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Flashcards in Quiz 8 Practice Problems Deck (108):
1

Which is the predominant type of collagen found in bone?

type I collagen

type II collagen

type III collagen

type IV collagen

type X collagen

 

type I collagen

Type I collagen is the principle type of collagen secreted by osteoblasts, it’s also the principle type of collagen found in connective tissue proper.

2

In developing cartilage, the most mature and differentiated areas are in:

 

The center of the cartilage.

The inner perichondrium.

The outer perichondrium.

The periphery of the cartilage next to the perichondrium.

 

The center of the Cartilage

The initial cartilage growth is appositional, as chondroblasts arise in the perichondrium and begin to secrete matrix. Thus, the oldest cartilage will be in the middle and the youngest at the periphery, under the perichondrium.

3

The blood clot initially forms at the site of a bone fracture is next replaced by:

Hyaline cartilage

Loose connective tissue

Both

Neither

 

Both:

Fibroblasts, myofibroblasts, osteoblasts, chondroblasts, and other cells invade the clot and begin secreting extracellular matrix. Thus, there is both hyaline cartilage and loose CT present and when that is replaced with bone, both endochondral and intramembranous ossification will be involved.

4

Compared to the hyaline cartilage in tracheal rings, articular cartilage lacks:

Chondrocytes

GAGs

Hyaluronic acid

Perichondrium

Type II collagen

 

Perichondrium

Articular cartilage arises from an “interzone” area of mesenchymal cells that forms the joint between two bones. This cartilage lacks a perichondrium, but contains all the other items listed; the lack of perichondrium provides the smooth surface necessary for proper joint function.

5

Without a perichondrium, articular cartilage lacks the normal source of: 

Chondroblasts

Fibroblasts

Lymphatics

Nerve cells

Smooth muscle

 

Chondroblasts

Technically this is not a good question, as you could make a case for answers a – d being correct. The perichondrium contains fibroblasts, lymphatics, and probably some nerve fibers, but also progenitor cells that can make chondroblasts. The best answer for thinking about cartilage growth and repair is ‘a’ because the perichondrium of other types of permanent cartilage provides the source of chondroblasts for growth and repair. Resident chondrocytes in articular cartilage are responsible for turnover and replacement of damaged areas.

6

Recently, almost every time you fall off your skateboard, you break a bone. In addition, you have recently developed kidney stones. A biopsy revealed your bones are thinner than normal. What change in cells do you expect to see in this biopsy?

 

An increased number of osteoclasts

A decreased number of osteoclasts

An increased number of osteoblasts

An increased number of osteocytes

A decreased number of chondrocytes

An Increased number of osteoclasts

A decrease in bone mass is expected to be the result of an imbalance in the activity or numbers of osteoclasts versus osteoblasts, with relative osteoblast activity increasing. This could be due to an increase in osteoclasts or a decrease in osteoblasts. An increase in kidney stones would suggest that osteoclast numbers have increased, since osteoclasts are responsible for increasing serum calcium levels and their numbers are increased by hormonal signaling.

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A

Adult bone, whether trabecular or compact, is lamellar.

8

Fibrocartilage differs from hyaline cartilage because fibrocartilage contains:

A perichondrium

Blood vessels

Large amounts of elastic fibers

Type I collagen

Type II collagen

Type I Collagen

Fibrocartilage, unlike hyaline and elastic cartilage, contains large amounts of type I collagen, though it also contains type II cartilage, as does hyaline cartilage, so that is not a distinction. Fibrocartilage lacks a perichondrium, blood vessels, or a significant number of elastic fibers.

9

In adult bone the collagen fibers of adjacent lamellae of an osteon are oriented:

Randomly

0 degrees to each other

90 degrees to each other

180 degrees to each other

 

90 Degrees to each other

Osteoblasts organize collagen fibers orthagonally in adjacent lamellae, which increases the strength of bone.

10

A researcher is investigating the use of mesenchymal stem cells (MSCs) as a therapy for osteoarthritis (OA), employing a goat model. OA can be induced in a goat’s knee joints by surgically removing the medial meniscus, followed by normal exercise. After surgery, some of the goats received an injection of labeled MSCs suspended in saline into the treated joint, control animals received only the saline. Later analysis reveals that the articular cartilage is significantly less degraded in the goats receiving MSCs. However, in these experiments no MSCs or cells derived from them were detected in the articular cartilage, although a small number of MSCs and MSC-derivatives were found elsewhere in the joint. The most likely explanation for this effect is that the MSCs and their few derivatives found in the joint are producing:

