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107 Cards in this Set

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Are fungi Prokaryotes or Eukaryotes?
Eukaryotes = very similar to our cells = very difficult to achieve selective toxicity
When are fungal infections most common?
Immunosuppressed patients
- incidence is on the rise

Superinfections
What type of Antibiotic is Amphotericin B?
Polyene
What is Amphotericin B's mechanism of action?
Binds to Ergosterol in fungal membranes and forms pores that allow leakage of electrolytes and disrupts homeostasis = AmphoTEARicin "tears" holes in fungal membranes
How is Amphotericin B administered?
IV or Intrathecal
- too big to be absorbed
Describe the distribution of Amphotericin B
widely distributed except for CNS
What is the half-life of Amphotericin B?
~ 2 weeks
Describe "Liposomal Amphotericin B"
Liposome has lower affinity for drug than does fungal membrane, higher affinity for drug than does the patients membrane (cholesterol) = decreases adverse effects
What is Amphotericin B clinically used for?
Severe Systemic mycoses

*used for wide range of fungal infections
**used for initial intervention, then switch to different anti-fungal for cure/maintenance
What adverse effect occurs frequently with Amphotericin B
Chills
Fever
Nausea
Vomiting
Headache

= Amphoterrible = bad malaise
What can be done to cut down the adverse effects of Amphotericin B?
premedicate with Anti-pyretics (reduce fever), anti-histamines, and analgesics
A common often irrevesible adverse effect of Amphotericin B which may be reduced by giving in the Liposomal form
Nephrotoxicity
What is the selectivity of Flucytosine based on?
it is activated by fungal Cytosine Deaminase -> 5-fluorouracil
What is the mechanism of action of Flucytosine?
inhibits DNA and RNA synthesis
Describe the distribution of Flucytosine
-orally effective
-widely distributed including CNS
How is Flucytosine excreted?
Urine = 10X's the serum level
What are the adverse effects of Flucytosine?
Low toxicity
Narrow spectrum antifungal used to treat Cryptococcus and some Candida
-should only be given when combo'ed with Amphotericin B or Itraconazole
Flucytosine
What 2 drugs is Flucytosine used in combination with due to resistance development?
Amphotericin B

Itraconazole
Anti-fungal drugs that inhibit Ergosterol synthesis from Lanosterol
Azoles
1st effective ORAL anti-fungal for systemic disease
Ketoconazole
Describe the distribution of Ketoconazole
Well distribution, except CNS
List the 4 adverse effects of Ketoconazole
1. GI symptoms
2. Hepatotoxicity
3. Blocks Adrenal Steroidogenesis = Gynecomastia in males
4. Alters drug metabolism
- Cyclosporine
- non-sedating histamines
Broader spectrum Azole with fewer adverse effects than Ketoconazole
Itraconazole
Water-soluble azole, good CSF delivery, more selective for fungal P450's
Fluconazole
DOC for Esophageal and invasive Candidiasis and Coccidiomycoses
Fluconazole
Co-DOC for Paracoccidioides and backup for Blastomyces and Histoplasma
Ketoconazole
DOC for Blastomycoses and Sporotrichoses
Itraconazole
Topical antifungal agent that is similar to Amphotericin B (binds to Ergosterol and disrupts membranes), but is too toxic for systemic use
Nystatin
What is the only reason Nystatin would be given orally?
in treatment of GI Fungal superinfection
List the 2 Systemic antifungal drugs used for Topical Infections
1. Griseofulvin
2. Terbinafine
Antifungal that is administered orally and concentrates in KERATINIZED tissue; used to treat RINGWORM ATHLETE'S FOOT
Griseofulvin
What is Griseofulvin's mechanism of action?
Interferes with microtubule function = disrupts mitosis
Similar pharmacokinetics to Griseofulvin, but also can be used topically
Terbinafine
Antifungal that inhibits Squalene Epoxidase (=inhibits Ergosterol synthesis) and is used to treat Onychomycosis
Terbinafine
Antifungals that blocks Ergosterol synthesis from Lanosterol
Azoles
2 species of Malaria that are only blood-born
Plasmodium falciparum
Plasmodium malariae
2 species of malaria that are in the LIVER and BLOOD
Vivax and Ovale

