Pharm Flashcards
(255 cards)
1
Q
TQ
Which 2 drugs disrupt DNA & RNA integrity by inhibiting purine ring biosynthesis and nucleotide interconversion?
A
6-Mercaptopurine
6-Thioguanine
2
Q
TQ
What is the mechanism of fludarabine (2-F-araA)?
A
Tumor cell kinases convert 2-F-araA to nucleotide triphosphates »_space; inserted into DNA/RNA and disrupts synthesis
3
Q
TQ
Name the drug.
Tumor cell kinases convert it to nucleotide analogs; inhibits DNA synthesis; also potent inhibitor of ribonucleotide reductase
A
Cladribine
2-Cl-deoxyadenosine
4
Q
What are the 4 purine antimetabolites?
A
6-Mercaptopurine (6-MP)
6-thioguanine (6-TG)
Fludarabine (2-F-araA)
Cladribine (2-Cl-deoxyadenosine)
5
Q
TQ
What is the therapeutic use of 6-MP?
A
Maintenance of remission in acute lymphocytic leukemia (ALL)
6
Q
TQ
What is the therapeutic use of 6-TG?
A
Acute non-lymphocytic leukemia (with daunorubicin & cytarabine)
7
Q
TQ
What are the 3 therapeutic uses of fludarabine (2-F-araA)?
A
Chronic lymphocytic leukemia (CLL) *
Hairy cell leukemia
Non-Hodgkin’s lymphoma (indolent-type)
8
Q
TQ
What are the 3 therapeutic uses of cladribine?
A
Hairy cell leukemia *
Non-Hodgkin’s lymphoma
Chronic lymphocytic leukemia (CLL)
9
Q
TQ
What are the 3 dose-limiting toxicities of 6-MP?
A
- Myelosuppression
- Dose adjustment with allopurinol or febuxostat (xanthine oxidase inhibitor) *
- Hepatotoxicity»_space; jaundice
10
Q
What are the 2 dose-limiting toxicities of 6-TG?
A
- Myelosuppression
- Hepatotoxicity with long term use
11
Q
What are the 2 dose-limiting toxicities of fludarabine (2-F-araA)?
A
- Myelosuppression
- Opportunistic infections
IV only to avoid intestinal bacteria generating toxic fluoroadenine.
12
Q
What are the 2 dose-limiting toxicities of cladribine?
A
- Myelosuppression
- Drug fever
13
Q
TQ
Explain the hepatic inactivation of 6-MP:
What 2 enzymes are at work?
What 2 inactive metabolites result?
A
6-MP goes into the liver….
- TPMT (thiopurine methyltransferase) »_space; Methyl-6-MP
- XO (xanthine oxidase) »_space; 6-Thiouric acid
14
Q
TQ
What is the first bioactivation enzyme as 6-MP meets the liver?
What is the resultant metabolite?
A
- Enzyme = HPRT
- Resultant metabolite = TIMP
15
Q
TQ
TIMP is turned into what 2 active nucleotide metabolites that are anti-neoplastic?
What 2 enzymes are used?
A
- 6-methyl-TIMP ribonucleotides (via TPMT)
- TXMP (via IMPDH)
16
Q
TQ
Which 2 liver enzymes inactivate 6-MP?
A
TPMT and XO
17
Q
TQ
Explain 6-MP toxicity due to drug interaction with gout meds.
A
- Gout meds (allopurinol & febuxostat) inhibit xanthine oxidase »_space; decreases uric acid
- Allopurinol & febuxostat inhibit metabolism of xanthine drugs (6-MP, azathioprine, theophylline) used in cancer chem, immunosuppression & asthma »_space; Risk of overexposure and requires dose adjustments
18
Q
TQ
Explain how chemotherapy can sometimes cause abrupt death of vast #’s of tumor cells, e.g., especially in leukemia or lymphoma.
What syndrome is this called?
A
Chemicals released from dying cells can produce hyperuricemia, hyperkalemia, hyperphosphatemia (hypocalcemia).
Tumor lysis syndrome
19
Q
TQ
Acute nephrotoxicity produced by excessive uric acid from tumor lysis syndrome is managed by co-administration of:
A
Allopurinol (a xanthine oxidase inhibitor)
20
Q
TQ
What is the problem with simultaneous administration of allopurinol & 6-MP?
How do you combat this problem?
A
Simultaneous administration of allopurinol & 6-MP chemotherapy can result in excessive exposure to 6-MP because it is metabolized (inactivated) by xanthine oxidase.
To avoid this problem, the dose of 6-MP must be reduced.
21
Q
What is pegloticase indicated for?
A
Hyperuricemia assoc with malignancy (tumor lysis syndrome)
22
Q
TQ
What is unique about 6-TG in terms of drug interaction with XO inhibitors?
A
6-TG bypasses the XO inactivation step.
Therefore, it has no drug interaction with XO inhibitors (allopurinol or febuxostat).
23
Q
TQ
6-TG is activated by what enzyme?
A
HPRT (makes 6-thio-GMP)
24
Q
6-thio-GMP is activated by kinases and reductases to make:
A
6-thio-dGTP
6-thio-GTP
25
TQ
| 6-TG is inactivated by what enzyme?
TPMT
26
TQ
| What is the risk and benefit assoc with the (H/H) genetic variant of TPMT (high TPMT activity)?
Risk: Relapse
Benefit: Lower toxicity
27
TQ
| What is the risk and benefit assoc with the (L/L) genetic variant of TPMT (low TPMT activity)?