Chondronectin

Cytokines

Hyaluronic acid

Matrix metalloproteinases

Type II collagen

cytokines

Since it is known that the behavior of chondrocytes is influenced by a number of cytokines and that a perturbation in these signals is likely to be involved in OA, the production of cytokines by MSCs is the most likely explanation for this result. The cytokines could be acting both on chondrocytes in the articular cartilage as well as on other cells in the joint to ameliorate the normally destructive series of events that produces OA. It is unlikely that the production of matrix components by a small number of MSCs outside of the articular cartilage would have any significant beneficial effect and increased production of protease by hypertrophic chondrocytes is known to be involved in the progression of OA

11

Hyaline cartilage differs from bone because it:

Contains Type I collagen fibers

Contains Type II collagen fibrils

Is composed of cells surrounded by fibers and matrix

Is covered by a layer of connective tissue

Is richly vascularized

 

Contains Type II collagen fibrils

The unique feature for cartilage on the list is the presence of type II collagen. In fact, type II collagen is only found in significant amounts in cartilage and one other place in the body; where do you think that is?: type II collagen is also found in the vitreous humor of the eye. Mature bone will only contain type I collagen, produced by osteoblasts. Both bone and cartilage is composed of cells surrounded by matrix and both can be covered with a layer of connective tissue. Hyaline cartilage is not directly vascularized.

12

Vitamin C is required for the proper assembly of collagen fibers due to its participation in:

Glycosylation reactions in the Golgi

mRNA processing

Peptide transport into the RER

Redox reactions

Vesicle transport from RER to Golgi

 

Redox Reactions:

Vitamin C is required for the redox reactions that result in the hydroxylation of proline and lysine residues on collagen.

13

Bone remodeling often does not occur normally in:

 

Adolescents prior to the closure of the epiphyseal growth plate

Adults after the closure of the epiphyseal growth plate

Newborns until they reach 6 months

Post-menopausal women

 

 

Post-menopausal women

The ability of osteoblasts to replace bone removed by osteoclasts during normal bone remodeling declines with increasing age; this is called senescent osteoporosis. This is seen more frequently in women after menopause. Remodeling is expected to occur normally in the other cases.

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B

15

The cells most active in the synthesis and secretion of osteoid are:

 

Osteoprogenitor cells

Osteoblasts

Osteocytes

Osteoclasts

Bone-lining cells

 

osteoblasts

Osteoblasts responsible for the synthesis of the bulk of osteoid and its mineralization. Those trapped in the matrix they are called osteocytes, which are then responsible for maintenance of bone.

16

An 8-year-old girl is seen in clinic because her parents are concerned about her lack of growth. Bone scans reveal that her epiphyseal growth plates are beginning to close prematurely. To slow the closure of the growth plate and to promote continued growth of her long bones, her pediatrician prescribes somatotropin (growth hormone) in order to:

Stimulate the hypertrophy of chondrocytes in the growth plate

Stimulate the maturation of osteoblasts to osteocytes

Stimulate the deposition of osteoid at the growth plate

Stimulate proliferation of chondrocytes in the growth plate

Stimulate the deposition of hydroxyapatite in the osteoid at the growth plate

 

Stimulate proliferation of chondrocytes in the growth plate

 

Somatotropin is responsible for stimulating mitotic activity of chondrocytes in growth plate cartilage until late adolescence when growth stops.

17

A 9-year-old boy is seen in the ED for a fractured rib that resulted from a minor fall. On X-ray, his bones appear unusually dense and additional imaging studies reveal that his bone marrow cavities are smaller than expected. A defect in what cell type is most likely responsible for this condition?

 

Chondroblasts

Chondrocytes

Osteoblasts

Osteoclasts

Osteocytes

 

Osteoclasts

This is a description of osteopetrosis, also called marble bone disease. It is due to a failure of osteoclasts to resorb bone at a normal rate. As a consequence, marrow cavities become smaller as they are filled in with bone. Although bones in this case are denser, they are not stronger, likely because of reduced bone remodeling: turnover and replacement of old bone with new. There are several forms of this disease, all of which appear to be caused by mutations in genes important for osteoclast activities.

18

1..   Individuals are shown with hand defects consistent with abnormal Shh function.  Discuss what kind of disruption of Shh expression/function may have occurred in each of the four cases shown and what other disorders you may want to screen for in each of these individuals.

