Antifungals and Antiviral Pharmacology Flashcards
What type of organism is a fungi? What is its main mechanism of damage?
eukaryotic
- closer to mammalian cells
most are dimorphic
mechanism of injury is cell disruption and death causing ranulomatous inflammation
What are the 4 different targets of antifungal medications? What are the common classes of antifungals in each?
Target…
cell wall = echinocandins
cell membrane = polyene/ -azoles / allyamines
nulceic acid synthesis = flucytosine
nuclear division = griseofulvin
What are the main features of fungal infections and their treatments?
fungal infections occur in immunocompromised individuals or those who have bee non antibiotics for a long time
Often antifungal treatment is for a long time
- can have adverse systemic effects = try and use topical and local treatment when possible
List 3 types of polyene drugs
amphotericin B
natamycin
nystatin
What kind of antifungal is amphotericin B? What is the mechanism of efficacy?
macrocyclic polyene
binds ergosterol in cell membranes and creates channels = leakage
auto-oxidizes and causes free radical formation in the presence of O2
What are the main characteristics of amphotericin B
concentration dependent
fungicidal
How is amphotericin B administered
IV or local administration
- poor GI absorbtion
the original formulation is given in dextrose
it is persistent in the body so intermittent treatment can be one (every other day in dogs
Describe the distribution ability of amphotericin B
poor penetration of the eye and CNS
What are the adverse effecs of amphotericin B
nephrotoxic
- toxic to the renal tubules, especially the distal tubules
- causes renal vasoconstriction and ischemia = low GFR
- worse if hyponatremic
phlebitis
fever
V+
What are the 4 different formulations of amphotericin B? Why are the other formulations made?
original formulation
liposome encapsulated
lipid complex
colloidal dispersion with cholesterol sulfate bilayer
= all formulations add lipid to increase hydrophobicity and reduce the concentration in the kidneys (reduce nephrotoxicity)
Describe the efficacy of amphotericin B
good efficacy against a range of fungi
very little resistance
How is natamycin administered
topical
it is toxic systemically
What is natamycin used for
keratomycosis
guttoral pouch mycosis
nasal aspergillosis
What is a main drawback of natamycin
expensive
How is nystatin adminstered
topical
there is no GI absorbtion so you can give PO for tx of oral and intestinal candida
toxic systemically
How is nystatin mainly used
combination with steroid or antibiotic in ointment
List 2 types of azoles
triazole
imidazole
What is the mechanism of action of azole antifungals
inhibit ergosterol synthesis via inhibiting cytochrome P450
This reduces cell membrane function
Are azole drugs fungicidal or fungistatic
fungistatic
How is triazole used? Give 2 examples
systemic with a long elimination
ex. itraconazole or fluconazole
How is imidazoles used? List 3 examples
topically
ex. ketoconazole (but can also give systemically)
- clotrimazole
- miconazole
What is a main adverse effect of imidazoles
they inhibit mammalian sterol synthesis - impact the endocrine system
What factors impact the pahrmacokinetics of azole drugs
potency and drug interactions depend on the affinity for the cytochrome P450
it is also impacted by inhibition of P glycoprotein efflux pumps
- impact the GI absorption and penetration of eye and CNS
How is ketoconazole administered?
topical and PO
What is ketoconazole used for in small animals and horses
SA
- malassezia
- candida
- not great for aspergillus or sporothrix
horse
- fungal keratitis
What are the adverse effects of ketoconazole? List 2 contraindications
inhibit cytochrome P450 = lots of drug interaction
inhibit testosterone and cortisol synthesis
hepatotoxic
v+
anorexia
worse in cats
not for pregnant or if they have liver disease
Describe the pharmacokinetics of ketoconazole
absorb
- soluble in acid (= give with food)
- poor GI absorption in horses
Distribute - in skin and SC
Metabolized - liver
Excrete - bile
for long term tx - 4-6wk
What is the first line treatment for systemic mycoses that are non life-threatening and non CNS related
itraconazole
What is itraconazole used for?
dermatophytes
all fungi except fusarium
What is the pharmacokinetics of itraconazole
absorb
- if given fed = higher AUC
- if given fasted = higher C max (recommended)
Distribute - accumulate in skin and har because it is lipophilic
How is itraconazole administered
pulse treatment - given periodically
because it can persist for weeks or months
give 2 consecutive days per week
- this is for skin treatment only
What are the adverse effects related to itraconazole
GI upset
hepatocellular toxicity
+/- teratogen
BUT it doesn’t inhibit testosterone or cortisol synthesis (more specific for fungal CYP450)
drug interactions
What are the pharmacokinetics of fluconazole
Absorb
- good PO
Distribute
- water soluble
- cross into eye and CNS
- not very protein bound
Excrete - urine (reduce the dose in patients with renal failure)
What is fluconazole used for mainly
candida
cryptococcus
not aspergillus
What are the adverse effects of fluconazole
few
How is miconazole administered? What is it used for?
