Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR

DEPT. OF PHARMACOLOGYSSIMS & RC.

ANTIVIRAL DRUGS (NON RETROVIRAL)

Classification of antiviral (non-retro viral) drugs

DNA polymerase inhibitors Purine analogues Acyclovir , Valcyclovir , Gancyclovir, Valganciclovir,

Famciclovir , Pencyclovir , Cidofovir, Adefovir, Entacavir , Vidarabine

Pyramidine analogues Idoxuridine , Trifluridine Telbivudine Non-nucleosides Foscarnet

Classification of antiviral (non-retro viral) drugs

M-RNA synthesis inhibitors Ribavirin, FomiversenInhibitors of viral penetration and uncoating Amantidine and Rimantidine, DocosanolNeuraminidase inhibitors Zanamavir , Oseltamavir, PeramavirImmunomodulators : Interferons, Palivizumab , Imiquimod

Life cycle of viruses and steps blocked by medicines

DNA POLYMERASE INHIBITORS Purine analogues-Acyclovir

Guanine nucleoside analogue Effective against HSV-1 and HSV-2, VZV, CMV, and EBV.The active metabolite of acyclovir inhibits herpes virus DNA replicationin two ways. Acyclovir triphosphate - competitive Inhibitor deoxyguanosine triphosphate (dGTP) into the viral DNA.

Acts as a chain terminator -because it lacks the 3 -hydroxy group necessary for further chain elongation.

Acyclovir

Pharmacokinetics :Acyclovir absorption is variable and incomplete following oral administration.

20% bound to plasma protein Amniotic fluid, placenta, and breast milk. Acyclovir is both filtered at the glomeruli and

actively secreted. The plasma half-life of acyclovir is 3 to 4 hours in

patients with normal kidney function and up to 20 hours in patients with renal impairment

Uses

Oral acyclovir - HSV-1 and HSV-2 infections, such as genital herpes, herpes encephalitis, herpes keratitis, herpes labialis, and neonatal herpes.

long-term suppression of recurrent HSV. Intravenous acyclovir -herpes simplex encephalitis,

neonatal HSV infection, and mucocutaneous HSV infection in immunocompromised individuals.

Acyclovir ointment is used in the treatment of initial genital herpes but is not effective for recurrent disease.

Uses

Ophthalmic acyclovir formulations are effective in the treatment of herpes keratoconjunctivitis.

Acyclovir reduces the extent and duration of VZV lesions

chickenpox treatment and prophylaxis in high- risk individuals.

Herpes zoster (shingles), Does not affect post herpetic neuralgia.

Adverse effects

Headache, nausea, and diarrhea. Skin rash, fatigue, fever, hair loss, and depression. Reversible renal dysfunction (azotemia) and

neurotoxicity (tremor, seizure, delirium) are dose- limiting toxicities of intravenous acyclovir.

Adequate hydration and slow drug infusion can minimize the risk of renal toxicity

Thrombotic thrombocytopenic purpura– hemolytic uremic syndrome (TTP–HUS)

Safe in Pregnancy

Acyclovir

Drug interaction –Probenacid , cyclosporine Resistance –Mutations resulting in decrease

in thymidine kinase activity. Altered substrate specificity Decreased affinity of viral DNA polymerase

Cidofovir

- acyclic phosphonate cytosine analogue - Herpes viruses including CMV, HSV-1, HSV-2, EBV,

and VZV. adenoviruses, papillomaviruses, polyomaviruses, and poxviruses.

Activation- requires metabolism to a diphosphate. -competes with deoxycytidine triphosphate (dCTP)

for access to viral DNA polymerase and also acts as an alternative substrate.

- slows replication - halts DNA polymerase activity.

Cidofovir-P/K

Pharmacokinetics : low oral bioavailability. T1/2- 2.6 hours, the diphosphate form -half life of 17 to 65 hours. A phosphocholine metabolite half-life 87 hours . is excreted unchanged by the kidney. Glomerular

filtration and probenecid-sensitive tubular secretion are responsible for cidofovir elimination

Weekly dosage

Cidofovir-Uses

-Treatment and prophylaxis of CMV retinitis in AIDS patients. -Treatment of acyclovir-resistant (viral thymidine

kinase-deficient) HSV infections, -Polyomavirus associated progressive multifocal

leukoencephalopathy, condylomata acuminata (anogenital warts), and

molluscum contagiosum.

Drug interaction

Probenecid with cidofovir . Probenecid carries its own adverse effects, including gastrointestinal upset.

