Download - Anti Fungal
ANTIVIRAL/ANTIFUNGAL ANTIVIRAL/ANTIFUNGAL AGENTSAGENTS
MA. LENY ALDA G. JUSAYAN, MD
Department of Pharmacology
ANTIVIRAL AGENTSANTIVIRAL AGENTS
VIRUSES:Single or double stranded DNA or RNA
enclosed in a protein – CAPSIDObligate intracellular parasiteReplication depends on synthetic processes of
the host cellAntiviral drugs must either block entry or exit
from cell or be active inside the host cell
VIRAL REPLICATION:VIRAL REPLICATION:
Adsorption and penetration into susceptible host cells
Uncoating of viral nucleic acid Synthesis of early regulatory proteins Synthesis of RNA or DNA Synthesis of late regulatory proteins Assembly (maturation) of viral particles Release from cells
ANTI-HERPES/ ANTI VZVANTI-HERPES/ ANTI VZV
ANTIHERPES/VZV AGENTSANTIHERPES/VZV AGENTS
ACYCLOVIR FAMCICLOVIR VALACYCLOVIR
PENCICLOVIR TRIFLURIDINE VIDARABINE DOCOSANOL
ACYCLOVIRACYCLOVIR
Acyclovir (9-[2-hydroxy) methyl]-9-H- guanine
Acyclic guanosine derivative against HSV1, HSV2, & VZV
Weaker activity against EBV, CMV, Human Herpes Virus 6
MECHANISM OF ACTION:MECHANISM OF ACTION:
REQUIRES 3 PHOSPHORYLATION STEPS:Converted to monophosphate derivative by
virus-specified thymidine kinase Selective activation of acyclovir Active metabolites accumulates only in infected
cellsConverted to di and triphosphate
compounds by the host’s cellular enzymes
EFFECTS:EFFECTS:
Acyclovir triphosphate inhibits viral DNA synthesis
Acts as a chain terminator because it lacks 3’ hydroxyl group
Competitive inhibition of deoxyGTP for viral DNA polymerase = binds to DNA template as irreversible complex
Cont.Cont.
RESISTANCE:• HSV: absence of partial production of
viral thymidine kinase, altered thymidine kinase substrate specificity, altered viral DNA polymerase
• VZV: mutation in VZV thymidine kinase, mutations in viral DNA polymerase
PHARMACOKINETICS:PHARMACOKINETICS: Oral bioavailability ranges from 15-20 % and
decreases with increasing dose, unaffected by food
Relative oral bioavailability increases to 3-5 fold approx. 70% following valacyclovir administration
Distributes widely in body fluids including vesicular fluid, aqueous humor & CSF
Concentrated in breast milk, amniotic fluid, & placenta
Percutaneous absorption is low
Half-life: 3 hours (normal renal function) 20 hours (anuria)
Readily cleared by dialysis but not by peritoneal dialysis
IV- treatment of choice for herpes simplexOral – herpes labialisTopical – high concentration in herpetic
lesions
THERAPEUTIC USES:THERAPEUTIC USES:
First and recurrent genital herpes:– 200 mg 5x daily for 10 days – oral– 5 mg/kg per 8 hrs – IVRecurrent: 400 mg 2x daily or 200 mg 3x
daily
THERAPEUTIC USES:THERAPEUTIC USES:
ACUTE HERPES ZOSTER (SHINGLES)SYSTEMIC ACYCLOVIR PROPHYLAXISHSV ENCEPHALITISVARICELLA ZOSTER VIRUS INFECTION
– higher dosesCMV PROPHYLAXIS
SIDE EFFECTS:SIDE EFFECTS:
TOPICAL PREPARATIONS- mucosal irritation & transient burning to genital lesions
ORAL – nausea, diarrhea, rash, headache,renal insufficiency, neurotoxicity
IV- renal insufficiency (crystalline nephropathy), CNS side effects
PENCICLOVIRPENCICLOVIR
Penciclovir (9-[4-hydroxy-3-hydroxymethylbut-1-yl]guanine)
An acyclic guanine nucleosideActive metabolite of famciclovirRecurrent herpes labialisTopical – 1% cream
MECHANISM OF ACTION:MECHANISM OF ACTION:
Inhibitor of viral DNA synthesis Initially phosphorylated by viral thymidine
kinase Penciclovir triphosphate is a competitive
inhibitor of viral DNA polymerase 100 fold less potent in inhibiting DNA
polymerase than acyclovir but present in higher concentration and prolonged periods in infected cells
THERAPEUTIC USES:THERAPEUTIC USES:
Intravenous form- 5 mg/kg per 8-12 hrs for 7 days is comparable to acyclovir in tx of mucocutaneous HSV infection
Topical 1% penciclovir cream applied every 2 hrs while awake for 4 days shortens healing time and symptoms by about 1 day in recurrent labial HSV
SIDE EFFECTS:SIDE EFFECTS:
Mutagenic at high concentrationsNo clinically important drug interactions
have identified
FAMCICLOVIRFAMCICLOVIRDiacetyl ester prodrug of 6 deoxy
penciclovir and lacks intrinsic viral activity
Rapidly converted to by first pass metabolism to PENCICLOVIR
HSV-1, HSV-2, VZV, EBV, HBV
FAMCICLOVIR:FAMCICLOVIR:
Comparable to valacyclovir in treating zoster and reducing associated pain in older adults
500 mg TID x 10 days is comparable to high dose of acyclovir in treating zoster in immunocompromised patients & in opthalmic zoster
Associated with dose-related reductions in Hepatitis B Virus DNA and transaminase levels in patients with chronic HBV hepatitis
Rapidly converted by first-pass metabolism to penciclovir
Does not cause chain termination– Lower affinity for viral DNA polymerase than
acyclovir triphosphate
Achieves a higher intracellular concentrations & more prolonged intracellular effect
PHARMACOKINETICS:PHARMACOKINETICS:
70% bioavailability after oral administrationIntracellular half life: 10 hrs – HSV 1
20 hrs – HSV 2
7 hrs- VZV
TRIFLURIDINETRIFLURIDINE(Trifluorothymidine)(Trifluorothymidine)
Flourinated pyrimidine nucleoside that has an in vitro inhibitory activity against HSV 1 & 2 , CMV, vaccinia certain adenoviruses
Inhibits viral DNA synthesis Does not require activation by viral thymidine
kinase Phosphorylated intracellularly into its active
form by host cellular enzymes Competes with thymidine triphosphate for
incorporation by viral DNA polymerase Incorporation into both viral and cellular DNA
prevents its systemic use
MECHANISM OF ACTION:MECHANISM OF ACTION:
Trifluridine monophosphate irreversibly inhibits thymidylate synthetase
Trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate incorporation into DNA by DNA polymerases
CLINICAL USES:CLINICAL USES:
Topical : 1% solutionPrimary keratoconjunctivitis & recurrent
epithelial keratitis due to HSV 1 & 2 Topical trifluridine is more active than
idoxuridine & comparable to vidarabine in HSV ocular infections
Combination with Interferon alfa – acyclovir resistant HSV infections
ADVERSE EFFECTS:ADVERSE EFFECTS:
Discomfort upon instillation Palpebral edemaHypersensensitivity reaction, irritations
& superficial punctate or epithelial keratopathy
VALACYCLOVIRVALACYCLOVIR
L- valyl ester of acyclovir Rapidly converted to acyclovir after oral
administration Serum levels are 3-5x greater than acylcovir
IV or oral Treatment of primary and recurrent genital
herpes & herpes zoster infections Prevents CMV disease in postransplant
patients Oral preparation
Elimination half-life: 2.5-3.0 hours High dose:
– gastrointestinal intolerance- Thrombotic microangiopathies (TTP,
hemolytic-uremic syndrome)
VIDARABINEVIDARABINE Adenosine analog with an in vitro activity
against HSV, VZV, & CMV Phosphorylated intracellularly by host
enzymes to form ara-ATP and then inhibits viral DNA polymerase
Vidarabine triphosphate is incorporated into both viral & cellular DNA
Decreases viral activity
Cont.Cont.
