Antifungals and antiparasitics Flashcards
Systemic drugs for subcutaneous and systemic mycoses
- Amphotericin B
- Flucytosine
- Azoles
- Echinocandins
Amphotericin B
- Polyeneantibiotic. Antifungal agent with the broadest spectrum of action.
- Amphotericin B binds to ergosterol, forming pores in the cell membrane.
- The pores allow leakage of intracellular ions and macromolecules, leading to cell death.
- Broad spectrum and fungicidal action: useful for nearly all life-threatening fungal infections.
- Often used as initial induction regimen to rapidly reduce fungal burden.
- Then patients continue therapy with an azole.
- Given by slow IV infusion.
- Amphotericin B is the preferred treatment for deep fungal infections during pregnancy.
Amphotericin B PK and SE
PK
• Amphotericin B is highly insoluble: formulated as deoxycholate colloidal suspension.
• Poorly absorbed from the GI tract.
• Must be given IV.
• Penetration into the CSF is extremely low.
• Intrathecal therapy may be necessary for meningeal disease.
SE
INFUSION-RELATED TOXICITY
• Nearly universal. Fever and chills, muscle spasms, vomiting, headache and hypotension.
• Can be attenuated by slowing infusion rate or decreasing daily dose.
• Pre-medication with antihistamines, glucocorticoids, antipyretics or meperidine can be helpful.
SLOWER TOXICITY
• Amphotericin B also binds to cholesterol and forms pores in mammalian cell membranes, leading to renal toxicity.
• Renal impairment occurs in nearly all patients.
• Anemia: due to reduced erythropoietin production.
• Intrathecal administration can cause seizures and serious neurological damage.
• Lipid formulations of amphotericin B have been developed to reduce nephrotoxicity.
• Amphotericin B is packaged in lipid carriers to reduce exposure to the nephron.
• Amphotec®, Abelcet®, and AmBisome® are the three FDA-approved lipid formulations.
• Nephrotoxicity is less common and less severe with the lipid formulations.
Flucytosine
- Synthetic pyrimidine antimetabolite. Fungistatic. Narrow spectrum.
- Indicated only for serious infections caused by susceptible strains of Candida and/or Cryptococcus.
- Should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis in order to avoid resistance.
- Taken by fungal cells via the enzyme cytosine permease.
- Converted intracellularly first to 5-fluorouracil(5- FU) and then to 5-fluorodeoxyuridine monophosphate (5-FdUMP) which inhibits thymidylate synthetase, thus blocking synthesis of dTMP.
- Fluorouridine triphosphate (5-FUTP) is also formed, which inhibits protein synthesis.
- Mammalian cells are unable to convert the parent drug to its active metabolites.
- Combination of flucytosine and amphotericin B is synergistic.
SE
• Result from metabolism (possibly by intestinal flora) to 5-fluorouracil.
• Bone marrow toxicity is the most common.
Azoles
- Relatively nontoxic oral drugs.
- Important role in systemic therapy.
- Classified as imidazoles or triazoles.
IMIDAZOLES
• Ketoconazole
• Miconazole
• Clotrimazole
TRIAZOLES • Itraconazole • Fluconazole • Voriconazole • Posaconazole
- The fungal cytochromeP450enzyme 14-a-sterol demethylase catalyzes the conversion of lanosterol to ergosterol.
- Azoles inhibit the enzyme, thus reducing ergosterol synthesis.
- This disrupts membrane function and increases permeability.
- Specificity of azole drugs results from their greater affinity for fungal than for human P450 enzymes.
- Imidazoles are less specific than triazoles.
SE
• Relatively nontoxic.
• Most common adverse reaction: minor GI upset.
Ketoconazole
- Due to its narrow spectrum and adverse effects ketoconazole is rarely used for systemic mycoses.
- Still used for superficial mycoses.
- Inhibits mammalian cytochrome P450 enzymes.
- Can decrease plasma testosterone levels and cause gynecomastia, decreased libido and loss of potency in men and menstrual irregularities in women.
- High doses may inhibit adrenal steroid synthesis and decrease plasma cortisol concentrations.
- Strong inhibitor of CYP3A4.It can potentiate the toxicities of several drugs such as warfarin and cyclosporine.
- Best absorbed at low gastric pH: antacids, H2 blockers or proton pump inhibitors interfere with absorption of ketoconazole.
