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OU PDA > Exam 3 > Flashcards

Exam 3 Flashcards

1
Q

Describe the structure in the prokaryotic ribosome

A
  • subunits: 50S + 30S = 70S
  • 50S has 34 different proteins, 5S rRNA, and 23S rRNA
  • 30S has 21 different proteins, 16S rRNA
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2
Q

Describe the structure in the eukaryotic ribosome

A
  • subunits: 60S + 40S = 80S
  • 60S has 28S and 5.8S rRNA
  • 40S has 18S rRNA
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3
Q

T/F: Microorganism synthesize small complex structures via nonribosomal protein synthesis.

A

FALSE; Microorganism synthesize LARGE complex structures via nonribosomal protein synthesis.

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4
Q

What are examples of some pharmaceutical agents that are synthesized via NRP?

A
  • cyclosporine
  • PCN
  • vancomycin
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5
Q

NRP

A

Nonribosomal Protein Synthesis

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6
Q

What are the four classes of drugs which target ribosomal protein?

A
  • Chloramphenicol
  • Macrolide antibiotics
  • Tetracyclines
  • Aminoglycosides
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7
Q

What is a mechanism for resistance for Chloramphenicol?

A

CAT: Chloramphenicol acetyl transferase; it acetylates one or both hydroxyl groups on Chloramphenicol and it can no longer bind to 50S

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8
Q

How does Chloramphenicol work?

A

binds to 50S subunit which inhibits peptide bond formation

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9
Q

What is the name for the active form of Chloramphenicol?

A

D-Threo

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10
Q

Which class of drug that target ribosomal protein is the most stable?

A

Aminoglycosides which is stable at pH of 2-11

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11
Q

How does Aminoglycosides work?

A

bind to 30S subunit which causes misreading of genetic code

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12
Q

How does resistance develop to Aminoglycosides?

A

there are at least 9 known active enzymes that do this:

  • adenylation of OH
  • phosphorylation of OH
  • acetylation of NH2
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13
Q

How is Aminoglycosides and PCN used in synergy?

A

PCN weakens the cell wall so that Aminoglycosides can enter the cell and reach its target

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14
Q

Characteristic of macrolides

A
  • 12, 14 or 16-member lactone ring (macrolide); odd # rings are possible
  • ketone group
  • glycosidically linked amino sugar and may also have a glycosidically linked neutral sugar
  • unstable basic compound
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15
Q

How does Macrolides work?

A

binds to 50S subunit which inhibits peptide bond formation

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16
Q

Describe the mechanism of resistance to Macrolides

A

bacteria undergoes genetic change which methylates an adenine at the binding site of the ribosome and Macrolide can no longer bind

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17
Q

How does Tetracylcines work?

A

prevents the binding of aminoacyl t-RNA

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18
Q

Describe the mechanism for resistance in Tetracyclines.

A
  • genetically modified ribosome protein binding site
  • efflux of antibiotic into the extracellular space; doesn’t happen to antibiotic molecule that is chelated with metal ion
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19
Q

Describe the peptidoglycan layer in gram positive and negative bacteria

A
  • gram positive: peptidoglycan much thicker layer outside the plasma membrane
  • gram negative: much thinner peptidoglycan layer between periplastic space (between inner and outer plasma membrane)
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20
Q

CWT site of action; what does it do?

A
  • cell wall transcriptidase
  • clips off the 5th alanine
  • attaches it to form a dimer
  • released from structure
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21
Q

Similarities and differences between penicllins and cephalosporins

A
  • both have beta lactam ring
  • penicillins has thiazolidine ring
  • cephalosporins have dihydrothiazine ring
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22
Q

What is also known as an octahydronaphthacene ring system?

A

tetracyclines

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23
Q

Molecularly, how does PCN work?

A

PCN is structurally similar to dAla-dAla; since 5th Ala is not covalently attached, it falls off; PCN is linked to the 4th dAla; PCN thio ring is covalently attached and does not fall off; CWT gets tied up and is not released

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24
Q

What does beta lactamase do?

A

similar to CWT, breaks open lactam ring and can disengage itself

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25
Q

Where can you find beta lactamase?

A
  • growing media of gram positive
  • periplastic space of gram negative
  • wants to kill PCN before it can take action
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26
Q

How does vancomycin work?

