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MS1 - MCBD > Week 3 Review > Flashcards

Week 3 Review Flashcards

1
Q

You made a drug that is a weak acid with a pKa of 6.9. You designed it to be absorbed by GI epithelial cells in the duodenum, where the pH is ~7.5. Will your drug easily cross the cell membrane?

A

Nope. Your drug has a lower pKa than the environment; it therefore is a stronger acid than the environment and will donate a proton –> A- + H+. Charged ions don’t like to cross membranes.

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2
Q

If a drug is in an environment where its pKa = pH of the environment, what proportion of drug is ionized?

A

50%!

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3
Q

What is LogP?

A

It indicates how lipid-soluble a drug is. High LogP = high solubility.

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4
Q

What are the two phases of drug metabolism?

A

Phase I and II

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5
Q

What enzymes are involved in Phase I drug metabolism? What do they do?

A

Cytochrome P450 enzymes add/unmask a polar functional group such as -OH, -SH, or -NH2 to increase reactivity.

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6
Q

What enzymes are involved in Phase II drug metabolism? What do they do?

A

Transferases conjugate the reactive group from Phase I with a large polar group. This increases water solubility and reduces the chance of drug reabsorption in the renal tubule.

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7
Q

Howard wants to be able to drink more beer without getting hungover. But since he is half asian, he underexpresses aldehyde dehydrogenase, which converts acetaldehyde (hangover molecule) to acetate –> acetyl coA. Howard would benefit from a(n) _________, which would increase his expression of this enzyme.

A

An inducer.

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8
Q

Cytochrome P450 enzymes are most commonly found in which organ? Specifically where in the cell are they?

A

Liver - on smooth ER

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9
Q

Name three specific CYP450 enzymes that play a role in drug metabolism.

A
  1. CYP2C9
  2. CYP2D6
  3. CYP3A4
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10
Q

What does p-glycoprotein do? What is the clinical significance of this?

A

It pumps drugs out of cells using ATP.

Inhibition of this –> more drug in cells.

Cancer cells may overexpress P-gp –> drug resistance

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11
Q

Drugs that are eliminated following zero-order kinetics are eliminated at a ________ rate.

A

constant rate (ie 2mg/L/hr)

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12
Q

Describe first-order drug elimination.

A

First-order kinetics = half life process; drug concentration is cut in half per unit time.

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13
Q

Intravenous, intramuscular, interosseous, and subcutaneous drug injection are all examples of the _________ route of administration.

A

parenteral

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14
Q

Oral, rectal, and buccal drug administration are all examples of the __________ route of drug administration.

A

enteral

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15
Q

What will have higher bioavailability: a drug administered parenterally or enterally?

A

A drug administered parenterally because it bypasses the liver (no first-pass metabolism) and goes straight into circulation.

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16
Q

What are the five pharmacokinetic equations we need to memorize?

A
  1. t 1/2 = .693 • Vd / CL
  2. CL = dose rate/Cp (steady state)
  3. Vd = dose / Cp
  4. loading dose = Vd • Cp / F
  5. maintenance dose = Cl • t • Cp / F
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17
Q

How many half lives does it take to eliminate a drug from a system and/or reach steady-state?

A

4-5

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18
Q

Amylase breaks down ________ and is made by the ________ and _______ ______.

A

breaks down carbohydrates, made by the pancreas and salivary glands

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19
Q

Describe how intestinal epithelial cells absorb glucose.

A

They use a Na+/glucose cotransporter. Na+ travels down its conc. gradient while glucose travels against its conc. gradient.

The Na+/K+ ATPase on the basolateral side of the cell is required to keep Na+ in the cell low so the Na+/glucose cotransporter can do its thing.

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20
Q

In a muscle that is undergoing anaerobic metabolism, glucose is converted to ________, which is further oxidized to ________.

A

glucose –> pyruvate –> lactate

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21
Q

In the Cori cycle, lactate produced by muscle goes in the bloodstream to the _______ for conversion back to _______.

A

liver takes lactate and converts it back to glucose (acetyl CoA is an intermediate)

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22
Q

What is the net ATP yield from glycolysis alone?

A

2

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23
Q

What product of glycolysis is used in the electron transport chain to ultimately build up a proton gradient?

A

NADH

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24
Q

Name three organs that store glycogen.

A

Liver, muscle, kidneys

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25
Q

Glycogen stores are depleted after roughly ____ hours of fasting.

A

30

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26
Q

The first step in glycogen synthesis is glucose-1-P. The second step is…?

