Anti-Fungal Antiviral Agents Flashcards
why might fungal infections be increasing (9)
- use of agents that disrupt normal host microflora - anti-biotics
- failure to develop a strong immune system or immunosuppressive drugs
- patient management that suppresses the immune response
- chemotherapy, HIV/AIDS, transplants, steroid treatment
- diabetes
- antibiotic use
- age
- invasive surgical procedures that introduce fungi (IV lines, etc)
- hospital acquired infection
what is the selective toxicity of antifungal agents
need to targe features of fungus not found in host
however fungi are eukaryotes like animals and humans
what are the sites of action of common antifungal drugs
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what are the classification of antifungal drugs
- superficial/systemic infection
- topical/systemic administration of drug
- antifungals/synthetic agents
- fungicidal/fungistatic
- chemical subclass
what are the chemical subclassification
- allylamines
- azoles
- polyenes
- glucan synthesis (cell wall) inhibitors
- antimetabolites
- griseofulvin
- other agents
what are the selective targets for antifungal drugs-1
ergosterol (rather than cholesterol) is the main fungal cell membrane sterol
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which 3 drug classes targe ergosterol in the fungal cell membrane
- allyalmines
- azoles
- amphotericin B (in the class called polyenes)
what is the pathway in biosynthesis of ergosterol
acetyl coA –> squalene (squalene epoxidase) –> lanosterol (14-sterol demethylase) –> ergosterol
what are allylamines (ex, mechanism of action, spectrum, side effects, routes, pharmacokinetics)
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)
what is azoles-1 topical (ex, mechanism of action, spectrum, side effects)
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
what are examples of veterinary licensced azoles
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what are azoles-2- systemic
triazoles for serious systemic mycoses
fluconazole, itraconazole, voriconazole and posaconazole
what is the drug of choice for histoplasmosis
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
what are the mechanisms of resistance to azole antifungal drugs (6)
- membrane changes lead to reduce drug uptake
- mutation of the target enzyme
- over production of target enzyme
- modification of the ergosterol biosynthesis pathway
- drug efflux due to up-regulation ABC transporters, MFS transporters
- biofilm formation
what are polyenes (ex, mechanism of action, spectrum, side effects, routes, pharmokinetics)
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
what is an example of a nystatin
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
what are the mechanisms of resistance to polyenes
amphoteracin B resistance rare
- linked to reduced ergosterol in fungal cell membrane
- forms cross membrane pores –> leads to cell leakage and cell death
- resistance linked to increased intracellular catalase reducing the oxidative killing mechanism of AmB
- innate resistance in some isolates of Candida lusitaniae, Aspergillus terreus, Scedosporium species, Lomentospora prolificans and Purpureocillium lilacinum
- fungicidal –> emergent resistance rate, cells killed not bathed in fungistatic agent allowing mutation resistance –> although observed in C. guilliermondii
what is another way antifungal drugs target fungal cells
fungal cells are eukaryotic but have a cell wall –> made up of B (1,3) and B(1,6) glucans
glucan synthesis inhibitors
what are examples of glucan synthesis inhibitors (ex, mechanism of action, spectrum, side effects, routes, pharmacokinetics)
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
what are the mechanisms of resistance to echinocandins
- inhibit glucan synthase which synthesizes beta glucan, a structural component of fungal cell walls
- structural integrity lost –> cidal in yeast, static in moulds
- many moulds resistant (not Aspergillus) most Candida species susceptible
- Candida parapsilosis innately less susceptible –> higher breakpoints
- 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
what are antimetabolites (ex, mechanism of action, spectrum, side effects, routes, pharamacokinetics)
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)
what are mechanim of resistance to flucytosine (5-FC)
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
what is griseofulvin (mechanism of action, spectrum, side effects, routes, pharmacokinetics)
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
what are iodides
may enhance immune response of host
what is whitfield’s ointment
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
what are other agents
propionic, salicylic and undecanoic acids
phenolic antiseptics (thymol)
hexachlophene
what are combination preparations
for ear infections
Aurizon contains
marbofloxacin
clotrimazole
dexamethasone
what is antiviral therapy and what are they used for in animals
drugs for
- feline herpesvirus 1 - ocular keratitis - acyclovir opthalmic ointment (idoxuridine/trifluoridine also)
- feline immunodeficiency virus - zidovudine - nuecleoside analogue that block viral reverse transcriptase
- canine herpesvirus 1 - ocular lesions –> idoxuridine/trifluoridine
- canine parvovirus 2 –> interferon-w
- influenza
targets: foot & mouth disease, bluetonge, swine fever, bovine viral diarrhea virus
what are the mechanisms of antiviral drugs
- antibodies
- ion channel blockers
- reverse transcriptase inhibitor
- dna polymerase
- neuroaminidase inhibitor
what are examples of antiviral drugs
- aciclovir
inhibits viral DNA polymerase
Hi specificity for herpes simplex
oral, iv, topical - wide distribution
uses FHV, viral eye infection
- amantadine and rimantadine
blocks viral M2 ion channel
influenze A
oral - well absorbed
minimal side effects
what is zidovudine (AZT)
nucleoside reverse transcriptase inhibitor
retroviruses
oral, iv
short term: minor reversible
side effects –> long term anemia, GIT
disturbances –> FLV, FIV
what is zanamivir (relenza) and oseltamivir (tamiflu)
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