antiviral agents chapter 49 katzung -...
TRANSCRIPT
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Antiviral agents
Chapter 49
katzung
Dr. Azadeh Mesripour (Ph.D)
Pharm.MUI
2015
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Antivirals
Viruses controlled by current antiviral therapy
• Cytomegalovirus (CMV)
• Hepatitis viruses
• Herpes viruses
• Human immunodeficiency virus (HIV)
• Influenza viruses (the “flu”)
• Varicella Zoster Virus ;Chickenpox, Shingles
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Antiviral Agents
• Cure depends on host immune systemto eradicate.
If patients are immunocompromized, may have recurrences.
• Many need to be activated by viral and cellular enzymes before exerting antiviral effect.
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Antiviral Drugs
attachment to host cell penetration
Uncoating DNA/RNA synthesis
assembley
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Anti Human Herpesvirus drugs
• Acyclovir (G)
• Famciclovir (G)
• Penciclovir (G)
• Ganciclovir (G)
• Cidofovir (C)
• Foscarnet
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Guanine
Acyclovir Ganciclovir
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Nucleoside AnaloguesGeneral Mechanism of Action
1. Taken up by cells
2. Converted by viral and cellualr enzymes to the triphosphate form.
3. The triphosphate form:
1. Inhibits viral DNA polymerase.
2. Or it may get incorporated into growing DNAleading to abnormal proteins or breakage.
Acyclovir (Zovirax)
• Used to suppress replication of:
– HSV-1(oral herpes), HSV-2(genital herpes),
VZV (Varicella – chickenpox or shingles)
• Drug of choice for treatment of initial and
recurrent episodes of these infections.
• Oral, topical, parenteral forms
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Acyclovirand Valacyclovir (prodrug, better availability)
A Guanine analogue for Herpes group (HSV-1,2 & VZV)
Acyclovir AcycloMP AcycloTP
Thymidine kinase Cellular kinases
Viral 200x affinity
of mammalian
1. Inhibits viral DNA polymerase selectively
2. Incorporated into DNA and terminates synthesis
Resistance:
1. ↓ activity of thymidine kinase
2. altered DNA polymerase
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• Bioavailability of oral
acyclovir is low (15–20%).
• Acyclovir is cleared
primarily by glomerular
filtration and tubular
secretion.
• T1/2=3 h in patients with
normal renal function and
20 h in patients with anuria.
• Diffuses readily into most
tissues (ie.CNS).
Oral acyclovir has multiple uses• In first episodes of genital herpes, oral
acyclovir shortens the duration of
symptoms by 2 days, the time to lesion
healing by4 days, and the duration of viral
shedding by 7 days.
• The risk of post-herpetic neuralgia is also
reduced if treatment is initiated early
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Oral acyclovir has multiple uses• In patients with varicella (if begun within
24 h after the onset).
• Acyclovir therapy significantly decreases
the total number of lesions, duration of
symptoms, and viral shedding
• However, because VZV is less susceptible
to acyclovir than HSV, higher doses are
required.
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Intravenous acyclovir
• Is the treatment of choice for herpes
simplex encephalitis,
• Neonatal HSV infection, and serious HSV
or VZV infections.
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Adverse effects
• Nausea, diarrhea, and headache may
occur.
• Iv infusion may be associated with
reversible renal toxicity (ie, crystalline
nephropathy or interstitial nephritis) or
neurologic effects (eg, tremors, delirium,
seizures).
• However, these are uncommon with
adequate hydration and avoidance of rapid
infusion rates. 17
Valacyclovir
• The l-valyl ester of acyclovir.
• Serum levels are 3-5 times greater than
those achieved with oral acyclovir(f=70%)
• Approximate serum levels achieved with iv
acyclovir. Oral
• Elimination half-life is 3 hours.
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Famciclovir
• Famciclovir Liver Penciclovir
(Guanine)
• Mechanism is like Acyclovir (but
not chain termination)
• Against HSV-1,2 & VZV
• Bioavailability Famciclovir: 70%
• Excretion: renal
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Famciclovir
• Adverse effects: headache, nausea, diarrhea
• One-day usage of famciclovir significantly
accelerates time to healing of recurrent genital
herpes and of herpes labialis.
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• Penciclovir: aginst recurrent
herpes (topical)
• Docosanol inhibits fusion
between the host cell plasma
membrane and the HSV
envelope, thereby preventing
viral entry into cells.
• Topical docosanol 10% cream is
available.
