Chemotherapeutic Agents

Antiviral Drugs

1
 Introduction

 Viruses are obligate intracellular parasites; with no metabolic machinery of their own.
 Depend completely on host cells (bacterial, plant, or animal) to reproduce/ multiply.
 Utilizes:

 Host metabolic enzymes

 Host ribosome for protein synthesis

 Viruses are the smallest parasites, typically ranging from 0.02 to 0.3 μm, although several very large
viruses up to 1 μm long (megavirus, pandoravirus)
 Antiviral agents must either block viral entry into or exit from the cell or be active inside the host cell.
 Structure of viruses
Virion: A free living (e.g. outside its host) complete, fully developed, infectious viral
particle.
Virus particles (virions) consist of two basic components:

1. Nucleic acid core: Single- or double-stranded RNA or DNA.

2. Protein coat “ Capsid”
• Capsid proteins are coded for by the virus genome.
• Shell to protect the viral genome from nucleases
• Attaches the virion to specific receptors exposed on the prospective host cell during
infection.
 Nucleocapsid: Nucleic acid core + Capsid

 “Envelope”: Lipid bilayer derived from the modified host cell membrane and
studded with an outer layer of virus encoded glycoproteins.
• The outer capsid and the envelope proteins of viruses are glycosylated and
important in determining the host range and antigenic composition of the virion.
 Enzymes required for first step of viral replication.
Structure of viruses
 Classification of Viruses

DNA viruses RNA Viruses

• Contain an DNA genome: double‐ • Contain an RNA genome: typically ssRNA,
stranded DNA (dsDNA) and rarely but may also contain dsRNA.
single‐stranded DNA (ssDNA). • Replicate using DNA‐dependent RNA
• Replicate using DNA‐dependent DNA polymerase or reverse transcriptase
polymerase (Retrovirus)
• Replication error rate less • Higher replication error rate of enzymes
• Lower mutation rates involved in RNA replication
Examples: • Higher mutation rates.
– Pox viruses (Small pox) Examples:
– Herpes Viruses (Chicken pox, shigles, – Retrovirus (AIDS)
cold sores) – Paramyxovirus (Measles, mumps)
– Adenovirus (sore throat, conjuctivitis) – Orthomyxovirus (Influenza)
– Papillomavirus (warts) – Rubella virus (German measles)
– Rhabdo virus (rabies)
– Hepadnavirus (Hepatitis B)
– Flavivirus (Dengue fever)
– Epstein-Barr virus
– Picornaviridae (Hepatitis A)
– Hepacivirus (Hepatitis C)
The Life Cycle of Virus
 The Life Cycle of Virus

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
Replication in DNA viruses: Transcription of viral DNA into mRNA by host RNA polymerase
followed by translation into virus specific proteins.
Replication in RNA viruses:
• Enzymes in virion synthesise its mRNA or the viral RNA serves as its own mRNA.
• Translated into various enzymes incl. RNA polymerase.
• Host cell nucleus usually not involved in viral replication.
Replication in retrovirus
• Contains reverse transcriptase (virus RNA dependent DNA polymearse) which makes a DNA
copy of viral RNA.
5. Assembly (maturation) of viral particles;
6. Release from the cell by budding or cell lysis
 CLASSIFICATION
1. Anti-Herpes virus
Idoxuridine, Acyclovir, Valacyclovir, Famciclovir, Ganciclovir, Foscarnet
2. Anti-Retrovirus
(a) Nucleoside reverse transcriptase inhibitors (NRTis):
Zidovudine (AZT), Didanosine, Zalcitabine, Stavudine, Lamivudine, Abacavir
(b) Nonnucleoside reverse transcriptase inhibitors(NNRTis):
Nevirapine, Efavirenz, Delavirdine
(c) Protease inhibitors:
Ritonavir, lndinavir, Nelfinavir, Saquinavir, Amprenavir, Lopinavir
3. Anti-Influenza virus
Amantadine, Rimantadine
4. Nonselective antiviral drugs
Ribavirin, Lamivudine, Adefovir dipivoxil, Interferon α
 ANTI-HERPES VIRUS AGENTS

• Infection with herpes simplex virus, commonly known as herpes

• 100 known herpes viruses, 8 routinely infect only humans
• Herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, human
herpesvirus 6 (variants A and B), human herpesvirus 7, and Kaposi's sarcoma virus or human herpesvirus
8.

