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ANTI-VIRAL

and
ANTI-FUNGAL
AGENTS
Viruses, what are they?

Viruses do not fit the pattern for a living


organism
Viruses are all parasites of the living
They cannot make anything on their own, they
use the cells materials to build themselves
Rogue DNA segment
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
General Principles of Viruses
Viruses are intracellular parasites, i.e. they
utilize:
Host metabolic enzymes
Host ribosome for protein synthesis
Structure of viruses
Nucleic acid core: DNA or RNA (never both)
Often contain crucial virus-specific enzymes
Surrounded by protein: capsid and sometimes an
outer lipid envelope
Complete viral particle: virion
Often visible by electron microscopy
Viral Replication
VIRAL REPLICATION
Viral attachment and entry (enfuvirtide, maravirox
docosanol, palivizumab)
Adsorption and penetration into susceptible host
cells (Globulins and interferon-)
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)
ALL ANTIVIRAL DRUGS ARE
VIRUSTATIC
Active only against replicating viruses
Do not affect latent virus
ANTI-VIRAL AGENTS
Agents To Treat HSV & VZV Infections
Acyclovir, Valacyclovir,
Famciclovir,Penciclovir
Docosanol, Trifluridine (Triflourothymidine)

Agents To Treat CMV Infections


Ganciclovir, Vanganciclovir, Cidofovir
Foscarnet (Phosphonoformic Acid), Maribavir
ANTI-VIRAL AGENTS
Antiretroviral Agents
NRTIs
Abacavir, Didanosine, Emtricitabine, Lamivudine
Stavudine, Tenofovir, Zalcitabine, Zidovudin,
Elucitabine
NNRTIs
Delavirdine, Efavirenz, Etravirine, Nevirapine
TMC-278, IDX899
Protease Iinhibitors
Atazanavir, Darunavir, Fosamprenavir, Indinavir
Lopinavir, Nelfinavir, Ritonavir, Saquinavir,
Tipranavir
Bracanavir
Antiretroviral Agents
Fusion Inhibitors
Enfuvirtide
CCR5 Receptor Antagonist
Maraviroc , Vicriviroc, PRO 140
ANTI-VIRAL AGENTS
Integrase Inhibitors
Raltegravir, Elvitegravir
Maturation Inhibitors
Bevirimat
CD4 Receptor Inhibitor
TNX-355
ANTI-VIRAL AGENTS
Antihepatitis Agents
Interferon alfa
Treatment of Hepatitis B Virus Infection
Adefovir dipivoxil, Entecavir, Lamivudin,
Telbivudine, Tenofovir

Nucleoside analog: Emtricitabine, Clevudine,


Valtorcitabine, Pradefovir, Alamfovir

Immunologic modulator: Thymosin alpha-1


ANTI-VIRAL AGENTS
Antihepatitis Agents
Treatment of Hepatitis C Infection
Ribavirin
Inhibitors of HCV RNA polymerase: Valopicitabine
Protease inhibitor: Telaprevir
Ribavirin analogs: Merimepodib
Anti-aminophospholipid antibody: Viramidine
Caspase inhibitor
Immunomodulator: Thymosin alpha-1
ANTI-VIRAL AGENTS
Anti-influenza Agents
Amantadine & Rimantadine
Osseltamivir & Zanamivir

Other Antiviral Agents


Interferons
Ribavirin
Palivizumab
Imiquimod
ANTI-HERPES
ANTI-VARICELLA ZOSTER
Agents To Treat HSV & VZV
Infection
Acyclovir
Valacyclovir
Famciclovir
Penciclovir
Docosanol
Trifluridine
(Triflourothymidine)
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)
Mechanism of action of Antiherpes
Agents
ACYCLOVIR:
Requires 3
PHOSPHORYLATION STEPS:
Converted to
monophosphate
derivative by virus-
specified thymidine
kinase

Converted to di and
triphosphate compounds
by the hosts cellular
enzymes
Mechanism of action of Antiherpes
Agents
Acyclovir triphosphate
inhibits viral DNA
synthesis by 2
mechanisms
Competitive inhibition
of deoxy-GTP for viral
DNA polymerase
binding to the DNA
template as an
irreversible complex

Acts as a chain
terminator because it
lacks 3 hydroxyl group
RESISTANCE
HSV: absence of partial production of viral
thymidine kinase, altered thymidine kinase
substrate specificity, and altered viral DNA
polymerase
VZV: mutation in VZV thymidine kinase and
mutations in viral DNA polymerase
Immunocompromised hosts
foscarnet, cidofovir, and trifluridine
(acyclovir resistant strain) cross resistance
occurs due to deficient thymidine kinase
activity
PHARMACOKINETICS
Oral bioavailability ranges from 15-20%
and decreases with increasing dose
Unaffected by food
IV & topical formulations
Clearance thru GF and TS
Half-life: 2.5-3 hrs in normal renal function
and 20 hrs in anuria
Distributes widely in body fluids
including vesicular fluid, aqueous
humor, and CSF
Concentrated in breast milk, amniotic
fluid, and placenta
Percutaneous absorption is low
Good corneal penetration
THERAPEUTIC USAGE
First and recurrent genital
herpes:
200 mg 5x daily for 10 days oral
5 mg/kg per 8 hrs IV

