ANTI-FUNGAL AGENTS

ANTI-VIRAL AGENTS
VIRUSES:
Single or double stranded DNA or RNA enclosed in a
protein CAPSID
Obligate intracellular parasite
Replication depends on synthetic processes of the
host cell
Anti-viral drugs must either block entry or exit from
cell or be active inside the host cell

VIRAL REPLICATION

Anti-influenza Agents
Amantadine Rimantadine
Neuraminidase Inhibitors
Oseltamivir (Tamiflu)
Zanamivir
Ribavirin
Palivizumab
Interferons
ENTRY INHIBITORS
ENFUVIRTIDE
MARAVIROX
INTEGRASE INHIBITORS
RALTEGRAVIR
Miscellaneous
Immuno-modulating Agents
Inosiplex
Isoprinosine
Foscarnet
IMQUIMOD
ANTI-HERPES
ANTI-VARICELLA ZOSTER
ACYCLOVIR
Acyclovir(9-[2-hydroxy methyl]9-H-guanine)
Acyclic guanosine derivative against
HSV1, HSV2, and VZV
Weaker activity against EBV, CMV
and Human Herpes Virus 6 (HHV 6)

Viral attachment and entry (enfuvirtide, maravirox

docosanol, palivizumab)
Adsorption and penetration into susceptible host cells
(Globulins and interferon-alpha)
Un-coating of viral nucleic acid (Amantadine)
Synthesis of early regulatory proteins (Fomivirsen)
Synthesis of RNA or DNA (RT Inhibitors)
Synthesis of late regulatory proteins
(Protease Inhibitors)
Packing and Assembly (maturation) of viral
particles (Rifampicin)
Release from cells (Neuraminidase Inhibitors)

Anti-RETROVIRAL Agents
Nucleoside RT inhibitors
Zidovudine Zalcitabine Didanosine
Stavudine
Lamivudine Abacavir
Emtricitabine
Non-nucleoside RT Inhibitors
Nevirapine Delavirdine Efavirenz
ANTI-VIRAL AGENTS
Anti-Herpes
Acyclovir
Famciclovir
Valacyclovir
Ganciclovir Valganciclovir Lamivudine
Vidarabine Idoxuridine
Trifluridine
Cidofovir
Sorivudine
Fomivirsen
Penciclovir
ANTI-Hepatitis B
Lamivudine
Adenofovir Dipivoxil
Entecavir
Interferon alfa-2b
Famciclovir
Telbivudine
Tenofovir
ANTI-Hepatitis C
Pegylated interferon alfa-2a and 2b
Ribavirin, interferon alfa 2a, 2b, alfacon
Protease Inhibitors
Saquinavir
Lopinavir/Ritonavir
Indinavir
Nelfinavir
Amprenavir
Darunavir
Atazanavir
Tipranavir
Fosamprenavir

MECHANISM OF ACTION
REQUIRES 3 PHOSPHORYLATION STEPS:
Converted to di and triphosphate compounds
by the hosts cellular enzymes
Converted to monophosphate derivative by
virus-specified thymidine kinase
Acyclovir triphosphate inhibits viral DNA
synthesis
Acts as a chain terminator because it lacks 3 hydroxyl group
Competitive inhibition of deoxy-GTP for viral DNA
polymerase

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

PHARMACOKINETICS

Oral bioavailability ranges from 10-30% and

decreases with increasing dose
Clearance thru GF and TS
Half-life: 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

First and recurrent genital herpes:

200 mg 5x daily for 10 days oral
5 mg/kg per 8 hrs IV

THERAPEUTIC USES

Recurrent:
400 mg 2x daily or 200 mg 3x daily
THERAPEUTIC USES

ACUTE HERPES ZOSTER (SHINGLES)

SYSTEMIC ACYCLOVIR PROPHYLAXIS
HSV ENCEPHALITIS ( IV form)
VARICELLA ZOSTER VIRUS INFECTION
CMV PROPHYLAXIS

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SIDE EFFECTS

TOPICAL PREPARATIONS- mucosal irritation and

transient burning to genital lesions
ORAL nausea, diarrhea, rash, headache, renal
insufficiency, and neurotoxicity
IV- renal insufficiency, CNS side effects