Structure
• Herpesviruses have a unique four-layered structure:
i. A core containing the large, double-stranded DNA genome
ii. Enclosed by an icosapentahedral capsid which is composed of
capsomers.
iii. The capsid is surrounded by an amorphous protein coat called
the tegument.
iv. It is encased in a glycoprotein-bearing lipid bilayer envelope.
 General Mechanism of Action:
a. Nucleoside Analogs

• Taken up by host cells

• Need to be phosphorylated to their active form, the
triphosphate form by viral and cellular enzymes.
• The triphosphate form inhibits polymerases by
 Competing with natural dNTP substrates and/or
 Incorporation into the growing DNA chain, where they
can often terminate DNA elongation.
• Nucleoside analogs, act as competitive inhibitors or
substrates for viral polymerases: Reduction in viral
DNA synthesis in infected cells.
 Acyclovir
• The era of selective antiviral therapy started with the discovery of acyclovir in 1977.
• Acyclic guanine nucleoside analog that lacks a 3′-hydroxyl on the side chain (Deoxiguanosine analogue)
• High specificity for herpes group of viruses.
• H. simplex type I is most sensitive followed by H. simplex type II > varicella-zoster virus= Epstein-Barr
virus
• Cytomegalovirus (CMV) is practically not affected.

• Selectivity of action depends on interaction with two

distinct viral proteins
i. HSV thymidine kinase: Cellular uptake and initial
phosphorylation
ii. DNA polymerase.
• Affinity of acyclovir for HSV thymidine kinase is ~200 times greater than for the mammalian enzyme.
• Acyclovir triphosphate is 30 times more potent against herpes virus enzyme than the host enzyme
• Low toxicity for host cells: A several hundred-fold chemotherapeutic index has been noted.
• Both H. simplex and varicella-zoster virus have been found to develop resistance to acyclovir during
therapy.

Pharmacokinetics :
• Only about 20% of an oral dose is absorbed.
• Distributed widely in body fluids, including vesicular fluid, aqueous humor, and cerebrospinal fluid
(CSF).
• Little plasma protein bound with CSF concentration that is 50% of plasma concentration.
• Concentrated in breast milk, amniotic fluid, and placenta
• Primarily excreted unchanged in urine, both by glomerular filtration and tubular secretion
• Plasma t1/2 is 2-3 hours.
 Therapeutic Uses

 Effective in patients with normal as well as deficient immune status

 Treatment of Herpes Simlex Virus (HSV) and Varcella Zoster virus (VZV) infections:
Genital Herpes simplex, Mucocutaneous H. simplex, H. simplex encephalitis, H. Simplex keratitis, Herpes
zoster
 Chickenpox (VZV) in children
 Drug of choice: reduces fever,. eruptions, hastens healing and prevents visceral complications
 Adverse effects

a. Topical: Stinging and burning sensation after each application.

b. Oral: The drug is well tolerated.
• Headache, nausea, malaise and some CNS effects are reported.
• very rarely with renal insufficiency or neurotoxicity
c. Intravenous:
• Rashes, sweating, emesis and fall in BP occur only in few patients.
• Dose-dependent decrease in g.f.r. is the most important toxicity; especially in those with preexisting
kidney disease; normalises on discontinuation of the drug.
• Neurological manifestations (1-4%): tremors, lethargy, disorientation, hallucinations, convulsions and
coma
 Neutropenia in neonates
 No teratogenic potential has been noted
 Valaciclovir

• Ester prodrug of acyclovir

• Improved oral bioavailability (55-70%): Active transport by peptide transporters in the intestine.
• Complete conversion to acyclovir by esterases during passage through intestine and liver.
• Higher plasma levels of acyclovir improves clinical efficacy in certain conditions.
Use:
Drug of choice: Herpes zoster
 Famciclovir

