Chapter 42 cumulative 4

Polyenes MOA

Fungicidal: Bind to ergosterol (required for fungal cell membrane) causing pores that leak electrolytes and other critical intracellular components leading to cell death.

Polyenes medications

Amphotericin B
Nystatin

Amphotericin B

Slow IV infusion,
Severe progressive fungal
infections
Systemic infections
Severe coccidioidomycosis
Cryptococcosis
Adverse effects : Nephrotoxicity causing acidosis and ion wasting
Black box warning for parenteral: use for treatment of progressive and potentially life threatening infections only
Infusion reactions:
Chills, fever, muscle spasm, headache, vomiting, hypotension
Drug Indications : Antineoplastics, steroids, digitalis: increased risk of hypokalemia, cardiotoxicity, renal toxicity.
Unique : Highly bound to plasma proteins

Excreted unchanged in the urine. Can be detected weeks after treatment has ceased

Nystatin

PO, topical
Intestinal candidiasis
GI cleanse pre-op
Vaginal candidiasis
Tinea pedis (diaper rash)
Adverse effects : large doses orally: diarrhea, nausea, vomiting
Unique : * Can be used in pregnant patients. No effect on fetal tissues

Echinocandins MOA

Fungicidal and fungistatic: Impair cell wall synthesis by inhibiting glucan synthase preventing production of glucan which is necessary for the cell wall.
Fungicidal: Candida species (including azole-resistant)
Fungistatic: Aspergillus species

Echinocandins medications

Caspofungin
Micafungin
Anidulafungin

Echinocandins Drug indications/ adverse effects

Drug Indications
Esophageal candidiasis
Systemic fungal infections (Invasive Aspergillus)
Candidemia Adverse Effects

Elevated liver enzymes (AST, ALT)
Fever
Headache
Diarrhea
Rash
Phlebitis

caspofungin

-fungin
Slow IV infusion
Dose needs to be adjusted in patients with moderate hepatic dysfunction

unique :
Drug interactions: CYP3A4 inducers; carbamazepine, dexamethasone, efavirenz, nevirapine, phenytoin, and rifampin; monitor plasma levels of tacrolimus if coadministered.

micafungin

-fungin
Slow IV infusion

Unique :
Drug Interactions: itraconazole, nifedipine, sirolimus, and cyclosporin: monitor plasma levels of these drugs for toxicity since micafungin can increase plasma levels.

anidulafungin

-fungin
Slow IV infusion

Unique :
*no clinically significant drug interactions likely due to lack of hepatic metabolism

Antimetabolites MOA

Fungicidal
1. Nucleic acid analog converted to 5-fluorouracil by the fungus leading to interruption of RNA synthesis through incorporation instead of uracil. The generates a flawed protein and inhibits synthesis of other essential proteins
2. Conversion to compound that inhibits fungal DNA preventing multiplication

Antimetabolite medication

flucytosine

Antimetabolite drug indications/adverse effects

Drug Indications
Fungal infections in combination with amphotericin B

Adverse : Adverse Effects
Renal toxicity (Special cautionary warning)
Bone marrow suppression
Jaundice
GI hemorrhage
Ulcerative colitis
Confusion
Hallucinations
Hearing loss
Paresthesia
Elevated liver enzymes
Abdominal bloating
Nausea
Vomiting
Headache

flucytosine

PO
Resistance especially among Candida species is common; not used alone or as first-line treatment
Drug can enter the cerebrospinal fluid

Azoles MOA

Fungicidal
Inhibit P450-dependent enzymes in the synthesis of ergosterol leading to faulty cell membranes allowing essential nutrients and ions to leak out causing cell destruction

Azole contraindications/ adverse effects

Use with caution in patients with congestive heart failure

Adverse :
QT interval prolongation
Hallucinations
Fever
Rash
Exfoliative dermatitis
Nausea
Vomiting
Diarrhea
Headache

fluconazole (Diflucan)

-azole
PO, parenteral

Candidiasis oroesophageal
Candidiasis UTI
Vaginal candidiasis
Candidiasis in bone marrow transplant
Cryptococcal/coccidioidal meningitis
Candidemia (with normal WBCs)