A

it surrounds itself around the two dAla-dAla so that it cannot be linked to another unit

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27
Q

Describe the mechanism for vancomycin resistance

A

since vanco is specific for dAla-dAla, bacteria can change the 5th Ala to Lac so that vanco cannot surround it; it has a vanco sensor

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28
Q

How do you treat bacterial infection that has a mycobacterial cell envelope structure?

A

isoniazid and pyridomycin inhibits mycolic acid synthesis; mycolic acid is needed for the cell wall

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29
Q

How does daptomycin work?

A

it inserts its lipid tail in the phospholipid bilayer enough to form a channel to form a leakage of its contents and kills the cell

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30
Q

How many different types of viruses are there in the flu?

A
  • type A can be transmitted between species

- type B cause infection only in human

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31
Q

With respect to viruses, how many types of hemagluttinin are there and what does it do?

A

18 different types; it binds to sialic acid and is taken up into the cell the multiply

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32
Q

With respect to viruses, how many types of neuraminidase are there and what does it do?

A

11 different types; chews up sialic acid because virus needs to get out of cell to infect other cells and sialic acid is in the way

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33
Q

What are plug drugs?

A

antivirals that target neuraminidase; it keeps them inside the cell they infected so they can’t infect neighboring cells

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34
Q

What are examples of plug drugs?

A
  • zanamivir

- tamiflu

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35
Q

What are examples of nucleoside antimetabolites and how do they act?

A
  • acyclovir and ganciclovir do not contain 3-hyrdoxyl group to support DNA synthesis
  • vidarabine has 3-hydroxyl group but is using arabinose sugar and OH is in opposite rotation; this slows down reaction
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36
Q

MOA of Thiocarbamate

A

Suppression of fungal squalene epoxidase to result in accumulation of squalene and decreased ergosterol

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37
Q

MOA of Allylamine

A

Suppression of fungal squalene epoxidase to result in accumulation of squalene and decreased ergosterol

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38
Q

MOA of Benzofuran cyclohexene

A

Binding to fungal DNA to cause malformation of spindle and cytoplasmic microtubules

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39
Q

MOA of Polyene

A

Binding to ergosterol in fungal cell membranes to result in membrane disorganization

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40
Q

MOA of Pyrimidine

A

Deamination by fungal cells to 5-fluorouracil which is incorporated into RNA in place of uracil or is converted to 5-fluorouracil-2’-deoxyuridylic acid which inhibits thymidine synthetase

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41
Q

MOA of Azole

A

inhibition of CYP450 that catalyzes 14a-demethylation of lanosterol to ergosterol, accumulation of 14-methylated sterols cause permeability disruption

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42
Q

What are the precursors for Ergosterol?

A

Squalene -> Squalene epoxide -> Lanosterol -> Ergosterol

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43
Q

Structure of polyene

A

Conjugated system of double bonds in large lactone rings

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44
Q

What are things to consider for selective drug action?

A
  • biochemical pathway
  • enzyme structure
  • cell structures
  • accumulation of drugs at target site
45
Q

What are the drugs which inhibit DHFR?

A
  • Trimethoprim - antibacterial
  • Pyrimethamine - antimalaria
  • Methotrexate - anticancer
46
Q

Methotrexate can inhibit bacterial DHFR but why is it used as an anticaner instead of antibacterial?

A

because it has a complex structure; also bacterial cells do not absorb it because they lack a transporter system

47
Q

What does disposition refer to?

A

total fate of a drug; ADME

48
Q

In general, how does metabolism affect the solubility of drugs?

A

it increases the solubility in order to increase excretion of the drug

49
Q

What can metabolism do to an active and inactive drug?

A
  • active drugs can be: inactive metabolite, active metabolite, reactive metabolite
  • inactive drugs can be: active metabolite
50
Q

Examples of morphine metabolite

A
  • active to inactive: Morphine → Morphine-3-glucuronid or -sulfate
  • active to active: Morphine → Morphine-6-glucuronid (more active)
  • inactive to active: Codeine → Morphine
51
Q

In general with respect to metabolism, what are the effects of phase I and phase II on hydrophilicity?

A
  • phase I: small increase in hydrophilicity

- phase II: large increase in hydrophilicity

52
Q

What are the components and consequences of phase I metabolism?

A
  • Oxidation, reduction, hydrolysis

- exposes xenobiotic molecule to: -OH, -NH2, -COOH, -SH

53
Q

What are the components and consequences of phase II metabolism?

A
  • conjugations of: glucuronidation, sulfation, glutathione, amino acid, acetylation, methylation
  • all except acetylation and methylation increase water solubility
54
Q

What is the most important enzyme in phase I metabolism?

