Transcript ANTI VIRAL Agents

ANTI VIRAL Agents
Kaukab Azim, MBBS, PhD
Modified by: iSRAA
Lecture No: 01
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
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
latent
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
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.
2.
3.
4.
1.
2.
3.
4.
Herpes virus (HSV 1 & HSV 2)
Varicella Zoster (VZV)
Cytomegalovirus (CMV)
Hepatitis B virus
Hepatitis C
HIV (Retro virus)
Respiratory syncytial virus
Influenza A & infl. B
viruses
Treatment of Influenza A
AMANTADINE
• MOA: Inhibits uncoating
no penetration
• Uses: Prophylaxis & treatment of influenza A
• It used to be active against influenza A, but not influenza B. As
in recent past seasons, there is a high prevalence (>99%) of
influenza A resistant to amantadine. Therefore it is no longer
recommended for Influenza A
• S/E:
CNS:
insomnia
&
restlessness
Livedo reticularis(*Livedo reticularis is a vascular
condition characterized by a purplish discoloration of the skin,
usually on the legs. This discoloration is described as lacy or
net-like in appearance and may be aggravated by cold
exposure.)
•  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
• 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
OSELTAMIVIR: Tamiflu
Treatment of HSV, VZV and CMV
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Acyclovir
Ganciclovir
Foscarnet
1st two are purine analogs
Acyclovir and Ganciclovir are prodrugs
Compete with dGTP for viral DNA- polymerase
& inhibit viral DNA synthesis
• 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 ptns)
Use in pregnancy:
• For 1st episode of genital Herps 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
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)
When acyclovir is effective as CMV
prophylaxis, why ganciclovir is used?
1. To treat lung, colon infection
2. Good in AIDS patients
3. Has less teratogenicity
FOSCARNET (alternate to Ganciclovir for CMV)
• Not a prodrug!
• Uses; CMV infections, Acyclovir-resistant HSV encephalitis
• MOA; Directly inhibits DNA polymerase
• Side Effect:
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Renal function, hypocalcaemia, teratogenic, mutagenic &
carcinogenic drug
• Drug Interactions:
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Cyclosporine (renal toxicity),
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Pentamidine (hypocalcaemia),
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Imipenem (seizures)
RIBAVIRIN:
Respiratory Syncytial Virus (given by aerosol only)
Hepatitis C
MOA:
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Synthetic analogue of nucleoside;
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Inhibits GTP synthesis
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Inhibits 5̀ capping of viral mRNA,
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Inhibits RNA- dependent RNA polymerase
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S/ E:
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Uses: Severe RSV infection with serious underlying respiratory, CV
problems or immuno compromised
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C.I: Pregnancy (EOL)
Headache, insomnia, anemia, teratogenesis
Lecture No:02
HEPATITIS B: Lamivudine (Anti-retro viral”ARV drug)
• Inhibits HBV-DNA polymerase & HIV- reversetranscriptase
by
competing
with
dCTP(*
Deoxycytidine triphosphate (dCTP edisoelcun a si )
esab enidimiryp eht sniatnoc taht etahpsohpirt
enisotyc)*
• 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;
• Reduces progression of liver disease in HBV
• S/E: Many, Flu-like syndrome, Bone marrow
suppression
HEPATITIS C: Peg-interferon  Ribavirin
*(Pegylation is the process of covalent
attachment of polyethyleneglycol(PEG)
polymer chain to another molecule{ normally
a drug OR therapeutic protein} and Ribavirin .PEG
gives the IFN- α better PK properties such as
solubility and half-life.*
PAPILLOMAVIRUS:
• Imiquimod- is a an immune response modifier
• For topical treatment of perianal & external genital
warts(*Benign growth on the skin)*
Stages in Retrovirus development
Why Body Defenses Disappear
Anti retroviral agents( HIV)
• 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
Non
NRTIS(NonNRTIs(Nucl
Nucleoside
eoside reverse
Protease inhibitors
reverse
transcriptase
transcriptase
Inhibitors )
Inhibitors )
Zidovidine
Nevirapine
Saquinavir
Didanosine
Delavirdine
Indinavir
Stavudine
Efavirenz
Ritonavir
Lamivudine
Atazanavir
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ART
Antiretroviral therapy (ART) is begun when:
– Symptomatic disease is present, regardless of CD+4
count and viral load (*CD(4 cluster of differentiation )4
sllec enummi fo ecafrus eht no dnuof nietorpocylg a si
segahporcam ,setyconom ,sllec repleh T sa hcus)*
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 associated 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
NRTIs
MAJOR TOXIC EFFECT
Zidovudine
Bone marrow suppression,
myopathy & lactic acidosis (LA)
Lamivudine
LESS TOXIC THAN ABOVE
Didanosine
NEUROPATHY, Hepatitis, LA,
PANCREATITIS
Abacavir
Stavudine
HYPERSENSITIVITY
REACTIONS, MYOPATHY
NEUROPATHY, Hepatitis, LA
PANCREATITIS (no myopathy)
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 DNA
Note: They are NOT pro drugs!
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 affect lipid profile. Toxicities
do not overlap with NRTIs
• Major toxicity: Skin rashes
Protease Inhibitors
(Do not need to be prodrugs)
• Saquinavir
• Indinavir
• Ritonavir
MOA:
• Blocks the protease enzyme(*Necessary 4 assembly of
HIV )*
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HIV protease cleaves newly synthesized polyproteins at
the appropriate places to create the mature protein
components of an infectious HIV virion.
• Can inhibit cell to cell spread of the virus
Toxicity
Saquinavir:
• GIT disturbances
Indinavir:
• “trunkal obesity” (Cushing-like syndrome)
• Nephrolithiasis (kidney stones)
• Hemolytic anemia
Ritonavir:
• Paresthesias
FUSION INHIBITORS
Enfuvirtide, Maraviroc
MOA:
• Prevents the fusion of HIV with the host cell
membrane
Uses:
• To treat AIDS which is progressing despite
HAART (“highly active antiretroviral therapy” )
INTEGRASE INHIBITOR
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#Integration of viral DNA into host DNA
First approved HIV-integrase inhibitor.
Raltegravir - integrase inhibitor
Use: Detectable viremia & treatment
failure in ptn with triple class experience
• Short term efficacy
• # conversion
Adherence
• It is currently recommended that antiretroviral
therapy be initiated with 2 NRTIs in combination
with an NNRTI, PI, or integrase inhibitor.
• 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
CONCLUSIONS
ART:
Delays disease progression
Prolongs survival
Reduces maternal to child transmission.
BUT: Therapy is still suboptimal
Complete suppression of viral replication has
not been achieved.
Drugs are toxic
Resistance is a major problem
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