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Antivirals

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Antivirals are highly toxic..

antiviral agents must either

block viral entry into or exit from the cell or

be active inside the host cell.

only work during viral replication

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Viral Structure

Viral genome size extends from one to 200 genes

single-stranded

double-stranded DNA genome

single-strand sense (positive-strand)

single-strand or segmented antisense (negative-strand)

double-strand segmented RNA genome

Viral nucleic acid:

usually enclosed in a capsid (protein shell consisting ofrepeating capsomers)

capsids containing nucleic acids are called nucleocapsids.

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Viral Replication: Antiviral agents can

potentially target any of these steps:

(1) attachment of the virus to the host cell;

(2) entry of the virus through the host cellmembrane;

(3) Penetration/uncoating of viral nucleic acid;(4) synthesis of early regulatory proteins, eg,

nucleic acid polymerases;

(5) synthesis of RNA or DNA;

(6) synthesis of late, structural proteins;

(7) assembly (maturation) of viral particles; and

(8) release from the cell.

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1

2 3

7

6

5

4

8

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Mechanism by which many viruses enter the cell: endocytosisInfluenza Virus – Adenoviruses- Herpes viruses

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 key characteristics: 

ability to enter the cells infected with virus

interfere with viral nucleic acid synthesis/ 

regulation interfere with ability of virus to bind to cells

stimulate body’s immune system 

Antiviral Drugs

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Mechanism of action of anti-herpes drugs

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Therapeutic uses of Acyclovir

1. Herpes simplex genitalis  – initial infection topical todecrease viral shedding - Oral acyclovir superior forinitial and recurrent infections

2. Mucocutaneous herpes simples of face andoropharynx

3. Varicella zoster virus (VSV) infections4. High doses effective for adults (shingles) and children

(chicken pox) if begun within 24 hours of rash5. Intravenous acyclovir is the treatment of choice for

herpes simplex encephalitis, neonatal HSVinfection, and serious HSV or VZV infections6. In immunocompromised patients with VZV infection,

intravenous acyclovir reduces the incidence ofcutaneous and visceral dissemination

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Acyclovir (Zovirax)

Adverse effects 

generally well tolerated.

Nausea, diarrhea, and headache have

occasionally been reported.

IV infusion may be associated withreversible renal dysfunction (due to

crystalline nephropathy) or neurologictoxicity (eg, tremors, delirium, seizures) Hydrate during & after infusion

Administer over 1 hour (IV)

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B. Foscarnet (Foscavir)

Uses:

An effective treatment for CMV retinitis,

is also used for treatment of CMV colitis,

CMV esophagitis,

Used for treatment of acyclovir-resistant HSVinfection, and acyclovir-resistant VZV

infection.

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Foscarnet (Foscavir) kinetics 

Although the mean plasma half-life is 3-6.8hours, up to 30% of foscarnet may bedeposited in bone, with a half-life of several

months. Clearance of foscarnet is primarily by the

kidney and is directly proportional tocreatinine clearance.

Serum drug concentrations are reducedapproximately 50% by hemodialysis.

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B. Foscarnet (Foscavir)

Adverse Effects:

electrolyte imbalances (hypo- or hypercalcemia, hypo- or

hyperphosphatemia, hypokalemia, and hypomagnesemia)

Major adverse effect is renal damage (Saline preloading

helps to prevent nephrotoxicity, as does avoidance of concomitantadministration of drugs with nephrotoxic potential (eg, amphotericin B,pentamidine, aminoglycosides).

Nausea, vomiting, anemia, elevation of liverenzymes, and fatigue have been reported; the risk of

anemia may be additive in patients receivingconcurrent zidovudine.

Central nervous system toxicities include headache,hallucinations, and seizures

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C. Famiciclovir (Famvir)

After oral administration, famciclovir is rapidlyconverted by first-pass metabolism topenciclovir.

