Term
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Definition
FUNGI THAT ONLY INFECT DEAD TISSUES
HAIR, SKIN, NAILS, ATHLETE’S FOOT, RINGWORM, ONYCHOMYCOSES |
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Term
| Drug of choice for cryptococcus infections |
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Definition
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Term
| drug of choice for Chromomycosis |
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Definition
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Term
| Drug of choice for pnuemocystis |
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Definition
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Term
| Mechanism of Amphotericin B |
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Definition
| Binds cholesterol and opens pores in membrane. Specific for ergosterol. |
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Term
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Definition
reserved for only the most serious systemic fungal infections
*Also used x some parasitic infections:
*1st x of primary amebic meningo-encephalitis
*2nd x American cutaneous or mucocutaneous leishmoniasis
*2nd for chronic suppression of Histo-plasmosis or Cryptococcus in AIDS pts |
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Term
| ABDE of Fungizone: The Orginial Prototype |
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Definition
*Fungizone is a colloidal suspension in 5% dextrose with Na+ deoxycholate
*Must be given IV or IT: other routes <5% absorpt.
*90-95% bound to cholesterol or lipoproteins which suggested new drug forms
*Doesn’t cross BBB well
*Excreted slowly as inactive metabolite by kidneys so no change needed for renal function if given alone |
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Term
Toxicities of Fungizone
Depend Greatly on the Route |
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Definition
Topical: irritation
Oral: n/v/d (*NB: one uses a related drug (Nystatin) if given orally)
IV: n/v/d + *chills & fever (50%), *nephrotoxicity (80%), headache, hypotension, & rapid breathing
IT: *UNIQUE CNS-RELATED TOXICITIES: headache, n/v, radiculitis, paresis, paresthesias, visual impairment |
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Term
| What is the limiting factor in determining the Rx length of fungizone |
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Definition
Nephrotoxicity. *Na+ loading with normal saline lessens this effect if pt can tolerate the fluid load
*NT due to increased plasma membrane permeability in kidney
*Reversible to total dose of 4 gm
*Kidney workup required prior to Rx |
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Term
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Definition
| All are as effective and have same spectrum. Side effects are less severe (especially nephrotoxicity. Major drawback is price. |
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Term
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Definition
| Best lipid Ampho B, but also most expensive. 50% lower frequency of nephrotoxicity, less severe infusion reactions. |
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Term
| Flucytosine mechanism of action |
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Definition
| Antimetabolite: CONVERTED TO 5-FUMP WHICH INHIBITS FUNGAL THYMIDYLATE SYNTHETASE SO DRUG IS FUNGISTATIC. |
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Term
| Flucytosine clinical applications |
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Definition
Monotherapy x Chromomycosis (1st choice)
Monotherapy x urinary Candidiasis (alternate)
Used with ampho B x Cryptococcus esp. for meningitis in AIDS pts. (It is superadditive & safer.) |
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Term
| Flucytosine major limitations |
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Definition
Resistance can occur during Rx
Must adjust for renal function as primarily excreted unchanged by glomerular filtration
Normal, t½ = 3-4 hr; with renal failure, t½ = 200 hr
If used with ampho B, remember amphoB’s nephrotox! |
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Term
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Definition
Potentially lethal dose-related bone marrow depress.
Enterocolitis with severe diarrhea (esp. freq. in combo with amphoB)
Rare CNS effects: headache, vertigo, confusion, hallucinations |
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Term
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Definition
ITRACONAZOLE
FLUCONAZOLE
VORICONAZOLE
POSACONAZOLE
(KETOCONAZOLE) |
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Term
| Properties Common to All Azoles |
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Definition
Ergosterol biosynthesis is reduced by inhibiting certain fungal P450 enzymes.
*Low conc = fungistatic; high conc = fungicidal
*They have very broad antifungal spectra
little fungal resistance (except for Zygomycetes
aren’t completely selective for fungi over man(inhibit certain CYPs).