A

2nd step is a glucosyltransferase reaction (addition of a UDP to glucose) to activate the glucose

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27
Q

Name the two major enzymes in glycogen synthesis (after UDP addition).

A

glycogen synthase and branching enzyme

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28
Q

Which two enzymes are involved in glycogen breakdown? What does each one do?

A

glycogen phosphorylase-a breaks alpha-1,4 linkages up until 5 units away from a branching point. Note that it is active when phosphorylated (fasting state - glucagon present - glucagon phosphorylates everything)

debranching enzyme breaks alpha-1,6 linkages (the branches)

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29
Q

Glucokinase is found primarily in the _______ (an organ). Describe its kinetic properties (Km, Vmax) with respect to hexokinase.

A

glucokinase is in the liver

it has a much lower affinity (higher Km) than hexokinase but has a much higher Vmax than hexokinase.

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30
Q

What does glucose-6-phosphatase do? What is the disease called when you don’t have it?

A

It converts glucose-6-P to glucose (last step in gluconeogenesis).

Disease is called Von Gierke’s/glucose-6-phosphatase deficiency

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31
Q

Name 5 symptoms of Von Gierke’s disease and explain the physiological/biochemical basis for each.

A
  1. Hypoglycemia: glucose is unable to enter the bloodstream
  2. Hyperuremia: high glucose-6-P concentrations increase the forward reaction of the pentose phosphate pathway, resulting in lots of purines. Purine degradation –> high uric acid concentrations.
  3. Lactic acidosis: high glucose-6-P concentrations increase the forward reaction of glycolysis. However, glycolysis is “over-run” causing a buildup of pyruvate and NADH. To continue glycolysis, NADH reduces pyruvate to lactic acid.
  4. Hyperlipidemia: high glucose-6-P concentrations increase the forward reaction of glycolysis, which ultimately resulting in an increase of acetyl-CoA concentration. The backed up Krebs cycle forces triglyceride synthesis –> doll face (chubby cheeks from excess fat storage) and xanthomas.
  5. Hepatomegaly: high glucose-6-P concentrations increase the forward reaction of glycogenesis.
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32
Q

How does neutralization of reactive oxygen species relate to the pentose-phosphate pathway?

A

The PPP generates NADPH, which is used to reduce oxidized glutathione –> reduced glutathione. Reduced glutathione is used to convert peroxides to water.

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33
Q

What does superoxide dismutase do?

A

Turns O2- into H2O2 (hydrogen peroxide) for subsequent reaction by glutathione reductase –> H20

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34
Q

What type of glucose transporters are found on muscle and adipose cells?

A

GLUT4

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35
Q

Are GLUT4 transporters found in the liver?

A

Nope

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36
Q

Explain the correlation between glucose-6-phosphate DH deficiency and increased RBC susceptibility to oxidative stress.

A

No G-6-P DH means that the PP pathway can’t run –> no NADPH to deal with ROS –> denaturation of cytoskeletal proteins in RBCs –> loss of cell shape –> lysis in microvasculature –> Heinz bodies on blood smear

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37
Q

Name four things that can cause oxidative stress.

A
  1. Infection
  2. Fava beans
  3. Sulfa drugs
  4. Antimalarial drugs
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38
Q

Irreversible, non-enzymatic addition of a sugar on the N-terminal end of a protein is called ________.

A

glycation

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39
Q

What is HbA1c and what is its clinical significance?

A

HbA1c is glycated hemoglobin. Used clinically to measure a person’s glycemic status over the long-term (~4 months)

40
Q

If someone has recently had dialysis or a blood transfusion, would taking their HbA1c level be a good idea?

A

Nope

41
Q

How are you going to remember the Ras/ERK pathway for tyrosine kinase receptor activation?

A

After ligand binding and tyrosine residue auto-phosphorylation…

Grab (Grb2) help (SOS guanine exchange factor) Ras, Ras goes and gets his twin brother Raf and they both go get Dr. MekErk.

42
Q

What does ERK 1/2 do?

A

It is a master cell cycle regulator

43
Q

What type of receptor are growth factor receptors? Which signaling pathway do they use?

A

Tyrosine kinase –> Ras/ERK pathway

44
Q

Name three different type of G-proteins involved in GPCR signaling.

A
  1. Gαs
  2. Gαi/o
  3. Gαq
45
Q

Describe the events that occur in GPCR signaling from activation to termination of a Gαsβγ-coupled receptor.