Recurrent:
400 mg 2x daily or 200 mg 3x daily
Shortens the duration of symptoms by
2 days, healing time by 4 days & viral
shedding duration by 7 days in 1st
episode of genital herpes
Recurrent: shortened by 1-2 days
Long-tem suppression w/ oral acyclovir for
recurrences decreases frequency of
symptomatic recurrences & asymptomatic
viral shedding dec. rate of sexual
transmission
Outbreaks may resume when discontinued
THERAPEUTIC USAGES
ACUTE HERPES ZOSTER (SHINGLES)
SYSTEMIC ACYCLOVIR PROPHYLAXIS
Patients undergoing organ transplantation
(oral or IV) to prevent reactivation of HSV
HSV-2 + HIV-1
HSV ENCEPHALITIS ( IV form)
VARICELLA ZOSTER VIRUS INFECTION
CMV PROPHYLAXIS
Recurrent Herpes labialis: oral acyclovir
only modestly beneficial
Significantly decreases total # lesions,
duration of symptoms & viral shedding in
varicella (if begun w/in 24hrs after onset of
rashes) or cutaneous zoster (if begun w/in
72hrs)
BUT higher doses required (less susceptible
to VZV than HSV)
Varicella (>2y/o): 800mg QID x 5 days
VZV: 800mg 5x/day x 7-10days
IV acyclovir
Treatment of choice for HSV encephalitis,
neonatal HSV & serious HSV or VZV
infections
Topical acyclovir cream
Less effective for 1 HSV infection
No benefit for recurrent genital herpes
SIDE EFFECTS

TOPICAL PREPARATIONS- mucosal


irritation and transient burning to genital
lesions
ORAL nausea, diarrhea, rash, headache,
renal insufficiency, and neurotoxicity
IV- renal insufficiency (reversible),CNS side
effects
Acyclovir: ADRs
Oral: Nausea, diarrhea, and headache
IV: Rashes, sweating and emesis and fall in
BP
Reversible renal dysfunction due to
crystalline nephropathy
Neurologic toxicity (eg, tremors, delirium,
seizures)
No Teratogenicity
10 years therapy
VALACYCLOVIR
L- valyl ester of acyclovir
Rapidly converted to acyclovir after oral
administration
Serum levels are 3-5x greater than
acyclovir
Treatment of 1 and recurrent genital
herpes and herpes zoster infections
Prevents CMV disease in post-transplant
patients
Oral Valaciclovir
1st episode genital herpes:
1000 mg bid 10 days
Recurrent genital herpes:
500 mg bid 3 days
Genital herpes in the HIV-infected host
5001000 mg bid 510 days
Genital herpes suppression
5001000 mg once daily
Dec. risk of sexual transmission
Genital herpes suppression in the HIV-
infected host
500 mg bid
Orolabial herpes
2000 mg bid 1 day
Varicella (age 12 years)
20 mg/d tid 5 days (maximum, 1 g tid)
Zoster 1 g tid 7 days
Pharmacokinetics

Oral bioavailability is 54%


CSF fluid levels are 50%
of those in serum
Elimination half-life: 2.5-3.3 hours
Generally well-tolerated
ADRs
Nausea, headache, vomiting, rash: rare
High doses: confusion, hallucinations,
seizures
AIDS patients: GIT intolerance, TTP, HUS
Transplant patients
FAMCICLOVIR
Diacetyl ester prodrug of 6 deoxy penciclovir and
rapidly converted to PENCICLOVIR by FIRST-PASS
metabolism
MOA:
Activation by phosphorylation catalyzed by virus-specified
thymidine kinase in infected cells
Competitive inhibition of viral DNA polymerase to block
DNA synthesis
Penciclovir does not cause chain termination
Oral form is approved for managing HSV and
VZV, EBV & HBV 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
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 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
ADRs
Generally well-tolerated
h/a, nausea, diarrhea may occur
Testicular toxicity w/ rptd doses
Mammary adenoCA
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 can not 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
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)
SIDE EFFECTS

Mutagenic at high concentrations


(IV form is not usually given)
No clinically important drug
interactions have identified
TRIFLURIDINE
Fluorinated pyrimidine nucleoside that
has an in vitro inhibitory activity against
HSV 1 & 2 , CMV, vaccinia 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
Cutaneous application alone or in
combination w/ interferon alpha for Rx
of acyclovir-resistant HSV infections
ADVERSE EFFECTS
Discomfort upon instillation
Palpebral edema
Hypersensensitivity reaction, irritations
and superficial punctate or epithelial
keratopathy
VIDARABINE
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
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
10% topical cream 5x/day
INVESTIGATION AGENTS
Valomaciclovir
Inhibits DNA polymerase
For acute VZV (shingles) & acute EBV
infections (infectious mononucleosis)
Agents To Treat CMV Infections

Drugs:
Ganciclovir
Valganciclovir
Foscarnet
Cidofovir
Maribavir
GANCICLOVIR

(9-[1,3-dihydroxy-2-prepoxymethyl]guanine)
Cyclic guanosine analog that requires
triphosphorylation for activation prior to
inhibiting viral DNA polymerase
Similar structure to acyclovir except in
having additional hydroxymethyl group on
the acyclic side chain
Mechanism of Action - Ganciclovir
Initial phosphorylation is
catalyzed by virus-
specified protein kinase
phosphotransferase UL97
in CMV-infected cells

requires
triphosphorylation for
activation prior to
inhibiting viral DNA
polymerase termination
of viral DNA elongation
MECHANISM OF ACTION
Monophosphorylated intracellularly by a virus-
induced enzyme
Phosphorylation is catalyzed by a viral thymidine
kinase during HSV, phosphotransferase UL97
encoded gene during CMV infection
Ganciclovir di & triphosphate formed by cellular
enzymes
Triphosphate is a competitive inhibitor of
deoxyguanosine triphosphate incorporation into
DNA inhibiting viral rather than cellular DNA
polymerase
Viral DNA incorporation causes cessation of DNA
chain elongation
PHARMACOKINETICS
IV, oral, intraocular implant
Poor oral bioavailability (6-
9%) following ingestion with
food and less in the fasting
state
CSF concentration are
approximately 50 % of
those in serum
Elimination half-life: 4 hrs
CLINICAL USES