Nephrotoxic agents (e.g., aminoglycosides, NSAIDs, amphotericin B, foscarnet) should not be given within 7 days of cidofovir administration.

ADR-Hypersensitivity reactions, Anterior uveitis and Neutropenia Potential human carcinogen- Embryotoxic and teratogenic effects

and to impair fertility . Nephrotoxicity, Proteinuria, azotemia, glycosuria, elevated serum

creatinine, and Rarely, Fanconi’s syndrome.

Famciclovir and Penciclovir

-diacetyl ester prodrug of the acyclic guanosine analogue 6-deoxypenciclovir. - HSV-1, HSV-2, VZV, and HBV. - After oral administration, famciclovir is converted to penciclovir by first-pass metabolism. Penciclovir triphosphate acts as a competitive inhibitor of viral DNA polymeraseResistance : Mutations in DNA polymerase or thymidine kinase may result in resistance. Acyclovir-resistant HSV strains

Pharmacokinetics:

Penciclovir is available as a topical cream Famciclovir ->converted to penciclovir by hepatic first-pass metabolism ->Bioavailability 77%. Penciclovir-t1/2 is 2 to 3 hours; however, the intracellular half-life of penciclovir triphosphate is 7 to 20 hours in infected cells. Eliminated unchanged by the kidney via glomerular filtration and active tubular secretion. The plasma half-life is increased in individuals with renal insufficiency.

Uses

Herpes labialis. Shortens the duration of lesion presence and pain Famciclovir -acute herpes zoster (shingles) Famciclovir -treatment of HSV Famciclovir -Recurrent genital herpes. For HIV-infected individuals- all recurrent

mucocutaneous HSV infections

Adverse effects:

Headache, nausea, and diarrhea. Hallucinations and urticaria Animal studies -Tumorigenic and impair

spermatogenesis. Dosage adjustment is necessary in individuals with

renal impairment. Famciclovir interact with probenecid -drugs

eliminated by renal tubular secretion. Increased blood levels of penciclovir or other

agents.

Ganciclovir and valganciclovir

Ganciclovir is an acyclic analogue of 2 de-oxyguanosine especially CMV.

Valganciclovir is the L-valyl ester prodrug of ganciclovir. Activation of ganciclovir --ganciclovir monophosphate Protein kinase pUL97 in CMV or thymidine kinase in

HSV. additional phosphorylations ganciclovir triphosphate

competes with dGTP incorporation into DNA chain termination

Ganciclovir triphosphate is up to 100-fold more concentrated in CMV-infected cells than in normal cells .

Pharmacokinetics

Resistance : Exposed to the drug for long periods . -Mutation of the protein kinase gene. -Mutations in the DNA polymerase . Pharmacokinetics : - Orally or intravenously Valganciclovir –orally - rapidly metabolized to

ganciclovir60% Intravenous -Ganciclovir -vitreous humor Ganciclovir- eliminated by glomerular filtration and active

tubular secretion. The T1/2-ganciclovir -3.5 hours (iv)and 4.8 hours (oral) Oral valganciclovir -4 hours. The intracellular half-life of

ganciclovir triphosphate is over 24 hours.

Uses

CMV retinitis in immunocompromised individuals, including those with AIDS, CMV infection in organ transplant recipients.

-CMV retinitis in AIDS , Ganciclovir -intravitreal implant -CMV retinitis

in AIDS patients. Resistance : Exposed to the drug for long

periods . -Mutation of the protein kinase gene. -Mutations in the DNA polymerase .

Adverse effects and D/I

-Myelosuppression Neutropenia and anemia (25 to 30% ) and

Thrombocytopenia( 5 to 10%). sperm production, teratogenesis, and tumor formation. Severe neutropenia -with zidovudine. Ganciclovir increases serum levels of didanosine,

whereas probenecid decreases ganciclovir elimination. Nephrotoxicity (e.g., amphotericin B, cyclosporine,

NSAIDs) are administered in conjunction with ganciclovir

Pyramidine analogues

Idoxuridine -is a water-soluble iodinated derivative of deoxyuridine -Inhibits several DNA viruses including HSV, VZV, vaccinia, and polyoma virus. MOA:The triphosphorylated metabolite of idoxuridine inhibits both

viral and cellular DNA synthesis Host cytotoxicity, Pharmacokinetics: Idoxuridine topical ophthalmic use

Uses : treatment of herpes simplex infections of the eyelid, conjunctiva, and cornea. soft tissue sarcoma

Adverse Events: local irritation, mild edema, itching, and photophobia. Corneal clouding and small punctate defects

in the corneal epithelium .

