Anti Virals and Anti

Fungals
Dr. JE Mamaat
 Anti-fungal and Anti-virals
► ANTI-VIRALS

Antiherpesvirus
► Acyclovir and Valacyclovir
► Gancyclivir and Valgancyclovir
► Famciclovir and Penciclovir
► Foscarnet
► Idxuridine

Anti-influenza
► Amantadine and Rimantadine
► Oseltamivir

Anti HIV
► NRTI
► Zidovudine
► Stayudine
► Didanosine
► Lamivudine
► Zalcitabine
NNRTI
► Nevirapine
► Efavirenz
► Delavirdine
 
Protease Inhibitors
► Saquinovir
► Ritonavir
► Nelfinavir
► Indinavir
Others:
► Immune globulin
► Interferon
POLYENE ANTIBIOTICS
AMPHOTERICIN B
► MOA: Binds to fungal cell membrane ergosterol creating pores
leading to increased cell permeability and loss of cellular constituents;

► Cholesterol, present in host cell membrane closely resemble ergosterol,

the polyenes bind to it as well, though with less affinity, thus the selectivity
of action of polyenes is low

► PK:Poorly absorbed in the GIT, primarily IV use

>90% protein bound, long plasma life
Poor meningeal penetration with or without inflammation
Primary route of elimination: hepatic metabolism

► AE: The toxicity of AMB is high

► Acute reactions: infusion related toxicity: chills, fever, dyspnea, rarely
hemodynamic collapse/hypotension; probably due to release of
proinflammatory cytokinase and does not appear due to histamine
release.

► Long term toxicity: Nephrotoxicity is the most common and most

serious long term toxicity – due to decreased glomerular and tubular
blood flow through its vasoconstrictive effects; occurs fairly uniformly
and is dose related; manifestations: kaliuresis and hypokalemia, fall in
serum bicarbonate (may proceed to renal tubular acidosis); decreased
in renal erythropoietin and anemia, rising BUN and creatinine.

► Anemia: due to bone marrow depression; reversible

► CNS toxicity: occurs only on intrathecal injection

New AMB formulations:

► AMB lipid complex (ABLC): contains 35% AMB incorporated in ribbon like
particles f dimyristoyl phospholipids
► AMB colloidal dispersion (ABCD): disc shaped particles containing 50%
each of AMB and cholesterol sulfate are prepared as aqueous dispersion
► Lipsomal AMB (small unilamellar vesicles; SUV): consist of 10% AMB
incorporated in uniform sized unilamellar liposomes made up of lecithin
and other phospholipids.

Special features:
► produce milder acute reactions (specially liposomal formulation) on IV
infusion
► can be used in patients not tolerating infusion of conventional AMB
► much lower nephrotoxicity
► cause minimal anemia
► Liposomal preparations delivers AMB specially to reticuloendothelial cells in
the liver and spleen
► However, some preparations, specially ABLC and ABCD produce lower AMB
levels and NONE of the lipid preparation has shown superior efficacy compared
to conventional AMB in prospective trials. They are very expensive.

Clinical use:
► DOC for nearly all life-threatening mycotic infections
► Broad spectrum of activity: yeasts, Candida sp., Cryptococcus
neoformans, endemic mycoses, Aspergillus fumigatus
 
NYSTATIN
 
► MOA is similar to that of amphotericin B
► Too toxic for systemic use; topical: virtually no adverse effects
► Use limited to topical treatment of superficial or local candidal infections –
oropharyngeal, vaginal intertriginous areas.
 
