Download ANTIVIRAL/ANTIFUNGAL AGENTS

ANTIVIRAL/ANTIFUNGAL
AGENTS
MA. LENY ALDA G. JUSAYAN, MD
Department of Pharmacology
ANTIVIRAL 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
 Antiviral drugs must either block entry or exit
from cell or be active inside the host cell
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 VZV
ACYCLOVIR
 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:

REQUIRES 3 PHOSPHORYLATION
STEPS:
 Converted to monophosphate derivative by
virus-specified thymidine kinase
 Converted to di and triphosphate
compounds by the host’s cellular enzymes
 Acyclovir triphosphate inhibits viral DNA
synthesis
Cont.
Acts as a chain terminator because it
lacks 3’ hydroxyl group
 Competitive inhibition of deoxyGTP for
viral DNA polymerase
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:





Oral bioavailability ranges from 10-30% and
decreases with increasing dose
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
THERAPEUTIC USES:

First and recurrent genital herpes:
– 200 mg 5x daily for 10 days – oral
– 5 mg/kg per 8 hrs – IV
Recurrent: 400 mg 2x daily or 200 mg 3x
daily
THERAPEUTIC USES:
ACUTE HERPES ZOSTER (SHINGLES)
 SYSTEMIC ACYCLOVIR PROPHYLAXIS
 HSV ENCEPHALITIS
 VARICELLA ZOSTER VIRUS INFECTION
 CMV PROPHYLAXIS

SIDE EFFECTS:
TOPICAL PREPARATIONS- mucosal
irritation & transient burning to genital
lesions
 ORAL – nausea, diarrhea, rash,
headache,renal insufficiency,
neurotoxicity
 IV- renal insufficiency, CNS side effects

PENCICLOVIR
Penciclovir (9-[4-hydroxy-3hydroxymethylbut-1-yl]guanine
 An acyclic guanine nucleoside
 Active metabolite of famciclovir
 Spectrum of activity & potency against
HSV & VZV is similar to acyclovir
 Inhibitory activity to HBV

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:
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:
Mutagenic at high concentrations
 No clinically important drug interactions
have identified

FAMCICLOVIR





Diacetyl ester prodrug of 6 deoxy penciclovir
and lacks intrinsic viral activity
Oral form is approved for managing HSV &
VZV infections
First episode genital herpes – 250 mg TID x
5-10 days
Recurrent genital herpes – 250 mg BID for 1
year
Herpes zoster of 3 days – 500 mg TID x 10
days is as effective as acyclovir in reducing
healing time and zoster asso. pain
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
TRIFLURIDINE

Flourinated pyrimidine nucleoside that has an
in vitro inhibitory activity against HSV 1 & 2 ,
CMV, vaccinia 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 & recurrent
epithelial keratitis due to HSV 1 & 2
 Topical trifluridine is more active than
idoxuridine & comparable to vidarabine
in HSV ocular infections

ADVERSE EFFECTS:
Discomfort upon instillation
 Palpebral edema
 Hypersensensitivity reaction, irritations
& superficial punctate or epithelial
keratopathy

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 & herpes zoster infections
Prevents CMV disease in postransplant
patients
VIDARABINE

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 vial & cellular DNA
 Rapidly metabolized in vivo to hypoxanthine
arabinoside through removal of 6-amino
group by adenosine deaminase – dec. viral
activity
Cont.
3% ointment – acute
keratoconjunctivitis, superficial keratitis,
recurrent epithelial keratitis (HSV1 &2)
 IV vidarabine – HSV
encephalitis,neonatal herpes, VZV
infection

ANTI-CMV AGENTS
GANCICLOVIR
(9-[1,3-dihydroxy-2-prpoxymethyl]guanine)
 Cyclic guanosine analog that requires
triphosphorylation for activation prior to
inhibiting viral DNA polymerase
 Similar structure to acyclovir except in
having additional hydroxymethyl group on
the acyclic side chain

MECHANISM OF ACTION:





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:
Oral bioavailability is 6-9% following
ingestion with food & 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

VALGANCICLCOVIR
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

CIDOFOVIR

(1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate)
 Cytidine 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 to viral DNA polymerase
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
 IV administration must be administered
with probenicid to block active tubular
secretion & decrease nephrotoxicity

