Antiviral Drugs
沈阳药科大学药物化学教研室
VIRUSES,Overview
Viruses are obligate intracellular parasites,which massively
multiply by diverting or,hijacking” the host cell biosynthetic
machinery.
Viruses were first defined as filterable infectious agents,based
on their small size and ability to cause disease (In 1892,Dr,
Iwanowski reported that filtered extracts of tobacco leaves with
mosaic disease could still infect other plants),
Viruses can range from the very small ~ 20 nm to the near
bacterial – 200× 200× 250 nm for the pox viruses such as
vaccinia,first described by light microscopy by Dr,Buist in 1887,
All classes of living organisms studied to date are the host to
viruses.
VIRUSES,Overview
Viruses can have their own satellite viruses,which borrow
proteins crucial for their multiplication from the,host” virus,e.g,
Hepatitis delta virus,which causes serious liver disease in
humans already infected with Hepatitis B virus.
Viruses alone have very little capacity to produce anything – in
the absence of the host they are usually entirely dormant (under
some conditions are able to make small amounts of nucleic
acid),
Viruses differ from bacteria and fungi,which are usually capable
of growth in the absence of host cells of other species,
The virus life cycle
the process is initiated by binding of the virus to its particular cellular
receptor,
The next step involves the delivery of the viral genome into the cell
The method of delivery as a sophisticated,molecular hypodermic
syringe” (bacteriophage of E,coli) or a,molecular bomb” – goes off
when the package is the appropriate host compartment,
The virus life cycle
Initiation phase
1,Attachment
2,Penetration
3,Uncoating
Replication phase
4,Gene expression
5,Genome replication
Release phase
6,Assembly
7,Maturation
8,Release,
VIRUSES,Structure and Properties
Viruses consist of particles containing a nucleic acid (RNA or
DNA),which encodes all the information necessary for
multiplication in the correct environment (host),
The nucleic acid constitutes the viral genome and is associated
with protein to form a nucleocapsid.
Depending on the presence or absence of lipid in the membrane,
viruses are termed enveloped or nonenveloped,respectively,
Viruses,Structure
Enveloped
Nonenveloped Adopted from PD Minor,2000
Viruses,Structure
Viruses contain a few proteins,lipids and nucleic acid which are
accurately replicated by the infected cell to give more virus,
The virus life cycle
Viral genome is encased in a package composed of proteins usually
encoded by the nucleic acid,and serving the functions of preserving
the genome until a new host is reached,and delivering it to the right
site,
Protecting the genome while it is in the environment – Enteroviruses,
such as poliovirus,are able to survive passage through the high
acidity of the stomach and infect the intestine,while closely related
viruses such as the rhinoviruses are not,
The delivery system of the virion requires the recognition of a cell as
a likely target,and this frequently involves a specific interaction
between the virus and a particular cell surface molecule
Problems of Antiviral Therapy
Viral infection is detected too late in the course of disease.
Massive proliferation and overwhelming intervention – virus,hijack”
host cells
Rapid evolution of viruses – high mutation rate of viral nucleic acid
polymerases,
compare,
Virus ……………….error in HIV RT 1 in 10 6 virions
Host ………………error in host polymerase 10 9 cells
Antiviral Therapy
Drugs affecting nucleic acid
synthesis –purines and pyrimidines
analogs
Inhibitors of RT (preventing
synthesis of viral DNA and proteins).
Protease inhibitors – affect synthesis
of late proteins and packaging
ACYCLOVIR (ay-SYE-kloe-veer)
Acyclic guanosine analog
N
N
N
N
O
NH
2
O
OH
Recommended for treat the symptoms of,
Chickenpox
Shingles
Herpes virus infections of the
genitals,skin,brain,and mucous
membranes (lips and mouth)
Herpes virus infections in
newborns
Recurrent genital herpes
infections
Does not cure herpes,but
helps relieve the pain and
discomfort and helps the
sores (if any) heal faster.
