Pharm Test 5

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Onychomycosis

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-terbinafine oral

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Tinea versicolor-

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ketoconazole

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Tinea pedis

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terbinafine

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candidiasis

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fluconazole

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Sporotrichosis

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itraconazole

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Cryptococcosis

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non-meningeal-fluconazole;
meningitis-amphotercin B + flucytosine then fluconazole alone or fluconazole alone

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tinea capitis

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terbenifine???

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Histoplasmosis

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itraconazole

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Blastomycosis

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amphotericin B then itraconazole

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Aspergillosis

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voriconazole

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Fusariosis

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amphotercin b, alt-posaconazole, or voriconazole

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systemic fungal infections do what and what fungus?

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Systemic-Soft tissue infection, Urinary tract infection, Pneumonia, Meningitis, Septicemia (Aspergillus
Blastomyces , Candida, Coccidioides, Cryptococcus, Histoplasma)

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subq fungal infections

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Subcutaneous-Puncture wounds- pseudallescheriasis , sporotrichosis

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superficial fungal infections

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Superficial-Nails, Skin, Mucous membranes Epidermophyton, Microsporum , Trichophyton , Candida albicans (yeast)

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amphotericin B

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Amphotericin B-Parenteral formulation, Extensive hepatic metabolism-Slowly excreted in the urine, Renal toxicity in 80% of patients, Lipid-based formulation reduces renal concentrations and subsequent toxicity; Poor CNS accumulation
Mechanism of action, Selectively binds ergosterol in fungal membranes--Results in increased membrane permeability and subsequent release of cytoplasmic components; used for a wide variety of fungi=used in resistance

polyene antibiotics

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nystatin

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polyene antibiotic
Structurally and functionally similar to amphotericin B, Useful only for candidiasis, Mechanism of action--Selectively binds ergosterol in fungal membranes, Results in increased membrane permeability and subsequent release of cytoplasmic components

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drug tx candida

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nystatin

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Itraconazole

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Oral preparation, Capsule, Absorbed best in the fed state; Solution, Absorbed best in the fasting state
Metabolized by CYP3A4 isoenzyme system, Many drug interactions, DOC blastomycosis (lung infection), Also indicated for onychomycosis (nail infection)=very popular used alot

Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane , Accumulation of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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Fluconazole

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Absorption is not affected by food or gastric acidity, > 90% renal elimination, Excellent BBB penetration
Uses, Prevention of cryptococcal meningitis in AIDS patients, Candidiasis, Esophagus, urinary tract and vagina

Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane , Accumulation of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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Voriconazole

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-“second-generation”, Enhanced activity against Aspergillus and Candida species, 60-100 times more potent than fluconazole against Candida (Yet fluconazole still listed as primary and voriconazole as alt.); primary adverse affect is PHOTOPHOBIA AND CHROMATOPSIA

Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane , Accumulation of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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Ketoconazole

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largely phased out b/c of more drug intx, less BBB penetration, lower activity

Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane , Accumulation of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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MOA of azoles

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Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane , Accumulation of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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POSACONAZOLE

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specifically indicated for prophylaxis in immunocomprimised individuals
type of voriconazole?

Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane , Accumulation of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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Clotrimazole

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Topical formulation, Candida, Mouth, Throat, Vagina, Vulva; Dermatophyte infections of the skin--Athlete’s foot, Jock itch, not effective against infections of SCALP OR NAILS
Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane , Accumulation of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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blastomycosis tx

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itraconazole
oral DOC

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Naftifine

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Allylamines: -Topical treatment of superficial dermatophyte infections,

Inhibit squalene monooxygenase (instrumental in conversion of squalene to lanosterol), Results in reduced ergosterol biosynthesis

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Terbinafine

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Oral treatment of onychomycosis, Accumulates in nails, skin and fat; used a lot; Inhibit squalene monooxygenase (instrumental in conversion of squalene to lanosterol), Results in reduced ergosterol biosynthesis

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caspofungin

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echinocandin
IV preparation; Inhibits the β(1,3)-D-glucan synthase enzyme complex-Prevents formation of β(1,3)-D-glucans in the fungal cell wall; Excellent activity against Candida species, Particularly azole-resistant infections;

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Anidulafungin

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echinocandin-also inhibits glucan synthase, indicated for intra-abdominal abscess caused by Candida species and esophageal candidiasis (same mech but diff target)
Inhibits the β(1,3)-D-glucan synthase enzyme complex-Prevents formation of β(1,3)-D-glucans in the fungal cell wall;