CLINICAL USES:

CMV, HSV 1, HSV 2, VZV, EBV, HHV-6, HHV8, adenoviruses, poxvirus, poliomyxoviruses,
HPV
 CMV retinitis
 Polyoma virus associated progressive
multifocal leukoencephalopathy syndrome
associated with AIDS
 Topical – recurrent genital herpes, anogenital
warts
FOSCARNET

Phosphonoformic acidinorganic pyrophosphate
analog that inhibits viral DNA polymerase, RNA
polymerase & HIV 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
 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 &
hypocalcemia
CLINICAL USES:
CMV retinitis, colitis, esophagitis
 Acyclovir- resistant HSV infection &
VZV infection
 HSV, VZV, CMV, EBV, HHV-6, HHV-8,
HIV

FOMIVERSEN
21mer-phosphorothioate oligonucleotide
 First 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

ANTIVIRAL DRUGS – DNA & RNA VIRUSES
DRUG
Acylovir
MECHANISM/
VIRAL
SELECTIVITY
Metabolized by
thymidine kinase
to triphosphate
Pencyclovir
CLINICAL
USE
Herpes
simplex 1 &
2, varicella
zoster
VIRAL
RESISTANCE
Produce
abnormal
thymidine kinase
UNDESIRABLE
SIDE EFFECTS
Skin irritation,
burning,
crystalline
nephropathy
L-valyl ester of
acyclovir
converted to
acyclovir
Herpes zoster
(shingles)
Idoxuridine
Phosphorylated
metabolite
incorporates into
DNA causing
strand breaks
Herpes
simplex
keratitis. No
effect on RNA
viruses
Famciclovir
Phosphorylated
by viral thymidine
kinase to
penciclovir
triiphosphate
Shortens
duration of
herpes zoster
& genital
herpes
Ganciclovir
Metabolized by
thymidine kinase
to triphosphate .
Preferentially
phosphorylated to
active drug in
CMV infected cells
CMV retinitis
& severe
systemic CMV
infections
NOTES
IV/PO. Administer
slowly. CNS
level=50% serum
level. Decrease dose
w/ kidney dysfunction
Topical
Oral HSV
(coldsores)
Valacyclovir
PHARMACOKINETI
CS
Resistance
develops
Some resistant
strains lack
thymidine
kinase. Cannot
activate drug.
Nausea, headache
PO. Slightly better oral
absorption than
acyclovir
No clear
advantage
over
acyclovir
Photophobia,
irritation of
conjunctiva &
eyelid
Eyedrops
Drug is a
halogenated
derivative of
deoxyuridine
Minimal toxicity.
Headache
PO. Decrease dose
with renal dysfunction.
Granulocytopenia,
thrombocytopenia
IV/PO. Excreted
unchanged in urine.
Decrease dose with
renal dysfunction.
Do not
coadminister
zidovudine
(granulocyto
penia) or
imipenemcilastatin
(seizures)
Cidofovir
Metabolized to
diphosphate
form. Otherwise
like ganciclovir.
CMV retinitis
Foscarnet
Analog of
pyrophosphate.
Competes for
pyrophosphate
site in viral but
not human, DNA
polymerase &
reverse
transcriptase
CMV retinitis
Amantadine
Prevents virus
from entering
susceptible cells
Rimantadine
Ribavirin
Nephrotoxicity
may be reduced
by hydration &
coadministration
of Probenicid.
Neutropenia.
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.
Treatment &
prophylaxis
of influenza A
Depression, CNS
toxicity, CHF,
orthostatic
hypotension,
urinary retention
PO. Excreted
unmetabolized.
Analog of
amantadine ,
inhibits viral
uncoating
Prophylaxis in
children
Fewer CNS side
effects, risk of
seizure
PO. Prolonged
elimination w/
renal or hepatic
dysfunction
Unknown
mechanism
RSV
Decreased
pulmonary
function.
Aerosol
administration.
Absorbed
systemically.
Deposited in bone
& teeth. Hydrate
patient during
therapy to protect
the kidney
May precipitate in
ventilator tubing.
ANTIRETROVIRAL
AGENTS
NUCLEOSIDE REVERSE
TRANSCRIPTASE
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
Lactic acidosis & severe hepatomegaly with
steatosis
ZIDOVUDINE
(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:
HIV – associated dementia &
thrombocytopenia
 Reduce rate of vertical transmission
(mother-newborn) by 23%

