Cardio Exam 2 Part 2

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1

What effect do diuretics have on blood volume?

Diuretics decrease blood volume (make you urinate/ lose water)

2

In regards to Diuretics, why is there an increase in renin in the body?

Diuretics decrease BV resulting in an increase in renin and an increase in RAAS

3

As blood volume increases, does arterial pressure increase or decrease?

increase

4

True or False: An increase in arterial pressure causes the kidneys to lose Na+ and water which returns extracellular fluid volume to normal.

True

5

Increased pressure causes excretion of water relates to what?

Pressure diuresis

6

Increased pressure causes excretion of salt refers to what?

Pressure natriuresis

7

What is where water and salt intake = renal water and salt output?

Equilibrium point

8

Increased renal output is related to what effects?

hemodynamic and hormonal

9

Where is the site of action for thiazide diuretics/ Na+ channel inhibitors?

Distal convoluted tubule

10

Where is the site of action for loop diuretics?

ascending loop

11

Where is the site of action for aldosterone antagonists?

Collecting tubules and ducts

12

67% of Na+ reabsorption occurs where?

Proximal convoluted tubule

13

25% of Na+ reabsorption occurs where?

ascending limb of loop of Henle

14

5% of Na+ reabsorption occurs where?

distal convoluted tubule and cortical collecting tubule

15

3% of Na+ reabsorption occurs where?

cortical collecting duct

16

Which cells are located along the collecting ducts?

  • principal
  • intercalated
17

Which cells are more prevalent along the collecting ducts?

  • Principal
18

What is the function of the principal cells?

  • Na+/ H2O balance
19

What is the function of the intercalated cells?

  • Acid/Base balance
20

What are the 2 sides to the early distal convoluted tubule cells?

  1. apical side
  2. basolateral side
21

The mitochondria of the distal convoluted tubule cells are located on which side?

basolateral side

22

Which major heart arteries supply oxygenated blood to the heart?

  • Left Main coronary (LM)
  • Right coronary (RA)
23

Most of the coronary oxygenated blood flow occurs during what?

diastole

24

What is the outermost layer of the arterial wall?

Adventitia

25

What is the middle layer of the arterial wall?

Media (contains smooth muscle cells)

26

What is the innermost layer of the arterial wall?

intima

27

The resistance to blood flow is a fluid dynamic concept proportional to which three general factors?

  • Vessel length
  • Vessel Radius
  • Blood viscosity
28

Perfusion of the heart occurs during what?

diastole

29

What is the myocardial oxygen consumption essentially?

The greater the demand for O2 in the heart, the greater the coronary blood flow.

30

Hardening or thickening of arterial walls due to fatty deposits on the intima, calcification, and/or chronically elevated hypertension is known as what?

Arteriosclerosis

31

Thickening of the walls of arterioles is known as what?

Arteriolosclerosis

32

A specific form of arteriosclerosis where the inner lining of the walls of arteries develop plaques is known as what?

Atherosclerosis

33

Which 3 competing theories explain atherosclerosis?

  • Inflammatory hypothesis
  • Cholesterol hypothesis
  • Senescence hypothesis
34

What is being described?

  • Results clearly indicated a correlation between coronary artery disease (CAD) risk with blood cholesterol levels. The role of LDL in the pathophysiology of atherosclerosis has been clearly demonstrated. The use of LDL-lowering agents (e.g., statins in particular) has significantly lowered CAD risk.

Framingham Heart Study

35

List the steps involved with the evolution of atherosclerotic plaque:

1. Accumulation of lipoproteins in the intima.

2. Oxidative stress results in cytokine elaboration.

3. Expression of adhesion molecules that bind leukocytes and chemoattractant molecules.

4. Blood myocytes encounter stimuli that augment their expression of scavenger receptors.

5. The scavenger receptors mediate the uptake of modified Low density lipid (mLDL) particles, which then develop into foam cells.