►THE AZOLES
► MOA:bind to and inhibit cytochrome p450 enzyme
lanosterol 14-demethlase responsible for demethylation of
lanosterol to ergosterol thus leading to decreased
ergosterol synthesis.
► Greater affinity for fungal cytochrome p450 toxicity profile and drug
interactions: imidazoles have lesser degree of specificity thus higher
incidence of drug interactions and side effects; the lower toxicity of
triazoles compares to imidazoles has correlated with their lower affinity
for mammalian CYP450 and lesser propensity to inhibit mammalian
sterol synthesis

► Broad-spectrum activity: Cryptococcus, Candida, endemic mycoses,

dermatophytes. Generally non-toxic. 
KETOCONAZOLE
► Good oral absorption but requires an acidic gastric environment
► High plasma protein binding
► Extensive metabolized by the liver and excreted in bile
► Penetration to CSF is negligible
► Greater propensity to inhibit mammalians cp450; less selectivity for fungal p450 than newer
azoles -> more side effects and significant drug interactions
Drug interactions:
► H2 blockers. PPI and antacids decrease oral absorption
► Rifampicin, Phenobarbital carbamazepine and phenytoin induce ketoconazole metabolism and
decrease efficacy
► KTZ inhibits cyp450 specially CYP3A4 -> inc blood levels of drugs including warfarin,
sulfonylureas, phenytoin, cyclosporine, diazepam, indinavir
► Dangerous interaction with terfenadine, astemizole, cisapride -> Torsades de pointes
► Useful in the treatment of cutaneous and mucous membrane dermatophytes and yeast
infections; systemic mycoses but does not exceed efficacy of AMB
AE: high doses cause significant reduction in testosterone synthesis and displacement of
testosterone from protein binding sites and blocks adrenal response to corticotrophin ->
gynecomastia, decreased sperm counts, libido; menstrual irregularities may occur due to
suppression of estradiol synthesis.
 
FLUCONAZOLE
► Does not require an acidic environment for oral absorption. High oral bioavailability.
► Long plasma half-life
► Penetrates widely into most tissues including normal and inflamed meninges
► Excreted unchanged in urine

AE: few side effects

► Has the least effect of all azoles on hepatic microsomal enzymes; higher selectivity
for fungal cytochrome P450 -> drug interaction is less common
► Does not inhibit steroid synthesis and anti androgenic and other endocrine side
effects have not occurred
► Azole of choice in the treatment and secondary prophylaxis of cryptococcal
meningitis (acceptable alternative to amphotericin B for mild cryptococcal
meningitis but superior to it in long term prevention of relapsing meningitis);
► Systemic and mucosal candidiasis; coccidioidal meningitis and hiptosplasmosis; (no
activity against Aspergillus)
ITRACONAZOLE
 
► Lipophilic, requires low gastric pH for absorption specially the tablet form;
solution is taken in fasted state; tablet and solution forms are not
interchangeable, solution preferred; solution achieves a higher peak
concentration
► Variable bioavailability
► Highly protein bound, large Vd
► Interacts with hepatic microsomal enzymes though less than ketoconazole
► Effectivity limited by reduced bioavailability
► Poor CSF penetration
► Has activity against Aspergillus; preferred over KTZ for most systemic
mycoses that are not associated with meningitis
► Broader spectrum of activity than KTZ or fluconazole; superior to
fluconazole for Histoplasmosis, Blastomycosis, Sporotrychosis and
Onychomycosis
► Well tolerated in low doses <200 mg/day; high doses >400 mg/day gastric
intolerance is significant, dizziness, pruritus, headache and hypokalemia
► Drug interaction profile similar to KTZ
FLUCYTOSINE
► Fluorinated analogue of cytosine
MOA: 5-FC taken up by fungal cells by cytosine premease then intracellularly
is converted to 5-FU by cytosine deaminase then to 5-fluorodeoxyuridylic
acid which is an inhibitor of thymidylate synthesis which is an important
component of DNA;
► Fungal selectivity of 5-FC depends on the fact that mammalian cells
(except some marrow cells) are unable to convert drug to active
metabolites;
PK: well absorbed; poorly protein bound; penetrates well into body fluids including
CSF; excreted in urine
AE: toxicity results to metabolism to toxic antineoplastic compound fluoruracil
► bone marrow toxicity
Clinical use: limited antifungal activity; not used as monotherapy due to
development of resistance;
► Useful as part of combination treatment with amphotericin B for cryptococcal
meningitis and with itraconazole for chromoblastomycosis
Characteristi AMB 5-FC KTZ FLU ITR
cs
Antifungal Broad Narrow Broad Broad Broad
spectrum
Water soluble No Yes Yes Yes Yes

