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ANTIVIRAL DRUGS

Dr. Gyanendra Raj Joshi

PharmD, RPh

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Virus :Obligate parasite Virus particles (virions)

consist of following parts:

• Genetic material (DNA or RNA).

• Protein coat (capsid) that surrounds nucleic acid.

• Envelope (contains lipids and lipoproteins) that surrounds the capsid when virus is outside a cell.

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DNA Virus:Pox virus( small pox)Herpes virusAdeno virus

( conjunctivitis , sore throat)

Hepadna virus ( HBV)Papilloma virus ( warts )

RNA virusRubella virus ( German Measles)Rhabdo virus ( rabies)Picorna virus ( polio, meningitis,

cold , Hepatitis A)Arena virus (lassa fever)Flavi virus (yellow fever , HCV)Orthomyxo virus (Influenza)Paramyxo virus (mumps ,

measles)Corona virus (cold , SARS)

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Viral infections

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Mechanism of action Major drugs

Block viral penetration/ uncoating Amantadine, enfuvirtide, maraviroc

Inhibit viral DNA polymerase Acyclovir , foscarnet, ganciclovir

Inhibit RNA polymerase Foscarnet , ribavirin

Inhibit viral Reverse transcriptase Zidovudine, didanosine,zalcitabine , lamivudine, stavudine, neprapine , efavirenz

Inhibit viral aspartate protease Indinavir, ritonavir, saquinavir , nelfinavir

Inhibit viral neuraminidase Zanamivir, oseltamivir

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1. Anti Herpes agents

AcyclovirValacyclovirFamciclovirGanciclovir Foscarnet Penciclovir Cidofovir Idoxuridine

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3. Anti HBV Agents Adefovir

Entacavir

4. Anti-Influenza Virus Amantadine Rimantadine

5. Nonselective Antiviral Drugs RibavirinLamivudine AdefovirInterferons

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Anti Herpes Drugs Herpesviridae family- HSV-1, HSV-2, VZV, CMV

Mouth, face skin, esophagus , brain----HSV-1Genitals , rectum, skin , hands, meninges----HSV-2

Arrest DNA synthesis by inhibiting viral DNA polymerase .

Most of them prodrugs

Require Viral and Host cellular enzymes ( eg. Thymidine deoxyguanosine kinase ) to phosphorylate them into active triphosphate form

Common mechanism of resistance is alteration in viral enzymes

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Mechanism of action of Anti Herpes agents

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Acyclovir

• Synthetic analogue of guanosine • Valacyclovir is a prodrug

Acyclovir monophosphate is phosphorylated to triphosphate , gets incorporated into Viral DNA and inhibits replication.

HSV thymidine kinase DNA polymerase Chain terminationSuicide inactivationSpectrum: HSV-1, HSV-2, VZVNever totally cure

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• Advantage:– No hematotoxicity, no myelosupression– Treatment of herpes encephalitis

• Resistance :– Absence or partial production of TK– Altered TK specificity– Altered viral DNA polymerase

• Adverse effects :– PEG base topical effects– Oral- nausea , vomiting , diarrhoea and headache – Dose dependent renal impairment , crystallie nephropathy– Neurological – lethargy , confusion , tremors – Rash , itching and phlebitis at injection site

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Ganciclovir

• Similar to acyclovir • First phosphorylation viral specific, TK in HSV,

Phosphotransferase (UL97) in CMV• Triphosphate form inhibits viral DNA

polymerase and causes chain termination• HSV, VZV, CMV reitinitis in HIV patients • Dose limiting hematotoxicity, mucositis , fever,

rash , crystalluria• Seizures in overdose

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Foscarnet

Inorganic pyrophosphate analog inhibitory for herpes and HIV

• Not an antimetabolite• Interacts directly with Viral DNA polymerase

or HIV reverse transcriptase • Blocks binding site of pyrophosphate and

inhibits cleavage • IV

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• Nephrotoxicity• Hypocalcemia• Acute tubular necrosis• Crystalluria• CNS – tremor, irritabilty, seizure , halluccination, • Rash, fever,nausea, vomiting• Anemia, LFT,ECG• Avoid pentamidine iv• CMV retinitis • Ganciclovir resistant infections in AIDS

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Anti-influenza agents • Amantadine/ rimantadine

– Tricyclic amines– Low concentration inhibits replication– Rimantadine more active , also for Trypanosoma brucei– Inhibit attachment, penetration and viral uncoating– M2 protein inhibition– Potentiate acid pH induced changes in hemaggluttin during intracellular

transfer– Minor Dose related GIT and CNS effects – Atropine like – Livedo reticularis– Insomnia – Loss of appetite – Teratogenic

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Oseltamivir/zanamivir

– Absorbed rapidly and cleaved to active carboxylate

– Selective inhibitor of vial neuraminidase and leads to viral aggregation and reduced spread

– Nausea , abdominal discomfort—given with food– Nasal and throat irritation– Flu like – Influenza A and B

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Ribavirin

• Monophosphorylated form inhibits IMP dehydrogenase and as a result depletes intracellular nucleotide reserves.