Risk: Myelosuppression and secondary malignancy
Benefit: Efficacy
28
TQ
| Which metabolite inhibits de novo purine synthesis?
TIMP
| the closest thing to inhibiting de novo purine synthesis
29
TQ
| What is the mechanism of fludarabine and cladribine?
Fludarabine and cladribine enter tumor cells by active transport.
Converted to nucleotide mono-, di-, and tri-phosphates, and deoxynucleotide di- and tri-phosphates.
These active metabolites inhibit DNA polymerase and have damaging effects as they're incorporated into DNA/RNA.
30
TQ
| Anti-metabolites act against tumor cells that are in what phase of the cell cycle?
S-phase
| DNA synthesis as chromosome duplicate
31
TQ
| With adjuvant therapy you can expect to see _ log kill.
2 log kill
32
What is the diagnostic threshold in terms of cell count?
10^9 cells = detectable tumor
33
TQ
| E.g., If detectable growth of a tumor levels off around age 52, would a cell cycle-specific agent be efficacious?
No...
If growth of the tumor is leveling off, an agent that acted on cells in S-phase would not help at all.
34
```
Drug class that inhibits tubulin polymerization (blocks assembly of microtubules):
Name 3 drugs in the class.
```
Vinca alkaloids.
- Vinblastine
- Vincristine
- Vinorelbine
35
```
Drug class that enhances tubulin polymerization (stabilizes microtubules so they're excessively long and don't work):
Name 2 drugs in the class.
```
Taxanes.
- Taxol (Paclitaxel)
- Taxotere (Docetaxel)
36
TQ
| What is the 3-drug therapeutic regimen for testicular cancer?
Vinblastine with bleomycin & cisplatin
37
Name 5 therapeutic uses for vincristine.
```
ALL (pediatric)
Lymphoma
Neuroblastoma
Wilms' tumor
Ewing's sarcoma
```
38
Therapeutic use for vinorelbine.
Advanced NSCL cancer (alone or with cisplatin)
39
What is the 2-drug therapeutic regimen for ovarian cancer?
Paclitaxel with cisplatin
40
Therapeutic use for docetaxel:
Advanced breast, ovarian recurrence
41
Taxanes are effective against:
Solid tumors
42
Main dose limiting toxicity of vincristine:
Neurotoxicity, peripheral neuropathy
43
Vinca alkaloids have a generic dose limiting toxicity of:
Bone marrow suppression
44
Taxanes have a generic dose limiting toxicity of:
Neutropenia, peripheral neuropathy
45
TQ
| What is the mechanism of vinca alkaloids?
-Bind to B-tubulin at the forming end of microtubules and inhibit polymerization ('fraying' end continues)
i.e., inhibit microtubule elongation
(rate of depolymerization > rate of polymerization)
46
TQ
| What is the mechanism of taxanes?
- Bind to B-tubulin at the forming end of microtubules (once taxanes reach the negative end, they inhibit 'fraying' disassembly)
i. e., enhanced tubulin polymerization >> excessively long microtubules that don't work
47
TQ
| Vinca alkaloids and taxanes are cell cycle-specific and act on cells in which phase?
M-phase
48
TQ
| Peripheral neuropathy or neuritis are adverse effects of:
Vinca alkaloids
| Taxanes
49
TQ
What is the name of an agent that works like taxanes, but does not produce MDR, and is used in breast cancer pts who have failed anthracycline antibiotic and taxane treatments?
Ixabepilone
50
TQ
| Multi-drug resistance is established in tumor cells through the expression of an efflux pump called:
P-glycoprotein
51
TQ
| Etoposide and teniposide are inhibitors of topoisomerase _, which cause what type of breaks in DNA?
Etoposide and teniposide:
- Inhibit topoisomerase II
- Double strand DNA breaks
52
TQ
| Irinotecan and topotecan are inhibitors of topoisomerase _, which cause what type of breaks in DNA?
Irinotecan and topotecan:
- Inhibit topoisomerase I
- Single strand DNA breaks
53
TQ
| 2 therapeutic uses of etoposide:
- Oat cell carcinoma of lung
| - Testicular cancer (with cisplatin & bleomycin)
54
TQ
| 2 therapeutic uses for teniposide:
- Glioma
| - Neuroblastoma
55
TQ
| Therapeutic use of irinotecan:
Metastatic colorectal cancer
56
TQ
| Main toxicity of irinotecan:
Severe diarrhea
57
TQ
E.g., Someone fails prior therapy, tries new therapy, had to halt it because pt had severe diarrhea. When I looked at cell damage, what did I find?
Single strand DNA break.
How we arrived at answer:
Treated with irinotecan... Topoisomerase I inhibitor... Single strand DNA break.
58
Leukopenia is a dose limiting toxicity of which drug class?
Epipodophyllotoxins:
- Etoposide
- Teniposide
59
Mechanism of topoisomerase inhibitors:
Bind to DNA-enzyme complex and create a 'persistently cleavable complex'
60
TQ
| Topoisomerase I inhibitors (captothecins – irinotecan and topotecan) work primarily in what phase of the cell cycle?
S phase
61
TQ
Topoisomerase II inhibitors (epipodophyllotoxins – etoposide and teniposide) work primarily in what 2 phases of the cell cycle?
S phase
| G2 phase
62
TQ
| Which antibiotic works through Fe2+/3+ mediated free radical generation, leading to DNA strand breaks?