Absorbed No Yes Yes Yes Yes

orally
Administered Yes Yes No Yes No
IV
Resistance (in No Yes No No No
vivo)
Nephrotoxicit Yes No No No No
y
Anemia Yes Mild No No No

Leukopenia No Yes No No No

GI upset Yes Yes Mild Mild Moderate

Overall High Medium Low Lowest Lowest

toxicity
GRISEOFULVIN

MOA: binds to microtubules responsible for mitotic spindle

formation leading to defective cell wall development; binds
to newly formed keratin protecting the skin from new
formation
► Ineffective topically
► Poor oral absorption but improved with microcrystalline
processing or when taken with fatty meals
► Well tolerated
► Oral fungistatic agent used in the systemic treatment of dermatophytosis; reserved for
cases with nail, hair or large body surface environment
TERBINAFINE
 
►Synthetic allylamine available for topical and systemic
(oral) use in the treatment of dermatophyte skin and nail
infections
MOA: reversible non-competitive inhibition of squalene
monooygenase (squalene epoxidase) which converts
squalene to lanosterol -> ergosterol;

► Keratophilic and fungicidal, accumulation of squalene within the fungal

cells appears to be responsible for its fungicidal activity
► Well tolerated; mammalian enzyme inhibited only by 1000 fold higher
concentrations of terbinafine
► Does not inhibit cytochrome p450
VIRUSES
► Obligate intracellular parasites
► To reproduce, viruses must enter the host cell, take over the host cell’s
mechanism for nucleic acid and protein synthesis and direct the host
cell to make new viral replication particles
► Chemotherapy interferes with any or all steps in the viral replication
cycle
► But because viral replication and host cell processes are linked, the
main problem in the chemotherapy of viruses is finding a drug that is
selectively toxic to the virus
► Viruses with specific tx: hyperviruses HSV1, HSV2, VZV, CMV; RSV;
Hepatitis B and C, HIV
ANTIHERPESVIRUS AGENTS
 
Acyclovir and Valacyclovir
MOA: acyclovir is converted t metabolites via 3 phosphorylation steps:
► Acyclovir acyclovir acyclovir diP acyclovir trip (active metabolite)
 
Herpes virus specific thymidine kinase
Acyclovir
 
Acyclovir monophosphate

Cellular Kinase
Inhibits herpes virus DNA polymerase competitively
Acyclovir
Triphosphate
Gets incorporated in viral DNA and stop lengthening of DNA
strand. The terminated DNA inhibits DNA polymerase irreversibly.
► Acyclovir triphosphate is a competitive inhibitor for the incorporation of
dGTP into viral DNA thus inhibiting DNA synthesis
► Acyclovir that is incorporated acts as a chain terminator because it lacks 3’OH
group necessary for elongation because it requires viral kinase for the initial
phosphorylation, acyclovir is selectively activated and accumulates only in
infected cells; greater inhibitory effect on viral DNA synthesis, low toxicity
for host cells.
PK:
► Valacyclovir rapidly and completely converted to acyclovir by intestinal and
hepatic first pass metabolism
► Only 20% of oral acyclovir higher is absorbed
► Bioavailability of acyclovir higher after oral Valacyclovir
► Low plasma protein binding
► Widely distributed attaining CSF concentrations that is 50% of plasma
► Excreted unchanged in urine by glomerular filtration and tubular secretion
Clinical Uses: Active against herpes group of virus. HSV I most sensitive followed by
HSV II>VZV=; CMV not affected
AE: generally well tolerated; IV may cause reversible renal dysfunction
► Secondary to crystalline nephropathy: neurologic toxicity