ADVERSE EFFECTS:
Myelosuppression – most common
 Thrombocytopenia, hyperpigmentation
of nails, myopathy, anxiety, confusion &
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 dATP
Chewable, dispersable tablet, enteric coated
Contains phenylalanine & Na
Should be taken on an empty stomach
Food, fluroquinolones & tetracycline should be
given 2 hrs before didanosine
ADVERSE EFFECTS:
Dose –dependent pancreatitis
 Painful peripheral distal neuropathy
 Diarrhea, hepatitis, esophageal
ulceration, cardiomyopathy
 CNS toxicity
 Precipitate gouty attacks
 Optic neuritis

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

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)
Thymidine analog
 High oral bioavailability, not food dependent
 Dose-related peripheral sensory neuropathy
 Pancreatitis, arthralgias, elevation of serum
aminotransferases
 Phosphorylation is reduced by stavudine

ABACAVIR






Guanosine analog
Well absorbed during oral administration
Metabolized by alcohol dehydrogenase&
glucuronosyltransferase to inactive metabolites
Fatal hypersensitivity reactions
Nausea, vomiting, diarrhea, headache, fatigue
Hyperglycemia, hypertriglyceridemia & lactic
acidosis
NUCLEOTIDE INHIBITOR
TENOFOVIR
Competitively inhibits HIV reverse
transcriptase & cause chain termination
after incorporation to DNA
 Indicated for use in combination with
other antiretroviaral agents

NON-NUCLEOSIDE REVERSE
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

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
 Causes severe life threatening rashes

DELAVIRDENE

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
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

SAQUINAVIR
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

RITONAVIR
An inhibitor of HIV 1 & HIV 2 proteases
 High bioavailability that is increased
with food
 Common adverse effects: GIT
disturbances, paresthesias, inc
aminotransferase level, altered taste,
hypertriglyceridemia

INDINAVIR
Specific inhibitor of the 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

AMPRENAVIR
Rapidly absorbed from the GIT & can
be taken w/ or w/o food
 High fat meals decrease absorption
 Common adverse effects: nausea,
vomiting, diarrhea, perioral
paresthesias, rash
 Steven johnson’s syndrome
 Inhibits CYP3A4 activity

FUSION INHIBITORS
ENFUVIRTIDE (T-20)
Newly approved antiretroviral agent
 Blocks entry into the cell
 Administered subcutaneously in
combination with other retroviral agents

ANTI-HEPATITIS AGENTS
LAMIVUDINE

Can be safely administered to patients
with decompensated liver disease
ADEFOVIR
Phosphorylated by cellular kinases to
the active diphosphate metabolite
 Competitively inhibits HBV DNA
polymerase
 Chain termination after incorporation
into viral replication

INTERFERON 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 2a

Approved for the treatment of chronic
hepatitis C, AIDS associated Kaposi’s
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-Hodgkin’s lymphoma, AIDS
related kaposi’s sarcoma, & chronic hepatitis C
PEGYLATED INTERFERON
ALFA
Recently introduced for treatment of
chronic hepatitis C
 Longer termina t ½ with slower
clearance

Interferon-
Interferon-β
Interferon-
Chronic hepatitis RelapsingChronic
B&C
remitting multiple granulomatous
sclerosis
disease
Genital warts
caused by
papilloma virus
Hairy- cell
leukemia
Kaposi’s sarcoma
RIBAVIRIN





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 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 w/n 48 hrs of
onset
Primary target is M2 proteins
ZANAMIVIR/OSELTAMIVIR
Neuroaminidase inhibitors
 Inhibits replication of both influenza A & B
 5 day course regimen for both influenza A &
B