topical
- can be IV but must monitor
keratomycoses
dermatophytoses
malassezia
How is clotimazole administered? How is it usually used?
topical only
combination with steroid or antibiotic for otitis treatment
How is enilconazole administered? What is it used for?
topical
dermatophyte
fungal sinusitis
How is the 1 main allyamine? What is its main mechanism of action?
terbinafine
fungicidal
inhibit ergosterol synthesis by inhibiting fungal CYP450 - specific for the fungal CYP
What is terbinafine used for
malassezia
systemic fungal infection of the skin/nail
What are the adverse effects of terbinafine
GI upset
hepatotoxic
What is the mechanism of action of flucytosine drugs
uptaken into fungal cells via cytosine permease
converted to 5-fluorouracil by cytosine deaminase
- chemotherapy agent
- incorporated into RNA = disrupt protein synthesis
- incorporated into DNA = disrupt DNA synthesis
What is flucytosine used for?
Adjunct treatment with amphotericin B for candida/cryptococcus
It is synergistic with amphotericin B and so you can lower the dose of amphotericin B when giving together
What is one drawback of using flucytosine
resistance is common
How does sodium iodide/potassium iodide work as an antifungal
mechanism is unknown
it is a systemic tx
What is Na/K iodide mainly used for
actinomycosis (lumpy jaw)
What are the adverse effects of Na/K iodide
lacrimation
hypersalivation
cough
dry scaly skin
tachycardia
thyroid dysfunction
abortion
infertility
careful when using in breeding/pregnant animals
How is lime sulfur administered? What type of antifungal is it? What is its mechanism of action?
topical
fungicide
unknown mechanism
What is lime sulfer used for? What is an adverse effect? What is another name for lime sulfur?
dermatophytoses
stinky
calcium polysulfide
How is chlorine used as an antifungal? What is it mainly used for
effective but irritates tissue
can use chlorine dioxide gas for white line disease
- ex. white lightning
What is the mechanism of efficacy of antivirals?
it targets steps in the replication cycle of the virus
they are all virostatic
timing of administration is important
What 4 conditions are antivirals used for?
herpes keratitis
equine herpes virus 1
herpes in psittiscine birds
FIP (remdesivir)
What additional type of drug can be used as an adjunct treatment with antivirals? Give an example
immunomodulators
ex. imiquimod
List 3 classes of antivirals and give examples of drugs within each class
nucleoside analogs
- acyclovir
- famcicylovir
- remdesivir
idoxuridane/trifluridine
L-lysine
What species is acyclovir mainly used in?
birds (mainly)
also horse/dog
How is acyclovir administered and absorbed?
PO
- dog = good
- cat/horse = poor
topical = cat eye
What is the mechanism of action of nucleoside analogs
similar structure to guanosine
phosphorylated by tyrosine kinase and DNA replication is prevented
it is fairly selective for virus
What is famciclovir used for?
feline herpes virus (systemic use in cats)
What are the pharmacokinetics of famciclovir
it is a prodrug and is converted to penciclovir
- complicated process in cats
must monitor renal function and adjust the dose for renal failure patients
How is idoxuridine and trifluridine administered? What is it used for
topical
herpes keratitis (ulcers iin young cats)
What is the mechanism of action of idoxuridine and trifluridine?
thymidine analog is incorporated into DNA synthesis and makes the DNA more breakable
good against DNA viruses
What are the adverse effects of idoxuridine and trifluridine
non specific for virus-infected cells = lots of adverse effects
topical use can cause conjunctival irritation
- trifluridine is more effective but can be more irritating
What is the mechanism of action of L-lysine? How is it administered
it blocks the availability of arginine
- it is controversial and may or may not reduce viral shedding and it may improve herpes conjunctivitis
PO
What is imiquimod? What is it used for?
immunomodulator
human genital warts
superficial basal cell carcinoma
equine aural plaques
equine sarcoids
What are the pharmacokinetics of remdesivir? What is its mechanism of action?
It is a prodrug and is converted to GS441524
It’s mechanism is that it is an adenosine analog
What is remdesivir used for? How is it administered?
FIP tx
remdesivir is given parenterally
GS441524 is given PO
What are the adverse effects of remdesivir and GS441524
remdesivir
- it is acidic (1.5 pH) and can cause vx site reaction
- it increases liver enzymes
- eosinophilia
- pruritus
- uroliths (rarely)
GS441524
- pruritus or urotliths (rare)
What should you expect when treating a cat with FIP with remdesivir?
get remdesivir with emergency drug release
expect improvement within 24-48hrs
monitor body weight