Trifluridine

Trifluridine is a fluorinated pyrimidine nucleoside -HSV-1 and HSV-2, vaccinia, adenoviruses. MOA: Activation of trifluridine 5 monophosphate

inhibits the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) by thymidylate synthetase.

Resistance alterations in thymidylate synthetase specificity.

Trifluridine

Pharmacokinetics :- topical instillation of trifluridine into the eyes. Its half-life is approximately 12 minutes.

Uses: Trifluridine (topical ophthalmic solution)- primary

keratoconjunctivitis, recurrent keratitis due to HSV-1 or HSV-2.

Unresponsive or intolerant to topical idoxuridine or vidarabine.

Adverse effects: Transient burning or stinging and palpebral edema.

-Superficial punctate keratopathy, epithelial keratopathy, hypersensitivity, stromal edema, irritation, keratitis sicca, hyperemia, and increased intraocular pressure.

Non-nucleosides Foscarnet

Foscarnet is an inorganic pyrophosphate analogue HSV-1, HSV-2, VZV, CMV, EBV, HBV, and HIV. Noncompetitive inhibitor of viral DNA polymerase and

reverse transcriptase Resistance -mutation of viral DNA polymerase. Pharmacokinetics : IV -14 to 17% bound to plasma

proteins. -accumulates in bone bimodal initial half-life of 4 to 8

hours and prolonged terminal elimination half-life of 45 to 130 hours.

- eliminated as unchanged drug glomerular filtration and active tubular secretion.

Foscarnet

Uses CMV retinitis in AIDS patients. refractory retinitis, Kaposi’s sarcoma Acyclovir- resistant mucocutaneous HSV infections in

immunocompromised individuals. Acyclovir-resistant VZV and nonretinitis forms of CMV

infection Adverse effects Nephrotoxicity -second week of induction therapy Serum creatinine levels may be elevated in up to 33 to

50% of patients; Dehydration, previous renal impairment, and

concurrent administration of other nephrotoxic drugs increase the risk of renal toxicity.

M-RNA synthesis inhibitorsRibavirin

-synthetic guanosine analogue -Influenza A and B, parainfluenza, RSV, HCV, HIV-1, and various herpesviruses, arena viruses, and paramyxo viruses. -inhibits the synthesis of viral mRNA ribavirin monophosphate, diphosphate, and triphosphate forms.Ribavirin monophosphate-- inhibits the guanosine triphosphate (GTP) synthesis Ribavirin triphosphate inhibits the 5 capping of viral mRNA with GTP increasing the mutation rate of RNA viruses nonviable progeny virions

Ribavirin

Resistance has not been documented in clinical isolates.

Pharmacokinetics : Aerosol respiratory tract secretions approximately 100 times

Oral absorption is rapid, and first-pass metabolism is extensive;

Ribavirin’s oral bioavailability is 64% -high-fat meal. Steady-state levels are reached after 4 weeks. Ribavirin triazole carboxylic acid metabolite urine The plasma half-life -9.5 hours The drug accumulates in erythrocytes, with a half-life of 40

days.

Ribavirin

Uses : Severe bronchiolitis or pneumonia due to RSV infection. Oral ribavirin in combination with interferon- α Intravenous ribavirin -Hantaan virus infection, Crimean or

Congo virus hemorrhagic fever, Lassa fever, and severe adenovirus infection.

Ribavirin monotherapy

Adverse effects Local adverse effects. Pulmonary function -chronic obstructive lung disease or asthma. Headache, conjunctivitis, rash, and rarely, bronchospasm. Oral and intravenous- hemolytic anemia

Ribavirin

With interferon-α - fatigue, nausea, insomnia, depression, and anemia, fatal or nonfatal pancreatitis.

Ribavirin is mutagenic, teratogenic, and embryotoxic

C/I- pregnant women ,Effective forms of contraception during ribavirin treatment .

Sickle cell anemia and other hemoglobinopathies,coronary disease ,severe renal impairment.

D/I-In vitro, ribavirin inhibits the phosphorylation reactions zidovudine and stavudine

Fomiversen

First antisense oligonucleotide immediate early region 2 (IE2) of CMV mRNA.

By binding to IE2 mRNA, fomivirsen prevents its translation to protein and thereby blocks viral replication. Because this mechanism of action is different from that of other antiviral agents, cross- resistance with other drugs used to treat CMV is unlikely.

Pharmacokinetics: Fomivirsen is injected directly into the vitreous humor of the eye.-->retina and iris over 3 to 5 days and is cleared from the vitreous humor within 7 to 10 days.