• Ester prodrug of a guanine nucleoside analogue penciclovir,

• Good oral bioavailability and prolonged intracellular t1/2 of the active triphosphate metabolite.
• Requires viral thymidine kinase for generation of the active DNA polymerase inhibitor.
• Inhibits H. simplex, H. zoster but not acyclovir-resistant strains.
• Some activity against hepatitis B virus (HBV) has been noted.
Use:
• Used as an alternative to acyclovir for genital or orolabial herpes and herpes zoster.
Adverse effects:
• Headache, nausea, loose motions, itching, rashes and mental confusion.
4. Ganciclovir
• Acyclic analogue of guanosine of 2’-deoxyguanosine.
• Active against all herpes viruses including H. simplex, H. zoster, E-B virus and cytomegalovirus (CMV).
• More active than acyclovir against CMV.
• Monophosphorylated intracellularly by viral thymidine kinase during HSV infection and by a viral
phosphotransferase encoded by the UL97 gene during CMV infection.
• Active triphosphate attains much higher concentrations inside CMV infected cells. t1/2 > 24 hrs.
• 1st antiviral agent approved for the treatment of infections caused by HCMV.
Adverse effects: Systemic toxicity of ganciclovir is high
• Myelosuppression: Bone marrow depression, neutropenia, thrombocytopenia.
• Rash, fever, vomiting, neuropsychiatric disturbances.
Therapeutic Use:
• Treatment of choice: Management of HCMV diseases
• Restricted to severe CMV infections (pneumonia/colitis) in immunocompromised (AIDS, transplant recipient)
• Intravenous infusion of 10 mg/kg/day has prevented blindness in AIDS patients with CMV retinitis.
5. Foscarnet
• Trisodium phosphonoformate, synthetic non-nucleoside analogue of pyrophosphate.
• Inhibits viral DNA polymerase and reverse transcriptase by binding directly to the pyrophosphate binding
site.
• Active against H. simplex (including strains resistant to acyclovir), CMV (including ganciclovir resistant
ones) and HIV.
• Minimal viral resistance
• Low viral selectivity
Adverse effects:
• Toxicity is high
• Nephrotocity: Damages kidney produces a renal diabetes like condition, acute renal failure
• Anaemia, phlebitis, tremor, convulsions and other neurological symptoms, hypocalcaemia.
Therapeutic Use:
1. CMV retinitis and other CMV infections in AIDS patients: 2nd line drug
2. Acyclovir-resistant mucocutaneous H. simplex type and varicella-zoster infections in AIDS patients.
 Retrovirus
• Retroviruses are enveloped RNA viruses
• The virion contains several enzymatic activities
o Necessary for early events in replication: Reverse transcriptase, ribonuclease H, and integrase
o Processing the virion proteins: Protease

Replication in retroviruses

• Reverse transcriptase enzyme: Virus RNA-dependent DNA

polymerase: Makes a DNA copy of the viral RNA.
• Provirus: DNA copy is integrated into the genome of the host
cell.
• Provirus DNA is transcribed into both new viral genome RNA as
well as mRNA for translation in the host into viral proteins
• Completed viruses are released by budding.
• Many retroviruses can replicate without killing the host cell.
 ANTI-RETROVIRUS DRUGS

• Useful in prolonging and improving the quality of life and postponing complications of Acquired
Immunodeficiency Syndrome (AIDS) or AIDS-related complex (ARC)
• Do not cure the infection.
• Clinical efficacy of antiretrovirus drugs:
a. Plasma HIV-RNA assays
b. CD4 lymphocyte count at regular intervals.