***must be treated with PRIMAQUINE
Only anti-malarial that affects liver schizonts
Primaquine
List the 5 Antimalarial drugs
1. Chloroquine
2. Mefloquine
3. Primaquine
4. Pyrimethamine-Sulfadoxine (Fansidar)
5. Artemisinin

*PC-MAP*
Anti-malarial that 1) alters metabolism of hemoglobin by parasite 2) blocks nucleic acid synthesis
Chloroquine
How is Chloroquine administered?
Oral or Parenteral
How is Chloroquine excreted?
Urine, 25% as metabolite
What is necessary for acute treatment with Chloroquine?
Loading dose
What is the Clinical use of Chloroquine?
1. Acute = curative for P. malariae and susceptible P. falciparum (BLOOD schizonts)
2. Prophylactic
Describe how to administer Prophylactic Chloroquine
Begin 1 week before travel, continue 4 weeks after return
What type of Plasmodium is Chloroquine effective against?
Blood schizonts
-P. falciparum
-P. malariae
Antimalarial with adverse effects such as: Pruritis, GI, mild headache

Avoid giving this drug to patients with Psoriasis
Chloroquine
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
What drug blocks the "P-glycoprotein" pumping mechanism of Chloroquine IN VITRO?
Verapamil
Anti-malarial that can only be taken ORALLY and is used in Prophylaxis or treatment of Chloroquine-resistant malaria
Mefloquine
Anti-malarial used in the treatment of Chloroquine resistant malaria with these adverse effects:
1. GI distress
2. CNS effects
3. Psychotropic effects
Mefloquine
What is Fansidar?
Anti-malarial Anti-folate combination = Pyrimethamine-Sulfadoxine
-Effective for Blood Schizonticide for P. Falciparum

- slow-acting; cannot be used alone for acute attacks
Fansidar = Pyrimethamine-Sulfadoxine
Tissue schizonticide = ?
Primaquine
What is the mechanism of action of Primaquine?
its metabolites are Intracellular oxidants
How is Primaquine used clinically?
Used in combo with Chloroquine for prophylaxis or CURE of P. vivax, P. ovale
Antimalarial that causes some GI distress and Hemolytic Anemia in G6PDH deficiency
Primaquine
Traditional Chinese anti-malarial medicine that is taken ORALLY and has a very SHORT HALF-LIFE
Artermisinin
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
What is Artermisinin particularly useful for?
Blood schizonticide
- multi-drug resistant P. falciparum
What is the drawback of Artermisinin?
Very hard to isolate and is expensive
-since short half-life, requires alot of doses
List the 4 Anti-protozoal drugs
1. Metronidazole
2. Trimethoprim-Sulfamethoxazole
3. Pyrimethamine-Sulfonamide
4. Pentamidine
Anti-protozoal drug that is a Nitroimidazole compound activated by electron donation and forms toxic metabolites inside the protozoal cell
Metronidazole
What sites is Metronidazole particularly effective?
Anaerobic/Hypoxic sites
How is Metronidazole administered?
Oral or IV
Well distributed Anti-protozoal
- CNS
- Bone
Metronidazole
How is Metronidazole cleared?
In urine following Hepatic metabolism
Anti-protozoal used for GI, extra-GI, and GU infections
-Trichomonaiasis, Giardiasis, Entamoeba