UNCLASSIFIED
PALIVIZUMAB

Prevention of RSV in high risk infants
IMQUIMOD
•Immune response modifier effective in
topical treatment of external genitalia &
perianal warts
ANTIVIRAL DRUGS - RETROVIRUSES
DRUG
MECHANISM &
VIRAL SELECTIVITY
CLINICAL
USE
VIRAL
RESISTANCE
Zidovudine
(AZT)
Thymidine analog is
incorporated into DNA
of hyman
immunodeficiency
viirus causing
termination of the viral
DNA chain
HIV.
Prevention
of
maternalfetal
transmissio
n of HIV
Mutations in
reverse
transcriptase
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
Stavudine
Metabolized to
stavudine triphosphate
w/c inhibits HIV
reverse transcriptase &
DNA polymerase.
HIV
PHARMACO
KINETICS
NOTES
Headaches,
nausea, myalgias,
anemia,
neutropenia,
macrocytosis
PO. Well
absorbed,
rapidly
metabolized
by liver
Acetamino
phen
increases
risk of
hematolog
ic toxicity
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
Peripheral
neuropathy
PO
Not
indicated
for initial
monothera
py of HIV
UNDESIRABLE
SIDE EFFECTS
Ritonavir
Indinavir
Saquinavir
Nelfinavir
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
interaction
s due to
P450
competitio
n
Nevirapine
Delavirdene
Nob-nucleoside
inhibitor of HIV reverse
transcriptase
HIV. Never
as
monothera
py due to
rapid
developme
nt of
resistance
Rapid
resistance
develops
due to
mutations in
reverse
transcriptas
e
Severe skin
rash, fever,
nausea,
headache
PO. Well
absorbed.
Nevirapine
crosses
placenta &
has better
CNS
penetration
than
Delavirdene
Delavirde
ne failed
to show
clinical
efficacy
when
added to
didanosin
e in
clinical
trial
ANTIFUNGAL AGENTS
SYSTEMIC ANTIFUNGAL
DRUGS FOR SYSTEMIC
INFECTION
AMPHOTERICN B





Discovered by Gold & coworkers in 1956
Produced by Streptomyces nodosus
Heptane macrolide w/ 7 conjugated double
bonds in the trans position & 3-amino-3,6dideoxymannose connected to the main ring
by a glycoside bond
Amphotericin polyene macrolide
Nearly insoluble in water
PREPARATIONS:
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
1)
CONT.
3) Unilamellar Vessicle Formulation
 Amphotercin B 50 mg + 350 mg of lipid
in 10% molar ratio
4) Amphotericin B Lipid Complex
• Amphotericin B 35% +
dimyristolphosphatidylcholine & glycerol
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:





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:

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:








Candida esophagitis
Meningitis caused by coccidioides
Mucormycoses
Invasive aspergillosis
Extracutaneous sporothrichosis
Cryptococcosis
Candida cystitis
Mycotic corneal ulcers & keratitis
ADVERSE REACTIONS:
INFUSION-RELATED TOXICITY:
 fever & chills, muscle spasms, vomiting,
headache, & hypotension
B) SLOWER TOXICITY:
 renal damage
o Reversible renal injury
o Irreversible renal injury- renal tubular injury
A)
FLUCYTOSINE (5-FC)

Discovered in 1957
 Fluorinated pyrimidine related to florouracil &
floxuridine
 Spectrum of activity is narrower than that of
amphotericin
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:
Taken up by fungal cells via CYTOSINE
PERMEASE
 Converted intracellularly to 5 FU 5fluorodeoxyuridine monophosphate & 5fluorouridine triphosphate inhibit RNA
& DNA synthesis

Cytosine permease
5-Flucytosine
5-FU
UMP pyrophosphate
5-FUMP
5-FUDP
Ribonucleide
reductase
5-F-dUMP
5-FUTP
RNA
Thymidine synthase
DUMP
dTMP
CLINICAL USE:
Cryptococcal meningitis
 Candida species
 Dermatiaceous 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 α-demethylase
Impair the biosynthsesis of ergosterol for the
cytoplasmic membraneaccumulation of 14-αmethylsterols
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:
Candida species
 Cryptococcus neoformans
 Endemic mycoses

DRUG INTERACTIONS:
All azole drugs affect mammalian cytochrome
P450 systems of enzymes
KETOCONAZOLE


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.
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:
Dose-dependent anorexia, nausea,
vomiting
 Inhibits steroid biosynthesis in patients
endocrine abnormalities

DRUG INTERACTIONS:
Increases cyclosporine levels
 Enhances arrythmogenic effects of
cissapride
 H2 antagonists increases gastric pH,
interfer with the absorption of
ketoconazole
 Rifamycins 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
rifamycins
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

