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ANTI-FUNGAL
AGENTS
Viruses, what are they?
Converted to di and
triphosphate compounds
by the hosts cellular
enzymes
Mechanism of action of Antiherpes
Agents
Acyclovir triphosphate
inhibits viral DNA
synthesis by 2
mechanisms
Competitive inhibition
of deoxy-GTP for viral
DNA polymerase
binding to the DNA
template as an
irreversible complex
Acts as a chain
terminator because it
lacks 3 hydroxyl group
RESISTANCE
HSV: absence of partial production of viral
thymidine kinase, altered thymidine kinase
substrate specificity, and altered viral DNA
polymerase
VZV: mutation in VZV thymidine kinase and
mutations in viral DNA polymerase
Immunocompromised hosts
foscarnet, cidofovir, and trifluridine
(acyclovir resistant strain) cross resistance
occurs due to deficient thymidine kinase
activity
PHARMACOKINETICS
Oral bioavailability ranges from 15-20%
and decreases with increasing dose
Unaffected by food
IV & topical formulations
Clearance thru GF and TS
Half-life: 2.5-3 hrs in normal renal function
and 20 hrs in anuria
Distributes widely in body fluids
including vesicular fluid, aqueous
humor, and CSF
Concentrated in breast milk, amniotic
fluid, and placenta
Percutaneous absorption is low
Good corneal penetration
THERAPEUTIC USAGE
First and recurrent genital
herpes:
200 mg 5x daily for 10 days oral
5 mg/kg per 8 hrs IV
Recurrent:
400 mg 2x daily or 200 mg 3x daily
Shortens the duration of symptoms by
2 days, healing time by 4 days & viral
shedding duration by 7 days in 1st
episode of genital herpes
Recurrent: shortened by 1-2 days
Long-tem suppression w/ oral acyclovir for
recurrences decreases frequency of
symptomatic recurrences & asymptomatic
viral shedding dec. rate of sexual
transmission
Outbreaks may resume when discontinued
THERAPEUTIC USAGES
ACUTE HERPES ZOSTER (SHINGLES)
SYSTEMIC ACYCLOVIR PROPHYLAXIS
Patients undergoing organ transplantation
(oral or IV) to prevent reactivation of HSV
HSV-2 + HIV-1
HSV ENCEPHALITIS ( IV form)
VARICELLA ZOSTER VIRUS INFECTION
CMV PROPHYLAXIS
Recurrent Herpes labialis: oral acyclovir
only modestly beneficial
Significantly decreases total # lesions,
duration of symptoms & viral shedding in
varicella (if begun w/in 24hrs after onset of
rashes) or cutaneous zoster (if begun w/in
72hrs)
BUT higher doses required (less susceptible
to VZV than HSV)
Varicella (>2y/o): 800mg QID x 5 days
VZV: 800mg 5x/day x 7-10days
IV acyclovir
Treatment of choice for HSV encephalitis,
neonatal HSV & serious HSV or VZV
infections
Topical acyclovir cream
Less effective for 1 HSV infection
No benefit for recurrent genital herpes
SIDE EFFECTS
Penciclovir (9-[4-hydroxy-3-
hydroxymethyl but-1-yl] guanine
An acyclic guanine nucleoside
Active metabolite of famciclovir
Spectrum of activity and potency against
HSV & VZV is similar to acyclovir
Inhibitory activity to HSV
MECHANISM OF ACTION
Drugs:
Ganciclovir
Valganciclovir
Foscarnet
Cidofovir
Maribavir
GANCICLOVIR
(9-[1,3-dihydroxy-2-prepoxymethyl]guanine)
Cyclic guanosine analog that requires
triphosphorylation for activation prior to
inhibiting viral DNA polymerase
Similar structure to acyclovir except in
having additional hydroxymethyl group on
the acyclic side chain
Mechanism of Action - Ganciclovir
Initial phosphorylation is
catalyzed by virus-
specified protein kinase
phosphotransferase UL97
in CMV-infected cells
requires
triphosphorylation for
activation prior to
inhibiting viral DNA
polymerase termination
of viral DNA elongation
MECHANISM OF ACTION
Monophosphorylated intracellularly by a virus-
induced enzyme
Phosphorylation is catalyzed by a viral thymidine
kinase during HSV, phosphotransferase UL97
encoded gene during CMV infection
Ganciclovir di & triphosphate formed by cellular
enzymes
Triphosphate is a competitive inhibitor of
deoxyguanosine triphosphate incorporation into