Delay progression of CMV retinitis in AIDS


IV form
CMV colitis & esophagitis - IV
CMV infection in transplant patient
CMV pneumonitis in combination w/
CMV Ig)
CMV retinitis
CMV, HSV1, HSV2, EBV & HHV-8
Ganciclovir Resistance
Increases with duration of usage
The more common mutation, UL97, results in
decreased levels of triphosphorylated (active)
form of ganciclovir
The less common UL54 mutation in DNA
polymerase results in higher levels of
resistance
Potential cross-resistance with cidofovir and
foscarnet
Addition of CMV hyperimmune globulin
ADVERSE REACTIONS
Myelosuppression
most common esp after IV administration
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
VALGANCICLOVIR
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 GF and TS

Usage: CMV retinitis in AIDS and for prevention


of CMV in high risk kidney, heart & kidney-
pancreas transplant.
CIDOFOVIR
(1-[(S)-3-hydroxy-2-(phosphonomethoxy)-
propyl]cytosine dihydrate)
Cytosine nucleoside analog with inhibitory
activity against CMV, HSV, VZV, EBV, HHV-
6, HHV-8, HPV, polyoma, pox, and
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 Probenecid to
block active tubular secretion
and decrease nephrotoxicity
CLINICAL USES
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

(Phosphonoformic Acid )
Mechanism of Action - Foscarnet
an inorganic Pyrophosphate
analog
(-) viral DNA & RNA polymerase
and HIV reverse transcriptase
directly without requiring
activation by phosphorylation

Reversibly blocks the


pyrophosphate binding site of the
viral polymerase

Inhibits cleavage of
pyrophosphate from
deoxynucleotide triphosphates
IV form only
Via infusion pump to avoid toxicity
Poor oral bioavailability & GIT intolerance
CSF concentrations: 43-67%
Mean plasma half-life: 3-7%
30% may be deposited in bone (half-life
several months)
Renal clearance
Titrate dose per patients creatinine clearance
SIDE EFFECTS
Nephrotoxicity
Symptomatic hypocalcemia
Saline loading may reduce the risk
of nephrotoxicity
Concurrent administration with
pentamidine exacerbates both
nephrotoxicity and hypocalcemia
Genital ulcerations, CNS toxicity
CLINICAL USES
CMV retinitis, colitis, esophagitis
Acyclovir- resistant HSV infection and VZV
infection
HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV
Gancyclovir + Foscarnet: superior in
delaying progression of CMV retinitis
Dec. incidence of Kaposis sarcoma w/ long
term use
Foscarnet
Resistance
In HSV and CMV
due to point mutations in the DNA polymerase
gene

Typically associated with prolonged or repeated


exposure to the drug

Mutations in the HIV-1 transcriptase gene


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
ANTI-RETROVIRAL
AGENTS
Combination therapy w/ maximally potent
agents
To reduce viral replication to the lowest
possible level
Decrease likelihood of emergence of
resistance
At least 3 antiretroviral agents
Important factors in selection of
agents:
Potency
Susceptibility
Tolerability
Convenience
Optimization of adherence
Anti-RETROVIRAL Agents
Nucleoside RT inhibitors
Zidovudine Zalcitabine Didanosine
Stavudine Lamivudine Abacavir
Emtricitabine

Non-nucleoside RT Inhibitors
Nevirapine Delavirdine Efavirenz
Anti-RETROVIRAL Agents
Nucleoside RT inhibitors
Zidovudine Zalcitabine Didanosine
Stavudine Lamivudine Abacavir
Emtricitabine
Mechanisms of Action - NRTIs
Act by competitive inhibition of
HIV-1 reverse transcriptase;
incorporation into the growing
viral DNA chain premature
chain termination (inhibition of
binding with the incoming
nucleotide)

Requires intracytoplasmic
activation as a result of
phosphorylation by cellular
enzymes to the triphosphate
form
Antiretroviral Agents - NRTIs

