Chemotherapy of Viral Diseases

1.         Limitations of Antiviral Drugs

a.         Difficulty in obtaining selective toxicity against viruses as their replication is intimately involved with the normal synthetic processes of the cell.

b.         Inefficacy of treatment:

i.          antiviral drugs are relatively ineffective because many cycles of viral replication occur during the incubation period when the patient is well.

ii.          by the time the patient has a recognizable systemic viral disease, the virus has spread throughout the body and it is too late to interdict it.

c.         Some viruses, e.g. herpesviruses, become latent within cells, and no current antiviral drug can eradicate them.

d.         The emergence of drug-resistant viral mutants.

e.         Prescription of antibiotics in viral infections:

i.          to prevent or treat serious superinfection of a viral disease (e.g. bacterial pneumonia complicating influenze or Pneumocystis carinii in AIDS).

ii.          to play safe pending the laboratory identification of the etiologic agent in the case of serious illnesses where there is a real possibility of a bacterial cause, as in meningitis or pneumonia.

2.         Targets for Antiviral Chemotherapy

3.         Clinical Application

a.         Methods of Delivery:

i.          oral route: most convenient for the patient.

ii.          nasal drops or sprays: may be acceptable for upper respiratory infections but can be irritating, whereas continuous delivery of aerosols through a face mask or oxygen tent is generally appropriate only for very sick hospitalized patients.

iii.         topical preparations (creams, ointments, etc.) are satisfactory for superficial infections of skin, genitalia, or eye, provided they are localized.

b.         Many experimental drugs have to be used in very high, potentially toxic concentrations because of poor solubility or poor penetration into cells.

c.         Delivery of antiviral concentrations of compounds into cells can sometimes be achieved by incorporating the drug into liposomes or by conjugating it to a hydrophobic membrane anchor.

d.         Minimizing emergence of drug-resistant mutants:

i.          antiviral agents should be used only when absolutely necessary, but administered in adequate dosage.

ii.          combined therapy, preferably using agents with distinct modes of action, minimizes the probability of emergence of resistant mutants.

e.         Clinical priorities:

i.          diseases against which no satisfactory vaccine is available, including those with a large number of different etiologic agents, are prime targets for antiviral chemotherapy.

ii.          effective chemotherapy is also needed to treat reactivation of latent infections such as herpes simplex and zoster.

f.          Chemoprophylaxis have a role in the prevention of complications, such as orchitis or meningoencephalitis in mums and in limiting the spread of diseases like hepatitis, mononucleosis, influenza, measles and rubella.

4.         Inhibition of early events

a.         Amantadine is a tricyclic compound that is used to prevent influenza A infections.

b.         It inhibits uncoating of the virus by binding to the matrix protein in the virion.

c.         The principle target of amantadine is the protein M2, a component of the influenza viral envelope that plays a key role in stabilizing the viral hemagglutinin.

d.         Absorption and penetration occur normally, but transcription by the virion RNA polymerase does not.

e.         Side effects are loss of concentration, insomnia, nervousness, light-headedness, drowsiness, anxiety, and confusion.

f.          Rimantadine is a similar drug with less side effects.

5.         Inhibition of Viral nucleic acid synthesis

a.         Acyclovir:

i.          a nucleoside analogue with a 3-carbon fragment in place of the normal sugar, ribose.

ii.          active primarily against herpes simplex virus types 1 and 2 and varicella-zoster virus; no activity against cytomegalovirus.

iii.         relatively nontoxic because it is incorporated preferentially into virus-infected cells due to the virus-encoded thymidine kinase, which phosphorylates acyclovir more effectively than does cellular thymidine kinase.

iv.         once the drug is phosphorylated to acyclovir monophosphate by the viral thymidine kinase, cellular kinases synthesize acyclovir triphosphate, which inhibits viral DNA polymerase more effectively than it inhibits cellular DNA polymerase.

v.         topical acyclovir is effective in the treatment of primary genital herpes and reduces the frequency of recurrences while it is being taken; however, it has no effect on latency or rate of recurrences after treatment is stopped.

vi.         acyclovir is the treatment of choice for herpes simplex virus type 1 encephalitis and is effective in preventing systemic infection by herpes simplex virus type 1 or varicella-zoster virus in immunocompromised patients.

vii.        it is not an effective treatment for herpes simplex virus type 1 recurrent lesions in immunocompetent hosts.

viii.       acyclovir levels must be carefully monitored in patients with dehydration or renal impairment, as the drug, which is excreted unchanged through the kidneys, is rather insoluble and crystalluria may occur.

