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ANTIVIRAL AGENTS
Viruses
 Viruses are obligate intracellular parasites, i.e. they utilize:
� Host metabolic enzymes
� Host ribosome for protein synthesis
 They cannot make anything on their own, they use the cell’s materials to build
themselves
Structure of viruses
Virus particles (virions) consist of following parts:
� Nucleic acid core: DNA or RNA
� Often contain virus-specific enzymes
� Surrounded by protein: “capsid”
� sometimes an outer lipid “envelope”
The Life Cycle of Viruses
1. Attachment of the virus to receptors on the host cell surface;
2. Entry of the virus through the host cell membrane;
3. Uncoating of viral nucleic acid;
4. Replication
Synthesis of early regulatory proteins, eg, nucleic acid polymerases;
Synthesis of new viral RNA or DNA;
Synthesis of late, structural proteins;
5. Assembly (maturation) of viral particles;
6. Release from the cell
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Many viruses infect a specific host cell
Many viral infections are self-limiting and require no medical treatment—ex.
Rhinoviruses that cause common cold.
Common viral infections such as the influenza, mumps, or chicken pox are
usually overcome by the body’s immune system.
Other viruses cause serious and even fatal disease & require aggressive therapy—
ex. HIV that causes AIDS.
Vaccines are often used to build up immunity before a viral infection occurs.
Common viral infections such as the influenza, mumps, or chicken pox are
usually overcome by the body’s immune system.
To be effective, antiviral agents must either block viral entry into or exit from the
cell or be active inside the host cell.
Antiviral Medications
 Antiviral drugs
 Used to treat infections caused by viruses other than HIV
 Antiretroviral drugs
 Used to treat infections caused by HIV, the virus that causes AIDS
 Herpes-Simplex Viruses
 HSV-1 (oral herpes)
 HSV-2 (genital herpes)
 Varicella Zoster Virus
 Chickenpox
 Shingles
 ANTIVIRAL DRUGS WORK BY:
1. Altering the cell’s genetic material so that the virus cannot use it to multiply, i.e.
acyclovir (inhibiting Viral enzymes, Host expression of viral proteins &
Assembly of viral proteins)
2. Preventing new virus formed from leaving the cell, i.e. amatadine.
CLASSIFICATION: Anti-influenza Agents
Amantadine · Rimantadine ·
 Anti-herpes virus agents
Acyclovir · Famciclovir · Foscarnet · Ganciclovir · Idoxuridine · Valacyclovir ·
 Antiretroviral Agents
 NRTIs
Zidovudine · Didanosine · Stavudine · Zalcitabine · Lamivudine · Abacavir ·
 NNRTI’s
Nevirapine · Efavirenz · Delavirdine
 Pis
Saquinavir · Indinavir · Ritonavir · Nelfinavir · Amprenavir · Lopinavir ·
 Other antiviral agents
Fomivirsen · Enfuvirtide · Imiquimod · Interferon · Ribavirin · Viramidine
Acyclovir & Congeners :
 Valacyclovir is a prodrug of Acyclovir with better bioavailability.
 Famciclovir is hydrolyzed to Penciclovir and has greatest bioavailability.
 Penciclovir is used only topically whereas Famciclovir can be administered
orally.
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PHARMACOLOGY OF ACYCLOVIR AND CONGENERS
 Acyclovir, Valacyclovir, Ganciclovir, Famciclovir, Penciclovir all are guanine
nucleoside analogs.
Mechanism of action of Acyclovir and congeners :
 All drugs are phosphorylated by a viral thymidine-kinase, then metabolized by
host cell kinases to nucleotide analogs.
 The analog inhibits viral DNA-polymerase
 Only actively replicating viruses are inhibited
MOA
1 ACTIVATION
2 INCORPORATION
ANTIVIRAL SPECTRUM :
 Acyclovir: HSV-1, HSV-2, VZV, Shingles.