*All azoles are teratogenic |
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Term
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Definition
| also inhibits enzymes involved in sex sterol & cortisol synthesis. Not used much anymore. Can also cause anorexia. |
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Term
| Major therapeutic advantages of the newer azoles over amphoB +/- flucytosine: |
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Definition
better tolerated than amphoB or flucytosine
can be given orally rather than IV
hospitalization isn’t required |
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Term
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Definition
1st choice for treatment &/or chronic suppression of histoplasmosis in AIDS patients
*Used for oral Rx of onychomycoses
*Capsules are dependent on gastric acidity for absorption (like ketoconazole); in contrast, the drug solution in more bioavailable on an empty stomach.
*Little itraconazole gets into:
the CSF (so don’t use it for meningitis)
the urine (so don’t use it for fungal UTIs) |
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Term
| Toxicities of Itraconazole |
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Definition
Contraindicated in pts with ventricular dysfunction; can cause hypocalcemia, edema, hypertension, & reduced myocardial function.
*IV itraconazole has cyclodextrin which accumulates in patients with reduced renal function. |
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Term
| Rx Uses of Fluconazole (Diflucan) |
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Definition
Agent of choice for chronic suppression of:
Cryptococcal infections in immunocompromised pts
Systemic or vaginal candidiasis
Recurrent candidiasis in HIV patients
*Used for both Cryptococcal & Coccidiodial meningitis because it gets into CSF so well
*Used in a single dose for vaginal yeast infections |
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Term
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Definition
PK properties equivalent after oral/IV administration
Gastric acidity is not important.
*Given only once per day bec. t½ = 30 hr.
*80% appears in urine unchanged
*Widely distributed throughout body
1 in saliva, .5-.9 in CSF and 10 in urine/skin |
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Term
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Definition
| #1 vs lethal invasive aspergillosis, very active against fusarium spp, and used as salvage therapy vs fusarium and scedosporium |
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Term
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Definition
metabolized primarily by CYP2C19 which exhibits genetic polymorphisms. Gastric acidity isn’t needed for absorption. Dosage must be adjusted in patients with mild/moderate cirrhosis
*Oral dosage adjustment not needed in patients with poor renal function as <2% is excreted in urine.
*Like itraconazole, IV Vfend contains cyclodextrin which builds up in pts with reduced renal flow |
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Term
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Definition
Unique visual changes 30%. Dermal photosensitivity, rash (6%)
*Rare:
Stevens-Johnson syndrome (like fluconazole)
Hallucinations, confusion (like flucytosine) |
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Term
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Definition
*Only azole that is active against Zygomycetes. Unique among azoles in that it must be taken with high-fat meals for adequate absorption (like griseofulvin). Approved for antifungal prophylaxis:
Of invasive Aspergillus and Candida
In pts with leukemia to prevent mycoses
*Has been used successfully to treat refractory mycoses
*Adverse effects similar to those of fluconazole. |
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Term
| Mechanism and name of echinocandins |
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Definition
Glucan sythesis blockers.
Caspofungin (Cancidas) [prototype]
Micafungin (Mycamine)
Anidulafungin (Eraxis) [newest] |
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Term
| Overview of Echinocandins |
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Definition
They are once-daily IV preps.
*They have very similar efficacies and toxicities.
*They block synthesis of (1,3)-D-glucan (a cell wall component) which explains their selectivity.
*They are 1st place drugs for Tx of oral/esophageal or systemic candidiasis; often useful even if fungi are resistant to azoles.
*They are useful as alternates for treatment of invasive Aspergillosis.
*Their clearance is by distribution so metabolism/inactivation does not involve CYP enzymes and there are fewer drug interactions.
*Like the azoles, they are embryotoxic/teratogentic (category C)
*They are generally well tolerated but adverse effects incl. phlebitis at injection site, anaphylaxis, hemolysis, (N/V/D, rash,…).