Most have activity against HIV-2 as well as HIV-1

Associated with mitochondrial toxicity

Lactic acidosis and hepatic steatosis may occur


fatal

D/C treatment: rapidly rising aminotransferase


levels, progressive hepatomegaly, or metabolic
acidosis
Guanosine analog
Well absorbed during oral
administration; unaffected by food
Metabolized by alcohol
dehydrogenase and glucuronosyl-
transferase to inactive metabolites
Fatal hypersensitivity reactions
w/in 6 wks of therapy
Nausea, vomiting, diarrhea,
headache, fatigue, abdominal pain
Hyperglycemia,
hypertriglyceridemia and lactic
acidosis
Co-administered w/ lamiduvine
Once-daily fixed-dose combination
Other ADRs
Respiratory symptoms
Rash
Used cautiously w/ existing cardiac risk
factors inc. risk of MI
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 toxicity:
Dosedependent pancreatitis
Painful peripheral distal
neuropathy
Diarrhea, hepatitis, esophageal
ulceration, cardiomyopathy
CNS toxicity
Precipitate gouty attacks
Optic neuritis
EMTRICITABINE
Formerly called FTC
Fluorinated analogue of LAMIVUDINE with a long
intracellular half-life(>39 hours)
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) & metronidazole or disulfiram
Co-infection w/ HIV & HBV shd be closely
monitored if treatment w/ emcitaribine is
interrupted or d/c risk of hepatitis flare
Most common side effects-HA, diarrhea,
hyper-pigmentation in palms and soles
Can not combine with LAMIVUDINE
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: do not combine with
zalcitabinemay inhibit intracellular
phosphorylation of one another thus
decreasing potency.
Approved for the treatment of chronic
Hepatitis B infection
STAVUDINE (d4T)
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
Inc. likelihood of developing lactic
acidosis, hepatic steatosis, lipodystrophy
Shd not use together zidovudine +
stavudine
TENOFOVIR
A cyclic nucleoside phosphonate analog of
adenosine
Competitively (-) HIV reverse transcriptase
Causes chain termination after
incorporation into DNA
Also approved for treatment of HBV
Tenofovir disoproxil fumarate: H20 soluble
prodrug of tenofovir
Co-administered w/ emcitaribine
OD, fixed-dose combination
Effective to preexposure prophylaxis
Reduces HIV acquisition in men who have
sex w/ men
Use of 1% tenofovir gel as vaginal
microbicide dec. incidence of
heterosexual HIV acquisition
ADRs
GI complaints most common
Diarrhea, n/v, flatulence
Rarely requires d/c of therapy
Lactose intolerance
Headache, asthenia
Proximal renal tubulopathy
Renal P04 & calcium losses, dec. Vit D3,
osteomalacia
Monitor bone density w/ long tem use & in children
Used w/ caution in patients at risk for renal
dysfunction
May develop ARF & Fanconis syndrome
Dec. fetal growth & reduction in fetal bone
porosity (monkeys)
ZALCITABINE (ddC)
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
ZIDOVUDINE
(Azidothymidine, AZT)
Deoxythymidine analog
1st antiretroviral agent approved
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
Eliminated by renal excretion following
glucoronidation 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
(mother-newborn) by 23%
ADVERSE EFFECTS
Myelosuppression most
common
Thrombocytopenia,
hyperpigmentation of nails,
myopathy, anxiety, confusion
and tremulousness
Fatal lactic acidosis & severe
hepatomegaly w/ steatosis
Non-nucleoside
RT Inhibitors
Nevirapine
Delavirdine
Efavirenz
Etavirine
NON-NUCLEOSIDE REVERSE
TRANSCRIPTASE
INHIBITORS(NNRTIs)
Bind directly to a site on the HIV 1 reverse
transcriptase
Block 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
Antiretroviral Agents - NNRTIs

Lack activity against HIV-2

Side effects:
GI tolerance
Skin rash Steven-Johnson syndrome

Metabolism by the CYP450 system

All are substrates for CYP3A4 & can act as inducers


(nevirapine) and inhibitors (delavirdine), or mixed inducers
& inhibitors (efavirenz, etravirine)
Antiretroviral Agents - NNRTIs
Drugs Pharmacokinetics Side Effects Drug Interactions

Delavirdine Oral bioavailability: 85%, Skin rash: 38% Antacids, H2-receptor


Plasma Protein Binding: 98% H/A, fatigue, nausea, LBM, blockers,
Low CSF levels serum transtransferase levels, Fosamprenavir,
Serum t1/2: 6 hrs Teratogenic VSD & other Rifabutin
malformations
Efavirenz t1/2: 40-55% CNS, Psychiatric symptoms, - methadone
Moderately absorbed: 45% GI, crystalluria, liver enzymes,
bioavailability after a high-fat meal serum cholesterol: 10-20%
Should be taken on an empty High rates of fetal
stomach abnormalities
Elimination: feces (remainders)
Bound to albumin: 99%
CSF levels: 0.03-1.2%
Etravirine Effective against those resistant to Rash, nausea, LBM, serum Itraconazole,
NNRTIs cholesterol, triglycerides, ketoconazole (dec)
Substrate & inducer of CYP3A4 glucose, hepatic transaminase Inc. voriconazole
Inhibitor of CYP2C9 & CYP2C19 levels concn.
Nevirapine Oral bioavailability: >90%, not food Rash, maculopapular eruption: Moderate inducer of
dependent 20% CYP3A metabolism
Highly lipophilic Elevated hepatic enzymes: Inducers of CYP3
CSF levels: 43% 20% system
Serum t1/2: 25-30 hours Fever, nausea, H/A, Inhibitors of CYP3A
Excretion: urine somnolence activity
Some Adverse Reactions of
Efavirenz
CNS s/s: dizziness,
drowsiness, insomnia,
nightmares, h/a
d/c therapy
Psychiatric symptoms
Depression, mania,
psychosis
d/c therapy
Protease Inhibitors

Saquinavir Lopinavir/Ritonavir
Indinavir Nelfinavir
Amprenavir Darunavir
Atazanavir Tipranavir
Fosamprenavir
Mechanisms of Action - PIs
Responsible for cleaving the
Gag and Gag-Pol gene
products translated into
polyproteins immature
budding particles final
structural proteins of the
mature virion core

Prevent the processing of


viral proteins into functional
conformations immature,
noninfectious viral particles
Antiretroviral Agents - PIs

Active against HIV-1 and HIV-2


Do not need IC activation
Do not undergo process of phosphorylation
SE: central obesity, buffalo humps, peripheral & facial
wasting, breast enlargement, Cushingoid appearance,
triglycerides, LDL levels, hyperglycemia & insulin
resistance, bone loss & osteoporosis, spontaneous
bleeding in patients with hemophilia A and B
Metabolized by CYP3A4
Antiretroviral Agents - PIs
Drugs Pharmacokinetics Side Effects Drug Interactions

Atazanavir Light meal enhanced LBM, N/V, abdominal pain, H/A Ritonavir,
bioavailability peripheral neuropathy, skin rash, omeprazole,
Requires acidic medium for indirect hyperbilirubinemia with indinavir, irinotecan,
absorption jaundice, hepatic enzymes, PR tenofovir, efavirenz
Penetrate both CSF & seminal interval prolongation, QTc
fluid interval
Plasma t1/2: 6-7 hrs
Elimination: biliary
Inhibitor of CYP3A4 &
CYP2C9

Darunavir Inhibits & metabolized by LBM, nausea, H/A, rash,


CYP3A enzyme system dyslipidemia, amylase & hepatic
transaminase levels, severe
hepatitis, sulfonamide allergy