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  1. Interpreting defects is something of an art, and therefore open to more than one possible answer.  However, the general concepts should be similar for all interpretations.  Cases with a triphalangial digit in the position of the thumb (cases 1, 2 and 4) would appear to be a transformation of this digit to a more caudal digit, suggesting excess Shh signaling or aberrant Hox-patterning of the limb bud.  In addition, case 4 looks very similar to experimental duplication of the ZPA on the cranial margin of the limb bud—so this could be the case here as well.  Case 3 (duplication of the caudal most digit) is curious—suggesting increased size of the ZPA in its normal location. 

19

.  Craniofacial stenosis syndromes caused by defective Fgf signaling are often associated with “sock foot deformity”  (see image).  Discuss how this condition arose during development (what molecular pathways and cellular events were perturbed).  How might altered Fgf signaling interact with the known molecular pathways regulating digit formation.  (This may require you to learn something about the role of Fgf in these processes on your own.)

As noted in the craniofacial lecture, foot and hand deformities are common in cases of craniofacial stenosis associated with excess Fgf signaling.  The “sock foot deformity” strongly suggests there has been a failure of programmed cell death in these individuals.  Although regulation of cell death is complex, substantial evidence suggests Fgf signaling inhibits BMP-mediated cell death.  During limb development, Fgfs from the AER maintain the progress zone and induce proliferation of cells in an undifferentiated state.  This strongly suggests that part of why syndactyly is seen in individuals with increased Fgf signaling is overproliferation of immature cells in the interdigit region.  Fgf signaling may also act to directly inhibit BMP or to stimulate Wnt signaling, thereby preventing cell death.

20

. Patients with Marfan syndrome are very tall, with an arm-span greater than their height, hypermobile joints and long digits (see diagram).  This syndrome is due to a defect in Fibrillin-1 that results in excels Tgf-beta signaling and an alteration in the function of mesenchymal stem cells (MSC) in the bone marrow (see diagram).  Based on this pathway, discuss the impact of the Fibrillin-1 mutations on bone formation and resorbtion, and relate it to the Marfan phenotype.

The most likely interpretation of the effect of Fibrillin-1 defects is an imbalance favoring bone decreased bone mass (see below).  This would be consistent some (but not all) aspects of the Marfan phenotype. The balance of bone growth to clearly changes over the life span—with Marfan patients showing increasingly fragile bones as they age.  Interestingly, the most medically critical aspect of this syndrome has to do with the structural role of Fibrillin 1 in the assembly of elastin fibers.  Marfan patients have enlarged aortae, due to a weak vascular wall, and are at increased risk for aortic rupture.

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44

The following procedure (Dorsal flexion) is performed during the MSK portion of a PE. Identify the following:

Muscles

Myotome

Nerve

Compartment

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49

The process of stretching before exercise is most likely to have which biochemical benefit?  

A. Activate gluconeogenesis in the liver

B. Activate glycolysis in the muscles

C. Increase blood flow to the muscles

D. Stimulate glycogenolysis in the liver

E. Stimulate the release of epinephrine

C

50

Picture yourself running up four flights of stairs. The increased muscle contraction (I’m sure that Dr. Morton would like you to know which muscles) will most likely lead to which of the following:

A. Activation of liver glycogen synthase

B. Activation of muscle acetyl CoA carboxylase-2

C. Activation of muscle phosphofructokinase-1

D. Inhibition of liver glycogen phosphorylase

E. Inhibition of muscle GLUT4 vesicle fusion

   

F. Inhibition of muscle malonyl CoA decarboxylase

C. Activation of muscle phosphofructokinase-1

51

A 5-year-old girl was diagnosed with a severe mitochondrial myopathy caused by a mutation in her mitochondrial chromosome. As a result, she will most likely have elevated levels of which of the following in her blood:

A. Bicarbonate

B. Glucose

C. Insulin

D. Ketones

E. Lactate

E. Lactate

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D

53

A 25-year-old female came to the clinic with primary complaints of muscle weakness and cramping. After further evaluation she was found to have a myopathic form of carnitine-palmitoyl transferase II deficiency. If she were to fast for 24 hours, she would be most likely to first develop weakness in which of the following muscle types?

  

Type I (slow oxidative)

   

Type IIa (fast oxidative)

   

Type IIb (fast glycolytic)

Type I (slow oxidative)

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B

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D

56

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From the micrograph, it would appear that the hair corresponds to the stratum corneum, as there seems to be a separate stratum granulosum layer in the surrounding epithelial sheath. However, some texts state that there are contributions from the stratum granulosum in hair, so both b and c could be true. This was mostly an exercise to get you to look at the epidermal layers in a different orientation.

57

What mechanoreceptors in the skin are responsible for sensing pressure, and where are they located?