Bleomycin
63
TQ
| Therapeutic use of bleomycin:
Testicular cancer
| with vinblastine, cisplatin or etoposide
64
Doxorubicin and epirubicin are primarily used for:
Solid tumors.
| -wide spectrum of use – breast, ovarian, lung, lymphoma, sarcoma, etc
65
TQ
| Daunorubicin and idarubicin are primarily used for:
Hematologic cancers (e.g., leukemia)
- Daunorubicin – leukemia (AML, ALL)
- Idarubicin – leukemia (AML, ALL, CML blast crisis)
66
Mitoxantrone is used for several cancers, such as:
Breast, prostate, non-Hodgkin's lymphoma
67
TQ
| The main toxicity associated with bleomycin is:
Pulmonary fibrosis
68
```
TQ
Anthracyclines (doxorubicin*, daunorubicin, epirubicin, idarubicin) have a dose limiting toxicity of:
```
Dilated cardiomyopathy *
Cardiotoxicity
CHF
69
What is the mechanism of anthracyclines?
Intercalate between DNA double helix and create distortions that disrupt DNA integrity and inhibit RNA synthesis & replication
70
TQ
| How does doxorubicin cause superoxide oxidative DNA damage?
- DOX combines with O2, which uses Cyp450 reductase to make superoxide from O2 and DOX Semi-quinone from DOX
- Superoxide (H2O2) then causes strand breaks in DNA
71
TQ
| Bleomycin causes damage to what 2 tissues?
Skin and lung
72
TQ
E.g., Pt presents with dyspnea and rales with dry cough and infiltrate while trying to treat his testicular cancer. What is the mechanism of the drug that he was prescribed?
Pulmonary fibrosis symptoms... Bleomycin... Fe2+/3+ mediated free radical generation >> oxidative DNA damage (strand breaks)
73
TQ
E.g., Pt presents with murmur and enlarged ventricles upon imaging study. Use of what drug caused these symptoms over time?
Doxorubicin
| or any anthracycline
74
TQ
| Bleomycin and anthracyclines are most active in which cell cycle phase?
G2 phase (a little S phase too)
75
Therapeutic use of dacarbazine (triazene; DNA alkylation):
Metastatic melanoma
76
Therapeutic use of procarbazine (triazene; DNA alkylation):
Metastatic glioma
77
Therapeutic use of temozolomide (triazene; DNA alkylation):
Treatment-resistant glioma and astrocytoma
78
Therapeutic use of carmustine and lomustine (nitrosourea; DNA alkylation):
Brain tumors, lymphoma, melanoma
79
Therapeutic use of streptozocin (nitrosourea; selective at islet ß cells):
Insulinomas
80
Name 3 nitrogen mustards.
| Which is the vesicant?
- Cyclophosphamide
- Ifosfamide
- Mechlorethamine (vesicant)
81
Therapeutic use of melphalan:
Multiple myeloma
82
Therapeutic use of chlorambucil:
CLL
83
Therapeutic use of busulfan:
CML
84
TQ
What are the 3 monofunctional agents?
What is their method of cross-linkage (i.e., alkylation)?
Dacarbazine
Procarbazine
Temozolomide
Cross-linkage = O6-G-methylation (puts a CH3 on a G)
85
TQ
| The G-G cross-linkage that skips 2 AAs describes what 3 drugs?
- N-mustards (cyclophosphamide, ifosfamide, mechlorethamine)
- Thiotepa
- Busulfan
86
TQ
The G-G cross-linkage that skips 1 AA describes what drug?
What is unique about this cross-linkage?
Mitomycin
| More difficult to repair
87
```
TQ
The G-C cross linkage at the same AA position describes what class of drugs?
```
Chloroethyl-nitrosoureas (carmustine, lomustine, streptozocin)
88
DNA alkylation/cross-linking can occur readily because these agents are cell cycle (specific/NON-specific).
DNA alkylation/cross-linking can occur readily because these agents are cell cycle NON-specific !!!
89
Cell cycle non-specific drugs are dependent on:
Dose (NOT schedule/timing)
90
TQ
| Which 2 repair enzymes confer insensitivity to DNA alkylating/cross-linking agents?
Guanine O6-alkyl transferase (OAT)
| Methyl guanine methyl transferase (MGMT)
91
TQ
| Resistance to DNA alkylating/cross-linking agents is achieved if cancer cells produce more:
Glutathione
92
-Instantaneous activation by water upon infusion >>
Potent vesicant can cause blisters, necrosis if extravasation occurs
-MOPP: Hodgkin's disease
Which drug is described?
Mechlorethamine
93
TQ
Mechanism of cyclophosphamide and ifosfamide:
What 2 metabolites result?
What major toxicity results?
- Activation by liver Cyp450 enzymes.
- Acrolein and phosphoramide mustard
- Acrolein – urotoxicity (hemorrhagic cystitis) ***
94
TQ
Nitrosoureas (e.g., carmustine, lomustine) are used primarily for:
Why?
Brain cancers
| -Lipophilic nature favors CNS distribution
95
TQ
| What is the dose limiting toxicity of nitrosoureas (e.g., carmustine, lomustine)?
Myelosuppression
96
TQ
| What is different between dacarbazine and temozolomide in terms of mechanism of action and therapeutic use?
