anti viral agents
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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
Indinavir
Oseltamivir
Reltegravir
Classes
• 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 Viruses1. Herpes virus (HSV 1 & HSV 2)2. Varicella Zoster (VZV)3. Cytomegalovirus (CMV)4. Hepatitis B virus
• RNA Viruses 1. Hepatitis C 2. HIV (Retro virus) 3. Respiratory syncytial virus 4. Influenza A & infl. B viruses
Treatment of Influenza AAMANTADINE
• MOA: Inhibits uncoating no penetration
• Uses: Prophylaxis & treatment, not for Influenza A • 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
• ACYCLOVIR• GANCICLOVIR• FOSCARNET • Compete with dGTP for viral DNA-
polymerase & 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
Acyclo-MP
Acyclo-DP
Acyclo-TP
(ACTIVE DRUG)
Viral thymidine kinase
Cell kinase
Cell kinase
Incorporated into growing DNA strand
Chain termination
Stops viral replication
Competes with dGTP for viral
polymerase
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
GANCICLOVIR1st 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 gancyclovir is used?
1. To treat lung, colon infection2. Good in AIDS pt.s3. Has less teratogenicity
FOSCARNET (alternate to Ganciclovir for CMV)
Not a prodrug!
Uses: CMV infections Acyclovir-resistant HSV encephalitis
MOA: Directly inhibits DNA polymerase
S. Effect: in Renal function, hypocalcaemia, teratogenic, mutagenic & carcinogenic drugDrug 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 5 ̀ capping of viral mRNA, RNA-dependant RNA polymeraseS/ E: Headache, insomnia, anemia, teratogenesisUses: Severe RSV infection with serious underlying respiratory, CV problems or immuno compromisedC.I: Pregnancy
HEPATITIS B: Lamivudine (ARV drug) • Inhibits HBV-DNA polymerase & HIV- reverse-
transcriptase by competing with dCTP • Uses:
1. Chronic Hepatitis B infection with evidence of active viral replication
• 2. HIV infectionSE: N/V, headache, insomnia, fatigue
HEPATITIS B: INTERFERONs
• Interferon -2b & INF- : CytokineBroad spectrum antivirals, Immuno modulator activity, Antiproliferative actions; progression of liverDz in HBVS/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. Lamivudine2. Ribavirin3. Oseltamivir
HEPATITIS C: Peg-interferon Ribavirin
PAPILLOMAVIRUS: Imiquimod
For topical treatment of perianal & external genital warts
Stages in Retrovirus development
Why Body Defenses Disappear
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 EFAVIRENZ RITONAVIR
Lamivudine 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
AZT
AZTmonophosphate
AZT diphosphate
AZT triphosphate
Thymidine kinase
(host)
Thymidylate kinase
Cell Kinase
Incorporated into
Viral DNA strand
Chain elongation is terminated at thymidine residues
(lack of 3’-OH group)
No viral DNA formed
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. Inhibitor2. CCR5 inhibitor3. Protease inhibitor
NRTIs MAJOR TOXIC EFFECT
ZIDOVUDINE Bone marrow suppression, myopathy & lactic acidosis (LA)
LAMIVUDINE LESS TOXIC THAN ABOVE
DIDANOSINE NEUROPATHY, Hepatitis (LA), PANCREATITIS
ABACAVIRHYPERSENSITIVITYREACTIONS, MYOPATHY
STAVUDINENEUROPATHY, 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: 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 DNA
Note: They are NOT pro drugs!
Pharmacokinetics Of NNRTIsWell 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 profileToxicities do not overlap with NRTIsMajor toxicity: Skin rashes
Drug InteractionsNevirapine INDUCES enzymes: P.Is
Contraceptives
Efavirenz……………. Zidovudine
Indinavir
Antiepileptics level
Delavirdine INHIBITS enzymes: P.Is
An HIV positive female developed rash after 3 Months of treatment e efavirenz & switched
to nevirapine. She is expected to have:
1. Impaired lipid profile2. Decreased OCP levels3. 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, non-infectious particles.
Can inhibit cell to cell spread of the virus
ToxicitySaquinavir: 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
• 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
Initial Treatment: Preferred Components
*Avoid in pregnant women and women with significant pregnancy potential. Alternate is nevirapine.**Emtricitabine can be used in place of lamivudine or vice versa & a fixed dose combination e
tenofovir-efavirenz reduces pill burden.
Efavirenz*
OR
Atazanavir + ritonavirFosamprenavir + ritonavir (BID)Lopinavir/ritonavir (BID)
NNRTI Option
PI Options
Tenofovir + emtricitabine**Zidovudine + lamivudine**Abacavir + lamivudine
+
NRTI Options
Initial Treatment: Alternative Components
*Nevirapine should not be initiated in treatment naïve-women with CD4 counts >250 cells/mm3 or treatment naive-men with CD4 counts >400 cells/mm3
**Atazanavir must be boosted with ritonavir if used in combination with tenofovir
Nevirapine*
OR
Atazanavir** FosamprenavirFosamprenavir + ritonavir (1x/day)Lopinavir/ritonavir (1x/day)
NNRTI Option
PI Options
Abacavir + lamivudine (preffered)
Didanosine + (emtricitabine or lamivudine)
NRTI Options
Antiretroviral Medications: Not Recommended in Initial
Treatment (2)
High pill burden/Dosing- inconvenienceEmer. of resistance
Amprenavir Amprenavir/ritonavir Indinavir (unboosted) Nelfinavir + saquinavir
Lack of data or reserve for specific strains
Tipranavir Darunavir Enfuvirtide
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
Antiretroviral Medications: Should not be offered at any time
• Antiretroviral components not recommended:– Didanosine + stavudine– Stavudine + zidovudine– Emtricitabine + lamivudine
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
end
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