(a) Nucleoside reverse transcriptase inhibitors (NRTis):

Zidovudine (AZT), Didanosine, Zalcitabine, Stavudine, Lamivudine, Abacavir
(b) Nonnucleoside reverse transcriptase inhibitors(NNRTis):
Nevirapine, Efavirenz, Delavirdine
(c) Protease inhibitors:
Ritonavir, lndinavir, Nelfinavir, Saquinavir, Amprenavir, Lopinavir
HIV Life cycle
 Nucleoside Reverse Transcriptase Inhibitors (NRTIS)

• NRTIs are structurally diverse analogs of the natural substrates of DNA synthesis .
• The approved NRTIs all lack the 3’-OH, get incorporated in viral DNA by reverse transcriptase (RT) and
act as chain terminators.
The NRTIs,
• They must be taken up by the host cell
• Phosphorylated (triphosphorylated at the 5′-hydroxyl) by cellular enzymes to convert them to their active
form, the NRTI triphosphates.
• The fully phosphorylated analogs block replication of the viral genome both by,
a. Competitively inhibiting incorporation of native nucleotides
b. Terminating elongation of nascent proviral DNA because they lack a 3′-hydroxyl group
 Prevent infection of susceptible cells but do not eradicate the virus from cells that already harbor
integrated proviral DNA.
 Zidovudine
• Thymidine analogue (3′-azido- 3′-deoxythymidine, AZT), the prototype NRTI.
• Phosphorylated by thymidine kinase, nucleoside diphosphate kinase
• Resistance: Point mutations which alter reverse transcriptase enzyme.
• Intracellular triphosphates have low affinity for human α and -β DNA polymerase
• Some are capable of inhibiting human mitochondrial enzyme DNA polymerase-γ
• Effective only against retroviruses
Pharmacokinetics
• The oral absorption of AZT is rapid, bioavailability is ~ 65%.
• Quickly cleared by hepatic glucuronidation (tl/2 =1 hr); intracellular t1/2 of active triphosphate is 3 hrs.
• 15-20% of the unchanged drug along with the metabolite is excreted in urine.
• Plasma protein binding is 30% and CSF level is ~ 50% of that in plasma.
• Crosses placenta and is found in milk.
 Therapeutic Uses

1. HIV infected patients only in combination with at least 2 other ARV drugs.
2. Prolong life in HIV infected individuals:
 HIV-RNA titer is reduced to undetectable levels and CD4 count increases progressively.
 Immune status is improved and opportunistic infections become less common.
 There is a sense of well-being and patients gain weight.
 Mortality among AIDS patients is reduced.
 Slow the progression of HIV infection, including escalation of AIDS-related complex to full blown AIDS
3. Reduces neurological manifestations: moderate HIV associated dementia
4. Standard choice
• Post-exposure prophylaxis of HIV: AZT, along with one or two other ARV drugs.
• Mother to offspring transmission: Can be reduced by more than 20%
 Given to parturient mother and then to the infant.
 Adverse Effects:

• Toxicity is mainly due to partial inhibition of cellular DNA polymerase.