3% ointment – acute keratoconjunctivitis, superficial keratitis, recurrent epithelial keratitis (HSV1 &2)
IV vidarabine – HSV encephalitis,neonatal herpes, VZV infection
DOCOSANOLDOCOSANOL
Saturated 22-carbon aliphatic alcohol Inhibits fusion between the plasma
membrane & HSV envelopePrevents viral entry into cells & subsequent
viral repliction10% topical cream- 5x daily
ANTI-CMV AGENTSANTI-CMV AGENTS
ANTI-CMV AGENTSANTI-CMV AGENTS
GANCICLOVIR CIDOFOVIR FOMIVERSEN
VALGANCICLOVIR FOSCARNET
GANCICLOVIRGANCICLOVIR
(9-[1,3-dihydroxy-2-prpoxymethyl]guanine)Acyclic 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:MECHANISM OF ACTION: Monophosphorylated intracellularly by a virus-
induced enzyme Phosphorylation is catalyzed by a viral thymidine
kinase during HSV, phosphotransferase encoded gene during CMV infection
Ganciclovir di & triphosphate formed by cellular enzymes
Triphosphate is a competitive inhibitor of deoxyguanosine triphosphate incorporation into DNA, inhibits viral rather than cellular DNA polymerase
Viral DNA incorporation causes cessation of DNA chain elongation
PHARMACOKINETICS:PHARMACOKINETICS:
Oral bioavailability is 6-9% following ingestion with food & less in the fasting state
CSF concentration are approximately 50 % of those in serum
IV, oral, intraocular implant
Elimination half life: 4 hoursIntracellular half-life: 18 hoursCleared by hemodialysis
CLINICAL USES:CLINICAL USES:
Delay progression of CMV retinitis in AIDS – IV ( foscarnet )
CMV colitis & esophagitis - IV CMV infection in transplant patient - IV/oral CMV pneumonitis CMV retinitis – intraocular implant/intravitreal
administration CMV, HSV1, HSV2, EBV & HHV-8
ADVERSE REACTIONS:ADVERSE REACTIONS:
MyelosuppressionCNS toxicityVitreous hemorrhage, retinal detachmentNeutropenia (2nd wk)CNS (headache, behavioral changes,
convulsions, coma)Infusion related phlebitis, azotemia, anemia,
rash, fever, liver function test abnormalities
DRUG INTERACTION:DRUG INTERACTION:
Additive myelosuppression– Zidovudine, azathioprine or mycophenolate
mofetil
Increase levels– Probenicid, trimethoprim
Increase levels of didanosine
VALGANCICLOVIRVALGANCICLOVIR
L- valyl ester prodrug of ganciclovir Hydrolyzed to active compound ganciclovir by
intestinal & hepatic enzymes Well absorbed & rapidly metabolized in
intestinal walls & liver to gancilovir CMV retinitis CMV disease in high risk kidney, heart, &
kidney-pancreas transplant patients
PHARMACOKINETICS:PHARMACOKINETICS:
Bioavailability after oral administration: 60%
Should be taken with foodElimination - renal
CIDOFOVIRCIDOFOVIR
(1-[(S)-3-hydroxy-2-(phosphonomethoxy)-propyl]cytosine dihydrate)
Cytosine nucleoside analog with inhibitory activity against human herpes, papiloma, polyoma, pox, & adenoviruses
Phosphorylation to active diphosphate is independent of viral enzymes
After phosphorylation it acts as potent inhibitor of and as an alternative substrate to viral DNA polymerase
Competitively inhibits DNA synthesis & becoming incorporated into viral DNA chain
PHARMACOKINETICS:PHARMACOKINETICS:
Penetration into the CNS or eye have not been well characterized
Terminal half-life is 2.6 hrs , cidofovir diphosphate half-life is 17-65 hrs
Poor CSF penetration IV administration must be administered with
probenicid (2-3 hours before infusion) to block active tubular secretion & decrease nephrotoxicity
CLINICAL USES:CLINICAL USES:
CMV, HSV 1, HSV 2, VZV, EBV, HHV-6, HHV-8, adenoviruses, poxvirus, poliomyxoviruses, HPV
CMV retinitisPolyoma virus associated progressive
multifocal leukoencephalopathy syndrome associated with AIDS
FOSCARNETFOSCARNET
Phosphonoformic acid inorganic pyrophosphate analog that inhibits viral DNA polymerase, RNA polymerase & HIV reverse transcriptase directly without requiring activation by phosphorylation
Taken up slowly by cells & does not undergo significant intracellular metabolism
Reversibly blocks the pyrophosphate binding site of the viral polymerase but not in human & transcriptase enzyme
Inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates
SIDE EFFECTS:SIDE EFFECTS:
Nephrotoxicity Symptomatic hypocalcemia or hypercalcemia Hyper or hypophosphatemia hypomagnesemia Saline preloading may reduce the risk of
nephrotoxicity Concurrent administration with pentamidine
exacerbates both nephrotoxicity & hypocalcemia
DRUG INTERACTION:DRUG INTERACTION: Nephrotoxic potential
– amphotericin B, pentamidine, aminoglycosides Hypocalcemia
– pentamidine Penile ulcerations
– foscarnet Anemia
– zidovudine CNS toxicity
– imipenem Chromosomal damage
– foscarnet
CLINICAL USES:CLINICAL USES:
CMV retinitis, colitis, esophagitisAcyclovir- resistant HSV infection &
VZV infectionHSV, VZV, CMV, EBV, HHV-6, HHV-8,
HIV
FOMIVERSENFOMIVERSEN
21mer-phosphorothioate oligonucleotideFirst FDA approved antisense therapy
Binding to target mRNA results in inhibiton of immediate early region 2 protein synthesis – inhibiting viral replication
Injected intravitreally in CMV retinitis
DRUG MECHANISM/VIRAL
SELECTIVITY
CLINICAL USE
VIRAL RESISTANCE
UNDESIRABLE SIDE EFFECTS
PHARMACOKINETICS
NOTES
Acylovir Metabolized by thymidine kinase to triphosphate
Herpes simplex 1 & 2, varicella zoster
Produce abnormal thymidine kinase
Skin irritation, burning, crystalline nephropathy
IV/PO. Administer slowly. CNS level=50% serum level. Decrease dose w/ kidney dysfunction
Pencyclovir Oral HSV (coldsores)
Topical
Valacyclovir L-valyl ester of acyclovir converted to acyclovir
Herpes zoster (shingles)
Nausea, headache PO. Slightly better oral absorption than acyclovir
No clear advantage over acyclovir
Idoxuridine Phosphorylated metabolite incorporates into DNA causing strand breaks
Herpes simplex keratitis. No effect on RNA viruses
Resistance develops
Photophobia, irritation of conjunctiva & eyelid
Eyedrops Drug is a halogenated derivative of deoxyuridine
Famciclovir Phosphorylated by viral thymidine kinase to penciclovir triiphosphate
Shortens duration of herpes zoster & genital herpes
Minimal toxicity. Headache
PO. Decrease dose with renal dysfunction.