Famciclovir and Penciclovir

► Famciclovir is converted to Penciclovir by first pass metabolism
MOA: similar to acyclovir: it is monophosphorylated by viral thymidine kinase then
converted to triphosphate form by a cellular kinase: Penciclovir triphosphate
acts as competitive of viral DNA polymerase:
► However does not cause chain termination
► Lower affinity for viral kinase than acyclovir triphosphate but within increased nd
prolonged intracellular concentrations
► Bioavailability of Penciclovir higher after oral Famciclovir
► Generally well tolerated
► Penciclovir is effected against HSV I, HSV II, VZV and EBV
Ganciclovir and Valganciclovir
MOA: same as acyclovir and causes chain termination.
► 100x more concentrated in infected cells that normal host cells: preferentially
incorporated into DNA by viral polymerase however, mammalian bone marrow cells
are sensitive to growth inhibition by ganciclovir
► Ganciclovir is poorly absorbed orally: Valganciclovir well absorbed from GIT and is
rapidly metabolized to ganciclovir
► Excreted uncharged by kidneys
► Treatment of CMV infection
AE: Myelosuppression is most common and serious side effect

 Idoxuridine
► Iodinated derivative of deoxyuridine that acts as a thymidine analogue that completes
with thymidine: gets incorporated in DNA so that faulty DNA is formed thus
inhibiting both viral and cellular DNA synthesis
► Virus selectivity is low; significant host toxicity-not used in treatment of systemic
viral infections
► Clinical use limited to herpes simplex infection of eyelid conjunctiva and cornea
Foscarnet
► Noncompetitive inhibitor of viral DNA polymerase and reverse transcriptase
by reversibly binding with pyrophosphate binding sites of viral enzyme;
straight chain phosphate unrelated to any nucleic acid precursor
► Does not require activation by phosphorylation
► Indicated for treatment of CMV retinitis acyclovir resistant HSV II and VZV
in AIDS patient
AE: renal toxicity, anemia, tremors and convulsions, hypoglycemia
 
 
ANTI-INFLUENZA AGENTS
 
Amantadine and Rimantadine
 
MOA: inhibits uncoating of viral RNA by inhibition of viral M protein that acts
as H channel
► Both have good oral absorption
► Amantadine the replication of the 3 antigenic subtypes of influenza A (HINI,
H2N2, H3N2) BUT NOT influenza B
AE: mild GI and neurologic complaints
Uses:
► Prophylaxis of influenza A2 during an epidemic of seasonal, especially in
high risk patients
► Treatment of influenza A2 illness
► Parkinsonism
► Rimantadine- more potent, long acting and better tolerated congener of
amantidine
Oseltamivir
► Analogue of neuramic acid which is a reversible antagonist of viral neuraminidase
► Prevention of release and spread or progeny virus
► Rapidly absorbed and metabolized
► Eliminated by the kidneys
AE: most frequent: nausea and vomiting; bronchitis, insomnia, vertigo
► Has activity against BOTH influenza A and influenza B
Clinical use
► Treatment of uncomplicated acute influenza in patients. 1 y/o; decrease duration of
illness by to 1.5 days when treatment is initiated within 48hours of onset
symptoms
► Prophylaxis of influenza in individuals > 13 y/o
 
ZANAMIVIR – oral bioavailability <5%, administered using
inhaler device; indicated in the treatment of uncomplicated
acute influenza A and B>7 y/o
 
Ribavirin
► Guanosine analogue that inhibits synthesis of viral mRNA
► Undergoes phosphorylation by host cell enzymes
► Oral absorption is rapid and first pass metabolism is extensive;
► Bioavailability increased when given with high fat meals; oral bioavailability is
50%
► Accumulates in the body and persists months after discontinuation
► When administered by aerosol, has minimal systemic absorption

