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107 Cards in this Set
- Front
- Back
Are fungi Prokaryotes or Eukaryotes?
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Eukaryotes = very similar to our cells = very difficult to achieve selective toxicity
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When are fungal infections most common?
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Immunosuppressed patients
- incidence is on the rise Superinfections |
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What type of Antibiotic is Amphotericin B?
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Polyene
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What is Amphotericin B's mechanism of action?
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Binds to Ergosterol in fungal membranes and forms pores that allow leakage of electrolytes and disrupts homeostasis = AmphoTEARicin "tears" holes in fungal membranes
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How is Amphotericin B administered?
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IV or Intrathecal
- too big to be absorbed |
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Describe the distribution of Amphotericin B
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widely distributed except for CNS
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What is the half-life of Amphotericin B?
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~ 2 weeks
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Describe "Liposomal Amphotericin B"
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Liposome has lower affinity for drug than does fungal membrane, higher affinity for drug than does the patients membrane (cholesterol) = decreases adverse effects
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What is Amphotericin B clinically used for?
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Severe Systemic mycoses
*used for wide range of fungal infections **used for initial intervention, then switch to different anti-fungal for cure/maintenance |
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What adverse effect occurs frequently with Amphotericin B
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Chills
Fever Nausea Vomiting Headache = Amphoterrible = bad malaise |
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What can be done to cut down the adverse effects of Amphotericin B?
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premedicate with Anti-pyretics (reduce fever), anti-histamines, and analgesics
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A common often irrevesible adverse effect of Amphotericin B which may be reduced by giving in the Liposomal form
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Nephrotoxicity
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What is the selectivity of Flucytosine based on?
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it is activated by fungal Cytosine Deaminase -> 5-fluorouracil
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What is the mechanism of action of Flucytosine?
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inhibits DNA and RNA synthesis
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Describe the distribution of Flucytosine
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-orally effective
-widely distributed including CNS |
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How is Flucytosine excreted?
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Urine = 10X's the serum level
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What are the adverse effects of Flucytosine?
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Low toxicity
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Narrow spectrum antifungal used to treat Cryptococcus and some Candida
-should only be given when combo'ed with Amphotericin B or Itraconazole |
Flucytosine
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What 2 drugs is Flucytosine used in combination with due to resistance development?
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Amphotericin B
Itraconazole |
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Anti-fungal drugs that inhibit Ergosterol synthesis from Lanosterol
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Azoles
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1st effective ORAL anti-fungal for systemic disease
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Ketoconazole
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Describe the distribution of Ketoconazole
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Well distribution, except CNS
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List the 4 adverse effects of Ketoconazole
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1. GI symptoms
2. Hepatotoxicity 3. Blocks Adrenal Steroidogenesis = Gynecomastia in males 4. Alters drug metabolism - Cyclosporine - non-sedating histamines |
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Broader spectrum Azole with fewer adverse effects than Ketoconazole
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Itraconazole
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Water-soluble azole, good CSF delivery, more selective for fungal P450's
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Fluconazole
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DOC for Esophageal and invasive Candidiasis and Coccidiomycoses
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Fluconazole
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Co-DOC for Paracoccidioides and backup for Blastomyces and Histoplasma
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Ketoconazole
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DOC for Blastomycoses and Sporotrichoses
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Itraconazole
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Topical antifungal agent that is similar to Amphotericin B (binds to Ergosterol and disrupts membranes), but is too toxic for systemic use
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Nystatin
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What is the only reason Nystatin would be given orally?
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in treatment of GI Fungal superinfection
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List the 2 Systemic antifungal drugs used for Topical Infections
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1. Griseofulvin
2. Terbinafine |
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Antifungal that is administered orally and concentrates in KERATINIZED tissue; used to treat RINGWORM ATHLETE'S FOOT
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Griseofulvin
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What is Griseofulvin's mechanism of action?
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Interferes with microtubule function = disrupts mitosis
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Similar pharmacokinetics to Griseofulvin, but also can be used topically
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Terbinafine
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Antifungal that inhibits Squalene Epoxidase (=inhibits Ergosterol synthesis) and is used to treat Onychomycosis
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Terbinafine
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Antifungals that blocks Ergosterol synthesis from Lanosterol
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Azoles
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2 species of Malaria that are only blood-born
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Plasmodium falciparum
Plasmodium malariae |
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2 species of malaria that are in the LIVER and BLOOD
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Vivax and Ovale
***must be treated with PRIMAQUINE |
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Only anti-malarial that affects liver schizonts
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Primaquine
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List the 5 Antimalarial drugs
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1. Chloroquine
2. Mefloquine 3. Primaquine 4. Pyrimethamine-Sulfadoxine (Fansidar) 5. Artemisinin *PC-MAP* |
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Anti-malarial that 1) alters metabolism of hemoglobin by parasite 2) blocks nucleic acid synthesis
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Chloroquine
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How is Chloroquine administered?