Ganciclovir Metabolized by thymidine kinase to triphosphate . Preferentially phosphorylated to active drug in CMV infected cells
CMV retinitis & severe systemic CMV infections
Some resistant strains lack thymidine kinase. Cannot activate drug.
Granulocytopenia, thrombocytopenia
IV/PO. Excreted unchanged in urine. Decrease dose with renal dysfunction.
Do not coadminister zidovudine (granulocytopenia) or imipenem-cilastatin (seizures)
ANTIVIRAL DRUGS – DNA & RNA VIRUSES
Cidofovir Metabolized to diphosphate form. Otherwise like ganciclovir.
CMV retinitis Nephrotoxicity may be reduced by hydration & coadministration of Probenicid. Neutropenia.
Foscarnet Analog of pyrophosphate. Competes for pyrophosphate site in viral but not human, DNA polymerase & reverse transcriptase
CMV retinitis Does not need phosphorylation, it is active against thymidine kinase –deficient strains
Renal toxicity, seizures, hypocalcemia, fever, anemia, diarrhea, nausea
IV. >80% excreted unchanged in the urine. CSF penetration variable. Reduce dose with renal dysfunction.
Deposited in bone & teeth. Hydrate patient during therapy to protect the kidney
Amantadine Prevents virus from entering susceptible cells
Treatment & prophylaxis of influenza A
Depression, CNS toxicity, CHF, orthostatic hypotension, urinary retention
PO. Excreted unmetabolized.
Rimantadine Analog of amantadine , inhibits viral uncoating
Prophylaxis in children
Fewer CNS side effects, risk of seizure
PO. Prolonged elimination w/ renal or hepatic dysfunction
Ribavirin Unknown mechanism
RSV Decreased pulmonary function.
Aerosol administration. Absorbed systemically.
May precipitate in ventilator tubing.
ANTIRETROVIRAL ANTIRETROVIRAL AGENTSAGENTS
STAGES OF HIV REPRODUCTIONHIV entry into the CD4 cells
HIV’s genetic information stored on a single stranded RNA instead of the double-stranded DNA
HIV uses an enzyme known as reverse transcriptase to convert its RNA into DNA
HIV DNA enters the nucleus of the CD4+ cell and inserts itself into the cell’s DNA
HIV DNA instructs the cell to make many copies of the original virus
New virus particles assembled and leave the cell ready to infect other CD4+ cells
Fusion Inhibitors Non-Nucleoside Reverse
Transcriptase Inhibitors
Nucleoside/NucleotideAnalogues
Protease Inhibitors
•A novel class of antiretroviral agents that inhibit the fusion of HIV with target cell membranes. •Fusion inhibitors are administered by subcutaneous injection.
•The newest class of antiretroviral agents, non-nucleoside transcriptase inhibitors (NNRTIs) •Stop HIV production by binding directly onto reverse transcriptase and preventing the conversion of RNA to DNA. •These drugs are called "non-nucleoside" inhibitors because even though they work at the same stage as nucleoside analogues, they act in a completely different way.
•The first effective class of antiretroviral drugs. •They act by incorporating themselves into the DNA of the virus, thereby stopping the building process. •The resulting DNA is incomplete and cannot create new virus
•Protease inhibitors work at the last stage of the virus reproduction cycle.• They prevent HIV from being successfully assembled and released from the infected CD4+ cell.