FLUCONAZOLE





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
VORICONAZOLE







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
SYSTEMIC ANTIFUNGAL
DRUGS FOR
MUCOCUTANEOUS
INFECTIONS
GRISEOFULVIN
Practically insoluble in water
 Fungistatic in vitro for dermatophytes
microsporum, epidermophytom &
trichophyton
 No effect on bacteria & other fungi

MECHANISM OF ACTION:

Production of multinucleate cells as`the drug
inhibits fungal mitosis
 Causes disruption of the mitotic spindle by
interacting with polymerized microtubules
 Deposited in the newly forming skin where it
binds to keratin
 Administered 2-6 wks for skin & hair
infections
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
 hepatitis

TERBINAFINE







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
OD X12 wks achieves 90% cure rate for
onychomycosis
TOPICAL ANTIFUNGAL
AGENTS

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
AGENTS
NYSTATIN
Polyene macrolide
 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

MICONAZOLE






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
CICLOPIROXAMINE
Broad spectrum
 Fungicidal to C. albicans, E. flocosum,
M. canis, T. mentagrophytes, T. rubrum
 Inhibits the growth of Malassezia furfur
 Penetrates the dermis

HALOPROGIN







Halogenated phenolic ether
Fungicidal to various species of
Epidermophyton, Pityrosporum,
Microsporum, Trichophyton & Candida
Poorly absorbed through the skin
Converted to thrichlorophenol in the body
Cream or solution BID X 2-4 wks
Principal use for tinea pedis
Tinea cruris, tinea versicolor, tinea corporis
NAFTIFENE
Inhibit squalene-2,3- epoxidase
 Inhibits biosynthesis of ergosterol
 Fungicidal activity
 1% cream or gel
 Topical treatment of tinea cruris & tinea
corporis
 Cutaneous candidiasis & tinea
versicolor

ANTIFUNGAL DRUGS
DRUG
Amphotericin B
ACTION
Disrupts plasma
membrane of
fungal cells,
greater affinity
for ergosterol
Nystatin
CLINICAL USE
UNDESIRABLE
EFFECTS
PHARMACOKINETICS
NOTES
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
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.
Itraconazole
Clotrimazole
Aspergillosis,
histoplasmosis,
coccidiomycosis,
sporotrichosis,
paracoccidiomyc
osis, tinea or
candidal
infections
unknown
Miconazole
Nausea, edema,
hepatitis. No
gynecomastia or
breast pain. Risk of
fatal cardiac
arrhythmias w/
terfenadine
No effect on
testosterone
synthesis
topical
DOC: candida
dermatophyte
infections of the
skin
Vaginal
candidiasis,
severe systemic
fungal infections
PO. Requires acidic
environment for
absorption
Phlebitis, pruritus,
nausea, fever, rash,
vomiting
Vaginal
suppositories/
topical/IV
Leucopenia, nausea,
diarrhea, Inc LFTs,
bone marrow
depression
Easily penetrates
CNS. Renal
excretion
Fungal
resistance
develops
Flucytosine
Deaminated to 5FU by the fungus.
Incorporated into
RNA. Metabolized
to 5-FdURD w/c
inhibits thymidilate
synthetase
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
ANTIFUNGAL AGENTS
UNDECYCLENIC 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
Whitfield’s ointment
 Combines fungistatic activity of benzoic
acid w/ keratolytic action of salicylic acid
 Mainly for the treatment of tinea pedis
 Eradication occurs after the infectd
stratum corneum is shed
 Salicylate accelerates the
desquamation

PROPIONIC ACID & CAPRYLIC
ACID
Treatment of dermatomycoses
 Low efficacy

POTASSIUM IODIDE

Treatment of mucocutaneous
sporotrichosis
POST-TEST
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Acyclovir
Amantadine
Zidovudine
Ganciclovir
Adefovir
A. Antiretroviral agent
B. Anti-Herpes/VZV
C. Anti-CMV
D. Anti-Influenza
E. Anti-Hepatitis
Amphotericin B
Griseofulvin
Haloprogin
Ketoconazole
nystatin
A. systemic infection
B. mucocutaneous infection
C. topical