Fomiversen

Fomivirsen exhibits minimal systemic absorption and is degraded locally by cellular exonucleases.

Uses Fomivirsen -CMV retinitis in patients with AIDS.

Adverse effects: Iritis, (25%) -topical corticosteroids. - Vitreitis IOT C/I- with cidofovir

Inhibitors of viral penetration and uncoating Amantidine and Rimantidine:

Amantadine is a synthetic tricyclic amine, and rimantadine is its α -methyl derivative. Both drugs inhibit the replication of the three antigenic subtypes of influenza A (H1N1, H2N2 and H3N2) , less activity against influenza B.

Mechanism Of Action - involves inhibition of the viral M2 protein, (H

channel) Blockade acid-mediated dissociation of the ribonucleoprotein complex -inhibited

The pH changes M2 inhibition alter the hemagglutinin inhibit viral assembly.

Amantidine and Rimantidine:

-Viral resistance -30% ,-failure of drug prophylaxis -Mutation in the transmembr- M2 protein

Pharmacokinetics : Amantadine -2 to 5 hours. T1/2- 17 hours -29 hours in the elderly. Eliminated unchanged by glomerular filtration and

tubular secretion. Rimantadine -5 to 7 hours. Its elimination half-life averages 25- 32 hours in the

elderly. -25% -unchanged drug ,75%- hydroxylated or conjugated metabolites.

Amantidine and Rimantidine:

Uses :-influenza A strains

Adverse effects:- Nausea, anorexia, dizziness, and insomnia Dose-related effects - amantadine than rimantadine. -Depression, impaired coordination, confusion, anxiety,

Cardiac arrhythmias, delirium, hallucinations long-term treatment may cause peripheral edema, Abrupt

withdrawal -neuroleptic malignant syndrome. -Seizures or worsen preexisting seizure disorders. Amantadine is teratogenic and Rimantadine - embryotoxic. Pregnancy and lactation.

Amantidine and Rimantidine:

Drug interactions:- Anticholinergic drugs, Thiazide–triamterene, trimethoprim–sulfamethoxazole, quinine, and quinidine increase plasma amantadine levels.

Cimetidine decreases rimantadine clearance, and aspirin and acetaminophen decrease rimantadine plasma levels.

Docosanol

Docosanol is a long-chain saturated alcohol HSV. CMV, influenza virus, and respiratory syncytial

virus. -Blocks the entry of the virion Docosanol cream -herpes labialis. Adverse effects -Skin irritation occurs infrequently.

Neuraminidase inhibitorsOseltamavir

Oseltamivir phosphate is the ethyl ester prodrug of oseltamivir carboxylate

- competitive antagonist of influenza A and B neuraminidase. Neuraminidase -then destroys these hemagglutinin

receptors cleavage of hemagglutinin receptors is required for the release of progeny virus from the host cell-inhibited

Spread of infection by allowing viral particles to penetrate the neuraminic acid–rich respiratory mucus and by preventing the clumping of virus that results from the binding of hemagglutinins to neuraminic acid residues on neighboring viral particles –inhibited

Resistant strains –mutations- neuraminidase

Oseltamavir

P/KOrally -80%- 2.5 to 5 hours. Plasma t1/2 -7 to 9 hours. Elimination -active tubular secretion and glomerular filtration. Uses :Oseltamivir - uncomplicated acute influenza in patients

aged 1 year and older. --Prophylaxis of influenza in individuals aged 13 and older.

Post- exposure prophylaxis Adverse effects: -Nausea and vomiting, Bronchitis, insomnia, and vertigo -Chronic cardiac or respiratory disease renal insufficiency; -Probenecid decreases the elimination of oseltamivir, No interference with antibody production in response to the

influenza vaccine.

Zanamivir

Zanamivir is a neuraminidase inhibitor with activity against influenza A and B strains. - reversible competitive antagonist of viral neuraminidase.

- inhibits the release of progeny virus, Resistant variants with hemagglutinin and/or

neuraminidase mutations Pharmacokinetics : bioavailability < 5% oral. breath-actuated inhaler device- 12 to 17%, -1.5

hours. Eliminated -by the kidneys t1/2.5 to 5 hours.

Zanamivir

Uses :- Uncomplicated acute influenza A and B virus Effective prophylaxis against influenza.