NUCLEOSIDE REVERSE NUCLEOSIDE REVERSE TRANSCRIPTASE TRANSCRIPTASE
INHIBITORS:INHIBITORS: Competitive inhibition of HIV 1 reverse transcriptase
& can be incorporated into the growing viral DNA chain to cause termination
Bind directly to HIV reverse transcriptase, block both DNA & RNA dependent DNA polymerase activities
Prevent transfer of information that would allow virus to replicate & survive
Activity against HIV 1, HIV 2 Mitochondrial toxicity – inhibition of mitochondrial
DNA polymerase gamma Lactic acidosis & severe hepatomegaly with steatosis
NUCLEOSIDE REVERSE NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS:TRANSCRIPTASE INHIBITORS:
ZIDOVUDINE DIDANOSINE STAVUDINE
LAMIVUDINE ZALCITABINE ABACAVIR EMTRICITABINE
ZIDOVUDINE ZIDOVUDINE (Azithymidine, AZT)(Azithymidine, AZT)
Deoxythymidine analog Decrease rate of clinical disease progression &
prolong survival of HIV infected individuals Well absorbed from the gut & distributed to most
body tissues & fluids Eliminated by renal excretion following
glucorinadation in the liver Combination therapy with other retroviral agents
enhance potency and delay resistance
CLINICAL USES:CLINICAL USES:HIV – associated dementia &
thrombocytopeniaReduce rate of vertical transmission
(mother-newborn) by 23% - 14 and 34 weeks of gestation and during labor
Newborn – syrup from birth – 6 weeks
ANTIRETROVIRAL AGENTS IN ANTIRETROVIRAL AGENTS IN PREGNANCY:PREGNANCY:NRTIs: Zidovudine, lamivudine,
didanosine, stavudine, abacavir, emtricitabine
NNRTIs: NevirapinePROTEASE INHIBITORS: Nelfinavir,
saquinavir S, indinavir, lopinavir, ritonavir
ADVERSE EFFECTS:ADVERSE EFFECTS:
Myelosuppression – most commonThrombocytopenia, hyperpigmentation
of nails, myopathy, anxiety, confusion & tremulousness
Fatal lactic acidosis & severe hepatomegaly w/ steatosis
DIDANOSINE (ddl)DIDANOSINE (ddl) Synthetic analog of deoxyadenosine Chewable, dispersable tablet, enteric coated Contains phenylalanine ( 36.5 mg) & Na (1380
mg) Should be taken on an empty stomach Food, fluroquinolones & tetracycline should be
given 2 hrs before didanosine Buffered powder (oral solution), chewable
tablests, enteric coated tablets
DRUG INTERACTIONDRUG INTERACTION
Interferes with the absorption of the ff. drugs: (powder and tablets)– indinavir, delavirdene, dapsone, itraconazole
PRECAUTIONS:PRECAUTIONS:
PhenylketonuriaNa restricted diets
ADVERSE EFFECTS:ADVERSE EFFECTS:
Dose –dependent pancreatitisPainful peripheral distal neuropathyDiarrhea, hepatitis, esophageal
ulceration, cardiomyopathyCNS toxicityPrecipitate gouty attacksOptic neuritis
LAMIVUDINE (3TC)LAMIVUDINE (3TC)
Cytosine analog ,synergistic with other antiretroviral nucleoside – Stavudine, Zidovudine
Oral bioavailability exceeds 80% & is not food dependent
Used in combination therapy Approved for the treatment of chronic
Hepatitis B infection
RESISTANCE:RESISTANCE:
M184V mutation in regimens that are not fully suppressive
K65R mutation is associated with reduced susceptibility to lamuvudine, abacavir, tenofovir and emcitricitabine
ADVERSE EFFECTS:ADVERSE EFFECTS:
Headache, insomnia, fatigue, gastrointestinal discomfort
DRUG INTERACTION:DRUG INTERACTION:
Increase lamivudine bioavailability– trimethoprim-sulfamethoxazole
Inhibit intracellular phosphorylation of one another in vitro (decrease potency)– zalcitabine
ZALCITABINE (ddC)ZALCITABINE (ddC)
Cytosine analog with synergistic anti-HIV1 activity with a variety of antiretrovirals against both zidovudine sensitive & resistant strains
Associated with dose-dependent peripheral neuropathy
Oral & esophageal ulcerations Increase bioavailability in combination w/
probenicid or cimetidine Decrease bioavailability in combination w/
antacids & metoclopramide
STAVUDINE (D4T)STAVUDINE (D4T)
Thymidine analogHigh oral bioavailability, not food dependentDose-related peripheral sensory neuropathyPancreatitis, arthralgias, elevation of serum
aminotransferases
ABACAVIR ABACAVIR Guanosine analog Well absorbed during oral administration (83%) Unaffected by food Metabolized by alcohol dehydrogenase &
glucuronosyltransferase to inactive metabolites Fatal hypersensitivity reactions Nausea, vomiting, diarrhea, headache, fatigue Hyperglycemia, hypertriglyceridemia & lactic
acidosis
RESISTANCE:RESISTANCE:
Requires at least 2 or 3 concomitant mutations:– M184V, L74V, D67N – develop slowly
K65R– reduced susceptibility to lamivudine, abacavir,
tenofovir and emtricitabine
EMTRICITABINE (FTC)EMTRICITABINE (FTC)
Flourinated analog of lamivudine Long intracellular half-life (>39 hours)Contains propylene glycolOral solutions contraindicated in children,
pregnant women, patients with renal & hepatic failure, using metronidazole & disulfiram
ADVERSE EFFECTS:ADVERSE EFFECTS:
Headache, diarrhea, nausea & astheniaHyperpigmentation of the palms/soles
USE OF ANTITRETROVIRAL USE OF ANTITRETROVIRAL DRUGS IN PREGNANCY:DRUGS IN PREGNANCY:NRTIs
– zidovudine, lamivudine– Didanosine, emtricitabine, stavudine, abacavir
NNRTIs– nevirapine
Protease inhibitors– nelfinavir, saquinavir-S– Indinavir, lopinavir, ritonavir
NUCLEOTIDE INHIBITORNUCLEOTIDE INHIBITOR
TENOFOVIRTENOFOVIR
Competitively inhibits HIV reverse transcriptase & cause chain termination after incorporation to DNA
Indicated for use in combination with other antiretroviral agents
NON-NUCLEOSIDE REVERSE NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR:TRANSCRIPTASE INHIBITOR: Bind directly to a site on the HIV –1 reverse
transcriptase Blockade of RNA & DNA dependent DNA
polymerase activities Binding site is near but distinct from that of
the NRTI’s Neither compete w/ nucleoside triphosphate
nor require phosphorylation to be active
NON-NUCLEOSIDE REVERSE NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS:TRANSCRIPTASE INHIBITORS:
NEVIRAPINE EFAVIRENZ
DELAVIRDENE
NEVIRAPINENEVIRAPINE
Oral bioavailability is > 90%Not food dependentUsed as a component of a combination
antiretroviral regimenEffective in the prevention of
transmission of HIV from mother to newborn
Causes severe life threatening rashes
DELAVIRDENEDELAVIRDENE
Oral bioavailability of about 85 % Metabolized to inactive metabolites by the
CYP3A & CYP2D6 P450 enzymes Plasma concentrations are reduced by
antacids, didanosine, phenytoin, phenobarbital, carbamazepine, rifabutin, rifampin, nelfinavir & saquinavir
