INTRODUCTION
Many viral illnesses are mild and/or self-limiting, but some are deadly (e.g. the now extinct smallpox, some strains of influenza, the global HIV-1 epidemic and various exotic dis- eases, including Marburg disease, and various encephalitides).
Some produce chronic disease (e.g. hepatitis B and C). Even the mild common cold is economically significant, as is its deadly relative SARS (severe acute respiratory syndrome). Patients who are immunocompromised, especially by HIV-1 infection, are at risk of serious illness from viruses that are seldom ser- ious in healthy individuals. Antiviral drug therapy is therefore increasingly important. Antiviral therapy is more difficult than antibacterial therapy because viruses are intimately incorpo- rated in host cells and the therapeutic targets are often similar to the equivalent enzymes/structures in human cells. To summarize these problems:
• Viral replication is intracellular, so drugs must penetrate cells in order to be effective.
• Viral replication usurps the metabolic processes of host cells.
• Although viral replication begins almost immediately after the host cell has been penetrated, the clinical signs and symptoms of infection often appear after peak viral replication is over.
Several events in the viral life cycle may prove susceptible as drug targets:
• when the virus is outside cells it is susceptible to antibody attack; however, finding drugs that are non-toxic but which can destroy viruses in this situation remains a challenge;
• viral coat attachment to the cell surface probably involves interaction between the virus coat and the cell membrane surface;
• penetration of the cell membrane can be prevented (e.g. for influenza A by amantadineor neuraminidase inhibitors);
• uncoating of the virus with release of viral nucleic acid intracellularly;
• viral nucleic acid acts as a template for new strands of nucleic acid that in turn direct the production of new viral components utilizing the host cell’s synthetic mechanisms.
Most non-HIV antiviral drugs act at this stage of viral replication;
• extracellular release of new viral particles.
Figure 45.2 summarizes the sites of action of antiviral drugs.
OTHER ANTIFUNGAL AGENTS GRISEOFULVIN
Uses
Griseofulvinis orally active, but its spectrum is limited to der- matophytes. It is concentrated in keratinized cells. It is given orally with meals and treatment is recommended for six weeks for skin infections and up to 12 months for nail infections.
Mechanism of action
Griseofulvinis concentrated in fungi and binds to tubulin, blocking polymerization of the microtubule, disrupting the mitotic spindle.
Adverse effects These include:
• headaches and mental dullness or inattention;
• diarrhoea or nausea;
• rashes and photosensitivity;
Pharmacokinetics
Griseofulvin is metabolized by the liver to inactive 6- demethylgriseofulvin, which is excreted in the urine. Less than 1% of the parent drug is excreted in the urine. Griseofulvin induces hepatic CYP450s and consequently can interact with many drugs.
FLUCYTOSINE (5-FLUOROCYTOSINE)
Flucytosineis used to treat systemic candidiasis and crypto- coccosis, provided that the strain is sensitive. Its spectrum is relatively restricted and acquired resistance is a major prob- lem. Consequently, it is only used in combination therapy (e.g.
withamphotericin B). It is deaminated to 5-fluorouracil in the fungus and converted to an antimetabolite 5-FdUMP. This inhibits thymidylate synthetase, impairing fungal DNA syn- thesis. Adverse effects include gastro-intestinal upset, leuko- penia and hepatitis. Flucytosine is well absorbed after oral administration and penetrates the CSF well (thus it is usefully combined with amphotericin Bto treat cryptococcal meningitis).
Key points
Echinocandin antifungal drugs
• Fungicidal activity against candida and aspergillus.
• They are administered by intravenous infusion.
• They inhibit 1,3-beta Dglucan synthase involved in the formation of glucan polysaccharide in certain fungal cell walls.
• They are generally well tolerated, but cause infusion phlebitis, fever and histamine release effects with rapid infusions, gastro-intestinal upsets, hepatitis and leukopenia.
• Few drug interactions: ciclosporin increases caspofungin AUC and micafungin increases the AUC of sirolimus and nifedipine.
ANTIVIRALDRUGTHERAPY(EXCLUDINGANTI-HIV DRUGS) 345
NUCLEOSIDE ANALOGUES ACICLOVIR
Uses
Acicloviris effective against herpes (simplex and zoster), but is much less active against cytomegalovirus (also a herpes virus).
Aciclovirand its analogues have replaced idoxuridine.
1. Aciclovirointment (3%) accelerates healing in herpetic keratitis. The efficacy of topical aciclovirin genital and labial herpes simplex has been unimpressive.
2. Aciclovirgiven orally accelerates healing in genital herpes. It is much less effective in secondary than in primary infection. It does not eliminate vaginal carriage, so Caesarean section is indicated to avoid neonatal herpes.
