Pbl Exam 3 Case 1

Front 1

1. Renal body fluid system for arterial pressure control

Back 1

When the body contains too much extracellular fluid, the blood volume and arterial pressure rise.

The rising pressure in turn has a direct effect to cause the kidneys to excrete the excess extracellular fluid, thus returning the pressure back toward normal.

Front 2

2. Pressure diuresis

Back 2

Increased urinary output due to increased arterial pressure

Front 3

3. Pressure natriuresis

Back 3

Increased sodium output due to increased arterial pressure

Front 4

4. Renal function in a normal person at arterial pressures of 50 mmHg, 100 mmHg, and 200 mmHg?

Back 4

50 mm Hg = no urine output

100 mm Hg = normal urine output

200 mm Hg = 6-8x normal urine output

Front 5

5. In high arterial pressures, when does the "negative balance" of fluid cease?

Back 5

In high arterial pressure, the renal output of water and salt is increased.

Therefore, the body loses fluid, the blood volume decreases, and the arterial pressure decreases.

This "negative balance" of fluid will not cease until the pressure falls all the way back to the equilibrium level.

Front 6

6. What happens if the arterial pressure falls below the equilibrium point?

Back 6

The intake of water and salt is greater than the output.

Therefore, the body fluid volume increases, blood volume increases, and the arterial pressure rises to the equilibrium point.

Front 7

7. Infinite feedback gain principle

Back 7

The return of the arterial pressure always exactly back to the equilibrium point

Front 8

8. What are the two determinants of the long term arterial pressure level?

Back 8

1. The level of salt and water intake

2. The degree of pressure shift of the renal output curve for water and salt

*It is impossible to change the long term mean arterial pressure level to a new value without changing one or both of these values

Front 9

9. Equation for arterial pressure

Back 9

Arterial pressure = (cardiac output) x (total peripheral resistance)

Front 10

10. Total peripheral resistance and equilibrium point

Back 10

Increasing resistance in the blood vessels everywhere else in the body besides in the kidneys DOES NOT change the equilibrium point.

Instead, the kidneys immediately begin to respond to the high arterial pressure, causing pressure diuresis and pressure natriuresis.

Front 11

11. Increased intrarenal vascular resistance and equilibrium point

Back 11

Many times when the total peripheral resistance increases, this increases the intrarenal vascular resistance at the same time, which can alter the function of the kidney and can cause hypertension.

However, it is the increase in renal resistance that is the culprit here, not the increased total peripheral resistance.

Front 12

12. What is the order of steps by which increased extracellular fluid volume elevates arterial pressure?

Six steps...

Back 12

1. Increased extracellular fluid volume
2. Increased blood volume
3. Increased mean circulatory fillling pressure
4. Increased venous return of blood to the heart
5. Increased cardiac output
6. Increased arterial pressure

Front 13

13. What are the two way in which an increase in CO can increase the arterial pressure?

Back 13

1. The direct effect of increased CO to increase the pressure

2. The indirect effect of to raise total peripheral vascular resistance thru autoregulation of blood flow.

Front 14

14. Autoregulation of blood flow

Back 14

Mean simply regulation of blood flow by the tissue itself.

Front 15

15. Which is more likely to elevate the arterial pressure - an increase in salt intake or an increase in water intake?

Back 15

An increase in salt intake is far more likely to elevate the arterial pressure than is an increase in water intake.

The reason for this is that pure water is normally excreted by the kidneys almost as rapidly as it is ingested, but salt is not excreted so easily.

As salt accumulates in the body it also indirectly increases the extracellular fluid volume.

Front 16

16. What are the two reasons by which an increased salt intake increases the extracellular fluid volume?

Back 16

1. An excess salt concentration in the extracellular fluid causes the osmolality of the fluid to increase, and this in turn stimulates the thirst center in the brain, making the person drink extra amounts of water to return to EC salt concentration to normal. This increases the EC fluid volume.

2. The increase in osmolality caused by the excess salt in the EC fluid also stimulates the HPA gland secretory mechanism to secrete increased quantitieis of antidiuretic hormone. The antidiuretic hormone then causes the kidneys to reabsorb greatly increased quantities of water from the renal tubular fluid, thereby diminishing the excreted volume of urine but increasing the EC fluid volume.

Front 17

17. What is the main determinant of the EC fluid volume?

Back 17

The amount of salt that accumulates in the body.

Front 18

18. Chronic hypertension

Back 18

The mean arterial pressure is greater than the upper range of the accepted normal measure.

Mean arterial pressure > 110 mm Hg is considered to be hypertensive.

Occurs when the systolic is > 135 mm Hg and the diastolic is > 90 mm Hg.

Front 19

19. Elevated arterial pressure and life expectancy

Back 19

Even moderate elevation of arterial pressure leads to shortened life expectancy.

At severely high pressures, mean arterial pressures 50% or more above normal - a person can expect to live no more than a few more years unless appropriately treated.

Front 20

20. What are the three way in which the lethal effects of hypertension are caused?

Back 20

1. Excess workload on the heart leads to early heart failure and coronary heart disease, often causing death as a result of a heart attack.

2. The high pressure frequently damages a major blood vessel in the brain, followed by death of major portions of the brain; this is a cerebral infarct (stroke).

3. High pressure almost always cause injury in the kidneys, producing many areas of renal destruction and, eventually, kidney failure, uremia, and death.

Front 21

21. Volume-loading hypertension

Back 21

Reduction of the kidney mass to 30% of normal greatly reduces the ability of the kidneys to excrete salt and water.

Therefore, salt and water accumulates in the body and in a few days raises the arterial pressure high enough to excrete the excess salt and water intake.

Front 22

22. What causes the initial slow rise in arterial pressure in volume-loading hypertension?

Back 22

There is an initial decrease in peripheral vascular resistance.

This decrease is caused the by the baroreceptor mechanism which tries to prevent the rise in pressure.

Front 23

23. Why is this baroreceptor compensation not maintained in volume-loading hypertension?

Back 23

After 2 - 4 days, the baroreceptors adapt (reset) and are no longer able to prevent the rise in pressure.

At this time, the arterial pressure rises almost to its full height b/c of the increase in cardiac output, even though the total peripheral resistance is still almost at the normal level.

Front 24

24. What are the secondary changes that occur during the next few weeks in volume-loading hypertension?

Back 24

1. Progressive increase in total peripheral resistance
2. Decrease in CO all the way to normal mainly as a result of the long term blood flow autoregulation mechanism.
3. Secondary increase in total peripheral resistance.

Front 25

25. In volume-loading hypertension, how does the EC fluid volume and blood volume return almost all the way back to normal along w/ the decrease in CO?

Back 25

Results from two factors:

1. The increase in arteriolar resistance decrease the capillary pressure, which allowed the fluid in the tissue spaces to be absorbed back into the blood.
2. The elevated arterial pressure now caused the kidneys to excrete the excess volume of fluid that had initially accumulated in the body.

Front 26

26. What is the final state of the circulation several weeks after the initial onset of volume loading?

Back 26

1. Hypertension
2. Marked increase in total peripheral resistance
3. Almost complete return of EC fluid volume and blood volume all the way back to normal along w/ the decrease in CO back to normal

Front 27

27. What are the two stages of volume-loading hypertension?

Back 27

1. First stage results from increased fluid volume causing increased CO. This increase in CO causes the hypertension

2. The second stage is characterized by high blood pressure and high total peripheral resistance but return of the CO so near to normal that the usual measuring techniques freq cannot detect an abnormally elevated CO

Front 28

28. Cause of increased total peripheral resistance in volume-loading hypertension

Back 28

Occurs after the hypertension has developed and, therefore, is secondary to the hypertension rather than being the cause of the hypertension.

Front 29

29. Volume-loading hypertension in patients on dialysis

Back 29

It is esp important to keep the patient's body fluid volume at a normal level. If this is not done and EC fluid volume is allowed to increase, hypertension almost invariably develops.

The hypertension that develops is a high peripheral resistance type of hypertension.

Front 30

30. Hypertension caused by primary aldosteronism

Back 30

This is another type of volume-loading hypertension that is caused by excess aldosterone in the body.

Aldosterone increase the rate of reabsorption of salt and water by the tubules of the kidneys, thereby reducing the loss of these in the urine while at the same time causing an increase in blood volume and EC fluid volume. Consequently, hypertension occurs.

Same principles apply here as for other types of volume-loading hypertension.

Front 31

31. Renin

Back 31

A protein enzyme released by the kidneys when the arterial pressure falls too low. In turn, it raises the arterial pressure in several ways, thus helping to correct the initial fall in pressure.

Front 32

32. Where is renin synthesized?

Back 32

Renin is synthesized and stored in an inactive form called prorenin in the juxtaglomerular cells (JG cells) of the kidneys.

Front 33

33. JG cells

Back 33

They are modified smooth muscle cells located in the walls of the afferent arterioles immediately proximal to the glomeruli.

When the arterial pressure falls, intrinsic reactions in the kidneys themselves cause many of the prorenin molecules in the JG cells to split and release renin.

Front 34

34. What is the importance of renin?

Back 34

It is an enzyme, not a vasoactive substance.

Renin acts enzymatically on another plasma protein, a globulin called angiotensin.

Front 35

35. Angiotensin and angiotensin I

Back 35

When renin acts on angiotensin, it causes the release of angiotensin I.

Angiotensin I has mile vasoconstrictor properties but not enough to cause significant changes in the circulatory function. The renin persists in the blood for 30 min to 1 hr and continues to cause formation of still more angiotensin I during this entire time.

Front 36

36. Angiotensin II

How long does it last in the blood?

Back 36

Within a few seconds to minutes after the formation of angiotensin I, two additional AA's are split from the angiotensin I to form the 8 AA peptide angiotensin II.

Angiotensin is an extremely powerful vasoconstrictor, and it also affects circulatory function in other ways as well.

However, it persists in the blood only for 1-2 minutes b/c it is rapidly inactivated by multiple blood an tissue enzymes called angiotensinases.

Front 37

37. Where does the conversion of angiotension I to angiotension II occur?

Back 37

Occurs almost entirely in the lungs while the blood flows thru the small vessels of the lungs, catalyzed by an enzyme called converting enzyme (ACE) that is present in the endothelium of the lung vessels.

Front 38

38. What are the two principal effects by which angiotensin II causes elevated arterial pressure?

Back 38

1. Causes vasoconstriction in many areas of the body (this occurs rapidly)

2. Decreases excretion of both salt and water by the kidneys. This effect, acting thru the EC fluid volume mechanism, is even more powerful than the acute vasoconstrictor mechanism in eventually raising arterial pressure.

Front 39

39. What is the purpose of the renin-angiotensin system?

Back 39

This system is powerful enough to return the arterial pressure at least halfway back to normal w/in a few minutes after severe hemorrhage.

Therefore, sometimes it can be of lifesaving service to the body, esp in circulatory shock.

Front 40

40. Is the renin-angiotensin system slow or fast acting?

Back 40

The renin-angiotensin system requires about 20 min to become fully active.

Therefore, it is somewhat slower to act for pressure control than are the nervous reflexes and the sympathetic norepinephrine-epinephrine system.

Front 41

41. How does angiotensin cause the kidneys to retain both salt and water?

Two major ways...

Back 41

1. Acts directly on the kidneys to cause salt and water retention

2. Causes the adrenal glands to secrete aldosterone, and the aldosterone in turn increases salt and water reabsorption by the kidney tubules.

Front 42

42. What happens when excess amts of angiotensin circulate in the blood?

Back 42

The entire long term renal-body fluid mechanism for arterial pressure control automatically becomes set to a higher arterial pressure level than normal.

Front 43

43. How does angiotension cause renal retention of salt and water?

Three ways...

Back 43

1. One major effect is to constrict the renal arterioles, thereby diminishing the blood flow thu the kidneys. As a result, less fluid filters thu the glomeruli in to the tubules.

2. The slow flow of blood reduces the pressure in the peritubular capillaries, which causes rapid reabsorption of fluid from the tubules.

3. Has important direct actions on the tubular cells themselves to increase tubular reabsorption of sodium and water.

The total results of all these effects is significant, sometimes decreasing urine output less than other fifth of normal.

Front 44

44. Stimulation of aldosterone by angiotensin

Back 44

Angiotensin is one of the most powerful stimulators of aldosterone secretion by the adrenal glands.