Concentrations increased by clarithromycin, fluoxetine, & ketoconazole
EFAVIRENZEFAVIRENZ
Principally metabolized by CYP3A4 &CYP2B6 to inactive hydroxylated metabolites
Principal adverse effects: CNS (dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria)
Pyschiatric symptoms rashes
PROTEASE INHIBITORSPROTEASE INHIBITORS
Responsible for cleaving precursor molecules (immature budding particles)
Results in the production of immature, non-infectious viral particles
Block protease activity within the HIV virus – essential for the maturation
Associated w/ spontaneous bleeding in hemophilia A & B
PROTEASE INHIBITORS:PROTEASE INHIBITORS:
SAQUINAVIR INDINAVIR AMPRENAVIR LOPRENAVIR/
RITONAVIR TIPRANAVIR
RITONAVIR NELFINAVIR ATAZANAVIR FOSAMPRENAVIR
SAQUINAVIRSAQUINAVIR
Saquinavir H- hard gel capsule – poor bioavailability, should be taken w/n 2 hrs after a fatty meal
Saquinavir S – soft gel capsule – improved absorption 3x than hard gel capsule
Subject to first pass-metabolism by CYP3A4 Levels are increased by ritonavir, nelfinavir,
delavirdene, indinavir, ketoconazole, clarithromycin, & grapefruit juice
RITONAVIRRITONAVIR
An inhibitor of HIV 1 & HIV 2 proteasesHigh bioavailability that is increased
with foodCommon adverse effects: GIT
disturbances, paresthesias, inc aminotransferase level, altered taste, hypertriglyceridemia
INDINAVIRINDINAVIR
Specific inhibitor of the HIV- 1 & HIV-2 proteases
Higher CSF penetrationMust be consumed in empty stomach
for maximal absorptionMost common adverse effects are
indirect hyperbilirubinemia & nephrolithiasis due to crystalization
NELFINAVIRNELFINAVIR
Higher absorption in the fed stateCommon adverse effects: diarrhea &
flatulence
AMPRENAVIRAMPRENAVIR
Rapidly absorbed from the GIT & can be taken w/ or w/o food
High fat meals decrease absorptionCommon adverse effects: nausea,
vomiting, diarrhea, perioral paresthesias, rash
Steven johnson’s syndromeInhibits CYP3A4 activity
LOPRINAVIR/RITONAVIRLOPRINAVIR/RITONAVIR
Combination that subtherapeutic doses of ritonavir inhibit the CYP3A mediated metabolism of lopinavir
Maintains potent viral suppression & prevents resistance
Ritonavir – pharmacokinetic enhancer
TIPRANAVIRTIPRANAVIR
Bioavailability is increased when taken with a fatty meal
Should be taken with ritonavirContraindicated in liver insufficiency, sulfa
allergy
FUSION INHIBITORSFUSION INHIBITORS
ENFUVIRTIDE (T-20)ENFUVIRTIDE (T-20)
Newly approved antiretroviral agentBlocks entry into the cellAdministered subcutaneously in
combination with other retroviral agents
ANTI-HEPATITIS AGENTSANTI-HEPATITIS AGENTS
ANTIHEPATITIS AGENTS:ANTIHEPATITIS AGENTS:
LAMIVUDINE INTERFERON ALFA INTERFERON ALFA
2b ENTECAVIR
ADEFOVIR DIPIVOXIL
INTERFERON ALFA 2a
PEGYLATED INTERFERON
LAMIVUDINELAMIVUDINE
Can be safely administered to patients with decompensated liver disease
ADEFOVIRADEFOVIR
Phosphorylated by cellular kinases to the active diphosphate metabolite
Competitively inhibits HBV DNA polymerase
Chain termination after incorporation into viral replication
INTERFERON ALFAINTERFERON ALFA
Endogenous proteins that exert complex antiviral immunomodulatory & antiproliferative activities through cellular metabolic process
Enzyme induction, suppression of cell proliferation, immunomodulatory activities & inhibition of viral replication
Inhibition of viral penetration & uncoating Treatment of both HBV & HCV
INTERFERON ALPHA 2aINTERFERON ALPHA 2a
Approved for the treatment of chronic hepatitis C, AIDS associated Kaposi’s sarcoma hairy cell leukemia, chronic myelogenous leukemia
INTERFERON ALPHA 2bINTERFERON ALPHA 2b
Only preparation licensed for treatment of HBV & acute HCV
Leads to loss of HbeAg, normalization of aminotransferases
Administered subcutaneously or intramuscularly
Hairy cell leukemia, malignant melanoma, follicular non-Hodgkin’s lymphoma, AIDS related kaposi’s sarcoma, & chronic hepatitis C
PEGYLATED INTERFERON PEGYLATED INTERFERON ALFAALFA
Recently introduced for treatment of chronic hepatitis C
Longer terminal t ½ with slower clearance
Interferon- Interferon-β Interferon-
Chronic hepatitis B & C
Relapsing-remitting multiple sclerosis
Chronic granulomatous disease
Genital warts caused by papilloma virus
Hairy- cell leukemia
Kaposi’s sarcoma
RIBAVIRINRIBAVIRIN
Guanosine analog that is phosphorylated intracellularly by host cell enzymes
Interferes w/ the synthesis of guanosine triphosphate
Inhibit capping of viral messenger RNA Inhibit viral RNA dependent RNA polymerase of
certain viruses Influenza A, parainfluenza, RSV,
paramyxoviruses, HCV & HIV 1
ANTI-INFLUENZA AGENTSANTI-INFLUENZA AGENTS
AMANTADINE/RIMANTADINEAMANTADINE/RIMANTADINE
(1-aminoadamantane hydrochloride) -methyl derivative - rimantadine Inhibits uncoating of viral RNA influenza A
within infected cell thus preventing replication Effectively reduce the duration of symptoms
of influenza when administered w/n 48 hrs of onset
Primary target is M2 proteins
ZANAMIVIR/OSELTAMIVIRZANAMIVIR/OSELTAMIVIR
Neuroaminidase inhibitorsInhibits replication of both influenza A & B5 day course regimen for both influenza A &
BDelivered by inhalation – ZANAMIVIROral - OSELTAMIVIR
UNCLASSIFIEDUNCLASSIFIED
PALIVIZUMABPALIVIZUMAB
Prevention of RSV in high risk infants
IMQUIMOD
•Immune response modifier effective in topical treatment of external genitalia & perianal warts
DRUG MECHANISM & VIRAL SELECTIVITY
CLINICAL USE
VIRAL RESISTANCE
UNDESIRABLE SIDE EFFECTS
PHARMACOKINETICS
NOTES
Zidovudine (AZT)
Thymidine analog is incorporated into DNA of hyman immunodeficiency viirus causing termination of the viral DNA chain
HIV. Prevention of maternal-fetal transmission of HIV
Mutations in reverse transcriptase
Headaches, nausea, myalgias, anemia, neutropenia, macrocytosis
PO. Well absorbed, rapidly metabolized by liver
Acetaminophen increases risk of hematologic toxicity
Didanosine (ddl)Zalcitabine (ddC)Lamivudine
-Metabolized intracellularly to dideoxynucleotide triphosphate that inhibits reverse transcriptase & incorporates into viral DNA.-Nucleotides fail to bind to ddATP bec it lacks free 3’ OH group
HIV Mutations in reverse transcriptase
Peripheral neuropathy, pancreatitis, diarrhea, headache, insomnia, vomiting, nausea, rash, abdominal pain
IV/PO. Partially metabolized in liver, excreted in the urine. Toxicity may be enhanced by renal or hepatic dysfunction.