 Ganciclovir / Cidofovir : CMV
 Famciclovir : Herpes genitalis and shingles
 Foscarnet : HSV, VZV, CMV, HIV
 Penciclovir : Herpes labialis
 Trifluridine : Herpetic keratoconjunctivitis
Pharmacokinetics of Acyclovir :
 Oral bioavailability ~ 20-30%
 Distribution in all body tissues including CNS
 Renal excretion: > 80%
 Half lives: 2-5 hours
 Administration: Topical, Oral , IV
Adverse effects of Acyclovir
◦ Oral: Nausea, diarrhea, and headache
◦ IV: Rashes, sweating and emesis and fall in BP
◦ Reversible renal dysfunction due to crystalline nephropathy
◦ Neurologic toxicity (eg, tremors, delirium, seizures)
◦ No Teratogenicity
Uses
1.
2.
3.
4.
5.
6.
Genital Herpes simplex: HSV –II
Mucocutaneous H. simplex: Type - I
H. simplex encephalitis: type – 1
H. simplex keratitis
H. zoster
Chicken pox
RESISTANCE
◦ HSV or VZV alteration in either the viral thymidine kinase or the DNA
polymerase → resistance
◦ Cross-resistance to valacyclovir, famciclovirand ganciclovir
◦ Agents such as foscarnet, cidofovir, and trifluridinedo not require
activation by viral thymidine kinase and thus have preserved activity
against the most prevalent acyclovir-resistant strains.
FAMCICLOVIR
 An ester prodrug of a guanine nucleoside analogue penciclovir
 P’kinetics: Good oral bioavailability and prolonged intracellular t ½ of the active
triphosphate metabolite.
 Mechanism: Like acyclovir, it needs viral thymidine kinase for generation of the active DNA
polymerase inhibitor.
 Spectrum: H. simplex, H. Zoster, hepatitis B virus (HBV).
 Use: An alternative to acyclovir for genital herpes and herpes zoster.
 Alternative to lamivudine in chronic hepatitis B.
 Side effects: Headache, nausea, loose motions, itching, rashes and mental confusion.
Other Nucleoside Analogs:
5. Cidofovir
a) Cytosine analog
b) Primary uses: I.V. use approved for CMV retinitis
c) Side effects: Nephrotoxicity
6. Idoxuridine
a) Iodinated thymidine analog
b) Primary use: herpes keratitis (topically)
c) Side effects: Pain, inflammation
7. Vidarabine
a) Adenosine analog
b) Primary uses: I.V. for herpes encephalitis and neonatal herpes
(most of uses have been replaced by acyclovir)
c) Side effects: Nephrotoxicity
ANTIRETROVIRAL DRUGS
HAART - Highly active antiretroviral therapy
 Includes at least three medications
◦ “cocktails”
 These medications work in different ways to reduce the viral load
RETROVIRUSES
 Virus has the enzyme reverse transcriptase as a part of the viral structure.
 A double-stranded DNA copy of the viral genome is produced.
 This copy can integrate into the host cell chromosome.
 Some retroviruses can cause tumors in animals: oncogenes
 Human immunodeficiency virus (HIV) is a retrovirus. This is the causative agent
of AIDS.