A

CYP450 with CYP3A being the most important

55
Q

Where is CYP450 located?

A
  • in ER membrane

- in microsomes (which is the precipitate of grinding tissue liver)

56
Q

What are microsomes?

A

membrane vesicles re-formed from pieces of ER when eukaryotic cells are broken up in the laboratory

57
Q

Explain the reaction catalyzed by CYP450 (cyp450 dependent reactions)

A
  • CYP450-dependent oxidation occurs at the ER membrane (adds O to molecule)
  • requires molecular O and NADPH along with CYP450 reductase (AKA NADPH oxidoreductase)
58
Q

CYP450-dependent oxidation can cause epoxidation and form toxic epoxides. What helps combats this?

A
  • EH = epoxide hydrolases

- gets rid of epoxides by converting epoxide to hydroxyl group

59
Q

Examples of CYP450-independent oxidation catalyzing enzymes

A
  • Flavin monooxygenase (FMO)
  • Amine oxidase
  • Dehydrogenations: alcohol dehydrogenase
60
Q

Properties of flavin mono-oxygenase (FMO)

A
  • not easily induced nor readily inhibited

- potential adverse drugdrug interactions are minimized

61
Q

Properties of dehydrogenase

A

helps get rid of ethanol in the body

62
Q

Examples of hydrolysis catalyzing enzymes

A
  • Epoxide hydrolase (EH)
  • Esterases
  • Peptide hydrolase
  • Lactone hydrolase
63
Q

Properties of esterases

A

converts ester prodrugs to their active metabolite

64
Q

Give an example of esterase clearing a drug (specifically the one in class she wanted us to know)

A
  • esterase clears succinylcholine which gives it a short half life
  • succinylcholine is used as a muscle relaxer in anesthesia
65
Q

What is the most important form of phase II metabolism?

A

Glucuronidation

66
Q

Players of Glucuronidation

A
  • Enzyme: Glucuronosyltransferase (UGT)
  • Cofactor: UDP-glucuronic acid (UDP-GA)
  • Conjugating agent: GA
67
Q

Properties of Glucuronidation

A
  • GA derived from glucose
  • UDP-GA is not selective
  • UGT in liver ER and microsome
  • increases molecular weight, water solubility, and excretion in urine and bile
68
Q

How is bilirubin cleared from the body?

A

undergo glucuronidation to be excreted

69
Q

What causes “blue baby syndrome” or “grey baby syndrome”?

A
  • babies have low UGT activity
  • chloramphenicol is cleared by glucuronidation
  • if chloramphenicol cannot be cleared from body, it causes hypotension
  • hypotension causes blue or grey skin
70
Q

Players of Sulfation

A
  • Enzyme: Sulfotransferases (SULs)
  • PAPS (made from ATP + sulfate group)
  • Conjugating agent: sulfate group
  • Targets: phenols, alcohols, amines
71
Q

How does APAP overdose work if APAP can be metabolized by sulfation and glucuronidation?

A

in APAP overdose, UDP-GA, PAPS, and GSH are depleted which allows formation of toxic metabolite NAPQI and for it to react with hepatic proteins -> hepatotoxicity

72
Q

Players of Glutathione

A
  • Enzymes: glutathione S-transferases (GSTs)
  • Cofactor: Glutathione (GSH)
  • Conjugating agent: Glutathione (GSH)
  • Targets: Electrophilic Functional Groups
73
Q

Properties of Glutathione

A
  • abundant in liver

- GSH conjugates excreted in urine as mercapturic acids

74
Q

Fates of NAPQI

A
  • formed by phase I metabolism

- can be prevented from build up in the body by: glucuronidation, sulfation, GSH conjugation

75
Q

Players of Acetylation

A
  • Enzyme: N-acetyltransferases (NATs), cytosolic enzyme
  • Cofactor: Acetyl coenzyme A
  • Targets: Aromatic amines, Alcohols
76
Q

Properties of Acetylation

A
  • primarily occur in liver
  • derivatives less water soluble
  • acetylation of aromatic N-OH groups form a toxic derivative (ex. isoniazid)
77
Q

Where are CYP450 reactions present?

A

in all tissues but most in the liver

78
Q

Describe the liver blood supply

A
  • 25% comes from hepatic artery (high O)
  • 75% comes from portal vein (low O)
  • well perfused; receives 30% cardiac output
79
Q

What does the portal triad consists of?

