Antifungals/ Antiparasitics Flashcards
What is the MOA of amphotericin B/nystatin?
binds egosterol and disrupts membrane stability; Forms pores in the membrane; allows leakage of K+; -static or -cidal depending on dose and fungal sensitivity
What is the mechanism of selectivity for fungi and resistance charactersitics amphotericin B/nystatin?
Affinity for ergosterol is 500X greater than for cholesterol; Resistance is rare but can occur due to decreased ergosterol content
What are the PK prop. of amphotericin B/nystatin?
Low solubility and poor oral absorption; conventional formulation given IV in a deoxycholate colloidal suspension
Newer formulations include lipid and liposomal complexes, colloidal suspensions
What are the uses for amphotericin B?
broad spectrum agent used for life-threatening systemic mycoses (boxed warning)
Initial induction regimen to rapidly reduce fungal burden, then replaced by an azole
What are the uses for Nystatin?
oral/topical for cutaneous, vaginal, mucosal, esophageal candidiasis; “swish and swallow”
What are the adverse reactions of amphotericin B?
Infusion-related effects, Renal toxicity, hematologic toxicity
What are the characteristics of infusion related effects to amphotericin B?
cytokine storm
What are the characteristics of renal toxicity to amphotericin B?
Vasoconstriction of renal afferent arterioles
Proximal tubular cell injury – hypokalemia
What are the characteristics of hematologic toxicity to amphotericin B?
myelosuppression resulting in anemia; thought to be due to decreased erythropoietin secretion
How can toxicity to kidneys and infusion reaction to amphotericin B be decreased?
Lipid-based formulations are less toxic
What is the MOA of flucytosine?
Active transport by cytosine permease; Converted to 5-FU by cytosine deaminase; 5-FU converted to 5-FdUMP, a potent inhibitor of thymidylate synthase; Fungistatic
How does resistance develop to flucytosine?
develops during monotherapy; due to mutations of permease and deaminase
What are the uses of flucytosine?
Narrow spectrum agent used to treat systemic candidiasis, Cryptococcus neoformans infections; Usually administered in combination with amphotericin B; synergistic effect is due to enhanced uptake of flucytosine
What are the PK prop of flucytosine?
orally absorbed and well distributed; dose reduction is necessary in renal insufficiency
What are the adverse reactions to flucytosine?
Hematologic – conversion to 5-FU by GI flora
Hepatoxicity – mild, reversible
What are the drug interactions with flucytosine?
Amphotericin B
Drugs that cause hematological toxicities
What is the MOA of griseofulvin?
binds tubulin, disrupting assembly of the mitotic spindle
Accumulates in keratin precursor cells
Allows new growth of skin, hair or nails to be free of fungal infection
Not active against Candida and is not useful in systemic mycoses
What are the uses of griseofulvin?
Administered orally to treat dermatophytic infections of hair, skin and nails
First-line agent for many years but has been replaced by allylamines and azoles
Commonly used in children for scalp ringworm
What are the adverse reactions of griseofulvin?
Headaches
Can precipitate attacks of acute intermittent porphyria in susceptible patients
Photosensitivity
What is the MOA of terbinafine?
inhibits squalene epoxidase
Prevents conversion of squalene to lanosterol
Causes accumulation of squalene, which is cytotoxic; action is fungicidal
What are the uses of terbinafine?
Topical use for ringworm infections caused by dermatophytes; less active against Candida species
Oral use for treatment of onychomycosis of toe- and fingernails; topical formulations cannot penetrate deeply enough into the cuticle
What are the adverse reactions to terbinafine
generally well tolerated orally
Drug interactions (2D6, 3A4)
Skin reactions
Disturbances of taste; Hepatotoxicity – fatalities have occurred but are rare; contraindicated in patients with liver disease
What is the MOA of azoles like fluconazole?
inhibit 14a-sterol demethylase
Prevents conversion of lanosterol to ergosterol
Causes destabilization of cell membrane and associated enzymes, and increased membrane permeability; action is fungistatic
What are the selectivity features of azoles like fluconazole?
Selectivity results from their greater affinity for fungal than for human CYPs
Triazoles are more selective than imidazoles
How should azoles susceptibility determined?
Sanford guide
What are the uses for azoles like fluconazole?
used topically or orally; active against many pathogenic fungi
Systemic mycoses – fluconazole for cryptococcal meningitis
Superficial mycoses including dermatophytes and Candida yeast infections
Vaginal yeast infections
Onychomycosis – topical (elfinaconazole)
What drugs are used for Bacterial vaginosis (Gardnerella vaginalis)?
metronidazole, clindamycin
What drugs are used for Candidal vulvovaginitis (Candida albicans)?
azoles
What drugs are used for Trichomoniasis (Trichomonas vaginitis)?
metronidazole, tinidazole
What adverse reactions are associated with azoles like fluconazole?
Most common is GI upset
Drug interactions – due to inhibition of human CYPs; can result in serious toxicity
Hepatotoxicity
Avoid during pregnancy
What is the prototype for a Newer class of agents called echinocandins that are semi-synthetic lipopeptides?
caspofungin
What is the MOA of caspofungin?
non-competitive inhibitors of b-(1,3)-D-glucan synthesis; action is fungicidal
What are the uses of caspofungin?
IV therapy of invasive aspergillosis
Persistent febrile neutropenia
Systemic candidiasis
What are the five types of malaria?
