ANTIVIRAL AGENTS

INCLUDING ANTI-HIV AGENTS

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HIV-virus
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HIV Life cycle
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HIV Life cycle
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Life cycle of HIV
HIV is a retrovirus that infects CD4+ cells.
1. Virus attachment
2. Fusion of the viral membrane (envelope) with the host
cell plasma membrane
3. Uncoating
4. The HIV DNA is integrated into the host cell genome
5. Gene transcription
6. The viral mRNA is translated into proteins on host cell
ribosomes.
7. The proteins assemble into immature virions
8. The virions undergo proteolytic cleavage, maturing
into fully infective virions.
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Classification of Antiviral agents
1. Anti- Retrovirus
a) Nucleoside reverse transcriptase inhibitors (NRTIs)
Zidovudine (AZT), Didanosine, Zalcitabine, Stavudine,
Lamivuldine, Abacavir
b) Nonnuleaside reverse transcriptase inhibitors (NNRTIs)
Nevirapine, Efavirenz, Delavirdine
c) Protease inibitors: Ritonavir, Indinavir, Nelfinavir, Saquinavir,
Amprenavir, Lopinavir
d) Inhibitor of HIV fusion with host cells: Enfurvitide
e) Integrase inhibitor : Ratelgravir
f) Chemokine receptor antagonist (CCR5): Maraviroc

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2. Anti-Herpes virus
Idoxuridine, Acyclovir, Valacyclovir, Famciclovir
Ganciclovir, Foscarnet, Trifluridine, Cidoclovir, Fomivirsen
3. Anti-Influenza virus
Amantadine, Rimantadine, Oseltamiv, Zanamivir
4. Anti-hepatitis virus/ nonselective antiviral drugs
Primarily for hepatitis B: Lamivuldine, Adefovir diplivoxil,
Tenofovir
Primarily for hepatitis C: Ribavirin, Intreferon α

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Pharmacology of Zidovuldine (AZT)

Zidovudine (3'-azido-3'-deoxythymidine; AZT)

It is a synthetic thymidine analog with potent in vitro activity

against a broad spectrum of retroviruses including HIV-1,HIV-2,
and human T-cell lymphotrophic viruses (HTLV) I and II
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Pharmacokinetics
Absorption: Rapid oral absorption, but bioavailability is ~65%.
Distribution:
1. Plasma protein binding 30% and CSF level is ~50% of
plasma level. It can crosses placenta.
2. Zidovudine also is detectable in breast milk, semen, and fetal
tissue.
3. Zidovudine concentrations are higher in the male genital tract
than in the peripheral circulation, suggesting active transport
or trapping.
Metabolism: It undergoes rapid first-pass hepatic metabolism by
conversion to 5-glucuronyl zidovudine by hepatic
glucuronidation .
Excretion: 15-20% of unchanged drug along with metabolite is
excreted in urine. t1/2 is 1hr.

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Mechanism of action

1.Like other nucleoside analogs, intracellular zidovudine is

phosphorylated by thymidine kinase to zidovudine 5'-
monophosphate, which is then phosphorylated by
thymidylate kinase to the diphosphate and by nucleoside
diphosphate kinase to zidovudine 5'-triphosphate.
2.Zidovudine 5'-triphosphate terminates the elongation of
proviral DNA because it is incorporated by reverse
transcriptase into nascent DNA but lacks a 3'-hydroxyl group.
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Adverse effects
1. Patients initiating zidovudine treatment often complain of fatigue,
malaise, myalgia, nausea, anorexia, headache, and insomnia.
2. Bone marrow suppression, mainly anemia and granulocytopenia,
3. Erythrocytic macrocytosis is seen in ~90% of all patients but
usually is not associated with anemia.
4. Chronic zidovudine administration has been associated with
nail hyperpigmentation.
5. Skeletal muscle myopathy
6. Serious hepatic toxicity, with or without steatosis and lactic
acidosis, is rare but can be fatal.
7. Risk factors for the lactic acidosis-steatosis syndrome include
female sex, obesity, and prolonged exposure to the drug.

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Interactions
1. Paracetamol, probenecid, fluconazole, atovaquone, and
valproic acid may increase plasma concentrations of
zidovudine probably through inhibition of glucuronosyl
transferase.
2. Stavudine and zidovudine compete for intracellular
phosphorylation and should not be used concomitantly.
(Mutual antagonism)

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Uses
1. Zidovudine is FDA-approved for the treatment of adults and
children with HIV infection and for preventing mother-to-
child transmission of HIV infection.
2. It is still recommended for post-exposure prophylaxis in
HIV-exposed healthcare workers

Brands
1. RETROVIR, ZIDOVIR 100mg cap, 300mg tab.

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Pharmacology of Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTIs)

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Mechanism of action

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1. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
bind to a hydrophobic pocket in the p66 subunit of the HIV-1
reverse transcriptase.

2. These compounds induce a conformational change in the

three-dimensional structure of the enzyme that greatly
reduces its activity, and thus they act as noncompetitive
inhibitors.