  

Meissner's corpuscles in the papillary dermis

  

Meissner's corpuscles in the hypodermis

  

Merkel cells in the epidermis

   

Pacinian corpuscles in the papillary dermis

   

Pacinian corpuscles in the hypodermis

Pacinian corpuscles are found in the hypodermis and deep in the dermis and respond to deep pressure and vibration. Meissner’s corpuscles are located in dermal papillae and respond to light touch. Merkel cells are found in the stratum basale and, in mice, respond to light touch — it’s assumed they have the same function in humans.

58

In what sublayer of the skin is melanin produced?

  

Stratum basale

   

Stratum corneum

   

Stratum granulosum

   

Stratum lucidum

   

Stratum spinosum

Stratum basale

Melanocytes are neural crest derived cells that reside in the stratum basale, along with Merkel cells and the keratinocyte stem cells and transit amplifying cells. There are also melanocytes in hair follicles, which add color to hairs. If the epidermis is damaged, melanocytes in adjacent hair follicles begin dividing and migrating to repopulate the surface epidermis.

59

You have generated a mutant mouse in which the neural crest cells fail to migrate to the skin. What is the fur color of this mouse?

  

Auburn (reddish-brown)

Blonde

Black 

Brown

Red

White

White

Melanocytes are derived from the neural crest in the embryo. If they fail to migrate to the skin, the hairs will lack pigment and be white.

60

A lack of which enzyme would generate the same coat color phenotype in a mouse as the mutant described above with a defect in neural crest migration?

  

aromatase

   

glutamate dehydrogenase

   

proline hydroxylase

   

transglutaminase

   

tyrosinase

Tyrosinase is an oxidase that in mammals is responsible for converting the amino acid L-tyrosine into L-dopa, which is the rate-limiting step in the production of melanin.

61

Which epidermal cell type is known to migrate out of the skin in response to a local infection?

  

Keratinocytes

   

Melanocytes

   

Langerhans cells

   

Merkel cells

Langerhans cells are derived from bone marrow precursors. When activated by inflammation in the skin, they migrate to lymph nodes carrying antigens and become dendritic cells, which present antigens to T cells. There are also dendritic cells in the adjacent dermis. Recent evidence suggests that in mice the dermal dendritic cells stimulate some types of immune responses in the skin, which Langerhans cells suppress. There is nothing simple about the immune system.

62

It is relatively common to deliver medications via a syringe. In a “subcutaneous injection,” the medication would be deposited within what layer?

  

Deep fascia

   

Epidermis

   

Hypodermis

   

Papillary dermis

   

Reticular dermis

Subcutaneous means “beneath the skin.” Subcutaneous injections are delivered into the hypodermis. Whether or not the hypodermis is considered part of the skin or a separate layer is debatable. The hypodermis may contain hair follicles, sweat glands, and Pacinian corpuscles, so it’s reasonable to consider it part of the skin. However, it is often considered to be a separate layer and called superficial fascia by gross anatomists. In any case, it consists of loose connective and adipose tissue and is less dense than the dermis, so it provides a good reservoir for injected material.

63

Compounds produced in which sublayer of the skin are most responsible for protection from dehydration in the dry Utah air?

  

Stratum basale

   

Stratum corneum

   

Stratum granulosum

   

Stratum lucidum

   

Stratum spinosum

Stratum granulosum

Keratinocytes in the stratum granulosum produce lamellar granules, which contain hydrophobic compounds that eventually coat the cross-linked keratin filaments in the stratum corneum. This hydrophobic coating creates a barrier that helps prevent the loss of fluid from the dermis.

64

A researcher injects radioactive thymidine into the blood stream of a mouse and then 15 minutes later injects a large amount of non-radioactive thymidine. This protocol ensures that the only detectable radioactivity in the mouse’s cells will be found in DNA that was synthesized during the 15 minutes after the initial injection. If small biopsies of skin from the mouse’s back are taken at intervals after the second injection, in what sublayer of the epidermis would she first expect to detect radioactivity?

Stratum basale

Stratum corneum

Stratum granulosum

Stratum lucidum

Stratum spinosum

Basale
While there may normally be a few cells dividing in the stratum spinosum, it is in the stratum basale that one finds stem cells and transit amplifying cells, which are far more mitotically active. Therefore, the first cells with detectable radioactivity should be in this layer.

65

If the researcher in the experiment described in the previous question continues to take small biopsies, in what sublayer would she next expect to detect radioactivity?

  

Stratum basale

Stratum corneum

Stratum granulosum

Stratum lucidum

Stratum spinosum

Stratum spinosum

The step in epidermal differentiation after the transit-amplifying cell involves cells losing contact with the basement membrane and entering the stratum spinosum. Therefore, it is in this layer that she should next expect to find some radioactive cells.