ACYCLOVIR,Use and Dosage
Agent Route Use Adult Dosage
Genital Herpes Treat,200mg 5x/d
HSV procititis 400mg q8h
Oral Varicella 800mg 4x/d
ACYCLOVIR Zoster 800mg 4x/d
Anti-CMV prophylaxis 200mg q8h
Intravenous Herpes encephalitis 5 mg/kg q8h
Varicella/Zoster
(Immunosuppressed)
10mg/kg q8h
ACYCLOVIR,Mechanisms
ACYCLOVIR
Viral thymidine kinase
Monophosphate
derivative
Host kinase(s)
Di- and triphosphate
analogs
Di- and triphosphates are only accumulated in infected cells
Prodrug – must be activated
(e.g,herpes simplex virus
thymidine kinase).
Modified Acyclovir inhibits
synthesis of viral DNA by:
1,Binding irreversibly to viral
DNA template
2,Termination of DNA
elongation after
incorporation into viral DNA
Step 1
Step 2
ACYCLOVIR,Mechanisms
Activation – conversion to Acyclovir
monophosphate (Acyclovir-MP)
Binds 200x more strongly to HS virus
thymidine kinase than to host TK
Viral TK phosphorylates 3x106 times
faster than host TK – Acyclovir-MP is
primarily produced in the infected cells
(Selectivity!!!).
The overall rate of conversion in
infected cells – 30-20-fold faster.
ACYCLOVIR
Viral thymidine
Kinase (TK)
Acyclovir-MP
Step 1
ACYCLOVIR,Mechanisms
Then host enzymes (kinases) work –
conversion of Acyclovir -MP to di- and
triphosphate derivatives.
Acyclovir-TP is incorporated into DNA
– no 3'-hydroxyl – elongation is
terminated and remains bound to DNA
polymerase causing its inhibition.
Acyclovir-DP
Acyclovir-TP
Host kinases
Acyclovir-MP
Step 2
3’-------------Acyclovir-TP
3’-----------------------------------------5’
StopDNA polymerase
ACYCLOVIR,Resistance
Develops as mutations in genes encoding
viral TK (mostly) and DNA polymerase.
TK-dependent resistance is cross-reactive
with resistance to Valacyclovir,Famciclovir,
and Ganciclovir.
ACYCLOVIR,Adverse Effects
Common (for I.V,only)
Pain,swelling,or redness at place of injection
Less common
– Abdominal or stomach pain; diarrhea
– Loss of appetite
– Headache,nausea or vomiting
– Unusual tiredness or weakness
– Renal insufficiency
– Neurological toxicity
Rare
Chills,fever,or sore throat; confusion; convulsions,pinpoint red
spots on skin,trembling.
for I.V,only
ACYCLOVIR,Drug Interactions
ACYCLOVIR Plus...
AZT (Zidovudine)
Increase antiviral activity in test tubes (inhibits DNA synthesis by
HIV RT by the same 2-step mechanism),
INTERFERON-a
Increase antiviral activity in test tubes,
PROBECENID
May increase Acyclovir levels in blood and decrease Acyclovir
clearance.
!
!
!
VALACYCLOVIR
An L-valyl ester derivative of ACYCLOVIR
Rapidly converted to Acyclovir after oral intake.
Blood concentrations – 3 - 5x greater than Acyclovir,
Other than dosing,there is no advantage over
Acyclovir.
Mechanism of Action,Adverse Effects as for
Acyclovir.
VALACYCLOVIR,Use and Dosage
Agent Route Use Adult Dosage
Primary Genital
Herpes 1g q12h
Recurrent Genital
Herpes 500mg q12h
VALACYCLOVIR Oral only Suppression of
Genital Herpes 500-1000mg/d
Zoster 1g q8h
Anti-CMV
prophylaxis
in transplantation
2g q6h
FAMCICLOVIR,(fam-SYE-kloe-veer)
A Prodrug - Diacetyl ester of 6-
deoxy Penciclovir.