3. Treatment of shingles (herpes zoster) should be started within 72 hours of the onset and is useful for patients with severe pain, although it shortens the illness only modestly.
4. In generalized herpes simplex or herpetic
meningoencephalitis,acicloviris given intravenously.
Mechanism of action
Aciclovirundergoes intracellular metabolic activation to its monophosphate, selectively in infected cells, by a specific thymidine kinase that is coded for by the virus but not by the host genome. Aciclovirmonophosphate is subsequently con- verted to the corresponding di- and triphosphate (ACIC-TP).
Absorption
Penetration
Uncoating Early transcription
Late transcription Early translation
Late translation Assembly
Oseltamivir Zanamivir Amantadine Interferons
Nucleoside analogues (Adefovir Lamivudine)
Oseltamivir Zanamivir Release
Replication
Figure 45.2:Sites of action of antiviral drugs.
(Adapted and updated from de Clercq E.
Biochemical Journal1982; 205: 1–13.)
The viral DNA polymerase is inhibited competitively by ACIC-TP from synthesizing nascent viral DNA.
Adverse effects These include:
1. a reversible rise in plasma urea and creatinine;
2. neurological disturbance;
3. rash;
4. nausea and vomiting;
5. hepatitis.
Contraindications
Acicloviris relatively contraindicated in pregnancy as it is an analogue of guanosine and so potentially teratogenic in the first trimester.
Pharmacokinetics
Aciclovirbioavailability is approximately 20% after adminis- tration of a standard (200 mg) dose orally, and may be dose dependent. The mean elimination t1/2ofacicloviris three hours and it crosses the blood–brain barrier producing a CSF concen- tration that is approximately 50% of that in plasma. Clearance is largely renal and includes an element of tubular secretion; renal impairment requires dose/schedule adjustment.
Drug interactions
Probenecid prolongs the half-life of aciclovir by 20% by inhibiting renal tubular secretion.
FOSCARNET (TRISODIUM PHOSPHONOFORMATE) Uses
Foscarnetis active against several important viruses, notably HIV-1 and all human herpes viruses, including aciclovir- resistant herpes viruses and cytomegalovirus (CMV). It is used to treat CMV infections (retinitis, pneumonitis, colitis and oesophagitis) and aciclovir-resistant herpes simplex virus (HSV) infections in immunocompetent and immunosup- pressed hosts. Foscarnetis given intravenously as loading dose followed by infusions. Dose reduction is required in patients with renal failure.
Mechanism of action
Foscarnet is a nucleotide analogue that acts as a non- competitive inhibitor of viral DNA polymerase and inhibits the reverse transcriptase from several retroviruses. It is inactive against eukaryotic DNA polymerases at concentrations that inhibit viral DNA replication.
Adverse effects
These include the following:
• nephrotoxicity: minimized by adequate hydration and dose reduction if the serum creatinine rises; monitoring of renal function is mandatory;
• central nervous system effects include irritability, anxiety and fits;
• nausea, vomiting and headache;
• thrombophlebitis;
• hypocalcaemia and hypomagnaesemia;
• hypoglycaemia (rare).
Pharmacokinetics
Foscarnetis poorly absorbed (2–5%) after oral administration.
Plasma concentrations decay in a triphasic manner and the terminal t1/2 is 18 hours. Foscarnet is excreted renally by glomerular filtration and tubular excretion. Approximately 20% remains in the body bound in bone.
Drug interactions
The nephrotoxicity of foscarnetis potentiated in the presence of other nephrotoxins, e.g. pentamidine,gentamicin,ciclosporin and amphotericin B. Administration with pentamidine can cause marked hypocalcaemia.
GANCICLOVIR (DIHYDROXYPROPOXYMETHYL- GUANINE, DHPG)
Uses
Ganciclovir, a guanine analogue, is used to treat sight- or life- threatening CMV infections (e.g. retinitis, pneumonitis, colitis and oesophagitis) in immunocompromised hosts. It also has potent activity against herpes viruses 1 and 2 and is used to treat aciclovir-resistant herpes. A loading dose is administered intra- venously followed by maintenance infusions. Oral ganciclovir is available for therapy despite its poor bioavailability and is only slightly less effective than intravenous therapy in CMV retinitis in AIDS patients. It is easier for the patients and less expensive. Intravitreal ganciclovir implants are effective in treating CMV retinitis and are more effective at suppressing pro- gression of disease than systemic ganciclovir.
Valgancicloviris the L-valyl ester prodrug of ganciclovir. It can be used orally on a twice daily schedule for initial control and suppression of CMV retinitis.