When the renin-angiotensin system becomes activated, the rate of aldosterone secretion usually also increases, and an important function of aldosterone is to cause marked increase in sodium reabsorption by the kidney tubules, thus increasing the total body extracellular fluid sodium.

Front 45

45. Angiotensin vs. aldosterone on kidney functioning

Back 45

The direct effect of angiotensin on the kidneys is perhaps 3x or more as potent as the indirect effect acting thru aldosterone - even though the indirect effect is the one most widely known.

Front 46

46. What is one of the most important functions of the renin-angiotensin system?

Back 46

To allow a person to eat either very small or very large amounts of salt w/o causing great changes in either EC fluid volume or arterial pressure.

Thus, the renin-angiotensin system is an automatic feedback mechanism that helps maintain the arterial pressure at or near the normal level even when salt intake is increased or decreased.

Front 47

47. Sequential events by which increased salt intake activates the automatic feedback mechanism

Back 47

1. Increased salt intake
2. Increased EC volume
3. Increased arterial pressure
4. Decreased renin and angiotensin
5. Decreased renal retention of salt and water
6. Return of EC volume almost to normal
7. Return of arterial pressure almost to normal.

Front 48

48. Types of hypertension in which angiotensin is involved

Back 48

1. Hypertension caused by a renin-secreting tumor
2. Infusion of angiotensin II

Front 49

49. "One kidney" Goldblatt hypertension

Back 49

50. When one kidney is removed and a constrictor is placed on the renal artery of the remaining kidney, the immediate effect is greatly reduced pressure in the renal artery beyond the constrictor. Then, within seconds or minutes, the systemic arterial pressure begins to rise and continues to rise for several days.

The pressure usually rises rapidly for the first hour or so, and this is followed by a slower additional rise during the next several days.

When the systemic arterial pressure reaches its new stable level, the renal arterial pressure will have returned almost all the way back to normal.

Early rise in arterial pressure is due to the renin-angiotensin vasoconstrictor mechanism. Second rise in arterial pressure is due to the retention of salt and water by the constricted kidneys and aldosterone.

In other words, the aortic pressure must rise high enough so that renal arterial pressure distal to the constrictor is enough to cause normal urine output.

Front 50

50. "Two kidney" Goldblatt hypertension

Back 50

Hypertension also can result when the artery to only one kidney is constricted while the artery to the other is normal.

This results from the constricted kidney secreting renin and retaining salt and water. Then the normal opposite kidney retains salt and water b/c of the renin produced by the ischemic kidney.

This renin causes formation of angiotensin II and aldosterone both which circulates the the opposite kidney.

Thus, both kidneys, but for different reasons become salt and water retainers and hypertension develops.

Front 51

51. Hypertension caused by diseased kidneys that secrete renin chronically

Back 51

Often, patchy areas of one or both kidneys are diseased and become ischemic b/c of local vascular constrictions, wheras other areas of the kidneys are normal.

When this occurs, almost identical effects occur as in the two kidney type of Goldblatt hypertension.

One of the most common causes of renal hypertension, esp in older patients, is such patchy ischemic kidney disease.

Front 52

52. Coarctation of the aorta and hypertension

Back 52

Blood flow to the lower body is carried by multiple, small collateral arteries, with much vascular resistance btwn the upper aorta and the lower aorta. Higher pressures in the upper body are needed to prevent ischemia in the kidneys.

Thus, pressure in the lower part of the body is normal while pressure in the upper body is elevated.

Front 53

53. Role of autoregulation in the hypertension caused by coarctation of the aorta

Back 53

Blood flow in the arms, where the pressure may be 40-60% above normal, is almost exactly normal.

Also, blood flow in the legs, where the pressure is not elevated, is almost exactly normal.

The only reasonable explanation is that long-term autoregulation develops so nearly completely that the local blood flow control mechanism have compensated almost 100% for the differences in pressure.

Thus, blood flow is controlled almost exactly in accord w/the needs of the tissue and not in accord w/the level of the pressure.

Front 54

54. Hypertension in preeclampsia

Back 54

One of the manifestations of preeclampsia is hyperstension that suually subsides after deliver of the baby.

Ischemia of the placenta and subsequent release by the placenta of toxic factors are believed to play a role in causing preeclampsia.

Specifically, substances released by the ischemic placenta cause dysfunction of vascular endothelial cells throughout the body.

This endothelial dysfunction decreases release of nitric oxide and other vasodilator substances, causing vasocontriction, decreased rate of fluid filtration from the glomeruli in to the renal tubules, impaired renal pressure natriuresis, and development of hypertension.

Front 55

55. What is another pathological abnormality that may contribute to hypertension in preeclampsia?

Back 55

Thickening of the kidney glomerular membranes (perhaps caused by an autoimmune process), which also reduces the rate of glomerular fluid filtration.

Front 56

56. Neurogenic hypertension

Back 56

Acute neurogenic hypertension can be caused by strong stimulation of the sympathetic nervous system.

Front 57

57. Sectioning the baroreceptor nerves

Back 57

Another type of acute neurogenic hypertension occurs when the nerves leading from the baroreceptors are cut or when the tractus solitarius is destroyed in each side of the medulla oblongata.

The sudden cessation of normal nerve signals from the baroreceptors increases the mean arterial pressure.

However, the pressure returns to nearly normal within about 2 days b/c the response of the vasomotor center to the absent baroreceptor signal fades away, which is called central "resetting".

Front 58

58. Two structural changes observed in the nephrons of kidneys in hereditary hypertension

Back 58

1. Increased preglomerular renal arterial resistance
2. Decreased permeability of the glomerular membranes

Front 59

59. Primary (essential) hypertension

Back 59

The hypertension is of unknown origin. There is a strong hereditary component, however, in most patients, excess weight gain and sedentary lifestyle appear to play a major role in causing hypertension.

Front 60

60. Characteristics of primary hypertension

Back 60

1. CO is increased
2. Sympathetic nerve activity, especially in the kidneys, is increased in overweight patients.
3. Angiotensin II and aldosterone levels are increased 2-3x in many obese patients.
4. The renal-pressure natriuresis mechanism is impaired, and the kidneys will not excrete adequate amounts of salt an water unless the arterial pressure is high or unless kidney function is somehow improved

Front 61

61. How is the renal-pressure natriuresis mechanism impaired in obese patients?

Back 61

Caused mainly by increased renal tubular reabsorption of salt and water due to increased sympathetic nerve activity and increased levels of angiotensin II and aldosterone.

Front 62

62. Salt sensitivity of blood

Back 62

Is not an all-or-none characteristic - it is a quantitative characteristic, with some individuals being more salt sensitive than others.

It is not a fixed characteristic either. Instead, blood pressure usually becomes more salt-sensitive as a personal ages.

Front 63

63. Reason for the difference between non-salt sensitive essential hypertension and salt-sensitive hypertension?

Back 63

Presumably related to structural or functional difference sin the kidneys of these two types of hypertensive patients.

Salt sensitive hypertension may occur w/different types of chronic renal disease due to gradual loss of the nephrons or to normal aging.

Front 64

64. Treatment of essential hypertension

Back 64

Lifestyle modifications

Vasodilator drugs that increase renal blood flow

Natriuretic or diuretic drugs that decrease tubular reabsorption of salt and water

Front 65

65. How do vasodilator drugs work?

Back 65

1. By inhibiting sympathetic nervous signals to the kidneys or by blocking the action of sympathetic transmitter substance on the renal vasculature

2. By directly relaxing the smooth muscle of the renal vasculature

3. By blocking the action of the renin-angiotensin system on the renal vasculature or renal tubules.

Front 66

66. How do natriuretic or diuretic drugs work?

Back 66

They decrease tubular reabsorption of salt and water by blocking active transport of sodium thru the tubular wall.

This blockage in turn also prevents the reabsorption of water.

Front 67

67. What are the rapidly acting pressure control mechanisms?

Back 67

1. The baroreceptor feedback mechanism
2. The central nervous system ischemic mechanism
3. The chemoreceptor mechanisms

Front 68

68. What are the pressure control mechanisms that act after many minutes?

Back 68

1. The renin-angiotensin vasoconstrictor mechanism
2. Stress-relaxation of the vasculature
3. Shift of fluid thru the tissue capillary walls in and out of the circulation to readjust the blood volume as needed.

Front 69

69. Stress-relaxation mechanism

Back 69

When the pressure in the blood vessels becomes too high, they become stretched and keep on stretching more and more for minutes or hours, as a result, the pressure in the vessels falls toward normal.

This continuing stretch of the vessels, called stress-relaxation, can serve as an intermediate term pressure buffer.

Front 70

70. Capillary fluid shift mechanism

Back 70

Means simply that any time capillary pressure falls too low, fluid is absorbed thru the capillary membranes from the tissues into the circulation, thus building up the blood volume and increasing the pressure in the circulation, and vice versa.

Front 71

71. What are the long term mechanisms for arterial pressure regulation?

Back 71

1. Renal body fluid pressure control mechanism
2. Renin-angiotensin and aldosterone systems.

Front 72

72. Lipid classifications

Back 72

1. Triglycerides
2. Phospholipids
3. Cholesterol

Front 73

73. Basic lipid moiety of the triglycerides and phospholipids

Back 73

Fatty acids, which are long chain hydrocarbon organic acids

Front 74

74. Similarity of cholesterol to fatty acids (even though it doesn't contain fatty acids)

Back 74

Although it doesn't contain fatty acids, its sterol nucleus is synthesized from portions of fatty acids molecules, thus giving it many of the physical and chemical properties of other lipids.

Front 75

75. Basic chemical structure of triglycerides

Three most common triglycerides in the body?

Back 75

3 long-chain fatty acids bound with 1 molecule of glycerol

Most common triglycerides:
1. Stearic acid (18 C fully saturated)
2. Oleic acid (18 C w/double bond in middle)
3. Palmitic acid (16 C fully saturated)

Front 76

76. Where are almost all the fats in the diet absorbed?

Back 76

In the intestines and then into the intestinal lymph (except for a few short chain fatty acids)

Front 77

77. Chylomicrons

Back 77

During digestion, most TAG are split into monoglycerides and fatty acids.

Then while passing thru the intestine, the monoglycerides and fatty acids are resynthesized into new molecules of TAGs that enter the lymph as minute dispersed droplets called chylomicrons.

Front 78

78. Movement and composition of chylomicrons

Back 78

Most of the chlesterol and phospholipids absorbed from the GI tract enter the chylomicrons.

The chylomicrons are then transported upward thu the thoracic ducts and emptied into the circulating venous blood.

Composed principally of TAGs but also:
9% phospholipids
3% cholesterol
1% apoprotein B

Front 79

79. Removal of chylomicrons

Back 79

May rise to 1-2% of the total plasma but have a half-life of less than 1 hr.

Both adipose tissue and the liver contain large quantities of lipoprotein lipase; this enzyme hydrolyzes the TAGs of chylomicrons thus releasing fatty acids and glycerol.

Fatty acids diffuse into the adipose cells and into liver cells; once inside, they are again synthesized into TAGs.

The lipase also causes hydrolysis of phospholipids; this, too, releases fatty acids to be stored in the cells in the same way.

Front 80

80. Transport of free fatty acids

Back 80

Fat must first be transported from adipose tissue mainly in the form of free fatty acids via hydrolysis of the TAGs back into fatty acids and glycerol.

Fatty acids ionize strongly in the plasma, and the ionic portion combines immediately w/albumin molecules of the plasma proteins.

Only about 3 molecules of fatty acid combine with each molecule of albumin, but as many as 30 molecules can combine w/a single albumin molecule when the need for fatty acid transport is extreme.

Front 81

81. Two classes of stimuli that play important roles in promoting TAG hydrolysis

Back 81

1. When the amt of glucose available to the fat cells is inadequate, one of the glucose breakdown products, α-glycerophosphate, is also available in insufficient quantities. B/c this substance is necessary to maintain the glycerol portion of TAGs, the result is hydrolysis of TAGs.

2. A hormone-sensitive cellular lipase can be activated by several hormones from the endocrine glands which also promotes rapid hydrolysis of TAGs.

Front 82

82. Two reasons for the small concentration of free fatty acids in the plasma during normal conditions

Back 82

1. Rate of turnover is extremely rapid (half the plasma fatty acid is replaced by new fatty acid every 2-3 minutes)

2. Conditions can increase the rate of utilization of fat for cellular energy and thus can increase the free fatty acid concentration in the blood when needed.