STAGES OF HIV REPRODUCTION
 HIV entry into the CD4 cells
 HIV’s genetic information stored on a single stranded RNA instead of the doublestranded DNA
 HIV uses an enzyme known as reverse transcriptase to convert its RNA into DNA
 HIV DNA enters the nucleus of the CD4+ cell and inserts itself into the cell’s
DNA
 HIV DNA instructs the cell to make many copies of the original virus
 New virus particles assembled and leave the cell ready to infect other
CD4+ cells
Antiretroviral Drugs
 Reverse transcriptase inhibitors (RTIs)
◦ Block activity of the enzyme reverse transcriptase, preventing production
of new viral DNA
 Reverse transcriptase inhibitors (RTIs)
◦ Nucleoside RTIs (NRTIs)
◦ Nonnucleoside RTIs (NNRTIs)
 Examples
abacavir (Ziagen)
delavirdine (Rescriptor)
didanosine (Videx)
lamivudine (Epivir)
stavudine (Zerit)
tenofovir (Viread)
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Are analogs of naturally occurring nucleotides
•Require phosphorylation to triphosphate form
•Competitively inhibit HIV-1 (and usually HIV-2) reverse transcriptase (RT)
•Are incorporated into viral DNA and cause chain termination
•Net effect is inhibition of viral DNA synthesis
•Block acute infection but are much less active against chronically infected cells
•Usually used in combination with other anti-HIV drugs
NRTI Mechanism of Action
 NRTIs mimic other nucleosides and are incorporated into the DNA strand
 They prevent the addition of the natural nucleosides into the DNA strand
 This halts the production of new virions
 Zidovudine (Azidothymidine):
 AZT is a deoxythymidine analog
Zidovudine– Prototype
MOA: Zidovudine triphosphate (Phosphorylated)
 When HIV infects a cell, reverse transcriptase copies the viral single stranded
RNA genome
into a double-stranded viral DNA
 The viral DNA is then integrated into the host chromosomal DNA
 Then, host cellular processes start transcribing viral RNA and mRNA to
reproduce the virus
 Regulatory and structural proteins are produced under the direction of viral
mRNA
 Zidovudine inhibits viral reverse transcriptase (RNA dependent DNA
polymerase)
 Zidovudine prevents infection of new cell by HIV, but not effective on already
infected host chromosomes
Zidovudine
 Resistance: Point mutation altering reverse transcriptase enzyme
 Kinetics:
◦ Bioavailability – 60-80%.
◦ t1/2 – 1 hour
◦ Conc. in CSF – 65% of that in plasma, crosses placenta and excreted in
milk
◦ Metabolism – Most of the drug is metabolized to in the liver, excreted in
the urine
 Unwanted effects:
◦ Blood dyscrasias – Anaemia and Neutropenia
◦ G.I disturbances – Nausea, vomiting, abdominal pain
◦ Myopathy, Myalgia
◦ Skin rash, Insomnia, Fever, Headaches, Abnormalities of liver function
 Drug Interaction:Paracetamol – AZT toxicity and azoles – inhibits AZT
metabolism
 Uses: HIV infection in combination with other drugs – minimum 2 other.
DIDANOSINE
 A purine nucleoside analogue
Mechanism: After intracellular conversion to didanosine triphosphate competes with ATP for
incorporation in viral DNA, inhibits HIV reverse transcriptase and terminates
proviral DNA.
 Spectrum:-Equivalent to AZT.
 Mutational resistance develops.
Kinetics: Oral absorption is erratic due to acid lability.
 T 1/2 - 1 to 1 .5 hr.
Side effects: peripheral neuropathy and rarely pancreatitis.
 Diarrhoea, abdominal pain and nausea.
Use: Used only in combination regimens.
STAVUDINE
 Thymidine analog
Mechanism:
 Inhibits HIV RT and causes DNA chain termination
Kinetics:
 It is well absorbed orally and rapidly metabolised (t ½ - 1 .5 hr).
Use:
 Advanced HIV in patients unresponsive to other therapies
Resistance:
 Not frequently observed
Side effects:
 Peripheral neuropathy, lipodystrophy and rarely pancreatitis
LAMIVUDINE
 Deoxycytidine analogue
Mechanism: Phosphorylated intracellularly and inhibits HIV reverse transcriptase as well as
hepatitis B virus (HBV) DNA polymerase.
 Its incorporation into DNA results in chain termination.
 Most human DNA polymerases are not affected and systemic toxicity is low.
Resistance: Mutation in HIV reverse transcriptase and HBV-DNA polymerase gives rise to
rapid lamivudine resistance.
Kinetics: Oral bioavailability is high and plasma T ½ longer (6-8 hours).
 Excreted unchanged in urine.
Uses: Used in combination with other anti-HIV drugs.
 Frequently used for chronic hepatitis B.