Oral famciclovir is effective for the treatmentof first and recurrent genital herpes, and forthe treatment of acute zoster

As with acyclovir, activation byphosphorylation is catalyzed by the virus-specified thymidine kinase in infected cells

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D. Valacyclovir (Valtrex) 

Prodrug form of acyclovir

Approved as oral therapy of herpes zoster incompetent hosts

Helped better than acyclovir in trials with pain& neuralgia

Rapid absorption

Not used in immunocompromised host -causes thrombotic thrombocytopenia purpura

 / hemolytic uremic syndrome – can be fatal

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E. Trifluridine (Viroptic)

A fluorinated pyrimidine nucleoside thatinhibits viral DNA synthesis in HSV-1,HSV-2, vaccinia, and some

adenoviruses.

Rx ocular infections Caused by HSVtype 1 & 2

Treats keratoconjunctivitis 1% solution.

Treats recurrent epithelial keratitis

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II. Agents to treat Cytomegalovirus

(CMV) infections

A. Ganciclovir

Requires tri-phosphorylation for activation

competitively inhibits viral DNA polymerase

in CMV-infected cells: first phosphorylation stepcatalyzed by viral specific protein kinase

in HSV-infected cells: first phosphorylation stepcatalyzed by thymidine kinase

Ganciclovir resistance due to either DNApolymerase mutations or protein kinase mutation

IV and oral route of administration 

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A. Ganciclovir

Clinical Use

IV ganciclovir indicated for CMV retinitis in HIVpatients.

Reduces CMV disease associated with organtransplantation

IV ganciclovir indicated for CMV pneumonitis inpatients with compromised immune systems

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A. Ganciclovir 

Adverse ReactionsMost common: myelosuppression, notablyneutropenia: bone marrow suppression limits this

drug's use in many patients.Myelosuppression additive in patients receivingboth ganciclovir and zidovudine

Oral route administration less likely to produce

myelosuppression than IV routeUnusual CNS toxicity may include headache,seizures, altered mental status

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B. Cidofovir (Vistide)

In contrast to ganciclovir, phosphorylation of cidofovirto the active diphosphate is independent of viralenzymes

New IV drug for CMV retinitis in AIDS

Fewer infusions needed

Major problem is kidney damage

Must receive probenecid (2 g at 3 hours before the

infusion and 1 g at 2 and 8 hours after), which blocksactive tubular secretion and decreasesnephrotoxicity. to infusion to decrease risk of renaldamage

Hydration needed

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Cidofovir adverse effects 

IV cidofovir casues a dose-dependentnephrotoxicity (prehydration using normalsaline).

Avoid concurrent administration of otherpotentially nephrotoxic agents (eg, amphotericin B,

aminoglycosides, nonsteroidal anti-inflammatory drugs,pentamidine, foscarnet)

Other potential side effects include uveitis, ocularhypotony, neutropenia (15%), and metabolic acidosis.Gastrointestinal intolerance, fever, and rash due to probenecid

may occur. 

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III. antiretroviral agents

Classification of antiretroviral drugs 

First – reverse transcriptase inhibitorssubclass:

Nucleoside reverse transcriptase inhibitors(NRTI’s)

Nonnucleoside reverse transcriptase inhibitors(NNRTI’s)

Second – protease inhibitors

Third: Fusion Inhibitors

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Nucleoside reverse transcriptase

inhibitors (NRTI’s): 1. Zidovudine 

Zidovudine was the first antiretroviralagent to be approved and has beenshown to decrease the rate of clinical

disease progression and prolongsurvival in HIV-infected individuals.

Efficacy has also been demonstrated in

the treatment of HIV-associateddementia and thrombocytopenia.

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Zidovudine in pregnancy

In pregnancy a regimen of oral zidovudinebeginning between 14 and 34 weeks ofgestation (100 mg five times a day),

intravenous zidovudine during labor (2 mg/kgover 1 hour, then 1 mg/kg/h by continuousinfusion), and zidovudine syrup to theneonate from birth through 6 weeks of age (2

mg/kg every 6 hours) has been shown toreduce the rate of vertical (mother-to-newborn) transmission of HIV by up to 23%.