66

Considering the experiment described above, what epidermal sublayer is not expected to contain detectable radioactivity?

  

Stratum basale

   

Stratum corneum

   

Stratum granulosum

   

Stratum lucidum

   

Stratum spinosum

Corneum

The radioactivity will be found in DNA in the nuclei of the keratinocytes and as all organelles are lost to form the stratum corneum, one would not expect to detect radioactivity in this sublayer. The thin skin of the back does not have a stratum lucidum.

67

Which epidermal area is expected to have the most heavily folded dermal papillae?

Areola

Axilla

Back

Fingertips

Scalp

 

Fingertips

The interdigitation of the dermal papillae and epidermal (rete) ridges increase the contact surface between the epidermis and dermis. These are most prominent in thick skin regions that experience the most mechanical stress, such as fingertips

68

Your patient is in extreme pain resulting in marked hyperventilation. Which of the following is likely to occur? Choose the one correct answer.

a. H+ concentration in arterial blood will fall but arterial PCO2 will rise

b. Arterial PCO2 will rise but arterial pH will fall

c. Arterial PCO2 and pH will both increase

d. The kidneys will act to compensate by excreting less acid

d. The kidneys will act to compensate by excreting less acid

69

Which of the following is likely to reduce alveolar ventilation? Choose the one correct answer.

a. High H+ concentration in arterial blood.

b. Low levels of HCO3 - in arterial blood.

c. High PCO2 in arterial blood.

d. None of the above.

  

d. None of the above.

70

A hospitalized patient has received an overdose of a powerful narcotic. Which of the following is likely to characterize this patient? Choose the one correct answer.

a. Alveolar ventilation will be increased and arterial PCO2 will be decreased.

b. Alveolar ventilation will be unchanged as will arterial pH.

c. Arterial pH will be higher than normal.

d. Arterial pH will he lower than normal.

d. Arterial pH will he lower than normal.

71

Given that the concentration of H+ in an arterial blood sample is 10-7.60 moles/L. What is the pH of the blood sample? Choose the one correct answer.

a. 6.70

b. 7.30

c. 7.60

d. 7.45

c. 7.60

72

Given the following arterial values, calculate the patient’s arterial pH.

a. 7.32

b. 7.60

c. 6.90

d. 7.40

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a. 7.32

73

Which of the following is the normal compensatory response to metabolic acidosis (eg. ketoacidosis)? Choose one correct answer

a. Alveolar ventilation will decrease.

b. Arterial PCO2 will increase.

c. Alveolar ventilation will increase.

d. Arterial PCO2 will remain unchanged.

  

c. Alveolar ventilation will increase.

 

74

A patient with a recent history of severe vomiting is likely to have which of the following primary (ie., uncompensated) acid-base disturbance? Choose the one correct answer.

a. Respiratory acidosis.

b. Metabolic alkalosis.

c. Metabolic acidosis.

d. Respiratory alkalosis.

  

b. Metabolic alkalosis.

 

75

A patient has the following arterial blood values.

Which of the following is the most likely explanation for the values. Choose the one
correct answer.

a. The patient has a primary (before compensation) respiratory acidosis.

b. The patient has a primary respiratory alkalosis.

c. The patient has a primary metabolic acidosis.

d. The patient has a primary metabolic alkalosis.

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b. The patient has a primary respiratory alkalosis.

 

76

Bone serves two distinct functions in the body: mechanical rigidity and homeostatic buffer. Based only on the evidence of which the body will sacrifice first under suboptimal nutritional conditions, which of these two functions is more fundamental to survival?

A. Homeostatic buffer

B. Mechanical Rigidity

Homeostatic buffer

77

The primary stimulus for increased parathyroid hormone (PTH) secretion is:

A. Decreased extracellular calcium

B. Decreased extracellular phosphate

C. Decreased intracellular calcium

D. Decreased intracellular phosphate

A. Decreased extracellular calcium

78

Elevated parathyroid hormone has what major indirect effect on bones:

A. Activate osteoblast activity

B. Activate osteoclast activity

C. Inhibit osteoblast activity

D. Inhibit osteoclast activity

B. Activate osteoclast activity

79

One result of increased PTH secretion is stimulation of urinary phosphate excretion. This increases ionized serum calcium by:

A. Activating osteoblast activity

B. Decreasing calcium-phosphate salt formation

C. Inhibiting 1,25-dihydroxy-vitamin D synthesis

B. Decreasing calcium-phosphate salt formation

80

The rate of bone resorption can be quantified by the amount of urinary hydroxyproline. This hydroxyproline is most likely released by the degradative turnover of: (Hint: this relates to the major function of vitamin C)