6. Intimal thickness increase because of muscle cell migration into the intima.

7. Smooth muscles divide and proliferate resulting with increased plaque formation.

8. Calcification can occur with cell death that contributes to the acellular fibrous capsule with a lipid-rich core.

36

What are the risk factors for atherosclerosis?

  • Gender
  • Genetics/family history
  • Obesity
  • Smoking
  • Increased levels of LDL or triglycerides
  • Decreased levels of HDL
  • Homocysteine
  • Saturated fat and trans fatty acid intake
  • Lack of exercise
  • Other diseases (e.g., diabetes, hypertension)
37

List the summary stages of atherosclerotic lesions:

  • Vascular endothelium is damaged or modified.
  • LDL enters into the intima tissues of dysfunctional vascular endothelium.
  • LDL is modified by macrophages.
  • Macrophages take up the modified LDL. This process continues because there is no negative feedback mechanism available.
  • Foam cells rupture and provide cholesterol, which forms crystalline deposits and inflammatory responses.
  • Additional macrophages are introduced.
  • Macrophages secret growth factors that stimulate proliferation and movement of smooth muscle cells that increases the intimal thickness and forms the atherosclerotic lesion.
  • Calcification occurs in later stages.
  • Lipoprotein (a) interrupts the plasminogen → plasmin conversion.
  • Thrombocytes and plasmatic coagulation factors can be activated.
38

Describe perutaneous myocardial intervention:

  • Narrowed targeted area (stenosis) is due to the accumulation of plaque
  • A balloon catheter with a stent is threaded to the targeted (narrow) area
  • Balloon is inflated to open up the narrowed site and push the plaque back into the walls.
  • The catheter is removed leaving the stent in place.
39

What is the rate limiting step for cholesterol formation?

HMG-CoA reductase

40

What is the defining feature of looking at an LDL particle?

ApoB-100

41

The following quote is from what?

  • “Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering.”

Cantos Clinical Trial

42

Fatty acids are formed via which rxn?

Esterification

43

The structure of cholesterol has 4 rings that have what kind of junction?

trans ring junction

44

The substituents of a cholesterol molecule have what kind of stereochemistry?

beta (substituents pointed towards you)

45

Cholesterol leads to the formation of what?

bile acids

46

Bile acids assist in what?

digestion

47

Which enzyme introduces a hydroxyl group onto cholesterol?

7 alpha-hydroxylase

48

Bile acids are circulated via what?

Enterohepatic circulation (bile acids get into the digestive tract and are recirculated back into the liver)

49

One of the main functions of what is to provide the right balance between structural rigidity and fluidity for membranes?

Cholesterol

50

Cholesterol is in what form when transported throughout the body?

ester form

51

Where is the origin of chylomicrons?

intestine

52

Where is the origin of VLDL?

liver

53

What are VLDL catabolism products?

  • IDL
  • LDL
54

What are origins of HDL?

  • Intestine
  • Liver
  • Plasma
55

Which lipoprotein is referred to as a remnant structure?

IDL

56

True or False: Lipoprotein particles have a polar surface composed of phospholipids and cholesterol.

True

57

What is found in the inner core of lipoproteins?

  • cholesterol esters (CE)
  • Triglycerides (TG)
58

What is found on the surface of lipoproteins that plays a functional role in binding to receptors, assisting with reactions, and maintains the structural integrity of the lipoprotein?

Apolipoproteins

59

Cholesterol and triglycerides come from our diets and what?

in vivo synthesis

60

List the major lipoproteins based on there size from greatest size to lowest size.

Chylomicrons > VLDL > IDL > LDL > HDL

61

Rank the lipoproteins based on their density. From highest density to lowest density.

HDL > LDL > IDL > VLDL > Chylomicrons

62

Why is LDL referred to as "bad cholesterol"?

LDL is carrying 45% cholesterol and is going into the periphery

63

Why is HDL referred to as "good cholesterol"?