Adverse effects: -Bronchospasm and impaired lung function -underlying

pulmonary disease. - Allergic reactions, including angioedema, C/I -Severe or decompensated chronic obstructive lung

disease or asthma -serious adverse pulmonary reactions. Moderate asthma Severe renal insufficiency

Other antiviral drugs -Immunoglobin –( γ-globulin, immunoglobulin [Ig] G)

Other antiviral drugs Immunoglobin ->( γ-globulin, immunoglobulin [Ig] G) -primarily of IgG and contains trace amounts of IgA

and IgM. inhibit viral penetration of host cells, opsonize viral

particles, activate complement, and stimulate cell-mediated immunity.

Pharmacokinetics: γ-Globulin im/iv - viral disorders. Protection lasts for 2 to 3 weeks after a single

injection, although for prolonged infections, injections can be repeated every 2 to 3 weeks.

( γ-globulin, immunoglobulin [Ig] G

Uses :- CMV, HBV, rabies, RSV , and VZV - heterogeneous human immune globulin solution- measles,

varicella, or rubella infection - adjunctive form of therapy with other therapeutic

approaches. Adverse effects : Hypersensitivity reactions -Anaphylactoid reaction, urticaria, angioedema, fever, and

injection site reactions. - flushing, dizziness, blood pressure changes, palpitations,

abdominal cramps, and dyspnea; Aseptic meningitis Interference- live virus vaccines (e.g., measles mumps,

rubella).

Interferons

-Potent antiviral, immunoregulatory, and antiproliferative effects

Interferon-α (type I, leukocyte) and Interferon - β (type I, fibroblast) Interferon- γ (type II, immune) -natural killer (NK)

cells and T lymphocytes inhibition of viral penetration, uncoating, mRNA

synthesis, translation, and/or virion assembly and release.

Interferons

Initiate the JAK-STAT signal transduction pathway 2 -5 –oligo adenylate synthetase (2 -5 OAS)- initiates the activation of a cellular ribonuclease that cleaves single-stranded RNAs,

Protein kinase phosphorylates and inactivates an elongation factor (eIF-2)

Interferons inflammatory cytokines, biological oxidants immune response.

Interferons-pharmacokinetics

Natural interferons ,recombinant interferons ,Monomethoxy polyethylene glycol (PEG; pegylated interferons).

Subcutaneously, intramuscularly, intravenously, or intralesionally (e.g., into genital warts).

-peak plasma levels within 4 to 8 hours within 16 to 36 hours.

Pegylated interferons 15 to 44 hours 48 to 72 hours.

Eliminated cellular uptake and catabolism in the kidney and liver

Interferons-Uses

Interferon- α -2a chronic hepatitis C, hairy cell leukemia, AIDS- related Kaposi’s sarcoma, and chronic phase Philadelphia chromosome–positive chronic myelogenous leukemia.

Interferon-α -2b Hairy cell leukemia, malignant melanoma, follicular lymphoma, condylomata acuminata, AIDS-related Kaposi’s sarcoma, and chronic hepatitis B and C.

Interferon-α -2b and RibavirinChronic hepatitis C. Interferon- α -n3 condylomata acuminata by

intralesional injection.

Interferons-Uses

Interferon alfacon-1 5 times Interferon α -2a or -2b.

Interferon alfacon-1 and peg interferon- α -2b chronic hepatitis C.

Interferon β -1a and interferon β -1b multiple sclerosis.

Interferon -1b chronic granulomatous disease , malignant osteopetrosis.

Interferons- Adverse effects

Flu like symptoms fever, chills, weakness, fatigue, myalgia, and arthralgia, (50% )of patients CNS complaints headache, dizziness, impaired memory and concentration, agitation, insomnia, and anxiety occur with regularity.

Depression interferon-α and interferon- β . Myelosuppression dose limiting Gastrointestinal symptoms nausea, vomiting, Elevation of hepatic enzymes Injection site reaction alopecia, fertility, cause

miscarriage .

Palivizumab

Palivizumab is a humanized monoclonal antibody F protein on the surface of RSV.

It contains 95% human and 5% murine antibody sequences

inhibits its ability to fuse with host cell membranes. Pharmacokinetics : prophylactically IM/monthly—RSV

season. T1/2- 20 days. Uses : Serious LRTI due to RSV. bronchopulmonary dysplasia or chronic lung disease Premature infants (less than 32 weeks gestation) Adverse effects : Mild erythema and pain Anaphylactoid reactions –protein.

Imiquimod

Imiquimod [1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4 amine]

Condylomata acuminata, molluscum contagiosum, HPV infections

Toll-like receptors TLR7 and TLR8 to boost innate immunity, interferons

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