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flucytosine

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Fluorinated pyrimidine analog, Accumulated by fungal cells, Converted to 5-fluorouracil (5-FU) by cytosine deaminase , Subsequent metabolites are Incorporates into fungal RNA and disrupts subsequent protein synthesis, Another metabolite, 5-fluorodeoxyuridylic acid potently inhibits thymidylate synthetase resulting in impaired DNA synthesis, Human cells lack cytosine deaminase

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griseofulvin

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Very lipophilic, Absorption is increased when taken with fatty meal, Induces P450 CYP3A4 , accumulates in keratin precursor cells of skin, hair and nails, Interacts with polymerized microtubules and disrupts their function, Binding sites are distinct from those of colchicine and vinca alkaloids (anti-inflammatory/gout and antineoplastic drugs respectively), Prevents mitosis of dermatophytes

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acyclovir

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Nucleoside analogue Phosphorylated by viral thymidine kinase, then converted to active metabolite by host kinase; Competitively inhibits DNA polymerase (no synthesis).
Additionally: incorporated into nascent viral DNA and terminates elongation.
ORAL, IV and topical
HSV: Oral therapy: Labialis, genitalis, proctitis
IV: Severe HSV, herpes, encephalitis, neonatal herpes
Topical: genitalis, mild labialis
VZV: (less effective for shingles than vala or fam)
Varicella: chicken pox
CMV prophylaxis
1st episode suppresion recurrent
TK must be intact
NO CMV TX. Resistance when viral thymidine kinase activity is lost (drug is not activated). All nucleoside analogues: Prevents viral replication and shedding; shortens time to heal.

DOES NOT ELIMINATE virus.
Renal excretion.
(Gancyclovir is more effective for CMV)
HSV>>VZV>EBV>>>>CMV

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valacyclovir

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Nucleoside analogue; prodrug of acyclovir
1st episode supp recurrent
dec shedding dec heal Time
Phosphorylated by viral thymidine kinase, then converted to active metabolite by host kinase; Competitively inhibits DNA polymerase.
ORAL!!! more than acyclovir
HSV: labialis, genitalis, proctitis
VZV: (shingles); prophylaxis of CMV
Resistance when viral thymidine kinase activity is lost (drug is not activated). See note above.
Renal excretion.
(Gancyclovir is more effective for CMV)

Less frequent dosing than acyclovir so better compliance.
does not elim virus
HSV>>VZV>EBV>>>>CMV

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famciclovir

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Nucleoside analogue Same as valacyclovir. ORAL
(Most bioavailable at 80%) HSV: labialis, genitalis,
proctitis

VZV: (shingles)

NO CMV at all Resistance when viral thymidine kinase activity is lost. See note above.
Renal AND fecal excretion.

Converts to penciclovir

Less frequent dosing than acyclovir so better compliance
dec shedding and Time to heal
does not eliminate virus
HSV>>VZV>EBV>>>>CMV

F=renal AND Fecal

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penciclovir

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Nucleoside analogue (The active metabolite of famciclovir after absorption) Topical HSV: recurrent labialis

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viral replication

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Entry into host cell, Uncoating of viral nucleic acid, Synthesis of early reg. proteins, i.e. nucleic acid polymerases, Synthesis of RNA and DNA , Synthesis of structural proteins, Assembly of viral particles, Release from cell

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nucleoside analoges

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Prodrugs which are initially phosphorylated by viral thymidine kinase (therefore selected for infected cells), Subsequently converted to active metabolite by host kinases, Competitively inhibit viral DNA polymerase; thereby, preventing synthesis of viral DNA, Acyclovir also incorporates into nascent viral DNA and terminates elongation (prevents addition of next nucleoside) resistance when thymidine kinase acitivty is lost;

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triluridine

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Nucleoside analogue
-- Topical ocular HSV: keratoconjunctivitis (NOTE: not in packet, but only drug listed in book that treats this; may be impt.) Well tolerated.