*Only micafungin (Mycamine) is FDA-approved as an alt. for prophylaxis of invasive Candida infections in patients undergoing hematopoietic stem cell transplantation |
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Term
| Name the SUPERFICIAL ANTIFUGAL AGENTS |
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Definition
NYSTATIN
GRISEOFULVIN
TERBINAFINE
MICONAZOLE & CLOTRIMAZOLE
OTC PREPARATIONS |
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Term
| Name the superficial oral antifungals |
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Definition
| griseofulvin, terbinafine(lamisil), itraconazole, posaconazole, flucanazole, voriconazole |
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Term
| Name the topical polyenes |
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Definition
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Term
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Definition
| miconazole(best), clotrimazole |
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Term
| Name the topical miscellaneous drugs |
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Definition
| terbanifine(lamisil), Tolnaftate(tinactin), ciclopirox, undecylenic acid |
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Term
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Definition
*Same as amphotericin B in terms of:
mechanism,
fungistatic at low but fungicidal at high conc
isn’t likely to meet resistance, and
isn’t well absorbed orally.
*Only used for superficial candidiasis (GI, skin, oropharyngeal, vaginal).
*Safe during pregnancy
*Oral use is less toxic than ampho B (only a unique bitter taste + some n/v/d)
*IV use is more toxic than ampho B |
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Term
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Definition
*Binds to fungal microtubules, blocks mitosis so primarily fungistatic
*Primarily used for difficult dermatophytic infections
*It produces symptomatic relief in 48 hr
*It is keratophilic in that it binds to keratin in skin, hair, nails
*It takes 1-2 months to clear skin & hair, 6-9 months for nails, & over a year for toenails
*Med Letter now prefers terbinafine, itra- or fluconazole
Toxicities:
*CNS (headache; rarely memory lapse & impaired judgment)
*Disulfram (Antabuse)-like effect (remember Rx is long-term; this is a major compliance issue) |
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Term
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Definition
*It is an agent of choice against dermato-phytic infections given orally or topically.
Like the azoles,
*It interferes with ergosterol biosynthesis, in this case by blocking squalene monooxygenase.
*It inhibits CYP2D6 with numerous DIs.
It is extensively used x onychomycoses
*Keratophilic like griseofulvin but faster, more reliable, quicker & cheaper
*Does not require EtOH abstinence
*Better/cheaper than itraconazole
*Oral for 3 months but nails discolored for 12 months; may still not cure |
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Term
| Miconazole and Clotrimazole |
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Definition
Mechanisms are similar to those of other azoles but mostly for topical application
*Both are used for fungal infection of skin/vagina/oral cavity; probably both are better than nystatin. |
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Term
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Definition
An agent of 1st choice for vaginal candidiasis but can cause intense irritation/itching; can be used during pregnancy (80-95% cure after 1 month).
*Miconazole = One of the best topical agents for Rx of dermatophytoses (even if severe) other than in the nails. |
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Term
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Definition
(Lotrimin)
Clotrimazole: too toxic for parenteral use
*Clotrimazole troches are especially good for oropharyngeal candidiasis (ca 100% if immunocompetent). |
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Term
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Definition
| For HPV. Mechanism not fully elucidated. utilizes toll-like receptor 7 and elicits immune response i.e. increase cytokines and IFN |
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Term
| Name the viral entry fusion drugs |
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Definition
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Term
| Name the viral uncoating inhibitors |
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Definition
| amantadine and rimantadine |
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Term
| Name the neuraminidase inhibitors |
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Definition
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Term
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Definition
| (Tamiflu) Inhibits neuraminidase (sialidase) that enables viruses to be released from infected cell. Used for influenza A or B. Oral Prodrug. |
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Term
| Adverse effects of Oseltamivir |
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Definition
| Associated with suicide and other psychiatric behaviors. Diarrhea, nausea, sinusitis |
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Term
| Amantadine and rimantidine mechanisms |
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Definition
| Interferes with viral uncoating. Inhibits M2 ion channel in influenza virus. Inhibits uncoating of virus in endosome |
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Term
| Amantadine and rimantidine uses |
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Definition
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Term
| Clearance of Amantadine and rimantidine |
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Definition
| Rimantidine is hepatic, amantidine is renal. |
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Term
| Amantadine and rimantidine adverse effects |
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Definition
GI and CNS complaints – high plasma concentrations are associated with serious neurotoxicity
Anti-Parkinson’s activity - more with amantadine than rimantadine – potential for interaction with other psychotropic drugs |
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Term
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Definition
Acyclovir and Ganciclovir and
Penciclovir |
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Term
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Definition
Activity: HSV, VZV, limited against CMV & EBV.