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Oral or Parenteral
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How is Chloroquine excreted?
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Urine, 25% as metabolite
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What is necessary for acute treatment with Chloroquine?
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Loading dose
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What is the Clinical use of Chloroquine?
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1. Acute = curative for P. malariae and susceptible P. falciparum (BLOOD schizonts)
2. Prophylactic |
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Describe how to administer Prophylactic Chloroquine
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Begin 1 week before travel, continue 4 weeks after return
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What type of Plasmodium is Chloroquine effective against?
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Blood schizonts
-P. falciparum -P. malariae |
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Antimalarial with adverse effects such as: Pruritis, GI, mild headache
Avoid giving this drug to patients with Psoriasis |
Chloroquine
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Chloroquine Resistance:
1. What parts of world 2. What species? 3. Mechanism? |
1. S. America, Africa, Asia
2. P. falciparum, increasing in P. vivax 3. "P-glycoprotein" pumping |
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What drug blocks the "P-glycoprotein" pumping mechanism of Chloroquine IN VITRO?
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Verapamil
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Anti-malarial that can only be taken ORALLY and is used in Prophylaxis or treatment of Chloroquine-resistant malaria
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Mefloquine
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Anti-malarial used in the treatment of Chloroquine resistant malaria with these adverse effects:
1. GI distress 2. CNS effects 3. Psychotropic effects |
Mefloquine
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What is Fansidar?
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Anti-malarial Anti-folate combination = Pyrimethamine-Sulfadoxine
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-Effective for Blood Schizonticide for P. Falciparum
- slow-acting; cannot be used alone for acute attacks |
Fansidar = Pyrimethamine-Sulfadoxine
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Tissue schizonticide = ?
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Primaquine
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What is the mechanism of action of Primaquine?
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its metabolites are Intracellular oxidants
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How is Primaquine used clinically?
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Used in combo with Chloroquine for prophylaxis or CURE of P. vivax, P. ovale
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Antimalarial that causes some GI distress and Hemolytic Anemia in G6PDH deficiency
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Primaquine
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Traditional Chinese anti-malarial medicine that is taken ORALLY and has a very SHORT HALF-LIFE
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Artermisinin
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Activated inside the Plasmodium -> free radical damage, alkylation
RAPIDLY-ACTING blood schizonticide—particularly useful for multi-drug resistant P. falciparum |
Artemisinin
**VS. FANSIDAR = SLOW-ACTING |
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What is Artermisinin particularly useful for?
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Blood schizonticide
- multi-drug resistant P. falciparum |
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What is the drawback of Artermisinin?
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Very hard to isolate and is expensive
-since short half-life, requires alot of doses |
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List the 4 Anti-protozoal drugs
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1. Metronidazole
2. Trimethoprim-Sulfamethoxazole 3. Pyrimethamine-Sulfonamide 4. Pentamidine |
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Anti-protozoal drug that is a Nitroimidazole compound activated by electron donation and forms toxic metabolites inside the protozoal cell
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Metronidazole
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What sites is Metronidazole particularly effective?
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Anaerobic/Hypoxic sites
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How is Metronidazole administered?
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Oral or IV
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Well distributed Anti-protozoal
- CNS - Bone |
Metronidazole
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How is Metronidazole cleared?
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In urine following Hepatic metabolism
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Anti-protozoal used for GI, extra-GI, and GU infections
-Trichomonaiasis, Giardiasis, Entamoeba -Anaerobic bacterial infections as well |
Metronidazole
**GET on the Anaerobic Metro |
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Anti-protozoal with these adverse effects:
1. Nausea, headache 2. Dry mouth 3. Leukopenia 4. Disulfarim effect = avoid alcohol |
Metronidazole
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Anti-protozoal with these pharmacokinetics:
-IV, IM or AEROSOL -Concentrates in liver, spleen, kidneys -Slowly released from those sites -Doesn't enter CNS |
Pentamidine
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Adverse effects of Pentamidine are less common with _____ administration
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Aerosol
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Antihelminthic used against:
-Pinworm (nematode)(Enterobius) -Hookworm (Necator) -Ascaris |
Mebendazole
*Me = Pin, Hook, Ascaris |
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Anti-helminthic that block microtubule synthesis = blocks vesicle and organelle movement
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Mebendazole
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What is a possible adverse effect of Mebendazole?