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ganciclovir

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Nucleoside analogue Same as valacyclovir. ORAL and IV DOC for CMV (oral for prophylaxis; IV or oral for CMV maintenance) Leukopenia
Thrombocytopenia 100x more active against CMV than acyclovir.
phosphorylated by viral kinase in CMV infected cells; comp inhib viral DNA poly

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cidofovir

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Nucleoside analogue Activated independent of viral enzymes. IV CMV: (alternate choice
after gan)
Maintenance CONTRAINDICATION: renal insufficiency and when taking aminoglycosides or Amphotericin B (due to add'n of renal toxicity)
Nephrotoxicity
Neutropenia
Metabolic acidosis

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foscarnet

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Nucleoside analogue (a pyrophosphate derivative) Activated independent of viral enzymes OR host kinases. Blocks pyrophosphate-binding sites on viral DNA polymerase (no attachment of nucleoside precursors to DNA) IV HSV: acyclovir-resistant
herpes genitalis
VZV: acyclovir-resistant
shingles
CMV: 2nd line
maintenance
(If gan-resistant
or if pt. had
severe
neutropenia rxn
to gan) Renal toxicity
Cardiac arrhythmias PREHYDRATION is a must due to renal toxicity.
no activation necessary!

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NTRIs

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Nucleoside Reverse Transcriptase Inhibitors (NTRI) , Synthetic derivatives of nucleosides, Converted to active triphosphate metabolite (nucleotide) by host kinases, Compete for entry into viral DNA (rxn which is catalyzed by reverse transcriptase), Cause DNA chain termination; Cross BBB, renal excretion

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didanosine

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Nucleoside Reverse Transcriptase Inhibitor (NRTI)
--Purine cogener-
Synthetic nucleoside  nucleotide by host kinases; nucleotide competes w/endogenous nucleoside triphospates for entry into viral DNA (rxn catalized by reverse transcriptase); DNA chain termination
oRAL (in combo)
HIV
Combo of different classes prevents resistance (2 NRTIs are often combined w/ NNRTI or a protease inhibitor)
Pancreatitis
Peripheral neuropathy (All NRTI) crosses BBB
Renal excretion

If adverse effects occur, pull back on dose, don't have to stop tx.

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lamivudine

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Nucleoside Reverse Transcriptase Inhibitor (NRTI)
--Pyrimidine cogener--
Synthetic nucleoside  nucleotide by host kinases; nucleotide competes w/endogenous nucleoside triphospates for entry into viral DNA (rxn catalized by reverse transcriptase); DNA chain termination
ORAL (in combo)
HIV Hep B
Combo of different classes prevents resistance (2 NRTIs are often combined w/ NNRTI or a protease inhibitor)
Lactic acidosis
Hepatic steatosis (All NRTI) crosses BBB
Renal excretion

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stavudine

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Nucleoside Reverse Transcriptase Inhibitor (NRTI)
--Pyrimidine cogener--
Synthetic nucleoside  nucleotide by host kinases; nucleotide competes w/endogenous nucleoside triphospates for entry into viral DNA (rxn catalized by reverse transcriptase); DNA chain termination
ORAL (in combo)
HIV
Combo of different classes prevents resistance (2 NRTIs are often combined w/ NNRTI or a protease inhibitor)
CAN NOT combo with zidovudine –antagonistic effect
Pancreatitis
(All NRTI) crosses BBB
Renal excretion

Can be used in lieu of zidovudine, if rxn.

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Emtricitabine

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Nucleoside Reverse Transcriptase Inhibitor (NRTI)
--Pyrimidine cogener--
Synthetic nucleoside  nucleotide by host kinases; nucleotide competes w/endogenous nucleoside triphospates for entry into viral DNA (rxn catalized by reverse transcriptase); DNA chain termination
ORAL (in combo)
HIV
Combo of different classes prevents resistance (2 NRTIs are often combined w/ NNRTI or a protease inhibitor) (All NRTI) crosses BBB
Renal excretion

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zidovudine

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AZT
Nucleoside Reverse Transcriptase Inhibitor (NRTI)
--Pyrimidine cogener--
Synthetic nucleoside  nucleotide by host kinases; nucleotide competes w/endogenous nucleoside triphospates for entry into viral DNA (rxn catalized by reverse transcriptase); DNA chain termination
ORAL (in combo) and IV
HIV
Combo of different classes prevents resistance (2 NRTIs are often combined w/ NNRTI or a protease inhibitor)
CAN NOT combo with stavudine –antagonistic effect
Bone marrow suppression
Anemia Neutropenia
(All NRTI) crosses BBB
Renal excretion

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NNRTI

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NNTRI-Do not require metabolic activation, Directly inhibit reverse transcriptase, Single-drug therapy increases risk of resistance, Rash is most common side effect; cross the BBB, renal and fecal excretion

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efavirenz

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Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Direct inhibition of reverse transcriptase (no activation req’d); disrupts catalytic site. ORAL HIV Combo req'd.
Interact'n with protease inhib.
Rash
CONTRAINDICATION: Pregnancy (teratogenic) Crosses BBB
Renal AND fecal excretion
Most POTENT NNRTI (once a day dosing)

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nevirapine

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Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Direct inhibition of reverse transcriptase (no activation req’d); disrupts catalytic site. ORAL HIV Combo req'd.