Plasmodium infect humans – falciparum, vivax, ovale, malariae, knowlesi; 300-500 million cases and 1 million deaths per year
What are the features of falciparum malaria?
most common and severe form; many strains are drug resistant; cerebral form of malaria is often lethal; 1400 per year in US
What are the features of vivax malaria?
milder but common form of malaria; can relapse due to dormant hypnozoites that remain in the liver; not affected by blood-stage antimalarials
What are the features of knowlesi malaria?
recently-recognized zoonotic infection found in Southeast Asia
What are the drugs used for prophylaxis of malaria?
chloroquine and primaquine
What are the drugs used for treatment of active or latent infection?
artemether/lumefantrine, chloroquine, and primaquine
What drugs are used to produce a clinical cure for the blood stage?
chloroquine and artemisinins
What drug is used to prodce the radical cure of relapsing (vivax, ovale) malaria?
primaquine
What two agents have significant gametocidal activity; no individual clinical benefit but this property disrupts disease transmission?
artemether and primaquine
Prophylactic agents must have what properties?
orally effective with long half-lives and low toxicity
What is the MOA of chloroquine?
Weak base becomes trapped in food vacuole
Digestion of hemoglobin liberates heme; parasite biocrystallizes heme to insoluble hemozoin
Chloroquine inhibits biocrystallization
Resistance due to mutated PfCRT
What are the uses of chloroquine?
clinical cure and prophylaxis against sensitive strains
Ineffective against most strains of P. falciparum in Africa, Asia and S. America
Prophylaxis and treatment during pregnancy
What are the adverse reactions to cholorquine?
Generally well tolerated in doses used for prophylaxis
In doses for clinical cure, can cause pruritis, headache and GI effects; high dose can provoke cardiovascular toxicity
What is artemether, MOA and PK properties?
Derived from the medicinal Chinese plant qinghao; MOA– unclear; formation of toxic free radicals; PK– rapid absorption and short half-life; not useful for prophylaxis
What are the uses of artemether?
Fixed-dose combination with lumefantrine (Coartem®); this long-acting “partner drug” sustains antimalarial activity
First-line oral treatment of MDR falciparum malaria in many endemic areas
IV artesunate has replaced quinidine for severe malaria
Inactive counterfeits are common
What are the uses of primaquine?
With chloroquine to achieve cure of vivax/ovale malaria
Terminal prophylaxis after completion of travel to endemic areas
Primary prophylaxis against all species
What are the adverse reactions to primaquine?
Generally well tolerated in G6PD-normal patients but may cause mild cyanosis
Prototype for drug-induced hemolytic anemia in G6PD deficiency
Contraindicated in all G6PD-deficient patients and in pregnant females in endemic regions because G6PD status of the fetus is unknown
What are Common Protozoal Infections in U.S.?
Trichmoniasis, giardiasis and amebiasis
The principal site of amebiasis infection is the GI; infection can be asymptomatic, mild to moderate, or severe
Classification is systemic or luminal
What is the MOA of metronidazole?
prodrug converted to DNA-damaging metabolite in anaerobes
What are the uses of metronidazole?
For amebiasis; given in combination with a luminal amebicide
What is the MOA of paromycin?
– aminoglycoside; not absorbed from the GI tract
What are the uses of paromycin?
Alone for asymptomatic amebiasis or in combination for amebic colitis/dysentery
Alternative to metronidazole in pregnancy
What are the adverse reactions to paromycin?
GI distress
What is the MOA of albendazole?
Inhibits polymerization of parasite ß-tubulin
Disrupts nematode motility and DNA replication
First-pass metabolism to sulfoxide
What are the uses of albednazole?
Cestode infections – neurocysticercosis and hydatid disease
Roundworm infections – ascariasis, hookworm, toxocariasis
Pinworm infection (enterobiasis) – single 400 mg dose repeated 2 weeks later
What are the adverse reactions to albednazole?
Teratogenic effects in animals; use should be avoided during pregnancy
Long term use can cause liver toxicity; liver function tests are needed
What is the MOA of praziquantel?
increases the permeability of cell membranes to Ca2+; results in paralysis, dislodgement and death
What are the uses of praziquantel?
schistosomiasis, trematode and cestode infections; alternative to albendazole for cysticercosis
What are the adverse reactions to praziquantel?
generally well tolerated; not clear whether symptoms are drug-related or due to release of proteins from dying worms
What is the MOA of pyrantel pamoate?
depolarizing neuromuscular blocker
Effective only within the GI tract
Causes persistent activation of N-ACh receptors and inhibition of AChE; results in spastic paralysis followed by expulsion
What are the uses for pyrantel pamoate?
OTC; Alternative to albendazole for ascariasis and enterobiasis
What are the adverse reactions to pyrantel pamoate?
generally well tolerated; will produce neuromuscular blockade if given parenterally
What is the MOA to Ivermectin?
immobilization by tonic paralysis
Activates glutamate-gated Cl– channels
Causes hyperpolarization of the cell membrane
P-glycoprotein keeps drug out of CNS
What are the uses for Ivermectin?
Broad spectrum agent used to treat infections by nematodes and arthropods in veterinary medicine
Onchocerciasis, lymphatic filariasis and intestinal nematodes in humans
What are the adverse reactions to Ivermectin?
Mazzotti reaction – in onchocerciasis; pruritis, rash, fever and lymphedema; due to immune reaction to dying worms
Teratogenic (cleft palate) in animal studies; should be avoided during pregnancy