VALACYCLOVIR

L- valyl ester of acyclovir

Rapidly converted to acyclovir after oral
administration
Serum levels are 3-5x greater than acylcovir
Treatment of primary and recurrent genital herpes
and herpes zoster infections
Prevents CMV disease in post-transplant patients

SIDE EFFECTS

Oral bioavailability is 54%s

CSF fluid levels are 50%
of those in serum
Elimination half-life: 2.5-3.3 hours
Generally well-tolerated

FAMCICLOVIR

Diacetyl ester prodrug of 6 deoxy penciclovir and

rapidly converted to PENCICLOVIR by FIRSTPASS
metabolism
Penciclovir does not cause chain termination
Oral form is approved for managing HSV and VZV
infections
First episode genital herpes
250 mg TID for 5-10 days
Recurrent genital herpes 250 mg BID for 1 year
Herpes zoster of 3 days 500 mg TID x 10 days It is
as effective as acyclovir in reducing healing time and
zoster associated pain
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 immuno-compromised
patients and in opthalmic zoster
Associated with dose-related reductions in Hepatitis
B Virus DNA and transaminase levels in patients with
chronic HBV hepatitis

Pharmacokinetics
Oral bioavailability: 70%
Intracellular half-life: 10 hours in HSV-1
infected cells
20 hours in HSV-2 infected cells
7 hours in VZV infected cells in vitro.
Excretion: primarily in the urine
PENCICLOVIR

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

Inhibitor of viral DNA synthesis

Initially phosphorylated by viral thymidine kinase
Penciclovir triphosphate has a lower affinity in
competitive inhibition of viral DNA polymerase thus
cannot cause chain termination
100 fold less potent in inhibiting DNA polymerase
than acyclovir but present in higher concentration and
prolonged period in infected cells

THERAPEUTIC USES

Mutagenic at high concentrations

(IV form is not usually given)
No clinically important drug interactions have
identified

TRIFLURIDINE

Pharmacokinetics

Intravenous form- 5 mg/kg per 8-12 hrs for 7 days is

comparable to acyclovir in treatment 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 HS.
(reserved usage)

Fluorinated pyrimidine nucleoside that has an in vitro

inhibitory activity against HSV 1 & 2 , CMV, vaccine
and certain adenoviruses
Inhibits viral DNA synthesis
Phosphorylated intracellularly into its active form by
cellular enzymes
Incorporation into both viral and cellular DNA
prevents its systemic use

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

Primary keratoconjunctivitis and recurrent epithelial

keratitis due to HSV 1 and 2
Topical trifluridine is more active than idoxuridine
and comparable to vidarabine in HSV ocular
infections

ADVERSE EFFECTS

Discomfort upon instillation

Palpebral edema
Hypersensensitivity reaction, irritations and
superficial punctate or epithelial keratopathy

Adenosine analog with an in vitro activity against

HSV, VZV, and CMV
Phosphorylated intracellularly by host enzymes to
form ara-ATP and then inhibits viral DNA
polymerase
Vidarabine triphosphate is incorporated into both
viral and cellular DNA
Rapidly metabolized in vivo to hypoxanthine
arabinoside through removal of 6-amino group by
adenosine deaminase decrease viral activity

VIDARABINE

Therapeutic Usages

3% ointment acute keratoconjunctivitis, superficial

keratitis, recurrent epithelial keratitis (HSV1 and 2)
IV vidarabine HSV encephalitis, neonatal herpes,
VZV infection

DOCOSANOL

Saturated 22-carbon aliphatic alcohol.

Inhibits FUSION between plasma membrane and

HSV envelope resulting in prevention of viral entry
into cells and subsequent viral replication.