HDL is carrying 20% cholesterol and goes back into the liver and undergoes degradation.

64

Which apolipoproteins are associated with Chlyomicrons?

  • B-48
  • E
  • C-II
65

Which apolipoproteins are associated with VLDL?

  • B-100
  • E
  • C-II
66

Which apolipoproteins are associated with IDL?

  • B-100
  • E
67

Which apolipoproteins are associated with LDL?

  • B-100
68

Which apolipoproteins are associated with HDL?

  • A-I
69

True or False: Major lipoproteins can be identified by various analytical methods.

True

70

List the steps to the exogenous pathway:

  • Dietary fats are absorbed and incorporated into chylomicrons (with B-48).
  • HDL particles transfer Apo E and Apo C.
  • Apo C (subtype C-II) promotes interactions between lipoprotein lipase (LPL) and chylomicrons.
  • Chylomicron remnants are removed from circulation via the liver mediated by apo E.
  • Some of the cholesterol in the liver is converted to bile acids and removed via the intestines.
71

Chylomicrons are really rich in what?

TG

72

Chylomicrons enter circulation via which system?

lymphatic system

73

What acts like a library, and transfers apo C and apo E to the chylomicron particle?

HDL

74

List the steps associated with the metabolism of chylomicron:

  • Apo C (subtype C-II) interacts with lipoprotein lipase (LPL) in adipose and muscle vascular capillary beds.
  • The triglycerides undergo a hydrolysis reaction that regenerates free fatty acids and glyceride.
75

The loss of triglycerides in chylomicron metabolism leads to the formation of what?

chylomicron remnant

76

Chylomicron remnants interact with what on the liver to be removed from circulation?

  • Lipoprotein-like receptor protein (LRP)
77

Which apoprotein interacts with LRP on the liver surface to remove chylomicron remnants from circulation?

apo E

78

TG hydrolysis occurs via what?

pancreatic lipase (which is a serine esterase)

79

What is the mechanism of lipase hydrolysis?

  • Catalytic triad relay
  • hydrolysis
80

List the steps of the endogenous pathway:

6. The liver inserts cholesterol and triglycerides into VLDL with apo B-100.

7. VLDL is converted to IDL by lipoprotein lipase (LPL) catabolism. Also, VLDL picks up apo C and apo E from HDL, as well as undergoing and exchange of triglycerides for cholesteryl ester via cholesteryl ester transfer protein (CETP).

8. 50% of IDL (intermediate-density lipoproteins) are the VLDL remnants which are cleared by liver receptors that require apo E.

9. 50% of IDL is catabolized by lipoprotein lipase (LPL) and hepatic lipase (HL). This process removes more triglyceride, apo E, and apo C generating LDL.

10. LDL is cleared from circulation by the liver via recognition of apo B-100.

81

List the steps associated with the formation of VLDL:

  • Cholesterol is esterified by ACAT in the liver.
  • Cholesteryl esters are packaged into particles that become the internal portion of VLDL
82

The formation of cholesterol esters via Acetyl CoA and ACAT occurs where?

ER of hepatocytes

83

Why does nature form cholesterol esters rather than simply using cholesterol?

Due to the hydrophobic effect

84

The hydrophobic effect is a process driven by what?

entropy

85

List the steps associated with the metabolism of VLDL:

  • HDL, acts like a library, and transfers apo C-II, apo C-III, and apo E to the VLDL nascent particle to generate VLDL.
  • Apo C (subtype C-II) interacts with lipoprotein lipase (LPL) in adipose and muscle vascular capillary beds.
  • The triglycerides undergo a hydrolysis reaction that regenerates free fatty acids and glyceride.
  • Apo C and apo E are transferred back to HDL.
86

The loss of triglycerides generates a new lipoprotein called a VLDL remnant, which is also known as what?

Intermediate Density Lipoprotein (IDL)

87

How is the VLDL remnant (IDL) metabolized?