Fosamprenavir Rapidly absorbed; H/A, nausea, LBM, perioral


(prodrug of metabolized by CYP3A4; parestheisas, depression, rash
amprenavir) taken with or without food,
high fat-meals absorption;
t1/2: 7-11 hours
Antiretroviral Agents - PIs
Drugs Pharmacokinetics Side Effects Drug Interaction
Indinavir Requires acidic Indirect
environment for optimum hyperbilirubinemia,
solubility; maximal nephrolithiasis,
absorption: 60-65%; serum thrombocytopenia,
t1/2: 1.5-2%; protein serum
binding: 60%; high CSF aminotransferase
penetration: 76%; levels, nausea, LBM,
excretion: fecal insomnia, dry throat &
skin; insulin
resistance, acute
hemolytic anemia,
thyroid adenoma

Lopinavir Well tolerated, food LBM, abdominal pain, RIF, disulfiram,


enhance bioavailability, PB: N/V, asthenia, metronidazole,
98-99%; t1/2: 5-6 hrs; cholesterol & efavirens, nevirapine,
metabolized by CYP3A triglycerides fosamprenavir
Antiretroviral Agents - PIs
Drugs Pharmacokinetics Side Effects Drug Interactions

Nelfinavir High absorption:70-80% LBM, flatulence Rifabutin, Saquinavir,


Metabolized by CYP3A Efavirenz
Excretion: feces
Plasma t1/2: 3.5-5 hours
Protein binding: 98%
Ritonavir High bioavailability: 75%, with food GI disturbances, paresthesias, Digoxin, theophylline
Protein binding: 98% altered taste, H/A, serum
Serum t1/2: 3.5 hours aminotransferase levels,
Metabolism: CYP3A & CYP2D6 triglycerides, cholesterol, creatine
isoforms kinase
Excretion: feces
Saquinavir Poor oral bioavailability: 4% GI discomfort, rhinitis Nelfinavir,
Protein binding: 97% omeprazole, digoxin,
Serum t1/2: 2 hours delavirdine or rifampin
Has a large volume of distribution, but
penetration to CSF: negligible
Excretion: feces

Tipranavir Bioavailability: poor GI discomfort, ras, Intracranial Valproic acid,


Metabolism: liver microsomal system hemorrhage, depression, omeprazole,
cholesterol, triglycerides, lovastatin,
amylase; WBC count simvastatin,
atorvastatin,
rusovastatin
Adverse Reactions of Protease
Inhibitors
Drug Interactions with Protease
Inhibitors
Summary of Protease Inhibitors
FUSION /ENTRY
INHIBITORS
ENFUVIRTIDE (T-20)

No activity against HIV-2


Administered by SC
Metabolism: proteolytic hydrolysis
Elimination t1/2: 3.8 hours
Adverse effects:
Local injection site reactions, hypersensitivity
reactions, eosinophilia, bacterial pneumonia
Mechanism of Action Fusion Inhibitor

Blocks entry into the cell

Binds to gp41 subunit of


the viral envelop
glycoprotein prevents
conformational changes
required for the fusion of
the viral & cellular
membranes

Resistance: mutation in
gp41 codons
Antiretroviral Agents CCR5 Receptor
Antagonists
Maraviroc
Absorption: rapid, 1-4 hours
Excretion: feces (>75%), urine (20%)
Excellent penetration: cervicovaginal fluid
Drug Interactions:
Delavirdine, ketoconazole, itraconazole, clarithromycin,
efavirenz, etravirine, rifampin, carbamazole, phenytoin, St.
Johns wort
Side effects:
Cough, respiratory infections, muscle/joint pains, LBM, sleep
disturbance, hepatic transaminase levels
Mechanism of Action CCR5 Receptor
Antagonist

Binds specifically &


selectively of CCR5-tropic
HIV into these cells to
CCR5 blocking entry

Resistance:
mutations in V3 loop of
gp120

Emergence of non-CCR5-
tropic virus or by changes
in viral tropism (gp160)
Antiretroviral Agents CCR5 Receptor
Antagonists
Antiretroviral Agents Integrase
Inhibitors
Raltegravir
Bioavailability: not established
Metabolism: glucuronidation
Does not interact with CYP450 system fewer
DI
Drug interactions:
Rifampin, efavirenz, etravirine, tipranavir/ritonavir, atazanavir,
magnesium, calcium, iron
Side effects:
LBM, nausea, dizziness, H/A, creatine phosphokinase, minimal
effects on serum lipids
Mechanism of Action Integrase
Inhibitors
Binds to integrase

Inhibits strand transfer,


(3rd & 5th step of
provirus integration)
interfering integration
of reverse-transcribed
HIV DNA into the
chromosomes of the
host cells
ANTI-HEPATITIS AGENTS
Antihepatitis Agents - Interferons
Types and Properties of Interferon

Interferon

Property Alpha Beta Gamma

Leukocyte IFN Fibroblast IFN Immune IFN


Previous designations
Type I Type I Type II

Genes >20 1 1

pH2 stability Stable Stable Labile

Viruses (RNA>DNA) Viruses(RNA>DNA)


Inducers Antigens, Mitogens
dsRNA dsRNA

Leukocytes,
Principal source Fibroblasts Lymphocytes
Epithelium
Antihepatitis Agents Interferons
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


Antihepatitis Agents
Interferon alfa
Administration: SC or IM
Elimination t1/2: 2-5 hours
Filtered at the glomerulus
Undergo rapid proteolytic degradation tubular
reabsorption
Liver metabolism biliary excretion (minor)
Adverse effects:
Flu-like syndrome, transient hepatic enzyme elevations,
neurotoxicities, myelosuppression, fatigue, weight loss, rash,
cough, myalgia, alopecia, tinnitus, reversible hearing loss,
retinopathy, pneumonitis, cardiotoxicity, thyroiditis
Antihepatitis Agents

