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 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 Viruses 1.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 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 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 Acyclo-MP Acyclo-DP Acyclo-TP (ACTIVE DRUG) Viral thymidine 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 ptns)

Use in pregnancy: For 1 st 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 1 st 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: Renal function, hypocalcaemia, teratogenic, mutagenic & carcinogenic drug Drug Interactions: Cyclosporine (renal toxicity), Pentamidine (hypocalcaemia), Imipenem (seizures)

RIBAVIRIN: Respiratory Syncytial Virus (given by aerosol only) Hepatitis C MOA: Synthetic analogue of nucleoside; Inhibits GTP synthesis Inhibits 5 ̀ capping of viral mRNA, Inhibits RNA- dependent RNA polymerase S/ E:Headache, insomnia, anemia, teratogenesis Uses: Severe RSV infection with serious underlying respiratory, CV problems or immuno compromised C.I: Pregnancy (EOL)

Lecture No:02 HEPATITIS B: Lamivudine (Anti-retro viral”ARV drug) Inhibits HBV-DNA polymerase & HIV- reverse- transcriptase by competing with dCTP(* Deoxycytidine triphosphate (dCTP) is a nucleoside triphosphate that contains the pyrimidine base cytosine)* 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 NRTIs( Nucl eoside reverse transcriptase Inhibitors ) Non NRTIS(Non- Nucleoside reverse transcriptase Inhibitors ) Protease inhibitors Zidovidine NevirapineSaquinavir Didanosine DelavirdineIndinavir Stavudine EfavirenzRitonavir Lamivudine Atazanavir

ART Antiretroviral therapy (ART) is begun when: – Symptomatic disease is present, regardless of CD+4 count and viral load (*CD4 (cluster of differentiation 4) is a glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages)* OR – Patient has CD+4 < 350 cells/mm 3 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

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

NRTIs MAJOR TOXIC EFFECT Zidovudine Bone marrow suppression, myopathy & lactic acidosis (LA) LamivudineLESS TOXIC THAN ABOVE Didanosine NEUROPATHY, Hepatitis, LA, PANCREATITIS Abacavir HYPERSENSITIVITY REACTIONS, MYOPATHY Stavudine 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 )* 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 #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

end