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Zidovudine (AZT) MOA: 

Zidovudine (azidothymidine, AZT):

activation by phosphorylation to the 5'-triphosphatederivative; phosphorylated by three cellular kinases;

active drug is a competitive inhibitor ofdeoxythymidine triphosphate;

active drug also chain-terminates proviral DNAsynthesis.

Activity (in vitro) against: HIV-1, HIV-2, human T cell

lymphotrophic viruses; .

Resistance: reverse transcriptase gene mutations

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resistance more frequent in advanced HIV infection

mutations at certain codons associated with 100-foldreduction in viral susceptibility to zidovudine.

oral and IV formulations available significant first passeffect results in a bioavailability of about 65%.

Hepatic disease (cirrhosis) reduces the clearance

significantly and requires dosage adjustment.

Renal disease may also require dosage adjustment.

Zidovudine (AZT)

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Adverse reactions

most common: myelosuppression (anemia,neutropenia) -- myelosuppression may be worse if thezidovudine is administered with other drugs that the

also cause bone marrow suppression Transient adverse reactions, resolving with continued

use, include GI intolerance, headache, insomnia.

Less frequent side effects: thrombocytopenia,

myopathy, acute cholestatic hepatitis: High-dose zidovudine therapy may cause CNS effects:

confusion, anxiety

Zidovudine (AZT)

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For HIV & should be combined with at least one otherantiretroviral drug

Adverse effects : pancreatitis

Hx of pancreatitis, alcoholism increases risks

Take drug 1 hour before meals or 2 hours after

Chew tablets or crush them and put in at least 1ounce of water

Powder should have 4 oz water (not fruit juice)

Buffer interferes with absorption of many drugs

Tablets contain Phenylalanine and Na

B. Didanosine (Videx, dideoxyinosine)

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Didanosine (Videx, dideoxyinosine)

adevrse effects 

The major clinical toxicity associated with didanosinetherapy is dose-dependent pancreatitis. Try to avoidin: alcoholism, hypertriglyceridemia, zalcitabine andstavudine,

painful peripheral distal neuropathy,

Diarrhea, hepatitis, esophageal ulceration,cardiomyopathy, and central nervous system toxicity(headache, irritability, insomnia).

Asymptomatic hyperuricemia may precipitate attacksof gout in susceptible individuals.

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Nonnucleoside reverse transcriptase

inhibitors (NNRTI’s) 

The NNRTIs bind directly to HIV-1 reverse transcriptase,resulting in blockade of RNA- and DNA-dependent DNApolymerase.

The binding site of NNRTIs is near to but distinct from that ofNRTIs.

Unlike the NRTI agents, NNRTIs neither compete withnucleoside triphosphates nor require phosphorylation to beactive.

NNRTI resistance occurs rapidly with monotherapy and canbe due to a single mutation (eg, K103N).

As a class, NNRTI agents tend to be associated with varyinglevels of gastrointestinal intolerance and skin rash, the latterof which may infrequently be serious (eg, Stevens-Johnsonsyndrome).

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A. Nevirapine (Viramune)

Oral – food doesn’t matter 

Lipid soluble

Hepatic metabolism

Excreted in urine & feces Resistance develops rapidly if used alone to

treat HIV

Most common S.E. is rash – can be severe

and life threatening Start with low dose and increase gradually

Increases metabolism of other drugs

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Similar to nevirapine

Side effects : same as nevirapine , plus:

Headache

Fatigue

GI intolerance

Elevated liver enzymes

Acidity enhances absorption Give withorange or cranberry juice

B. Delavirdine (Rescriptor)

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Protease inhibitors

By preventing cleavage of the Gag-Pol polyprotein,protease inhibitors (PIs) result in the production ofimmature, noninfectious viral particles

most effective drugs available

All inhibit cytochrome P450 – dosage is a challenge(most ritonavir)

Resistance problem

Cross resistance with classification

Never used alone – always with 2 other drugs(NNRTI or NRTI) Saquenavir (Invirase)

Indinavir (Crixivan)Nelfinavir (Viralept)

Ritonavir (Norvir)

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A. Nelfinavir (Viracept)

Action and use: 

Adults and children as young as 2 years old

Combine with NRTI

Food increases absorption

Adverse effects:

Diarrhea

Decreases metabolism of other drugs Give with water, soy formula – not acidic

foods or juices

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Anti-influenza agents

Influenza virus strains are classified by theircore proteins (ie, A, B, or C), species of origin(eg, avian, swine), and geographic site ofisolation.

