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Module 7 > Anti-Fungal Antiviral Agents > Flashcards

Anti-Fungal Antiviral Agents Flashcards

1
Q

why might fungal infections be increasing (9)

A
  1. use of agents that disrupt normal host microflora - anti-biotics
  2. failure to develop a strong immune system or immunosuppressive drugs
  3. patient management that suppresses the immune response
  4. chemotherapy, HIV/AIDS, transplants, steroid treatment
  5. diabetes
  6. antibiotic use
  7. age
  8. invasive surgical procedures that introduce fungi (IV lines, etc)
  9. hospital acquired infection
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2
Q

what is the selective toxicity of antifungal agents

A

need to targe features of fungus not found in host

however fungi are eukaryotes like animals and humans

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3
Q

what are the sites of action of common antifungal drugs

A
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4
Q

what are the classification of antifungal drugs

A
  1. superficial/systemic infection
  2. topical/systemic administration of drug
  3. antifungals/synthetic agents
  4. fungicidal/fungistatic
  5. chemical subclass
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5
Q

what are the chemical subclassification

A
  1. allylamines
  2. azoles
  3. polyenes
  4. glucan synthesis (cell wall) inhibitors
  5. antimetabolites
  6. griseofulvin
  7. other agents
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6
Q

what are the selective targets for antifungal drugs-1

A

ergosterol (rather than cholesterol) is the main fungal cell membrane sterol

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7
Q

which 3 drug classes targe ergosterol in the fungal cell membrane

A
  1. allyalmines
  2. azoles
  3. amphotericin B (in the class called polyenes)
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8
Q

what is the pathway in biosynthesis of ergosterol

A

acetyl coA –> squalene (squalene epoxidase) –> lanosterol (14-sterol demethylase) –> ergosterol

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9
Q

what are allylamines (ex, mechanism of action, spectrum, side effects, routes, pharmacokinetics)

A

dermatophyte infections only

ex: terbinafine

mechanism of action: inhibits ergosterol biosynthesis via inhibition of squalene epoxidase (fungicidal)

spectrum: dermatophytes

side effects: generally transient and mild (GIT and skin)

routes: oral and topical
pharmacokinetics: highly lipophilic (persists in skin)

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10
Q

what is azoles-1 topical (ex, mechanism of action, spectrum, side effects)

A

examples: clotrimazole; enilconazole, miconazole –> lots of topical azoles (main use is topical for superficial mucous membrane and skin infection)

mechanism of action: inhibition of cytP450 dependent 14-sterol de-methylase

spectrum: broad spectrum (generally fungistatic; prolonged treatment)

side effects: GIT, anorexia, hepatotoxicity, suppression of steroid production (ketoconazole), teratogenic

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11
Q

what are examples of veterinary licensced azoles

A
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12
Q

what are azoles-2- systemic

A

triazoles for serious systemic mycoses

fluconazole, itraconazole, voriconazole and posaconazole

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13
Q

what is the drug of choice for histoplasmosis

A

intraconazole: drug of choice for histoplasmosis
routes: oral

fluconazole, itraconazole: lipophilic, highly plasma protein bound, hepatic metabolism and excretion in feces

fluconazole: water soluble and can be given i.v minimally plasma protein bound, minimally metabolized, 80% excreted by kidney unchanged

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14
Q

what are the mechanisms of resistance to azole antifungal drugs (6)

A
  1. membrane changes lead to reduce drug uptake
  2. mutation of the target enzyme
  3. over production of target enzyme
  4. modification of the ergosterol biosynthesis pathway
  5. drug efflux due to up-regulation ABC transporters, MFS transporters
  6. biofilm formation
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15
Q

what are polyenes (ex, mechanism of action, spectrum, side effects, routes, pharmokinetics)

A

examples: amphotericin B, nystatin

mechanism of action: binds to ergosterol, disrupts osmotic integrity of the membrane by forming pores –> ions leak from cell –> cidal and oxidative damage

spectrum: broad spectrum

side effects: nephrotoxicity (i.v), hypokalemia, thrombophlebitis

routes: depends on preparation –> nystatin topical
pharmacokinetics: poorly water soluble (amphotericin B is forms a colloid in solution for injection), poor absorption from GIR

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16
Q

what is an example of a nystatin

A

spectrum of nystatin is broad but topical version mainly for yeast infection in skin

for otitis externa in dogs and cats

also contains a drug that kills ear mites and an anti-inflammatory drug

canaural

17
Q

what are the mechanisms of resistance to polyenes

A

amphoteracin B resistance rare

  1. linked to reduced ergosterol in fungal cell membrane
  2. forms cross membrane pores –> leads to cell leakage and cell death
  3. resistance linked to increased intracellular catalase reducing the oxidative killing mechanism of AmB
  4. innate resistance in some isolates of Candida lusitaniae, Aspergillus terreus, Scedosporium species, Lomentospora prolificans and Purpureocillium lilacinum
  5. fungicidal –> emergent resistance rate, cells killed not bathed in fungistatic agent allowing mutation resistance –> although observed in C. guilliermondii
18
Q

what is another way antifungal drugs target fungal cells

A

fungal cells are eukaryotic but have a cell wall –> made up of B (1,3) and B(1,6) glucans

glucan synthesis inhibitors

19
Q

what are examples of glucan synthesis inhibitors (ex, mechanism of action, spectrum, side effects, routes, pharmacokinetics)