Bioavailability,70 %
Rapidly converted to Penciclovir in
the body.
Activated (phosphorylated) by viral
TK.
Modus Operandi – direct inhibition of
viral DNA polymerase (no effects of
DNA elongation).
Has lower affinity to viral TK than
Acyclovir,but higher intracellular
concentration.
Intracellular T1/2 of Penciclovir-TP is
7-20 hrs.
N
N
N
N
O
O
O
CH
3
C H
3
O
NH
2
Famciclovir
FAMCICLOVIR,Use and Dosage
Agent Route Use Adult Dosage
Recur,Genital Herpes 125mg q12h 5d
FAMCICLOVIR Oral Genital Herpes suppression
250mg q12h
up to 365 d
Genital Herpes in AIDS 500mg q12h 7d
Zoster 500mg q8h 7d
FAMCICLOVIR,Adverse Effects
Generally – well tolerated
Common
– Headache
Less common
– Diarrhea
– Nausea,dizziness or vomiting
– Unusual tiredness or weakness
Rare
– Other side effects not listed above.
GANCICLOVIR,(gan-SYE-kloe-vir)
Another acyclic analog of guanosine
Bioavailability - 6-9 % only
A prodrug that is activated by either
virus TK (HSV) or phosphotransferase
(UL97 in CMV)
Resistance occurred due to mutations
in the drug targets:
– Phosphotransferase (most often) gene
– TK gene
– Sometimes in both
Cross-resistance with strains resistant
to Acyclovir (TK deficiency)
N
N
N
O
O
OH
O H
NH
2
Ganciclovir
GANCICLOVIR,Use and Dosage
Available in oral and I.V,forms
Bioavailability is only 6-9 %
T1/2 @ 2-4 hrs
Excretion by renal system (check for creatinine clearance
index)
1.4 mg/h
1 implant q5-8 moCMV Retinitis
Intraocular
implant
5mg/kg q12h 2 w
then 5 mg/kg/d
CMV Retinitis,Colitis,
Esophagitis
I.V.
1g q8hCMV Retinitis (treatment
or prophylaxis)
Oral
Adult DosageUseRouteAgent
GANCICLOVIR,Adverse Effects
Common
Sore throat,fever,unusual bleeding or bruising
Less common
– Mood or other mental changes
– Nervousness
– Pain at place of injection
– Skin rash
– Tremor
– Unusual tiredness and weakness
Rare
– Abdominal or stomach pain; loss of appetite; nausea and vomiting.
CIDOFOVIR,(si-DOF-o-veer)
Cidofovir is a cytosine nucleotide
analog.
Active against HSV,CMV,EBV and
others,but mainly is used to treat the
symptoms of CMV retinitis in AIDS
patients.
A prodrug phosphorylated by viral
kinases only,
Mechanism of action,inhibition of
DNA polymerase and stops the
elongation of DNA after incorporation.
Resistance – a point mutation in gene
encoding viral DNA polymerase
N
N
O H
O
N H
2
O
H
H
P
O
O H
O H
CIDOFOVIR,Use and Dosage
Available as an injection form
T1/2 in blood only 2.6 hrs,but T1/2 intracellularly 20-60 hrs
Excretion by renal system (check for creatinine clearance index)
Topical form – for treatment of the recurrent genital herpes
Agent Route Use Adult Dosage
CIDOFOVIR I.V,CMV retinitis
Induction:
5 mg/kg q7d
Maintenance:
5 mg/kg q14d
To decrease nephrotoxicity - must be injected with:
Probenecid 2g 3 h prior and 1 g at 2 and 8 hrs after injection
CIDOFOVIR,Adverse Effects
Common – for I.V,only
– A dose-dependent nephrotoxicity (monitor for serum
creatinine and urine protein)
Less common
– Uveitis
– Ocular hypotony
– Hypersensitivity (Probenecid-related)
Rare
– Neutropenia
– Metabolic acidosis
CIDOFOVIR,Drug Interactions
Increases T1/2 of many drugs including,
– Penicillin
– oral hypoglycemics
– Rifampin
– Ciprofloxacin
– Acetaminophen
– Acyclovir
– Benzodiazepines
– Ganciclovir,Theophylline,Furosemide,and others.