Influenza A, the only strain that causespandemics, is classified into 16 H(hemagglutinin) and 9 N (neuraminidase)known subtypes based on surface proteins.

Although influenza B viruses usually infectonly people, influenza A viruses can infect avariety of animal hosts.

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Anti-influenza agents

A. Amantadine (Symmetrel, Symadine) 

For prophylaxis & Rx of infections caused bytype A influenza virus (only A – not B)

Used for Parkinson’s disease

Action not understood

Absorbed well orally

Should not be given in pregnancy-teratogenic

The most common adverse effects are GIT(nausea, anorexia) and CNS (nervousness,difficulty in concentrating, insomnia, light-headedness)

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A. Amantadine

Side Effects:

CNS : use with caution with epilepsy orpsychosis

caution with CHF or peripheral edema Don’t use with pregnancy / lactation – 

teratogenic & embrotoxic (in rats)

First PO viral drug in clinical use

Given 24 to 48 hours after onset of symptoms

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B. Rimantadine (Flumadine)

Only used for prophylaxis and Rx ofinfluenza-A virus infections

Oral administration – excreted renally

Side effects: Nervousness

Lightheadness

Sleep disturbances Fatigue

Difficulty in concentration

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Anti-hepatitis agents

Interferon alfa – human interferons

INTERFERON ALFA (S.C. or I.M)

Interferons are host cytokines that exert complex antiviral,immunomodulatory, and antiproliferative activities.

Interferon (IFN)-alfa appears to function by:

1. induction of intracellular signals following binding to specific cellmembrane receptors, resulting in

2. inhibition of viral penetration, translation, transcription, proteinprocessing, maturation, and release, as well as

3. increased expression of major histocompatibility complexantigens,

4. enhanced phagocytic activity of macrophages, and

5. augmentation of the proliferation and survival of cytotoxic T cells.

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INTERFERON ALFA

Side Effects:

1. a flu-like syndrome (ie, headache, fevers, chills, myalgias, andmalaise) that occurs within 6 hours after dosing in more than30% of patients during the first week of therapy and tends to

resolve upon continued administration.2. Transient hepatic enzyme elevations may occur in the first 8-12weeks of therapy and appear to be more common inresponders.

3. during chronic therapy neurotoxicities (mood disorders,depression, somnolence, confusion, seizures),

myelosuppression, profound fatigue, weight loss, rash, cough,myalgia, alopecia, tinnitus, reversible hearing loss, retinopathy,pneumonitis, and possibly cardiotoxicity.

4. Induction of autoantibodies may occur, causing exacerbation orunmasking of autoimmune or thyroid disease

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Varicella zoster

human herpes simplex virus type 3, causativeagent of chickenpox and shingles.

herpes

<dermatology> Any inflammatory skin disease caused by a herpes virus andcharacterised by the formation of clusters of

small vesicles. When used alone, the term may refer to herpes simplex or to herpeszoster.

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herpes zoster

<virology> A reactivation of the same Herpesvirus that is responsible for chicken pox. This

results in a painful blistery red rash that isconfined to one side of the body.

The zoster rash affects one nerve distribution or dermatome. Facial rash can lead to optic

nerve involvement with resultant blindness.

Synonym: shingles.

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herpes simplex

<virology> The Herpes simplex virus isresponsible for several different infections in

humans: gingivostomatitis (in children),pharyngitis, oral and lip lesions (recurrent Herpes simplex type 1), proctitis, (type 2) andgenital herpes (type 2).