A. 1,25-dihydroxy-vitamin D

B. Collagen

C. Hydroxyapatite

D. Parathyroid hormone (PTH)

 

  

B. Collagen

81

The conversion of vitamin D (cholecalciferol) to the activated form (1,25-dihydroxycholecalciferol) occurs:

A. In the kidney

B. In the liver

C. First by hydroxylation in the kidney, with a second hydroxylation in the liver

D. First by hydroxylation in the liver, with a second hydroxylation in the kidney

D. First by hydroxylation in the liver, with a second hydroxylation in the kidney

82

Parathyroid hormone (PTH) increases dietary calcium absorption primarily by which mechanism:

A. Directly increasing the transcription of intestinal calcium transporters

B. Inhibiting the absorption of dietary phosphate

C. Stimulating hydroxylation at the 1 position of 25-hydroxy-vitamin D

C. Stimulating hydroxylation at the 1 position of 25-hydroxy-vitamin D

83

A 35-year-old African American woman came to the clinic because of leg pains. She is wearing a full-body Muslim veil. She walks with a slight waddling gait and says that she has difficulty climbing stairs. She takes no vitamins or other nutritional supplements. The most likely diagnosis for this patient is:

A. Osteogenesis imperfecta

B. Osteomalacia

C. Osteopenia

D. Osteoporosis

E. Osteomyelitis

  

B. Osteomalacia

 

84

Referring again to the patient in question 8, her symptoms were most likely caused by increased bone resorption due to elevated serum:

A. Calcium

B. Calcitonin

C. Insulin-like growth factor

D. Parathyroid hormone

E. Phosphorous

F. 25(OH)D

D. Parathyroid hormone

85

A 17 year-old boy is brought to the emergency department by a group of his friends after ingesting a number of “purple hearts” (aka Phenobarbital). He is unconscious with a HR 47, RR 7, BP 72/38, and T 35.5. The emergency department staff initiate supportive care by securing his airway with an endotracheal tube, placing large bore IV’s, and beginning fluid resuscitation. What could be done to speed the elimination of phenobarbital (a weak acid with a pKa=7.2)? 

Reabsorption in DCT of kidney is passive and charged drugs will be excreted.  (harder for polar to diffuse anywhere!)  So making the environment so that the weak acid will be charged by making the environment of the urine more basic will lead to more excretion!

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86

A 69 year-old woman with coronary artery disease not amenable to surgical or percutaneous coronary intervention is prescribed nitroglycerin, a coronary artery vasodilator, for the management of her angina symptoms. In follow-up two weeks later, she reports that the nitroglycerin does not seem to be working. Further questioning reveals that she has been swallowing the nitroglycerin tablets that are intended for sublingual administration. What is the most likely reason for treatment failure? 

Bioavailability as well as the Rates of Absorption, Distribution, and Elimination may impact clinical drug effects. (e.g. gentamycin exhibits concentration dependent killing and time dependent toxicity)

Administration of drugs by unintended routes may alter the clinical effects.

This patient has been incorrectly taking her nitroglycerin by mouth; the drug is subject to extensive first-pass

hepatic metabolism. The intended sublingual administration route bypasses first-pass metabolism. 

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A 63 year-old man with chronic renal insufficiency has infective endocarditis of his mechanical prosthetic mitral valve. The causative organism is methicillin-resistant S. aureus and prolonged vancomycin antibiotic therapy is indicated. Vancomycin is eliminated as unchanged drug primarily by glomerular filtration. How should the vancomycin dosing be adjusted to account for this patient’s renal insufficiency? 

Protein bound drugs will remain in the plasma...

Impaired renal function may necessitate dosing adjustments for renally eliminated drugs that have toxicities. This may involve adjustments to the maintenance dose and/or dosing interval to decrease the ‘rate of drug in’ to match the diminished ‘rate of drug out’.

Cumulative exposure toxicities may occur with some drugs (e.g. gentamicin, doxorubicin, bleomycin).

Vancomycin exhibits time-dependent microbial killing. It is associated with ‘red man syndrome,’ ototoxicity, and nephrotoxicity. 

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A 41 year-old woman with a history of depression is being evaluated in the emergency department 6 hours after an apparent suicide attempt with ingestion of approximately 45 regular-strength acetaminophen tablets. Acetaminophen is eliminated from the body by renal excretion of the three non-toxic metabolites depicted in the figure at the right. How could potential hepatotoxicity be diminished or prevented? 