Trifluridine
• phosphorylated by host cell enzymes
• Incorporation of triphosphate into both viral
and host DNA prevents its systemic use.
• Application of a 1% solution is effective in
treating keratoconjunctivitis and recurrent
epithelial keratitis due to HSV-1 or HSV-2.
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AGENTS TO TREAT
CYTOMEGALOVIRUS (CMV)
INFECTIONS
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• CMV infections occur
primarily in the setting
of advanced
immunosuppression .
• Clinical reactivation of
CMV infection after
organ transplantation
is still prevalent.
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Ganciclovir
• Mechanism is like Acyclovir
• Active against all Herpes viruses specially CMV(100 times more than acyclovir)
• Drug of choice for CMV infections
• Low oral bioavailability (6-9%); given I.V.
• Most common adverse effect: bone marrow suppression (leukopenia 40%, thrombocytopenia 20%) and rarely CNS effects(headache, behavioral changes, psychosis, coma, convulsions).
Valganciclovir
• An L-valyl ester prodrug of ganciclovir
• After oral administration, it rapidly
hydrolyzed to ganciclovir by esterases in
the intestinal wall and liver.
• Valganciclovir is well absorbed;
• F oral valganciclovir is 60%
• It is recommended that the drug be taken
with food.
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Cidofovir• A cytosine analog
• Is independent to viral enzymes,
effective against resistant strains.
• Mainly for HSV-2 & CMV
• Excretion: renal (probencid reduce
tubular secretion).
• Only IV
• Active metabolites with long t1/2
(60h)
• Adverse effects:
• Nephrotoxicity(+probencid)
• Uveitis,
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Foscarnet• An inorganic pyrophosphate
analog.
• Direct inhibition of DNA
polymerase, RNA polymerase and
HIV reverseTranscriptase
• Only IV
• Up to 30% of foscarnet deposits in
bone, with a half-life of several
months.
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Foscarnet
• Active against:
– HSV-1,2; VZV; CMV;
–
• Adverse effects:
– Nephrotoxicity
– Hypocalcemia (chelates divalent cations)
– CNS (tremor, irritability, seizure)
• Active against:
– HSV-1,2; VZV;
Only used for resistant virus to Acyclovir and
Ganciclovir
– genital ulcers
• In order to reduce renal toxicity;
1) Slow infusion rate
2) Preloading with N/S
3) Avoid other nephrotoxics
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Antiviral Drugs for Influenza
• Are effective for both early treatment
and chemoprophylaxis of influenza
infections.
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Classes of Influenza Antiviral Drugs
M2 inhibitors
• Amantadine
• Rimantadine
Neuraminidase
inhibitors
• Oseltamivir
• Zanamivir31
Amantadine, Rimantadine
• Chemically related
• Orally administered (100 mg tablets and
syrup for children)
• Activity against influenza A viruses only.
• Have comparable antiviral and clinical
activities when used for prophylaxis or
treatment.
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Amantadine, Rimantadine
Mechanism of Action
• Interfere with the function of the
transmembrane domain of the M2 protein
of influenza A viruses.
• Decrease the release of influenza A
viral particles into the host cell.
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Amantadine, Rimantadine
Treatment (3-5 days)
• Decreases length of illness due to
influenza A by about 1 day.
• Must be started within 2 days of
illness.
• Dose adjustments required for
relatively small decreases in renal
function.
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Adverse Effects
Gastrointestinal: nausea, vomiting
Commonly associated with dose-related minor
CNS side effects;
– anxiousness, difficulty concentrating,
insomnia, lightheadedness
•More serious side effects (eg,delirium,
hallucinations,agitation, and seizures
Rimantadine similar reactions, but less common
than amantadine;
• in part related to lower plasma drug
concentrations.35
Neuraminidase Inhibitors
Oseltamivir, Zanamivir
Have activity against both
influenza A and influenza B
viruses.
Chemically related, but have
different routes of
administration.
Reduce the number of viral
particles released from
infected cells.36
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• Oseltamivir (prodrug); Orally
administered: 75 mg tablets and syrup for
children.
•Zanamivir; Inhalational delivery of dry
powered drug.
Approved for treatment and prophylaxis
of influenza A and B
Treatment 1 year(O), 7years(Z)
Chemoprophylaxis 13 years
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Oseltamivir, Zanamivir
Treatment: 5 Days
Treatment
Must be administered < 48 hours after onset of
illness.
Reduce symptoms and decrease length of
illness due to influenza A & B virus infections by
approximately 1 day.
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Oseltamivir Adverse Effects
Potential adverse effects include:
• nausea, vomiting, and headache.
