Flucytosine

Prodrug: 5 fluorocytosine-->5-flurouracil (5-FU)

MoA: 1)Transported into cell by fungal specific enzyme CYTOSINE PERMEASE 2)Metabolism: 5 fluorocytosine-->5 fluorouracil by CYTOSINE DEAMINASE

    a.  5FU-->5FUMP-->5FdUMP-->inhibits Thymidylate synthetase (impairs DNA synthesis)

    b. 5FUMP-->5FUTP-->altered RNA synthesis (incorp. into mRNA-->miscoding during translation)

TX: serious systemic fungal infections; used with Amphotericin B; Candidal Endocarditis (lipid prep AmB), Candidal Endophthalmitis, Cryptococcemia, meningitis (AmBD)

ADR: GI, Hepatic, Bone marrow suppression

BBW: caution in renal impairment; monitor hematological, renal, & hepatic func.

*PO, w/o Food, excreted in urine, Pregnancy C

Amphotericin B-->Polyene

FungiCIDAL         

AmBD (regular prep); L-AmB, ABLC, ABCD (lipid formulations-->higher distribution in liver, spleen & lung, therefore lower incidence of renal toxicity & dysfunction)

MoA: Binds to ERGOSTEROL and forms pores which increase membrane permeability

TX: Histoplasmosis, Blastomycosis, Coccidioidomycosis (primary fungal infections); Mucormycosis, Cryptococcal, Cutaneous and mucosal candida, Aspergillosis (Opportunistic)
ADR: 1) Infusion reactions: GI, Thrombophlebitis, Fever, chills, hypotension 2) Delayed:Renal dysfunction/nephrotoxicity, vascular, azotemia (increase of nitrogenous products in blood) 3)Blood Dyscrasias: due to decreased Epoeietin; normochromic & macrocytic anemia 4) GI 5) Skin rash *6)Granulocyte infusions may produce pulmonary toxicity (mostly with LIPID formulations)
BBW: DO NOT use in NON-invasive forms of fungal disease in pt. w/ normal neutrophil counts

 *Highly protein bound, highest concentration in the kidney, Pregnancy B, IV

Nystatin-->Polyene

MoA: See Amphotericin B

TX: Local GI infections ONLY

      1. [image]                     2. [image] 

Azoles

MoA: alter fungal membrane permeability/function; Competitive inhibitor of CYP450 3A dependent lanosterol 14-α demethylase (blocks lanosterol-->ergosterol)-->inhibits ergosterol synthesis

     Binds to P450-->N3 binds to ferric iron in fungal P450 heme; N1 affinity for apoprotein important too

1. Imidazoles: can also inhibit HUMAN CYP450

2. Triazoles: selective for fungal 

Ketoconazole-->Imidazole

FungiSTATIC 

MoA: Competitive inhibitor of CYP450 3A dependent lanosterol-14-α-demethylase (blocks lanosterol>ergosterol); altered cell membrane permeability and function

TX: Dermatophytes (Primary-->T. vesicolor  Alternative-->T. corporis, T. cruris, T. pedis), Paracoccidioidmycoses (alternative)

ADR: GI (dose-dependent), Hepatic (BBW), Dermatological, Endocrinological abnormalities (cortesol & sex hormones are mediated by CYP450 which is blocked by ketoconazole so sex abnormalities & adrenal insufficiency may occur), HTN

DIs: Inducers of CYP450 (PPIs, antacids, rifampin) can lower keto's level; Keto can increase Warfarin levels

BBW: rare but FATAL hepatitis, usually w/in 3 mo. increase risk female & age
*PO, w/ FOOD (high fat/acidic, low carb), bile, Pregnancy C

Itraconazole-->Triazole

FungiSTATIC

MoA: see Ketoconazole

Admin:Capsule (normal, NOT mucositis), Oral Solution--HPBCD (mucositis, bone marrow transplant, HIV, infants/children, chemo) IV (if CrCl<30ml/min discontinue & give orally)

TX: Blastomycoses** (CNS), Dermatophytes (Onychomycosis--Primary), Histoplasmosis**, Paracoccidioidmycoses, Sporotrichiosis; Alternative: Cryptococcosis** (non-meningitis/AIDS), dematiaceous molds. **DO NOT use if life-threatening

ADR: well tolerated GI, Skin, CNS, Metabolic (hypertriglycerdemia, hypokalemia), Other (pedal edema, decreased testosterone-->rare) *600mg.day: HTN, adrenal insufficiency, lower limb edema

BBW: Do NOT use in patients w/ evidence of ventricular dysfunction or history of CHF (chronic/untreated)--itraconazole can produce negative inotropic effect

