Deja Ch 2.2 Antiviral Flashcards
1
Q
What enzyme adds the first phosphate to acyclovir?
A
Viral thymidine kinase
2
Q
True or False? Monophosphorylated acyclovir is converted to the triphosphate form by viral enzymes.
A
False (host cell kinases are responsible for these reactions)
3
Q
How does acyclovir triphosphate work as an antiviral agent?
A
Inhibits viral DNA replication by competing with deoxyguanosine triphosphate for viral DNA polymerase; incorporated into the viral DNA molecule and acts as a chain terminator
4
Q
How does acyclovir triphosphate work as a chain terminator?
A
Lacks the ribosyl 3’ hydroxyl group
5
Q
How do viruses become resistant to acyclovir?
A
Downregulation of viral thymidine kinase; lacking thymidine kinase altogether; altered specificity of viral thymidine kinase; altered specificity of viral DNA polymerase
6
Q
Acyclovir is effective in treating which virus types?
A
Herpes simplex virus (HSV) 1 and 2; varicella-zoster virus (VZV). Acyclovir is 10 _ more potent against HSV than VZV
7
Q
Is acyclovir effective in treating postherpetic neuralgia?
A
No (only effective against acute neuritis)
8
Q
What is the oral bioavailability of acyclovir?
A
15%-30%. There is minimal systemic distribution after topical application.
9
Q
What is the half-life of acyclovir in adults?
A
2.5-3 hours
10
Q
Why is it necessary to maintain adequate hydration in patients receiving IV acyclovir therapy?
A
To prevent crystalluria or interstitial nephritis. Slow infusion additionally helps to avoid these adverse reactions.
11
Q
What is the name of the prodrug that is converted to acyclovir and L-valine by first-pass metabolism?
A
Valacyclovir
12
Q
What is the advantage of valacyclovir over acyclovir?
A
Higher oral bioavailability of 54%-70%
13
Q
Famciclovir is a prodrug that is metabolized to what active metabolite?
A
Penciclovir
14
Q
What is the bioavailability of penciclovir after oral administration of famciclovir?
A
70%
15
Q
Is famciclovir effective in viral strains resistant to acyclovir secondary to mutated DNA polymerase?
A
Yes
16
Q
Is famciclovir effective in viral strains resistant to acyclovir secondary to lack of thymidine kinase?
A
No
17
Q
What is the mechanism of action of ganciclovir?
A
Phosphorylated to a substrate which competitively inhibits binding of deoxyguanosine triphosphate to DNA polymerase, thereby inhibiting viral DNA synthesis
18
Q
Does ganciclovir have chain-terminating ability?
A
No
19
Q
Ganciclovir is effective in treating which virus types?
A
HSV; VZV; human herpes virus (HHV)-6 and 8; cytomegalovirus (CMV). Activity against CMV is 100 _ greater than acyclovir. It may be used intraocularly for CMV retinitis.
20
Q
What is the advantage of valganciclovir over its parent drug ganciclovir?
A
Valganciclovir (the valine ester) has up to 60% better oral availability than ganciclovir.
21
Q
What is ganciclovir’s dose-limiting adverse effect?
A
Myelosuppression; thrombocytopenia; anemia; leukopenia
22
Q
What are the adverse effects of ganciclovir?
A
Crystalluria; mucositis; rash; fever; hepatotoxicity; seizures; diarrhea; nausea; hematotoxicity
23
Q
What is cidofovir used for?
A
CMV retinitis most commonly. It also has activity against HSV-1 and 2, varicella zoster virus (VZV), Epstein-Barr virus (EBV), HHV-6 and 8, adenovirus, poxviruses, polyomaviruses, and human papilloma virus (HPV).
24
Q
What antiviral agent is a pyrophosphate analogue that acts as an inhibitor of viral RNA and DNA polymerase and HIV reverse transcriptase?
A
Foscarnet
25
Does foscarnet require activation by thymidine kinase?
No
26
Foscarnet is effective in treating which virus types?
Acyclovir-resistant HSV and VZV; ganciclovir-resistant CMV
27
Does foscarnet cause hematotoxicity?
Yes
28
What are the major adverse effects of foscarnet?
Hematotoxicity; fever; seizures; electrolyte abnormalities; nausea; vomiting; diarrhea
29
What types of electrolyte abnormalities can foscarnet cause?