•Fatigue and diarrhea have also been reported
and are more common with prophylactic use
• Fewer GI symptoms if given with food.
• Only 1-2 % stop because of adverse events.
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Zanamivir Adverse Effects
Nasal & throat discomfort.
Headache
Cough
Use in pts with pre-existing lower airway tract
disease associated infrequently with
bronchospasm.
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Viral hepatitis
• Hepatitis B;
Adefovir, lamivudine
• Hepatitis C;
interferon alfa 2a , alfa 2b and ribavirin
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INTERFERON ALFA
• Some have proven useful in both HBV and
HCV
• Interferon alfa-2a and interferon alfa-2b
may be administered either SC or IM.
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• Alfa interferons are filtered at the
glomerulus and
• Liver metabolism and subsequent biliary
excretion are considered minor pathways.
• The use of pegylated interferon alfa-2a
and alfa-2b, and steadier concentrations,
thus allowing for less frequent dosing.
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Adverse reactions
• flu-like syndrome, occurs within 6 hours
• Transient hepatic enzyme elevations
• during chronic therapy: neurotoxicities
myelosuppression, profound fatigue, weight
loss, rash, cough, myalgia, alopecia, tinnitus,
reversible hearing loss, retinopathy,
pneumonitis, and possibly cardiotoxicity.
• Induction of autoantibodies may occur,
causing exacerbation or unmasking of
autoimmune disease45
Contraindications & Caution
• Hepatic decompensation, autoimmune
disease, and history of cardiac arrhythmia.
• Caution is advised in psychiatric disease,
epilepsy, thyroid disease, cardiac disease,
severe renal insufficiency, and cytopenia.
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drug-drug interactions
• Increased theophylline and methadone
levels.
• Co-administration with didanosine
increase risk of hepatic failure,
• Co-administration with zidovudine may
exacerbate cytopenias.
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HBV therapy
The goals:
• The suppression of HBV DNA to
undetectable levels,
• Seroconversion of HBag from positive to
negative,
• Reduction in elevated hepatic transaminase
levels.
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Oral drugs: now considered the
first line of therapy
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HCV infection
• In contrast to the treatment of patients with
chronic HBV infection,
• The primary goal of treatment in patients
with HCV infection is viral eradication.
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Adverse effects: A dose dependent
hemolytic anemia occurs in 10–20%
of patients. Other potential adverse
effects are depression, fatigue.
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HIV life cycle
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AIDS
• Hallmark: depletion of CD4 lymphocytes
cellular immunodeficiency
• Etiology: worldwide HIV-1
west africa HIV-2
• HIV-2 is resistant to NNRTIs
• Patient is susceptible to various infections
(TB, Candidiasis, CMV) & malignancies.
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Classification of
1- Attachment & fusion inhibitors
– Enfuvirtide (T20)
2- Nucleoside Reverse Transcriptase inhibitors
– Zidovudine*, Stavudine, Didanosine, Lamivudine*
3- Non-nucleoside Reverse Transcriptaseinhibitors (NNRTI)
– Delavirdine, Efavirenz, Nevirapine *
4- Protease inhibitors
– Indinavir, Saquinavir, Ritonavir*, Nelfinavir
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Principles of treatment
• Life long therapy !
• Combination therapy; at least 2 drugs (otherwise ?)
• Non-adherence to regimens therapeutic
failure (recurrences), drug resistance,
limitation of future options & death
• NRTIs are the cornerstone of therapy.
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NRTIs
• NRTIs are prodrugs: activation by
phosphorylation by host cell enzymes.
• All are inhibitors of RT (by competition).
• RNA Reverse Transcriptase DNA
• Incorporation into DNA terminates chain
elongation.
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NNRTIs
• Activation by phosphorylation is not needed.
• All are inhibitors of RT (by conformational
changes).
• RNA Reverse Transcriptase DNA
• Effective just against HIV-1
• Are metabolized by CYP450 enzymes ? (drug
interactions)
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Protease Inhibitors
• HIV protease is essential for viral infectivity.
• Protease cleaves the viral polyprotein into
active viral enzymes (RT, protease,
integrase).
• PIs make viruses to be immature &
noninfectious.
• Are metabolized by CYP450 enzymes
• CYP3A4 inhibitors as well.
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Protease Inhibitors
• Adverse effects:
– GI (nausea, vomiting, diarrhea)
– Paresthesias
– Diabetes
– Cholestrol & TG
• In prolonged administration:
– Fat redistribution (central)
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