DIs: see Ketoconazole

*PO/IV, w/FOOD-->Capsule, w/o FOOD-->Solution,  Pregnancy C

Fluconazole-->Triazole

FungiSTATIC

MoA: See Ketoconazole

TX:Candidiasis (EXCELLENT), Cryptococcuc (non-meningitis/AIDS), Onychomycosis; Alternative: other Dermatophytes

ADR:well tolerated--GI, Dermatological (exfoliative derm.), *Chronic (>6 months) TX-->alopecia, anorexia, headache

DIs: LOTS!...increases Phenytoin, Cyclosporine & Warfarin levels; Fluconazole decreased by Rifamycins, Cimetidine; increased by Hydrochlorothiazides

*Crosses BBB, urine, CYP 2C9, 3A4, 2C19, Pregnancy D

Voriconazole-->Triazole

FungiSTATIC

MoA: See Ketoconazole

TX: Aspergillus (invasive), Blastomycosis (CNS), Dematiaceous molds, Candida spp, Scedosporium, Fusarium spp; Alternative-->Coccidioidmycosis

ADR: Hepatic toxicity (usually immunocompromised), GI, CNS, Ophthalmic, prolonged QT, High doses-->hypoglycemia, pneumonitis, confusion/hallucinations, in immunosuppressed-->greater risk squamous cell carcinoma

DIs: drugs that inhibit/induce 3A4, 2C9, 2C19; drugs prolong QT interval, high fat meals DECREASES AUC & Cmax

*CrCl,50ml/min-->take off IV, switch to PO

*Tablets contain Lactose so do not give if lactose intolerant

*Crosses BBB, urine, WITHOUT food, Pregnancy D

Posaconazole-->Triazole

FungiCIDAL & STATIC

MoA: See Ketoconazole, EXCEPT binds to CYP51-->more potent inhibitor

**Extended side chain enables tighter binding to CYP51, thus less susceptible to mutation in enzyme

TX: Prevention Candida (STATIC) & Aspergillus (CIDAL) in severely immunocompromised, Oropharyngeal Candidiasis; Alternative: Chromoblastomycosis, Fusariosis, Mucormycosis

ADRs: usually mild-->GI, Liver, CNS (H/A, dizziness), Skin, decreases in serum K+ levels

DIs: inhibits CYP 3A4

*Take during or immeadiately after meal, acidic & fat, feces, PO, Pregnancy C, split doses increases absorption, NO renal adjustment

Miconazole-->Imidazole

FungiSTATIC

MoA: exact unknown; similar to Ketoconazole; alters permeability of cell membrane, may also alter RNA & DNA metabolism or produce intracellular accumulation of peroxides

TX: systemic Psedudoallescheriosis (IV) & skin/vaginal Candida & dermatophytes

ADRs: Injection site phlebitis, rash, purritus, GI, fever, chills, decreased serum sodium, hyperlipemia, Cardiac (arrhythmia, tachycardia), Hematologic (decreased hematocrit, thrombocytopenia)

DIs: Amphotericin B-->antagonize, Oral anticoagulants-->enhance, similar interactions as Ketoconazole

*IV/Top, urine, CYP450, Pregnancy C

Terbinafine-->Allylamine

FungiCIDAL-->several times more potetnt than naftifine

MoA: inhibits squaline epoxidase (key enzyme in sterol biosynthesis)-->alters cell membrane=DEATH

TX: Dermatophytes: Onychomycosis--Primary, T. pedis/capitis/corporis/cruris--Alternative, Chromoblastomycosis (Tertiary), Sprortrichosis (Alternative)

ADR: Changes in ocular lens and retina, neutropenia, GI, Liver enzyme abnormalities, Skin, Taste disturbances (2x more likely in women)

BBW: DO NOT use in patients w/ acute or chronic liver disease

DIs: Cimetidine increases Terbenafine, Rifampin decreases terbinafine

*PO, w/ or w/o FOOD, High protein binding, accumulates in sebum, skin, hair, & nail, CYP 2C8, 2C9, 2C19, 1A2, 3A4, urine, Pregnancy B

Naftifine-->Allylamine

MoA: See Terbinafine

TX: skin infections

Caspofungin-->Echinocandin

FungiCIDAL    Forms salts w/ 2 acetates w/ 2 free NH2

MoA: NON-COMPETITIVE inhibition of beta-1,3-D-glucan synthase-->no beta-1,3-D-glucan-->disruption of creation of fungal cell wall