Hyper- or hypocalcemia; hyper- or hypomagnesemia; hyper- or hypophosphatemia; hypokalemia
30
True of False? Amantadine is effective in treating both influenza A and B.
False (it is effective against the influenza A virus only)
31
What is the antiviral mechanism of action of amantadine?
Blocks the uncoating of influenza A virus, thereby preventing penetration of the virus into host cells
32
What other noninfectious disease processes is amantadine used for?
Parkinson disease; drug-induced extrapyramidal symptoms. It also increases dopamine levels in the synaptic cleft by either inhibiting reuptake into presynaptic neurons or by increasing release from presynaptic neurons. It may have anticholinergic effects.
33
What are the adverse effects of amantadine?
Seizures; insomnia; nervousness; livedo reticularis; orthostatic hypotension; peripheral edema; dry nose; xerostomia; nausea; anorexia
34
What is livedo reticularis?
A purplish discoloration of the skin caused by dilation of capillaries and venules secondary to stasis or changes in underlying blood vessels
35
Name two drugs that inhibit neuraminidase of both influenza A and B, thereby decreasing the likelihood of viral penetration into host cells:
Oseltamivir; zanamivir
36
Which neuraminidase inhibitor has an oral inhalational route of administration?
Zanamivir
37
Ribavirin is effective in treating which virus types?
Respiratory syncytial virus (RSV); influenza A and B; hepatitis C virus (HCV)
38
Ribavirin is used in conjunction with what other drug to treat HCV?
Interferon-alpha (IFN-_)
39
What are the adverse effects of ribavirin?
Anemia; neutropenia; thrombocytopenia; anorexia; headache; conjunctivitis; nausea; pharyngitis; lacrimation; alopecia; rash; flu-like syndrome; teratogenicity (pregnancy category X)
40
Name the major adverse effects of IFN-_:
Flu-like symptoms; depression; alopecia; insomnia; nausea
41
What is the name of the only available nucleotide reverse transcriptase inhibitor?
Tenofovir
42
Give examples of nucleoside reverse transcriptase inhibitors (NRTIs):
Zidovudine (AZT); stavudine (d4T); lamivudine (3TC); didanosine (ddl); abacavir (ABC); emtricitabine (FTC)
43
What adverse effect(s) are associated with all NRTIs?
Lactic acidosis with hepatic steatosis
44
What is the general mechanism of action of NRTIs?
Interference with HIV viral RNA-dependent DNA polymerase resulting in inhibition of HIV viral replication
45
What two NRTIs are thymidine analogs?
Zidovudine; stavudine
46
What NRTI is an adenosine analog?
Didanosine
47
What NRTI is a guanosine analog?
Abacavir
48
What two NRTIs are cytosine analogs?
1. Emtricitabine 2. Lamivudine
49
Which NRTI should not be rechallenged if hypersensitivity is expected?
Abacavir (symptoms include fever, rash, nausea, vomiting, malaise, fatigue, and respiratory dysfunction)
50
Which NRTI can cause hyperuricemia?
Didanosine
51
Which two NRTIs can cause pancreatitis?
1. Didanosine 2. Stavudine (dose-limiting effect)
52
Which two NRTIs can cause peripheral neuropathy?
1. Didanosine 2. Stavudine (dose-limiting effect)
53
What is didanosine's dose-limiting adverse effect?
Pancreatitis
54
What is stavudine's dose-limiting adverse effect?
Peripheral neuropathy
55
What are the main adverse effects of AZT?
Anemia and neutropenia (dose-limiting effect/potentiated by vitamin B12); headache; nausea; insomnia; body aches; lactic acidosis
56
What is the dose-limiting adverse effect of AZT?
Hematotoxicity
57
What antiretroviral agent can cause Fanconi syndrome?
Tenofovir. Fanconi syndrome is impairment of the proximal tubule resulting in increased phosphate and calcium losses.
58
What NRTI can cause altered LFTs, lipoatrophy, hyperlipidemia, and ascending paresis?
Stavudine
59
Name three nonnucleoside reverse transcriptase inhibitors (NNRTIs):
1. Delavirdine 2. Efavirenz 3. Nevirapine
60
What is the mechanism of action of efavirenz?