• Bone marrow suppression:
 Anaemia and neutropenia
 Most important and dose-related.
 Occurs most often in individuals with advanced HIV disease and very low CD4 counts
• Nausea, anorexia, abdominal pain, headache, insomnia and myalgia: Resolve within the first few
weeks of treatment
• Skeletal muscle myopathy: Associated with depletion of mitochondrial DNA, consequence of
inhibition of DNA polymerase-γ
• Lactic acidosis, hepatomegaly, convulsions and encephalopathy are infrequent.
• Chronic zidovudine administration has been associated with nail hyperpigmentation.
 Didanosine
• Analogue of deoxyadenosine, intracellular conversion to didanosine triphosphate competes with ATP
• Antiretroviral activity of didanosine is equivalent to AZT.
Pharmacokinetics:
• Oral absorption of didanosine is erratic due to acid lability.
• Metabolized as well as excreted unchanged; tl/2 =1 to 1.5 hr.
• CSF level reaches ~ 20% of plasma conc.
• Does not cause myelosuppression.
Adverse effects:
• The major dose-related toxicity: Penpheral neuropathy and rarely pancreatitis.
• Diarrhoea, abdominal pain and nausea .
Uses
• Mutational resistance develops, but only few AZT resistant mutants are non-responsive to didanosine also.
• Used only in combination regimens.
 Stavudine
• 2′,3′- didehydro-2′,3′-dideoxythymidine (d4T): Thymidine analogue, acts in the same way as AZT.
• By utilizing the same thymidine kinase for activation, AZT antagonises the effect of stavudine.
• Thymidine kinase has a higher affinity for zidovudine than for stavudine.
Pharmacokinetics:
• Well absorbed orally and rapidly metabolized (t1/2 = 1.5 hr).
• CSF level reaches ~ 55% of plasma conc.
• Undergoes active tubular secretion, and renal elimination accounts for ~40% of parent drug.
Adverse effects:
• Serious toxicies which have restricted its use.
• Peripheral neuropathy, lipodystrophy and rarely pancreatitis
Uses:
• Anti-HIV efficacy of stavudine is comparable to AZT.
• Used in combination regimens.
 Lamivudine
• (–)2′, 3′-dideoxy, 3′-thiacytidine (3TC), Deoxycytidine analogue
• Phosphorylated intracellularly by deoxycytidine kinase, and undergoes further phosphorylation by
deoxycytidine monophosphate kinase and nucleoside diphosphate kinase
• Inhibits HIV reverse transcriptase as well as hepatitis B virus (HBV) DNA polymerase.
• Lamivudine has low affinity for human DNA polymerases: Low toxicity to the host.
• Used in combination with other anti-HIV drugs, and appears to be as effective as AZT.
• Frequently used for chronic hepatitis B.
Adverse effects:
• Generally well tolerated: One of the least toxic antiretroviral drugs
• Headache, fatigue, nausea, anorexia, abdominal pain, Neutropenia: Reported at higher than recommended
doses.
• Pancreatitis and neuropathy are rare.
 Abacavir
• Synthetic carbocyclic Guanosine analogue
• Initially monophosphorylated by adenosine phosphotransferase.
• The monophosphate is then converted to (−)-carbovir 3′-monophosphate, which is then phosphorylated to
the di- and triphosphates by cellular kinases
• Carbovir 5′-triphosphate terminates the elongation of proviral DNA
• More effective than most other nucleoside reverse transcriptase inhibitors.
• Oral bioavailability is >80% regardless of food intake.
• Metabolism to the 5′-carboxylic acid derivative catalyzed by alcohol dehydrogenase, and by glucuronidation
to the 5′-glucuronide
• Plasma tl/2 is 1-1.5 hour, intracellular tl/2 of active metabolite is > 12 hours.
• Used in HIV-1 infection, in combination with other antiretroviral agents.
Adverse effects:
• Unique and potentially fatal hypersensitivity syndrome: Fever, abdominal pain, and other gastrointestinal
(GI) complaints; a mild maculopapular rash; and malaise or fatigue.
• Worsens with continued treatment
 Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Chemically diverse nucleoside unrelated compounds.