Limited utility as a single agent therapy because of viral resistance
Stavudine Metabolized to stavudine triphosphate w/c inhibits HIV reverse transcriptase & DNA polymerase. Prevents DNA elongation.
HIV Peripheral neuropathy
PO Not indicated for initial monotherapy of HIV
ANTIVIRAL DRUGS - RETROVIRUSES
RitonavirIndinavirSaquinavirNelfinavir
Inhibts HIV protease .Results in immature virion
HIV Mutations in protease sequence reduce affinity of protease inhibitors
GI distress, headache, neurologic symptoms. Indinavir associated w/ increase risk for kidney stones
PO. Metabolized by P450 in liver. Reduce dose in patients with liver disease. Poor CNS penetration
Potentially serious drug interactions due to P450 competition
NevirapineDelavirdene
Nob-nucleoside inhibitor of HIV reverse transcriptase
HIV. Never as monotherapy due to rapid development of resistance
Rapid resistance develops due to mutations in reverse transcriptase
Severe skin rash, fever, nausea, headache
PO. Well absorbed. Nevirapine crosses placenta & has better CNS penetration than Delavirdene
Delavirdene failed to show clinical efficacy when added to didanosine in clinical trial
POST-TESTPOST-TEST
1. Inhibits step # 1 in HIV replication:A. NRTI B. fusion inhibitors
2. Inhibits step #2 in HIV replication:A. fusion B. NNRTIs
3. Inhibits step # 3 in HIV replication:A. protease inhibitors B. NRTIs
4. Inhibits step #4 in HIV replication:A. protease inhibitors B. NRTIs
5. Virus that undergoes endocytosis:A. HIV B. influenza
6. Enzyme inhibited by antiretroviral agents:A. reverse transcriptase B. DNA polymerase
7. Drug for influenza A infection:A. Amantadine B. zidovudine
8. Drug used for HIV that is used in the tx of HBV:A. lamivudine B. amantadine
9. Drug used in the treatment of RSV:A. amantadine B. rimantadine
10. Drug used in the treatment of perianal warts:A. imquimod B. amantadine
ANTIFUNGAL AGENTSANTIFUNGAL AGENTS
SYSTEMIC ANTIFUNGAL SYSTEMIC ANTIFUNGAL DRUGS FOR SYSTEMIC DRUGS FOR SYSTEMIC
INFECTIONINFECTION
AMPHOTERICN BAMPHOTERICN B
Polyene antifungal Discovered by Gold & coworkers in 1956 Produced by Streptomyces nodosus Heptane macrolide w/ 7 conjugated double
bonds in the trans position & 3-amino-3,6- dideoxymannose connected to the main ring by a glycoside bond
Amphotericin polyene macrolide Nearly insoluble in water
PREPARATIONS:PREPARATIONS:
1) Colloidal suspension of amphotericin B & Na deoxycholate (DOC) –IV
• 50 mg amphotericin B, 41 mg deoxycholate
• Addition of electrolyte to infusion solution causes colloid to aggregate
2) Amphotericin B Colloidal Dispersion• contains roughly equimolar amounts of
Amphotericin B & cholesteryl sulfate• Forms a colloidal solution when
dispersed in aqueous solution
CONT. CONT.
3) Unilamellar Vessicle FormulationAmphotercin B 50 mg + 350 mg of lipid
in 10% molar ratio
4) Amphotericin B Lipid Complex• Amphotericin B 35% +
dimyristolphosphatidylcholine & glycerol
ANTIFUNGAL ACTIVITY:ANTIFUNGAL ACTIVITY:
Candida sp., C. neoformans, B. dermatidis, H. capsulatum, Sporothrix schenkii, C. immitis, Paracoccidioides brazilienzes, Aspergillus sp., Penicilium marneffei, Mucormycosis
Limited activity to Leishmania, braziliensis, Naegleria fowleri
No antibacterial activity
PHARMACOKINETICS:PHARMACOKINETICS:
Poorly absorbed from the GIT Oral preparation is only effective in fungi
within the lumen of the GIT Serum t ½ is 15 days Widely distributed in tissues 2-3% CSF concentration
MECHANISM OF ACTION:MECHANISM OF ACTION:
Antifungal activity depends on the binding with ERGOSTEROL
Alters the permeability of the cell by forming amphotericin B associated pores in the cell membrane
Combines with lipids along the double rich bond & associates with H2O molecules along the OH-rich side
Pores allow leakage of intracellular ions & macromolecules CELL DEATH
THERAPEUTIC USES:THERAPEUTIC USES:
Candida esophagitis Meningitis caused by coccidioides Mucormycoses Invasive aspergillosis Extracutaneous sporothrichosis Cryptococcosis Candida cystitis Mycotic corneal ulcers & keratitis
ADVERSE REACTIONS:ADVERSE REACTIONS:
A) INFUSION-RELATED TOXICITY: fever & chills, muscle spasms, vomiting,
headache, & hypotension
B) SLOWER TOXICITY: renal damage
o Reversible renal injuryo Irreversible renal injury- renal tubular injury
FLUCYTOSINE (5-FC)FLUCYTOSINE (5-FC)
antimetabolite Discovered in 1957 Fluorinated pyrimidine related to florouracil &
floxuridine Spectrum of activity is narrower than that of
amphotericin
PHARMACOKINETICS:PHARMACOKINETICS:
Available in oral preparation Well absorbed (>90%) with serum Concentration peaking 1-2 hrs Poorly protein bound Penetrates well body fluids & CSF T ½ is 3-4 hrs
MECHANISM OF ACTION:MECHANISM OF ACTION:
Taken up by fungal cells via CYTOSINE PERMEASE
Converted intracellularly to 5 FU 5-fluorodeoxyuridine monophosphate & 5-fluorouridine triphosphate inhibit RNA & DNA synthesis
5-FU 5-FlucytosineCytosine permease
UMP pyrophosphate
5-FUMP 5-FUDP 5-FUTP
Ribonucleide reductase
5-F-dUMP
RNA
Thymidine synthase
DUMP dTMP
CLINICAL USE:CLINICAL USE:
Cryptococcal meningitisCandida speciesDermatiaceous molds that cause
chromoblastomycosis
ADVERSE EFFECTS:ADVERSE EFFECTS:
Leukopenia & thrombocytopeniaRashNausea/vomiting, diarrhea, severe
enterocolitis
AZOLES:AZOLES:
IMIDAZOLES :KetoconazoleMiconazoleClotrimazole
TRIAZOLES:ItraconazoleFluconazoleVoriconzaole
MECHANISM OF ACTION:MECHANISM OF ACTION: Inhibition of sterol 14 α-demethylase Impair the biosynthsesis of ergosterol for the
cytoplasmic membrane accumulation of 14-α-methylsterols
Impairing functions of membrane bound enzymes such as ATPase & enzymes of electron transport system inhibits growth of fungi
Reduction of ergosterol synthesis by inhibition of cytochrome P450 enzymes
Specificity for fungal than human cytochrome P450 enzymes
CLINICAL USES:CLINICAL USES:
Candida speciesCryptococcus neoformansEndemic mycoses
DRUG INTERACTIONS:
All azole drugs affect mammalian cytochrome P450 systems of enzymes
KETOCONAZOLEKETOCONAZOLE
First oral azole introduced into clinical use Increase propensity to inhibit mammalian
cytochrome P450 enzymes Less selective for fungal P450 Inhibition of mammalian P450 interferes with
biosynthesis of adrenal & gonadal steroid hormones
Interaction with P450 enzymes can alter the metabolism of other drugs leading to enhanced toxicity
Cont.Cont.