Mechanism of action
Ganciclovir is metabolized intracellularly to its monophos- phate in herpes-infected cells by the virally encoded thymi- dine kinase. It undergoes further phosphorylation by host kinases to its triphosphate anabolite which competitively inhibits the CMV (or HSV) DNA polymerase. If it is incorp- orated into nascent viral DNA, it causes chain termination.
Ganciclovir is concentrated ten-fold in infected cells com- pared to uninfected cells.
Adverse effects These include:
• neutropenia and bone marrow suppression
(thrombocytopenia and less often anaemia); cell counts usually return to normal within two to five days of discontinuing the drug;
• temporary or possibly permanent inhibition of spermatogenesis or oogenesis;
• phlebitis and pain at intravenous infusion site;
• rashes and fever;
• gastro-intestinal upsets;
• transient increases in liver enzymes and serum creatinine in underhydrated patients.
Contraindications
Gancicloviris contraindicated in pregnancy (it is teratogenic in animals) and in breast-feeding women.
Pharmacokinetics
Only 4–7.5% of an oral dose of ganciclovir is absorbed.
Valganciclovir is well absorbed orally and is converted to 346 FUNGAL AND NON-HIVVIRAL INFECTIONS
Key points
Aciclovir and its analogues
• Aciclovir is an acyclic guanosine analogue that is active against the herpes virus.
• Aciclovir and its analogues are initially phosphorylated by virally coded thymidine kinase and further
phosphorylated intracellularly to their triphosphate form, which inhibits the viral DNA polymerase.
• They are used to treat oral herpes simplex (topical), genital herpes simplex (oral therapy) and herpes encephalitis (intravenous therapy).
• Aciclovir has low oral bioavailability.
• Famciclovir (prodrug of penciclovir) and valaciclovir (an aciclovir prodrug) have much greater bioavailability than aciclovir.
• Aciclovir side-effects are mild: increased creatinine levels, rashes, hepatitis and gastro-intestinal disturbances.
• Viral resistance to aciclovir is an increasing problem.
ANTIVIRALDRUGTHERAPY(EXCLUDINGANTI-HIV DRUGS) 347
ganciclovir, yielding a ganciclovir bioavailability of 60%.
Ganciclovirhas a mean elimination t1/2of between two and five hours and is virtually totally excreted by the kidney. Dose reduction is needed in renal failure.
Drug interactions
Probenecid reduces renal clearance of ganciclovir.
Antineoplastic drugs, co-trimoxazole and amphotericin B increase its toxic effects on rapidly dividing tissues including bone marrow, skin and gut epithelium. Zidovudine (AZT) should not be given concomitantly with ganciclovirbecause of the potentiation of bone marrow suppression.
The pharmacology and therapeutics of other available nucleoside analogue anti-herpes drugs are shown in Table 45.3.
RIBAVIRIN (TRIBAVIRIN) Uses
Ribavirinis active against a number of RNA and DNA (HSV-1 and HSV-2, influenza) viruses. It is used to treat hepatitis C (combined with interferon) or bronchiolitis secondary to respiratory syncytial virus infection in infants and children.
Administration for bronchiolitis is via aerosol inhalation.
Mechanism of action
Ribavirinis taken up into cells and phosphorylated to trib- avirin 5-monophosphate by adenosine kinase and is then
phosphorylated to its di- and triphosphates by other cellular kinases. Ribavirin-triphosphate inhibits the guanylation reac- tion in the formation of the 5cap of mRNA and inhibits viral RNA methyltransferase. It has little or no effect on mam- malian RNA methyltransferase.
Adverse effects
Systemic administration can cause:
• dose-related haemolytic anaemia and haematopoietic suppression;
• rigors (during infusion);
• rash, pruritus;
• teratogenesis.
No systemic adverse effects of ribavirinhave been reported following administration by aerosol or nebulizer.
General adverse effects include:
• worsening respiration and bacterial pneumonia (super-infection);
• pneumothorax;
• teratogenesis (a concern even with aerosol exposure of healthcare workers).
Pharmacokinetics
Following nebulized administration, only small amounts of ribavirinare absorbed systemically.
Table 45.3:Summary of available aciclovir-like antiviral agents
Druga Use Side effects Pharmacokinetics Other specific comments
Famciclovir Herpes simplex virus See aciclovir Prodrug of penciclovir. High bioavailability (HSV) and recurrent Bioavailability of penciclovir is prodrug of penciclovir.
genital HSV varicella 77% from famciclovir. t1/2is 2.5 h. Aciclovir-resistant isolates
zoster (VZV) Renal excretion are cross-resistant
Penciclovir Systemic therapy, for See aciclovir. Bioavailability is very good. t1/2 High bioavailability. Viral HSV and VZV and Same as placebo for is 2.5 h. Renal excretion (in renal DNA polymerase hepatitis B. Topical topical use failure t1/218 h). Intracellular not as sensitive to
therapy for HSV triphosphate is longer lasting Pen-Triphosphate.