Side effects: headache, fatigue, nausea, anorexia, abdominal pain.
 Pancreatitis and neuropathy are rare.
ZALCITABINE
 Deoxycytosine analog
 Mechanism: Inhibits HIV RT and causes DNA chain termination
 Bioavailability reduced by food
 Primary use: In combination with zidovudine (produces synergistic effects)
 Resistance: Viral mutation
 Side effects: Peripheral neuropathy; oral & esophageal ulcerations
ABACAVIR
 Guanosine analog
 Newer agent that seems to be more effective than earlier NRTIs
 Mechanism: Inhibits HIV RT and causes DNA chain termination
 Good oral oral absorption; bioavailability not reduced by food
 Resistance: Develops more slowly
 Side effects: Hypersensitivity reactions (may be fatal)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
 Bind to RT at a different site than nucleoside reverse transcriptase inhibitors
(NRTIs)
 Do not require phosphorylation to inhibit the HIV RT
 Do not compete with nucleoside triphosphates for incorporation into DNA
 Bind to RT’s active site and block RNA- and DNA-dependent DNA polymerase
 cross resistance is common among different NNRTis
 No cross resistance with NRTIs or protease inhibitors (below)
 Rapid development of resistance by viral mutation
 Used in combination antiretroviral therapy
 Metabolized by cytochrome P450 enzyme complex
 Interactions with drugs which are metabolized by certain cytochrome P450
enzymes
 Frequently require dosage reduction in patients with compromised liver function
 They are more potent than AZT on HIV -1, but do not inhibit HIV -2.
NNRTI MECHANISM OF ACTION
 NNRTIs also inhibit the viral reverse transcriptase enzyme but have a different
mechanism of action compared to NRTIs
 NNRTIs bind directly to the reverse transcriptase enzyme
NEVIRAPINE (NVP)
 Well absorbed orally
 Metabolized in liver
 T ½ - 30 hours
 Modestly induce CYP 3A4, 2D6 enzymes and enhance their own metabolism as
well as that of other drugs.
 Side effects:- Rashes (commonest), nausea, headache , Fever and rise in liver
enzymes can occur.
 Hepatotoxic.
 Avoid enzyme inducers (rifampin) and enzyme inhibitors (ketoconazole).
 The NNRTis are indicated in combination regimens for HlV
EFAVIRENZ (EFV)
 Oral absorption is incomplete
 T ½ is longer - 48 hours
 Modestly induce CYP 3A4, 2D6 enzymes and enhance their own metabolism as
well as that of other drugs.
 Side effects:-headache, rashes, dizziness, insomnia
 It induces the metabolism of certain drugs and inhibits that of others.
 Indicated in combination regimens for HlV
DELAVIRDINE
 Good oral bioavailability; reduced by antacids
 Side effects: Skin rash, can be teratogenic (avoid pregnancy during therapy)
PROTEASE INHIBITORS
 SAQUINAVIR
 INDINAVIR
 AMPRENAVIR
 RITONAVIR
 NELFINAVIR
MECHANISM OF ACTION
 An aspartic protease enzyme encoded by HIV is involved in the production of
structural proteins and enzymes (including reverse transcriptase) of the virus.
 The large viral polyprotein is broken into various functional components by this
enzyme.
 This protease acts at a late step in HIV replication, i.e. maturation of the new virus
particles when the RNA genome acquires the core proteins and enzymes.
 They bind to the protease molecule, interfere with its cleaving function, and are
more effective viral inhibitors than AZT.
 They act at a late step of viral cycle, they are effective in both newly and
chronically infected cells.
 Under their influence, HIV-infected cells produce immature viral progeny-hence
prevent further rounds of infection
PHARMACOKINETICS
 Oral bioavailability of Pis is variable (IDV and RTV -65 % , NFV >20%, SQV
15%)
 Plasma t ½ ranges from 2-5 hours.
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All are extensively metabolized by CYP3A4 and other CYP isoenzymes.