Dacarbazine
- I.V., Cyp450 activation
- MTIC (activated metabolite)
- Metastatic melanoma
Temozolomide (penetrates CNS)
- P.O., spontaneous (H+)
- MTIC (activated metabolite)
- Refractory anaplastic astrocytoma and glioblastoma
97
TQ
| The status of which enzyme in the tumor influences the efficacy of temozolomide?
MGMT
- Low MGMT = susceptible
- High MGMT = Refractory
98
TQ
| Epigenetic 'silencing' of MGMT is a biomarker for the efficacy of which drug?
Tomozolomide
99
- Platinum–Cl- complex
- Stable in plasma and high Cl- milieu
- Hydrolyses in cell to active agent
- Complex elimination due to cell uptake
Which drug is described?
Cisplatin
100
What is the more stable analog of cisplatin?
carboplatin
101
TQ
| Therapeutic use of cisplatin:
- Testicular cancer (with bleomycin, vinblastine or etoposide)
- Ovarian cancer
- NSCL
102
TQ
| 3 dose limiting toxicities of cisplatin:
- Renal failure (nephrotoxicity) ***
- N/V
- Ototoxicity – acoustic nerve damage
103
TQ
| Therapeutic use of carboplatin:
Ovarian cancer
104
Dose limiting toxicity of carboplatin:
Neutropenia
105
TQ
| Therapeutic use of oxaliplatin:
Colorectal cancer
| FOLFOX regimen – Folinic acid, FU, Oxaliplatin
106
2 dose limiting toxicities of oxaliplatin:
- Neutropenia
| - Cold-induced neuropathy
107
How do cisplatin and related compounds enter cells?
Diffusion and Cu2+ transporter
108
TQ
When is cisplatin nephrotoxicity seen?
How does it manifest?
After 10 days of cisplatin administration.
- Decr GFR
- Incr serum creatinine
- Decr serum Mg2+ and K+
109
2 Bcr-Abl tyrosine kinase inhibitors:
Imatinib
| Dasatinib
110
TQ
Imatinib is an effective treatment for:
What is the mechanism?
CML
Imatinib occupies the ATP cofactor binding site on Bcr-Abl, inhibiting transfer of phosphate to tyrosine on substrates.
111
TQ
| Imatinib-resistant CML is treated with:
Dasatinib
112
TQ
| Imatinib targets which 3 tyrosine kinases?
Bcr-Abl
c-kit
PDGFR (a RTK)
113
TQ
| 2 therapeutic uses of imatinib:
CML
| GIST
114
TQ
| Dasatinib targets which 2 tyrosine kinases?
Bcr-Abl
| Src family
115
TQ
| 2 therapeutic uses of dasatinib:
Imatinib-resistant CML
| Ph+ ALL
116
What would you give for imatinib-resistant GIST?
Sunitinib
117
TQ
| The overexpression of which ErbB family member is commonly assoc with breast cancer?
HER2 (ErbB2)
118
TQ
Which RTK inhibitor acts on both EGFR and HER2?
Used in:
-Lapatinib – breast cancer
119
TQ
Which 2 RTK inhibitors act only on EGFR?
Both used in:
Gefitinib
Erlotinib
Both used in NSCLC
120
TQ
Which RTK inhibitor acts on c-kit, PDGFR, and VEGFR?
Used in:
Sunitinib – GIST and RCC*
121
TQ
Which agent inhibits RAF kinase?
Used in:
so'RAF'enib – RCC* and HCC
122
TQ
Vemurafenib specifically inhibits mutant:
What kind of cancer?
BRAF V600E
Metastatic malignant melanoma
123
TQ
| BCR-ABL is targeted by what 2 drugs?
Imatinib
| Dasatinib
124
TQ
| EGFR is targeted by which 2 drugs and which 2 antibodies?
EGFR:
Drugs = Erlotinib & Gefitinib
Abs = Cetuximab & Panitumumab
125
TQ
| HER2 is targeted by which drug and which antibody?
HER2:
Drug = Lapatinib
Ab = Trastuzumab
126
TQ
| PDGFR and VEGFR are targeted by which 2 drugs?
Sunitinib
| Sorafinib
127
TQ
| VEGF-ligand is targeted by which antibody?
Bevacizumab
128
Therapeutic uses of cetuximab (targets EGFR):
Colorectal; head & neck
| tumors with KRAS mutation are unresponsive
129
Therapeutic use of panitumumab (targets EGFR):
```
Colorectal cancer
(except KRAS mutations)
```
130
TQ
| Therapeutic use of trastuzumab (targets HER2):
HER2+ breast cancer
131
TQ
| Therapeutic use of bevacizumab (targets VEGF-ligand):
Renal cell carcinoma
132
TQ
| Why is mutational status of KRAS a determinant of response to antibodies that inhibit EGFR activation?
A mutation in RAS can bypass inhibition of EGFR tyrosine kinase, so Abs that inhibit EGFR activation would become null.
133
TQ
| Which 3 angiogenesis inhibitors (2 drugs, 1 Ab) are used to treat renal cell carcinoma (RCC)?
- Sunitinib
- Sorafenib
- Bevacizumab
134
TQ
Rituximab is approved for the treatment of:
Would P-glycoprotein have an effect on this drug?
CD20+ B-cell cancers:
B-cell lymphoma (Non-hodgkin lymphoma)
B-cell leukemia (chronic lymphocytic leukemia – CLL)
P-glycoprotein would not have an effect on Rituximab because the drug acts on the cell exterior.