Only for orolabial HERPES

ANTI-CMV AGENTS
GANCICLOVIR

(9-[1,3-dihydroxy-2-prepoxymethyl]guanine)

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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

CLINICAL USES

MECHANISM OF ACTION

Monophosphorylated intracellularly by a virusinduced 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

Oral bioavailability is 6-9% following ingestion with

food and less in the fasting state
CSF concentration are approximately 50 % of those
in serum

CLINICAL USES

Delay progression of CMV retinitis in AIDS

CMV colitis & esophagitis
CMV infection in transplant patient
CMV pneumonitis
CMV retinitis
CMV, HSV1, HSV2, EBV & HHV-8

ADVERSE REACTIONS

Myelosuppression
CNS toxicity
Vitreous hemorrhage, retinal detachment
Neutropenia (2nd wk)
CNS (headache, behavioral changes, convulsions,
coma)
Infusion related phlebitis, azotemia, anemia, rash,
fever, liver function test abnormalities

L- valyl ester prodrug of ganciclovir

Hydrolyzed to active compound ganciclovir by
intestinal and hepatic enzymes
Well absorbed (60%) & rapidly metabolized in
intestinal walls & liver to ganciclovir
Renal excretion thru GN and TS
Usage:CMV retinitis in AIDS and for prevention of
CMV in high risk kidney, heart transplant.

CIDOFOVIR

(1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate)
Cytidine nucleoside analog with inhibitory activity
against human herpes, papilloma, polyoma, pox, and
adenoviruses
Phosphorylation to active disphosphate is
independent of viral enzymes
After phosphorylation; it acts as potent inhibitor to
viral DNA polymerase

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

Phosphonoformic Acid Inorganic Pyrophosphate

analog that inhibits viral DNA polymerase, RNA
polymerase and HIV transcriptase directly without
requiring activation by phosphorylation
Taken up slowly by cells and does not undergo
significant intracellular metabolism
Reversibly blocks the pyrophosphate binding site of
the viral polymerase
Inhibits cleavage of pyrophosphate from
deoxynucleotide triphosphates

SIDE EFFECTS
Nephrotoxicity
Symptomatic hypocalcemia
Saline loading may reduce the risk of
nephrotoxicity
Concurrent administration with
pentamidine exacerbates both
nephrotoxicity and hypocalcemia
CLINICAL USES

CMV retinitis, colitis, esophagitis

Acyclovir- resistant HSV infection and VZV
infection
HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV
FOMIVIRSEN
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

ANTIRETROVIRAL AGENTS
NUCLEOSIDE REVERSE TRANSCRIPTASE
INHIBITORS(NRTIs)

Competitive inhibition of HIV 1 reverse

transcriptase and can be incorporated into the
growing viral DNA chain to cause termination
Requires intracytoplasmic activation as a result of
phosphorylation by cellular enzymes to the
triphosphate form
Activity against HIV 1, HIV 2
Lactic acidosis & severe hepatomegaly with steatosis

ZIDOVUDINE
(Azithymidine, AZT)

PHARMACOKINETICS

CMV, HSV 1, HSV 2, VZV, EBV, HHV-6,HHV8,

adenovirus, poxvirus, poliomyxovirus, Human
papilloma virus
CMV retinitis
Polyoma virus associated progressive multifocal
leukoencephalopathy syndrome associated with
AIDS
Topical recurrent genital herpes, anogenital warts

FOSCARNET

VALGANCICLOVIR

IV administration must be administered with

probenecid to block active tubular secretion and
decrease nephrotoxicity

Deoxythymidine analog
Decrease rate of clinical disease progression and
prolong survival of HIV infected individuals
Well absorbed from the gut and distributed
to most body tissues & fluids

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Eliminated by renal excretion following

glucorinadation in the liver
Combination therapy with other anti-retroviral agents
enhance potency and delay resistance

CLINICAL USES
HIV associated dementia &
thrombocytopenia
Reduce rate of vertical transmission (mothernewborn) by 23%
ADVERSE EFFECTS

Myelosuppression most common

Thrombocytopenia, hyperpigmentation of nails,
myopathy, anxiety, confusion and tremulousness
Fatal lactic acidosis & severe hepatomegaly w/
steatosis