The Pis interact with many drugs.
Nelfinavir and ritonavir induce their own metabolism
Monotherapy in previously AZT treated patients reduced HIV viral levels
viral resistance developed slowly.
Combination of NRTis with Pis more effective than either drug given alone.
Current recommendations are to use a PI in combination with either two NRTis or
one NRTI + one NNRTI.
ADVERSE EFFECTS
 Gastrointestinal intolerance, asthenia, headache, dizziness, limb and facial
tingling, numbness and rashes.
 Lipodystrophy (abdominal obesity, buffalo hump with wasting of limbs and face)
and dyslipidaemia (raised triglycerides and cholesterol)
 Risk of urinary calculi
1. Saquinavir
a. Poor to adequate oral bioavailability
b. Side effects: Fairly well tolerated with mild GI discomfort
c. Usually used in combination with Ritonavir (see below)
2. Ritonavir
a. Good oral bioavailability when given with food
b. Side effects: GI disturbances, peripheral or oral sensations, elevated
serum triglycerides and aminotransferase levels
3. Indinavir
a. Excellent oral bioavailability when given on empty stomach
b. Side effects: Hyperbilirubinemia and nephrolithiasis (crystals forming
in the kidneys)
4. Nelfinavir
a. Oral bioavailability increased with food
b. Side effects: Diarrhea
5. Amprenavir
a. Good oral bioavailability when given with or without food
b. Efficacy increases when combined with two nucleoside RT
inhibitors
c. Side effects: GI disturbances & rashes
FUSION INHIBITOR
ENFUVIRTIDE
 Synthetic peptide
 Acts by binding to HIV-1 envelope glycoprotein (gp41) and preventing fusion of
viral and cellular membranes.
 Entry of the virus into the cell is thus blocked.
 It is not active against HIV-2.
 No cross resistance with other classes of ARV drugs occurs.
 Administered s.c.
 it is used as add on drug to an optimized regimen in patients who have failed
many earlier regimens.
ANTI INFLUENZA AGENTS
AMANTADINE
 A tricyclic amine
 Inhibits replication of influenza A virus.
 Act at an early step (possibly uncoating) as well as at a late step (viral assembly)
in viral replication.
 A protein 'M2' which acts as an ion channel is the targets of action.
 Resistance :- By mutation causing amino acid substitutions in the M 2 protein.
 Well absorbed orally and excreted unchanged in urine
 T ½ 16 hr.
Adverse effects: Nausea, anorexia, insomnia, dizziness, nightmares, lack of mental concentration,
hallucinations, Ankle edema
Use:
 Prophylaxis of influenza A
 Parkinsonism
Contraindications:
 Epilepsy and other CNS disease; gastric ulcer, pregnancy.
RIMANTADINE
 More potent
 Long-acting
 T ½ - 30 hr
 Better tolerated
 Oral bioavailability is higher and it is largely metabolized.
 Clinical application is similar to amantadine.
 Amantadine resistant virus is resistant to rimantadine as well.
Neuraminidase inhibitor
 Inhibit neuraminidase enzyme of influenza
◦ Enzyme essential for release of virus
◦ Examples: zanamivir and oseltamivir
OSELTAMIVIR (TAMIFLU)
 A broader-spectrum activity
 Covering influenza A (amantadine sensitive as well as resistant), influenza B and
avian-influenza (bird flu) H5N1 and other strains.
 An ester prodrug that is rapidly and nearly complete absorption in intestine and by
liver to the active form oseltamivir carboxylate.
 Excreted by the kidney
 T ½ - 6-10 hours.
 It acts by inhibiting influenza virus neuraminidase enzyme which is needed for
release of progeny virions from the infected cell.
 Indication:-For treatment of influenza A, B and bird flu.
 Side effects :-Nausea and abdominal pain due to gastric irritation, headache,
diarrhoea, cough and insomnia, Skin reactions.
