includes nystatin and amphotericin B

they insert into the fungal cell wall adjacent to ergosterol = make a pore where potassium, sodium, and calcium leak out

they are fungistatic and fungicidal

antifungal - polyene class

Locally administered - often used as a mouthwash for oral thrush

it is too nephrotoxic to be used systemically

Gold standard for treatment of systemic fungal infection

it is toxic, but it is systemically administered because it is the most effective drug available for systemic fungal infections; given in suspension called Amphotericin B Deoxycolate

broad antifungal spectrum

fungicidal and fungistatic

poorly absorbed orally; ADMIN: IV

stored in tissues (it is lipophillic); mostly metabolized; slowly excreted in the urine; HALF LIFE = 15 days

Adverse effects:

Hypersensitivity reactions

 anaphylaxis

fever, chills, headache

GI disturbances

arthralgia

myalgia

thrombophilebitis

hypotension

decreased renal function (usually doesn't recover)

(Patients usually develop tolerance to these adverse effects)

antifungal class

includes: ketoconazole, itraconazole, fluconazole, voriconazole

inhibit lanosterol 14-alpha-demethylase (a fungal cytochrome P450) - this enzyme is required for conversion of lanosterol to ergosterol --> ergosterol percursors are inserted into the membrane instead = TOXIC!!!

all are potentially hepatotoxic

1st generation: Ketoconazole, itraconazole, fluconazole

2nd generation: Voriconazole

Broad spectrum of antifungal activity (against Blastomyces, candida, cryptococcus, coccidoides, hisplasma, Paracoccidioides, and Sporothrix)

azole antifungal drug

Oldest of azole drugs

it is a potent inhibitor of the cytochrome P450 3A4 enzyme system

Adverse: 1) Hepatotoxicity (primarily hepatocellular type) - rare fatalities

2) rare cases of anaphylaxis

3) Drug interactions (because inhibitor of P450 3A4)

= inhibits astemizole and cisapride = may prolong QT intervals

4) inhibits human sex steroid biosynthesis (P450s) = gyenecomastia, testicular atrophy

need high stomach acidity for absorption (so drink soda when you take it) (cola drinks increase absorption; PPIs decrease absorp.)

azole antifungal drug

it is highly lipophillic - deposits in tissues, including skin/cornea; starting to replace ketoconzole

inhibits only drug metabolism (CYP 3A4)

should not be administered for the treatment of onychomycosis (fungal infection of nails) in patients with evidence of ventricular dysfunction such as CHF

azole antifungal

high oral bioavailability! widely distrubuted into body tissues and fluids (has high aqueous solubility, so in many body fluids; distributes well into CSF)

Adverse: POTENT CYP2C9 inhibitor and a moderate CYP 3A4 inhibitor

Teratogen in high doses

second-generation antifungal triazole

enhanced target activity and specificity

not a first line drug, but used in invasive fungal infections (i.e., invasive aspergillosis)

in vitro studies, it was an inhibitor of CYP P450, CYP 2C19, CYP2C9, CYP3A4

Antifungal

inhibits in biosynthesis pathway of ergosterol; inhibitors of squalene epoxidase (Also, a P450)

allylamine class of antifungals

is highly lipohilic and keratophilic

MOA: potent noncompetitive inhibitor of fungal squalene epoxidase and prevents squalene epoxidation (important early step in synthesis of ergosterol)

Use: dermatophytes, molds, dimorphic fungi, C. neoformans, Candida, Aspergillus; onychomytosis

synergistic interactions with Amphotericin B; also with azoles (esp against Aspergillus)

antifungal class

interfere with fungal cell wall synthesis

includes: andiulafungin, caspofungin, micafungin

inhibit synthesis of beta-1,3-D-diglucans (causes cell lysis)

these are very expensive and are rarely used

for invasive aspergillosis in patients that doen't respond to other antifungals

echinocandins antifungal class

interfere with fungal cell wall synthesis

inhibit synthesis of beta-1,3-D-diglucans (causes cell lysis)

these are very expensive and are rarely used

for invasive aspergillosis in patients that doen't respond to other antifungals

echinocandins antifungal class

interfere with fungal cell wall synthesis

inhibit synthesis of beta-1,3-D-diglucans (causes cell lysis)

these are very expensive and are rarely used

for invasive aspergillosis in patients that doen't respond to other antifungals

echinocandins antifungal class

interfere with fungal cell wall synthesis

inhibit synthesis of beta-1,3-D-diglucans (causes cell lysis)

these are very expensive and are rarely used

for invasive aspergillosis in patients that doen't respond to other antifungals

miscellaneous antifungal

taken up by the fungus-specific enzyme cytosine permease and converted by cytosine deaminase to 5-flurouracil --> RNA miscoding and inhibits DNA synthesis --> inhibition of protein synthesis

synergistic with amphotericin B (so you can lower the dose of amp. B)

Resistance develops rapidly if it is used as a single agent

Admin: oral (well absorbed from GI; widely distributed throughout body) - excreted into urine

