Hydralazine is an orally administered arteriolar vasodilator that is sometimes used in the treatment of hypertension and in combination with isosorbide dinitrate, in the treatment of heart failure.

Front 337

337. Hydralazine

Back 337

MOA: Proposed mechanisms include membrane hyperpolarization, potassium channel activation, and inhibition of IP3-induced calcium release from sarcoplasmic reticulum in vascular smooth muscle cells.

PURPOSE: Moderate to severe hypertension, severe heart failure

ADVERSE: Agranulocytosis, leukopenia, hepatotoxicity, SLE, headache, palpitations, tachycardia, anorexia, diarrhea

CONTRA: Dissecting aortic aneurysm, coronary artery disease, mitral valvular rheumatic heart disease

Front 338

338. Therapeutic considerations for hydralazine

Back 338

Arteriolar dilation > venous dilation

1. Typically used in combo w/a beta-blocker and a diuretic in the treatment of hypertension.
2. Used in combo w/isosorbide dinitrate for heart failure; combination formulation w/isosorbide dinitrate may have morbidity and mortality benefits in Blacks with advanced heart failure.
3. Concomitant use of diazoxide and MOA inhibit may cause severe hypotension.
4. Hydralazine typically has low bioavailability b/c of extensive first pass hepatic metabolism, which depends on whether the patient is a slow or fast acetylator.

A rare adverse effect is the development of a reversible SLE-like syndrome; this effect occurs chiefly in slow acetylators.

Front 339

339. What are the H2 receptor antagonists, and how do they work?

Back 339

1. Cimetidine
2. Ranitidine
3. Famotidine
4. Nizatidine

H2 receptor antagonists reversibly and competitively inhibit the binding of histamine to H2 receptors, resutling suppression of gastric acid secretion.

H2 receptor antagonists also indirectly decrease gastrin- and acetylcholine-induced gastric acid secretion.

Front 340

340. Cimetidine

Back 340

MOA: Decrease acid secretion by inhibiting histamine binding to H2 receptors on parietal cells.

PURPOSE: Peptic ulcer disease, GERD, erosive esophagitis, gastric acid hypersecretion

ADVERSE: Necrotizing enterocolitis in fetus or newborn, agranulocytosis, psychotic disorder; headache, dizziness, arthralgia, myalgia, constipation, diarrhea, gynecomastia, galactorrhea, loss of libido

CONTRA: hypersensitivity to cimetidine

NOTES: Cimetidine reduces the cytochrome P450-mediated metabolism of certain drugs, including warfarin, theophylline, phenytoin, lidocaine, and quinidine, delaying the clearance and increasing the plasma levels of these drugs.

*Cimetidine crosses the placenta and is secreted into breast milk, and is therefore not recommended for use during pregnancy or when nursing.

Front 341

341. Ranitidine, famotidine, nizatidine

Back 341

MOA: Decrease acid secretion by inhibiting histamine binding to H2 receptors on parietal cells.

PURPOSE: Peptic ulcer disease, GERD, erosive esophagitis, gastric acid hypersecretion

ADVERSE: Necrotizing enterocolitis in fetus or newborn, pancreatitis; headache, dizziness, arthralgia, myalgia, constipation, diarrhea

CONTRA: Hypersensitivity to ranitidine, famotidine, or nizatidine

NOTES: Ranitidine can be given IV to treat hypersecretory conditions or to treat patients who are not able to tolerate the oral formulation.

Bioavailability of nizatidine is higher than that of other H2 receptor antagonists

Front 342

342. What are the proton pump inhibitors, and how do they work?

Back 342

1. Omeprazole
2. Esomeprazole
3. Lansoprazole
4. Pantoprazole
5. Rabeprazole

Proton pump inhibitors block the parietal cell H⁺/K⁺-ATPase (proton pump). Compared to H2 receptor antagonists, proton pump inhibitors are superior at suppressing acid secretion and promoting peptic ulcer healing.