135
TQ
What does bortezomib (i.v.) target?
Used in:
Bortezomib:
- Targets 26S proteasome
- Multiple myeloma, mantle cell lymphoma
136
TQ
What does vorinostat (p.o.) target?
Used in:
Vorinostat:
- Histone deacetylase (HDAC) inhibitor
- Cutaneous T-cell lymphoma
137
TQ
What does anastrozole target?
Used in:
Anastrozole:
- Aromatase inhibitor
- Estrogen-dependent breast cancer (post-menopausal women)
138
TQ
What does exemestane target?
Used in:
Exemestane:
- Aromatase *inactivator*
- Advanced breast cancer
139
Toxicities from cancer chemotherapies:
- N/V – ?
- Myelosuppression – ?
- Diarrhea – ?
- Cystitis – ?
- Neuropathy – ?
- Pulmonary fibrosis – ?
- Cardiotoxicity – ?
- Renal failure – ?
Toxicities from cancer chemotherapies:
- N/V – Dacarbazine
- Myelosuppression – Dacarbazine
- Diarrhea – Irinotecan
- Cystitis – Cyclophosphamide (acrolein)
- Neuropathy – Vinblastine
- Pulmonary fibrosis – Bleomycin
- Cardiotoxicity – Anthracyclines (doxorubicin) and Trastuzumab
- Renal failure – Cisplatin
140
TQ
| What are the toxicities of the ABVD regimen (used for Hodgkin's lymphoma)?
Adriamycin (doxorubicin) – cardiotoxicity
Bleomycin – pulmonary fibrosis
Vinblastine – peripheral neuropathy
Dacarbazine – N/V, myelosuppression
141
TQ
ABVD Regimen
Activity: Anti-mitotic (M-phase active agent) that destabilizes microtubules; causes peripheral neuropathy.
Vinblastine
142
TQ
ABVD Regimen
Activity: Anti-tumor antibiotic; causes pulmonary fibrosis.
Bleomycin
143
TQ
ABVD Regimen
Activity: DNA damage as an intercalating agent; causes dilated cardiomyopathy.
Adriamycin (aka Doxorubicin*)
144
TQ
ABVD Regimen
Activity: DNA damage as an alkylating agent; causes marrow suppression.
Dacarbazine
145
TQ
What is the CHOP regimen for Non-Hodgkin's lymphoma?
What are the toxicities of each drug?
Cyclophosphamide – hemorrhagic cystitis (due to acrolein)
Hydroxy-daunorubicin (Doxorubicin) – cardiotoxicity (dilated cardiomyopathy)
Oncovorin (Vincristine) – peripheral neuropathy
Prednisone – hyperglycemia, osteopenia
146
What are the 2 molecular etiologies of chemotherapy-induced N/V?
1. Direct activation of medullary CTZ – activates 5-HT3, D2, and substance P neurokinin (NK1) receptors.
2. Cell damage of GI tract – Serotonin released from enterochromaffin cells activates 5-HT3 receptors and NK1 receptors on extrinsic intestinal vagal and spinal afferent nerves.
147
TQ
| What is unique about the 5-HT3 receptor?
The 5-HT3 receptor subtype is the only channel that's NOT coupled to a G protein... 5-HT3 is instead coupled to a direct ion (Na+, 2K+) channel
148
Name 4 anti-emetic 5-HT3 receptor antagonists and their HLs.
Ondansetron (i.v., oral) – 4h
Granisetron (i.v., oral, patch) – 10h
Dolasetron (oral only) – 8h
Palonosetron (i.v., oral) – 40h
149
TQ
| 5-HT3 receptor antagonists are used for (acute/delayed) emesis assoc with CINV.
5-HT3 receptor antagonists are used for ACUTE emesis assoc with CINV.
150
Main adverse effect of 5-HT3 receptor antagonists:
QTc prolongation
151
TQ
Delayed emesis is most common after high-dose:
What anti-emetic would you give?
```
Cisplatin
Give Aprepitant (NK1 receptor antagonist, competes with substance P)
```
152
TQ
| What is the 3-drug regimen for high emetic risk?
5-HT3 receptor antagonist (-setron)
Aprepitant
Dexamethasone
153
TQ
| What is the 2-drug regimen for moderate emetic risk?
5-HT3 receptor antagonist (-setron)
| Dexamethasone
154
What is given for low emetic risk?
Dexamethasone
155
TQ
| Anticipatory emesis should be treated with:
Benzodiazepines (e.g., lorazepam)
156
TQ
When neutrophil count < 0.5 it is an oncology emergency.
What should be given?
G-CSF (filgrastim)
| GM-CSF (sargramostim)
157
TQ
| Main adverse effect of G-CSF and GM-CSF:
Bone pain
158
TQ
| Oprelvekin (IL-11) increases platelets and is used for:
Prevention! ...NOT for the treatment of thrombocytopenia.
159
Explain leucovorin rescue.
Leucovorin bypasses the blocked DHFR enzyme and replenishes the folate pool of normal cells. It can moderate toxicity assoc with HDMTX.
160
TQ
| What is given with cyclophosphamide as prophylaxis for hemorrhagic cystitis?
MESNA (a sulfhydryl agent) – reacts with acrolein to diminish its toxic effect on the bladder
161
TQ
| When would you use the protectant agent Dexrasoxane?
Doxorubicin cardiotoxicity
162
TQ
| When would you use the protectant agent Amifostine?