Adverse: *** potentially lethal bone marrow depression

GI uupset

rash

hepatic dysfunction

Inhibit the enzyme neuraminidase (this enzyme removes the sialic acid residues from the surface of the virus particles in order to prevent clumping)

Antiviral tx inhibits enzymes, so sialic acid residues are present and the virus clumps = NOT INFECTIVE

Active against influenza A and B and H1N1

oseltamivir = orally administered

zanamivir = inhalation (taken as powder - could be irritating = bronchospasm)

ADVERSE EFFECTS: reports of self-injury delirium (suicides) in children with use of oseltamivir

resistance becoming a greater problem

Broad spectrum antiviral

guanosine analogue with wide range of antiviral activity (against influenza, RSV, parainfluenza, adenovirus, Hanta virus)

drug is rapidly phosphorylated by intracellular enzymes and the triphosphate version inhibits viral RNA polymerase and competitively inhibits guanosine triphosphate-dependent 5' capping of influenza viral messenger RNA

also depletes cellular guanine pools

approved for tx of genotype 1 HCV when used in combination with ribavirin

both inhibit HCV replication by inhibiting viral serine protease

ribavirin + pg INF-α-2b + either boceprevir or telaprevir

So now it is a 3 drug regime

most are nucleoside analogs that require metabolism to nucleotides (via phosphorylation and metabolic activation)

the 3' -OH group is important for extension of linkage (this is where the drugs interfere)

includes: acyclovir, valacyclovir, famciclovir, ganciclovir, valaganciclovir

require metabolic activation to the triphosphate to exert their antiviral activity

look at acyclovir's mechanism for general idea

nucleoside antiviral

MOA: initial phosphorylation is carried out by the VIRAL thymidine kinase --> drug is only activated in virus infected cells --> further converted to di- and triphosphates by MAMMALIAN enzymes

triphosphate is: (a) inhibitor of viral DNA polymerase

(b) incorporated into viral DNA = leads to premature chain termination since it lacks a 3'-OH group

Resistance: by Herpes virus is due to loss of viral thymidine kinase activity and causes cross resistance to valacyclovir and famciclovir

USES: HSV-1, HSV-2, VZV, and EBV (not curative and only affects virus that is actively replicating)

has low bioavailability when given orally; IV is preferred route for tx of serious infections of HSV and VZV - topical tx of genital herpes

Adverse: Headaches and GI disturbances; rarely: reversible nephropathy

L-valine ester of acyclovir - this drug metabolized to acyclovir after oral administration

Plasma concentration of acyclovir following high doses of oral valacyclovir can resemble those flollowing IV acyclovir

is an ester prodrug of PENCICLOVIR - similar to acyclovir, but does not cause chain termination

activity against HSV-1, HSV-2, VZV, and EBV

adverse: headache, diarrhea

nucleoside analogue that is structurally similar to acyclovir; structural modification accounts for enhanced acitivty against CMV and for drug's greater toxicity - potent inhibitor of herpes virus DNA repilcation, inhibitor of and a substrate for viral DNA polymerase

phosphorylation is initially by viral TK

acyclovir is a more potent inhibitor of CMV, but is a poor substrate for intitial phosphyorylation catalyzed by the CMV kinase

used in AIDS pts against CMV - Retinitis and colits, espohagitis; Now used in transplantation

Adverse: dose-liming toxicities and granulocytopenia and thrombocytopenia (usually reversible) --> More toxic than acyclovir

non-nucleoside antivirals

binds to the phosphate binding site of viral DNA or RNA polymerase and HIV reverse transcriptase and inhibits the enzyme

used to treat resistant CMV retinitis and acyclovir-resistant HSV and VZV

less well tolerated than ganciclovir

Adverse: headache, fatigue, nausea, renal impairment

mentioned in class, but not in notes

- too toxic for systemic use

- DNA strand breaks when incorp.

- local application in eye --> herpes simplex keratoconjunctivitis

 (Highly Active AntiRetroviral Therapy)

paradigm for the tx of HIV

based on several observations:

(a) HIV rapidly becomes resistant when a single drug is used (similar to TB)

(b) survivorship is inversely related to the circulating level of HIV RNA in the blood

(c)survivorship is positively correlated with CD4 count

Treat aggressively and keep viral load (HIV RNA) as low as possible, while maintaining the CD4 count

also includes psychoscoial aspects of dz (treat with counseling)

1) Nucleoside/nucleotide reverse transcriptase inhibitors (nRTI) ~ acyclovir

2) non-nucleoside reverse transcriptase inhibitors (nnRTI)

3) HIV portease inhibitors (PI) - (integration of viral pro DNA into human)

4) fusion inhibitor

5) entry inhibitor

6) integrase inhibitor

(4&5 = antiviral experienced patients - alternative tx)

• option 1) 2 nRTIs plus a nnRTI

or

option 2) 2 nRTIs plus a ritonavir-boosted PI

or

option 3) integrase inhibitor plus 2 nRTIs

The currently preferred regimens:

• tenofovir plus emtricitabine (both nRTIs) plus efavirenz (nnRTI)
• tenofovir plus emtricitabine plus either [atazanavir with ritonavir] or [darunavir with ritonavir]
• preferred integrase inhibitor combination is raltegravir plus tenofovir and emtricitabine

a lot like acyclovir because they lack 3'-OH

includes:

• emtricitabine
• tenofovir
• abacavir
• lamivudinedidanosine
• zidovudine

MOA: all of these are purine or pyrimidine analogs that require intracellular phosphorylation to triphosphate forms. The nRTI triphosphates act as:

1) competitive inhibitors of HIV reverse transcritpase

2) are incorporated into the growing proviral DNA chain and act as chain terminators

when these drugs are used as single agens to treat HIV

Cross resistance is common, but often confined to drugs with similar structures (2 drugs that both contain thymidine)

lactic acidosis, hepatic steatosis, peripheral neuropathy, myopathy, and lipoatrophy

thought to be due to the fact that all these drugs inhibit mitochondrial DNA polymerase-γ => mitochondrial dysfunction

granulocytopenia --> newer agents less likely to inhibit enzyme (this is tenofovir and emtricitabine)

no metabolic activation necessary --> active against HIV1 only

includes: Efavirenz and nevirapine

the parent compound is active and no intracellular metabolism is necessary --> these drugs bind in a noncompetitive fashion to a hydrophobic pocket near the active site of the reverse transcriptase and 'lock' the enzyme into an inactive state

all can cause rash!! (frequently self-limiting)

metabolized by P450 enzymes, so drug interactions can occur with protease inhibitors and many other drugs (and patients are often on multiple drugs)

nnRTIs are active against HIV-1 and are inactive against HIV-2 strains

isolates resistant to nRTIs and protease inhibitors remain sensitive to nnRTI, but cross resistance is common within the nnRTI class

inhibits later process (processing of GAG and gag-pol proteins) = virus cannot mature and becomes less infective

includes the following drugs:

• atazaavir
• darunavir
• fosamprenavir
• lopinavir
• ritonavir - protease boosting . . .
• saquinavir

inhibit both HIV-1 and HIV-2

resistance to these drugs develops rapidly when these drugs used alone; cross-resistance among PIs appears to be common

• GI intolerance: diarrhea, nausea, vomit
• increased aminotransferase activity
• increased bleeding in hemophiliacs
• hyperglycemia
• new onset or worsening diabetes
• insulin resistance
• fat wasting
• redistribution (bufflo hump)
• metabolized by P450 - some of these drugs induce P450 and other inhibit P450
• avoid RIFAMPIN (which is a potent CYP3A4 inducer and it decreases the effectiveness of the protease inhibitors

Most cases there is cross-resistance

drug is: raltegravir

prevents insertion of HIV DNA into the human genome

well tolerated drug

class sparing: hold back one or more classes so that if you do get resistance, you have a backup drug

so this drug is used in patients who have failed therapy

enfuvirtide (this drug is a protein that is injected subQ)

prevents the HIV envelope from fusing the celle membrane of CD4 cells and thereby blocks viral entry and replication

drug target is : gp41 and preventing a conformational change required to permit fusion of HIV with the cell membrane

- combined with 2 other drugs

- used when other forms of therapy have failed

- cannot fuse with receptor

maraviroc - well tolerated

binds CCR5 (coreceptor for HIV) on the surface of CD4+ cells --> prevents entry into the cell

does not bind CXCR4, so HIV that uses CXCR4 as the coreceptor is resistant to the drug

non of these drugs are curative ...

HIV lipodystrophy syndrome:

• Fat redistrubution: loss of fat from face, butt, arms; redeposited in abdomen and buffalo hump
• elevated cholesterol and TGs
• hyperglycemia: insulin resistance
• seen with most regimens, especially those using older nRTIs

nRTI

newer drug - less likely to inhibit mitochondrial DNA polymerase-γ

nRTI

newer agent = less likely to inhibit mitochondrial DNA polymerase-gamma

nRTI

peripheral neuropathy

nRTI

neutropenia, anemia --> give EPO

nnRTI

Adverse: CNS/ pysch problems

teratogenic

nnRTI

Rash is most frequent adverse effect

HIV protease inhibitor

protease boosting - subtheraputic dose to inhibit P450 metabolism of therapeutic protease inhibitor (inhibit CYP3A4 and prevent metabolism)

integrase inhibitor

prevents HIV DNA insertion into the human genome

well tolerated

class sparing drug - use when HIV is resistant to other treatments

fusion inhibitor

protein is injected subQ

its target it gp41

prevents a conformational change required to permit fusion of HIV with the cell membrane - CANNOT fuse with receptor

• it is combined with 2 other drugs

• used when other forms of therapy have failed

entry inhibitor

well tolerated

binds CCR5, NOT CXCR4