Binds directly to reverse transcriptase and blocks the RNA-and DNA-dependent DNA polymerase activity of reverse transcriptase
61
What is the class adverse effect(s) of the NNRTIs?
Rash
62
Which NNRTI can cause hepatitis and hepatic necrosis?
Nevirapine
63
Which NNRTI can cause abnormal dreams, impaired concentration, dizziness, and altered LFTs?
Efavirenz
64
Which NNRT can produce a false-positive urine test for Cannabis?
Efavirenz (in about 50% of patients)
65
Do NNRTIs require metabolic activation?
No
66
Do NRTIs require metabolic activation?
Yes
67
What is the name of the drug that inhibits fusion of the HIV-1 virus with CD4 cells by binding to and blocking the conformational change in gp41 required for membrane fusion and entry into CD4 cells?
Enfuvirtide (fusion inhibitor)
68
What are the adverse effects of enfuvirtide?
Pain, induration, erythema, and nodules at the injection site; nausea; vomiting; diarrhea; fatigue
69
Give examples of protease inhibitors:
Atazanavir; indinavir; lopinavir; fosamprenavir; nelfinavir; ritonavir; saquinavir; tipranavir; amprenavir; darunavir
70
What adverse effect(s) are associated with the protease inhibitors?
Hepatotoxicity; fat maldistribution; insulin resistance; osteonecrosis; increased bleeding in hemophiliac patients
71
Are protease inhibitors metabolized by P-450 enzymes?
Yes
72
Do protease inhibitors inhibit or induce P-450 enzymes?
They inhibit P-450 enzymes.
73
What is HIV protease responsible for?
Cleaves the Gag-Pol polyprotein of HIV (the gag region of the gene codes for structural proteins whereas the Pol region of the gene codes for protease, reverse transcriptase, and integrase)
74
The combination of atazanavir and indinavir can cause what possible adverse effect?
Hyperbilirubinemia
75
Patients with sulfonamide allergy should use caution when taking which two protease inhibitors?
1. Tipranavir 2. Fosamprenavir
76
Which protease inhibitor can cause an altered taste sensation?
Ritonavir
77
Which two protease inhibitors can cause asthenia (lack of strength)?
1. Lopinavir 2. Ritonavir
78
Which protease inhibitor can cause kidney stone formation?
Indinavir
79
Which protease inhibitor can cause numbness around the mouth?
Ritonavir
80
What type of prophylaxis is given to a person stuck with a potentially HIV contaminated needle?
Zidovudine and lamivudine for 1 month (protease inhibitor should be added for high-risk exposures)
81
How is maternal-fetal HIV transmission prevented in mothers?
Zidovudine beginning at 14-34 weeks' gestation and continued until start of labor; during labor and delivery, zidovudine until the umbilical cord is clamped
82
How is maternal-fetal HIV transmission prevented in neonates?
Zidovudine started 8-12 hours after birth and continued for 6 weeks
83
Amebiasis is generally treated with what drug combination?
Metronidazole and diloxanide
84
What is the mechanism of action of metronidazole?
Mixed amebicide (effective against both luminal and systemic forms of disease); nitro group of metronidazole acts as an electron acceptor, thereby forming reduced cytotoxic compounds that lead to inhibition of protein synthesis and DNA strand breakage
85
What are the adverse effects of metronidazole?
Nausea; vomiting; metallic taste sensation; disulfiram-like reaction
86
Give examples of medications that can cause a disulfiram-like reaction:
Metronidazole; chlorpropamide; cefotetan; cefamandole; cefoperazone
87
What is the antimicrobial spectrum of metronidazole?
Entamoeba histolytica; Giardia lamblia; Trichomonas vaginalis; bacterial anaerobes; C. difficile
88
Metronidazole is contraindicated in which trimester of pregnancy?
First trimester during organogenesis since teratogenicity has not been effectively ruled out
89
Can metronidazole cross the blood-brain barrier (BBB)?
Yes
90
What is the mechanism of action of diloxanide?
Luminal amebicide (effective against luminal forms of disease) used in the treatment of asymptomatic amoebic cyst passers
91
What are the adverse effects of diloxanide?
Contraindicated in pregnancy and children less than 2 years old; dry mouth; pruritus; flatulence
92
What are the four species of Plasmodium
1. Malariae 2. Falciparum 3. Vivax 4. Ovale
93
What is the most dangerous/life-threatening Plasmodium species?