Front 83

83. Lipoproteins

Back 83

After all the chylomicrons have been removed from the blood, more than 95% of all the lipids int he plasma are in the form of lipoprotein.

These are small particles containing TAGs, cholesterol, phospholipids and protein.

Total concentration of lipoproteins in plasma avgs about 700 mg/dl

Front 84

84. Breakdown of lipoproteins into individual constituents

Back 84

Cholesterol: 180
Phopsholipids: 160
TAGs: 160
Protein: 200

Numbers are in mg/dl of plasma

Front 85

85. Four types of lipoproteins

Back 85

1. VLDLs
-contain high concentrations of TAGs and moderate amoutn of cholesterol and phospholipids

2. Intermediate-density lipoproteins
-these are VLDLs in which TAGs have been removed so the concentrations of cholesterol and phospholipids are increased.

3. LDLs
-derived from intermediate density lipoproteins; almost all the TAGs removed, leaving an especially high concentration of cholesterol and phospholipids

4. HDLs
-contain a high concentration of protein (50%), but much smaller concentration of cholesterol and phospholipids.

Front 86

86. Formation of lipoproteins - where does it occur?

Back 86

Formed in the liver and intestinal epithelium during the absorption of fatty acids from the intestines.

Front 87

87. Primary function of lipoproteins

Back 87

Transport their lipid components in the blood

VLDLs transport TAGs synthesized in liver to adipose tissue; other lipoproteins are esp important int he different stages of phosopholipid and cholesterol transport from the liver to peripheral tissues or vice versa.

Front 88

88. Adipose tissue

Back 88

Fat deposits; major function is storage of TAGs until they are needed to provide energy elsewhere in the body.

Also provides heat insulation

Front 89

89. Adipocytes

Back 89

The fat cells of adipose tissue are modified fibroblasts that store almost pure TAGs in quantities as great as 80-95% of the cell volume

TAGs inside the fat cells are generally in a liquid form; the fatty acid chains of the cell TAGs can either shorten or lengthen to remain in a liquid state in response to temp changes. This is particularly important, b/c only liquid fat can be hydrolyzed and transported from the cells.

They can also synthesize small amts of fatty acids and carbs.

Front 90

90. Exchange of fat between the adipose tissue and the blood

Back 90

Large quantities of lipases are present in adipose tissue; some enzymes catalyze the deposition of cell TAGs from the chylomicrons and lipoproteins.

Others, when activated by hormones, cause splitting of the TAGs of the fat cells to release free fatty acids

The TAGs in fat cells are renewed about once every 2-3 weeks, thus emphasizing the dynamic state of storage fat.

Front 91

91. Functions of the liver in lipid metabolism

Back 91

1. Degrade fatty acids into small compounds that can be used for energy
2. Synthesize TAGs mainly from carbs, but to a lesser extent from proteins as well
3. Synthesize other lipids from fatty acids, esp cholesterol and phospholipids.

Front 92

92. Conditions in which large quantities of TAGs appear in liver

Back 92

1. During the early stages of starvation
2. Diabetes
3. Any other condition in which fat instead of carbs is being used for energy

Large quantities of TAGs are mobilized from adipose tissue, transported as free fatty acids, and redeposited as TAGs in the liver where the initial stages of much of fat degradation begin

Front 93

93. Desaturation of fatty acids

Back 93

Liver cells are much more capable than other tissues of desaturating fatty acids, so that liver TAGs normally are much more unsaturated than the TAGs of adipose tissue

Desaturation is accomplished by dehydrogenase in the liver cells.

Front 94

94. Hydrolysis of TAGs

Can all cells use fatty acids for energy?

Back 94

Both the fatty acids and the glycerol are transported int he blood to the active tissues, where they will be oxidized to give energy.

Almost all cells, except brain tissue and RBCs can use fatty acids for energy.

Front 95

95. Entry of fatty acids into the mitochondria

Back 95

Degradation and oxidation of fatty acids occur only in the mitochondria.

The carrier mediated process of transport uses carnitine as a carrier substance.

Once inside the mitochondria, fatty acids split away from carnitine and are degraded and oxidized.

Front 96

96. Formation of acyl-CoA by β-oxidation of fatty acids

Back 96

Progressive release of 2-carbon segments in the form of acyl-CoA

1. Combination of fatty acid with CoA
2. The β carbon of the fatty acyl-CoA binds with an oxygen molecule and becomes oxidized
3. The two carbon portion of the molecule is split off to release acetyl-CoA into the cell fluid.
4. Simultaneously, another CoA molecule binds at the end of the remaining portion of the fatty acid molecule and forms a new fatty acyl-CoA. This time, however, the molecuel is shorter b/c of the loss of the first acetyl-CoA from its terminal end.

The shorter fatty acyl-CoA reenters the process and the cycle repeats.

Front 97

97. Oxidation of acetyl-CoA

Back 97

The acetyl-CoA formed by β-oxidation of fatty acids in the mitochondria enter immediately into the citric acid cycle; they combine first w/oxaloacetic acid to form citric acid, which is then degraded into CO2 and hydrogen atoms. The hydrogen is oxidized by the chemiosmotic oxidative system of the mitochondria.

Large amts of ATP are liberated.

Front 98

98. Formation of ATP from stearic acid

How many molecules of ATP can be formed?

Back 98

A total of 148 molecules of ATP are formed during the complete oxidation of 1 molecule of stearic acid.

However, two high-energy bonds are consumed in the initial combination of CoA w/the stearic acid molecule, making a net gain of 146 molecules of ATP.

Front 99

99. Formation of acetoacetic acid in the liver

Back 99

A large share of the initial degradation of fatty acids occurs int he liver, esp when excessive amts of lipids are being used for energy.

However, the liver only uses a small proportion of the fatty acids for its own intrinsic metabolic process.

Two molecule of acetyl-CoA condense to form one molecule of acetoacetic acid.

Part of the acetoacetic acid is also converted to β-hydroxybutyic acid, and minute quantities are converted into acetone.

Front 100

100. Transport of acetoacetic acid in the blood

Back 100

Acetoacetic acid, β-hydroxybutyric acid, and acetone diffuse freely thru the liver cell membranes an are transported by the blood to the peripheral tissues where they diffuse in the cell and acetyl-CoA molecules are formed.

These in turn enter the citric acid cycle and are oxidized for energy.

There is small concentration of these compounds in the blood, but large quantities are actually transported.

Front 101

101. Ketosis and starvation, diabetes, and other diseases

Back 101

When essentially no carbs are metabolized, almost all the energy of the body must come from metabolism of fat; tremendous quantities of fatty acids become available to the peripheral tissue cells to be used for energy, and to the liver cells, where much of the fatty acids is converted to ketone bodies.

Front 102

102. Limitations in the amt of ketone bodies that can be oxidized

Back 102

One of the products of carb metabolism is the oxaloacetate that is required to bind with acetyl-CoA before it can be processed in the citric acid cycle.

Therefore, deficiency of oxaloacetate derived from carbs limits the entry of acety-CoA into the citric acid cycle, and when there is a simultaneous outpouring of large quantities of acetoacetic acid and other ketone bodies from the liver, the blood concentrations of acetoacetic acid and β-hydroxybutyric acid sometimes rise to as high as 20x normal, thus leading to extreme acidosis.

Front 103

103. Synthesis of TAGs from carbs

Where does this occur?

Back 103

Occurs in the liver, but minute quantities are synthesized in the adipose tissue itself; TAGs from the liver are transported mainly in VLDL to adipose tissue where they are stored.

Front 104

104. Conversion of acetyl-CoA into fatty acids

Back 104

The first step occurs during normal degradation of glucose by the glycolytic system

Uses malonyl-CoA and NADPH as the principal intermediates in the polymerization process

Front 105

105. Importance of α-glycerophosphate

Back 105

Once the synthesized fatty acid chains have grown to contain 14-18 carbons, they bind with glycerol to form TAGs

The glycerol portion of TAGs is furnished by α-glycerophosphate, which is another product derived from the glycolytic scheme of glucose degradation.

Front 106

106. Efficiency of carb conversion to fat

Back 106

Only about 15% of the original energy in the glucose is lost in the form of heat; the remaining 85% is transferred to the stored TAGs

Front 107

107. Importance of fat synthesis

Back 107

1. Only a few hundred gms of glycogen can be stored in the liver, the skeletal muscle and other tissues of the body put together; however, many kgs of fat can be stored.

Therefore, fat synthesis provides a means by which the energy of excess ingested carbs and proteins can be stored for later use.

2. Each gram of fat contains almost 2 and a half times the calories of energy contained in glycogen; we can store much more fat than carbs which is very important for storage.

Front 108

108. Failure to synthesize fats from carbs in the absence of insulin

Back 108

When no insulin is available, as occurs in serious diabetes mellitus, fats are poorly synthesized, if at all, for the following reasons:

1. When insulin is not available, glucose does not enter the fat and liver cells satisfactorily, so that little of the acetyl-CoA and NADPH needed for fat synthesis can be derived from glucose.

2. Lack of glucose in the fat cells greatly reduces the availability of α-glycerophosphate, which also makes it difficult for the tissues to form TAGs.

Front 109

109. Synthesis of TAGs from proteins

Back 109

Many AAs can be converted into acetyl-CoA which can then be synthesized into TAGs

Front 110

110. Body's natural preference for energy storage

Back 110

Carbs are preferred over fats when excess of carbs are present.

When excess quantities of α-glycerophosphate are present (in the case of excess carbs), the excess α-glycerophosphate binds free fatty acids in the form of stored TAGs; as a result, the equilibrium between free fatty acids and TAGs shift towards stored TAGs.

Consequently, only minute quantities of fatty acids are available to be used for energy.

Front 111

111. Promotion of conversion of carbs to fat

Back 111

The first step is the rate limiting step in the synthesis of fatty acids which is the carboxylation of acetyl-CoA to form malonyl-Coa; the rate is controlled primarily by the enzyme acetyl-CoA carboxylase, the activity of which is accelerated int the presence of intermediates of the citric acid cycle.

When excess carbs are being used, these intermediates increase, automatically causing increased synthesis of fatty acids.

Front 112

112. Epinephrine and norepinephrine and fat utilization

Back 112

Released by the adrenal medullae during exercise as a result of sympathetic stimulation

They directly activate hormone-sensitive TAG lipase, which is present in abundance in the fat cells and causes rapid breakdown of TAGs and mobilization of fatty acids.

Front 113

113. Stress and fat utilization

Back 113

Stress causes large quantities of corticotropin to be released by the anterior pituitary gland and this causes extra quantities of glucocorticoids to be secreted; both corticotropin and glucocorticoids activate hormone sensitive TAG lipase.

When corticotropin and glucocorticoids are secreted in excessive amts for long periods (Cushing syndrome), fats are freq mobilized to such a great extent that ketosis results.

Thus, corticotropin and glucocorticoids are said to have a ketogenic effect.

Front 114

114. Growth hormone

Back 114

GH has a similar effect to but weaker than that of corticotropin and glucocorticoids in activating hormone-sensitive lipase. Therefore, growth hormone can also have a mild ketogenic effect.

Front 115

115. Thyroid hormone and mobilization of fat

Back 115

Causes rapid mobilization of fat which is believed to result indirectly from an increased overall rate of energy metabolism in all cells of the body under the influence of this hormone.

The resulting reduction in acetyl-CoA and other intermediates of both fat and carb metabolism in the cells is a stimulus for fat mobilization.

Front 116

116. Hereditary obesity

Back 116

Can be caused by ineffective mobilization of fat from adipose tissue by tissue lipase, while synthesis and storage of fat continue normally.

Front 117

117. Phospholipids

Back 117

Chemical structures are variant but their basic properties are similar b/c they are all lipid soluble.

Transported in lipoproteins and used throughout the body for various structural purposes

Front 118

118. Formation of phospholipids

Back 118

Synthesized in all cells in body; rate of formation is governed to some extent by usual factors that control overall rate of fat metabolism b/c, when TAGs are deposited in the liver, the rate of phospholipid formation increases

Front 119

119. Choline

Back 119

Either obtained in diet or synthesized in the body; it is needed for the formation of lecithin, because choline is the nitrogenous base of the lecithin molecule.

Front 120

120. Inositol

Back 120

plays an important role as the structural basis for a number of secondary messengers in eukaryotic cells, including inositol phosphates, phosphatidylinositol (PI) and phosphatidylinositol phosphate (PIP) lipids.