(7–20 h) than aciclovir Aciclovir-resistant isolates are cross-resistant.
Valaciclovir HSV infection but L-Valyl ester of aciclovir. Rapid absorption bioavailability High bioavailability.
uncertainty about Haemolytic–uraemic / is 54%. Converted to aciclovir Aciclovir-resistant isolates VZV and CMV TTP syndrome in before phosphorylation are cross-resistant
in future immunosuppressed
individuals
Cidofovir Intravenous therapy See ganciclovir, but has Plasma t1/2of cidofovir is 2.6 h CMV isolates resistant to for HSV and CMV been noted to cause and of cidofovir diphosphate ganciclovir are sensitive.
renal failure (active) is 17–30 h. Cidofovir is Not to be used in patients renally eliminated with renal failure
aOther drugs in the antiviral arena with recent availability or undergoing further clinical development include sorivudine (nucleoside analogue for VZV) n-Docosanol (topical cream for recurrent herpes labialis) and Fomiversen (an antisense phosphorothioate oligonucleotide complementary to human CMV immediate–early mRNA, used in AIDS patients).
348 FUNGAL AND NON-HIVVIRAL INFECTIONS
ANTI-INFLUENZA AGENTS AMANTADINE (OR RIMANTADINE)
Amantadineis effective in preventing the spread of influenza A and has an unrelated action in Parkinson’s disease (Chapter 21).
Its usefulness as an antiviral agent is limited to influenza A. Its mode of action is unknown. Prophylaxis with amantadinehas an advantage over immunization in that the latter can be inef- fective when a new antigenic variant arises in the community and spreads too rapidly for a killed virus vaccine to be prepared and administered. Prophylaxis with amantadineduring an epi- demic should be considered for people at special risk (e.g.
patients with severe cardiac or lung disease, or healthcare per- sonnel).Amantadine is less effective during periods of anti- genic variation than during periods of relative antigenic stability. Treating established influenza with amantadine within the first 48 hours may ameliorate symptoms. The mean eliminationt1/2is 12 hours and elimination is via renal excre- tion. Thus, dose reductions are needed when amantadine is given to patients with renal failure.
Adverse effects These include:
• dizziness, nervousness and headaches;
• livedo reticularis.
OSELTAMIVIR PHOSPHATE
Oseltamivir phosphateis an ethyl ester prodrug of oseltamivir carboxylate. It is used to prevent and treat influenza A and B infections, when given orally twice a day for five days.
Oseltamivir carboxylateis an analogue of sialic acid and is a competitive inhibitor of the influenza virus neuraminidase that cleaves the terminal sialic acid residues and destroys the receptors recognized by viral haemagglutinin present on the cell surface of progeny virions and in respiratory secretions.
Neuraminidase activity is needed for release of new virions from infected cells. When oseltamivir carboxylatebinds to the neuraminidase it causes a conformational change at the active site, thereby inhibiting sialic acid cleavage. This leads to viral aggregation at the cell surface and reduced viral spread in the respiratory tract. Adverse effects include headache, nausea, vomiting and abdominal discomfort (noted more frequently in patients with active influenza than if the agent is used for prophylaxis). Adverse effects are reduced by taking the drug with food. Oral oseltamivir phosphateis absorbed orally and de-esterified by gastro-intestinal and hepatic esterases to the active carboxylate. The bioavailability of the carboxylate approaches 80% and its mean elimination t1/2is between six and ten hours. Both parent and metabolite are eliminated by renal tubular secretion. No clinically significant drug interactions have been defined, but probenaciddoubles the half-life of the active carboxylate. Resistant influenza isolates have mutations in the N1 and N2 neuraminidases, but these variants have reduced virulence in animal models. Activity against the dreaded H5N1 avian flu strain is not proven.
ZANAMIVIR
This is another inhibitor of influenza virus neuraminidase enzymes. If given early during influenza A or B infection via intranasal route it is effective in reducing symptoms.
Key points
Antiviral therapy
• Selective toxicity for viruses is more difficult to achieve than for fungi or bacteria.
• Viruses survive and proliferate inside human cells and often use human cellular enzymes and processes to carry out their replicative process.
• Certain viruses encode virus-specific enzymes that can be targeted (e.g. herpes virus and aciclovir; CMV virus and its DNA polymerase which is a target for ganciclovir).