Unique : Water-soluble, almost complete absorption after oral dose
Excreted in urine largely unchanged
High penetration into cerebrospinal fluid
Can be administered with single daily dosage
Drug interactions: antacids, tetracyclines, H2-receptor antagonists

voriconazole

-azole
PO, parenteral

Serious candidiasis
Serious Aspergillus infections

Additional adverse effects: visual disturbances ex: blurred vision and photosensitivity

Drug interactions: drugs metabolized by CYP3A4 enzymes

itraconazole

-azole
PO

Histoplasmosis
Blastomycosis
Paracoccidioidomycosis
Invasive aspergillosis
Fungal meningitis
Onychomycosis

Unique: Absorption increases when taken with food.
* Black box warnings: reassess continuation of therapy if symptoms of CHF develop; pimozide, quinidine, dofetilide: serious arrhythmias and death have occurred
Contraindication: History of congestive heart failure
Drug interactions: antacids, tetracyclines, H2-receptor antagonists

miconazole (Monistat)

-azole

Topical

Cutaneous candidiasis
Dermatophytic infections
Vaginal yeast infections

posaconazole

-azole

PO (oral suspension)

Oropharyngeal candidiasis
Invasive aspergillus and candidemia

Unique : Broadest spectrum azole
Highly effective against yeast and opportunistic infections: useful for treatment of immunocompromised patients (HIV or chemotherapy)
Drug interactions: drugs metabolized by CYP3A4 enzymes

Antifungals misc. Griseofulvin

Fungistatic: Binds keratin preventing fungi from using the protein for nutrients; Also binds lipid constituents of growing fungi and inhibiting mitosis

Dermatophytic infections

Contraindications: Acute intermittent porphyria
Hepatic failure
Pregnancy

Adverse effects: Adverse Effects
Diarrhea
Dyspepsia
Serum enzymes may be elevated
Pruritis
Taste disturbances
Nausea
Abdominal pain
Urticaria
Rash
Visual disturbances

Unique : Drug must be continued for extended periods to completely clear the infection

Allylamines

MOA :Fungicidal: Similar to azoles

Dermatophytic infections (Tinea pedis, T. cruris, T. corporis)
Onychomycosis

Contraindications: Chronic or acute liver disease
Pregnancy

Adverse : Adverse Effects
Diarrhea
Dyspepsia
Serum enzymes may be elevated
Pruritis
Taste disturbances
Nausea
Abdominal pain
Urticaria
Rash
Visual disturbances

Allylamines medication

Terbinafine (Lamisil)

amantadine and rimantadine

MOA prevent influenza virus uncoating its nucleoside and releasing viral DNA into the cell.

Influenza A prophylaxis

ADVERSE: Hypotension, congestive heart failure, slurred speech, ataxia, lethargy, irritability

Contraindications : Use with caution with anticholinergics.
Impaired liver or renal function
Epilepsy
Psychosis
Pregnancy

*No impact on other strains
Recommended for high-risk patients
*amantadine now more commonly used in Parkinson's disease

oseltamivir (Tamiflu) MOA

neuraminidase inhibitors - sialic acid analog to preferentially attach to viral surface protein preventing release of viral clones. Host cell penetration and infection is inhibited.

zanamivir (Relenza) MOA

neuraminidase inhibitors - sialic acid analog to preferentially attach to viral surface protein preventing release of viral clones. Host cell penetration and infection is inhibited.

oseltamivir (Tamiflu)

PO

Influenza A, B, H1N1 prophylaxis and treatment
Abdominal pain

Patients must have been symptomatic for less than 3 days for use as treatment.

zanamivir (Relenza)

Inhalation

Influenza A, B, H1N1 prophylaxis and treatment
Bronchospasm
Use caution in patients with asthma

Patients must have been symptomatic for less than 3 days for use as treatment.
Discontinue if evidence of bronchospasm or reduced pulmonary function

Acyclovir, valacyclovir, idoxuridine, ganciclovir MOA

nucleoside analogs: incorporated into viral DNA and prevent synthesis

Docosanol (Abreva) MOA

Works in healthy cells to inhibit viral fusion with the cell membrane and prevent further infection

acyclovir (Zovirax)