It is also needed for the formation of some cephalins

Front 121

121. Specific uses of phospholipids

Back 121

1. Constituent of lipoproteins in the blood and are essential for the formation and function of most o fthese.
2. Thromboplastin (tissue factor), which is needed to initiate the clotting process, is composed mainly of one of the cephalins
3. Large quantities of sphingomyelin are present in the nervous system; this substance acts as an electrical insulator in the myelin sheath around nerve fibers.
4. Phospholipids are donors of phosphate radicals when these radicals are needed for different chemical reactions in the tissues.
5. Participation in the formation of structural elements - mainly membranes - in cells throughout the body.

Front 122

122. Formation of cholesterol

Back 122

Cholesterol formed by cells of the body is called endogenous cholesterol; essentially all endogenous cholesterol is formed by the liver, but all other cells in the body form at least some cholesterol.

Front 123

123. Four factors that affect plasma cholesterol concentration

Back 123

1. Increase in the amount of cholesterol ingested each day; inhibits the most essential enzyme for endogenous synthesis of cholesterol; thus providing an intrinsic feedback control system to prevent an excessive increase in plasma cholesterol concentration.
2. A highly saturated fat diet increase blood cholesterol concentration. This results from increased fat deposition in the liver, which then provides increased quantities of acetyl-CoA in the liver cells for the production of cholesterol.
3. Ingestion of fat containing highly unsaturated fatty acids usually depresses the blood cholesterol concentration of slight to moderate amt.
4. Lack of insulin or thyroid hormone increases the blood cholesterol concentration, caused by changes in the degree of activation of specific enzymes responsible for the metabolism of substances

Front 124

124. Four specific uses of cholesterol in the body

Back 124

1. Adrenal glands to form adrenocortical hormones
2. Ovaries to form progesterone and estrogen
3. Testes to form testosterone
4. Precipitated in the corneum in skin to make the skin highly resistant to losing/absorption of water and to the action of many chemical agents

Front 125

125. Fluidity of the cell membrane

Back 125

Ratio of membrane cholesterol to phosholipids is important in fluidity of cell membranes

The polar parts of the phospholipids also reduce interfacial tension between cell membranes and the surrounding fluids.

Front 126

126. Basic causes of atherosclerosis

Back 126

1. Increased LDLs
2. Familial hypercholesterolemia
3. Physical inactivity and obesity
4. Diabetes
5. Hypertension
6. Hyperlipidemia
7. Cigarette smoking

Front 127

127. Excess iron in the blood can lead to...

Back 127

Atherosclerosis, perhaps by forming free radicals in the blood that damage the vessel wall

Front 128

128. Apoprotein A

Back 128

About 1/4 of all people have a special type of LDL called lipoprotein A; containing an additional protein that almost doubles the incidence of atherosclerosis

Front 129

129. Familial hypercholesterolemia

Back 129

Disease in which the person inherits defective genes for the the formation of LDL receptors on the membrane surfaces of the body's cells.

As a result, the liver cannot absorb intermediate or low density lipoproteins and cholesterol machinery of the liver cells goes on a rampage, producing new cholesterol; it is no longer response to the feedback inhibition of too much plasma cholesterol

Front 130

130. Oat bran and atherosclerosis

Back 130

Binds bile acids and increases the proportion of liver cholesterol that forms new bile acids rather than forming new LDLs and athrogenic plaque.

Resin agents can also be used to bind bile acids in the gut and increase their fecal excretion, thereby reducing cholesterol synthesis by the liver

Front 131

131. Elevated serum amylase

Back 131

Amylase is produced only in the salivary glands and the acinar cells of the pancreas.

Digests dietary starch

Thus, elevated serum amylase can be a sign of pancreatitits, or salivary gland lesions, such as mumps, can also increase serum amylase.

Front 132

132. Four diverse functions of lipids

Back 132

1. Fuel and storage for energy generation
-Fatty acids (fuel)
-TAGs (storage)

2. Building blocks for cell membranes
-Cholesterol
-Glycerophospholipids
-Sphingolipids

3. Signaling molecules
-Steroid hormones
-Eicosanoids

4. Fat-soluble vitamin transport
-A, D, E, & K

Front 133

133. Overview of TAG metabolism during fasting

Back 133

Two types of TAGs:
1. Dietary
2. Synthesized by liver

1. TAG is cleaved into glycerol and fatty acid components, which are released from adipose tissue
2. Fatty acids are used by muscle for energy, or are taken up by the liver and converted to ketone bodies
3. The glycerol component is taken up by the liver and converted to glucose via gluconeogenesis
4. The liver becomes the net exporter of glucose

Front 134

134. Where are short and medium chain TAGs digested?

Back 134

Mouth and stomach

Front 135

135. Importance of pancreas in digestion of TAGs

Back 135

Secretes bicarbonate, lipase, and colipase into the lumen of the small intestine thru the common bile duct

Bicarbonate neutralizes the contents by raising pH

Front 136

136. Lipase

Back 136

Enzyme that cleaves the ester bond that exists between the fatty acids and the glycerol backbone to yield 2 free fatty acids and 2-monoacylglycerol

Front 137

137. Colipase

Back 137

Binds to the fat and lipase and stimulates ester bond hydrolysis via pancreatic lipase activity

Bile salts inhibit pancreatic lipase activity by coating the substrate and not allowing the enzyme access

The colipase relieves the bile salt inhibition by allowing TAGs to enter the active site of the lipase, which enhances lipase activity

Front 138

138. What three things occur after pancreatic lipase hydrolyzes fatty acids?

Back 138

1. Fatty acids and 2-monoacylglycerol are packaged into micelles by bile salts. Micelles are absorbed by the intestinal epithelial cells.

2. Inside the intestinal epithelial cells, the fatty acids and 2-monoacylglycerol are brought back together to the form TAGs, which is packaged into a chylomicron particle.

3. The chylomicrons are then dumped into the lymphatics and eventually end up in the bloodstream.

Front 139

139. Specific site of action for lipases

Back 139

Lingual, gastric, and pancreatic lipases hydrolyze TAGs at position #1 and #3 to yield 2-monoacylgylcerol and 2 free fatty acids.

Front 140

140. What are the two lipase activators?

Back 140

1. Colipase
2. HCO3- (bicarbonate)
-raises the intestinal pH to a more optimal level for lipase activity

Front 141

141. Where do esterases and phosholipases function?

Back 141

In the intestinal lumen

Front 142

142. Where are bile salts synthesized?

Where are they stored?

Back 142

Synthesized in the liver from cholesterol
-contain more hydroxyl groups than cholesterol which increases solubility
-contain a polar side chain

Stored in the gallbladder
-Cholescystokinin stimulates contraction of the gallbladder to release bile salts

Front 143

143. What do micelles contain?

Five things...

Back 143

1. Bile salts
2. 2-monoacylglycerols
3. Dietary free fatty acids (> 12 C's)
4. Dietary cholesterol
5. Dietary fat soluble vitamins

Front 144

144. Absorption of lipids occurs in what part of the digestive tract?

Back 144

Micelle components (except bile salts) are absorbed by intestinal epithelial cells int eh duodenum and jejunum.

Front 145

145. What occurs in the ileum?

Back 145

Bile salts are absorbed in the ileum and return to the liver, which secretes them again (enterohepatic cycle)

Front 146

146. What lipids do not require bile salts for absorption and thus are not packaged into chylomicrons?

How are they absorbed?

Back 146

Short and medium chain fatty acids do not require bile salts for their absorption.

They diffuse across the cell membranes of the intestinal cells directly into the portal vein.

They are transported in the blood bound to serum albumin instead of chylomicrons.

*They supply the much needed energy source in those patients with lipid digestion deficiencies.

Front 147

147. What is the clinical significance in patients with a deficiency in bile salt formation?

Back 147

They have a deficit in long chain fatty acid absorption

Front 148

148. What is the clinical significance in patients with a deficiency in lipoprotein lipase activity?

Back 148

They have a deficit in long chain fatty acid delivery to cells, especially to muscle and heart cells.

Front 149

149. Where does the reformation of TAGs occur?

Back 149

Within intestinal epithelial cells (enterocytes)

Front 150

150. Where does TAG reformation take place?

What are the three steps in TAG reformation?

Back 150

Following their absorption into intestinal epithelial cells the free FA are reassembled into TAGs inside the smooth ER

1. FA must first be activated into fatty acyl-CoA
2. Fatty acyl-CoAs are then sequentially esterified on the #1 and #3 position of 2-monoacylglycerol to reform TAGs
3. TAGs are incorporated in the core of a developing chylomicron

Front 151

151. Assembly of chylomicrons

Where does each step occur?

Back 151

Occurs w/in the intestinal epithelial cells

1. TAGs are reassembled in the sER
2. Apo B48 protein is synthesized in the rER
3. Chylomicron packaging occurs in the golgi apparatus
4. Chylomicrons are secreted via exocytosis into the lymphatics

Front 152

152. Structure of a lipoprotein particle

Back 152

All lipoprotein particles contain a lipid and protein component

The core of the lipoprotein particle is insoluble and is comprised of phospholipids tails, TAGs and cholesterol esters

The outside of the particle contains protein components that help solubilize the lipoprotein so it can travel thru the blood stream.

Front 153

153. Chylomicron vs. VLDL function

Back 153

Chylomicrons deliver dietary fat to the muscle for fuel and to the adipose tissue for storage

VLDL particles shuttle newly synthesized fat from the liver to the adipose tissue.

Front 154

154. Apo C-II

Four things...

Back 154

1. Activates lipoprotein lipase in adipose and muscle tissue
2. LPL hydrolyzes TAGs to glycerol and FAs
3. The free FAs are taken up by muscle and adipose tissue
4. In the process, chylomicron remants are generated

Front 155

155. Apo E

Back 155

The ligand for the Apo E receptor in the liver

This allows the chylomicron remnants to be taken back up by the liver.

Front 156

156. Where does synthesis of chylomicrons NOT take place?

Back 156

Liver

Front 157

157. Lipoprotein lipase

Back 157

LPL is an enzyme that is attached to the basement membrane of the endothelial cells that line the capillary walls of both muscle and adipose tissue

LPL is activated by Apo C-II present on chylomicrons and VLDL particles

Front 158

158. Activity of LPL during the fasting state

Back 158

Muscle LPL is more active than adipose LPL

LPL affinity for TAGs is much higher in muscle than adipose tissues, so muscles absorb TAGs much more easily

Front 159

159. Activity of LPL during the fed state

Back 159

Adipose LPL is most active

This is when TAG rich lipoproteins (chylomicrons and VLDLs) are greatly elevated in the plasma

Insulin stimulates LPL synthesis in the well fed state

Front 160

160. Where are Apo B-48 and Apo B-100 derived from?

Back 160

Derived from the same gene (B-apoprotein gene) located on chromosome 2

It is transcribed and translated in the liver to produce Apo B-100

In intestinal cells, RNA editing converts a cytosine to an uracil, producing a stop codon.

Consequently, this forms Apo B-48, which is 48% the size of Apo B-100

Front 161

161. Although the intestinal concentrations of pancreatic lipase and bile salts are low in the newborn infant, how is the fat of human milk still readily absorbed?

Back 161

Lingual and gastric lipases produced by the infant partially compensate for the lower levels of pancreatic lipase

The human mammary gland also produces lipases that enter the milk. One of these lipases, which requires lower levels of bile salts than pancreatic lipase, is not activated by stomach acid and functions in the intestines for a number of hours.

Front 162

162. Gallstones and dietary fat digestion

Back 162

Less soluble forms of bilirubin tend to precipitate as gallstones that are rich in calcium bilirubinate

Most pass harmlessly into the small intestine but larger stones may become entrapped in the common bile duct where they can block the flow of bile salts into the intestinal lumen.

As a result, dietary fats cannot be readily emulsified and digested.

Front 163

163. Acute and chronic pancreatitis

What labs support this Dx?

Back 163

Elevated serum levels of pancreatic amylase and lipase are consistent w/this Dx.

The elevated levels are a result of their escape from the inflamed exocrine cells of the pancreas into the surrounding pancreatic veins.

Can be related to chronic and excessive EtOH consumption

Front 164

164. Steoatorrhea

Back 164

Patients w/pancreatitis have bulky, glistening, yellow-brown and foul smelling stools that float.

Caused by malabsorption of dietary fats caused by a lack of pancreatic secretions, particularly pancreatic lipase

Can also be caused by insufficient production or secretion of bile salts so those with gallstones can also develop this.