Reaches the keratinocytes efficiently Concentration in vaginal fluids is
approaches that in plasma
THERAPEUTIC USES:THERAPEUTIC USES:
Blastomycosis, histoplasmosis, coccidiodomycosis, pseudallescheriasis
Paracoccidiodomycosis, ringworm, tinea versicolor, chronic mucocutaneous candidiasis
Candida vulvovaginitis, oral & esophageal candidiasis
ADVERSE REACTIONS:ADVERSE REACTIONS:
Dose-dependent anorexia, nausea, vomiting
Inhibits steroid biosynthesis in patients endocrine abnormalities
DRUG INTERACTIONS:DRUG INTERACTIONS:
Increases cyclosporine levelsEnhances arrythmogenic effects of
cissaprideH2 antagonists increases gastric pH,
interfere with the absorption of ketoconazole
Rifamycins increased hepatic metabolism
ITRACONAZOLEITRACONAZOLE
Available in capsule & solutions (oral & IV) Capsule form is best absorbed in the fed
state Oral solution is best absorbed in the fasting
state Metabolized in the liver by the CYP3A4
isoenzyme system Does not affect mammalian steroid synthesis Reduced bioavailability when taken with
rifamycins
Cont.Cont.
Azole of choice for dimorphic fungi histoplasma, blastomyces, sporothrix
Oral solution is effective for use in oropharyngeal & esophageal candidiasis
Onychomycosis can be treated with either 200 mg OD X 12 wks or as 200 mg BID X 1 wk out of each month
FLUCONAZOLEFLUCONAZOLE Fluorinated bistriazole Good water solubility & CSF penetration Azole of choice in the treatment & secondary
prophylaxis of cryptococcal meningitis Available in oral & IV form plasma concentrations of astemizole,
cissapride, cyclosporine, rifampin, rifabutin, sulfonylureas, theophylline & warfarin
VORICONAZOLEVORICONAZOLE Newest triazole to enter clinical trials Availabale in oral & IV Well absorbed orally with bioavailability >90% Low propensity to inhibit mammalian
cytochrome P450 Same as itraconazole in its spectrum of
action Good activity against candida species fluconazole-resistant species such as C.
krusei, dimorphic fungi, pathogenic molds including aspergillus
ECHINOCANDINSECHINOCANDINS
Large cyclic peptides linked to a long chain fatty acid
Caspofungin, micafungin, anidulafunginCandida and aspergillus but not
cryptococcus neoformansIV forms only
MECHANISM OF ACTIONMECHANISM OF ACTION
Inhibits the synthesis of β (1-3) glucan Disruption of the fungal cell wall and cell death The glucan synthesis inhibitors are, collectively,
agents that are presumed to block fungal wall synthesis
Inhibition of this enzyme results in depletion of glucan polymers in the fungal cell, resulting in an abnormally weak cell wall unable to withstand osmotic stress
CLINICAL USE:CLINICAL USE:
CASPOFUNGIN Disseminated mucocutaneous candida infections Empiric antifungal therapy during febrile
neutropenia
MICAFUNGIN Mucocutaneous candidiasis Prophylaxis of candida infections in bone marrow
transplant patients
ANIDULAFUNGIN– esophageal candidiasis– Invasive candidiasis– septicemia
SYSTEMIC ANTIFUNGAL SYSTEMIC ANTIFUNGAL DRUGS FOR DRUGS FOR
MUCOCUTANEOUS MUCOCUTANEOUS INFECTIONSINFECTIONS
GRISEOFULVINGRISEOFULVIN
Practically insoluble in waterFungistatic in vitro for dermatophytes
microsporum, epidermophytom & trichophyton
No effect on bacteria & other fungi
MECHANISM OF ACTION:MECHANISM OF ACTION:
Production of multinucleate cells as the drug inhibits fungal mitosis
Causes disruption of the mitotic spindle by interacting with polymerized microtubules – critical step in cellular division
Deposited in the newly forming skin where it binds to keratin
Administered 2-6 wks for skin & hair infections
THERAPEUTIC USES:THERAPEUTIC USES:
Mycotic disease of the skin, hair & nails due to Microsporum, Trichophyton, or Epidermophyton
Tinea capitis (M. canis)Ringworm of the glabrous skinTinea corporis, cruris (T. rubrum, T.