- Poor penetration in the CSF.
Fluconazole
- DOC in esophageal, oropharyngeal, vaginal or urinary candidiasis.
- DOC in invasive Candida infections. Amphotericin B is preferred for severe candidemia when infection is caused by strains that may be fluconazole-resistant and for patients who recently received fluconazole or are immunocompromised.
- DOC for most infections due to Coccidioides.
- DOC for consolidation and maintenance therapy of cryptococcal meningitis after induction therapy with amphotericin B.
- Alternative to amphotericin B for patients with criptococcal meningitis whose disease is not severe.
- DOC for initial and secondary prophylaxis against cryptoccocal meningitis.
- Ineffective against Aspergillus or other filamentous fungi.
- Good CSF penetration.
- High oral bioavailability.
- Available in oral and IV formulations.
- Moderate inhibitor of CYP3A4.
- Strong inhibitor of CYP2C9: can increase plasma levels of phenytoin, zidovudine and warfarin.
Itraconazole
- Preferred azole for mycoses due to the dimorphic fungi Blastomyces, Sporothrix and Histoplasma.
- Effective against Aspergillus, but has been replaced by voriconazole for this indication.
- Used for dermatophytoses and onychomycosis.
- Metabolized primarily by CYP3A4.
- Strong inhibitor of CYP3A4. May cause potentially fatal arrhythmias when given concurrently with cisapride or quinidine.
- Poor bioavailability.
- Penetrates poorly in CSF.
- Absorption reduced by antacids, H2 blockers and proton pump inhibitors.
Voriconazole
- Spectrum similar to itraconazole.
- DOC for invasive aspergillosis.
- Transient visual disturbances occur in up to 30% of patients.
- Voriconazole is metabolized by and inhibits CYP2C19, CYP2C9 and CYP3A4.
- The significant number of drug interactions due to its metabolism through the various hepatic enzymes may limit its use.
Posaconazole
- Spectrum similar to itraconazole,but it has activity against Zygomycetes such as Mucor.
- Inhibits CYP3A4.
Echinocandins: Caspofungin
- Large cyclic peptides linked to a long-chain fatty acid.
- Active against candida and aspergillus but not Cryptococcus neoformans.
- Only available IV.
- Inhibit synthesis of B(1-3)-D-glucans in the fungal cell wall.
- This results in disruption of the fungal cell wall and cell death.
Systemic drugs for superficial mycoses
- Griseofulvin
- Terbinafine
- Ketoconazole
- Fluconazole
- Itraconazole
Griseofulvin
• Only use: treatment of dermatophytosis.
• Severe dermatophytoses of the skin,hair,and nails.
• Largely replaced by newer antifungal drugs like itraconazole and terbinafine.
• Induces P450 enzymes: increases metabolism of a number of drugs, including warfarin.
• Absorption improved when given with fatty
foods.
• Disrupts mitotic spindle and inhibits mitosis
Terbinafine
- Allylamine.
- Available in oral formulation.
- Like griseofulvin it accumulates in keratin but is much more effective in onychomycosis.
- Inhibition of squalene epoxidase prevents synthesis of ergosterol.
- It also causes accumulation of toxic levels of squalene in the fungal cell.
SE
• GI upsets, rash, headache, taste disturbances.
• Terbinafine doesn’t affect the P450 system -> no drug interactions.
Topical drugs for superficial mycoses
- Nystatin
- Amphotericin B - topical form for candidiasis
- Clotrimazole - common
- Miconazole - common
- Ketoconazole - for tinea cruris and tinea corporis
- Terbinafine
Nystatin
- Polyenemacrolide.
- Structurally similar to amphotericin B.
- Same mechanism of action.
- Too toxic for IV administration.
- Used only for candidiasis.
- Supplied in preparations for cutaneous, vaginal, or oral administration.
- Not absorbed from the GI tract, skin, or vagina.
- As a result it has little significant toxicity.
PCP
- DOC: co-trimoxazole.
- Co-trimoxazole is also DOC for prevention of P jiroveci infection in immunocompromised individuals.
Alternative therapiesare: • Clindamycin + primaquine • Dapsone + trimethoprim • Atovaquone • Pentamidine • Patients with moderate-to-severe disease should also be given prednisone.