!
FOSCARNET,(foss-KAR-net)
Inorganic pyrophosphate compound which inhibits:
– DNA polymerase
– RNA polymerase
– HIV Reverse Transcriptase
Resistance after long use and due to mutations in
DNA/RNA/RT polymerases
O P
O
O
O
O
3N a+Foscarnet
FOSCARNET,Use and Dosage
Only I.V,form due to poor bioavailability of oral
Concentration is reduced by 50 % after a 3-h hemodialysis
Concentration in CSF is ~ 50% of blood levels
~ 30 % of Foscarnet is deposited in bones (T1/2 up to several months)
Agent Route Use Adult Dosage
I.V.
CMV retinitis
Acyclovir resistant
infections
CMV colitis
Induction,60 mg/kg q8h
Maintenance,90-120 mg/kg/d
40 mg/kg q8-12h
60mg/kg q8hF
OSC
AR
NE
T
FOSCARNET,Adverse Effects
NB! Foscarnet may cause or worsen anemia
Common
– Increased or decreased frequency of urination or amount of
urine; increased thirst
Uncommon
– Convulsions (seizures); fever,chills,and sore throat; muscle
twitching; pain at place of injection.
Rare
– Sores or ulcers on the mouth or throat,penis,or vulva
FOSCARNET,Drug Interactions
Nephrotoxic agents
Combination pain medicine containing acetaminophen and
aspirin (e.g.,Excedrin) or other salicylates
Cyclosporine
Deferoxamine
Lithium
Anti-infective agents
!
沈阳药科大学药物化学教研室
VIRUSES,Overview
Viruses are obligate intracellular parasites,which massively
multiply by diverting or,hijacking” the host cell biosynthetic
machinery.
Viruses were first defined as filterable infectious agents,based
on their small size and ability to cause disease (In 1892,Dr,
Iwanowski reported that filtered extracts of tobacco leaves with
mosaic disease could still infect other plants),
Viruses can range from the very small ~ 20 nm to the near
bacterial – 200× 200× 250 nm for the pox viruses such as
vaccinia,first described by light microscopy by Dr,Buist in 1887,
All classes of living organisms studied to date are the host to
viruses.
VIRUSES,Overview
Viruses can have their own satellite viruses,which borrow
proteins crucial for their multiplication from the,host” virus,e.g,
Hepatitis delta virus,which causes serious liver disease in
humans already infected with Hepatitis B virus.
Viruses alone have very little capacity to produce anything – in
the absence of the host they are usually entirely dormant (under
some conditions are able to make small amounts of nucleic
acid),
Viruses differ from bacteria and fungi,which are usually capable
of growth in the absence of host cells of other species,
The virus life cycle
the process is initiated by binding of the virus to its particular cellular
receptor,
The next step involves the delivery of the viral genome into the cell
The method of delivery as a sophisticated,molecular hypodermic
syringe” (bacteriophage of E,coli) or a,molecular bomb” – goes off
when the package is the appropriate host compartment,
The virus life cycle
Initiation phase
1,Attachment
2,Penetration
3,Uncoating
Replication phase
4,Gene expression
5,Genome replication
Release phase
6,Assembly
7,Maturation
8,Release,
VIRUSES,Structure and Properties
Viruses consist of particles containing a nucleic acid (RNA or
DNA),which encodes all the information necessary for
multiplication in the correct environment (host),
The nucleic acid constitutes the viral genome and is associated
with protein to form a nucleocapsid.