Front 343

343. How are all the proton pump inhibitors prodrugs?

MOA in depth here...

Back 343

All the proton pump inhibitors are prodrugs that require activation in the acidic environment of the parietal cell canaliculus. Oral formulations are enteric-coated to prevent premature activation.

The prodrug is converted to its active sulfenamide form in the acidic environment and the sulfenamide reacts w/a cysteine residue on the H⁺/K⁺-ATPase to form a covalent disulfide bond. Covalent binding of the drugs inhibits the activity of the proton pump irreversibly, leading to prolonged and nearly complete suppression of acid secretion.

In order for acid secretion to resume, the parietal cell must synthesize new H⁺/K⁺-ATPase molecules, a process that requires approx 18 hours.

Front 344

344. Omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole

Back 344

MOA: Decrease acid secretion by blocking H⁺/K⁺-ATPase on parietal cells

PURPOSE: Peptic ulcer disease, GERD, erosive esophagitis, gastric acid hypersecretion, H. pylori GI tract infection

ADVERSE: Pancreatitis, hepatotoxicity, interstitial nephritis, headache, diarrhea, rash, GI discomfort, anorexia, asthenia, back pain

CONTRA: Hypersensitivity to omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole

Front 345

345. Therapeutic considerations for proton pump inhibitors

Back 345

1. Proton pump inhibitors are metabolized in the liver by CYP2C19 and CYP3A4.
2. Pantoprazole can be given IV as an alternative therapy in patients who are not able to tolerate oral pantoprazole.
3. Drug interaction w/ketoconazole or itraconazole due to the acid environment required for absorption of these azole drugs.
4. Rabeprazole and lansoprazole appear to have a significantly faster onset of action than omeprazole and pantoprazole.

Front 346

346. How do proton pump inhibitors compare to H2 receptor antagonists for healing of NSAID associated gastric and duodenal ulcers when the patient continues NSAID use?

Back 346

Proton pump inhibitors are superior for healing of NSAID associated gastric and duodenal ulcers when the patient continues NSAID use, most likely b/c proton pump inhibitors are better able to sustain a constant increase in gastric pH.

Front 347

347. Should PPIs be used during pregnancy?

Back 347

The safety of PPIs in pregnancy is not established; therefore, the use of PPIs during pregnancy is discouraged.

PPIs also cross the human placental barrier.

Front 348

348. What are some important adverse effects from PPIs?

Back 348

1. On occasion, PPIs cause such a large decrease in acid secretion that enteric infections (i.e. Salmonella) occur b/c the ingested bacteria are not killed by stomach acid.
2. Due to decreased stomach acid secretion, a resultant increase in plasma gastrin release occurs. The trophic effects of gastrin can induce hyperplasia of ECL cells and parietal cells in the gastric mucosa.
3. Patients with Zollinger-Ellison syndrome usually develop ECL and parietal cell hyperplasia and some develop carcinoid tumors, but not increase in carcinoid tumors has been found in Zollinger-Ellison patients taking PPIs.
4. Hypergastrinemia can also result in rebound hypersecretion of acid upon discontinuation of the proton pump inhibitor.

Front 349

349. What is dicyclomine, and what is it used for?

Back 349

Anticholinergic agents such as dicyclomine antagonize muscarinic ACh receptors on parietal cells and thereby decrease gastric acid secretion.

However, anticholinergic agents are seldom used in the treatment of peptic ulcer disease b/c they are not as effective as H2 receptor antagonists or PPIs.

These agents also have many adverse effects, including dry mouth, blurred vision, cardiac arrhythmia, and urinary retention.