Rash; hepatotoxicity
Induces P450 system  drug interactions (including ↓ effect of protease inhibitors) Crosses BBB
Renal AND fecal excretion

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atazanavir

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Protease Inhibitor Binds active site of HIV protease; production of immature, noninfectious viral particles. ORAL HIV Combo of different classes prevents resistance (2 NRTIs are often combined w/a protease inhibitor)
Interaction with NNRTI
(in book: hyperbilirubinemia, PR interval prolongation)

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lopinavir

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Protease Inhibitor Binds active site of HIV protease; production of immature, noninfectious viral particles. ORAL HIV (Combo req'd.)
Interaction with NNRTI (in book: GI intolerance)

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ritonavir

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Inhibitor of Protease Inhibitor Inhibits metabolism of protease inhibitors; increases ½ life of other protease inhibitors. ORAL HIV (in book: GI intolerance, hepatitis, inhibition of other drugs: antiarrythmics, opioids, tricyclic antidepressants) Ritonavir + Lopinavir are combo of choice

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enfuvirtide

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Fusion Inhibitor Inhibits fusion of HIV with host cell. Specifically binds gp41, blocking viral entry. SubQ injection (2x daily) HIV (in book: injection site rxns, hypersensitivity rxns) Good alternative when resistance or intolerance occurs w/other drug classes.

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amantadine

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Synthetic tricycylic amine compound Prevents uncoating (inhibits viral M2 proton selective ion channel) of influenza A particles after cell entry. This channel is needed for acidification and subsequent uncoating and nucleic acid transfer from the endosome into the host cell cytoplasm

ORAL (also liquid preps for kids) Influenza A Not effective against Influenza B
REDUCE dose in renal
insufficiency.
Crosses BBB, so more negative
CNS effects. Give w/in 48 hrs: Reduces severity and duration.

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rimantadine

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Synthetic tricycylic amine compound Prevents uncoating (inhibits viral M2 proton selective ion channel) of influenza A particles after cell entry. This channel is needed for acidification and subsequent uncoating and nucleic acid transfer from the endosome into the host cell cytoplasm

ORAL (also liquid preps for kids) Influenza A (DOC) Not effective against Influenza B
REDUCE dose in renal
insufficiency.
DOES NOT cross BBB, so less
side effects. Give w/in 48 hrs: Reduces severity and duration.

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oseltamivir

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Neuraminidase inhibitor Inhibit neuraminidase so that virions can not be released from surface of infected cell. ORAL Influenza A and B
(prophylaxis and
treatment)
Dose reduction NOT necessary in renal insufficiency Give w/in 48 hrs: Reduces severity and duration.
Viral neuraminidase inactivates mucus by breaking linkages. The inhibitor allows our mucus to be active against the virus.

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zanamivir

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Neuraminidase inhibitor Inhibit neuraminidase so that virions can not be released from surface of infected cell. NASAL Influenza A and B Dose reduction NOT necessary in renal insufficiency Viral neuraminidase inactivates mucus by breaking linkages. The inhibitor allows our mucus to be active against the virus.

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protease inhibitors

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Bind to the active site of HIV protease, Results in the production of immature, noninfectious viral particles; Atazanavir, Lopinavir, Ritonavir ; Inhibits metabolism of other PI so given in combination to increase half-life of others; Lopinavir + ritonavir is PI combo of choice

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fusion inhibitors

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Inhibits fusion of HIV with host cell, gp120 directs virus to host cell, gp41 fascilitates viral entry
Enfuvirtide binds gp41; s.c. injection,

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ribavirin

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Guanosine analog Inhibits synthesis of viral nucleic acid d/t reduced guanosine triphosphate levels; Inhibits host cell nucleic acid synthesis. Aerosol (RSV)
IV (HCV) RSV
Hep C (in combo with
IFN-α2b drugs)
(In book: Teratogenic)

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IFNa

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Interferon A DNA recombinant; Signals immune pathways; induction of antiviral proteins in the host cells. (Boosts hosts immune response) SubQ or IM Hep B
Hep C (in combo w/
ribavirin)
(in book: also papillomaviruses, Kaposi's sarcoma, hairy cell leukemia, genital warts, CML, mal. melanoma, multiple myeloma, renal ca.) -- Recall that lamivudine (an NRTI) also treats Hep B.

alone for RSV