mentagrophytes)Hyperlkeratosis (T. rubrum)
ADVERSE REACTIONS:ADVERSE REACTIONS:
Allergic syndromehepatitis
TERBINAFINETERBINAFINE Synthetic allylamine Available in oral formulation Used in the treatment of dermatophytoses especially
onychomycosis Keratophillic, fungicidal Inhibits the enzyme SQUALENE EPOXIDASE Leads to the accumulation of the sterol squalene Allylamines work in a conceptually similar fashion to azole
antifungals by inhibiting the synthesis of ergosterol Allylamines act at an earlier step in the ergosterol synthesis
pathway OD X12 wks achieves 90% cure rate for onychomycosis
TOPICAL ANTIFUNGAL TOPICAL ANTIFUNGAL AGENTSAGENTS
Superficial fungal infections confined to the striatum corneum, squamous mucosa or cornea
Ringworm, candidiasis, tinea versicolor, tinea nigra, fungal keratitis
Not successful for mycoses of the nails & hair No place for the treatment of subcutaneous
mycosis
POLYENE ANTIFUNGAL POLYENE ANTIFUNGAL AGENTSAGENTS
NYSTATINNYSTATIN
Polyene macrolideStructurally similar to Amphotericin BToxic for parenteral administrationAvailable in creams, ointments,
suppositoriesOropharyngeal thrush, vaginal
candidiasis, intertriginous candidal infections
AMPHOTERICIN BAMPHOTERICIN B
Topical form (Fungizone)Cutaneous & mucocutaneous
candidiasisLotion, ointment & cream
IMIDAZOLE & TRIAZOLE FOR IMIDAZOLE & TRIAZOLE FOR TOPICAL USE:TOPICAL USE:
CLOTRIMAZOLECLOTRIMAZOLE
Available as 1% cream, lotion, & solution
1% or 2% vaginal cream or vaginal tablets
Skin applications – BIDVaginal applications – 100 mg tab OD
at bedtime X 7 days or 200 mg OD X 3 days
MICONAZOLEMICONAZOLE Readily penetrates the striatum corneum of
the skin Persists for >4 days after application Safe for use during pregnancy for vaginal
use Ointment, cream, solution, spray, powder
or lotion Vaginal cream, suppositories Tinea pedis, tinea cruris, & tinea versicolor
CICLOPIROXAMINECICLOPIROXAMINE
Broad spectrumFungicidal to C. albicans, E. flocosum,
M. canis, T. mentagrophytes, T. rubrumInhibits the growth of Malassezia furfurPenetrates the dermis
HALOPROGINHALOPROGIN
Halogenated phenolic ether Fungicidal to various species of
Epidermophyton, Pityrosporum, Microsporum, Trichophyton & Candida
Poorly absorbed through the skin Converted to thrichlorophenol in the body Cream or solution BID X 2-4 wks Principal use for tinea pedis Tinea cruris, tinea versicolor, tinea corporis
NAFTIFENENAFTIFENE
Inhibit squalene-2,3- epoxidaseInhibits biosynthesis of ergosterolFungicidal activity1% cream or gelTopical treatment of tinea cruris & tinea
corporisCutaneous candidiasis & tinea
versicolor
DRUG ACTION CLINICAL USE UNDESIRABLE EFFECTS
PHARMACOKINETICS NOTES
Amphotericin B Disrupts plasma membrane of fungal cells, greater affinity for ergosterol
DOC: systemic fungal infections, fungal meningitis & fungal urinary tract infections
Poor therapeutic index (toxic at therapeutic dose). Fever & chills, nephrotoxicity, nausea, headache, thrombophlebitis, anemia, hepatotoxicity, cardiotoxicity
Slow IV for systemic infections; intrathecal for meningitis, bladder irrigation for cystitis. No need to reduce dose with renal dysfunction.
CBC, urinalysis, liver enzymes, BUN, Crea, & electrolytes should be checked before and during tx
Nystatin DOC: Intestinal candidiasis or oral thrush
Few adverse effects
PO. Negligible absorption, fecal excretion
.
Ketoconazole Impairs synthesis pf ergosterol
DOC: P. brasiliensis, thrush, chronic mucocutaneous candidiasis, dermatophytes
Nausea, diarrhea, headaches, rsh, dizziness, fatal hepatic necrosis, gynecomastia.Risk of cardiac arrhythmia with Terfenadine
PO. Acid pH required for dissolution. Absorption decreased by food, antacids, cimetidine
Follow LFTs. Stop during signs of liver abnormalities
Fluconazole Inhibits fungal cytochrome P450. Damages plasma membrane by inhibiting sterol demethylation
Systemic histoplasmosis, blastomycosis, coccidiomycosis or sporotrichosis. Opportunistic cryptococcosis, candidiasis, candidal thrush, vaginitis, esophagitis
Nausea, headache, rash, vomiting, diarrhea
PO/IV. Long half life. Excellent penetration of CSF, eye, urine. Hepatic metabolism
No effect on testosterone synthesis.
ANTIFUNGAL DRUGS
Itraconazole Aspergillosis, histoplasmosis, coccidiomycosis, sporotrichosis, paracoccidiomycosis, tinea or candidal infections
Nausea, edema, hepatitis. No gynecomastia or breast pain. Risk of fatal cardiac arrhythmias w/ terfenadine
PO. Requires acidic environment for absorption
No effect on testosterone synthesis
Clotrimazole unknown DOC: candida dermatophyte infections of the skin
topical
Miconazole Vaginal candidiasis, severe systemic fungal infections
Phlebitis, pruritus, nausea, fever, rash, vomiting
Vaginal suppositories/ topical/IV
Flucytosine Deaminated to 5-FU by the fungus. Incorporated into RNA. Metabolized to 5-FdURD w/c inhibits thymidilate synthetase
Leucopenia, nausea, diarrhea, Inc LFTs, bone marrow depression
Easily penetrates CNS. Renal excretion
Fungal resistance develops
Griseofulvin Interferes w/ synthesis & polymerization of nucleic acids
Dermatophytes of hair, skin, & nails. Up to 6 months tx may be required
Headaches, GI upset, dec memory & judgement, leucopenia, teratogenic
PO. Water insoluble, powder absorbed fairly well, administration w/ fatty meal aids absorption
Contraindicated w/ pregnant women. Drug binds to keratin of growing tissues
Terbinafine Inhibits squalene epoxidase that converts squalene to ergosterol in fungi
Toenail infection due to trichophyton species
Neutropenia, skin infections, ophthalmic toxicity
PO. Long half life. Good tissue penetration
Monitor blood counts
MISCELLANEOUS MISCELLANEOUS ANTIFUNGAL AGENTSANTIFUNGAL AGENTS
UNDECYCLENIC ACIDUNDECYCLENIC ACID
Yellow liquid with a characteristic rancid odor
Fungistatic, fungicidal w/ prolonged useFoam, ointment, cream, powder, spray
powder, soap & liquidRingworm, tinea pedis
BENZOIC ACID & SALICYLIC BENZOIC ACID & SALICYLIC ACIDACID
Whitfield’s ointmentCombines fungistatic activity of benzoic
acid w/ keratolytic action of salicylic acidMainly for the treatment of tinea pedisEradication occurs after the infectd
stratum corneum is shedSalicylate accelerates the
desquamation
PROPIONIC ACID & CAPRYLIC PROPIONIC ACID & CAPRYLIC ACIDACID
Treatment of dermatomycosesLow efficacy
POTASSIUM IODIDEPOTASSIUM IODIDE
Treatment of mucocutaneous sporotrichosis