Falciparum
94
What are the three stages of the malarial parasite life cycle primarily targeted by antimalarial drugs?
1. Erythrocytic stage 2. Exoerythrocytic stage 3. Gametocytic stage
95
What is the oldest antimalarial drug still in use?
Quinine ("Jesuit Bark")
96
Quinine has been replaced by which antimalarial drug?
Chloroquine (more potent and less toxic than quinine)
97
What drugs are effective against the exoerythrocytic forms of malaria?
Primaquine; atovaquone + proguanil (Malarone)
98
What drug is effective against the gametocytic (hepatic) forms of malaria?
Primaquine
99
Is primaquine effective against erythrocytic forms of malaria?
No
100
Give examples of antimalarial drugs that are effective against the erythrocytic forms of malaria:
Hydroxychloroquine; chloroquine; mefloquine; pyrimethamine; quinine; atovaquone + proguanil; artemisinin
101
What drug is effective against relapsing forms of P. vivax and P. ovale malarias?
Primaquine. To prevent recurrence of infection, hepatic forms of these parasites must be eliminated.
102
What are the adverse effects of primaquine?
Hemolytic anemia in patients with G6PD deficiency; methemoglobinemia; agranulocytosis
103
What is the drug of choice for acute attacks of malaria caused by chloroquine-sensitive strains of P. falciparum and P. vivax?
Chloroquine
104
Does chloroquine have a large or small Vd?
Large
105
What is the mechanism of action of chloroquine?
It concentrates within parasite food vacuoles and raises pH leading to inhibition of growth; inhibits hemoglobin metabolism and utilization by parasites; concentrates within parasite vacuoles and raises pH leading to inhibition of growth; binds to ferriprotoporphyrin IX leading to membrane damage; inhibits DNA and RNA polymerase
106
What continents contain the largest repositories of chloroquine-resistant P. falciparuml
Africa, Asia
107
What are the adverse effects of chloroquine?
ECG changes (quinidine-like effects); headaches; pruritus; mucosal pigmentary changes (blue-black); photosensitivity; nausea; vomiting; diarrhea; aplastic anemia; agranulocytosis; neutropenia; thrombocytopenia; retinopathy; tinnitus; reduced hearing
108
Chloroquine is contraindicated in patients with what disease states?
Porphyria; psoriasis
109
What are the major adverse effects of quinine?
Cinchonism (nausea, vomiting, diarrhea, tinnitus, vertigo); hemolytic anemia; digoxin toxicity
110
What other medication can cause cinchonism?
Quinidine
111
Is quinine acidic or basic?
Basic
112
How can the urinary excretion of quinine (or chloroquine) be enhanced?
Acidification of the urine
113
Name two newer antimalarials that are chemically related to quinine:
1. Halofantrine 2. Lumefantrine
114
What can be used to acidify the urine?
Ammonium chloride
115
What is the mechanism of action of pyrimethamine?
Inhibits nucleic acid and protein metabolism in the parasites; plasmodial dihydrofolate reductase (DHFR) inhibitor
116
The antimalarial effects of pyrimethamine can be potentiated by combining it with which drugs?
Sulfonamides (synergistic blockade of folic acid synthesis).
117
How is folate-deficient megaloblastic anemia reversed in patients taking pyrimethamine?
Leucovorin
118
What is the mechanism of action of leucovorin?
As a reduced form of folic acid, leucovorin supplies human cells with the necessary cofactor blocked by DHFR inhibitors.
119
What kind of compounds are the antimalarial drug artemisinin and its derivatives?
Sesquiterpene lactones (the active ingredient in a 2000-year-old Chinese herb—Qing Hao).
120
What is the antimalarial mechanism of action of artemisinin?
It is thought that it is activated by heme to irreversibly decompose generating free radicals that form adducts mostly with proteins and lipids.
121
Give examples of antimalarial drugs used in artemisinin combination therapies (ACT):
Pyrimethamine/sulfadoxine (Fansidar), mefloquine, amodiaquine
122
What is the name of the most promising antimalarial vaccine?
RTS-S/AS02A or Mosquirix
123
Which genetic diseases/conditions may help protect against malarial infections?