Depending on the presence or absence of lipid in the membrane,
viruses are termed enveloped or nonenveloped,respectively,
Viruses,Structure
Enveloped
Nonenveloped Adopted from PD Minor,2000
Viruses,Structure
Viruses contain a few proteins,lipids and nucleic acid which are
accurately replicated by the infected cell to give more virus,
The virus life cycle
Viral genome is encased in a package composed of proteins usually
encoded by the nucleic acid,and serving the functions of preserving
the genome until a new host is reached,and delivering it to the right
site,
Protecting the genome while it is in the environment – Enteroviruses,
such as poliovirus,are able to survive passage through the high
acidity of the stomach and infect the intestine,while closely related
viruses such as the rhinoviruses are not,
The delivery system of the virion requires the recognition of a cell as
a likely target,and this frequently involves a specific interaction
between the virus and a particular cell surface molecule
Problems of Antiviral Therapy
Viral infection is detected too late in the course of disease.
Massive proliferation and overwhelming intervention – virus,hijack”
host cells
Rapid evolution of viruses – high mutation rate of viral nucleic acid
polymerases,
compare,
Virus ……………….error in HIV RT 1 in 10 6 virions
Host ………………error in host polymerase 10 9 cells
Antiviral Therapy
Drugs affecting nucleic acid
synthesis –purines and pyrimidines
analogs
Inhibitors of RT (preventing
synthesis of viral DNA and proteins).
Protease inhibitors – affect synthesis
of late proteins and packaging
ACYCLOVIR (ay-SYE-kloe-veer)
Acyclic guanosine analog
N
N
N
N
O
NH
2
O
OH
Recommended for treat the symptoms of,
Chickenpox
Shingles
Herpes virus infections of the
genitals,skin,brain,and mucous
membranes (lips and mouth)
Herpes virus infections in
newborns
Recurrent genital herpes
infections
Does not cure herpes,but
helps relieve the pain and
discomfort and helps the
sores (if any) heal faster.
ACYCLOVIR,Use and Dosage
Agent Route Use Adult Dosage
Genital Herpes Treat,200mg 5x/d
HSV procititis 400mg q8h
Oral Varicella 800mg 4x/d
ACYCLOVIR Zoster 800mg 4x/d
Anti-CMV prophylaxis 200mg q8h
Intravenous Herpes encephalitis 5 mg/kg q8h
Varicella/Zoster
(Immunosuppressed)
10mg/kg q8h
ACYCLOVIR,Mechanisms
ACYCLOVIR
Viral thymidine kinase
Monophosphate
derivative
Host kinase(s)
Di- and triphosphate
analogs
Di- and triphosphates are only accumulated in infected cells
Prodrug – must be activated
(e.g,herpes simplex virus
thymidine kinase).
Modified Acyclovir inhibits
synthesis of viral DNA by:
1,Binding irreversibly to viral
DNA template
2,Termination of DNA
elongation after
incorporation into viral DNA
Step 1
Step 2
ACYCLOVIR,Mechanisms
Activation – conversion to Acyclovir
monophosphate (Acyclovir-MP)
Binds 200x more strongly to HS virus
thymidine kinase than to host TK
Viral TK phosphorylates 3x106 times
faster than host TK – Acyclovir-MP is
primarily produced in the infected cells
(Selectivity!!!).
The overall rate of conversion in
infected cells – 30-20-fold faster.
ACYCLOVIR
Viral thymidine
Kinase (TK)
Acyclovir-MP
Step 1
ACYCLOVIR,Mechanisms
Then host enzymes (kinases) work –
conversion of Acyclovir -MP to di- and
triphosphate derivatives.
Acyclovir-TP is incorporated into DNA
– no 3'-hydroxyl – elongation is
terminated and remains bound to DNA
polymerase causing its inhibition.
