Transcript ANTI VIRAL Agents

ANTI VIRAL Agents
Kaukab Azim, MBBS, PhD
Viruses
Features of Antiviral Drugs
•Purine or pyrimidine analogs
•Prodrugs must be phosphorylated
•Antivirals have a narrow spectrum of action
•Inhibit active replication; do not kill latent
viruses, need host immune response
•Resistance is common
•Synergistic effects when given together
•Efficacy relates to con. in infected cells
•Start therapy early for optimal efficacy
A good antiviral drug will
Interfere with a viral specific function
Only kill virus-infected cells
Prevent viral replication
Sites Of Anti Viral Drug Action
Enfuvirtide, maraviroc
Reltegravir
Oseltamivir
Indinavir
B
C
D
Classes
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Class I Antinfluenza agents
Class II Antiherpetic agents
Class III Antiviral for HBV & HCV
Class IV Antiretroviral therapy (ART)
Class V Agents against human Papiloma
virus and RSV
Viruses susceptible to drug therapy
• DNA Viruses
• RNA Viruses
1. Herpes virus (HSV 1 &
1. Hepatitis C
HSV 2)
2. HIV (Retro
2. Varicella Zoster
virus)
(VZV)
3. Respiratory
3. Cytomegalovirus
syncytial virus
(CMV)
4. Influenza A &
4. Hepatitis B virus
infl. B viruses
Treatment of Influenza A
AMANTADINE
• MOA: Inhibits uncoating
no penetration
• Uses: Prophylaxis & treatment,
• S/E: CNS: insomnia & restlessness
Livedo reticularis
•  dose in renal dysfunction
• Good alternative to a vaccine in the elderly or in
immuno compromised patients
OSELTAMIVIR: Tamiflu
• Prophylaxis and treatment of Influenza
A and B
• Neuraminidase inhibitor
OSELTAMIVIR: Tamiflu
• Flu virus attaches to host cell membrane –
hemagglutinin on viral envelope binds to
sialic acid moiety in glycoprotein of cell
membranes
• Neuraminidase enzyme cleaves viral
attachment
• Neuraminidase inhibitor keep the virus
tethered to the host cell membrane; prevent it
from being released and thus spreading to
other cells
Treatment of HSV, VZV and CMV
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ACYCLOVIR
GANCICLOVIR
FOSCARNET
Compete with dGTP for viral DNApolymerase & inhibit viral DNA synthesis
• 1st two are purine analogs
• Acyclovir and Ganciclovir are prodrugs
• Foscarnet acts directly on DNA
polymerase
ACYCLOVIR: guanine analog
MOA: Inhibits HSV replication
Acyclovir
Stops viral replication
Viral thymidine kinase
Acyclo-MP
Cell kinase
Acyclo-DP
Competes with
dGTP for viral
polymerase
Chain termination
Cell kinase
Acyclo-TP
(ACTIVE DRUG)
Incorporated into
growing DNA strand
USES of ACYCLOVIR
• Genital Herpes: 1st episode
 viral shedding,  duration
of symptoms
• Orolabial herpes:
Topical/ oral acyclovir
(penciclovir)
• Herpes encephalitis: Acyclovir I/V
• Varicella zoster: Oral, till all lesions
encrusted
I/V in disseminated CNS
or Visceral infection
• Cytomegalovirus: Prophylaxis only (prevent
CMV infection in
transplant patients)
Use in pregnancy: for 1st episode of genital H.
to prevent neonatal herpes (H.pneumonia)
Side effects: NEPHROTOXIC
(reversible crystalline nephropathy)
Encephalopathy (rare)
Resistance:
Mutations occur in the thymidine kinase gene
causing an enzyme that does not
phosphorylate acyclovir
Occurs more in HIV+ive people
A 23-year-old man had recurrent genital herpes which was effectively treated each
time by acyclovir. The patient asked his physician why the treatment was not able to
prevent recurrence. Which of the following was most likely the answer of the
physician?
A) Acyclovir has a very short duration of action
B) Recurrence is due to a new contact with infected partners
*C) Antiviral drugs have no effect on the latent state of viral diseases
D) Recurrence is due to a hypersensitivity reaction to viral proteins
E) Resistant to acyclovir is the rule after one cycle of therapy
GANCICLOVIR
1st drug effective against CMV
Uses: Cytomegalovirus (CMV):
Acute infection (retinitis, pneumonia in AIDS)
Prophylactic (in transplant patients, AIDS)
S/E: Bone marrow toxicity
(granulocytopenia & thrombocytopenia)
Drug Interactions:
DO NOT give with ZIDOVUDINE (overlapping
myelosuppression toxicities)
A 31-year-old man with AIDS was recently diagnosed with cytomegalovirus
pneumonia. The patient’s current medications included zidovudine,
didanosine and saquinavir. An IV therapy with ganciclovir was started.