Cisplatin nephrotoxicity
163
Mechanism of amphotericin (drug class = polyene):
Binds ergosterol (unique to fungi); forms membrane pores that allow leakage of electrolytes.
-AmphoTERicin "TEARs" holes in the fungal membrane by forming pores.
164
Amphotericin B toxicities at the onset of infusion:
Fever/chills ("shake and bake")
Hypotension
Anemia
Nephrotoxicity (later onset)
165
Amphotericin B causes direct damage to the distal tubule membrane, leading to wasting of which electrolytes?
Arteriole constriction results, so what happens to the GFR?
Na+
K+
Mg2+
Arteriole constriction >> Decreased GFR
166
TQ
| Treatment for mucormycosis (zygomycosis):
Amphotericin B
167
TQ
| Treatment for cryptococcal meningitis:
Amphotericin B + 5-FC (flucytosine)
168
TQ
| Mechanism of flucytosine:
Inhibits DNA and RNA biosynthesis by conversion to 5-fluorouracil (5-FU) by cytosine deaminase.
169
Resistance limits 5-FC clinical use.
| 2 ways resistance to 5-FC develops:
- Intrinsic resistance – mutated cytosine permease
| - Acquired resistance – mutated cytosine deaminase
170
TQ
| Treatment for invasive fungal infection (unresponsive to other therapy):
Amphotericin B
171
What are the 3 echinocandin agents?
Caspofungin
Micafungin
Anidulafungin
172
TQ
| Mechanism of echinocandins (caspofungin, micafungin, anidulafungin):
Inhibits cell wall synthesis by inhibiting synthesis of ß-(1,3)-glucan synthase.
173
How are echinocandins (e.g., caspofungin) metabolized?
Hepatic metabolism
174
TQ
| 2 clinical uses of echinocandins (e.g., caspofungin):
- Invasive aspergillosis
| - Invasive Candida
175
TQ
| Mechanism of azoles (imidazoles & triazoles):
Inhibit fungal sterol (ergosterol) synthesis by inhibiting the CYP450 enzyme (lanosterol 14-a-demethylase) that converts lanosterol to ergosterol.
i.e., inhibit Lanosterol >> Ergosterol biosynthetic pathway
176
TQ
| 4 fungal resistance mechanisms to azoles:
- Mutation of lanosterol-14a-demethylase
- Overexpression of lanosterol-14a-demethylase
- Energy-dependent efflux systems
- Changes in sterol and/or phospholipid composition of fungal cell membrane (decreased permeability)
177
How is fluconazole cleared?
Renally (75%)
178
Which 3 triazoles can you give for Candida?
Fluconazole
Itraconazole
Voriconazole
179
TQ
| Which triazole is given for Aspergillus?
Voriconazole
180
TQ
| Which triazole is given for Cryptococcus neoformans?
Fluconazole
181
TQ
Which triazole is front line / recommended for Blastomyces, Coccidioides, and Histoplasmosis (true pathogenic infections)?
Itraconazole
| -Broad spectrum
182
TQ
| What is the toxicity assoc with ketoconazole?
- Testosterone synthesis inhibition (gynecomastia)
| - Liver dysfunction (inhibits CYP450)
183
TQ
| Which 2 triazoles are readily absorbed with excellent distribution including CSF?
Fluconazole
| Voriconazole
184
- Like ketoconazole, it requires gastric acidity to dissolve.
- Antacids, PPI, H2-antagonists
- Poor CSF penetration
Which agent?
Itraconazole
185
TQ
| 2 triazoles that are both strong inhibitors of hepatic CYP450 and enhance renal toxicity
Voriconazole
| Itraconazole
186
T/F: Avoid all triazoles in pregnancy.
TRUE
187
T/F: All triazoles can damage liver.
TRUE
188
T/F: Voriconazole disturbs vision.
TRUE
189
TQ
2 fluconazole indications:
-Narrow spectrum
- Candida albicans *
| - Cryptococcus (with Ampho-B)
190
TQ
What is the drug of choice for invasive aspergillosis?
-Also used for candidiasis resistant to fluconazole (e.g., C krusei, C glabrata)
Voriconazole
191
Antifungal drugs targeting ergosterol:
| 3 polyenes:
- Amphotericin B
- Nystatin
- Natamycin
192
Antifungal drugs targeting ergosterol:
| 2 allylamines:
- Terbinafine
| - Naftitine
193
TQ
Indicated for ophthalmological fungal conditions:
-Fungal keratitis, conjunctivitis, blepharitis
Natamycin
| -Fungicidal
194
```
TQ
Indicated for mouth (oropharyngeal) and digestive tract fungal conditions:
-Esophageal, pharyngeal (i.e., thrush)
-"Topical" action in intestinal lumen
-Candida ONLY
```
Nystatin
195
TQ
| Mechanism of allylamines (terbinafine, naftifine):
- Inhibits the fungal enzyme squalene-2,3-epoxidase >>
| - Inhibits lanosterol synthesis
196
TQ
Clinical use of allylamines (e.g., terbinafine):
-Localized infection = topical application
-Often fungicidal
```
Cutaneous dermatophytosis
(especially fungal infections of finger or toe nails)
-Tinea cruris ("jock" itch)
-Tinea corporis (ringworm)
-Tinea pedis (athlete's foot)
-Tinea unguium (nails)
```
197
TQ
| Indicated for widespread Tinea corporis (ringworm):
Terbinafine
| oral route for systemic delivery
198
TQ
| Azole indicated for oropharyngeal candidiasis:
Clotrimazole (aka troche)
199
TQ
| An immunocompromised host with oropharyngeal candidiasis may also need add what azole?