A
  1. Ligand binds to receptor
  2. Gαs-GDPβγ comes over so the receptor can do a nucleotide exchange (GDP for GTP)
  3. Gαs-GTP dissociates from βγ
  4. Gαs-GTP activates adenylate cyclase.
  5. cAMP concentration increases
  6. cAMP activates PKA
  7. PKA phosphorylates -OH groups on serine and threonine residues
  8. GTPase on the Gαs hydrolyzes GTP –> GDP to turn off.
46
Q

What does Gαi/o do?

A

Inhibits adenylate cyclase –> decrease in cAMP

47
Q

What does Gαq do?

A

Activates PLCβ –> PIP2 cleavage –> IP3 and DAG.

IP3 binds to IP3 receptors on SER –> Ca2+ release.

DAG activates PKC.

48
Q

What do arrestins do to GPCRs?

A

They bind to phosphorylated GPCRs (GRKs phosphorylate them) to keep the receptor from activating G proteins or trigger endocytosis of the receptor.

49
Q

How does Gαs turn off?

A

It has intrinsic GTPase activity that will hydrolyze GTP –> GDP to turn off

50
Q

What kind of receptor is the insulin receptor? Outline the steps in the receptor pathway.

A

RTK

Ligand binds –> autophosphorylation –> IRS1 binds to phosphorylated tyrosine residues and activates/phosphorylates PI3K –> PIP2 phosphorylation –> PIP3 –> AKT phosphorylation and activation

51
Q

Phosphotyrosine residues of some RTKs can bind and activate ________, which also cleaves PIP2 to IP3 and DAG –> increase in Ca2+ and PKC activation. This is an example of _________.

A

PLCgamma

this is convergence

52
Q

Some Gαi and Gαq subunits can activate ADAM17, which can cleave EGFR ligands from cell membranes → activation of ________. This is called _________.

A

EGFR ligands bind to and activate RTKs.

This is called transactivation

53
Q

Where are steroid hormone receptors located in the cell?

A

Nucleus (stuck on promoter sequences on DNA) or in the cytoplasm.

54
Q

Hormone receptors are _________ (monomers or dimers) that upregulate transcription after binding their hormone. Nuclear hormone receptors __________ transcription when they are not hormone-bound, and upregulate transcription once they bind their hormone.

A

Hormone receptors are dimers (or the cytoplasmic ones dimerize after binding hormone)

Nuclear hormone receptors repress/downregulate transcription when not bound to hormone

55
Q

Chylomicrons that are formed in intestinal epithelial cells enter the lymphatic system through ________.

A

lacteals

56
Q

Which organ makes bile? What precursor molecule is used to make bile? What does it do?

A

Liver makes it from cholesterol. It emulsifies fats –> micelles

57
Q

After chylomicrons enter the bloodstream, ______ (an enzyme) breaks TAGs down to FFAs and glycerol for uptake by cells like muscle cells and adipocytes.

A

LPL (lipoprotein lipase)

58
Q

When the body needs to get some FFAs into the blood, ______ (an enzyme) in adipocytes breaks down TAGs into FFAs and glycerol for release into the blood. What does inulin do to this enzyme?

A

Hormone sensitive lipase. Insulin inhibits it

59
Q

In the first step of ketone body synthesis, two ________ are combined to form acetoacetyl coA.

A

two acetyl coAs

60
Q

Name two ketone bodies.

A

β-hydroxbutyrate and acetoacetate

61
Q

Name the four cellular responses to stress.

A
  1. Hypertrophy
  2. Hyperplasia
  3. Atrophy
  4. Metaplasia
62
Q

Loss of innervation can cause ________. The mechanism for this is self-degradation by lysosomal enzymes in a process called ________.

A

atrophy

autophagy

63
Q

The substitution of columnar epithelium for the stratified squamous epithelium at the squamocolumnar junction in the esophagus is an example of _________.

A

metaplasia

64
Q

Name four morphological changes that occur during reversible cell injury.

A
  1. ER dilation with detachment of polysomes
  2. Plasma membrane swelling
  3. Plasma membrane blebbing
  4. Loss of microvilli
65
Q

Name three bad things that reactive oxygen species can do to cells.

A
  1. Lipid peroxidation
  2. DNA fragmentation
  3. Protein crosslinking
66
Q

What does catalase do?

A

Turns hydrogen peroxide into water

67
Q

What does superoxide dismutase do?

A

Turns O2- into hydrogen peroxide

68
Q

Can vitamins somehow deal with ROS?

A

Yeah

69
Q

What are the three fancy words for nuclear changes seen during irreversible cell damage? Briefly describe each.

A
  1. Pyknosis: chromatin condensation
  2. Karyorrhexis: fragmentation of nucleus (chocolate chip cookie)
  3. Karyolysis: no more nucleus
70
Q

Cells shrink during ________, whereas during ________ cells will swell.