Front 165

165. Fat soluble vitamin deficiency

Back 165

The fat soluble vitamins (A, D, E, & K) are absorbed from micelles along w/long chain FAs and 2-monoacylglycerols

Prolonged obstruction of the duct that carries exocrine secretions from the pancreas and gallbladder into the intestine can lead to a deficiency in these vitamins

Front 166

166. Olestra

Back 166

An artificial fat substitute with a sweet taste that consists of a sucrose molecule to which fatty acids are esterified to the hydroxyl groups.

These fatty acids attached to a sucrose are resistant to hydrolysis by pancreatic lipase so Olestra passes thru the intestine intact and is eliminated in the feces

*Can carry with it fat soluble vitamins so need to supplement diet

Front 167

167. Which types of lipoproteins coalesce and float to the top of a test tube of blood if allowed to stand overnight?

Why?

Back 167

Chylomicrons are the least dense of the blood lipoproteins; thus they will float to the top of the test tube.

Occurs when blood of patients with hyperproteinemias have elevated chylomicron levels.

Front 168

168. Orlistat

How does it work?

Back 168

Inhibits the activity of pancreatic lipase which leads to reduced fat digestin and absorption and a reduced caloric yield from the diet.

Drug works by forming a covalent bond w/the active site serine residues of both gastric and pancreatic lipase, thereby inhibiting their activities.

Approx 30% of the dietary fat absorption is inhibited.

Can lead to gastric distress b/c of intestinal gas formation due to passage of nondigested fat

Front 169

169. Heparin and LPL

Back 169

Isolated heparin can also bind to LPL and dislodge it from the capillary wall.

This leads to a loss of LPL activity and an increase in TAG content in the blood.

Front 170

170. Abetalipoproteinemia

Back 170

There is an absence of small apolipoprotein B particles; mutations in the microsomal triglyceride transfer protein (MTP) gene has been associated with this condition. Inherited via autosomal recessive disorder

Front 171

171. Significance of abetalipoproteinemia?

Back 171

Abetalipoproteinemia affects the absorption of dietary fats, cholesterol, and certain vitamins. People affected by this disorder are not able to make certain lipoproteins.

This leads to a multiple vitamin deficiency, affecting the fat-soluble vitamin A, vitamin D, vitamin E, and vitamin K. However, many of the observed effects are due to vitamin E deficiency in particular.

Low levels of plasma chylomicrons are also characteristic.

Front 172

172. Signs and symptoms of abetalipoproteinemia?

Back 172

Usually appear in the first few months of life.

* Failure to grow in infancy
* Weight loss
* Steatorrhea
* Mental developmental delay
* Muscle weakness
* Vomiting
* Progressive decreased vision
* Balance and coordination problems

Many of the signs and symptoms result from severe lipid soluble vitamin deficiency

Front 173

173. Equation to determine LDL cholesterol levels

Back 173

LDL = total cholesterol - [HDL + TAG/5]

Front 174

174. What is a key regulatory point in human sterol metabolism?

Back 174

Cholesterol absorption by intestinal cells b/c it ultimately determines what percentage of the 1,000 mg of biliary cholesterol produced by the liver each day and what percentage of the 300 mg of dietary cholesterol entering the gut per day is eventually absorbed into the blood.

In normal people, approx 55% of this intestinal pool enters the blood through the enterocyte each day.

Front 175

175. What is the mechanism that removes unwanted or excessive cholesterol and plant sterols from the enterocyte?

Back 175

The transport of sterols out of the enterocyte and into the gut lumen is related to the products of genes that code for the ATP binding cassette (ABC) protein family, ABC1, ABCG5, and AGCG8.

These proteins couple ATP hydrolysis to the transport of unwanted or excessive cholesterol and plant sterols from the enterocyte back into the gut lumen.

Front 176

176. How is cholesterol eliminated from the body?

Back 176

It cannot be metabolized to CO2 and water and is therefore eliminated from the body principally in the feces as unabsorbed sterols and bile acids.

Front 177

177. ABC proteins

Back 177

Their expression increases the amount of sterols present in the gut lumen, with the potential to increase elimination of the sterols into the feces.

Front 178

178. Phytosterolemia

Back 178

Rare autosomal disease AKA sitosterolemia

A defect in the function of either ABCG5 or ABCG8 occurs in the enterocytes, which leads to accumulation of cholesterol and phytosterols within these cells.

They eventually reach the bloodstream, markedly elevating the level of cholesterols in the blood.

This accounts for the increased cardiovascular morbidity in individuals with this disorder.

Front 179

179. Cholesterol structure

Back 179

It is an alicyclic compound whose basic structure includes the perhydrocyclopentanophenanthrene nucleus containing four fused rings.

In its free form, the cholesterol molecule contains 27 C's, a simple hydroxyl group at C3, a double bond between C5 and C6, an eight membered hydrocarbon chain attached to C17 in the D ring, a methyl group attached to C10, and a second methyl group (C18) attached to C13)

Front 180

180. About how much of the plasma cholesterol exists in the free or unesterified form?

Back 180

Approx 1/3 of the plasma cholesterol exists in the free or unesterified form

The reamining 2/3's exist as cholesterol esters.

Front 181

181. What can be inferred from cholesterol's structure?

Back 181

The structure suggests that its synthesis involves multimolecular interactions and significant reducing power.

All 27 C's are derived from one precursor, acetyl CoA.

Front 182

182. Where does the reducing power of cholesterol synthesis come from?

Back 182

NADPH provided by the G6PD of the hexose monophosphate shunt pathway.

Front 183

183. Where does cholesterol synthesis occur, and what does it require?

Back 183

Occurs in the cytosol

Requires hydrolysis of high energy thioester bonds of acetyl CoA and phosphoanhydride bonds of ATP.

Front 184

184. What are the four stages of cholesterol synthesis?

Back 184

1. Synthesis of mevalonate from acetyl CoA

2. Conversion of mevalonate to two activated isoprenes

3. Condensation of six activated 5-carbon isoprenes to form the 30-carbon squalene

4. Conversion of squalene to the four-ring steroid nucleus

Front 185

185. Stage 1 part 1 of cholesterol synthesis

What is significant about this stage?

Back 185

The synthesis of mevalonate is the committed, rate-limiting step in cholesterol formation.

Two molecuels of acetyle CoA condense, forming acetoacetyl CoA, which then condenses w/a third molecule of acetyl CoA to yield the 6-carbon β-hydroxy-β-methylglutaryl-CoA (HMG-CoA).

Front 186

186. Stage 1 part 2 of cholesterol synthesis

What is significant about this stage?

Back 186

The committed step and major point of regulation of cholesterol synthesis in stage 1 involves reduction of HMG-CoA to mevalonate, which is catalyzed by HMG-CoA reductase.

The reducing equivalents for this reaction are donated by two molecules of NADPH

Front 187

187. HMG-CoA reductase

Back 187

An enzyme that is embedded int he membrane of the ER

Contains eight membrane-spanning domains, and the amino-terminal domain, which faces the cytoplasm, contains the enzymatic activity.

Front 188

188. How is the rate of synthesis of HMG-CoA reductase mRNA controlled?

Back 188

The rate of synthesis of HMG-CoA reductase mRNA is controlled by one of the family of sterol-regulatory element binding proteins (SREBPs)

Front 189

189. SREBPs

Back 189

These transcription factors belong to the helix-loop-helix-leucine zipper family of transcripton factors.

They specifically enhance transcription of the HMG-CoA reductase gene by binding to the sterol-regulatory element (SRE) upstream of the gene, which increases the rate of transcription.

Front 190

190. SCAP and regulation of transcription of the reductase gene

Back 190

SREBPs, after syntehsis, are integral proteins of the ER.

The SREBP is bound to SCAP (SREBP cleavage activating protein) in the ER membrane when cholesterol levels are high.

When cholesterol levels drop, the sterol leaves its SCAP binding site, and the SREBP:SCAP complex is transported to the golgi apparatus

When sterol levels rise, the sterols bind to SCAP and prevent translocation of the complex to the golgi, leading to a decrease in transcription of the reductase gene

Front 191

191. Proteolytic degradation of HMG-CoA reductase

Back 191

Rising levels of cholesterol and bile salts in the cells that synthesize these molecules also may cause a change in the oligomerization state of the membrane domain of HMG-CoA reductase, rendering the enzyme more susceptible to proteolysis which decreases its activity.

Front 192

192. How else is the activity of HMG-CoA regulated?

Five specific influences...

Back 192

Also regulated by phosphorylation and dephosphorylation

1. Elevated glucagon levels increase phosphorylation of the enzyme, thereby deactivating it.
2. Hyperinsulinemia increases the activity of the reductase by activating phophatases, which dephosphorylate the reductase.
3. Increased levels of intracellular sterols also may increase phosphorylation
4. Thyroid hormone increases enzyme activity
5. Glucocorticoids decrease its activity

Front 193

193. Cholesterol synthesis and ATP levels

Back 193

When ATP levels are low, cholesterol synthesis decreases

When ATP levels are high, it increases.

Front 194

194. Stage 2

What are the two main products formed at the end of this stage?

Back 194

Three phosphate groups are transferred from three moles of ATP to mevalonate.

The purpose of the phosphate transfers is to activate both C5 and the hydroxyl group on C3 for further reactions.

First product is an activated isoprene called ∆3-isopentyl pyrophosphate

Second activated isoprene product is formed when ∆3-isopentyl pyrophosphate is isomerized to dimethylallyl pyrophosphate

Front 195

195. Stage 3

What is the end product of this stage?

Back 195

Involves the head-to-tail condensation of isopentenylpyrophosphate and dimethylallyl pyrophosphate to produce geranyl pyrophosphate

This product then undergoes another head-to-tail condensation resulting in farnesyl pyrophosphate.

Afterwards, two moles of this farnesyl undergo a head to head fusion and then both pyrophosphate groups are removed to form squalene.

Front 196

196. Squalene

Back 196

End product of stage 3

Contains 30 carbons (24 in the main chain and 6 in the methyl group branches)

Front 197

197. Stage 4

Back 197

Enzyme squalene monooxygenase added a single oxygen atom from O2 to the end of the squalene molecule, forming an epoxide.

NADPH then reduces the other oxygen atom of O2 to H2O.

The epoxide undergoes cyclization to form lanosterol, a sterol w/the four ring structure.

Many subsequent reactions then lead to cholesterol from lanosterol.

Front 198

198. Where does most of the production of cholesterol occur?

Where else does it occur?

Back 198

Liver cells

Also occurs int he gut, adrenal cortex, and the gonads (as well as the placenta in pregnant women)

Front 199

199. The bulk of synthesized cholesterol is secreted from the hepatocyte as one of what three moieties?

Back 199

1. Cholesterol esters
2. Biliary cholesterol
3. Bile acids

Front 200

200. ACAT (acyl-CoA-cholesterol acyl transferase)

Back 200

Catalyzes cholesterol ester production in the liver.

Catalyzes the transfer of a FA from CoA to the hydroxyl group on C3 of cholesterol.

Front 201

201. Low vs. high cholesterol diets

Back 201

Low: the liver synthesizes approx 800 mg cholesterol per day to replace bile salts and cholesterol lost in the feces

High: Suppresses the rate of hepatic cholesterol synthesis (feedback repression)

Front 202

202. Bile salt synthesis reactions

Back 202

Bile salts are synthesized in the liver from cholesterol by reactions that hydroxylate the steroid nucleus and cleave the side chain.

Front 203

203. Bile salt synthesis (First step)

What can inhibit this step?

Back 203

The first and rate-limiting reaction occurs when a α-hydroxyl group is added to C7.

The activity of the 7α-hydroxylase that catalyzes this step is decreased by an increase in bile salt concentration

Front 204

204. Bile salt synthesis (formation of two sets of bile salts)

Back 204

Two sets of compounds are produced;

One has α-hydroxyl groups at postions 3, 7, and 12 and produces the cholic acid series of bile salts

The other set has α-hydroxyl groups only at positions 3 and 7 and produces the chenocholic acid series.

Front 205

205. pKa of bile acids

Back 205

pKa = 6

In the intestinal lumen, which normally has a pH of 6, approx 50% of the molecules present are protonated and 50% are ionized, which form bile salts.

Front 206

206. Conjugation of bile salts

Back 206

The carboxyl group at the end of the side chain of the bile salts is activated by a reaction that requires ATP and CoA.

