Inhibit viral uncoating by blocking M2 proton channel in the viral envelope

Normally, acidification allows release of ribosomal nuclear particles and dissemination of virus because acidity triggers membrane fusion

Amantadine and Rimantadine only effective against influenza A 

Do not prevent formation of antibodies when flu vaccine is given

Amantadine (Symmetrel)

Can alleviate symptoms if given within the first 48 hours and can also be used prophylactically

Oral administration and rapidly absorbed from GI tract

Amantadine is not metabolized and is excreted straight to urine, so might need doseage adjustments; in contrast, rimantadine will only need dose reductions when creatinine levels are really too low 

Amantadine readily crosses blood brain barrier - known to cause release of dopamine from CNS (initial therapy for Parkinson's Disease)

Rimantadine has lower risk of CNS adverse effects

Both drugs have atropine like effects and can cause livedo reticularis; more serious side effects if given with anticholinergics

SE: anorexia, nausea, peripheral edema, minor CNS effects like nervousness and anxiety

Active against both influenza A & B

Work best when administered early - within 48 hours, can improve symptoms by 1 day

For Zanamivir, administration within 30 hours improves symptoms by 3 days

For both drugs, reduction in influenza related complications and both can be used prophylactically 

Zanamivir has poor oral bioavailability; comes as a dry powder which is inhaled

90% of the absorbed material is excreted in urine

Oseltamivir is an ethy ester prodrug that is well absorbed from GI tract - will be de-esterified in liver and bioavailability will be 80% - excreted unchanged in the urine 

Nausea/vomiting/headache in 15% of the patients for both

Zanamivir can also cause bronchospasm in asthamtics 

Acyclovir 

MOA: phosphorylated vy viral thymidine kinase, and then cellular kinases (host) phosphorylate 2 more times; inhibit DNA polymerase and will bind to DNA to terminate chain elongation

Resistant strains are primarily due to altered viral thymidine kinase 

Oral acyclovir is effective, especially if patient has sensitivity

Trifulridine may be used topically, but would have unacceptable toxicity if used systemically

Ganciclovir may also be used topically

Herpes Simplex Type 2 is most common

Topical therapy is not effective for recurrent herpes

Oral therapy is good at preventing recurrence up to one year, but protective effect disappears when drug does 

Intravenous acyclovir is used in mucocutaneous infections in the immunocompromised patient

IV!

The drug is administered intravenously, topically, and orally; minimal systemic absorption after topical administration

Bioavailability is only 15-30% when given orally; but some of the analogues have greater bioavailability 

Widely distributed in tissue; acyclovir is eliminated by glomerular filtration and tubular secretion; metabolized by small extent 

1% incidence of encephalopathy, lethargy, confusion, tremor, coma, some nephrotoxicity due to crystaluria 

Renal insufficiency with IV dose 

Very similar to acyclovir (zovirax) except that it has additionaly hydroxymethyl group - 100x more active against cytomegalovirus retinitis 

Clinical use: combined use of ganciclovir and anti-CMV antibody has good effects against pneumonia caused by CMV in kidney transplant patients 

Significant improvement in survival rate 

Oral bioavailability is extremely low; oral route is used for maintenance route

IV used for acute treatment

Prodrug valganciclovir can be used orally; also used as an ocular implant 

Most common side effect is bone marrow suppression; there are also CNS effects in 5-15% of patients

Because of its toxicity, the drug is only used to treat cytomegalovirus infection 

Less specific for DNA polymerase than acyclovir, so can be more toxic 

Consider administering with Colony stimulating factor 

Alternative for cytomegalovirus retinitis

Acyclovir resistant HSV and VSV

Not a nucleoside analogue, IV generally 

Phosphonate derivative - inhibits DNA polymerase and reverse transcriptase by interacting with pyrophosphate binding site

More expensive and generally less well tolerated than ganciclovir (cytovene) because of large volumes of liquid that need to be infused 

Most prominent side effect: reduced renal function 

Considered a nucleotide analogue because it mimics deoxycytidine monophosphate

Doesn't require viral kinases for phosphorylation 

May also be used against herpes infections resistant to acyclovir 

Nephrotoxicity is major toxicity - must be administered by IV with probenicid - probenicid prolongs half life and prevents kidney toxicity

Also will cause neutropenia 

IV Only

Inhibits RNA polymerase by competing with both GTP and ATP

Depletes virally infected cell of GTP by inhibition inosine monophosphate dehydrogenase

Inhibits N7 methyl transferase; blocks capping of mRNA

Because of multiple mechanisms of action, development of resistant strains is less likely

Active in tissue culture against 85% viruses studied, yet drug isn't toxic to cells

Used against influenza A&B, also RSV

Used incombination with IFN in hep C

Used as an aerosol to treat RSV and can cause upper airway irritation 

Used orally with IFN in hep C and can cause hemolytic anemia

Also teratogenic 

new drug for CMV retinitis

anti-sense mRNA for a protein necessary for viral replication

Must be injected intravitreally

Side effects is local irritation

Synthesis is induced by viruses

Viral genes --> derepression of host cell genes --> rapid production of IFN --> binds nearby cells after being released into EC space --> induces protein kinase that phosphorylates and inactivates an initiation factor thereby inhibiting viral protein synthesis 

Additionally, cellular endonuclease is activated that degrades viral mRNA

Finally, phosphodiesterase is activated and degrades the terminal nucleotides of tRNA, also inhibiting peptide elongation 

Because it's a peptide, it's administered subQ or intramuscularily

Chronic hep c- combo of interferon with ribavarin is much more effective than interferonn alone

after 48 weeks of treatment, the rate of relapse is decreased with the combination 

neutropenia resulting in flu like symptoms: fever, chills, fatigue

Ribovarin will cause a hemolytic anemia

hairy cell leukemia, AIDS related Kaposi's sarcoma, and genital warts (condyloma acuminatum) 

IFN, if given early, can prevent dissemination of herpes zoster in cancer patients 

Topical administration in combo with other viral agents is effective in herpes keratoconjuctivitis 

CMV retinitis, colitis, esophagitis

CMV prophylaxis in HIV patients 

Used topically in HSV ocular infections

Nucleoside analogue; phosphorylated form inhibits DNA polymerase

SE: local irritation

Effective against acyclovir resistant strains; too toxic for systemic useage

Inhaled in RSV in children, and oral in combination with IFN for hep C

Aerosol has also been used for influenza

IV can be used for Lassa fever

Can cause myelosuppresion

Ribovarin is contraindicated in pregnancy

When used as aerosol, also careful monitoring for respiratory function is needed