DNA inhibiting viral rather than cellular DNA
polymerase
Viral DNA incorporation causes cessation of DNA
chain elongation
PHARMACOKINETICS
IV, oral, intraocular implant
Poor oral bioavailability (6-
9%) following ingestion with
food and less in the fasting
state
CSF concentration are
approximately 50 % of
those in serum
Elimination half-life: 4 hrs
CLINICAL USES
(Phosphonoformic Acid )
Mechanism of Action - Foscarnet
an inorganic Pyrophosphate
analog
(-) viral DNA & RNA polymerase
and HIV reverse transcriptase
directly without requiring
activation by phosphorylation
Inhibits cleavage of
pyrophosphate from
deoxynucleotide triphosphates
IV form only
Via infusion pump to avoid toxicity
Poor oral bioavailability & GIT intolerance
CSF concentrations: 43-67%
Mean plasma half-life: 3-7%
30% may be deposited in bone (half-life
several months)
Renal clearance
Titrate dose per patients creatinine clearance
SIDE EFFECTS
Nephrotoxicity
Symptomatic hypocalcemia
Saline loading may reduce the risk
of nephrotoxicity
Concurrent administration with
pentamidine exacerbates both
nephrotoxicity and hypocalcemia
Genital ulcerations, CNS toxicity
CLINICAL USES
CMV retinitis, colitis, esophagitis
Acyclovir- resistant HSV infection and VZV
infection
HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV
Gancyclovir + Foscarnet: superior in
delaying progression of CMV retinitis
Dec. incidence of Kaposis sarcoma w/ long
term use
Foscarnet
Resistance
In HSV and CMV
due to point mutations in the DNA polymerase
gene
21 mer-phosphorothioate oligonucleotide
First FDA approved anti-sense therapy.
Binding to target mRNA results in
inhibition of immediate early region 2
protein synthesis inhibiting viral
replication
Injected intravitreally in CMV retinitis in
AIDS
ANTI-RETROVIRAL
AGENTS
Combination therapy w/ maximally potent
agents
To reduce viral replication to the lowest
possible level
Decrease likelihood of emergence of
resistance
At least 3 antiretroviral agents
Important factors in selection of
agents:
Potency
Susceptibility
Tolerability
Convenience
Optimization of adherence
Anti-RETROVIRAL Agents
Nucleoside RT inhibitors
Zidovudine Zalcitabine Didanosine
Stavudine Lamivudine Abacavir
Emtricitabine
Non-nucleoside RT Inhibitors
Nevirapine Delavirdine Efavirenz
Anti-RETROVIRAL Agents
Nucleoside RT inhibitors
Zidovudine Zalcitabine Didanosine
Stavudine Lamivudine Abacavir
Emtricitabine
Mechanisms of Action - NRTIs
Act by competitive inhibition of
HIV-1 reverse transcriptase;
incorporation into the growing
viral DNA chain premature
chain termination (inhibition of
binding with the incoming
nucleotide)
Requires intracytoplasmic
activation as a result of
phosphorylation by cellular
enzymes to the triphosphate
form
Antiretroviral Agents - NRTIs
Side effects:
GI tolerance
Skin rash Steven-Johnson syndrome
Saquinavir Lopinavir/Ritonavir
Indinavir Nelfinavir
Amprenavir Darunavir
Atazanavir Tipranavir
Fosamprenavir
Mechanisms of Action - PIs
Responsible for cleaving the
Gag and Gag-Pol gene
products translated into
polyproteins immature
budding particles final
structural proteins of the
mature virion core
Atazanavir Light meal enhanced LBM, N/V, abdominal pain, H/A Ritonavir,
bioavailability peripheral neuropathy, skin rash, omeprazole,
Requires acidic medium for indirect hyperbilirubinemia with indinavir, irinotecan,
absorption jaundice, hepatic enzymes, PR tenofovir, efavirenz
Penetrate both CSF & seminal interval prolongation, QTc
fluid interval
Plasma t1/2: 6-7 hrs
Elimination: biliary
Inhibitor of CYP3A4 &
CYP2C9
Resistance: mutation in
gp41 codons
Antiretroviral Agents CCR5 Receptor
Antagonists
Maraviroc
Absorption: rapid, 1-4 hours
Excretion: feces (>75%), urine (20%)
Excellent penetration: cervicovaginal fluid
Drug Interactions:
Delavirdine, ketoconazole, itraconazole, clarithromycin,
efavirenz, etravirine, rifampin, carbamazole, phenytoin, St.