The patient in this case has consumed excessive acetaminophen such that the normal primary routes of elimination through Phase II glucuronidation and sulfation are exhibiting zero-order elimination with an increase in Phase I CYP450 metabolism to a reactive intermediate called N-acetyl-p-benzoquinone imine (NAPQI).

This NAPQI intermediate may then be conjugated by glutathione to a non-toxic mercaptopuric acid conjugate. If glutathione stores are depleted, the NAPQI reacts with hepatic enzymes and causes hepatocyte damage.

Administration of N-acetylcysteine increases acetaminophen detoxification by increasing glutathione synthesis and/or acting as a glutathione substitute. 

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89

A 63 year-old woman who takes warfarin for chronic atrial fibrillation requires a statin lipid lowering agent due to persistently elevated cholesterol. After two weeks of therapy with fluvastatin she develops a large bruise after accidently striking a door frame. How can this be explained? What should be done? (adapted from Sandsen. Drug-Drug Interaction Primer. 2007) 

The patient appears to be experiencing increased anticoagulant effects from her warfarin coincident with starting fluvastatin.

Warfarin is eliminated by hepatic metabolism (predominantly P450 enzymes) and renal excretion of inactive metabolites. CYP2C9 is primarily responsible for warfarin’s S-enantiomer metabolism; the S-enantiomer is 2- 5X more potent than the R-enantiomer.

Fluvastatin is eliminated by hepatic metabolism (predominantly CYP2C9) and fecal excretion.

If fluvastatin is continued, close monitoring and warfarin dose adjustments may be required. Alternatively, fluvastatin could be switched to pravastatin which is not metabolized by P-450. 

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what happens to drugs in the Proximal convoluted tubule?

they are active and passivly transported, protein bound drugs can be secreted (into the filtrate)

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What happens to drugs in the glomerulus?

passive movement of drugs, but the protien bound ones would remain in the plasma

92

what happens to drugs in the distal convoluted tubule?

passive transport of the drug, with charged drugs being excreted into the urine. 

93

what is the Workhourse enzyme for processing drugs in the liver

3A4

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The bottle neck enzyme for processing drugs in the liver.

2D6

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1st order elimination is a constant ...... of drug being eliminated

Fraction

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zero order elimination is a constant ........of drug being eliminated

amount.

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How do I know the ration of protonated vs. unprotonated form of my drug?

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98

1. A 16-year-old boy was rushed to the ER after his mother found him extremely lethargic and confused. His mother notes that during the past 2 weeks he has had flu-like symptoms, he has been drinking large amounts, and has complained of not being able to focus on schoolwork. Upon examination his mucus membranes were dry and acetone could be smelled on his breath. His blood was sent for analysis.

A. What is the most likely diagnosis?
B. What would his blood values for the following most likely

be relative to normal (>, = or

β-hyroxybutyrate (normal

Diabetes,

Glucose High

beta-Hyroxybutyrate high

pH low

99

 A six year-old girl was brought to the clinic because she had severe muscle pain and cramping when she tried to play soccer. AVer her first soccer prac

She most likely has (a/an):

A.  FaHy acid oxida

B.  Galactosemia

C.  Glucose 6-phosphatase deficiency

D.  Glucose 6-phosphate dehydrogenase deficiency

E.  Glycogen storage disease

F.  Hereditary fructose intolerance

G.  Lipoprotein lipase deficiency

H.  Mitochondrial DNA muta

I.  Urea cycle defect 

E.  Glycogen storage disease 

You would see a problem with glucose pathway such as a lack of lactate when exercising and if it was in muscle then you would see muscle breakdown with exercise (myoglobin in urine or creatine kinase in blood)

100

A 37-year old man presented with fever, chills, headache and overall weakness. He recently returned from a trip to Egypt. Analysis of his blood smear revealed plasmodia. He was treated with primaquine. Two days later he presented with shortness of breath

and darkly colored urine. He most likely has (a/an):

A.  FaHy acid oxida

B.  Galactosemia

C.  Glucose 6-phosphatase deficiency

D.  Glucose 6-phosphate dehydrogenase deficiency

E.  Glycogen storage disease

F.  Hereditary fructose intolerance

G.  Lipoprotein lipase deficiency

H.  Mitochondrial DNA muta

I.  Urea cycle defect 

  Glucose 6-phosphate dehydrogenase deficiency 

It would lead to an inability to produce NADPH and an inability to handle oxidative stress (this is the only way red blood cells can handle oxidative stress) which would lead to hemolytic anemia (breaking of blood cells)

101

3. A baby boy who was born healthy at home began vomi

reducing sugar. He most likely has (a/an):