  • Approximately 50% of the VLDL remnant (IDL) interacts with the LDL receptor (LDL) on the liver and is removed from circulation. This is mediated by apo E.
  • The other 50% of the VLDL remnant is hydrolyzed by hepatic lipase (HL) to produce low-density lipoprotein (LDL) .
88

It should be noted that with the loss of the apo C and apo E particles, the newly generated Low Density Lipoprotein (LDL) has only one apolipoprotein associated with it. This is the original what, which is recognized by the LDL receptor?

apo B-100

89

LDL is rich in what?

cholesterol

90

The uptake of LDL is done by what?

  • Liver (75%)
  • Extrahepatic tissues (25%)
91

Molecular defects in the LDL receptor results in what?

FH

92

What are the effects of LDL internalization?

  • Decrease in HMG CoA Reductase
  • Increase in ACAT
  • Decrease in LDL receptors
93

Nascent HDL is converted into mature HDL via what?

LCAT

94

Uptake of HDL by liver and steroid hormone-producing tissues is carried out by what?

SR-BI Receptors

95

The transfer of HDL cholesterol to VLDL, IDL, IDL for transport to the liver is carried out by what?

CETP

96

CETP's role involves the exchange of what?

Cholesterol esters (CE) and Triglycerides (TG) between VLDL and HDL

97

The following quote is from what clinical trial?

  • “After comprehensive evaluation, we have concluded that the clinical profile for anacetrapib does not support regulatory filings”

REVEAL clinical trial (showed that the CETP inhibitor is no longer being pursued)

98

Which clinical trial involved the drug Canakinumab and showed that there was a link to inflammation?

CANTOS

99

An excess plasma concentration of cholesterol, cholesterol esters, triglycerides, and/or phospholipids is known as what?

hyperlipidemia

100

An increase in the concentration of soluble lipid proteins is known as what?

Hypolipoproteinemia

101

True or False: High LDL and Low HDL are both risk factors for CHD.

True

102

Which statin is the most potent?

Rosuvastatin

103

Rank the potency of the statins from greatest to least (among Simvastatin, Rosuvastatin, and Atorvastatin):

Rosuvastatin > Atorvastatin > Simvastatin

104

What is used for turning cholesterol into cholesterol esters?

ACAT

105

What are the type 1 statins?

  • Lovastatin
  • Pravastatin
  • Simvastatin
106

What are the type 2 statins?

  • Fluvastatin
  • Atorvastatin
  • Rosuvastatin
  • Pitavastatin
107

Which type 1 statins are prodrugs and why?

  • Simvastatin
  • Lovastatin
    • both have lactone ring system
108

Which statin has just an R stereochemistry?

Atorvastatin

109

What is the function of the parafluorophenyl ring on type 2 statins?

metabolic blocker

110

Rank the statins based on their IC50.

Rosuvastatin (5 nM) > Atorvastatin (8 nM) > Simvastatin (11 nM) > Fluvastatin (28 nM)

111

Which statins do NOT cross the BBB?

  • Pravastatin
  • Rosuvastatin
    • have more polar groups
112

Which statins are metabolized by 3A4?

  • Lovastatin
  • Simvastatin
  • Atorvastatin
113

Which statins are metabolized by 2C9?

  • Fluvastatin
  • Rosuvastatin
  • Pitavastatin
114

Which statin is metabolized by sulfation?

Pravastatin

115

Atorvastatin can be hydroxylated in what positions?

  • ortho
  • para
116

Which statins are neutral?

  • lovastatin
  • simvastatin
    • no carboxylic acid groups/ no basic nitrogens
117

Which statins are acidic?

  • Pravastatin
    • carboxylic acids and no nitrogens
  • Fluvastatin
  • Atorvastatin
    • carboxylic acids and nitrogens are are not basic
118

Which statins are amphoteric?