Johns wort
Side effects:
Cough, respiratory infections, muscle/joint pains, LBM, sleep
disturbance, hepatic transaminase levels
Mechanism of Action CCR5 Receptor
Antagonist
Resistance:
mutations in V3 loop of
gp120
Emergence of non-CCR5-
tropic virus or by changes
in viral tropism (gp160)
Antiretroviral Agents CCR5 Receptor
Antagonists
Antiretroviral Agents Integrase
Inhibitors
Raltegravir
Bioavailability: not established
Metabolism: glucuronidation
Does not interact with CYP450 system fewer
DI
Drug interactions:
Rifampin, efavirenz, etravirine, tipranavir/ritonavir, atazanavir,
magnesium, calcium, iron
Side effects:
LBM, nausea, dizziness, H/A, creatine phosphokinase, minimal
effects on serum lipids
Mechanism of Action Integrase
Inhibitors
Binds to integrase
Interferon
Genes >20 1 1
Leukocytes,
Principal source Fibroblasts Lymphocytes
Epithelium
Antihepatitis Agents Interferons
Endogenous proteins that exert
complex antiviral
immunomodulatory &
antiproliferative activities through
cellular metabolic process
Interferon alfa
Contraindications:
Hepatic decompensation
Autoimmune disease
History of cardiac arrhythmias
Drug interactions:
Theophylline, methadone
Didanosine
zidovudine
ANTI-Hepatitis B
Lamivudine
Adenofovir Dipivoxil
Entecavir
Interferon 2b
Famciclovir
Telbivudine
Tenofovir
ANTI-Hepatitis C
Pegylated interferon alfa-2a and 2b
Ribavirin, interferon alfa 2a, 2b, alfacon
Treatment of HBV Infection
Goals:
Sustain suppression of HBV replication
slowing of progression of hepatic disease
Prevention of complications
Use as an antiretroviral
INVESTIGATIONAL AGENTS
Nucleoside analog: Emtricitabine, Clevudine, Valtorcitabine,
Pradefovir, Alamifovir
Immunologic modulator: Thymosin alpha-1
Treatment of HCV Infections
Goal:
Viral eradication [achievement of sustained
viral response (SVR)]
Absence of detectable viremia for 6 months after
completion of therapy
Regression of cirrhosis
AMANTADINE/RIMANTADINE
Rimantadine: 4-10x more active than
amantadine
Amantadine
well absorbed, 67% protein bound, plasma half-
life is 12-18 hours & varies by creatinine
clearance
Nasal secretion and salivary levels approximate
those in serum; CSF levels are 52-96% of those
in the serum
excreted unchanged in the urine
Rimantadine
40% protein-bound
half-life of 24-36 hours
Nasal mucus concentrations: average 50% higher
than those in plasma
undergoes extensive metabolism by hydroxylation,
conjugation, and glucuronidation before urinary
excretion
Anti-influenza Agents
Oseltamivir/Zanamivir
Neuroaminidase
inhibitors
Inhibits replication of
both influenza A & B
Excretion: urine
Serum t is 15 days
altered mechanism of
metabolism of
flucytosine to 5
fluorouracil, due to
mutation in cytosine
deaminase.