Which of the following adverse effects could be most likely predicted from
the concurrent administration of ganciclovir and the antiretroviral drugs?
A) Anemia and neutropenia *
B) Retinal detachment
C) Cataract
D)Sexual dysfunction
E) Hyperglycemia
F) Lactic acidosis
FOSCARNET (alternate to Ganciclovir for CMV)
Not a prodrug!
Uses:
CMV infections
Acyclovir-resistant HSV encephalitis
MOA:
Directly inhibits DNA polymerase
S. Effect: Decrease in Renal function,
hypocalcaemia, teratogenic, mutagenic & carcinogenic
drug
Drug Interactions:
Cyclosporine (renal toxicity), Pentamidine
(hypocalcaemia), Imipenem (seizures)
Wide Spectrum anti viral
RIBAVIRIN:
Respiratory Syncytial Virus (given by aerosol only)
Hepatitis C
MOA: Synthetic
analogue of nucleoside; inhibits GTP synthesis & ,
inhibits 5̀ capping of viral mRNA, RNA-dependant
RNA polymerase (MAO not known exactly)
S/ E: Headache, insomnia, anemia, teratogenesis
Uses: Severe RSV infection with serious underlying
respiratory, CV problems or immuno compromised
C.I: Pregnancy
HEPATITIS B: Lamivudine (ARV drug)
• Inhibits HBV-DNA polymerase & HIV- reversetranscriptase by competing with dCTP
• Uses:
1. Chronic Hepatitis B infection
with evidence of active viral replication
• 2. HIV infection
SE: N/V, headache, insomnia, fatigue
HEPATITIS B: INTERFERONs
• Interferon -2b & INF- : Cytokine
Broad spectrum antivirals, Immuno modulator
activity, Antiproliferative
actions;
progression of liver
Dz in HBV
S/E: Many, Flu-like
syndrome, Bone marrow suppression
A 10-days old baby girl/ an AIDS pt. e
low CD+4/ or bone marrow transplant
pt. is suffering from RSV pneumonitis,
what is the treatment of choice?
1. Lamivudine
2. Ribavirin
3. Oseltamivir
HEPATITIS C: Peg-interferon 
Ribavirin
PAPILLOMAVIRUS: Imiquimod
For topical
treatment of
perianal &
external genital
warts (cream)
Stages in Retrovirus development
Anti retroviral agents
• 4-5 big classes
1) Protease Inhibitors
2) Nucleoside reverse transcriptase
Inhibitors
3) Non-nucleoside reverse
transcriptase inhibitors
4) Fusion Inhibitors
5) Integrase inhibitors
Retrovirus & Anti retroviral agents
Drugs in different classes
NRTIs
Non NRTIS
Protease
inhibitors
Zidovidine
NEVIRAPINE
SAQUINAVIR
Didanosine DELAVIRDINE INDINAVIR
Stavudine
Lamivudine
EFAVIRENZ
RITONAVIR
ATAZANAVIR
ART
• Antiretroviral therapy (ART) is begun when:
Symptomatic disease is present, regardless of
CD+4 count and viral load
OR
• Patient has CD+4 < 350 cells/mm3 with any
value of RNA copies per milliliter
– OR
• Plasma HIV RNA viral load>10,000-20,000/ml
• HIV infection assoc with lots of symptoms
Malaise, fever, blood disorders, neurological,
opportunistic infections etc. difficult to separate
these effects from the side effects of the drugs
Zidovudine (NRTIS)
• Inhibit reverse transcriptase – prevent conversion of
viral RNA to DNA
• All NRTIs nucleoside analogs e.g. Zidovudine
(azidothymidine- AZT) a thymidine analog
• NRTIs: narrow therapeutic window, dose limiting
toxicities (mainly due to mitochondrial toxicity and
inhibition of cellular DNA polymerases)
• In toxicity– withdraw drug until symptoms clear or
become tolerable OR the drug has to be
discontinued
No viral DNA formed
AZT
Thymidine kinase
(host)
AZTmonophosphate
Thymidylate kinase
AZT diphosphate
Chain elongation is
terminated at
thymidine residues
(lack of 3’-OH group)
Cell Kinase
Incorporated into
AZT triphosphate
Viral DNA strand
Resistance
• Major cause of treatment failure
•  Likelihood of resistance:
 duration of therapy
Advancing disease
• Due to point mutations in reverse transcriptase
enzyme
• 33% patients on monotherapy with AZT become
resistant within a year
• Use a combination of NRTIs so that there are
different point mutations
• R5 viral strains & Maraviroc (new; fusion inhibitor)
Maraviroc is a:
1. Reverse T. Inhibitor
2. CCR5 inhibitor
3. Protease inhibitor
NRTIs
MAJOR TOXIC EFFECT
Bone marrow suppression,
ZIDOVUDINE
myopathy & lactic acidosis (LA)
LAMIVUDINE LESS TOXIC THAN ABOVE
NEUROPATHY, Hepatitis (LA),
DIDANOSINE
PANCREATITIS
ABACAVIR
STAVUDINE
HYPERSENSITIVITY
REACTIONS, MYOPATHY
NEUROPATHY, Hepatitis (LA)
PANCREATITIS (no myopathy)
Maykota, a 42 year old company executive
visited his physician complaining of mouth sores.