TX:Invasive aspergillus infections resistant to other treatment; empirical tx of fever and neutropenia; Candidemia; Invasive Candidiasis; Esophageal Candidiasis

ADRs: Pyrexia, diarrhea, increased LFT, hypokalemia, infusion reactions, hepatic dysfunction

DIs: CYP inducers may lower plasma levels of Caspofungin, tacrolimus, Ciclosporin, Rifampin

*IV, urine & feces, NO renal adjustment, Pregnancy C, semisynthetic lipopeptide

Micafungin-->Echinocandin

FungiCIDAL

Forms salts w/ 2 acetates w/ 2 free NH2

MoA: NON-COMPETITIVE inhibition of beta-1,3-D-glucan synthase-->no beta-1,3-D-glucan-->disruption of creation of fungal cell wall

TX: Candidemia, invasive candidiasis, esophageal candidiasis, prophylaxis of candidal infections in patients undergoing stem cell transplant

ADRs: Infusion reactions, Metabolism & nutrition disorders, diarrhea, hypokalemia, hepatic dysfunction

DIs: Ciclosporine & Nefidipine

*IV, feces, Pregnancy C

Griseofulvin-->Antifungal antibiotic

Fungi

MoA: inibits mitosis through disruption of mitotic spindle

TX: Alternative: T. corporis/pedis/cruris/capitis

ADRs: Allergic rxn, GI, H/A, dizziness, blood dyscrasias (bone marrow suppression), heptotoxicity, parasthesis of hands and feet, photosensitivity, lupus-like syndrome

DIs: Barbituates decrease levels

*PO, CYP 3A4, urine, Pregnancy C

Ciclopirox

Ciclopirox

Fungi

MoA: unknown; may act as chelator of Fe and Al which are required for fungla enzymes that detoxify peroxide and other reactive oxygen species

TX:

     Loprox cream & lotion-->T. pedic/cruris/corporis

     Loprox gel & shampoo-->T. pedis/cruris & seborrheic dermatitis

     Penlac-->topical for mild-mod onychomycosis **Removal of unatteched infected nail monthly is required...flammable

ADRs:

     Loprox: pruritis, burning, worsening of S/Sx

     Penlac: nail disorders, burning, erythema of proximal nail bed

DIs: reduce effectiveness of systemic agents?

Quinoline

Historically excellent choice

TX: Malaria

MoA: unknown

1.  [image]      2.[image]

Quinolines & Analogues

1. Mefloquine

      4-Quinoline methanols-->can cause depression & suicidal thoughts

            Another e.g. Cinochona alkaloids

2. Primaquine

      8-Aminoquinolines

1. [image] 2.[image]

Quinolines & Analogs

1. Quinacrine

      9-Aminoacridines

2. Hydroxychloroquine

      7-Chloro-4-aminoquinolines-->have become standard anti-malarials

         Another E.g.-->Chloroquine

1.[image]  2.[image]

Quinolines and Analogs

Later generation chlroquines-->for chloroquine resistant strains of P. falciparaum

     1. Amidiaquine

     2. Tebuquine-->t-butyl group reduces cross-resistance

Both active but CHRONIC ACTIVITY

*If phenyl-Cl in Tebuqine replaced with propyl or isoproyl, may promising and decrease toxicity

Artemisinin & Analogs

Developed in China from Artemisia annua plant; active ingred. in ginghaosu (tea)

1, 2, 4-trioxosequiterpene...**Endoperoxide is essential

Limited bioavailability & hydrolytically unstable

MoA: irreversibly decomposes, generating free radicals that alkylate & oxidizes proteins and lipids...activated by intra-parasitic heme

TX: Malaria & Hemorrhoids

Other E.g.: Artemether, Artesunate, Arteether

[image][image]

Coartem (artemether/lumefantrine)

1:6 fixed dose combination

MoA: inhibit nucleic acid and protein synthesis

TX: Malaria

Halofantrine

MoA: unknown, but does prolong QT interval

TX: malaria

*Major metabolite (n-Butyl halfatrine) is equally active

**Erratic GI absorption

***Contraindicated in use of drugs known to prolong QT interval

[image][image]

Malarone (Atovaquone/Proguanil HCl)

250mg:100mg

MoA:

   Atovaquone-->selective inhibitor of parasite mitochondrial electron transport

                           -->FQ derivative  

   Proguanil-->primarily by metabolite cycloguanil (via CYP2C19) a     DHF reductase inhibitor

TX: Malaria

**Synergistic effect

Halogenated Uridines-->Idoxuridine

1st class anti-DNA virals

NucleoSIDE

Ribose

Analog of thymidine; triphosphate is incorporated in the place of thymidine-->false base pairing