PO, IV

Genital herpes: initial and chronic
HSV 1 & 2
Shingles, chickenpox
CMV in bone marrow or renal transplant
Fetal CMV prophylaxis

Adverse : Blurred vision
Injections site irritation
Fatigue

valacyclovir (Valtrex)

PO

Genital herpes: recurrent and suppression
HSV 1 & 2
Shingles, chickenpox

docosanol (Abreva)

topical

Cold sores

Unique : **Not categorized as an antiviral because it works on healthy cells!

idoxuridine (Herplex)

ophthalmic

HSV of the eye
Keratoconjunctivitis
Epithelial keratitis

Unique : Irritation
Edema of eyelids/cornea
Small corneal defects
Sensitivity to bright light

ganciclovir

IV, PO, ophthalmic

CMV

Unique : **Black box warning: granulocytopenia, anemia, thrombocytopenia

Ribavirin MOA

guanosine replacement, full mechanism unknown though to interfere with RNA and DNA synthesis

Entecavir MOA

nucleoside reverse transcriptase inhibitor

Sofosbuvir MOA

RNA polymerase inhibitor

All antiviral adverse effects

Adverse Effects (All antivirals)
Nausea
Gastritis
GI pain
Vomiting
Diarrhea
Arthralgia
Myalgia
Headache
Confusion
Dizziness
Insomnia
Allergic reactions
Hypertension
Edema
Rash
*Drug specific additional adverse effects seen below!

ribavirin

Inhaled, PO

RSV
Severe lower respiratory infections in infants and young children
Hepatitis C infection

Contraindications:
*Teratogenic do not use in pregnant women or male partners

Unique :
*Black box warning: sudden deterioration of respiratory function

entecavir

PO

Hepatitis B

*Black box warning: lactic acidosis

sofosbuvir

PO

Hepatitis C in combination with other drugs

Chemokine coreceptor 5 (CCR5) antagonist MOA

binds CCR5 receptor and blocks HIV attachment and infection of the host cell.

Fusion Inhibitor MOA

peptide that prevents completion of the HIV fusion sequence blocking pore formation and viral penetration.

Nucleoside reverse transcriptase inhibitors (NRTIs) MOA

purine/pyrimidine nucleoside analogs that inhibit reverse transcriptase when incorporated into the viral DNA preventing viral synthesis and decreasing replication and infection

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) MOA

bind directly to RT and block viral protein synthesis

maraviroc

PO
Black box: hepatotoxicity, systemic allergic reaction

Used with ongoing viral replication, evidence of CCR5-tropic virus, and resistance to multiple antiretrovirals.

CCR5 Antagonists medication

maraviroc

Fusion inhibitor medication

enfuvirtide

zidovudine (AZT, Retrovir)

PO

Neutropenia
Nephrotoxicity

Nephrotoxic drugs

Unique :
Contributor to renal toxicity with other nephrotoxic drugs ex. amphotericin B

tenofovir

PO

Unique :
Can be used for Hepatitis B as well
Used in combination for PrEP and PEP

Nevirapine

PO

Black box: severe life-threatening hepatotoxicity
Skin reactions

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) medications

zidovudine (AZT, Retrovir)

tenofovir

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) medication

nevirapine

HIV protease inhibitors MOA

inhibit protease enzyme essential for final assembly of new viruses preventing release

HIV integrase strand transfer inhibitors MOA

inhibit integration of viral DNA into human DNA

HIV protease inhibitors medication

indinavir

indinavir

PO

Adverse: Nephrotoxicity

Unique: Hydration is recommended with dosing to minimize renal tissue damage

HIV integrase strand transfer inhibitors medications

raltegravir

raltegravir

PO

Unique:
Used in for PEP as well

Preexposure Prophylaxis (PrEP)

emtricitabine/tenofovir (Truvada)

PO

Unique:
Two NRTI drug combination
Must have HIV-negative status to begin and follow-up every 3 months

Postexposure Prophylaxis (PEP)

emtricitabine/tenofovir (Truvada) PLUS raltegravir or dolutegravir

PO

Unique:
Typically for health care worker exposure
Can be used for nonoccupational PEP (nPEP)
Initiate immediately following exposure (within 72 hours to be effective)
Recommended to be taken for 28 days.