On questioning he stated that he had been
feeling unwell for the past couple of weeks. He
felt tired and had lost his appetite.
On examination, the physician noted white
plaques in his mouth and a generalised
lymphadenopathy.
Results
ELISA:
HIV positive
CD4+ count: 350 mm3
mouth swab positive for Candida albicans
The physician decided to prescribe antiretroviral
drugs for him and clotrimazole or nystatin for
the Candida infection.
The antiretroviral drugs he was prescribed were
a combination of efavirenz, lamivudine and
abacavir (treatment naive patient)
These 3 drugs are typical of the HAART
regimen. 2 NRTIs together are synergistic.
HAART: Highly Active Anti Retroviral Therapy
Now called ART:Antiretroviral Therapy (ART)
NON NUCLEOSIDE REVERSE TRANSCRIPTASE
INHIBITORS (NNRTIs)
•NEVIRAPINE
•Delavirdine
•Efavirenz
MOA: Bind directly to reverse transcriptase
Allosteric inhibition of enzyme function
Blocks transcription of viral RNA to
Note: They are NOT pro drugs!
DNA
Pharmacokinetics Of NNRTIs
Well absorbed orally
Enter CNS (nevirapine more than the others)
Metabolized in the liver by cytochrome P450 enzymes
Excreted by the kidney
Lot of potential (cyp450) for drug interactions
Toxicity: Relatively low toxicity, also effect lipid profile
Toxicities do not overlap with NRTIs
Major toxicity: Skin rashes
Drug Interactions
Nevirapine INDUCES enzymes:  P.Is (protease inhibitors)
(saquinavir, ritonavir, indinavir, nelfinavir, amprenavir)
 Contraceptives
Efavirenz…………….
 Zidovudine
 Indinavir
 Antiepileptics level
Delavirdine INHIBITS enzymes: P.Is
An HIV positive female developed rash
after 3 Months of treatment with efavirenz
& switched to nevirapine. She is expected
to have:
1. Impaired lipid profile
2. Decreased OCP levels
3. Increased biliary excretion
Protease Inhibitors
(Do not need to be prodrugs)
• SAQUINAVIR
• Indinavir
• Ritonavir
MOA: Blocks the protease enzyme
Prevent the cleavage of the gag and gag-pol protein
precursors causing the formation of immature, noninfectious particles.
Can inhibit cell to cell spread of the virus
Gag is a polyprotein and is an acronym for Group Antigens (ag).
Pol is the reverse transcriptase.
Env in the envelope protein.
Toxicity
Saquinavir: GIT disturbances
Indinavir: “trunkal obesity”
(Cushing-like syndrome)
Nephrolithiasis (kidney stones)
Hemolytic anemia
Ritonavir: Paresthesias
Drug Interactions
All INHIBIT cytochrome P450 enzymes
High potential for drug interactions!
Ketoconazole:  toxicity of saquinavir
Delavirdine:  toxicity of saquinavir
and indinavir
Rifampin:  efficacy of all P.Is
Ritonavir:  rifampin toxicity
FUSION INHIBITORS
ENFUVIRTIDE, Maraviroc
MOA: Prevents the fusion of HIV
with the host cell membrane
Uses: To treat AIDS which is
progressing despite HAART
Integrase inhibitor
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Integration of viral DNA into host DNA
First approved HIV-integrase inhibit.
Raltegravir - integrase inhibitor
Use: Detectable viremia & treatment failure in
pt e triple class experience
• Short term efficacy
Adherence
• A major determinant of degree and
duration of viral suppression
• Poor adherence associated with virologic
failure
• Optimal suppression requires 90-95%
adherence
• Suboptimal adherence is common
Antiretroviral Medications: Should
not be offered at any time
• Regimens not recommended:
– Monotherapy (except possibly zidovudine to prevent
perinatal HIV transmission)
3-NRTI regimen (except abacavir/lamivudine/
zidovudine and possibly lamivudine/zidovudine +
tenofovir
– NRTI-sparing regimens
A 43-year-old man with AIDS presented to his physician with a complaint of
multiple painful ulcers in tongue and palate. Exfoliative cytology was done
which led to the diagnosis of herpes simplex infection, and a therapy with oral
acyclovir was initiated. Two weeks later no improvement was seen and the
dose of the drug was increased but without success. Which of the following
was most likely the cause of failure of acyclovir therapy?
A) Mutation of aspartate protease
B) Viral transpeptidase deficiency
* C) Viral thymidine kinase deficiency
D) Viral neuraminidase deficiency
E) Mutation of reverse transcriptase
end