DIDANOSINE (ddl)

Synthetic analog of deoxyadenosine

Activity is potentiated by hydroxyurea due to
depletion of intraocular pools of d-ATP
Chewable, dispersable tablet, enteric coated
Contains phenylalanine and Na
Should be taken on an empty stomach
Food, fluroquinolones and tetracycline
should be given 2 hrs before didanosine

ADVERSE EFFECTS

Most major clinical toxocity:

Dose dependent pancreatitis
Painful peripheral distal neuropathy
Diarrhea, hepatitis, esophageal ulceration,
cardiomyopathy
CNS toxicity
Precipitate gouty attacks
Optic neuritis

STAVUDINE (d4T)

LAMIVUDINE (3TC)
Cytosine analog ,synergistic with other antiretroviral
nucleoside Stavudine, Zidovudine
Oral bioavailability exceeds 80% and it is not food
dependent
Elimination in urine is UNCHANGED
Used in combination therapy
NOTE: no combination with zalcitabine-may inhibit
intracellular phosphorylation of one another thus
decreasing potency.
Approved for the treatment of chronic Hepatitis B
infection

ZALCITABINE (ddC)

Thymidine analog
High oral bioavailability, not food dependent
Renal excretion thru GF and TS
Major dose-limiting toxicity:
Dose-related peripheral sensory neuropathy
Pancreatitis, arthralgias, elevation of serum
aminotransferases
Phosphorylation is reduced by zidovudine

ABACAVIR

Guanosine analog
Well absorbed during oral administration
Metabolized by alcohol dehydrogenase and
glucuronosyl-transferase to inactive metabolites
Fatal hypersensitivity reactions
Nausea, vomiting, diarrhea, headache, fatigue
Hyperglycemia, hypertriglyceridemia and lactic
acidosis

NUCLEOTIDE INHIBITOR

EMTRICITABINE
Formerly called FTC
Fluorinated analogue of LAMIVUDINE with a long
intracellular half-life(>39 hrs)
Oral bioavailability: 93%
CSF level is LOW
Mean plasma half-line: 8-9 hours
Renal excretion thru GF and TS
Contraindicated in children, pregnant women, and
patients with renal and hepatic failure (propylene
glycol)
Most common side effects-HA, diarrhea,
hyper-pigmentation in palms and soles
Can not combine with LAMIVUDINE

Cytosine analog with synergistic anti-HIV1 activity

with a variety of antiretrovirals against both
zidovudine sensitive and resistant strains
Associated with dose-dependent peripheral
neuropathy
Oral and esophageal ulcerations
Increase bioavailability in combination with
probenecid or cimetidine
Decrease bioavailability in combination with antacids
and metoclopramide

TENOFOVIR

Acyclic nucleoside phosphonate competitively

inhibits HIV reverse transcriptase and cause chain
termination after incorporation to DNA.
Indicated for use in combination with other
antiretroviral agents

Pharmacokinetics

Oral bioavailability: 25% without food 39-40% after

a high-fat meal
Serum half life: 17 hours and intracellular half-line is
prolonged at more than 60 hours
Renal elimination thru GF and TS

Common Side Effects: GIT complaints

NON-NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS(NNRTIs)

Bind directly to a site on the HIV 1 reverse

transcriptase
Blockade of RNA and DNA dependent DNA
polymerase activities
Binding site is near but distinct from that of the
NRTIs
Neither compete with nucleoside triphosphate nor
require phosphorylation to be active

NEVIRAPINE

Oral bioavailability is > 90%

Not food dependent
Used as a component of a combination antiretroviral
regimen
Effective in the prevention of transmission of HIV
from mother to newborn

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DELAVIRDINE

ENFUVIRTIDE (T-20)

Causes severe life threatening rashes

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

EFAVIRENZ

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 INHIBITORS

Protease--responsible for cleaving precursor

molecules (immature budding particles)
PI---result in the production of immature, noninfectious viral particles
Associated w/ spontaneous bleeding in hemophilia A
&B
Do not undergo process of phosphorylation