  • Rosuvastatin
  • Pitavastatin
    • acid and base built in
119

What are the adverse effects of the statins?

  • GI upset
  • Muscle weakness
  • Rhabdomyolysis (rare)
120

Which drug is converted into the active co-factors NAD+ and NADP+ by reacting with 5-posphoribosyl-1-pyrophosphate (PRPP)?

Niacin

121

What is the main adverse side effect associated with niacin?

  • flushing
122

Which drug's MOA is through the activation of the nuclear transcription factor PPARα, peroxisome proliferator-activated receptor, which are expressed in tissues that metabolize fatty acids (e.g., the heart, liver, kidney, and muscle.)?

Fibrates

123

Fibrates stimulate what?

LPL

124

Which drugs stay in the intestines and are not absorbed into the bloodstream?

Bile acid sequestrants

125

What is the MOA of bile acid sequestrants.

Not allowing bile acids to re-enter the liver --> therefore, not allowing for the negative feedback loop associated with 7 alpha-hydroxylase

126

Which drug belongs to the cholesterol absorption inhibitor class?

  • Ezetimibe (Zetia)
127

Which clinical trial concluded that when added to statin therapy, that Zetia had more lowering of cholesterol and reduced CV outcomes?

IMPROVE-IT clinical trial

128

Which drug's MOA involves inhibition of the absorption of cholesterol at the brush border of the small intestine. It is selective and does not interfere with absorption lipids, lipid soluble vitamins, and/or triglycerides?

Ezetimibe (Zetia)

129

As for drug targets, what do beta-blockers affect?

  • HR
  • Contractility
130

For standard catecholamines, which enantiomer has greater reactivity?

R

131

For non-selective beta-blockers, which enantiomer has greater reactivity?

S

132

As for drug targets, what do ACE-inhibitors affect?

  • Blood volume
  • Venous tone
    • = SV
  • Circulating regulators
133

List the steps to an amide hydrolysis:

  • Step 1: protonation takes place
  • Step 2: Water attacks
  • Step 3: Loss of proton/protonation of Nitrogen
  • Step 4: Double bond formed and loss of amine
134

As for drug targets, what do ARBs affect?

  • Blood volume
  • Venous tone
    • = SV
  • Circulating regulators
135

ARBs block Ang II from binding to what?

AT1 receptor

136

Which ARBs are prodrugs?

  • Candesartan
  • Olemsartan
  • Azilsartan
137

As for drug targets, what do CCBs affect?

  • HR (some)
  • Contractility
  • Venous tone
  • Peripheral resistance
138

Which calcium ion channel is being described?

  • Slow inward, long-lasting current; phase 2 of myocytes and phases 4 and 0 of SA and AV nodal cells

L-type (ICa)

139

Which calcium ion channel is being described?

  • Transient current; contributes to phase 4 pacemaker current in SA and AV nodal cells

T-type (IC a)

140

The L-type channels are associated with which phase of the cardiac action potential?

Phase 2

141

The T-type channels are associated with what?

initial nodal depolarization

142

Rank the following based on vasodilation. From highest vasodilation effect to lowest.

  • Diltiazem
  • Verapamil
  • Dihydropyridines
  • Dihydropyridines > Diltiazem > Verapamil
143

Rank the following based on negative ionotropic effect. From highest negative ionotropic effect to lowest.

  • Diltiazem
  • Verapamil
  • Dihydropyridines
  • Verapamil > Diltiazem > Dihydropyridines
144

Rank the following based on suppress AV node conduction. From highest to lowest.

  • Diltiazem
  • Verapamil
  • Dihydropyridines
  • Verapamil > Diltiazem > Dihydropyridines
145

Which CCB is part of the phenylalkyl amines?

Verapamil

146

Which CCB is part of the Benzothiazepines?

Diltiazem

147

True or False: The aromatic ring is not co-planar with 1,4-dihydropyridine ring in the CCBs.

True