Clinical Use: Ribavirin aerosol – high risk infants and young children with severe
RSV bronchiolitis or pneumonia; oral Ribavirin- in combination with interferon
against hepatitis C; influenza A and B

AE: aerosolized- local reaction; systemic –hemolytic anemia

► Mutagenic, teratogenic, embryotoxic, contraindicated in pregnant women and the
male partners of pregnant women
 
 
ANTI-HIV
Viral Replication
► Viral entry: gp 120 in the surface of viral envelope
attaches to CD4 surface glycoprotein of target cell then
undergoes conformational change that allows it to bind
with chemokine receptors (CXCR for CD4-T calls or
CCR5 for macrophages)
Viral reverse transcriptase synthesize DNA using viral
RNA as template.
► DNA integrates into host genome by integrase; viral
transcription to viral proteins and progeny viral RNA
ASSEMBLY maturation in which polyproteins
are cleaved by protease.
Drug Therapy of HIV Infection
►The replicative cycle of HIV presents many opportunities for the targeting of anti-viral agents.
The replicative cycle of HIV presents many opportunities for the targeting of anti-viral agents.
► The drugs in clinical uses are classified as NRTIs, NNRTIs, NTRTIs and PI
► Single agents are seldom used to treat HIV infection. Multidrug therapy is used to counteract the
rapid mutation rate of HIV and to minimize drug toxicity. HAART (Highly Active Anti Retroviral
Therapy) uses combination of PI and RTI. In this system, drugs working by different mechanism
produce a sequential blockade of steps required for viral reproduction. 

NUCLEOSIDE REVERSE TRANSCRIPTASE

INHIBITORS
(NRTIs) 
► Undergoes phosphorylation to triphophates by the host kinase, compete with
nucleoside triphosphate for access to reverse transcriptase
► Block HIV replication and therefore the infection of new cells but have little effect
on cells already infected with the virus
► Lack 3’OH group thus their incorporation into DNA results in chain termination
► Inhibits cellular and mitochondrial DNA, polymerase and kinase toxicity
► ALL NRTIs can produce a potentially fatal syndrome of lactic acidosis and severe
hepatomegaly with hepatic necrosis; women alcoholics, obesity, prolong nucleoside
exposure are risk factors for liver disease increases risk for lactic acidosis.
 Common Side Effects Comments
Agent Dose Administration

Zidovudine 200 mg tid or 300 mg Food interferes with Bone marrow toxicity Avoid concurrent
bid absorption anemia, neutropenia, myelosuppressive
nausea, insomnia drugs
Ribavirin inhibits
activity of ZDV;
ZDV inhibits
stavudine activity
Dose adjustment
needed in renal
impairment
Stavudine 30-40 mg bid Peripheral neuropathy; Avoid concurrent use
lactic acidosis most of ZDV
common with
stavudine
Didanosine 150-200 mg bid 30 min before or 2 hrs Main unwanted Contains antacid Not
after meals; food effects: dose related combined with
interferes with pain and sensory loss Zalcitabine
absorption in the feet Dose related
pancreatitis

Lamivudine 150 mg bid or 300 mg Best tolerated NRTI Avoid use with
qd Zalcitabine – inhibit
each other; Active
against HBV
Zalcitabine 0.75 mg tid Avoid use with antacid Peripheral Neuropathy Avoid neuropathic
or food drugs

Abacivir Rash, hypersensitivity Do not rechallenge

Reaction after
Hypersensitivity
Reaction
Nucleotide Reverse Transcriptase Inhibitor
Tenofovir
► Converted by cellular enzymes to triphosphate which completes with dATP for
access to reverse transcriptase and causes chain termination following its
incorporation
► Generally well tolerated
► Produces less mitochondrial toxicity than NRTIs
 