3. Because the binding site for NNRTIs is virus-strain-specific,

the approved agents are active against HIV-1 but not HIV-2
or other retroviruses and should not be used to treat HIV-2.

4. These compounds also have no activity against host cell DNA

polymerases.

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Nevirapine: It has good oral bioavailability, and penetrates into
the CSF. It is metabolised in the liver, and the metabolite is
excreted in the urine. Nevirapine can prevent mother-to-baby
transmission of HIV if given to the parturient mother and the
neonate.
Brands: NEVIVIR, NEVIRETRO 200mg tab. B.D

Efavirenz : It is given orally, once daily, because of its plasma

half-life (∼50 h). It is 99% bound to plasma albumin, and its CSF
concentration is ∼1% of that in the plasma. Nevertheless, its
major adverse effects are insomnia, bad dreams and sometimes
psychotic symptoms. It is also teratogenic if used in early
pregnancy.
Brands: EFAVIR, VIRANZ 200mg tab., EVIRENZ 200mg cap,
600mg tab. OD

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Pharmacology of Protease inhibitors
The HIV protease inhibitors are designer drugs based on
molecular characterization of the active site of the viral enzyme.
(Structure based drug design)

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Pharmacology of Saquinavir
HIV protease inhibitors are peptide-like chemicals that
competitively inhibit the action of the virus aspartyl protease

Pharmacokinetics
Absorption: Fractional oral bioavailability is low (~4%) owing
mainly to extensive first-pass metabolism and so this drug
should always be given in combination with ritonavir.
Distribution: Low doses of ritonavir increase the saquinavir
steady-state AUC by 20- to 30-fold, allowing administration
once or twice daily.
Metabolism : Substances that inhibit intestinal but not hepatic
CYP3A4, such as grapefruit juice, increase the saquinavir
AUC by 3-fold at most. Saquinavir is metabolized primarily
by intestinal and hepatic CYP3A4; its metabolites are not
known to be active against HIV-1.
Elimination: The parent drug and its metabolites are eliminated
through the biliary system and feces (>95% of drug), with
minimal urinary excretion (<3%).
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• Mechanism of action

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1. They bind to protease molecule, interfere with its cleaving
function.

2. They act at a late step of viral cycle , they are effective in both
newly and chronically infected cells.

3. Under their influence, HIV infected cells produce immature

noninfectious viral progeny.

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Adverse drug reactions
1. GIT intolerance, asthenia, numbness and rashes.

2. Lipodystrophy

3. Dyslipidaemia

4. Diabetes may increase

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Precautions and Interactions
1. Co-administration of inducers of CYP3A4 such as rifampin,
phenytoin, or carbamazepine lowers saquinavir concentrations
and should be avoided.
2. The effect of nevirapine or efavirenz on saquinavir may be
partially or completely reversed with ritonavir.
3. Most drug interactions seen with saquinavir/ritonavir reflect
the effect of the boosting agent.

Dose: 1000mg BD (with RTV 100mg)

Brands: SAQUIN 200mg tab.

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Other anti HIV agents:
Inhibitor of HIV fusion with host cells (Entry Inhibitors)
Enfuvirtide: Enfuvirtide is a synthetic 36-amino-acid peptide. The drug binds
to the gp41 subunit of the viral envelope glycoprotein, preventing the
conformational changes required for the fusion of the viral and cellular
membranes. Enfuvirtide is administered subcutaneously in combination with
other anti-HIV agents in previously drug-treated patients with persistent HIV-1
replication despite ongoing therapy. Its metabolism via hydrolysis. Injection
site reactions and hypersensitivity may occur. An increased incidence of
bacterial pneumonia has been reported.
Chemokine receptor antagonist (CCR5)
Maraviroc: HIV-1 infection begins with attachment of an HIV envelope
protein called gp120 to CD4 molecules on surfaces of helper T cells. The
attachment of many HIV strains involves a transmembrane chemokine receptor
CCR5. This receptor, a human protein, is the target for maraviroc, which
blocks viral attachment. Maraviroc is used orally and has good tissue
penetration. Adverse effects of maraviroc include cough, diarrhea, muscle and
joint pain, and increases in hepatic transaminases.

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Integrase inhibitor:
Raltegravir blocks the catalytic activity of the HIV-encoded
integrase, thus preventing integration of virus DNA into the host
chromosome. Raltegravir has potent activity against both HIV-1
and HIV-2, with an in vitro IC95 range of 6-30 nM. Raltegravir
retains activity against viruses that have become resistant to
antiretroviral agents of other classes because of its unique
mechanism of action.