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Embryotoxicity
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Effective treatment for all schistosomes, some Trematodes (flukes) and Cestodes (tapeworms)
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Praziquantel
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Antihelminthic that increases membrane permeability to Ca2+, resulting in contraction and paralysis
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Praziquantel
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-Wide spectrum anti-helmintic
-rapidly and completely metabolized in liver, conjugates excreted in urine -interferes with microtubule aggregation, alters glucose uptake |
Albendazole
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What is Ribavirin's mechanism of action?
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Inhibits Viral Nucleic Acid Synthesis
- Blocks GTP formation - inhibits viral mRNA capping *inhibits IMP dehydrogenase |
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How is Ribavirin activated?
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by HOST (not viral!!!) kinases
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What is ORAL Ribavirin used for and what is combined with it?
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Hep C with Interferon-alpha
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Ribavirin can be used as an aerosol for _____ and orally for _____
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RSV
HCV |
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Antiviral with these possible adverse effects:
1. Teratogen and embryotoxin 2. Dose-dependent anemia |
Ribavirin
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What is Acyclovir an analogue of?
How is Acyclovir activated? |
Guanosine
by VIRAL Thymidine Kinase |
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How can Acyclovir be administered?
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Oral
IV Topical to treat active periods *used to manage, not cure |
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Acyclovir mechanism:
-initial phosphorylation requires __1__ -subsequent phosphorylations use __2__ -Acyclovir __3__ is substrate for __4__ Polymerase -Incorporation of Acyclovir causes __5__ |
1. Viral kinase
2. host enzymes 3. triphosphate 4. viral 5. chain termination, inhibition of DNA Pol |
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What viruses are resistant to Acyclovir?
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Thymidine kinase negative viruses
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What is Acyclovir clinically used for?
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Herpes simplex virus
Varicella-zoster virus |
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What is Valacyclovir?
What is its advantage? |
-Valine ester of Acyclovir = Pro-drug
-High bioavailability b/c amino acidtransporters in the GI avidly take it up = Serum levels 5X those obtained with Oral Acyclovir |
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Major drug used for Cytomegalovirus
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Ganciclovir
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What is Ganciclovir's mechanism of action?
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-Initial Phosphorylation by Viral Kinase
-preferentially inhibits CMV DNA polymerase |
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How can Ganciclovir be administered?
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1. primarily IV
2. Oral is available for maintenance 3. Ocular implants for CMV retinitis (contact lens-like) |
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How many days is treatment with Ganciclovir used for?
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14 days
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Explain why Ganciclovir can be more toxic than Acyclovir
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1. Better substrate than Acyclovir for host kinases = activated in uninfected cells
2. Triphosphate is better substrate than Acyclovir Triphosphate for host polymerases = incorporated into host DNA |
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Antiviral that can have these ADR's:
1. Myelosuppression - leukopenia - neutropenia 2. CNS toxicity -headaches, behavioral changes, seizures 3. Teratogenic, carcinogenic in animals |
Gancyclovir
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Directly inhibits Viral Polymerases (DNA, RNA, RT)
- binds to the pyrophosphate binding site of the enzyme = Pyrophosphate analog |
Foscarnet
*not an anti-metabolite ***pyroFOSphate = Foscarnet |
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Antiviral with these properties:
-Ganciclovir-resistant CMV -Acyclovir-resistant HSV -Synergistic with Ganciclovir against CMV |
Foscarnet
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How is Foscarnet administered?
How cleared? |
IV
Urine |
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DeoxyCytidine analog that is a phosphonate-monophosphate analog
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Cidofovir = competitive inhibitor of viral DNA synthesis; incorporated into viral DNA
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What is the adverse effect of Foscarnet and how is it dealt with?
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Nephrotoxic
Give saline pre-load to try to pee out drug ASAP |
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1. How is Cidofovir administered?
2. What needs to be co-administered and why? 3. What is it used for clinically? 4. Adverse effect? |
1. IV only
2. Probenicid due to active tubular secretion 3. CMV retinitis 4. Dose-dependent nephrotoxicity |
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Antifungal that can block Adrenal Steroidogenesis and cause Gynecomastia in males
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Ketoconazole
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Antifungal that alters the drug metabolism of Cyclosporine and non-sedating antihistamines
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Ketoconazole
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1st effective oral azole that has GI and Hepatotoxicity as adverse effects
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Ketoconazole
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Antifungal that inhibits Ergosterol synthesis from Lanosterol and is used to treat Cryptococcal Meningitis in AIDS patients
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Fluconazole
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Aerosol anti-protozoal used for the treatment/prophylaxis against Pneumocystis Pneumonia in the immunosuppressed
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Pentamidine
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Anti-protozoal with these adverse effects:
-Can cause respiratory stimulation followed by depression of respiratory rate; hypotension, anemia -Adverse effects less common with aerosol administration |
Pentamidine
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