MoA: destabilize/alter H bonds between nucleic acids-->alter DNA structure

TX:

      Idoxuridine-->ophthalmic for HSV keratoconjuctivitis

      Trifluorothymidine-->HSV1 & 2

NucleoSIDE

NucleoTIDE

DNA linkage

3'

5'

Base

NucleoSIDE-->unphosphorylated

NucleoTIDE-->phosphorylated

DNA Linkage-->3'-5' phosphodiester linkage

3'-->elongation

5'-->phosphorylation

Base-->pairing

1. [image] 2.[image]

 3.[image] 4. [image]

1. Adenine

2. Cytosine

3. Guanine

4. Thymine

A & G-->pyrimadines  C & T-->purines

1.[image] 

2.[image]

1. Acyclovir (9-[(2-hydroxyethoxy)methyl]guanine)

NucleoSIDE

Missing 2'OH-->recognized as DNA

Prodrug-->6-deoxy acyclovir (missing carbonyl)

**Must be converted to triphosphate by viral thymidine kinase

MoA: inhibits viral DNA synthesis-->incorporated into viral chain then elongation terminated (b/c missing 3'OH)

TX: HSV-1 & HSV-2, Varicella (VZV), Epstein-Barr (EBV)

ADR: N/V/HA, neurotoxicity, reversible renal dysfunction

DIs: Zidovudine, Valoproate, Merperidine

*IV, urine

2. Valacyclovir-->amino-acid ester prodrug-->enhanced GI absorption

Cidofovir

NucleoTIDE analog of CYTOSINE-->actual nucleotides are not used as drug b/c won't be able to get into cell...phosphoNATE group can get into cell

MoA:converted to diphosphate analog that acts as a competitive inhibitor of dCTP as an alternate substrate for DNA polymerase (selectively inhibits DNA polymerase)

TX: HSV-1 & 2 (acyclovir-resistant), VZV, EBV, CMV retinitis in AIDS pts

ADR: N/V/D, rash, asthenia, anterior uveitis

BBW: Nephrotoxicity (dose related), neutropenia, only for CMV retinits in AIDS

Pregnancy X

*Give with Probenecid to decrease elimination rate, IV, urine

1.[image]

2. [image]

1. Famciclovir

NucleoSIDE

Diacetyl ester prodrug of Penciclovir (#2)-->after admin, deacetylated (hydrolysis) & oxidized to form Penciclovir (only active metabolite) in order to be phosphorylated

MoA: inhibits viral DNA synthesis; NOT a chain terminator

TX: HSV-1 & 2, VZV

ADR: N/D/HA, neutropenia, encephalitis

*PO, urine

Ganciclovir

NucleoSIDE-->acyclic deoxyguanosine analog

Valgancyclovir-->prodrug

MoA: selective inhibitor of VDNA polymerase; chain terminator

TX: greater activity againts CMV & EBV than acyclovir in AIDS, CMV retinitis, HSV

ADR: N/V/CNS (HA, psychosis, confusion, convulsion, coma)

DIs: increased nephrotoxicity w/ AGs, AmpB, cyclosporine, tacromilis

BBW: Myelosuppression

*Urine, PO, IV, implant

1. [image]  2. [image]

1. Vidarabine

NucleoSIDE analog of adenosine-->Arabinose sugar

Deaminated rapidly by adenine deaminase (host enzyme)-->arabinosyl hypoxanthine (weak antiviral)

MoA:intereferes w/ cprrect purine position & effective H bond formation w/ adjacent OH; destabilize duplex chain-->falls apart

TX: HSV 1 & 2 encephalitis, oint for HSV keratoconjunctivitis

2. Ribavirin

NuceloSIDE analog of guanine AND adenine-->NH2 & C=O can rotate to mimic both

Ribose sugar

MoA: inhibits VRNA polymerase, mRNA, & nucleic acid synthesis

TX: BROAD SPECTRUM (b/c of switching), Influ A & B, HSV 1&2, measles, acute hepatitis, serious RSV infection, delay onset of full blown AIDS

Entecavir

NucleoSIDE analog of guanosine

MoA: selectively inhibits HBV (hep B) polymerase (RT)-->even though missing 2' OH (mimic DNA), will stop RNA synthesis b/c RT uses DNA to make RNA

TX: HBV

Oseltamivir

MoA: Neuraminidase Inhibitor (prevents cleavage)

*Ethyl ester prodrug requiring ester hydrolysis for conversion to active form (Oseltamivir carboxylase)

TX: influenza pt >1y/o