Itraconazole
200
TQ
Azole indicated for vulvovaginal candidiasis:
-Multi-day cream – (2)
-Once-a-day – (2)
- Multi-day cream – Clotrimazole 1%, Miconazole 2%
| - Once-a-day – Clotrimazole, Tiaconazole
201
TQ
| Indicated for candiduria:
Fluconazole
| 75% renal excretion
202
TQ
| Mechanism of griseofulvin:
- Interferes with microtubule function (tubulin, microtubule proteins – MAP); disrupts mitosis *
- Deposits in keratin-containing tissues (e.g., nails)
203
TQ
| Clinical use of griseofulvin (p.o.):
- Oral treatment of superficial infections
| - Inhibits growth of dermatophytes (tinea, ringworm) *
204
TQ
| Main contraindication of oral Terbinafine:
Pregnancy
205
TQ
| Adverse effect of griseofulvin:
- CYP450 induction
| - Avoid alcohol
206
TQ
| 2 clinical uses of acyclovir, famciclovir (penciclovir), valacyclovir:
HSV and VZV
207
TQ
Drug indicated for acyclovir-resistant HSV/VZV:
Foscarnet
208
5 drugs for CMV infections:
- Ganciclovir
- Valganciclovir
- Cidofovir
- Foscarnet
- Fomivirsen
209
TQ
| Mechanism of acyclovir (ACV) and penciclovir (PCV):
Monophosphorylated by HSV/VZV thymidine kinase *
- Guanosine analog
- Triphosphate formed by cellular kinases *
- Preferentially inhibits viral DNA polymerase by chain termination *
210
TQ
| Mechanism of ganciclovir (GCV):
5'-monophosphate formed by a CMV viral kinase (UL97 kinase) *
- Guanosine analog
- Triphosphate formed by cellular kinases *
- Preferentially inhibits viral DNA polymerase *
211
TQ
What is the mechanism of resistance against ACV and PCV?
What is the mechanism of resistance against GCV?
- Deficit (TK-) or mutation in thymidine kinase >> resistance to ACV and PCV
- Deficit (UL97-) or mutation in UL97 kinase >> resistance to GCV
For TQ: Think about what you'd see in a petri dish with:
1) No drug + HSV >> HSV-infected cells in dish
2) Acyclovir + HSV(wt) >> Small amt of HSV-infected cells
3) Acyclovir + HSV(TK-) >> HSV-infected cells (due to TK deficit)
212
TQ
Acyclovir is most active against:
(Valacyclovir (pro-drug) has similar spectrum)
HSV-1 ≥ HSV-2
| NOT CMV
213
TQ
| What is the toxicity of acyclovir?
Obstructive crystalline nephropathy >> acute renal failure *
-Minimize by hydration
May also present with neurologic toxicity in pts with renal failure.
214
TQ
| Ganciclovir is most active against:
CMV
215
TQ
| 2 clinical indications for ganciclovir:
- CMV retinitis in immunocompromised pts
| - prevention of CMV dz in transplant pts
216
TQ
| 2 ganciclovir toxicities / complications:
- Bone marrow suppression (leukopenia, neutropenia, thrombocytopenia)
- Renal toxicity
217
TQ
| Which 3 antiviral nucleoside agents do NOT require phosphorylation by viral kinase?
Cidofovir
Vidarabine
Trifluridine
218
TQ
| Why is trifluridine unique among the 3 antiviral nucleoside agents which do NOT undergo viral-mediated phosphorylation?
In addition to trifluridine being tri-phosphorylated and inhibiting viral DNA pol (like cidofovir and vidarabine)...
Trifluridine also can be monophosphorylated to inhibit viral thymidylate synthetase ***
219
TQ
| Main clinical use of cidofovir:
CMV retinitis in HIV pts
| ophthalmic CMV infections
220
TQ
| Cidofovir toxicity:
Nephrotoxicity
221
TQ
| What do you co-administer cidofovir with to decrease nephrotoxicity?
Probenecid
222
TQ
| What would you give for HSV or VZV keratitis and HSV keratoconjunctivitis in immunocompromised pts?
Vidarabine
223
TQ
| What is the drug of choice for HSV keratoconjunctivitis and recurrent epithelial keratitis?
Trifluridine
224
TQ
| Mechanism of foscarnet:
Viral DNA polymerase inhibitor that binds to the pyrophosphate-binding site of the enzyme.
(Does not require activation by viral kinase)
FOScarnet = pyroFOSphate analog
225
TQ
| 2 clinical uses of foscarnet:
- CMV retinitis (when ganciclovir fails)
| - Acyclovir-resistant HSV & VZV
226
TQ
Toxicity of foscarnet:
Major complication of foscarnet (due to Ca2+ chelation):
- Nephrotoxicity
| - Hypocalcemia
227
- An anti-sense oligonucleotide that disrupts CMV replication
- Active against CMV resistant to ganciclovir & foscarnet
- Administered intravitreally (CMV retinitis)
Fomiversen
228
- Approved by FDA to shorten healing time of cold sores
| - Blocks virus entry into cells
Docosanol (aka Abreva)
229
TQ
| What is the one major contraindication when using IFN-a or PEG-IFN-a for treatment of chronic HBV infection?