Resistance: Altered/deficient TK
Side effects – generally well tolerated
Local irritation topically (rash, phlebitis, etc.)
CNS & nephrotoxicity particularly in renal impaired patients |
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Term
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Definition
Activity: CMV (much greater activity than acyclovir), HSV, VZV, human herpes virus 6.
Less dependent of TK so it is more toxic. DLT is myelosuppression(bone marrow toxicity) |
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Term
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Definition
Cytosine analog. IV only. Not TK dependant. DLT = nephrotoxicity. Resistance: mutated viral DNA polymerase. Activity
CMV, HSV, VZV, EBV, HHV-6,
HPV secondary to gancyclovir and
acyclovir in compromised patients |
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Term
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Definition
| Mimics pyrophosphate. IV. accumulates in bone. Many side effects due to it's ability to chelate calcium. DLT is nephrotoxicity and hypocalcemia. Activity: HSV, VZV, CMV, HHV-6, HIV |
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Term
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Definition
| Mimics pyrophosphate. IV. accumulates in bone. Many side effects due to it's ability to chelate calcium. DLT is nephrotoxicity and hypocalcemia. Activity: HSV, VZV, CMV, HHV-6, HIV |
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Term
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Definition
| Available only as an opthalmic. active against herpes viruses but lack specificity for the viral infection. Mechanism: inhibition of thymidylic phosphorylase |
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Term
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Definition
CMV retinintis
First anti-sense therapy for viral infection
Inhibits CMV replication through sequence specific & nonspecific mechanisms including inhibiting virus binding |
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Term
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Definition
Activity: combination therapy for HCV with INF, also used for HSV, ZVZ & RSV
Mechanism of Action
Purine nucleoside, inhibits 5’ capping of mRNA, interferes with guanine nucleotide synthesis
Notable ADME: T½ life dependent on delivery mode
Side effects
Mild conjuctival irritation, rash, and wheezing
Bone marrow suppression
May be teratogenic, embryotoxic, oncogenic, or gonadotoxic
Therefore systemic administration limited to serious infections |
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Term
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Definition
For hepatitis. failed as HIV drug
Mechanism: AMP nucleotide analog that inhibits reverse transcriptase (similar to NRTI)
Main benefit – longer time to develop resistance |
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Term
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Definition
For hepatitis. still used to combat HIV
Mechanism: nucleoside reverse transcriptase inhibitor |
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Term
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Definition
| associated with mutations in the pol gene that encodes for the reverse transcriptase enzyme |
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Term
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Definition
associated the lactic acidosis with hepatomegaly with steatosis(fatty change)
Depending on agent: hematoxicity, peripheral neuropathy are common |
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Term
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Definition
| zidovudine, lamivudine, tenofovir, emtricitabine, adefovir |
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Term
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Definition
AZT. Need to take orally 2-6 times a day (compliance)
Crosses BBB, placenta, and excreted in milk
Resistance: specific mutations to reverse transcriptase
Lots of Adverse Effects
DLT are granulocytopenia and anemia
Severe headache, nausea, vomiting, insomnia and myalgia
Nail pigmentation, myopathy, neurotoxicities |
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Term
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Definition
Used in combination therapy Once daily dosing
Can reverse zidovudine resistance
Renal function critical for dosing
Also approved for Hepatitis B and C |
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Term
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Definition
Used in combination therapy. Similar to, but more potent than lamivudine (4-10×)
Develops similar resistance as lamivudine |
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Term
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Definition
Used in combination therapy. Oral, ester prodrug formulation – better absorption in fasting state
Poor outcomes when combined: (abacavir, lamivudine & tenofovir) or (didanosine, lamivudine & tenofovir) |
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Term
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Definition
| combines emtricitabine, tenofovir, plus the NNRTI efavirenz |
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Term
| NNRTI activity, metabolism, resistance and toxicity |
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Definition
Not active against HIV-2. All NNRTIs are metabolized via hepatic cytochrome P450 (CYP) and primarily excreted as metabolites in the urine. Prone to drug interactions.