b.         Ganciclovir:

i.          a nucleoside analogue of guanosine with a 4-carbon fragment in place of the normal sugar, ribose.

ii.          acyclovir and ganciclovir cause chain termination because they lack a hydroxyl group in the 3’ position.

iii.         it is more active against cytomegalovirus than acyclovir.

iv.         it is effective in the treatment of retinitis caused by cytomegalovirus in AIDS patients and may be useful in other disseminated infections caused by this virus.

c.         Vidarabine:

i.          a nucleoside analogue with arabinose in place of the normal sugar, ribose.

ii.          on entering the cell, the drug is phosphorylated by cellular kinases to triphosphate, which inhibits the herpesvirus-encoded DNA polymerase more effectively than the cellular DNA polymerase.

iii.         effective against herpes simplex virus type 1 infections such as encephalitis and keratitis but is less effective and more toxic than acyclovir.

d.         Idoxuridine:

i.          a nucleoside analogue in which the methyl group of thymidine is replaced by an iodine atom.

ii.          the drug is phosphorylated to the triphosphate by cellular kinases and incorporated into DNA.

iii.         has a high frequency of mismatched pairing to guanine and causes formation of faulty progeny DNA and mRNA.

iv.         because it is incorporated into normal cell DNA as well as viral DNA, it is too toxic to be used systemically.

v.         it is clinically useful in the topical treatment of herpes simplex virus keratoconjunctivitis.

e.         Foscarnet:

i.          a pyrophosphate analogue which inhibits DNA polymerases of all herpesviruses, especially HSV and CMV.

ii.          inhibits reverse transcriptase of HIV.

iii.         foscarnet in the form a cream accelerates healing of recurrent facial or genital herpes lesions.

iv.         given systemically to halt the progression of cytomegalovirus infections in immunocompromised patients.

v.         it accumulates in bone and is too toxic for the kidneys to be advocated for infections that are not life-threatening.

f.          Ribavirin:

i.          inhibits the cellular enzyme IMP dehydrogenase, decreasing the pool of GTP, thereby inhibiting the synthesis of guanine nucleotides, which are essential for both DNA and RNA viruses.

ii.          oral or intravenous ribavirin reduces mortality from infections with Lassa and Hantaan viruses.

iii.         ribavirin aerosol is used clinically to treat pneumonitis caused by respiratory syncytial virus in infants and to treat severe influenza B infections.

6.         Inhibitors of Reverse Transcriptase

a.         The selective toxicity of azidothymidine (AZT), dideoxyinosine, and dideoxycytidine is based on their ability to inhibit DNA synthesis by the reverse transcriptase of HIV to a greater extent by DNA polymerase in human cells.

b.         Mode of action of AZT:

i.          AZT is phosphorylated by cellular kinases to AZT triphosphate.

ii.          AZT triphosphate inhibits HIV reverse transcriptase.

iii.         AZT triphosphate is incorporated into the growing HIV DNA chain, leading to premature chain termination.

iv.         AZT monophosphate competes successfully for the enzyme thymidylate kinase, resulting in depletion of the intracellular pool of thymidine triphosphate.

c.         Pharmacokinetics of AZT:

i.          rapidly absorbed following oral administration.

ii.          rapidly metabolized by hepatic glucuronidation so that the drug needs to be given 2 or 3 times daily.

d.         Side effects of AZT:

i.          macrocytic anemia and granulocytopenia.

ii.          headache, nausea, and insomnia.

iii.         myopathy resulting in reversible wasting of proximal muscle groups.

e.         Problems of long-term use:

i.          toxicity

ii.          emergence of drug-resistant mutants.

iii.         minimized by combined chemotherapy or alternating courses of different drugs.

f.          Dideoxyinosine & Dideoxycytidine:

i.          effective against DNA synthesis by reverse transcriptase of HIV.

ii.          used to treat patients with AIDS who are intolerant of or resistant to AZT.

iii.         main side effects are pancreatitis and peripheral neuropathy.

7.         Inhibition of viral protein synthesis

a.         Interferon:

i.          recombinant alpha interferon is effective in the treatment of some patients with chronic hepatitis B and chronic hepatitis C infections.

ii.          causes regression of condylomata acuminata lesions.

b.         Methisazone:

i.          specifically inhibits the synthesis of poxviruses, such as smallpox and vaccinia viruses, by blocking translation of mRNA.

ii.          used to treat rare, severe side effects of the smallpox vaccine, e.g. disseminated vaccinia.