 
NON-NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS (NNRTIS)
► Inhibits viral reverse transcriptase by binding to adjacent to its active site inducing
conformational changes that causes enzyme inactivation
► DO NOT require phosphorylation for activation
► Undergoes significant metabolism by and induction of cytochrome p450 enzymes
adverse effects and multiple drug interactions
 Agents Dose Administration Common Side Comments
Effects

Efavirenz 600mg qid Not to be taken by Dizziness, insomnia, Embryotoxic,

fatty meals rash, increase teratogenoc
transaminase

Nevirapine 200 mg bid Oral bio A 90% not Hepatic toxicity,

food dependent skin reactions (SJS,
TEN,
hypersensitivity)
headache

Delaviridine Low gastric acidity Most common; rash

decrease absorption with pruritis
PROTEASE INHIBITORS
► Protease required for production of mature infective
virus, cleaves polyproteins into structural and active
enzymes
► Can produce nausea, vomiting, diarrhea and
paresthesias; hyperglycemia and insulin resistance:
hypercholesterolemia and hypertriglyceridemia; fat
distribution is common.
► Interacts with a large number of drugs –by and
inhibit cytochrome p450 enzymes
 Agents Dose Administration Common Side Comments
Effects

Saquinavir Within 2 hours of a Nausea, diarrhea Multiple nursing

full meal; food (high interactions
fat meal) inc Less potent inhibitors
absorption of CYTP450

Ritonavir 600 mg bid With food first pass Nausea, diarrhea, Most potent inhibitor
metabolism paresthesias, hepatitis of CYP3A4

Indinavir 800mg tid With water or other Nephrolithiasis Liver Drug interactions
liquids; a hr before or function
2 hrs after meal abnormalities

Nelfinavir 750 mg tid or 1250 With food Diarrhea, nausea Low incidence of
mg bid side effects
FUSION INHIBITOR
ENFUVITIDE
► Binds to qp41 sub-unit of the glycoprotein preventing conformational changes
required for the viral cellular membranes
► Administered subcutaneous; highly protein bund; metabolized by proteolytic
hydrolysis
AE: local reactions
 
ANTI-HEPATITIS
► Lamivudine
ADEFOVIR
► Analogue of adenosine monophosphate phosphorylated by
cellular kinases to active metabolites then competitively
inhibits HBV DNA polymerase and results in chain
termination
IMMUNE GLOBULIN
► Inhibits viral penetration; opsonize viral particles, active complement, stimulate
cell- mediated immunity
► Administered parenterally
► Protection lasts for 2-3 weeks
► Specific immune globulin against CMV, HBV, rabies, RSV, VZV
AE: hypersensitivity reactions; infusion related reactions- flushing, dizziness, BP
changes; aseptic meningitis syndrome; can interfere with response to live virus
vaccines
 

INTERFERON
► Inhibits viral penetrations, uncoating, mRNA synthesis, translation, assembly and release
► Interferon alpha and beta exert the most potent anti-viral effects
Clinical Uses:
► Interferon alpha 2a-chronic hep C
► Interferon alpha 2b- chronic hep B and C
AE: flu-like symptoms; neurotoxicity, Myelosuppression, thyroid dysfunction, hypotension, transient arrhythmias,
alopecia, liver dysfunction
► Pegylated interferon alpha- a linear or branched polyethylene glycol (PEG) miety is attached to interferon
longer half life and slowed clearance; superior efficacy but more expensive
► Peginterferon alpha-2a and Peginterferon alpha-2b-used for chronic hepatitis C
 Acyclovir
Acyclovir Famcyclovir
Famcyclovir Acyclovir
Ganciclovir
Famcyclovir
Ganciclovir
Ganciclovir

► Anti-Viral Actions of Purine and Pyrimidine Analogs

Acyclovir
Famcyclovir
Ganciclovir

Viral
Kinase

Nucelotide
Zidovudine analogues
Idoxiridine
Vidarabine Host
Cytarabine kinase
cell
Inhibition of
viral DNA
polymerase