Front 350

350. What are the antacids?

Back 350

1. Aluminum hydroxide
2. Magnesium hydroxide
3. Sodium bicarbonate
4. Calcium carbonate

Front 351

351. Aluminum hydroxide

Back 351

MOA: Neutralize gastric acid

PURPOSE: Symptomatic relief of dyspepsia associated w/peptic ulcer disease, gastritis, GERD, or hiatal hernia

ADVERSE: Phosphate depletion (severe weakness, malaise, and anorexia); constipation, osteomalacia in patients with renal failure

CONTRA: hypersensitivity

NOTES: All antacids can potentially increase or decrease the rate or extent of absorption of concurrently administered oral drugs by changing transit time or by binding the drug.

Front 352

352. Magnesium hydroxide

Back 352

MOA: Neutralize gastric acid

PURPOSE: Symptomatic relief of dyspepsia associated w/peptic ulcer disease, gastritis, GERD, or hiatal hernia

ADVERSE: Diarrhea, hypermagnesemia (in patients w/renal failure)

CONTRA: Hypersensitivity

Front 353

353. Sodium bicarbonate

Back 353

MOA: Neutralize gastric acid

PURPOSE: Symptomatic relief of dyspepsia, metabolic acidosis, urinary alkalinization, uric acid renal stones, diarrhea

ADVERSE: Abdominal cramps, flatulence, alkalosis, vomiting

CONTRA: Respiratory alkalosis, hypocalcemia, hypochloremia

NOTES: Significant sodium retention in patients with hypertension or fluid overload

Front 354

354. Calcium carbonate

Back 354

MOA: Neutralize gastric acid

PURPOSE: Symptomatic relief of dyspepsia, osteoporosis

ADVERSE: Hypercalcemia, nausea, vomiting, anorexia

CONTRA: Severe renal deficiency

NOTES: Hypercalcemia can occur in patients w/impaired renal function.

Front 355

355. What are the names of the two coating agents, and what are they used for?

Back 355

Sucralfate and colloidal bismuth

Coating agents are used to alleviate the symptoms of peptic ulcer disease by coating gastric mucosa with a protective layer

Front 356

356. Sucralfate

Back 356

MOA: This is a complex salt of sucrose sulfate and aluminum hydroxide a. It has little ability to alter gastric pH. Instead, in the acidic environment of the stomach, this compelx forms a viscous gel that binds to positively charged proteins and thereby adheres to gastric epithelial cells. The gel protects the luminal surface of the stomach from degradation by acid and pepsin.

PURPOSE: Peptic ulcer disease, gastric ulcer disease, GERD

ADVERSE: Aluminum accumulation and toxicity in patients w/renal impairment, constipation

CONTRA: Hypersensitivity

NOTES: Decreased effectiveness of quinolones (.e.g ciprofloxacin) b/c of chelation and decreased absorption.

Front 357

357. Colloidal bismuth

Back 357

MOA: Bismuth salts combine w/mucus glycoproteins to form a barrier that protects an ulcer from further damage to form a barrier that protects an ulcer from further damage by acid and pepsin. Bismuth agents may stimulate mucosal bicarb and postaglandin E2 secretion and thereby also protect the mucosa from acid and pepsin degradation.

PURPOSE: Peptic ulcer disease, gastric ulcer disease, GERD, diarrhea w/associated abdominal cramps

ADVERSE: Darkening of the tongue and/or stool, nausea, vomiting

CONTRA: Known allergy to aspirin or other nonaspirin salicylates

NOTES: Freq used as a component of a multidrug regimen for eradication of H. pylori b/c bismuth impedes growth of the organism.
-Reduces absorption of tetracyclines, likely thru chelation or by reducing solubility as a result of increasing gastric pH.
-Acute bismuth intoxication is manifested by GI disturbance, stomatitis, discoloration of mucous membranes, and potential for kidney and liver damage.

Front 358

358. What is misoprostol and what is it used for?

Back 358

Misoprostol is a prostaglandin analogue used to prevent NSAID-induced peptic ulcers. Its most frequently adverse effects are abdominal discomfort and diarrhea.

In clinical practice, these adverse effects often interfere with patient compliance. Misoprostol is contraindicated in women who are pregnant b/c of the possibility of generating uterine contractions that could result in abortion.