Acyclovir-DP
Acyclovir-TP
Host kinases
Acyclovir-MP
Step 2
3’-------------Acyclovir-TP
3’-----------------------------------------5’
StopDNA polymerase
ACYCLOVIR,Resistance
Develops as mutations in genes encoding
viral TK (mostly) and DNA polymerase.
TK-dependent resistance is cross-reactive
with resistance to Valacyclovir,Famciclovir,
and Ganciclovir.
ACYCLOVIR,Adverse Effects
Common (for I.V,only)
Pain,swelling,or redness at place of injection
Less common
– Abdominal or stomach pain; diarrhea
– Loss of appetite
– Headache,nausea or vomiting
– Unusual tiredness or weakness
– Renal insufficiency
– Neurological toxicity
Rare
Chills,fever,or sore throat; confusion; convulsions,pinpoint red
spots on skin,trembling.
for I.V,only
ACYCLOVIR,Drug Interactions
ACYCLOVIR Plus...
AZT (Zidovudine)
Increase antiviral activity in test tubes (inhibits DNA synthesis by
HIV RT by the same 2-step mechanism),
INTERFERON-a
Increase antiviral activity in test tubes,
PROBECENID
May increase Acyclovir levels in blood and decrease Acyclovir
clearance.
!
!
!
VALACYCLOVIR
An L-valyl ester derivative of ACYCLOVIR
Rapidly converted to Acyclovir after oral intake.
Blood concentrations – 3 - 5x greater than Acyclovir,
Other than dosing,there is no advantage over
Acyclovir.
Mechanism of Action,Adverse Effects as for
Acyclovir.
VALACYCLOVIR,Use and Dosage
Agent Route Use Adult Dosage
Primary Genital
Herpes 1g q12h
Recurrent Genital
Herpes 500mg q12h
VALACYCLOVIR Oral only Suppression of
Genital Herpes 500-1000mg/d
Zoster 1g q8h
Anti-CMV
prophylaxis
in transplantation
2g q6h
FAMCICLOVIR,(fam-SYE-kloe-veer)
A Prodrug - Diacetyl ester of 6-
deoxy Penciclovir.
Bioavailability,70 %
Rapidly converted to Penciclovir in
the body.
Activated (phosphorylated) by viral
TK.
Modus Operandi – direct inhibition of
viral DNA polymerase (no effects of
DNA elongation).
Has lower affinity to viral TK than
Acyclovir,but higher intracellular
concentration.
Intracellular T1/2 of Penciclovir-TP is
7-20 hrs.
N
N
N
N
O
O
O
CH
3
C H
3
O
NH
2
Famciclovir
FAMCICLOVIR,Use and Dosage
Agent Route Use Adult Dosage
Recur,Genital Herpes 125mg q12h 5d
FAMCICLOVIR Oral Genital Herpes suppression
250mg q12h
up to 365 d
Genital Herpes in AIDS 500mg q12h 7d
Zoster 500mg q8h 7d
FAMCICLOVIR,Adverse Effects
Generally – well tolerated
Common
– Headache
Less common
– Diarrhea
– Nausea,dizziness or vomiting
– Unusual tiredness or weakness
Rare
– Other side effects not listed above.
GANCICLOVIR,(gan-SYE-kloe-vir)
Another acyclic analog of guanosine
Bioavailability - 6-9 % only
A prodrug that is activated by either
virus TK (HSV) or phosphotransferase
(UL97 in CMV)
Resistance occurred due to mutations
in the drug targets:
– Phosphotransferase (most often) gene
– TK gene
– Sometimes in both
Cross-resistance with strains resistant
to Acyclovir (TK deficiency)
N
N
N
O
O
OH
O H
NH
2
Ganciclovir
GANCICLOVIR,Use and Dosage
Available in oral and I.V,forms
Bioavailability is only 6-9 %
T1/2 @ 2-4 hrs
Excretion by renal system (check for creatinine clearance
index)
1.4 mg/h
1 implant q5-8 moCMV Retinitis
Intraocular
implant
5mg/kg q12h 2 w
then 5 mg/kg/d
CMV Retinitis,Colitis,
Esophagitis
I.V.