A

echinocandins

severe systemic mycoses only

ex: caspofungin, anidulafungin, micafungin

mechanism of action: block synthesis of B(1,3) glucan

spectrum: candida & aspergillus species

side effects: minimal

routes: I.V
pharmacokinetics: water solube, highly plasma protein bound, eliminated in urine and feces as metabolites

20
Q

what are the mechanisms of resistance to echinocandins

A
  1. inhibit glucan synthase which synthesizes beta glucan, a structural component of fungal cell walls
  2. structural integrity lost –> cidal in yeast, static in moulds
  3. many moulds resistant (not Aspergillus) most Candida species susceptible
  4. Candida parapsilosis innately less susceptible –> higher breakpoints
  5. various FKS1 (glucan synthase subunit) mutations identified also FKS2 and 3 genes all of which encode the target enzyme and up regulation of chitin synthesis –> rescue mechanism
21
Q

what are antimetabolites (ex, mechanism of action, spectrum, side effects, routes, pharamacokinetics)

A

ex: flucytosine (5-fluorocytosine converted to 5- fluorouracil by cytosine deaminase) –> combination therapy for severe yeast infections only

mechanism of action: incorporation of 5-FU into RNA disrupts protein synthesis (fungicidal) and further conversion of 5-FU to fluorodeoxyuridine monophosphate inhibits thymidylate synthase which interferes with DNA synthesis

spectrum: narrow; cryptococcus; candida species

side effects: generally well tolerated

routes: oral
pharmacokinetics: excreted unchanged by kidney

often combined with amphotericin B (synergism)

22
Q

what are mechanim of resistance to flucytosine (5-FC)

A

sensitive: cascade of active enzymes, cytosine permease to take up the drug, cytosine deaminase and phosphorylase to metabolize it to its toxic form –> disrupts RNA to DNA synthesis

5-FC converted to 5-FU (fluorouracil) miscoded RNA or DNA

loss of reduction in activity in any of the enzymes (but most commonly the phosphorylase) leads to primary emergent resistance

common during treatment –> rarely used as monotherapy always combined with AmB

23
Q

what is griseofulvin (mechanism of action, spectrum, side effects, routes, pharmacokinetics)

A

mechanism of action: selectively deposited in newly formed keratin inhibits mitosis, disorganizes the spindle microtubules (fungistatic)

spectrum: narrow spectrum (dermatophytes)

side effects: idiosyncratic reaction in cats, teratogenic

routes: oral with high fat diet
pharmacokinetics: poorly water soluble, hepatic metabolism and fecal elimination

no longer liscened for food producing animals in UK. only horses

24
Q

what are iodides

A

may enhance immune response of host

25
Q

what is whitfield’s ointment

A

benzoic acid and salicylic acid an emulsifying base have been used traditionally

for treating dermatophyte infections of the skin

though old-fashioned and a little messy

cheap + effective

26
Q

what are other agents

A

propionic, salicylic and undecanoic acids

phenolic antiseptics (thymol)

hexachlophene

27
Q

what are combination preparations

A

for ear infections

Aurizon contains

marbofloxacin

clotrimazole

dexamethasone

28
Q

what is antiviral therapy and what are they used for in animals

A

drugs for

  1. feline herpesvirus 1 - ocular keratitis - acyclovir opthalmic ointment (idoxuridine/trifluoridine also)
  2. feline immunodeficiency virus - zidovudine - nuecleoside analogue that block viral reverse transcriptase
  3. canine herpesvirus 1 - ocular lesions –> idoxuridine/trifluoridine
  4. canine parvovirus 2 –> interferon-w
  5. influenza
    targets: foot & mouth disease, bluetonge, swine fever, bovine viral diarrhea virus
29
Q

what are the mechanisms of antiviral drugs

A
  1. antibodies
  2. ion channel blockers
  3. reverse transcriptase inhibitor
  4. dna polymerase
  5. neuroaminidase inhibitor
30
Q

what are examples of antiviral drugs

A
  1. aciclovir

inhibits viral DNA polymerase

Hi specificity for herpes simplex

oral, iv, topical - wide distribution

uses FHV, viral eye infection

  1. amantadine and rimantadine

blocks viral M2 ion channel

influenze A

oral - well absorbed

minimal side effects

31
Q

what is zidovudine (AZT)

A

nucleoside reverse transcriptase inhibitor

retroviruses

oral, iv

short term: minor reversible

side effects –> long term anemia, GIT

disturbances –> FLV, FIV

32
Q

what is zanamivir (relenza) and oseltamivir (tamiflu)

A

treatment and prophylaxis of influenza A and B

neuraminidase inhibitor; stops new viruses emerging

recently used against H1N1 and H5N1

also active against canine parvovirus, feline panleukopenia, kennel cough and canine flu

Module 7 (50 decks)

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