A
  • portal vein
  • hepatic artery
  • bile duct
80
Q

Define acinus

A

functional unit of the liver; located between two central veins

81
Q

Zone 1

A

periportal zone, high oxygen

82
Q

Zone 3

A

pericentral zone, low oxygen, CYP3A4 expressed around this area

83
Q

Why does necrosis tend to start at Zone 3? (with respect to APAP overdose)

A
  • rich in cyp which forms the toxic form of APAP

- low in GSH and sulfation

84
Q

What are some high ER (extraction ratio) drugs that we need to consider? [was in red text on her slides]

A
  • cocaine
  • morphine
  • nitroglycerin
85
Q

How does grapefruit juice (GFJ) affect the concentration of statins?

A
  • GFJ inhibits CYP450
  • which inhibits first pass effect
  • does now allow statin to be metabolized
  • concentration of statin increases -> overdose -> rhabdomyolysis
86
Q

What are two well known cyp inducers?

A
  • Rifampin

- St. John’s wort

87
Q

What does inducers do?

A

they raise the concentration / activity of cyp enzymes which increases metabolism which decrease drug concentration / activity

88
Q

What are CYP3A4 inhibitors? (red text on her slides)

A
  • grapefruit juice
  • ketoconzaole
  • ritonavir
  • cyclosporine
89
Q

Define pharmacodynamics

A

what the drug is doing to the body; mechanism of action which depends on chemical structure and drug concentration

90
Q

What are factors to consider when wanting to achieve optimal concentration of drug at receptor site?

A
  • dose administered

- PK of drug (ADME)

91
Q

Define pharmacokinetics

A

what the body is doing to the drug

92
Q

What is the difference between serum and plasma?

A
  • plasma contains fibrin and soluble clotting factors
  • serum does not contain fibrin and clotting factors
  • drug concentration should be relatively same in both unless your drug binds to clotting factors
93
Q

Define the PK compartments

A
  • one compartments for well perfused tissues: drug distributes rapidly and uniformly
  • two compartments for poorly perfused tissues: central and peripheral compartment and slow distribution between the two
94
Q

The rates of plasma concentration are determined by what two processes?

A
  • rate of appearance into plasma

- rate of elimination from plasma

95
Q

Define first order absorption

A

rate of absorption of dependent on the amount of drug available for absorption

96
Q

With respect to absorption and elimination, what is Cmax?

A

when Ka = Ke

97
Q

MSC

A

Maximum Safety concentration

98
Q

MTC

A

Minimum toxic concentration

99
Q

What is a second messenger?

A

molecule that is part of the cascade of events that translates ligand binding into a cellular response

100
Q

Properties of ligand-gated ion channels

A
  • very rapid
  • depol and hyperpol
  • in neurotranmission, cardiac conduction, muscle contraction
101
Q

Properties of transmembrane G protein-coupled receptors (GPCRs)

A
  • has 7 transmembrane proteins
  • adrenergic receptors, opioid receptors
  • agonist binds -> GEF adds GTP to α-GDP -> activated -> β and γ subunit falls off to do other things
102
Q

Properties of enzyme-linked receptors

A

ligand binds -> dimerization -> autophosphorylation

103
Q

Properties of intracellular receptors

A

enter cell membrane -> bind to receptor -> R* -> binds to DNA

104
Q

What happens when NE or EPI binds to the beta receptors?

A

Gs activates adenylate cyclase to convert ATP to cAMP -> kinase -> phosphorylation -> response

105
Q

What happens when NE or EPI binds to the alpha receptors?

A

Gi inhibits adenylate cyclase from producing cAMP -> decreased concentrations of cAMP

106
Q

What happens when NE or EPI binds to the alpha or beta receptor?

A

alpha subunit of Gq falls off and attaches to phopholipase C -> PIP2 -> IP3 + DAG -> kinase -> phosphorylation -> response

107
Q

NOS

A
  • nitric oxide synthase
  • makes NO from arginine
  • there are three different isoforms
  • NO acts as vasodilator
108
Q

Cyclic Guanosine mono-phosphate (cGMP)

A
  • vasodilator
  • synthesized from GTP
  • broken down by phosphodiesterase (PDE)
109
Q

Gβγ subunits

A
  • increase activity of inward potassium channels

- increase phosphatidyl inositol-3-kinase enzyme (PI3K)

OU PDA (8 decks)

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