Interferon alfa
Contraindications:
Hepatic decompensation
Autoimmune disease
History of cardiac arrhythmias

Drug interactions:
Theophylline, methadone
Didanosine
zidovudine
ANTI-Hepatitis B
Lamivudine
Adenofovir Dipivoxil
Entecavir
Interferon 2b
Famciclovir
Telbivudine
Tenofovir

ANTI-Hepatitis C
Pegylated interferon alfa-2a and 2b
Ribavirin, interferon alfa 2a, 2b, alfacon
Treatment of HBV Infection
Goals:
Sustain suppression of HBV replication
slowing of progression of hepatic disease

Prevention of complications

Reduction of the need for liver transplantation


Suppression of HBV DNA to undetectable levels
Seroconversion of HBeAg from positive to negative
Reduction in elevated hepatic transaminase levels
Treatment of HBV Infection
Drugs MOA Pharmacokinetics Side effects Drug
intraction
s
Adefovir dipivoxil competitively inhibits Bioavailability: 59%, Nephrotoxicity ( serum carnitine
HBV DNA polymerase unaffected by meals; creatinine, serum levels
chain termination Rapid and completely phosphorus); Headache;
after incorporation into hydrolyzed to the parent Diarrhea, abdominal
the viral DNA compound by intestinal pain; Asthenia; Lactic
and blood esterases; acidosis & hepatic
Protein binding: <5% ; steatosis
Intracellular half-life: 5-18 mitochondrial
hours; dysfunction; Embryotoxic
Excretion: glomerular in rats at high doses;
filtration & active tubular Genotoxic in preclinical
secretion studies

Entecavir competitively inhibits all Bioavailability: approaches Headache, fatigue,


3 functions of HBV 100%, decreased by food dizziness, and nausea
DNA polymerase, Intracellular half-life: 15 Lung adenomas and
including base priming, hours carcinomas in mice
reverse transcription of Excretion: kidneys Hepatic adenomas and
the negative strand and Well tolerated carcinomas in rats and
synthesis of the mice
positive strand of HBV Vascular tumors in mice
DNA Brain gliomas and skin
fibromas in rats
Treatment of HBV Infection
Drugs MOA Pharmacokinetics Side effects Drug
interactio
ns
Lamivudine Inhibits HBV DNA Intracellular half-life: 17-19 Has excellent safety
polymerase and hours profile
HIV transcriptase
by competing
with
deoxycytidine
triphosphate
chain termination
Telbivudine Phosphorylated by cellular kinases to Fatigue, headache, No known
the active triphosphate form abdominal pain, interaction
-Intracellular half-life: 14 hours
upper respiratory s with
-Competitively inhibits HBV DNA
polymerase incorporation into viral infection CYP450
DNA and chain termination Increased creatine system or
-Not active in vitro against HIV-1 phosphokinase levels other
Bioavailability: unaffected by food Nausea/vomiting drugs
Plasma protein binding: 3% Peripheral
Distribution: wide
neuropathy under
Serum half-life: 15 hours
Excretion: renal evaluation
No known metabolites Lactic acidosis,
severe hepatomegaly
with steatosis
Flare of hepatitis after
discontinuation
LAMIVUDINE

Can be safely administered to


patients with decompensated liver
disease associated with chronic
Hepatitis B infection
ENTECAVIR
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.
Treatment of HBV Infection
Tenofovir
A nucleoside analog of adenosine

Use as an antiretroviral

Maintains activity against lamivudine- and entecavir-resistant isolates


but has reduced activity against adefovir-resistant strains

Showed a significantly higher rate of complete response, defined as


serum HBV DNA levels less than 400 copies/ml as well as histologic
improvement

INVESTIGATIONAL AGENTS
Nucleoside analog: Emtricitabine, Clevudine, Valtorcitabine,
Pradefovir, Alamifovir
Immunologic modulator: Thymosin alpha-1
Treatment of HCV Infections
Goal:
Viral eradication [achievement of sustained
viral response (SVR)]
Absence of detectable viremia for 6 months after
completion of therapy

Improvement in liver histology

Reduction in risk of hepatocellular carcinoma

Regression of cirrhosis

Treatment of HCV Infections


Ribavirin
It appears:
to interfere with the synthesis of guanosine triphosphate
to inhibit capping viral messenger RNA
to inhibit the viral RNA-dependent polymerase of certain viruses

inhibits the replication of a wide range of viral DNA & RNA


viruses, including influenza A and B, parainfluenza, RSV,
paramyxoviruses, HCV, and HIV-1

Oral bioavailability: 45-64%


Plasma protein binding: negligible
Volume of distribution: large CSF levels: 70%
Elimination: urine
Treatment of HCV Infections
Ribavirin
Adverse effects:
Dose-dependent hemolytic anemia 10-20% of patients
Depression, fatigue, irritability, rash, cough, insomnia
Nausea and pruritus
Contraindications:
Uncorrected anemia, ESRD, Ischemic vascular disease
Pregnancy (teratogenic and embryogenic in animals as well
as mutagenic in mammalian cells
INVESTIGATIONAL AGENTS
Inhibitors of the HCV RNA polymerase: Valopicitabine
PIs: Telaprevir; Ribavirin analogs: Merimepodib
Anti-aminophospholipid antibody: Viramidine; Caspase
inhibitor
Immunomodulator: Thymosin alpha-1
INTERFERON