• Non-competitive inhibitors and do not directly interfere with the binding of either the dNTP or the nucleic
acid substrates of reverse transcriptase.
• NNRTIs bind at the NNRTI-binding pocket (NNIBP), a hydrophobic pocket adjacent to the polymerase
active site (catalytic site).
• Binding site for NNRTIs is virus-strain-specific.
• Potent activity against HIV-1 but not HIV-2
• No activity against host cell DNA polymerases.
• Indicated in combination regimens for HIV, and have succeeded in reducing HIV-RNA levels when an
earlier regimen has failed.
 Nevirapine
• Dipyridodiazepinone NNRTI
• A single mutation in reverse transcriptase leads to the development of resistance.
• Cross-resistance extends to efavirenz and delavirdine, but not with NRTIs or PIs.
Pharmacokinetics:
• Well absorbed orally, bioavailability is not altered by food or antacids.
• Bioavailability > 90% and CSF level is 45% of plasma.
• Readily crosses the placenta and has been found in breast milk
• Extensively metabolized in liver by oxidative metabolism involving CYP3A4 and CYP2B6, t1/2 of 30 hours.
Therapeutic Use:
• Can prevent mother to baby transmission of HIV if given to the parturient mother and the neonate.
Adverse Effects
• Potentially hepatotoxic, rashes (commonest), nausea, headache are the usual side effects.
• Avoid enzyme inducers (rifampin) and enzyme inhibitors (ketoconazole).
 Efavirenz
• 1,4-dihydro-2H-3,1-benzoxazin-2-one
Pharmacokinetics:
• Oral absorption is incomplete (50%),.
• tl/2 is longer (48 hours), once daily oral administration
• 99% bound to plasma albumin and CSF concentration is ~ 1% of plasma (low CSF-to-plasma ratio of 0.01).
• Totally metabolized via oxidative metabolism, mainly by CYP2B6 and to a lesser extent by CYP3A4.
Adverse effects:
• CNS or psychiatric side effects: Dizziness, impaired concentration, dysphoria, vivid or disturbing dreams,
and insomnia. Episodes of frank psychosis (depression, hallucinations, and/or mania)
• Rashes, headaches
• Teratogenic
 Both NVP and EFV modestly induce CYP 3A4, 2D6 enzymes and enhance their own metabolism as well as
that of other drugs.
 Retroviral Protease Inhibitors
• Interfere with the cleaving function of aspartic protease by binding at the cleavage site.
• The preferred cleavage site for this enzyme is the N-terminal side of proline residues, especially between
phenylalanine and proline (phenylalanine-proline cleavage site )
• More effective viral inhibitors than AZT.
• Effective in both newly and chronically infected cells since they act at a late step of viral cycle.
• Under their influence, HIV-infected cells produce immature noninfectious viral progeny- hence prevent
further rounds of infection.
• Infected patients treated with HIV protease inhibitors as sole agents experienced a 100- to 1000-fold mean
decrease in plasma HIV RNA concentrations within 12 weeks, an effect similar in magnitude to that
produced by NNRTIs
• Five protease inhibitors are marketed in India against HIV
Indinavir (IDV), Nelfinavir (NFV), Saquinavir (SQV), Ritonavir (RTV) and Lopinavir
 Pharmacokinetics
Absorption:
• Generally given orally.
• Oral bioavailability of PIs is variable (IDV and RTV -65%, NFV >20%, SQV 15%).
Distribution:
• Highly plasma protein bound
• Plasma t1/2 ranges from 2-5 hours.
• CSF levels are negligible with saquinqvir and highest with indinavir (76% of plasma conc.)
Metabolism and Excretion:
• Undergo hepatic oxidative metabolism.
• All except nelfinavir are metabolized predominantly by CYP3A4 (and nelfinavir’s major metabolite is cleared
by CYP3A4).
 All (especially ritonavir and lopinavir) are potent inhibitors of CYP3A4
 Ritonavir, Nelfinavir and Lopinavir: Autoinduction of metabolism
 Adverse Effects
 Most prominent:
• Gastrointestinal intolerance: Nausea, vomiting, and diarrhea
• Resolve within 4 weeks of the start of the treatment.
• Asthenia, headache, dizziness, limb and facial tingling, numbness and rashes.
 Particular concern:
• Lipodystrophy: Abdominal obesity, buffalo hump with wasting of limbs and face
• Dyslipidaemia: Raised triglycerides and cholesterol which may necessitate hypolipidaemic drugs.
• Exacerbation of diabetes
• lndinavir crystalises in urine and increases risk of urinary calculi.
 Potential for metabolic drug interactions
Indinavir:
• Peptidomimetic hydroxyethylene HIV protease inhibitor
• 10-fold more potent against the HIV-1 protease than that of HIV-2
• Absorbed rapidly after oral administration, with peak concentrations achieved in ~1 hour
• Lowest protein binding of the HIV protease inhibitors: Higher fractional CSF penetration
• G.I. intolerance is common
• Crystalluria and nephrolithiasis excess fluids must be consumed to avoid nephrolithiasis.
2. Nelfinavir :
• It is to be taken with meals and bioavailability is erratic.
• Often produces diarrhoea and flatulence
• Clinical efficacy may be somewhat lower than other PIs.
3. Ritonavir:
• It is a potent PI; also a potent cytochrome inhibitor.
• Drug interactions, nausea, diarrhoea, paresthesias, fatigue and lipid abnormalities are prominent.
Saquinavir:
• Peptidomimetic hydroxyethylamine.
• Transition state analog of a phenylalanine-proline cleavage site in one of the native substrate sequences
for the HIV aspartyl protease
• Oral bioavailability is low (~4%) owing mainly to extensive first-pass metabolism
• Metabolized primarily by intestinal and hepatic CYP3A4
• Two types of formulations (hard gel and soft gel capsules)
• Side effects are frequent; photosensitivity can occur.
• lt is a weak inhibitor of CYP3A4.
• Given in combination with ritonavir.
5. Lopinavir:
• It is available only in combination with ritonavir to improve bioavailability.
• Diarrhoea, abdominal pain, nausea and dyslipidaemias are more common.
 'Highly Active Antiretroviral Therapy' (HAART)