The CoA derivatives can react w/either glycine or taurine, forming amides that are known as conjugated bile salts.

Glycocholic acid and glycochenocholic acid are formed when salts conjugate w/glycine

Taurocholic acid and taurochenocholic acid are formed when salts conjugate w/glycine

Front 207

207. Glycine vs. taurine conjugation

How does this affect ionization?

Back 207

Glycocholic acid and glycochenocholic acid have a pKa of 4

Taurocholic acid and taurochenocholic acid have a pKa of 2

Therefore, compared w/glycoconjugates, an even greater percentage of the tauroconjugates are ionized in the lumen of the gut.

The lower the pKa, the better the detergent

Front 208

208. Breakdown of bile salts

Back 208

Intestinal bacteria deconjugate and dehydroxylate the bile salts, removing the glycine and taurine residues and the hydroxyl group at position 7.

These deconjugated and dehydroxylated bile salts are less soluble and therefore are less readily resorbed from the intestinal lumen.

Front 209

209. Secondary bile salts

Give an example of one...?

Back 209

Bile salts that lack a hydroxyl group at position 7 are called secondary bile salts.

Lithocholic acid is the least soluble bile salt; its major fate is excretion.

Front 210

210. Efficiency of enterohepatic circulation

Back 210

Less than 5% of the bile salts entering the gut are excreted in the feces each day.

Very efficient I would say...

Front 211

211. Three important functions of apoproteins...

Back 211

1. Add to the hydrophilicity and structural stability of the particle
2. Activate certain enzymes required for normal lipoprotein metabolism
3. Act as ligands on the surface of the lipoprotein that target specific receptors on peripheral tissues that require lipoprotein delivery for their innate cellular functions.

Front 212

212. Chylomicrons

Back 212

These are the largest of the lipoproteins and the least dense because of their rich TAG content.

They are synthesized from dietary lipids within the epithelial cells of the small intestine and then secreted into the lymphatics and bloodstream via the left subclavian vein.

Front 213

213. What are the major apoproteins of chylomicrons?

Back 213

1. ApoB-48
2. ApoC-II
3. ApoE

Front 214

214. ApoC-II

Back 214

Activates lipoprotein lipase which allows LPL to hydrolyze the chylomicrons, leading to the release of free FAs

Front 215

215. Chylomicron remnants

Back 215

The partially hydrolyzed chylomicrons remaining in the bloodstream, now partly depleted of their core TAGs, have lost their apoCII but still retain their ApoE and ApoB-48.

Receptors in the plasma membranes of the liver cells bind to ApoE on the surface of these remnants, allowing them to be taken up by the liver.

Front 216

216. Nascent VLDLs

Back 216

If dietary intake is in excess, the excess carbs are converted to TAGs, which, along w/free and esterified cholesterol, phospholipids, and ApoB-100 are packaged to form nascent VLDL

Front 217

217. Mature VLDLs

Back 217

The nascent VLDLs are secreted from the liver into the bloodstream, where they accept ApoCII and ApoE from circulating HDL particles

Front 218

218. VLDL remnants

Back 218

Approx 50% of these remnants are taken up from the blood by liver cells thru the binding of VLDL ApoE to the hepatocyte plasma membrane ApoE receptor, followed by endocytic internalization of the VLDL remnant.

Front 219

219. What happens to the other half of the VLDL remnants?

Back 219

he other half are into taken up by the liver but, instead, have additional core TAGs removed to form IDL.

Front 220

220. LDLs

Back 220

With the removal of addition TAGs from IDL thru hepatic TAG lipase within hepatic sinusoids, LDL is generated from IDL.

LDLs are rich in cholesterol and cholesterol esters.

Front 221

221. Transport of LDLs

Back 221

60% of the LDL is transported back to the liver, where its ApoB-100 binds to the liver cells.

The remaining 40% of LDLs are carried to extrahepatic tissues (i.e. adrenocortical and gonadal cells) that also have ApoB-100 receptors where they are internalized.

Front 222

222. What happens to excess LDLs in the blood?

Back 222

If the receptor mediated uptake system is saturated, the LDLs are now more readily available for non-specific uptake of LDL by macrophages (scavenger cells) present near the endothelial cells of artieries.

Possible explanation for the inflammatory response in atherosclerosis

Front 223

223. Synthesis of HDL (3 methods)

Back 223

1. Synthesis of nascent HDL by the liver and intestine
2. From budding of apoproteins from chylomicrons and VLDL particles as they are digested by LPL. The apoproteins and shells can then accumulate more lipid.
3. From free ApoAI, which may be shed from other circulating lipoproteins

Front 224

224. HDL composition

Back 224

Shells contains phospholipids, free cholesterol, and a variety of apoproteins, i.e. ApoAl, ApoAII, ApoCI, and ApoCII. Very low levels of TAGs or cholesterol esters are found in the hollow core.

Front 225

225. Maturation of nascent HDL

Back 225

Nacent HDL particles accumulate phospholipids and cholesterol from cells lining blood vessels.

As the central hollow core of nascent HDLs fills w/cholesterol esters, HDL takes on a more globular shape to eventually form the mature HDL particle

Does not require enzymatic activity.

Front 226

226. Reverse cholesterol transport

Back 226

HDL particles have the ability to remove cholesterol from cholesterol-laden cells and to return the cholesterol to the liver.

Requires a directional movement of cholesterol from the cell to the lipoprotein particles. This is done via ABC1

Front 227

227. ABC1

Back 227

Uses ATP hydrolysis to move cholesterol from inner leaflet of the membrane to the outer leaflet.

Once moved to the outer membrane, the HDL particle can accept it, but if the cholesterol is not modified within the HDL particle, the cholesterol can leave by the same route it entered.

Front 228

228. How is the cholesterol trapped/modified in the HDL particle?

Back 228

The HDL particle acquires the enzyme LCAT from the circulation

LCAT transfers a FA to form a cholesterol ester which migrates to the core of the HDL particle and is no longer free to return to the cell.

Front 229

229. Mutations in the ATP-binding cassette 1 protein

Back 229

Include familial HDL deficiency and Tangier disease.

Cholesterol depleted HDL cannot transport free cholesterol from cells that lack the ability to express this protein.

As a consequence, HDL is rapidly degraded.

Front 230

230. Clearance of HDL

Back 230

Can bind to hepatocytes but the primary means is thru its uptake by the scavenger receptor SR-B1.

Once bound to the receptor, its cholesterol and cholesterol esters are transferred into the cells.

Without the cholesterol and its esters, the HDL particle dissociates form the SR-B1 receptor and reenters circulation.

Front 231

231. What else does HDL do?

Back 231

Exchanges apoproteins and lipids w/other lipoproteins in the blood via CETP

Front 232

232. CEPT (cholesterol ester transfer protein)

Back 232

HDL can transport cholesterol esters and free cholesterol to circulating TAG rich lipoproteins such as VLDL and VLDL remnants.

In exchange, TAGs from the latter lipoproteins are transferred to HDL.

The greater the concentration of TAG rich lipoproteins int eh blood, the greater will be the rate of these exchanges.

Front 233

233. How do lipoproteins enter cells?

Back 233

Via receptor mediated endocytosis

Front 234

234. Structure of the LDL receptor

What are the six regions?

Back 234

1. LDL binding domain
2. EGF like domain/Transducin-beta subunit-like domain
3. N-linked oligosaccharide domain
4. O-linked oligosaccharide domain
5. Transmembrane domain
6. Intracellular domain

Front 235

235. Four classes of mutations involving LDL receptors

Back 235

1. Null alleles that either direct the synthesis of no protein at all or a protein that cannot be precipitated by antibodies to the LDL receptor.
2. The alleles encode proteins, but they cannot be transported to the cell surface.
3. Encodes proteins that reach the cell surface but cannot bind LDL normally.
4. Encodes proteins that reach the surface and bind LDL but fail to cluster and internalize the LDL particles

End result is accumulation of LDL in the blood b/c cells cannot take up these particles at a normal rate.

Front 236

236. LDL receptor-related protein (LRP)

Back 236

Structurally related ot the LDL receptor but recognizes a broader spectrum of ligands.

In addition to lipoproteins, it binds the blood proteins alpha-2-macroglobulin and tPA and its inhibitors.

Also recognizes the ApoE of lipoproteins and binds remnants of produced by the digestion of teh triacylglycerols of chylomicrons and VLDL by LPL

Thus one of its functions is believed to be clearing these remnants from the blood.

Front 237

237. Locations of LRP

Back 237

Abundant in the cell membranes of the liver, brain, and placenta. In contrast to the LDL receptor, synthesis of the LRP receptor is not significantly affected by an increase in the intracellular concentration of cholesterol.

However, insulin causes the # of these receptors on the cell surface to increase.

Front 238

238. Macrophage scavenger receptor

Back 238

Variety of these receptors.

SR-B1 is used primarily for HDL binding, whereas the scavenger receptors expressed on macrophases are SR-A1 and SR-A2.

Modification of LDL freq involves oxidative damage, so these receptors allow the cells to take up damaged LDL long after intracellular cholesterol levels are elevated.

Front 239

239. Layers of the artery from the inside out (6 layers)

Back 239

1. Intima
2. Subintimal ECM
3. Tunica media
4. Internal elastic lamina
5. External elastic lamina
6. Adventitia

Front 240

240. Cholesterol is the precursor of what five classes of steroid hormones?

Back 240

1. Glucocorticoids
2. Mineralcorticoids
3. Androgens
4. Estrogens
5. Progestins

Front 241

241. Synthesis of cortisol vs. aldosterone vs. adrenal androgens vs. testosterone

Where does this take place?

Back 241

Cortisol: zona fasciculata

Aldosterone: zona glomerulosa

Adrenal androgens: zona reticulosum

Testosterone: Leydig cells in testes

Front 242

242. CAH

What are the three types?

Back 242

Most common deficiency is that of 21-α-hydroxylase, the activity of which is necessary to convert progesterone to 11-deoxycorticosterone and 17-α-hydroxy progesterone to 11-deoxycortisol. Reduces both cortisol and aldosterone production without affecting androgen production. If the enzyme deficiency is severe, it leads to an overabundance of androgens.

Can also involve deficiency in 11-β-hydroxylase, which results in the accumulation of 11-deoxycorticosterone. Causes hypertension May increase levels of adrenal androgens int eh blood.

Can also involve 17-α-hydroxylase deficiency which leads to an increase in aldosterone excess and hypertension but no virilization.

Front 243

243. DOC (Deoxycorticosterone)

Back 243

Although aldosterone is the major mineralocorticoid in humans, excessive production of a weaker mineralocorticoid, DOC, which occurs in patients w/a deficiency of the 11-hydroxylase may lead to clinical signs and symptoms of mineralocorticoid excess even though aldosterone secretion is suppressed in these patients.

Front 244

244. DHEAS

Back 244

The serum concentration of the stable metabolite of DHEA is used as a measure of adrenal androgen production in hyperadrogenic patients w/diffuse excessive growth of secondary sexual hair.

Front 245

245. Rickets

Back 245

A disorder of young children caused by a deficiency of vitamin D. Low levels of calcium and phosphorus in the blood are associated w/skeletal deformities in these children.

Front 246

246. Primary hypercholesterolemia

Back 246

Characterized by elevated levels of plasma cholesterol and LDL cholesterol, with normal levels of triglycerides.

Front 247

247. Causes of primary hypercholesterolemia

Back 247

1. Familial hypercholesterolemia
2. Familial defective apoB100
3. Polygenic hypercholesterolemia

Front 248

248. Clinical features of familial hypercholesterolemia (heterozygous)

Back 248

1. High total plasma cholesterol concentrations
2. Tendon xanthomas
3. Arcus corneae (deposition of cholesterol in the cornea)

Front 249

249. Clinical features of familial hypercholesterolemia (homozygous)

Back 249

1. Very high total plasma cholesterol concentrations
2. Cardiovascular disease presents prior to age 20
3. Tendon xanthomas
4. Arcus corneae (deposition of cholesterol in the cornea)

Front 250

250. Inhibitors of cholesterol synthesis (statins)

How do they work?

Back 250

HMG CoA reductase inhibitors competetively inhibit the activity of HMG CoA reductase, the rate-limiting enzyme in cholesterol synthesis.

This decreases the cellular cholesterol concentration which activates a cellular signaling cascade culminating in the activation of SREBP2, which up-regulates the expression of the gene encoding the LDL receptor.