SAQUINAVIR

Saquinavir H- hard gel capsule poor bioavailability,

should be taken within 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,
delavirdine, indinavir, ketoconazole, clarithromycin,
& grapefruit juice

ANTI-HEPATITIS AGENTS
LAMIVUDINE

Can be safely administered to patients with

decompensated liver disease associated with chronic
Hepatitis B infection

Phosphorylated by cellular kinases to the active

diphosphate metabolite
Competitively inhibits HBV DNA polymerase
Chain termination after incorporation into viral
replication

ADEFOVIR

ENTECAVIR

An inhibitor of HIV 1 & HIV 2 proteases

High bioavailability that is increased with food
Common adverse effects: GIT disturbances,
paresthesias, increase aminotransferase level, altered
taste, hypertriglyceridemia

INDINAVIR

Specific inhibitor of HIV- 1 & HIV-2 proteases

Higher CSF penetration
Must be consumed in empty stomach for maximal
absorption
Most common adverse effects are indirect
hyperbilirubinemia & nephrolithiasis due to
crystalization

NELFINAVIR

Higher absorption in the fed state

Common adverse effects: diarrhea & flatulence

Rapidly absorbed from the GIT and can be taken with

or without food
High fat meals decrease absorption
Common adverse effects: nausea, vomiting, diarrhea,
peri-oral paresthesias, rash
Steven Johnsons syndrome
Inhibits CYP3A4 activity

AMPRENAVIR

FUSION INHIBITOR

Oral guanosine nucleoside analog

Competitively inhibits all 3 functions of HBV DNA
polymerasebase priming, reverse transcription of
negative strand and synthesis of positive strand of
HBV DNA.
Taken by empty stomach half life 15 hours
Significantly HIGHER rates of HBV DNA viral
suppression than lamivudine.

INTERFERON alpha

RITONAVIR

Newly approved antiretroviral agent

Blocks entry into the cell
A synthetic 36-amino acid peptide binds to the gp41
subunit of the viral envelope glycoprotein thus
preventing the conformational changes required for
the fusion of the viral and cellular membranes
Administered subcutaneously in combination with
other retroviral agents

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 2a
Approved for the treatment of chronic Hepatitis C,
AIDS associated Kaposis sarcoma, hairy cell
leukemia,
chronic myelogenous leukemia

INTERFERON 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-Hodgkins lymphoma, AIDS related kaposis
sarcoma, & chronic Hepatitis C

PEGYLATED INTERFERON ALFA

Recently introduced for treatment of chronic hepatitis

C
Longer duration with slower clearance
RIBAVIRIN
Guanosine analog that is phosphorylated
intracellularly by host cell enzymes
Interferes w/ the synthesis of guanosine triphosphate
Inhibit capping of viral messenger RNA

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Inhibit viral RNA dependent RNA polymerase of

certain viruses
Influenza A, parainfluenza, RSV, paramyxoviruses,
HCV & HIV 1

Amphotericin B 35% +
dimyristolphosphatidylcholine & glycerol

ANTIFUNGAL ACTIVITY

ANTI-INFLUENZA AGENTS
AMANTADINE/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 within 48 hrs of onset
Primary target is M2 proteins

OSELTAMIVIR/Zanamivir

Neuroaminidase inhibitors
Inhibits replication of both influenza A & B
5 day course regimen for both influenza A & B
NOTE: Treatment for Bird Flu
Resistance to H1N1 but not to zanamivir
H3N2 and B---both susceptible

UNCLASSIFIED
PALIVIZUMAB

Prevention of RSV in high risk infantspremature

and those with broncho dysplasia and congenital
heart disease.
Humanized monoclonal antibody