• Aggressive treatment aimed at suppressing plasma viral load to undetectable levels (<50 copies of HIV-
RNA/ml)
• Goal of therapy: Maximally and durably inhibit viral replication to attain and maintain effective immune
response towards potential microbial pathogens.
• Greater the suppression of viral replication, lesser is the chance of emergence of drug resistant virus.
• Dramatically improved the prognosis of the disease
• Therapy with 3 antiretroviral drugs is considered optimal.

A typical HAART combination would involve,

 2 nucleoside reverse transcriptase inhibitor with either a non-nucleoside reverse transcriptase inhibitor or 1 or
more protease inhibitors.
 HIV replication is inhibited, presence of HIV RNA in plasma is reduced to undetectable levels and patient
survival is prolonged.
 No specific combination can be considered optimal initial regimen for all patients.
 Choice has to be made on the basis of efficacy, durability, tolerability, convenience, drug interactions,
impact on future options and cost.

Limitations
• Regimen is complex and has many unwanted effects.
• Compliance is difficult and lifelong treatment is necessary.
• Failure to completely eradicate HIV: A small number survive within the resting CD4 lymphocytes and
invariably give rise to relapse when treatment is discontinued.
• Resistance: HIV reverse transcriptase is highly copying error prone giving rise to mutations and
development of resistance, leading to failure of treatment.
• Preferred regimens: Zidovudine + Lamivudine + Efavirenz (PI sparring: NRTI + NNRTI)
Zidovudine + Lamivudine + Lopinavir (NRTI + PI)
 Anti-Influenza Virus
1. Amantadine
• A tricyclic amine unrelated to any nucleic acid precursor
Mechanism of Action
• Inhibits replication of influenza A virus (a myxovirus).
• Acts at an early step (possibly uncoating) as well as at a late step (viral assembly) in viral replication.
• Target of action: Influenza A virus M2 protein, an integral membrane protein that functions as an ion
channel.
• By interfering with this function of the M2 protein, the drugs inhibit,
i. The acid-mediated dissociation of the ribonucleoprotein complex early in replication
ii. Potentiate acidic pH–induced conformational changes in the hemagglutinin during its intracellular
transport later in replication.
Resistance:
• Mutation causing amino acid substitutions in the M2 protein.
Pharmacokinetics:
Well absorbed orally, t1/2= 16 hrs
Excreted unchanged in urine over 2-3 days
Therapeutic Uses:
1. Prophylaxis of influenza A2: During an epidemic or seasonal, especially in high risk patients.
• It does not interfere with antibody response to influenza vaccination; both may be given together.
2. Treatment of influenza (A2) illness:
A modest therapeutic effect (reduction in fever, congestion and cough) occurs if the drug is given quickly
after the symptoms appear.
Adverse effects:
• Generally well tolerated
• Nausea, anorexia, insomnia, dizziness, nightmares, lack of mental concentration, rarely hallucinations .
• Ankle edema occurs due to local vasoconstriction.
2. Rimantadine
• α-methyl derivative of Amantadine (α-methyl-1-adamantane methylamine hydrochloride)
• It is a more potent, long-acting (t1/2= 30 hr) and better tolerated congener of amantadine.
• Oral bioavailability is higher and it is largely metabolized.
• Dose and clinical application is similar to amantadine.
• Amantadine resistant virus is resistant to rimantadine as well.
 Oseltamivir (TAMIFLU):
• Recently developed antiinfluenza virus drug.
• Ester prodrug, rapidly and nearly completely hydrolysed into the active form oseltamivir carboxylate.
• Inhibits influenza virus neuraminidase enzyme, needed for release of progeny virions from the infected
cell. Spread of the virus in the body is thus checked.
• Broader-spectrum activity covering influenza A (amantadine sensitive as well as resistant), influenza B and
avian-influenza (bird flu) H5N1 and other strains.
• The active metabolite is not metabolized further and excreted by the kidney with a t1/2 of 6-10 hours.
Adverse effects:
• Nausea and abdominal pain due to gastric irritation (reduced by taking the drug with food), headache,
diarrhoea, cough and insomnia.
• Skin reactions have been reported.
Therapeutic Use:
• Indicated both for prophylaxis as well as treatment of influenza A, B and bird flu.
• Started at the onset of symptoms, reduces the severity and duration
Mechanism of Action
 Nonselective Antiviral Drugs: Ribavirin