Metronidazole
- Mixed antiamebic. Amebicide of choice for treating invasive amebiasis
- Patients should receive a luminal amebicide in addition after treatment with metronidazole
Other Clinical Applications • Giardia lamblia • Trichomonas vaginalis • Anaerobic cocci • Anaerobic Gram-negative bacilli • Combination regimens for H.pylori eradication
MOA
• Once absorbed, metronidazole is non-enzymatically reduced by reacting with reduced ferredoxin
• This reduction causes the production of cytotoxic compounds
• The cytotoxic compounds bind to proteins & DNA, resulting in unstable molecules and cell death
PK
• Oral
• Well distributed (inc. vaginal & seminal fluids, saliva, breast milk & CSF)
• Undergoes hepatic oxidation & glucuronidation (CYP P450’s)
SE • GI distress • Disulfiram-like reaction (avoid alcohol intake) • Unpleasant metallic taste • Oral moniliasis • Dark coloration of urine • Leukopenia, dizziness, ataxia. • Safety in pregnancy NOT established
Tinidazole
- Mixed antiamebic. 2nd generation nitroimidazole
- Similar to metronidazole but better tolerated and has shorter treatment course
Clinical Applications • Amebiasis • Amebic liver abscess • Giardiasis • Trichomoniasis
SE
• Same as metronidazole but reports indicate shorter duration of effects with tinidazole
Diloxanide furoate
- Luminal antiamebic. Used as sole agent for treatment of asymptomatic amebiasis
- Converted in gut to diloxanide freebase active form
SE
• Mild (GI distress)
Not currently available in US – however remains luminal amebicide of choice
Iodoquinol
- Luminal antiamebic. Orally active against luminal trophozoite and cyst forms of E.histolytica
- Used as an alternative to diloxanide furoate for mild- severe infections
SE
• Rash, diarrhea, dose-related peripheral neuropathy (inc. optic atrophy/neuritis)
• Long term use should be avoided (due to risk of optic neuritis)
Paromomycin
- Luminal antiamebic. Aminoglycoside antibiotic
- Effective only against luminal forms of E.histolytica and tapeworm
- Sometimes used with tetracyclines for mild intestinal disease
- Alternative agent for cryptosporidiosis in AIDS patient
MOA
• Amebicidal (causes cell membranes to leak)
• Interferes with bacterial protein synthesis (binds to 30S ribosomal subunits)
• Reduces intestinal flora population
SE
• GI distress & diarrhea
• Systemic absorption may lead to headaches, dizziness, rashes and arthralgia
Chloroquine
- Systemic antiamebic. Used in combination with metronidazole & diloxanide furoate
- Eliminates trophozoites in liver abscesses
Emetine, dihydroemetine
- Backup drugs for treatment of severe intestinal or hepatic amebiasis
- Used in combination with a luminal agent
- Inhibit protein synthesis by blocking ribosomal movement along messenger RNA
PK
• IM or SC
• Concentrate in liver (persists for 1 month)
• Slowly metabolized & eliminated
SE • Pain at site of injection • Transient nausea • Cardiotoxicity • Neuromuscular weakness • Dizziness • Rash
Albendazole
• Used in the treatment of cestodal infestations, such as cysticercosis (Taenia solium larvae) and hydatid disease (Echinococcus granulosis)
MOA
• Inhibits microtubule synthesis & glucose uptake
• ATP production is decreased resulting in worm immobilization and death
PK
• Oral (erratically absorbed, enhanced by high-fat meal)
• Extensive first-pass metabolism, including rapid sulfoxidation to active metabolite
SE
•Short course therapy (1-3 days) = mild & transient (headache, nausea)
• Hydatid treatment (3 months) = risk of hepatotoxicity, agranulocytosis or pancytopenia
• Treatment is associated with inflammatory responses to dying parasites in CNS (headache, vomiting, hyperthermia, convulsions, mental changes)
• Contraindicated in pregnancy & children < 2y (FDA Category C)
Mebendazole
Drug of choice in the treatment of infections by:
• Whipworm (Trichuris trichiura)
• Pin worm (Enterobius vermicularis)
• Hookworms (Necator americanus & Ancylostoma duodenale)
• Roundworm (Ascariasis lumbricoides)
MOA
• Inhibits formation of helminth microtubules
• Irreversibly blocks glucose uptake
• Affected parasites are expelled with feces
PK