IMQUIMOD

Immune response modifier effective in topical

treatment of external genitalia & perianal warts

ANTI-FUNGAL AGENTS
SYSTEMIC ANTIFUNGAL DRUGS FOR
SYSTEMIC INFECTIONS
AMPHOTERICIN B

Discovered by Gold & co-workers 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
1) Colloidal suspension of amphotericin B
and 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
3)
Unilamellar Vesicle Formulation
Amphotercin B 50 mg + 350 mg of lipid in 10%
molar ratio
4)
Amphotericin B Lipid Complex

Candida species, 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

Poorly absorbed from the GIT

Oral preparation is only effective in fungi within the
lumen of the GIT
Serum t is 15 days
Widely distributed in tissues
2-3% CSF concentration

MECHANISM OF ACTION

Antifungal activity depends on the binding with

ERGOSTEROL
Alters the permeability of the cell by forming
amphotericin B associated pores or channels
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

Candida esophagitis
Meningitis caused by coccidioides
Mucormycoses
Invasive aspergillosis
Extracutaneous sporotrichosis
Cryptococcosis
Candida cystitis
Mycotic corneal ulcers & keratitis

ADVERSE REACTIONS
A) INFUSION-RELATED TOXICITY: Immediate
fever & chills, muscle spasms, vomiting, headache, &
hypotension
B) SLOWER TOXICITY: Delayed
renal damage
o Reversible renal injury
o Irreversible renal injury- renal tubular injury

FLUCYTOSINE (5-FC)

Discovered in 1957
Fluorinated pyrimidine related to fluorouracil &
fluoxuridine
Spectrum of activity is narrower than that of
amphotericin
Given to delay the development of resistant strains
Synergistic to another anti-fungal agent

PHARMACOKINETICS

Available in oral preparation

Well absorbed (>90%) with serum
Concentration peaking 1-2 hrs
Poorly protein bound
Penetrates well body fluids & CSF
T is 3-4 hrs

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

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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

THERAPEUTIC USES

Blastomycosis, histoplasmosis, coccidiodomycosis,

pseudallescheriasis
Paracoccidiodomycosis, ringworm,
tinea versicolor, chronic mucocutaneous candidiasis
Candida vulvovaginitis, oral & esophageal
candidiasis

ADVERSE REACTIONS
CLINICAL USAGES

Cryptococcal meningitis
Candida species
Dematiaceous molds that cause chromoblastomycosis

ADVERSE EFFECTS

Leukopenia & thrombocytopenia

Rash
Nausea/vomiting, diarrhea,
severe enterocolitis

AZOLES
IMIDAZOLES :
Ketoconazole
Miconazole
Clotrimazole
TRIAZOLES:
Itraconazole
Fluconazole
Voriconzaole
MECHANISM OF ACTION

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
Most common-GIT upset
Increased liver enzymes

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

KETOCONAZOLE

Dose-dependent anorexia, nausea, vomiting

Inhibits steroid biosynthesis in patients endocrine
abnormalities

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

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 rifampicin
Most potent among all azoles.
Azole of choice for dimorphic fungi histoplasma,
blastomyces, sporotrix
Used exclusivelydermatophytoses and
onychomycosis
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

FLUCONAZOLE

Fluorinated bistriazole
Good water solubility & CSF penetration
Azole of choice in the treatment & secondary
prophylaxis of cryptococcal meningitis.
Most commonly usedmucocutaneous candidiasis.
Least effect of all azoles on hepatic microsomal
enzymes.
Widest therapeutic index.
Displays no activity against aspergillus or other
filamentous fungi.
Prophylacticreduce fungal disease in bone marrow
transplant recipients and AIDS patientsbut danger
of developing resistant strain.
Available in oral & IV form
plasma concentrations of astemizole, cisapride,
cyclosporine, rifampicin, rifabutin, sulfonylureas,
theophylline & warfarin

VORICONAZOLE

Newest triazole to enter clinical trials

Availabale in oral & IV
Well absorbed orally with bioavailability >90%
Low propensity to inhibit mammalian cytochrome
P450

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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
Azole of choice for invasive aspergillosis.