• Purine nucleoside analogue

• Broad-spectrum antiviral activity: Influenza A and B, respiratory syncytial virus and many other DNA
and double stranded RNA viruses.

Mechanism of action:
• Its mono- and triphosphate derivatives generated intracellularly inhibit GTP and viral RNA synthesis.

Pharamcokinetics:
• Oral bioavailability of ribavirin is ~50%.
• Accumulates in the body and persists months after discontinuation.
• Principal routes of elimination: Hepatic metabolism and renal excretion of ribavirin and its metabolites
Adverse effects
• Dose-related reversible anemia owing to extravascular hemolysis and suppression of bone marrow.
• The aerosol can cause irritation of mucosae and bronchospasm.
• Occasional reversible deterioration in pulmonary function
• Teratogenic.

Therapeutic Uses:
• Influenza A/B and measles in immunosuppressed patients
• Herpes virus infections, acute hepatitis,.
• Combined with interferon: Standard treatment for chronic hepatitis C.
• Nebulized ribavirin: Respiratory syncytial virus, broncholitis in infants and children, particularly those with
congenital heart disease, prematurity or other high risk conditions.
 Interferon α
• Low molecular weight glycoprotein cytokines produced by host cells in response to viral infections and
some other inducers.
• Host specific: Those produced by another species have poor activity in man.
• Three types of human interferons (α, β andγ) have been produced by recombinant DNA technology.
• Only interferon α2A and α2B have antiviral activity.

Mechanism of action
• Nonspecific antiviral as well as other complex effects
on immunity and cell proliferation.
• Bind to specific cell surface receptors and affect viral
replication at multiple steps: viral penetration,
synthesis of viral mRNA, assembly of viral particles
and their release
• Direct or indirect suppression of viral protein
synthesis, i.e. inhibition of translation.
Adverse effects:
1. Flu-like symptoms: fatigue, aches and pains, malaise, fever, dizziness, anorexia, taste and visual disturbances:
develop a few hours after each injection, but become milder later.
2. Neurotoxicity: numbness, neuropathy, tremor, sleepiness, rarely convulsions.
3. Myelosuppression: neutropenia, thrombocytopenia.
4. Thyroid dysfunction (hypo as well as hyper).
5. Hypotension, transient arrhythmias, alopecia and liver dysfunction.
Therapeutic Uses
1. Chronic hepatitis B and C
2. AIDS-related Kaposi's sarcoma
3. Condyloma acuminata caused by papilloma virus
4. H. simplex, H. zoster and CMV infections in immunocompromised patients: Interferon is inferior to acyclovir/
ganciclovir; may be used as second line / adjuvant drug.
5. Rhinoviral cold: Prophylactic
6. Chronic myelogenous leukaemia and multiple myeloma.
 ANTI-RETROVIRUS DRUGS

Fig.. Sites of action of drugs for human immunodeficiency virus (HIV) infection.
Enfuvirtide inhibits the fusion of HIV with host CD4 cell membranes. After the virus penetrates
the host cell and becomes uncoated, the viral RNA is transcribed by reverse transcriptase to
form viral DNA. Viral DNA is incorporated into the host genome in the cell nucleus by HIV
integrase. The viral DNA is then transcribed to RNA. Viral RNA is incorporated into new virions
and is translated to synthesize polyproteins. The polyproteins are cleaved into viral proteins
by HIV protease as the new virions are released from the cell.