A

apoptosis - cells shrink

necrosis - cells swell

71
Q

_________ necrosis results from ischemia/infarction in most tissues except in the CNS.

A

Coagulative

72
Q

Preservation of the structural outline of dead cells is characteristic of which type of necrosis?

A

Coagulative

73
Q

Coagulative necrosis in the lungs is called a “wet pulmonary infarct” because the lungs have a dual ______ _______.

A

blood supply

74
Q

What tissues in the body predominantly undergo liquefactive necrosis?

A

Brain/CNS

75
Q

Liquefactive necrosis is characterized by the release of lysosomal enzymes by _______ and ______ ______that digest the tissue.

A

neutrophils and dead cells

76
Q

Can a bacterial abscess result in liquefactive necrosis? Why?

A

Yeah, cuz neutrophils come and try to eat everything.

77
Q

Dry gangrene occurs is a type of _______ necrosis that occurs when peripheral tissue is infarcted. Superimposition of gangrene with an anaerobic bacterial infection results in…?

A

type of coagulative necrosis

wet gangrene = dry gangrene + anaerobic infection

78
Q

Why do TB/fungal infections result in caseous necrosis?

A

When macrophages eat M. Tuberculosis and fungi there is a release of lipids from bacterial cell walls.

79
Q

Necrotizing granuloma is often seen with what type of infection? What are multinucleated giant cells often associated with?

A

TB!

TB!

80
Q

_________ necrosis is characterized by deposition of proteins like fibrin into blood vessel walls.

A

Fibrinoid

81
Q

Malignant hypertension and immune vasculitis can lead to _______ necrosis.

A

fibrinoid

82
Q

Fat necrosis typically occurs in the ________ (an organ) and is a result of digestive enzymes that liquefy fat membranes, leading to saponification and ________.

A

pancreas

saponification and calcification

83
Q

Briefly describe the sequence of events that occur during the intrinsic pathway of apoptosis.

A
  1. Cell stress leads to leakage of cytochrome C from mitochondria.
  2. Initiator caspases are activated.
  3. p53 arrests cell cycle and activates Bax.
  4. Bax is pro-apoptotic and inactivates Bcl2 (anti-apoptotic).
  5. Without Bcl2, cytochrome C leaks out of mitochondria like crazy and binds to Apaf-1, forming the apoptosome.
  6. Apoptosome activates executioner caspases.
84
Q

Bax, Bak, Bid, and Bim are _________, whereas Bcl2 is ________.

A

pro-apoptotic

Bcl2 is the only one we learned about that is anti-apoptotic

85
Q

In the extrinsic apoptotic pathway, _____ or _____ bind to extracellular “death” receptors, leading to a signaling cascade that ultimately activates _________ for apoptosis.

A

Fas or TNF bind to receptors

ultimately leads to activation of caspases

86
Q

Arachidonate is released from _________ in cell membranes by the enzyme _________ for eventual use as signaling molecules.

A

glycerophospholipids/membrane lipids –> arachidonate

phospholipase A2 is the enzyme

87
Q

What are eicosanoids?

A

Eicosanoids are the signaling molecules that originate from arachidonate - prosgaglandins, lipoxins, and leukotrienes

88
Q

Cyclooxygenase enzymes form which two major families of signaling molecules?

A

Prostaglandins and thromboxanes

89
Q

True or false: COX-1 is constitutively expressed for homeostatic functions, while COX-2 expression is induced by inflammatory cytokines.

A

tru dat

90
Q

What specific enzyme do corticosteroids inhibit?

A

Phospholipase A2

91
Q

Lipoxygenases convert arachidonate to ________ and ________.

A

leukotrienes and lipoxins

92
Q

NSAIDs inhibit which enzymes?

A

COX enzymes

93
Q

Which two classes of eicosanoids generally have antagonistic effects?

A

Thromboxanes and prostaglandins

94
Q

Which specific eicosanoid promotes vasodilation and decreases platelet aggregation?

A

PGI2 (prostacyclin)

95
Q

Which specific eicosanoid causes histamine release from mast cells to induce bronchoconstriction and vasodilation?

A

PGD2

96
Q

Which specific eicosanoid causes pain via sensitization of neurons, Na+ resporbtion in kidneys, and promotes house-keeping functions in gastric mucosa?

A

PGE2

97
Q

Why can chronic NSAID use potentially cause gastric ulcers?

A

NSAIDs block COX enzymes –> no PGE2 production (PGE2 stimulates production of gastric mucosa)

MS1 - MCBD (17 decks)

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