Increased LDL receptor expression causes increased uptake of plasma LDL and thus decreases plasma LDL cholesterol concentration.

Front 251

251. What are the therapeutic benefits of statins?

AKA "pleiotropic effects of statins"

Back 251

1. Plaque stabilization
2. Improvement of coronary endothelial function via improved response to endothelial NO
3. Inhibition of platelet thrombus formation
4. Anti-inflammatory function

Front 252

252. What are statins used to treat?

Back 252

Effective in lowering plasma cholesterol levels in all types of hyperlipidemias, except homozygous familial hypercholesterolemia

Front 253

253. Dose-response relationship of statins

Back 253

Non-linear; the largest effect occurs w/the starting dose.

Each subsequent doubling of the dose produces, on average, an additional 6% LDL reduction. This is sometimes referred to as the "rule of 6's"

Front 254

254. What are the six statins?

Back 254

1. Lovastatin
2. Pravastatin
3. Simvastatin
4. Fluvastatin
5. Atorvastatin
6. Rosuvastatin

Front 255

255. Pharmacokinetics of statins

Back 255

Pravastatin and fluvastatin are almost completely absorbed after oral admin

Oral does of lavastatin and simvastatin are absorbed from 30-50% but they are active as such.

Lovastatin and simvastatin must be hydrolyzed to their acid forms first.

Primary action of these drugs is on the liver via first pass extraction

Excretion takes place thru the bile and feces.

Front 256

256. Potency of the statins

Back 256

Atorvastatin and rosuvastatin are the most potent.

Fluvastatin is the least potent.

Front 257

257. Metabolism of the statins

Back 257

Lovasatin, simvastatin, and atorvastatin are metabolized by p450 3A4

Other p450 mediated pathways metabolize fluvastatin.

Pravastatin and rosuvastatin are not metabolized via the cytochrom p450 pathway.

Front 258

258. Adverse effects of statins on liver

Back 258

High potency statins can cause elevations in ALT and AST levels but these are rarely indicative of hepatotoxicity, and most likely reflect an adaptive response of liver to changes in cholesterol homeostasis.

Front 259

259. Adverse effects of statins on muscle

Back 259

Myopathy and/or myositis with rhabdomyolysis (disintegration or dissolution of muscle) have been reported.

Plasma creatine kinase levels are not useful for routine monitoring of statin-treated patients.

Front 260

260. Drug interactions with statins

Back 260

They increase warfarin levels.

Thus, it is important to evaluate PT times frequently.

Consider choosing a statin not metabolized via p450s in patients who are currently taking drugs metabolized by p450s.

Front 261

261. Contraindications of statins

Back 261

Pregancy and nursing mothers

and

Acute liver disease

Front 262

262. Inhibitors of bile acid absorption

How do they work?

Back 262

They are anion exchange resins that bind negatively charged bile acids and bile salts in the small intestine.

The resin/bile acid complex is excreted in the feces, thus preventing the bile acids form returning to the liver via enterohepatic circulation.

Lower the bile acid concentration causes hepatocytes to increase conversion of cholesterol to bile acids via up regulation of 7α-hydroylase, the rate-limiting enzyme in bile acid synthesis.

This results in a decreased intracellular cholesterol concentration, which activates an increased hepatic uptake of cholesterol-containing LDL particles, leading to a fall in plasma LDL.

Front 263

263. What are these inhibitors of bile acid absorption used for?

Back 263

1. Hypercholesterolemia (Type II hyperlipidemias)
2. Pruritus caused by accumulation of bile acids in patients w/biliary obstruction (cholestyramine only)

Used to decrease LDL levels

Front 264

264. What the the inhibitors of bile acid absorption?

Back 264

1. Cholestyramine
2. Colestipol
3. Colesevalam

Front 265

265. Phamacokinetics of inhibitors of bile acid absorption

Back 265

Cholestyramine, colestipol and colesevalam are taken orally.

They are insoluble in water and are very large; thus they are neither absorbed nor metabolically altered by the intestine.

In order to maximize the binding of these agents to bile acids, drug administration is timed so that the drugs are present in the small intestine following a meal.

Front 266

266. Adverse effects of inhibitors of bile acid absorption

Back 266

GI: Constipation, nausea, bloating, and dyspepsia

Impaired absorptions: at high doses, cholestyramine and colesevalam impair the absorption of the fat-soluble vitamins, and thus can cause a vitamin k deficiency.

Front 267

267. Drug interactions of inhibitors of bile acid absorption

Back 267

Cholestyramine and colestipol interfere with the intestinal absorption of many drugs, i.e. tetracycline, phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin, and tiazide diuretics.

Therefore, drugs should be taken at least one hour the bile acid binding resins

Front 268

268. Contraindications of inhibitors of bile acid absorption

Back 268

1. Complete biliary obstruction
2. Hyperlipidemia types III, IV, or V (hypertriglyceridemia)

Front 269

269. Other uses for inhibitors of bile acid absorption?

Back 269

Second line agents for lipid reduction; used mainly to treat hypercholesterolemia in young patients and patients for whom statins alone do not provided sufficient LDL reduction.

Front 270

270. Inhibitors of cholesterol absorption

How do they work?

Back 270

Ezetimibe selectively inhibits intestinal absorption of dietary and biliary cholesterol in the small intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver.

It does this by inhibiting its uptake thru the brush border protein NPC1L1.

This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood.

It lowers LDL cholesterol by 17% and TAGs by 6% and increases the HDL by 1.3%.

Front 271

271. Metabolism of ezetimibe

Back 271

Rapidly metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion.

Levels are increased w/coadministation of cyclosporine and fibrates.

Front 272

272. What is ezetimibe used to treat?

Back 272

1. Primary hypercholesterolemia
2. Familial hypercholesterolemia
3. Sitosterolemia

Front 273

273. Adverse effects of ezetimibe

Back 273

Elevated liver function tests, myopathy, dyspepsia, arthralgia, myalgia, and headache

Front 274

274. Contraindications of ezetimibe

Back 274

Acute liver disease

Persistently elevated liver function tests when coadministered w/a statin

Front 275

275. Fibrates

How do they work?

Back 275

Agonists of peroxisome proliferator-activated receptor α(PPARα).

PPARα functions as a ligand-activated transcription factor. Upon binding to its natural ligan or hypolipidemic drugs, PPARs are activated.

PPAR regulates the expression of genes encoding for proteins involved in lipoprotein structure and function.

Fibrate mediated gene expression leads to decreased TAGs by increasing the expression of LPL and decreasing ApoCII concentration.

Also increases the levels of HDL via increasing the expression of ApoAI and ApoAII.

Front 276

276. What are fibrates used to treat?

Back 276

Hypertriglyceridemias:

1. Isolated hypertriglyceridemia
2. Hypertriglyceridemia w/low HDL
3. Type III dysbetalipoproteinemia

Front 277

277. What the names of the fibrates?

Back 277

1. Fenofibrate
2. Gemfibrozil

Front 278

278. Pharmacokinetics of fibrates

Back 278

Both drugs are absorbed completely after an oral does.

Distributed widely, bound to albumin.

Excreted in the urine as their glucuronide conjugates

Front 279

279. Adverse effects of fibrates

Back 279

Elevated liver function tests, myopathy when coadministered with a stain, arrhythmias

Also, dyspepsia, myalgia, gallstones, and xerostomia (dry mouth)

*Fenofibrate has fewer GI and myopathy adverse effects than gemfibrozil

Front 280

280. Drug interactions with fibrates

Back 280

Both fibrates compete with the coumarin anticoagulants for binding sites on plasma proteins, thus transiently potentiating anticoagulant activity.

These drugs may increase the clearance of cyclosporine.

Front 281

281. Contraindications of fibrates

Back 281

1. Concomitant gemfibrozil and cerivastatin administration
2. Preexisting gallbladder disease
3. Hepatic dysfunction
4. Severe renal impairment

*Safety of these agents in pregnant or lactating women has not been established.

Front 282

282. Niacin

Back 282

Niacin can reduce LDL and is the most effective agent for increasing HDL levels. Can be used in combo with statins.

Front 283

283. How does niacin work?

Back 283

It reduces free fatty acid release from adipose tissue (lypolysis) and increases plasma residence time for ApoAI

Also causes a decrease in liver TAG synthesis, which is required for VLDL production. LDL is derived from VLDL in the plasma and thus the reason for the subsequent decrease in LDL.

Front 284

284. Therapeutic uses for niacin

Back 284

1. Isolated low HDL
2. Low HDL w/mildly elevated LDL or TAGs
3. Familial combined hyperlipidemia

Front 285

285. Adverse effects of niacin

Back 285

Hepatotoxicity, GI bleeding, flushing, pruritus, hyperuricemia, and gout, impaired insulin sensitivity, myopathy

Front 286

286. Contraindications of niacin

Back 286

1. Active liver disease
2. Active peptic ulcer
3. Arterial bleeding

Front 287

287. Pharmacokinetics of niacin

Back 287

Administered orally; it is converted in the body to nicotinamide, which is incorporated into the cofactor NAD+.

Excreted in the urine.

Front 288

288. How can the flushing caused by niacin be prevented in the early stages of treatment?

Back 288

Pretreatment with aspirin

Front 289

289. Ischemic heart disease (IHD)

The clinical manifestations of IHD can be divided into what four syndromes?

Back 289

Group of closely related syndromes resulting from myocardial ischemia; an imbalance between the supply (perfusion) and demand of the heart for oxygenated blood.

Can be divided into four syndromes:
1. Myocardial infarction
2. Angina pectoris
3. Chronic IHD w/heart failure
4. Sudden cardiac death

Front 290

290. What is the cause of myocardial ischemia in more than 90% of cases?

Back 290

Reduction in coronary blood flow due to atherosclerotic coronary arterial obstruction.

In most cases, there is a long period of silent, slowly progressive coronary atherosclerosis before these disorders become manifest.

Thus, IHD is often termed CAD or coronary heart disease

Front 291

291. What three conditions aggravate ischemia?

Back 291

1. Increases in cardiac energy demand (hypertrophy)

2. Diminished availability of blood or O2 due to lowered systemic blood pressure (shock or hypoxemia)

3. Increased heart rate which decreases coronary blood supply.

Front 292

292. The risk of developing detectable IHD depends on what?

Back 292

Regarding atheromatous plaques:
1. Number
2. Distribution
3. Structure
4. Degree of narrowing they cause

Front 293

293. Epidemiology of IHD

Back 293

Leading cause of death for both males and females int he US and other industrialized nations

Nearly 500,000 Americans dies of IHD each year

However, the death rate has fallen in the US by approx 50% since 1963

Front 294

294. Why the 50% fall in IHD death rate since 1963?

Back 294

1. Prevention achieved by modification of determinants of risk, such as smoking, elevated blood cholesterol, hypertension, and a sedentary lifestyle

2. Diagnostic and therapeutic advances, allowing earlier, more effective, and safer treatments.

Front 295

295. Pathogenesis of IHD

Back 295

The dominant influence in the causation of the IHD syndromes is diminished coronary perfusion relative to myocardial demand, owing largely to a complex and dynamic interaction among fixed atherosclerotic narrowing of the epicardial coronary arteries, intraluminal thrombosis overlying a disrupted atherosclerotic plaque, platelet aggregation, and vasospasm.

Front 296

296. Causes of coronary atherosclerosis

What degrees of stenosis are associated w/clinical symptoms?

Back 296

Clinical manifestations are generally due to progressive encroachment of the lumen leading to stenosis or to acute plaque disruption w/thrombosis which compromises blood flow.

Obstructive lesion of 75% or greater generally causes symptomatic ischemia induced by exercise

90% stenosis can lead to inadequate coronary blood flow, even at rest.

Front 297

297. Common locations of stenosing plaques

Back 297

Can happen anywhere but tend to predominate within:

1. First several cm of the LAD and LCX
2. Along entire length of RCA

Front 298

298. Role of acute plaque change

Back 298

In most patients, myocardial ischemia underlying unstable angina, acute MI, and sudden cardiac death is precipitated by abrupt plaque change followed by thrombosis.

Often, the initiating event is disruption of a previously only partially stenosing plaque w/any of the following:
1. Rupture/fissuring
2. Erosion/ulceration
3. Hemorrhage into the atheroma

Front 299

299. What are vulnerable plaques?

Back 299

Plaques that contain large areas of foam cells and extracellular lipids and those in which the fibrous caps are thin or contain few smooth muscle cells or have clusters of inflammatory cells.