1g q8hCMV Retinitis (treatment
or prophylaxis)
Oral
Adult DosageUseRouteAgent
GANCICLOVIR,Adverse Effects
Common
Sore throat,fever,unusual bleeding or bruising
Less common
– Mood or other mental changes
– Nervousness
– Pain at place of injection
– Skin rash
– Tremor
– Unusual tiredness and weakness
Rare
– Abdominal or stomach pain; loss of appetite; nausea and vomiting.
CIDOFOVIR,(si-DOF-o-veer)
Cidofovir is a cytosine nucleotide
analog.
Active against HSV,CMV,EBV and
others,but mainly is used to treat the
symptoms of CMV retinitis in AIDS
patients.
A prodrug phosphorylated by viral
kinases only,
Mechanism of action,inhibition of
DNA polymerase and stops the
elongation of DNA after incorporation.
Resistance – a point mutation in gene
encoding viral DNA polymerase
N
N
O H
O
N H
2
O
H
H
P
O
O H
O H
CIDOFOVIR,Use and Dosage
Available as an injection form
T1/2 in blood only 2.6 hrs,but T1/2 intracellularly 20-60 hrs
Excretion by renal system (check for creatinine clearance index)
Topical form – for treatment of the recurrent genital herpes
Agent Route Use Adult Dosage
CIDOFOVIR I.V,CMV retinitis
Induction:
5 mg/kg q7d
Maintenance:
5 mg/kg q14d
To decrease nephrotoxicity - must be injected with:
Probenecid 2g 3 h prior and 1 g at 2 and 8 hrs after injection
CIDOFOVIR,Adverse Effects
Common – for I.V,only
– A dose-dependent nephrotoxicity (monitor for serum
creatinine and urine protein)
Less common
– Uveitis
– Ocular hypotony
– Hypersensitivity (Probenecid-related)
Rare
– Neutropenia
– Metabolic acidosis
CIDOFOVIR,Drug Interactions
Increases T1/2 of many drugs including,
– Penicillin
– oral hypoglycemics
– Rifampin
– Ciprofloxacin
– Acetaminophen
– Acyclovir
– Benzodiazepines
– Ganciclovir,Theophylline,Furosemide,and others.
!
FOSCARNET,(foss-KAR-net)
Inorganic pyrophosphate compound which inhibits:
– DNA polymerase
– RNA polymerase
– HIV Reverse Transcriptase
Resistance after long use and due to mutations in
DNA/RNA/RT polymerases
O P
O
O
O
O
3N a+Foscarnet
FOSCARNET,Use and Dosage
Only I.V,form due to poor bioavailability of oral
Concentration is reduced by 50 % after a 3-h hemodialysis
Concentration in CSF is ~ 50% of blood levels
~ 30 % of Foscarnet is deposited in bones (T1/2 up to several months)
Agent Route Use Adult Dosage
I.V.
CMV retinitis
Acyclovir resistant
infections
CMV colitis
Induction,60 mg/kg q8h
Maintenance,90-120 mg/kg/d
40 mg/kg q8-12h
60mg/kg q8hF
OSC
AR
NE
T
FOSCARNET,Adverse Effects
NB! Foscarnet may cause or worsen anemia
Common
– Increased or decreased frequency of urination or amount of
urine; increased thirst
Uncommon
– Convulsions (seizures); fever,chills,and sore throat; muscle
twitching; pain at place of injection.
Rare
– Sores or ulcers on the mouth or throat,penis,or vulva
FOSCARNET,Drug Interactions
Nephrotoxic agents
Combination pain medicine containing acetaminophen and
aspirin (e.g.,Excedrin) or other salicylates
Cyclosporine
Deferoxamine
Lithium
Anti-infective agents
!
