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
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
3
Q
T/F: Microorganism synthesize small complex structures via nonribosomal protein synthesis.
A
FALSE; Microorganism synthesize LARGE complex structures via nonribosomal protein synthesis.
4
Q
What are examples of some pharmaceutical agents that are synthesized via NRP?
A
- cyclosporine
- PCN
- vancomycin
5
Q
NRP
A
Nonribosomal Protein Synthesis
6
Q
What are the four classes of drugs which target ribosomal protein?
A
- Chloramphenicol
- Macrolide antibiotics
- Tetracyclines
- Aminoglycosides
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
8
Q
How does Chloramphenicol work?
A
binds to 50S subunit which inhibits peptide bond formation
9
Q
What is the name for the active form of Chloramphenicol?
A
D-Threo
10
Q
Which class of drug that target ribosomal protein is the most stable?
A
Aminoglycosides which is stable at pH of 2-11
11
Q
How does Aminoglycosides work?
A
bind to 30S subunit which causes misreading of genetic code
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
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
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
15
Q
How does Macrolides work?
A
binds to 50S subunit which inhibits peptide bond formation
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
17
Q
How does Tetracylcines work?
A
prevents the binding of aminoacyl t-RNA
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
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)
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
21
Q
Similarities and differences between penicllins and cephalosporins
A
- both have beta lactam ring
- penicillins has thiazolidine ring
- cephalosporins have dihydrothiazine ring
22
Q
What is also known as an octahydronaphthacene ring system?
A
tetracyclines
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
24
Q
What does beta lactamase do?
A
similar to CWT, breaks open lactam ring and can disengage itself
25
Where can you find beta lactamase?
- growing media of gram positive
- periplastic space of gram negative
- wants to kill PCN before it can take action
26
How does vancomycin work?
it surrounds itself around the two dAla-dAla so that it cannot be linked to another unit
27
Describe the mechanism for vancomycin resistance
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
28
How do you treat bacterial infection that has a mycobacterial cell envelope structure?
isoniazid and pyridomycin inhibits mycolic acid synthesis; mycolic acid is needed for the cell wall
29
How does daptomycin work?
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
30
How many different types of viruses are there in the flu?
- type A can be transmitted between species
| - type B cause infection only in human
31
With respect to viruses, how many types of hemagluttinin are there and what does it do?
18 different types; it binds to sialic acid and is taken up into the cell the multiply
32
With respect to viruses, how many types of neuraminidase are there and what does it do?
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
33
What are plug drugs?
antivirals that target neuraminidase; it keeps them inside the cell they infected so they can't infect neighboring cells
34
What are examples of plug drugs?
- zanamivir
| - tamiflu
35
What are examples of nucleoside antimetabolites and how do they act?
- 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
36
MOA of Thiocarbamate
Suppression of fungal squalene epoxidase to result in accumulation of squalene and decreased ergosterol
37
MOA of Allylamine
Suppression of fungal squalene epoxidase to result in accumulation of squalene and decreased ergosterol
38
MOA of Benzofuran cyclohexene
Binding to fungal DNA to cause malformation of spindle and cytoplasmic microtubules
39
MOA of Polyene
Binding to ergosterol in fungal cell membranes to result in membrane disorganization
40
MOA of Pyrimidine
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
41
MOA of Azole
inhibition of CYP450 that catalyzes 14a-demethylation of lanosterol to ergosterol, accumulation of 14-methylated sterols cause permeability disruption
42
What are the precursors for Ergosterol?
Squalene -> Squalene epoxide -> Lanosterol -> Ergosterol
43
Structure of polyene
Conjugated system of double bonds in large lactone rings
44
What are things to consider for selective drug action?
- biochemical pathway
- enzyme structure
- cell structures
- accumulation of drugs at target site
45
What are the drugs which inhibit DHFR?