-Anaerobic bacterial infections as well
Metronidazole

**GET on the Anaerobic Metro
Anti-protozoal with these adverse effects:
1. Nausea, headache
2. Dry mouth
3. Leukopenia
4. Disulfarim effect = avoid alcohol
Metronidazole
Anti-protozoal with these pharmacokinetics:
-IV, IM or AEROSOL
-Concentrates in liver, spleen, kidneys
-Slowly released from those sites
-Doesn't enter CNS
Pentamidine
Adverse effects of Pentamidine are less common with _____ administration
Aerosol
Antihelminthic used against:
-Pinworm (nematode)(Enterobius)
-Hookworm (Necator)
-Ascaris
Mebendazole

*Me = Pin, Hook, Ascaris
Anti-helminthic that block microtubule synthesis = blocks vesicle and organelle movement
Mebendazole
What is a possible adverse effect of Mebendazole?
Embryotoxicity
Effective treatment for all schistosomes, some Trematodes (flukes) and Cestodes (tapeworms)
Praziquantel
Antihelminthic that increases membrane permeability to Ca2+, resulting in contraction and paralysis
Praziquantel
-Wide spectrum anti-helmintic
-rapidly and completely metabolized in liver, conjugates excreted in urine
-interferes with microtubule aggregation, alters glucose uptake
Albendazole
What is Ribavirin's mechanism of action?
Inhibits Viral Nucleic Acid Synthesis
- Blocks GTP formation
- inhibits viral mRNA capping

*inhibits IMP dehydrogenase
How is Ribavirin activated?
by HOST (not viral!!!) kinases
What is ORAL Ribavirin used for and what is combined with it?
Hep C with Interferon-alpha
Ribavirin can be used as an aerosol for _____ and orally for _____
RSV

HCV
Antiviral with these possible adverse effects:
1. Teratogen and embryotoxin
2. Dose-dependent anemia
Ribavirin
What is Acyclovir an analogue of?

How is Acyclovir activated?
Guanosine

by VIRAL Thymidine Kinase
How can Acyclovir be administered?
Oral
IV
Topical to treat active periods

*used to manage, not cure
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
What viruses are resistant to Acyclovir?
Thymidine kinase negative viruses
What is Acyclovir clinically used for?
Herpes simplex virus

Varicella-zoster virus
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
Major drug used for Cytomegalovirus
Ganciclovir
What is Ganciclovir's mechanism of action?
-Initial Phosphorylation by Viral Kinase
-preferentially inhibits CMV DNA polymerase
How can Ganciclovir be administered?
1. primarily IV
2. Oral is available for maintenance
3. Ocular implants for CMV retinitis (contact lens-like)
How many days is treatment with Ganciclovir used for?
14 days
Explain why Ganciclovir can be more toxic than Acyclovir
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
Antiviral that can have these ADR's:
1. Myelosuppression
- leukopenia
- neutropenia
2. CNS toxicity
-headaches, behavioral changes, seizures
3. Teratogenic, carcinogenic in animals
Gancyclovir
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
Antiviral with these properties:
-Ganciclovir-resistant CMV
-Acyclovir-resistant HSV
-Synergistic with Ganciclovir against CMV
Foscarnet
How is Foscarnet administered?
How cleared?
IV

Urine
DeoxyCytidine analog that is a phosphonate-monophosphate analog
Cidofovir = competitive inhibitor of viral DNA synthesis; incorporated into viral DNA
What is the adverse effect of Foscarnet and how is it dealt with?
Nephrotoxic

Give saline pre-load to try to pee out drug ASAP
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
Antifungal that can block Adrenal Steroidogenesis and cause Gynecomastia in males
Ketoconazole
Antifungal that alters the drug metabolism of Cyclosporine and non-sedating antihistamines
Ketoconazole
1st effective oral azole that has GI and Hepatotoxicity as adverse effects
Ketoconazole
Antifungal that inhibits Ergosterol synthesis from Lanosterol and is used to treat Cryptococcal Meningitis in AIDS patients
Fluconazole
Aerosol anti-protozoal used for the treatment/prophylaxis against Pneumocystis Pneumonia in the immunosuppressed
Pentamidine
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