• Triphosphate inhibits viral RNA polymerase and end capping of viral RNA

• Used as an adjunct to IFN in HCV infection• Management of respiratory syncytial virus • Lassa fever • Hematotoxic• Upper airway irritation• Teratogenic

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Anti hepatitis agents

• Adefovir dipivoxil– Acyclic phosphonate

nucleotide of adenosine monophosphate

– Adefovir diphosphate is competitive inhibitor of DNA polymerase and reverse transcriptase

– Chain terminator – Chronic HBV– Lamivudine resistant HBV

strains

– Reduced carnitine – Dose related

nephrotoxicity/tubular dysfunction

– Headache , abdominal discomfort, diarrhoea , asthenia

– Hepatotoxicity ,lymphoid toxicity

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Interferons

• Potent cytokines • Antiviral, immunomodulating and antiproliferative • Synthesised by host cells • Types – – α, β- all cells, stimulate MHC antigen– γ - T lymphocytes / NK cells

• Pegylated interferon• Inhibit protein synthesis , activate

endoribonuclease

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• Acute influenza like syndrome – fever , chills, headache, myalgia , arthralgia, nausea , vomiting and diarrhorea

• Tolerance• Dose limiting –

myleosuppression• Neurotoxicity- confusion• Hepatotoxicity

• Condyloma acuminata( genital warts )

• Chronic HCV, HBV• Kaposi Sarcoma in HIV• Multiple sclerosis

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Anti HIV Agents/Anti Retroviral Agents

i. Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Zidovudine (AZT)Didanosine (DDI)Emtricitabine (FTC)Lamivudine (3TC)Zalcitabine (ddC)Abacavir (ABC)

ii. Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)

Tenofovir Disproxil Fumarate

iii. Non-nucleoside reverse Transcriptase Inhibitors ( NNRTIS)

Delavirdine Efavirenz Nevirapine Etravirine

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iv. Protease Inhibitors Amprenavir AtazanavirDarunavir Fosamprenavir Indinavir Lopinavir Ritonavir Nelfinavir SaquinavirTipranivir

v. Fusion Inhibitors:

EnfuviritideMaraviroc

vi. Integrase Inhibitor :

Raltegravir

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Reverse Transcriptase Inhibitors

• NRTIs :Inactive until phosphorylated by human cellular

kinases Used together with protease inhibitors

• NNRTIs:– Not prodrugs – No myelosupression– Efavirenz, nevirapine

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Side effects of NRTIs

• Zidovudine AZT– hematotoxicity– Headache , myalgia , myopathy , peripheral

neuropathy• Didanosine DDI– Pancreatitis– Peripheral neuropathy, hyperuricemia, liver

dysfunction

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• Zalcitabine DDC– Peripheral neuropathy– GI distress, pancreatitis, neutropenia, rash

• Stavudine D4T– Peripheral neuropathy– Myelosupression

• Lamivudine 3TC– GI effects and neutropenia

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• ADRs of Efavirenz (a NNRTI)– Not during pregnancy– Dizziness– Vivid dreams

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Protease inhibitors

• Aspartate protease (pol gene encoded) cleaves precursor polypeptides to form the proteins of mature virion core

• Selective to dipeptide structure of viral proteins

• Combined with NRTIs• Indinavir , ritonavir

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Adverse effects of PI

• Paresthesia• Diarrhoea• Nausea and vomiting• Hypertriglyceridemia• Hyperglycemia• Hypercholesterolemia

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Fusion inhibitors

Enfuvirtide :• Binds gp41 and inhibits

fusion of HIV to CD4+ cells

• injection site reactions (pain, hardening of skin, erythema, nodules, cysts, itch)

Maraviroc :• Blocks CCR5 on T cell

surface to prevent viral entry

• hepatotoxicityallergic reactions (systemic), skin rash, fever, abd. pain, muscle/joint pain, cough, URTI, sleep disturbances

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HIV treatment guidelines

• 99% cell kill • Need of Combination therapy• CD4 cell count (≥350/mm3)

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Highly Active Anti Retroviral therapy

Combinations :1) 2 NNRTI+ PIEfavirenz + nevirapine + atazanavir/ritonavirnevirapine + etravirine + lopinavir/ritonavir2) 2 NRTI+ PITenofovir + emtricitabine + ritonavirAbacavir + lamivudine + ritonavirZidovudine + lamivudine +ritonavir

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Combinations to avoid:• Didanosine+Zalcitabine• Stavudine + zidovudine

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HIV Postexposure Prophylaxis (PEP)

Contact with blood /fluid or blood transfusionSharp injury or needle stick of HIV infected

NRTIs for 28 days/ with triple therapy (dual NRTIs plus a boosted PI)

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Prevention of mother-to-child-transmission

• Start Zidovudine (AZT) from 28 weeks or as soon as possible thereafter, be provided with single-dose Nevirapine (NVP) when entering labour, and be given AZT+3TC for one week following delivery

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Quick Review of Antiviral Agents

• Anti herpetics• Anti influenza agents • Anti hepatitis viral infections • Anti retroviral drugs