- Trimethoprim - antibacterial
- Pyrimethamine - antimalaria
- Methotrexate - anticancer
46
Methotrexate can inhibit bacterial DHFR but why is it used as an anticaner instead of antibacterial?
because it has a complex structure; also bacterial cells do not absorb it because they lack a transporter system
47
What does disposition refer to?
total fate of a drug; ADME
48
In general, how does metabolism affect the solubility of drugs?
it increases the solubility in order to increase excretion of the drug
49
What can metabolism do to an active and inactive drug?
- active drugs can be: inactive metabolite, active metabolite, reactive metabolite
- inactive drugs can be: active metabolite
50
Examples of morphine metabolite
- active to inactive: Morphine → Morphine-3-glucuronid or -sulfate
- active to active: Morphine → Morphine-6-glucuronid (more active)
- inactive to active: Codeine → Morphine
51
In general with respect to metabolism, what are the effects of phase I and phase II on hydrophilicity?
- phase I: small increase in hydrophilicity
| - phase II: large increase in hydrophilicity
52
What are the components and consequences of phase I metabolism?
- Oxidation, reduction, hydrolysis
| - exposes xenobiotic molecule to: -OH, -NH2, -COOH, -SH
53
What are the components and consequences of phase II metabolism?
- conjugations of: glucuronidation, sulfation, glutathione, amino acid, acetylation, methylation
- all except acetylation and methylation increase water solubility
54
What is the most important enzyme in phase I metabolism?
CYP450 with CYP3A being the most important
55
Where is CYP450 located?
- in ER membrane
| - in microsomes (which is the precipitate of grinding tissue liver)
56
What are microsomes?
membrane vesicles re-formed from pieces of ER when eukaryotic cells are broken up in the laboratory
57
Explain the reaction catalyzed by CYP450 (cyp450 dependent reactions)
- 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
CYP450-dependent oxidation can cause epoxidation and form toxic epoxides. What helps combats this?
- EH = epoxide hydrolases
| - gets rid of epoxides by converting epoxide to hydroxyl group
59
Examples of CYP450-independent oxidation catalyzing enzymes
- Flavin monooxygenase (FMO)
- Amine oxidase
- Dehydrogenations: alcohol dehydrogenase
60
Properties of flavin mono-oxygenase (FMO)
- not easily induced nor readily inhibited
| - potential adverse drugdrug interactions are minimized
61
Properties of dehydrogenase
helps get rid of ethanol in the body
62
Examples of hydrolysis catalyzing enzymes
- Epoxide hydrolase (EH)
- Esterases
- Peptide hydrolase
- Lactone hydrolase
63
Properties of esterases
converts ester prodrugs to their active metabolite
64
Give an example of esterase clearing a drug (specifically the one in class she wanted us to know)
- esterase clears succinylcholine which gives it a short half life
- succinylcholine is used as a muscle relaxer in anesthesia
65
What is the most important form of phase II metabolism?
Glucuronidation
66
Players of Glucuronidation
- Enzyme: Glucuronosyltransferase (UGT)
- Cofactor: UDP-glucuronic acid (UDP-GA)
- Conjugating agent: GA
67
Properties of Glucuronidation
- 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
How is bilirubin cleared from the body?
undergo glucuronidation to be excreted
69
What causes "blue baby syndrome" or "grey baby syndrome"?
- 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
Players of Sulfation
- Enzyme: Sulfotransferases (SULs)
- PAPS (made from ATP + sulfate group)
- Conjugating agent: sulfate group
- Targets: phenols, alcohols, amines
71
How does APAP overdose work if APAP can be metabolized by sulfation and glucuronidation?