A.  FaHy acid oxida

B.  Galactosemia

C.  Glucose 6-phosphatase deficiency

D.  Glucose 6-phosphate dehydrogenase deficiency

E.  Glycogen storage disease

F.  Hereditary fructose intolerance

G.  Lipoprotein lipase deficiency

H.  Mitochondrial DNA muta

I.  Urea cycle defect 

Galactosemia 

An inability to break down galactose (a sugar substrate of lactose)(Galactase 1 phosphate uridil transferase) would lead to a build up of G1P (phosphorilated galactose) and could lead to liver problems and cataracts

102

4. A full-term neonate who was healthy at birth stopped

feeding at ~30 hours. He became lethargic with hypotonia,

began vomi

comatose. His blood glucose was 68 mg/dL (normal 60-80

mg/dL), blood pH 7.44 (normal = 7.40 ± 0.05) and blood

ammonia was 700 μM/L (normal ≤ 50 μM/L). He most likely has (a/an):

A.  FaHy acid oxida

B.  Galactosemia

C.  Glucose 6-phosphatase deficiency

D.  Glucose 6-phosphate dehydrogenase deficiency

E.  Glycogen storage disease

F.  Hereditary fructose intolerance

G.  Lipoprotein lipase deficiency

H.  Mitochondrial DNA muta

I.  Urea cycle defect 

I.  Urea cycle defect 

it would produce a very high blood level of ammonia (think liver and urea cycle)! it would lead to neurologic issues (urea is neurotoxin)

103

5. An 8-year-old boy presented to clinic with a recent episode of pancrea2500

mg/dL; ref

A.  FaHy acid oxida

B.  Galactosemia

C.  Glucose 6-phosphatase deficiency

D.  Glucose 6-phosphate dehydrogenase deficiency

E.  Glycogen storage disease

F.  Hereditary fructose intolerance

G.  Lipoprotein lipase deficiency

H.  Mitochondrial DNA muta

I.  Urea cycle defect 

G.  Lipoprotein lipase deficiency 

it would lead to very high blood levels of lipids!  and this could lead to pancreatitis.

104

6. A 7-month-old girl was brought to the hospital in a coma. She recovered following glucose infusion. She did not have any newborn screens. Physical examina

nonketo

A.  FaHy acid oxida

B.  Galactosemia

C.  Glucose 6-phosphatase deficiency

D.  Glucose 6-phosphate dehydrogenase deficiency

E.  Glycogen storage disease

F.  Hereditary fructose intolerance

G.  Lipoprotein lipase deficiency

H.  Mitochondrial DNA muta

I.  Urea cycle defect 

A.  FaHy acid oxida

it could produce an inability to use fatty acids for long term energy and breakdown of muscle.  A medium chain oxydation deficiency would lead to a build up of medium chain fatty acids, and no energy in the liver to make gluconeogenisis and an over-use of glucose

105

A 5-month old boy is brought to the physician because of episodes of irritability during the previous 2-months. The episodes occur 3-4 hours aVer feeding. Physical examina

does not increase. He most likely has:

A.  FaHy acid oxida

B.  Galactosemia

C.  Glucose 6-phosphate dehydrogenase deficiency

D.  Glycogen storage disease

E.  Hereditary fructose intolerance

F.  Lipoprotein lipase deficiency

G.  Mitochondrial DNA muta

H.  Urea cycle defect 

D.  Glycogen storage disease 

You would see a problem with glucose pathway such as a lack of lactate when exercising and if it was in muscle then you would see muscle breakdown with exercise (myoglobin in urine or creatine kinase in blood)  In this case you see a problem in the liver being able to send out glucose...and liver uses a lot of glycogen as a source of that gllucose...

106

A 28-year-old woman presented with frontal headaches, vomi

experienced muscle weakness and recurrent headaches. Her cerebral spinal fluid (CSF) and plasma lactate levels are 10.3 mmol/l (ref.

A.  FaHy acid oxida

B.  Galactosemia

C.  Glucose 6-phosphatase deficiency

D.  Glucose 6-phosphate dehydrogenase deficiency

E.  Glycogen storage disease

F.  Hereditary fructose intolerance

G.  Lipoprotein lipase deficiency

H.  Mitochondrial DNA muta

I.  Urea cycle defect 

H.  Mitochondrial DNA muta

Very high lactate levels!  The whole funciton of mitochondria is blocked...therefore a lot of anerobic metabolism!

107

waht would high ALT and AST in the blood tell us

Liver Problems!

108

what would hypoglycemia with fasting point to?!

a problem in the metabolism of the liver!