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Guidelines for HIV treatment
1. Use of combination treatment known as highly active
antiretroviral therapy (HAART).
2. Monotherapy is contraindicated
3. Combinations avoided
i. Zidovudine + Stavudine: Pharmacodynamic antagonism
ii. Stavudine + Didanosine: Increased toxicity (Lactic acidosis)
iii. Lamivudine + Didanosine: Clinically not additive
4. Preferred regimens
i. 2NRTIs+ NNRTI
Zidovudine + Lamivudine +Efavirenz
ii. 2NRTIs+ PI
Zidovudine + Lamivudine + Lopinavir

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2. Anti-Herpes virus agents
Infection with herpes simplex virus type 1 (HSV-1) typically
causes diseases of the mouth, face, skin, esophagus, or brain.
Herpes simplex virus type 2 (HSV-2) usually causes infections
of the genitals, rectum, skin, hands, or meninges. Both cause
serious infections in neonates.

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Pharmacology of Acyclovir (Acycloguanosine)

Acyclovir is an acyclic guanine nucleoside analog that lacks a

3'-hydroxyl on the side chain. Valacyclovir is the L-valyl
ester prodrug of acyclovir.

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Pharmacokinetics of Acyclovir
Absorption: Acyclovir can be administered by the topical, oral, and
intravenous routes. Because of its short half-life, oral
administration requires multiple daily doses of acyclovir.
Distribution: It is distributes widely in body fluids, including
vesicular fluid, aqueous humor, and cerebrospinal fluid (CSF).
Acyclovir is concentrated in breast milk, amniotic fluid, and
placenta.
Metabolism: Valacyclovir is converted rapidly and virtually
completely to acyclovir after oral administration in healthy adults
by first-pass intestinal and hepatic metabolism through enzymatic
hydrolysis. 9-carboxymethoxymethylguanine or minor
metabolites are formed.
Excretion: The mean plasma elimination t1/2 of acyclovir is ~2.5
hours . Renal excretion of un-metabolized acyclovir by glomerular
filtration and tubular secretion is the principal route of elimination.
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Mechanism of action

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Adverse drug reactions
1. Oral acyclovir has been associated infrequently with nausea,
diarrhea, rash, or headache and very rarely with renal
insufficiency or neurotoxicity.
2. Valacyclovir also may be associated with headache, nausea,
diarrhea, nephrotoxicity, and central nervous system (CNS)
symptoms.
3. High doses of valacyclovir have been associated with
confusion and hallucinations, nephrotoxicity, and
uncommonly, severe thrombocytopenic syndromes, sometimes
fatal, in immunocompromised patients.

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Drug Interactions
1. Severe somnolence and lethargy may occur with combinations
of zidovudine and acyclovir.
2. Concomitant cyclosporine and probably other nephrotoxic
agents enhance the risk of nephrotoxicity.
3. Probenecid decreases the acyclovir renal clearance and
prolongs the elimination t1/2.
4. Acyclovir may decrease the renal clearance of other drugs
eliminated by active renal secretion, such as methotrexate.

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Uses
1. Genital Herpes simplex
2. Mucocutaneous H. simplex
3. H.simplex encephalitis
4. H. simplex keratitis
5. H. zoster
6. Chickenpox

Brands: ZOVIRAX 200mg tab, 250mg/vail for i.v inj.

CYCLOVIR 200mg tab, 5% skin cream
VALVIR 0.5 g, 1.0g tabs

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Anti-Influenza Agents
Four drugs are currently approved for the treatment and
prevention of influenza virus infection like H5N1 avian influenza
and the novel 2009 influenza A H1N1, of swine origin.

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Mechanism of action
Amantadine
1.Inhibit an early step in replication of the influenza A (but not
influenza B) virus.
2.They prevent "uncoating" by binding to a protein M2. This
protein functions as a proton ion channel required at the onset
of infection to permit acidification of the virus
Oseltamivir and Zanamivir
1.These drugs are inhibitors of neuraminidases produced by
influenza A and B and are currently active against both H3N2
and H1N1 strains.
2.These viral enzymes cleave sialic acid residues from viral
proteins and surface proteins of infected cells.
3.They function to promote virion release and to prevent
clumping of newly released virions. By interfering with these
actions, neuraminidase inhibitors impede viral spread.
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Non-selective antiviral drugs
Mechanism of action
Ribavirin
1. Ribavirin inhibits the replication of a wide range of DNA and
RNA viruses, including influenza A and B, parainfluenza,
respiratory syncytial virus (RSV), paramyxoviruses, HCV,
and HIV.
2. Although the precise antiviral mechanism of ribavirin is not
known, the drug inhibits guanosine triphosphate formation,
prevents capping of viral mRNA, and can block RNA-
dependent RNA polymerases.

Adefovir diplivoxil
Adefovir dipivoxil is the prodrug of adefovir, which following its
phosphorylation by cellular kinases, competitively inhibits HBV
DNA polymerase and results in chain termination after
incorporation into the viral DNA.
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Intreferon α
1.IFN- α is a cytokine that acts through host cell surface
receptors increasing the activity of Janus kinases (JAKS).
2. These enzymes phosphorylate signal transducers and activators
of transcription (STATS) to increase the formation of antiviral
proteins.
3. The selective antiviral action of IFN- α is primarily due to
activation of a host cell ribonuclease that preferentially
degrades viral mRNA. IFN- α also promotes formation of
natural killer cells that destroy infected liver cells.

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