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 2a

Approved for the treatment of chronic


Hepatitis C, AIDS associated Kaposis
sarcoma, hairy cell leukemia,
chronic myelogenous leukemia
INTERFERON 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
Recently introduced for treatment of
chronic hepatitis C
Longer duration with slower clearance
ANTI-INFLUENZA AGENTS
Anti-influenza Agents
Influenza virus strains are
classified by their core proteins
(A, B, or C), species of origin
(avian, swine), and geographic
site of isolation

Influenza A, the only strain that


causes pandemics, is classified
into 16 H (hemagglutinin) and 9
N (neuramidase) based on
surface proteins

Influenza B viruses usually


infect only people, influenza A
viruses can infect a variety of
animal hosts
Influenza A subtypes H1N1: swine flu
H1N1, H1N2, H3N2
1st influenza pandemic
Avian influenza subtypes
Highly species-specific, Circulating strains of
rarely cross specie barrier to H5N1 & H1 & H3
infect humans & cats
strains (seasonal flu)
H5 & H7 subtypes resistant to aantadine
H5N1, H7N7, H7N3 & rimantadine
Cause both human & avian
dse.
H5N1: endemic in southeast
Asia ; person to person
spread rare
AMANTADINE/RIMANTADINE
(1-aminoadamantane
hydrochloride)
-methyl derivative - rimantadine
(-) uncoating of viral RNA
influenza A w/n infected cell
prevent replication
Reduce the duration of
symptoms of influenza when
administered w/in 48 hrs of onset
Primary target is M2 proteins
Anti-influenza Agents

AMANTADINE/RIMANTADINE
Rimantadine: 4-10x more active than
amantadine
Amantadine
well absorbed, 67% protein bound, plasma half-
life is 12-18 hours & varies by creatinine
clearance
Nasal secretion and salivary levels approximate
those in serum; CSF levels are 52-96% of those
in the serum
excreted unchanged in the urine
Rimantadine
40% protein-bound
half-life of 24-36 hours
Nasal mucus concentrations: average 50% higher
than those in plasma
undergoes extensive metabolism by hydroxylation,
conjugation, and glucuronidation before urinary
excretion
Anti-influenza Agents

Oseltamivir/Zanamivir
Neuroaminidase
inhibitors

Inhibits replication of
both influenza A & B

5 day course regimen


for both influenza A & B
(-) release of progeny influenza virus from
infected host cells stop spread of
infection w/in respiratory tract
Competitively (-) & reversibly interact w/
active enzyme (-) neuraminidase
activity clumping of newly released
influenza virions to each other & to the
membrane of infected cell
OSELTAMIVIR/Zanamivir
Neuroaminidase inhibitors
NOTE: Treatment for Bird Flu
Resistance to H1N1 but not to
zanamivir
H3N2 and B---both susceptible
Anti-influenza Agents
Oseltamivir
Orally administered, food does not interfere
with absorption
Bioavailability: 80%
Plasma protein binding: low
Half-life: 6-10 hours
Active metabolite: oseltamivir carboxylate
Excretion: GF/TS (urine)
AE: N/V, abdominal pain (5-10%), H/A, fatigue
& diarrhea
Anti-influenza Agents
Zanamivir
Delivered directly to the RT via inhalation

Pulmonary t1/2: 2.8 hours

Excretion: urine

AEs: cough, bronchospasm, reversible decrease


in pulmonary function, transient & throat
discomfort
Resistance: point mutations in the viral
hemagglutinin or neuraminidase genes
UNCLASSIFIED
INTERFERONS
Intralesional injection of IFN alfa-2b or
alfa-n3
Treatment of condylomata acuminata
RIBAVIRIN
Aerosolized : administered by nebulizer
20mg/ml x 12-18 hrs/day
Children & infants w/ RSV bronchiolitis or
PNM
For influenza A & B infections
Low systemic absorption
Well tolerated
A/e: conjunctival/bronchial irritation, may
precipitate on contact lenses
IV ribavirin:
Dec. mortality in Lassa fever & other hgic
fevers when started early
(-) West Nile virus
Measles pneumonitis, encephalitides
Severe lower tract influenza or parainfluenza
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
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
ANTIFUNGAL ACTIVITY
Antifungal Activity
Candida species, C. neoformans, H.
capsulatum, Sporothrix schenkii
Blastomyces dermatitidis, Coccidioides
immitis, Aspergillus fumigatus, Mucormycosis
Paracoccidioides brazilienzes, Penicilium
marneffei
Limited activity to Leishmania, braziliensis,
Naegleria fowleri
No antibacterial activity
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
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


Amphotericin B
Resistance:
ergeosterol binding is impaired
Decreasing the membrane concentration of
ergosterol

By target modifying the sterol target molecule to


reduce its affinity for the drug
Amphotericin B
Clinical Use:
IV infusion, 0.5 1 mg/kg/d:
severe fungal pneumonia, severe cryptococcal
meningitis, disseminated iinfections:
histoplasmosis or coccodioidomycosis
Local or topical:
mycotic corneal ulcers & keratitis
Local injection: fungal arthritis
Bladder irrigation: candiduria
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 (shake and bake
syndrome), muscle spasms, vomiting,
headache, & hypotension
B) SLOWER/CUMMULATIVE
TOXICITY: Delayed
renal damage
o Reversible renal injury
o Irreversible renal injury- renal
tubular injury
Abnormal liver function tests
anemia
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
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
FLUCYTOSINE (5-FC)
Resistance:
Monotherapy