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
Players of Glutathione
- Enzymes: glutathione S-transferases (GSTs)
- Cofactor: Glutathione (GSH)
- Conjugating agent: Glutathione (GSH)
- Targets: Electrophilic Functional Groups
73
Properties of Glutathione
- abundant in liver
| - GSH conjugates excreted in urine as mercapturic acids
74
Fates of NAPQI
- formed by phase I metabolism
| - can be prevented from build up in the body by: glucuronidation, sulfation, GSH conjugation
75
Players of Acetylation
- Enzyme: N-acetyltransferases (NATs), cytosolic enzyme
- Cofactor: Acetyl coenzyme A
- Targets: Aromatic amines, Alcohols
76
Properties of Acetylation
- primarily occur in liver
- derivatives less water soluble
- acetylation of aromatic N-OH groups form a toxic derivative (ex. isoniazid)
77
Where are CYP450 reactions present?
in all tissues but most in the liver
78
Describe the liver blood supply
- 25% comes from hepatic artery (high O)
- 75% comes from portal vein (low O)
- well perfused; receives 30% cardiac output
79
What does the portal triad consists of?
- portal vein
- hepatic artery
- bile duct
80
Define acinus
functional unit of the liver; located between two central veins
81
Zone 1
periportal zone, high oxygen
82
Zone 3
pericentral zone, low oxygen, CYP3A4 expressed around this area
83
Why does necrosis tend to start at Zone 3? (with respect to APAP overdose)
- rich in cyp which forms the toxic form of APAP
| - low in GSH and sulfation
84
What are some high ER (extraction ratio) drugs that we need to consider? [was in red text on her slides]
- cocaine
- morphine
- nitroglycerin
85
How does grapefruit juice (GFJ) affect the concentration of statins?
- GFJ inhibits CYP450
- which inhibits first pass effect
- does now allow statin to be metabolized
- concentration of statin increases -> overdose -> rhabdomyolysis
86
What are two well known cyp inducers?
- Rifampin
| - St. John's wort
87
What does inducers do?
they raise the concentration / activity of cyp enzymes which increases metabolism which decrease drug concentration / activity
88
What are CYP3A4 inhibitors? (red text on her slides)
- grapefruit juice
- ketoconzaole
- ritonavir
- cyclosporine
89
Define pharmacodynamics
what the drug is doing to the body; mechanism of action which depends on chemical structure and drug concentration
90
What are factors to consider when wanting to achieve optimal concentration of drug at receptor site?
- dose administered
| - PK of drug (ADME)
91
Define pharmacokinetics
what the body is doing to the drug
92
What is the difference between serum and plasma?
- 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
Define the PK compartments
- 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
The rates of plasma concentration are determined by what two processes?
- rate of appearance into plasma
| - rate of elimination from plasma
95
Define first order absorption
rate of absorption of dependent on the amount of drug available for absorption
96
With respect to absorption and elimination, what is Cmax?
when Ka = Ke
97
MSC
Maximum Safety concentration
98
MTC
Minimum toxic concentration
99
What is a second messenger?
molecule that is part of the cascade of events that translates ligand binding into a cellular response
100
Properties of ligand-gated ion channels
- very rapid
- depol and hyperpol
- in neurotranmission, cardiac conduction, muscle contraction
101
Properties of transmembrane G protein-coupled receptors (GPCRs)
- 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
Properties of enzyme-linked receptors
ligand binds -> dimerization -> autophosphorylation
103
Properties of intracellular receptors
enter cell membrane -> bind to receptor -> R* -> binds to DNA
104
What happens when NE or EPI binds to the beta receptors?
Gs activates adenylate cyclase to convert ATP to cAMP -> kinase -> phosphorylation -> response
105
What happens when NE or EPI binds to the alpha receptors?
Gi inhibits adenylate cyclase from producing cAMP -> decreased concentrations of cAMP
106
What happens when NE or EPI binds to the alpha or beta receptor?
alpha subunit of Gq falls off and attaches to phopholipase C -> PIP2 -> IP3 + DAG -> kinase -> phosphorylation -> response
107
NOS
- nitric oxide synthase
- makes NO from arginine
- there are three different isoforms
- NO acts as vasodilator
108
Cyclic Guanosine mono-phosphate (cGMP)
- vasodilator
- synthesized from GTP
- broken down by phosphodiesterase (PDE)
109
Gβγ subunits
- increase activity of inward potassium channels
| - increase phosphatidyl inositol-3-kinase enzyme (PI3K)
OU PDA
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