IFN-a or PEG-IFN-a can be dangerous in decompensated cirrhosis!!!
Pts with:
- Ascites
- Encephalopathy
- Variceal bleeding
- Coagulopathy
- Hepatocellular carcinoma
230
TQ
| Step-by-step action by IFN-a binding to IFN receptor:
1) IFN:receptor binding activates JAK1 & Tyk2 receptor-associated tyrosine kinases.
2) JAK1 & Tyk2 phosphorylate IFN receptor.
3) Phospho-IFN receptor recruits STATs.
4) JAK1 & Tyk2 phosphorylate STATs.
5) Phospho-STATs "undock" from IFN receptor, then dimerize.
6) Phospho-STATs *relocalize to the nucleus*
7) ISGF3:DNA complex upregulates transcription of Interferon Stimulated Genes (ISG).
231
TQ
| Explain the ISG pathway that ultimately leads to viral RNA degradation.
```
ISG >>
2'5'-OAS (+ATP) >>
2'5'-AAA >>
Activates ribonuclease L >>
Degrades viral RNA!
```
232
TQ
| Explain the ISG pathway that ultimately leads to the inhibition of viral protein synthesis.
ISG >>
PKR (+ATP) >>
Phospho-eIF >>
Inhibits viral protein synthesis!
233
TQ
| IFN-a (via IFN-gamma) favors cell-mediated immunity (Th1 / Th2) phenotype.
IFN-a favors Th1 phenotype
234
TQ
| How do you know that seroconversion is progressing when given PEG-IFN-a?
You know seroconversion is progression when there's a hepatitis 'flare' ...
-ALT increases
235
4 adverse effects of IFN-a:
- Flu-like syndrome after injection (fever/chills, myalgia, arthralgia) *
- Fatigue and mental depression
- Bone marrow toxicity (neutropenia) *
- Neurotoxicity (behavioral changes)
236
Which 2 NRTIs are approved for treatment of both HIV and HBV?
Which 2 NRTIs are nucleoTide monophosphates?
For HIV and HBV: Tenofovir (adenosine analog) and Lamivudine (cytosine analog)
nucleoTides: Tenofovir and Adefovir (adenosine analogs)
237
What is unique about NRTIs in terms of pts with decompensated cirrhosis?
NRTIs can be given to pts with decompensated cirrhosis!
238
TQ
| 2 resistance mechanisms of HBV to NRTIs:
- Impaired purine/pyrimidine kinase activity
| - Mutation of DNA polymerase
239
How do we know that resistance by HBV involves impaired purine/pyrimidine kinase activity?
Because nucleoTide analogs (adefovir and tenofovir) are useful in pts resistant to nucleoSide analogs (lamivudine, entecavir and telbivudine).
240
TQ
| What is the mutant DNA pol / Reverse Transcriptase segment which confers resistance by HBV to lamivudine (LAM)?
YMDD becomes YVDD
241
TQ
Breakthrough infection due to antiviral drug resistance...
For lamivudine or telbivudine resistance:
Add adefovir or switch to tenofovir.
242
TQ
Breakthrough infection due to antiviral drug resistance...
For entecavir resistance:
Add tenofovir.
243
TQ
Breakthrough infection due to antiviral drug resistance...
For adefovir resistance:
Add lamivudine, telbivudine or entecavir.
244
TQ
| First-line oral anti-HBV 2-drug regimen:
Tenofovir (TDF) and Entecavir (ETV)
245
TQ
| Second-line oral anti-HBV 2-drug regimen:
Lamivudine (LAM) and Telbivudine (TBV)
246
Which NRTI for HBV has the best pregnancy profile?
Tenofovir (TDF) – Category B
247
Which NRTI for HBV is the worst at eliminating HBV DNA (worst antiviral effect) after 1 year?
Which NRTI is the best?
```
Worst = Adefovir (20%)
Best = Tenofovir (80%)
```
248
Which NRTI for HBV has the most resistance (worst)?
| Which NRTI has the least (best)?
```
Worst = Lamivudine
Best = Tenofovir
```
249
TQ
Long-term efficacy of lamivudine is limited by frequent emergence of drug-resistant HBV.
What is the mutation?
YMDD >> YVDD mutant in catalytic domain of HBV polymerase
250
TQ
| What is the 3-drug regimen for HCV infection since 2011?
PEG-IFN + ribavirin + oral protease inhibitor (telaprevir or boceprevir)
(24-48 weeks)
251
How do some HCV strains have partial resistance to IFN-a?
If HCV genome encodes proteins that negate interferon stimulated genes (ISGs – 2'5'-OAS, PKR, ADAR, MxA...).
252
TQ
| Mechanism of Ribavirin:
- Ribavirin-monoP inhibits IMP dehydrogenase (inhibits synthesis of guanine nucleotides) *
- Ribavirin-triP inhibits RNA-dependent RNA polymerase (inhibits RNA replication)
- Ribavirin-triP also leads to lethal mutagenesis and 'defective' HCV
253
TQ
| 2 Ribavirin toxicities/adverse effects:
- Hemolytic anemia
| - Severe teratogen
254
Both telaprevir and boceprevir interfere with HCV replication by inhibiting what key viral enzyme?
NS3/4A serine protease
255
TQ
| What is the 3-drug regimen for HCV infection?
- PEG-interferon
- Ribavirin
- Boceprevir or telaprevir