altered mechanism of
metabolism of
flucytosine to 5
fluorouracil, due to
mutation in cytosine
deaminase.
FLUCYTOSINE (5-FC)
Pharmacokinetics Clinical Uses:
Available in oral preparation
Cryptococcal meningitis
Well absorbed (>90%) with
serum Candida species
Peak serum Concentration: Dematiaceous molds
1-2 hrs (chromoblastomycosis)
Poorly protein bound
Penetrates well body fluids &
CSF
Adverse Effects:
T is 3-4 hrs - Anemia, leukopenia,
thrombocytopenia
Elimination: GF
Rash, n/v, diarrhea
- Toxic enterocolitis
CLINICAL USAGES
Cryptococcal meningitis
Candida species
Dematiaceous molds that cause
chromoblastomycosis
AZOLES
IMIDAZOLES :
Ketoconazole
Miconazole
Clotrimazole
TRIAZOLES:
Itraconazole
Fluconazole
Voriconzaole
Azoles
Inhibition of sterol 14 -
demethylase
Impair the biosynthsesis of
ergosterol for the cytoplasmic
membraneaccumulation of 14-
-methylsterols
Impairing functions of membrane
bound enzymes such as ATPase
& enzymes of electron transport
systeminhibits growth of
fungi
Reduction of ergosterol
synthesis by inhibition of
cytochrome P450 enzymes
Specificity for fungal than human
cytochrome P450
enzymes(imidazole v.s triazole)
CLINICAL USES
Candida species
Cryptococcus neoformans
Endemic mycoses
ADVERSE EFFECTS
Relatively non-toxic; clinical hepatitis (rare)
Most common-GIT upset
Increased liver enzymes
DRUG INTERACTIONS
All azole drugs affect mammalian cytochrome
P450 systems of enzymes
KETOCONAZOLE
1st oral azole introduced into clinical use
Inc. propensity to inhibit mammalian
cytochrome P450 enzymes
interferes with biosynthesis of adrenal &
gonadal steroid hormones
Less selective for fungal P450
Interaction with P450 enzymes can alter
the metabolism of other drugs leading to
enhanced toxicity
Reaches the keratinocytes efficiently
Concentration in vaginal fluids is
approaches that in plasma
Dose: 200mg OD/BID
THERAPEUTIC USES
Cutaneous infections caused by
epidermophyton, microsporum, trichophyton
sp.
Blastomycosis, histoplasmosis,
coccidiodomycosis, pseudallescheriasis
Paracoccidiodomycosis, ringworm,
tinea versicolor, chronic mucocutaneous
candidiasis
Candida vulvovaginitis, oral & esophageal
candidiasis
ADVERSE REACTIONS
Dose-dependent anorexia, nausea,
vomiting, pruritis
Inhibits steroid biosynthesis in patients
endocrine abnormalities
Gynecomastia, inc. liver enzyme levels,
hepatitis
DRUG INTERACTIONS
Increases cyclosporine levels
Enhances arrythmogenic effects of
cisapride
H2 antagonists increases gastric pH,
interfere with the absorption of
ketoconazole
Rifampicin- increased hepatic
metabolism
ITRACONAZOLE

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 fordermatophytoses 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
week 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 used
mucocutaneous candidiasis.
Least effect of all azoles on hepatic
microsomal enzymes.
Widest therapeutic index.
FLUCONAZOLE
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
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.
POSACONAZOLE
Newest triazole; liquid oral formulation
800mg/d, BID/TID
Better absorption when taken w/ high fat
meals
Broadest spectrum of azole family
Against candida & aspergillus
Prophylaxis of fungal infections during
induction therapy for leukemia & allogenic
BM transplant pxs. w/ GVH dse.
Indications
Itraconazole DOC for dimorphic fungi
histoplasmosis, Blastomycoses, sporothrix
Fluconazole DOC for the treatment & 2ndary
prophylaxis of cryptococcal meningitis
Most commonly used for the treatment of
mucocutaneous candidiasis
Voriconazole treatment of choice for invasive
aspergillosis
Posaconazole the only azole with significant
activity against the agents of zygomycosis &
mucormycosis
ECHINOCANDINS
Large cyclic peptides linked to a long-
chain fatty acid.
CASPOFUNGIN, MICAFUNGIN, and
ANIDULAFUNGIN.
Active against candidiasis and
aspergilus BUT not Crytococcus
neoformans.
ECHINOCANDINS

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.
ECHINOCANDINS
CASPOFUNGIN
disseminated & mucocutaneous candida infections
with febrile neutropenia.
ONLY as a salvage therapy for invasive aspergillosis
when failed with ampothericin and voriconazole.
MICAFUNGIN
mucocutaneous candidiasis & prophylaxis of candida
infections in bone marrow transplant patients.
ANIDULAFUNGIN
esophageal 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

Deposited in newly forming skin where


it binds to keratin, protecting the skin for
new infection.
administered 2-6 weeks to allow the
replacement of infected keratin by resistant
new skin, hair and nail structures.
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)
Hyperkeratosis (T. rubrum)
ADVERSE REACTIONS

Allergic syndrome (serum


sickness, Hepatitis
Drug interactions with
warfarin and phenobarbital.
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 which is toxic to the organism.
OD X12 wks achieves 90% cure rate for
onychomycosis.
Rare side effectsGIT upset and HA
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
MICONAZOLE
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
TOLNAFTATE
Can not treat candida species
Used as topical solution
Used in tinea cruris and other tineasis
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 trichlorophenol in the body
Cream or solution BID X 2-4 wks
Principal use for tinea pedis
Tinea cruris, tinea versicolor, tinea corporis
NAFTIFINE
Inhibit squalene-2,3- epoxidase
Inhibits biosynthesis of ergosterol
Fungicidal activity
1% cream or gel
Topical treatment of tinea cruris & tinea
corporis
Cutaneous candidiasis & tinea
versicolor
MISCELLANEOUS
ANTIFUNGAL AGENTS
UNDECYLENIC ACID

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
Whitfields ointment
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
PROPIONIC ACID & CAPRYLIC
ACID

Treatment of dermatomycoses
Low efficacy
POTASSIUM IODIDE

Treatment of mucocutaneous
sporotrichosis