FLUCYTOSINE (5-FC)
Pharmacokinetics Clinical Uses:
Available in oral preparation
Cryptococcal meningitis
Well absorbed (>90%) with
serum Candida species
Peak serum Concentration: Dematiaceous molds
1-2 hrs (chromoblastomycosis)
Poorly protein bound
Penetrates well body fluids &
CSF
Adverse Effects:
T is 3-4 hrs - Anemia, leukopenia,
thrombocytopenia
Elimination: GF
Rash, n/v, diarrhea
- Toxic enterocolitis
CLINICAL USAGES
Cryptococcal meningitis
Candida species
Dematiaceous molds that cause
chromoblastomycosis
AZOLES
IMIDAZOLES :
Ketoconazole
Miconazole
Clotrimazole
TRIAZOLES:
Itraconazole
Fluconazole
Voriconzaole
Azoles
Inhibition of sterol 14 -
demethylase
Impair the biosynthsesis of
ergosterol for the cytoplasmic
membraneaccumulation of 14-
-methylsterols
Impairing functions of membrane
bound enzymes such as ATPase
& enzymes of electron transport
systeminhibits growth of
fungi
Reduction of ergosterol
synthesis by inhibition of
cytochrome P450 enzymes
Specificity for fungal than human
cytochrome P450
enzymes(imidazole v.s triazole)
CLINICAL USES
Candida species
Cryptococcus neoformans
Endemic mycoses
ADVERSE EFFECTS
Relatively non-toxic; clinical hepatitis (rare)
Most common-GIT upset
Increased liver enzymes
DRUG INTERACTIONS
All azole drugs affect mammalian cytochrome
P450 systems of enzymes
KETOCONAZOLE
1st oral azole introduced into clinical use
Inc. propensity to inhibit mammalian
cytochrome P450 enzymes
interferes with biosynthesis of adrenal &
gonadal steroid hormones
Less selective for fungal P450
Interaction with P450 enzymes can alter
the metabolism of other drugs leading to
enhanced toxicity
Reaches the keratinocytes efficiently
Concentration in vaginal fluids is
approaches that in plasma
Dose: 200mg OD/BID
THERAPEUTIC USES
Cutaneous infections caused by
epidermophyton, microsporum, trichophyton
sp.
Blastomycosis, histoplasmosis,
coccidiodomycosis, pseudallescheriasis
Paracoccidiodomycosis, ringworm,
tinea versicolor, chronic mucocutaneous
candidiasis
Candida vulvovaginitis, oral & esophageal
candidiasis
ADVERSE REACTIONS
Dose-dependent anorexia, nausea,
vomiting, pruritis
Inhibits steroid biosynthesis in patients
endocrine abnormalities
Gynecomastia, inc. liver enzyme levels,
hepatitis
DRUG INTERACTIONS
Increases cyclosporine levels
Enhances arrythmogenic effects of
cisapride
H2 antagonists increases gastric pH,
interfere with the absorption of
ketoconazole
Rifampicin- increased hepatic
metabolism
ITRACONAZOLE
Broad spectrum
Fungicidal to C. albicans, E. flocosum,
M. canis, T. mentagrophytes, T. rubrum
Inhibits the growth of Malassezia furfur
Penetrates the dermis
HALOPROGIN
Halogenated phenolic ether
Fungicidal to various species of
Epidermophyton, Pityrosporum,
Microsporum, Trichophyton & Candida
Poorly absorbed through the skin
Converted to trichlorophenol in the body
Cream or solution BID X 2-4 wks
Principal use for tinea pedis
Tinea cruris, tinea versicolor, tinea corporis
NAFTIFINE
Inhibit squalene-2,3- epoxidase
Inhibits biosynthesis of ergosterol
Fungicidal activity
1% cream or gel
Topical treatment of tinea cruris & tinea
corporis
Cutaneous candidiasis & tinea
versicolor
MISCELLANEOUS
ANTIFUNGAL AGENTS
UNDECYLENIC ACID
Treatment of dermatomycoses
Low efficacy
POTASSIUM IODIDE
Treatment of mucocutaneous
sporotrichosis