• Oral (chewable) – nearly insoluble in aqueous solution, take with high-fat meal
• Undergoes first-pass metabolism to inactive compounds
SE
• Abdominal pain, diarrhea, headache, dizziness
• Contraindicated in pregnancy (FDA Category C)
• Use with caution in children < 2
• Use with caution in patients with cirrhosis
Thiabendazole
Effective in treatment of strongyloidiasis caused by Strongyloides stercoralis (threadworm), cutaneous larva migrans, and early stages of trichinosis
MOA
• Affects microtubular aggregation
PK
• Oral
• Nearly insoluble in H20
SE
• More toxic than other benzimidazoles
• Dizziness, anorexia, nausea, vomiting
• CNS disturbances (dizziness -> seizures)
• Cases of erythema multiforme & Stevens-Johnson reported
• Contraindicated in pregnancy (FDA Category C)
• Should not be used in presence of liver or kidney disease
Ivermectin
Drug of choice for the treatment of onchocerciasis (Onchocerca volvulus), cutaneous larva migrans & strongyloides
MOA
• GABA agonist
• Cl- influx increases leading to hyperpolarization of nerve/muscle cell. Death occurs due to paralysis of parasite
PK
• Oral (does not cross BBB)
SE
• Mazotti-like reactions with onchoceriasis (fever, dizziness, somnolence, hypotension)
• Contraindicated in pregnancy (FDA Category C)
• Contraindicated in meningitis (may cross BBB)
• Best to avoid concomitant use of ivermectin & other drugs that enhance GABAergic activity (eg, barbiturates, benzodiazepines)
Piperazine
Alternative drug for treatment of pinworm & roundworm infections
MOA
• GABA agonist
• Expulsion of worm occurs by peristalsis
CI
• Patients with seizure disorders
Pyrantel pamoate
Effective in treatment of infections by roundworms, pinworms and hookworms
MOA
• Acts as a depolarizing, neuromuscular-blocker (causes persistent activation of parasite’s nicotinic receptors by release of acetylcholine & inhibition of cholinesterase)
PK
• Poorly absorbed orally (exerts effects in intestinal tract)
SE
• Mild (nausea, vomiting, diarrhea)
Diethylcarbamazine
Drug of choice for treatment of lymphatic filariasis, loiasis & tropical eosinophilia.
MOA
• Immobilizes microfilariae & renders them susceptible to host defense mechanisms
PK
• Oral (rapidly absorbed with meals)
SE
• Most AE thought to be due to host responses following damage/death of parasite
• Fever, malaise, rash, myalgias, arthralgias, headache
• Leukocytosis (common)
• Antihistamines or steroids can be coadministered
Doxycycline
- Tetracycline antibiotic.
- Macrofilaricidal activity against Wuchereria bancrofti.
- Also active against onchocerciasis
MOA
• Acts indirectly by killing Wolbachia (intracellular bacterial symbiont of filarial parasites)
Praziquantel
- Drug of choice for all forms of schistosomiasis & most trematode & cestode infections
- Cysticercosis – albendazole is drug of choice (praziquantel has similar efficacy)
MOA
• Increases permeability of cell membrane to calcium, causing contracture & paralysis of worm musculature, resulting in detachment of suckers from blood vessel walls.
PK
• Oral
• Extensive first-pass metabolism (CYPs)
• Inactive metabolites excreted via urine & bile
SE
• Drowsiness, dizziness, malasie, anorexia & GI upsets
• Drug interactions (CYP P450)
• Contraindicated in pregnancy & nursing mothers (FDA Category B)
• Contraindicated for treatment of ocular cysticercosis (destruction of organism may damage eye)
Bithionol
- Drug of choice for fasciolosis (sheep liver fluke)
- Alternative drug for pulmonary paragonimiasis
MOA
• Inhibition of helminth’s electron transport chain (probably)
Niclosamide
• 2nd line drug for treatment of most cestode infections
• Use is uncommon due to excellent efficacy of
praziquantel
• No longer available in US
MOA
• Inhibition of the parasite’s mitochondrial phosphorylation of ADP. Anaerobic metabolism may also be inhibited
• Drug is lethal for cestode’s scolex & segments of cestodes but not for the ova
PK
• Laxative is admin. prior to niclosamide (oral) to purge bowel of all dead segments in order to preclude digestions & liberation of ova (may lead to cysticercosis)
• Alcohol should be avoided within 1 day of dose
• Safety has not been established in pregnancy or children <2