Resistance: mutations in reverse transcriptase enzyme
General Toxicity: Rash is a common toxicity |
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Term
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Definition
NNRTI. Once daily dosing
Inducer/inhibitor of CYP3A4
Causes CNS symptoms. Should not be given with H2- blockers, proton pump inhibitors, or certain HMG-CoA reductase inhibitors |
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Term
| Protease inhibitors mechanism, ADME, resistance, and toxicity |
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Definition
Mechanism: PIs inhibit HIV-1 protease which is required for the HIV virion to mature
Notable ADME: All PIs are metabolized via hepatic cytochrome P450 (CYP) 3A4 and have varying inhibitory effects.
Resistance: Resistance to protease inhibitors occurs due to mutations in the protease genes
General Toxicity: All PIs are also associated with GI intolerance including nausea, vomiting, and diarrhea. Lipodystrophy has been associated with PIs with variable frequency |
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Term
| Name the HIV-1 protease inhibitors |
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Definition
| saquinavir-HGC, ritonavir, lopinavir(used in combination with ritonavir) |
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Term
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Definition
1st protease inhibitor approved – designed using computational chemistry
Poor bioavailability due to extensive first pass metabolism – weakest inhibitor of liver CYP3A4 |
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Term
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Definition
1st protease inhibitor approved – designed using computational chemistry
Poor bioavailability due to extensive first pass metabolism – weakest inhibitor of liver CYP3A4 |
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Term
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Definition
| formulated with a small amount of ritonavir leading to increased and sustained blood levels of lopinavir; lopinavir is the active antiviral agent |
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Term
| Enfuvirtide mechanism, use and toxicity |
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Definition
HIV fusion inhibitor. Mechanism
Mimics region of gp41, constraining necessary conformation changes
Prevents HIV:T cell fusion, prevents infection
Decreases viral load and increases time to drug failure
Use
Given to treatment experienced patients – Salvage therapy
Notable ADME:
Subcutaneous injection, T½ = 3hr
Not P450 metabolized, catabolized by proteolytic enzymes
Injection site reactions, diarrhea, nausea, fatigue |
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Term
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Definition
| fusion inhibitor. Chemokine receptor (CCR5) antagonists-prevent virus binding |
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Term
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Definition
Inhibits integrase – therefore inhibits viral integration & replication
NOT metabolized by CYP enzymes – eliminated by UGT1A1 |
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Term
| Preventative antiretroviral |
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Definition
Start within 72 hours of potential exposure
Administer triple drug regimen
NNRTI-based: Efavirenz + (Lamivudine or emtricitabine) + (zidovudine or tenofovir)
PI-based: Lopinavir/ritonavir + (Lamivudine or emtricitabine) + zidovudine
Continue treatment for 28 days |
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Term
| Toxicities of fluconazole |
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Definition
Most common - Headache, GI problems (2-4%; dry mouth, N/V/D), skin rash (2% w poss SJS)
*Rarely causes prolongation of QT intervals or abnormal liver function. |
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Term
| Which two azoles can cause a build up of cyclodextrin |
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Definition
| itraconazole and voriconazole |
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Term
| Which two antifungals should be taken with high fat meals |
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Definition
| posaconazole, griseofulvin |
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Term
| 1st place drugs for Tx of oral/esophageal or systemic candidiasis |
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Definition
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