These plaques are most likely to rupture.

Front 300

300. Strength of the fibrous caps

Back 300

The fibrous cap undergoes continuous remodeling; balance of synthetic and degradative activity of collagen, the major structural component of the fibrous cap accounts for its mechanical strength and determines plaque stability and prognosis

Front 301

301. Collagen found in fibrous caps of plaques comes from where and how is it degraded?

Back 301

Is produced by smooth muscle cells and degraded by action of metalloproteinases.

Metalloproteinases are elaborated by macrophages and atheroma.

Front 302

302. Adrenergic stimulation and correlations between timing of MI's

Back 302

Can elevate physical stresses on the plaque thru systemic hypertension or local vasospasm.

This is the reason why most MI's occur in the morning; due to the extra sympathetic stimulation upon awakening.

Front 303

303. What degree of stenosis is most commonly associated w/plaque disruption?

Back 303

50% or less

Front 304

304. What are four indications of inflammation associated w/plaque disruption?

Back 304

1. Increased adhesion proteins expressed in endothelial cells
2. Accumulation of T cells and macrophages in arterial wall
3. Presence of cytokines (TNF, IL-6, and IFN-γ)
4. High levels of metalloproteinases

Front 305

305. C-reactive protein (CRP)

Back 305

Acute phase reactant made in the liver that has been suggested as a predictor of risk of coronary heart disease

Front 306

306. Mural thrombus

Back 306

Incomplete thrombus; may wax and wane with time.

Can embolize from a coronary artery; it is a potent activator of multiple growth related signals in smooth muscle cells which can contribute to the growth of atherosclerotic lesions.

Front 307

307. What four vasoconstrictive things can contribute to plaque disruption?

Back 307

Compromises lumen size and by increasing local mechanical forces; can potentiate plaque disruption stimulated by:

1. Circulating adrenergic agonists
2. Locally released platelet contents
3. Impaired secretion of endothelial cell relaxing factors relative to contractive factors due to atheroma associated endothelial dysfunction
4. Mediates released from perivascular inflammatory cells.

Front 308

308. Stable angina

Back 308

Results from increases in Mvo2 that outstrip the ability of markedly stenosed coronary arteries to increase O2 deliver but is not usually associated with plaque disruption.

Front 309

309. Unstable angina

Back 309

Derives from sudden change in plaque morphology; which induces partially occlusive platelet aggregation or mural thrombus and vasoconstriction leading to severe but transient reductions in coronary blood flow.

Front 310

310. Sudden cardiac death

Back 310

Frequently involves a coronary lesion in which disrupted plaque and often partial thrombus and possible embolus have led to regional myocardial ischemia that induces a fatal ventricular arrhythmia.

Front 311

311. Angina pectoris

Back 311

Symptom complex of ischemic heart disease characterized by paroxysmal and usually recurrent attacks usually of substernal or precordial chest discomfort (described as constricting, squeezing, choking, or knifelike)

Caused by transient myocardial ischemia that falls short of inducing cellular necrosis but defines MI.

Front 312

312. Three overlapping patterns of angina pectoris

What are they caused by?

Back 312

1. Stable or typical angina
2. Prinzmetal's or variant angina
3. Unstable or crescendo angina

Caused by varying combos of increased myocardial demand and decreased myocardial perfusion owing to fixed stenosing plaques, disrupted plaques, vasospasms, thrombosis, platelet aggregation, and embolization.

Front 313

313. Stable angina

Back 313

AKA typical angina pectoris b/c it is the most common form.

It is caused by reduction of coronary blood perfusion to a critical level by chronic stenosing, coronary atherosclerosis.

It is usually relieved by rest or nitro

Also, local vasospasm may contribute to imbalance between supply and demand.

Front 314

314. Prinzmetal's variant angina

Back 314

Uncommon pattern of episodic angina that occurs at rest and is due to coronary artery spasm.

Usually have elevated ST segment indicative of transmural ischemia

Anginal attacks are unrelated to physical activity, HR, or BP

Treatment includes nitro and calcium channel blockers.

Front 315

315. Crescendo or unstable angina

Back 315

Pattern of pain that occurs w/progressively increasing frequency.

Is precipitated w/progressively less effort, often occurs at rest, and tends to be of more prolonged duration.

It is sometimes referred to as "pre-infarction" angina

Front 316

316. Transmural MI

Back 316

Most MI's are of this type; ischemic necrosis involves the full or nearly full thickness of the ventricular wall and the distribution of a single coronary artery.

Usually associated w/coronary atherosclerosis, acute plaque change, and superimposed thrombosis

Front 317

317. Subendocardial MI (AKA non-transmural MI)

Back 317

Area of ischemic necrosis limited to inner 1/3 or at most 1/2 of ventricular wall.

Under some circumstances it may extend laterally beyond the perfusion territory of a single coronary artery.

It can occur as a result of plaque disruption, followed by coronary thrombus that becomes lysed before myocardial necrosis extends across the major thickness of the wall.

Can also result from sufficiently prolonged and severe reduction in systemic BP

Front 318

318. Incidence and risk factors of MI

Back 318

Can occur at any age but freq arises w/increasing age w/predispositions to atherosclerosis (hyeprtension, smoking, diabetes, hypercholesterolemia, and hyperlipoprotenia)

Men have increased risk compared to women but this difference declines w/advancing age

Decreasing estrogen in women following menopause (HRT does not protect against MI)

Front 319

319. Sequence of event in typical MI

(Five of them)

Back 319

1. Initial event is sudden change in the morphology of atheromatous plaque
2. Platelets undergo adhesion, aggregation, activation, and release of potent aggregators
3. Vasospasm stimulated by platelet aggregation and release of mediators
4. Other mediators activate extrinsic pathway of coagulation, adding to bulk of thrombus
5. Thrombus evolves to completely occlude the lumen of coronary vessel

Front 320

320. Associated mechanisms in acute transmural MI that are not associated w/plaque thrombus

Back 320

1. Vasospasm
2. Emboli from left atrium associated w/atrial fibrillation
3. Unexplained

Front 321

321. Three myocardial responses to MI

Back 321

1. Biochemical
-cessation of aerobic glycolysis within seconds leading to inadequate production of high energy phosphates and accumulation of breakdown products

2. Functional
-Myocardial function is extremely sensitive to severe ischemia; loss of contractility occurs w/in 60 s of onset

3. Ultrastructural changes
-Myofibrillar relaxation, glycogen depletion, cell and mitochondrial swelling

Early changes are potentially reversible

Front 322

322. Prominent mechanism of cell death following MI

Back 322

Coagulative necrosis

Apoptosis may also be important but are uncertain about this.

Necrosis begins approx 30 min after coronary occlusion

If restoration of blood flow (reperfusion) follows briefer periods of blood interruption (<20min) loss of cell viability can be prevented.

Front 323

323. Irreversible injury of ischemic myocytes

Back 323

First occurs in subendocardial zone; with this extended ischemia, a wave front of cell death moves thru the myocardium to involve progressively more of the transmural thickness of the ischemic zone.

Front 324

324. Factors that determine location, size, and morphological features of acute MI

Seven of them...

Back 324

1. Location, severity, and rate of devel of coronary atherosclerotic obstruction
2. The size of the vascular bed perfused by the obstructed vessel
3. Duration of the occlusion
4. Metabolic/oxygen needs of myocardium at risk
5. Extent of collateral blood vessels
6. Presence, site and severity of coronary arterial spasm
7. Other factors such as alterations in blood pressure, HR, and cardiac rhythm

Front 325

325. Infarct modification by reperfusion

Back 325

Best accomplished by restoration of coronary blood flow via thrombolysis, balloon angioplasty, or coronary artery bypass graft.

Front 326

326. Compare and contrast reperfusion therapies

Back 326

Thrombolysis can remove thrombus occluding CA, but does not significantly alter underlying disrupted atherosclerotic plaque that initiated it

PTCA eliminates thrombotic occlusion and can relieve some of the original obstruction caused by plaque

CABG provides flow around the obstruction

Front 327

327. Contraction bands

Back 327

Visible on microscopic exam of post MI myocardium

Are intensely eosinophilic transverse bands composed of closely packed hypercontracted sarcomeres most likely produced by exaggerated contraction of myofibrils at the instant perfusion is re-established at which time internal portions of an already dead cell w/damaged membranes are exposed to high concentration of calcium ions from plasma.

Front 328

328. Clinical features of MI

Four...

Back 328

Diagnosed by typical symptoms, biochemical evidence and ECG pattern

1. Rapid weak pulse and often profuse sweating
2. Dyspnea due to impaired contractility of ischemic myocardium
3. Q waves post MI
4. Increased blood concentrations of myoglobin, cardiac troponins T and I, creatine kinase, lactate dehydrogenase, and many others

Front 329

329. Changes in biochemical markers with MI

Back 329

Rise in CK-MB 2-4 hrs after onset of MI; peaks at about 24 hrs and returns to normal w/in approx 72 hrs.

Troponin levels are elevated for approx 10 days after MI

Front 330

330. Consequences and or complications of MI

Back 330

1. Contractile dysfunction
2. Arrythmias
3. Myocardial rupture
4. Pericarditis
5. Right ventricular infarction
6. Infarct extension
7. Infarct expansion
8. Mural thrombus
9. Ventricular aneurysm
10. Papillary muscle dysfunction
11. Progressive right heart failure

Front 331

331. Anterior vs. Posterior infarcts

Which one has a worse prognosis?

Back 331

Patients w/anterior infarcts have substantially worse prognosis than those w/posterior infarcts

Front 332

332. Ventricular remodeling

Back 332

Both necrotic zone and non-infarcted segments of the ventricle undergo progressive changes in size, shape, and thickness comprising early wall thinning, healing, hypertrophy and dilation, and late aneurysm formation

Front 333

333. Chronic ischemic heart disease

Back 333

AKA ischemic cardiomyopathy

Usually constitutes post infarction cardiac decomp owing to exhaustion of the compensatory hypertrophy of non-infarcted viable myocardium that is itself in jeopardy of ischemic injury

Dx rests largely on exclusion of other forms of cardiac involvement

Front 334

334. Sudden cardiac death

What are eight the non-atherosclerotic causes?

Back 334

Often a complication and first clinical manifestation of ischemic heart disease

With decreasing age of victim, the following non-atherosclerotic causes become increasingly possible:
1. Congenital/structural or coronary arterial abnormalities
2. Aortic valve stenosis
3. Mitral valve prolapse
4. Myocarditis
5. Dilated or hypertrophic cardiomyopathy
6. Pulmonary hypertension
7. Hereditary or acquired abnormalities of cardiac conduction system
8. Isolated hypertrophy, hypertensive, or unknown cardiac event

Front 335

335. Ultimate mechanism of sudden cardiac death

Back 335

Lethal arrythmia, although ischemic injury can impinge upon the conduction system and create electrocardiac instability

In most cases, fatal arrythmia is triggered by electrical irritability of myocardium that may be distant from the conduction system induced by ischemia or other cellular induced abnormalities

Front 336

336. Romano-Ward syndrome

Back 336

Autosomal dominant; long Q-T syndrome which causes heightened cardiac excitability and episodic ventricular arrythmias

Front 337

337. Systemic hypertensive heart disease

Involves which side of the heart?

What are the minimal criteria for Dx?

Back 337

Left sided; minimal criteria for Dx:
1. Left ventricular hypertrophy in absence of other cardiovascular pathology that might have induced it
2. History of pathological evidence of hypertension

Front 338

338. Compensated hypertensive heart disease

Back 338

May be asymptomatic and suspected only in the appropriate clinical setting by ECG or echocardiographic indications of left ventricular enlargement

Other causes for such hypertrophy must be excluded

Front 339

339. Cor pulmonale

Left or right sided?

Back 339

AKA pulmonary hypertensive heart disease

Consists of right ventricular hypertrophy, dilation, and potentially failure secondary to pulmonary hypertension caused by disorders of the lungs or pulmonary vasculature

Right sided counterpart of systemic hypertensive heart disease

May be acute or chronic depending on suddenness of development of hypertension

Front 340

340. Acute cor pulmonale

and

Chronic cor pulmonale

Back 340

Acute:
Follows massive pulmonary embolism

Chronic:
Usually implies right ventricular hypertrophy secondary to prolonged pressure overload caused by obstruction of the pulmonary arteries or arterioles or compression or obliteration of septal capillaries