Sickle cell trait; G6PD deficiency
124
Trypanosoma cruzi is responsible for causing what disease?
American trypanosomiasis (Chagas disease)
125
T. brucei gambiense and T. brucei rhodesiense are responsible for causing what disease?
African trypanosomiasis (sleeping sickness)
126
What drug is used as a suppressive agent in patients with acute T. cruzi infections?
Nifurtimox
127
What is the mechanism of action of nifurtimox?
Forms intracellular oxygen-free radicals which are toxic to the parasite because of its lack of catalase (oxygen radical scavenger)
128
What drug is used to treat African sleeping sickness with CNS involvement?
Eflornithine for West African trypanosomiasis; melarsoprol for East African trypanosomiasis
129
What are the adverse events of melarsoprol?
Hypersensitivity; abdominal pain; vomiting; hemolytic anemia in patients with G6PD deficiency; encephalopathy
130
What two drugs are used in the early stages of African sleeping sickness?
1. Pentamidine (first choice for West African sleeping sickness) 2. Suramin (first choice for East African sleeping sickness)
131
Does pentamidine cross the BBB?
No. Therefore it cannot be used for late trypanosomiasis with CNS involvement.
132
What are the two routes of administration of pentamidine?
1. IV 2. Aerosol
133
What fungus is pentamidine commonly used to treat?
Pneumocystis carinii
134
What drug combination is used for prophylaxis against P. carinii?
Trimethoprim-sulfamethoxazole
135
What is the treatment of choice for T. gondii?
Pyrimethamine + sulfadiazine
136
How do humans become infected with T. gondii?
Ingestion of undercooked, infected meat; contact with infected cats
137
Can pregnant mothers transmit T. gondii to the fetus?
Yes (remember TORCH syndromes)
138
What are the three types of leishmaniasis infections?
1. Visceral 2. Cutaneous 3. Mucocutaneous
139
What is the drug of choice for treating leishmaniasis?
Stibogluconate (pentavalent antimony compound)
140
What is another name for the nematodes?
Roundworms
141
What is another name for the trematodes?
Flukes
142
What is another name for the cestodes?
Tapeworms
143
What drug is commonly used to treat trematode infections?
Praziquantel
144
What is the mechanism of action of praziquantel?
Increases cell permeability to calcium, thereby increasing contractions with subsequent paralysis of musculature
145
What is the mechanism of action of mebendazole?
It irreversibly blocks glucose uptake; inhibits microtubule polymerization
146
What are the adverse effects of mebendazole?
Diarrhea; abdominal pain; contraindicated during pregnancy
147
What is the mechanism of action of albendazole?
It interferes with microtubule polymerization; inhibits adenosine triphosphate (ATP) production thereby depleting energy availability
148
What is the mechanism of action of thiabendazole?
Inhibits helminth-specific mitochondrial fumarate reductase
149
What types of cutaneous adverse effects are caused by thiabendazole?
Stevens-Johnson syndrome; erythema multiforme
150
What is the mechanism of action of pyrantel?
Depolarizing neuromuscular blocker thereby causing paralysis of musculature
151
What types of helminths are affected by praziquantel?
Trematodes; cestodes
152
What types of helminths are affected by mebendazole?
Nematodes
153
What types of helminths are affected by pyrantel?
Nematodes
154
What is the drug of choice for treating Enterobius vermicularis?
Mebendazole
155
What is the common name for E. vermicularis?
Pinworm
156
What is the drug of choice for treating Onchocerca volvulus (onchocerciasis or river blindness)?
Ivermectin
157
What is the mechanism of action of ivermectin?
Acts at helminthic gamma-aminobutyric acid (GABA) receptors, thereby enhancing influx of chloride and causing hyperpolarization and paralysis
158
Why does onchocerciasis potentially lead to blindness?
A bacteria (Wolbachia sp.) that colonizes many parasitic worms, including the nematode that causes onchocerciasis, is an important factor in the inflammatory response that leads to blindness.
159
What is another name for onchocerciasis?
River blindness
160
What drug is commonly used to treat cestode infections?
Niclosamide
161
What is the mechanism of action of niclosamide?
Inhibits mitochondrial phosphorylation of ADP to ATP, thereby depleting energy availability
162
Is niclosamide active against the ova of cestodes?
No; only active against cestode's scolex and segments