ZANAMIVIR
 Another influenza virus (A, B, avian strains) neuraminidase inhibitor
 Administered by inhalation as a powder due to very low oral bioavailability.
 Excreted by the kidney
 T ½ - 2-5 hours
 The mechanism of action, clinical utility and efficacy of zanamivir are similar to
that of oseltamivir.
 side effects:-Headache, dizziness, nausea and rashes, bronchospasm.
 severe in asthmatics; contraindicated in them.
NONSELECTIVE ANTIVIRAL DRUGS
 Interferons
 Ribavirin
 Adefovirdipivoxil
RIBAVIRIN
 Purine nucleoside analogue
 Broad-spectrum activity, including influenza A and B, respiratory syncytial virus
and many other DNA and double stranded RNA viruses.
 Its mono- and triphosphate derivatives generated intracellularly inhibit GTP and
viral RNA synthesis and have other sites of action as well.
 No viral resistance
 Oral bioavailability is -50%.
 Accumulates in the body and persists months after discontinuation.
Indications: Used in influenza A/B and measles in immunosuppressed patients as well as for
herpes virus infections, acute hepatitis,
 Combined with interferon a, for chronic hepatitis C.
 Nebulized ribavirin used for respiratory syncytial virus broncholitis in infants and
children.
 Shown efficacy in some rare viral infections.
Adverse effects: Anaemia, haemolysis, CNS and g.i. symptoms.
 Teratogenic.
 Irritation of mucosa and bronchospasm.
ADEFOVIR DIPIVOXIL
 Diesterprodrug of AMP analogue
 Active against hepatitis B virus (HBV) and some other DNA viruses.
 Esterases in the intestine and liver release the active drug during absorption to
attain oral bioavailability of -60%, which is then distributed in whole body water.
 Plasma t ½ -7 hours
Mechanism: On entering cells, adefovir (a monophosphate) is phosphorylated to the
diphosphate which has high affinity for HBV DNA polymerase.
 This enzyme is inhibited and adefovir itself gets incorporated in the viral DNA
resulting in termination of the DNA chain.
Indication: In chronic hepatitis B, in lamivudine-resistant cases.
 No cross resistance
Side effects : Sore throat, headache, weakness, abdominal pain and flu syndrome.
 Nephrotoxicity at higher doses and in those with preexisting renal insufficiency.
Interferons
Interferons (IFNs) are natural proteins produced by the cells of the immune systems in
response to challenges by foreign agents such as viruses, bacteria, parasites and tumor
cells.
 Antiviral, immune modulating and anti-proliferative actions
 Three classes of interferons – α , β, γ
 α and β interferons are produced by all the cells in response to viral infections
 γ interferons are produced only by T lymphocyte and NK cells in response to
cytokines – immune regulating effects
 γ has less anti-viral activity compared to α and β interferons
Mechanism of action of Interferons :
 Induction of the following enzymes:
1) a protein kinase which inhibits protein synthesis
2) anoligo-adenylate synthase which leads to degradation of viral mRNA
3) a phosphodiesterase which inhibit t-RNA
The action of these enzymes leads toan inhibition of translation
Pharmacokinetics : Interferons
 Oral bioavailability: < 1%
 Administered S.C, and I.V
 Distribution in all body tissues, except CNS and eye.
 Half lives: 1-4 hours
Adverse effects
 Flu-like symptoms-fatigue, aches and pains, fever, dizziness, anorexia, taste and
visual disturbances
 Neurotoxicity-numbness,neuropathy, tremor, sleepiness, rarely convulsions.
 Myelosuppression-neutropenia, thrombocytopenia.
 Thyroid dysfunction (hypo as well as hyper).
 Hypotension, transient arrhythmias, alopecia and liver dysfunction.
Uses
 Chronic hepatitis B and C
 AIDS-related Kaposi's sarcoma
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Condylomaacuminata caused by papilloma virus
H. simplex, H. zoster and CMV infections in immunocompromised patients
Rhinoviral cold
In chronic myelogenous leukaemia and multiple myeloma.