ECHINOCANDINS
Large cyclic peptides linked to a long-chain fatty
acid.
CASPOFUNGIN, MICAFUNGIN, and
ANIDULAFUNGIN.
Active against candidiasis and aspergilus BUT not
Crytococcus neoformans.
Act at the level of the FUNGAL CELL by inhibiting
the synthesis of B(1-3) glucan resulting in the
disruption of the fungal cell wall and cell death.
ONLY available in IV form.
Extremely well tolerated with minor GIT upset and
flushing.
CASPOFUNGINdisseminated and mucocutaneous
candida infections with febrile neutropenia. ONLY as
a salvage therapy for invasive aspergillosis when
failed with ampothericin and voriconazole.
MICAFUNGINmucocutaneous candidiasis and
prophylaxis of candida infections in bone marrow
transplant patients.
ANIDULAFUNGINesophageal candidiasis and
invasive candidiasis with septicemia.

SYSTEMIC ANTIFUNGAL DRUGS FOR

MUCOCUTANEOUS INFECTIONS
GRISEOFULVIN

Practically insoluble in water

Absorption improves when given with fatty foods.
Fungistatic in vitro for dermatophytes microsporum,
epidermophyton & trichophyton
No effect on bacteria & other fungi

MECHANISM OF ACTION

Production of multinucleated cells as the drug

inhibits fungal mitosis
Causes disruption of the mitotic spindle by
interacting with polymerized microtubules

THERAPEUTIC USES

Mycotic disease of the skin, hair & nails due to

Microsporum, Trichophyton, or Epidermophyton
Tinea capitis (M. canis)
Ringworm of the glabrous skin
Tinea corporis, cruris (T. rubrum,
T. mentagrophytes)
Hyperlkeratosis (T. rubrum)

ADVERSE REACTIONS

Allergic syndrome like serum sickness

Hepatitis
Drug interactions with warfarin and phenobarbital.

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
which is toxic to the organism.
OD X12 wks achieves 90% cure rate for
onychomycosis.
Rare side effectsGIT upset and HA

TERBINAFINE

TOPICAL ANTIFUNGAL AGENTS

Superficial fungal infections confined to the

stratum 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 AGENTS

NYSTATIN

Polyene macrolide
Streptomyces noursei
Structurally similar to Amphotericin B
Toxic for parenteral administration
Available in creams, ointments, suppositories
Oropharyngeal thrush, vaginal candidiasis,
intertriginous candidal infections

AMPHOTERICIN B

Topical form (Fungizone)

Cutaneous & mucocutaneous candidiasis
Lotion, ointment & cream

IMIDAZOLE & TRIAZOLE FOR TOPICAL

USE
CLOTRIMAZOLE

Available as 1% cream, lotion, & solution

1% or 2% vaginal cream or vaginal tablets
Skin applications BID
Vaginal applications 100 mg tab OD at bedtime X 7
days or 200 mg OD X 3 days

Readily penetrates the stratum 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

MICONAZOLE

TOLNAFTATE

Can not treat candida species

Used as topical solution
Used in tinea cruris and other tineasis

Broad spectrum
Fungicidal to C. albicans, E. flocosum, M. canis, T.
mentagrophytes, T. rubrum
Inhibits the growth of Malassezia furfur
Penetrates the dermis

CICLOPIROXAMINE

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

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Cutaneous candidiasis & tinea versicolor

MISCELLANEOUS ANTIFUNGAL AGENTS

UNDECYLENIC ACID

Yellow liquid with a characteristic rancid odor

Fungistatic, fungicidal w/ prolonged use
Foam, ointment, cream, powder, spray powder, soap
& liquid
Ringworm, tinea pedis

BENZOIC ACID & SALICYLIC ACID

Combines fungistatic activity of benzoic acid w/

keratolytic action of salicylic acid
Mainly for the treatment of tinea pedis
Eradication occurs after the infected stratum corneum
is shed
Salicylate accelerates the desquamation

Treatment of dermatomycoses
Low efficacy

Treatment of mucocutaneous sporotrichosis

PROPIONIC ACID & CAPRYLIC ACID

POTASSIUM IODIDE

Whitfields ointment

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