Antiviral Chemotherapy & Prophylaxis

1. Antiviral Chemotherapy& Prophylaxis Dr Hayder B Sahib PhD Pharmacology

2. Antiviral drugs can exert their actions at several stages of viral replication including 1- viral entry 2- nucleic acid synthesis 3- late protein synthesis and processing 4- final stages of viral packaging 5- virion release

5. ANTIHERPES DRUGS A. Acyclovir (Acycloguanosine) • Mechanisms Acycloviris a guanosine analog active against herpes simplex virus (HSV-1, HSV-2) and varicella-zoster virus (VZV). The drug is activated to form acyclovir triphosphate, which interferes with viral synthesis in 2 ways. 1- It acts as a competitive substrate for DNA polymerase 2- leads to chain termination after its incorporation into viral DNA.

6. Resistance of HSV can involve • 1- changes in viral DNA polymerase. • 2- lack thymidine kinase, the enzyme involved in the initial viral-specific phosphorylation of acyclovir. • Such strains are cross-resistant to famciclovir, ganciclovir, and valacyclovir.

8. A. Acyclovir (Acycloguanosine) 2. Pharmacokinetics Acyclovir can be administered by the topical, oral, and intravenous routes. Because of its short half-life, oral administration requires multiple daily doses. Renal excretion is the major route of elimination, and dosage should be reduced in patients with renal impairment. 3. Clinical uses and toxicityOral acyclovir is commonly used 1- for the treatment of mucocutaneous and genital herpes lesions 2- for prophylaxis in AIDS and in other immunocompromised patients. The oral drug may cause GI distress and headache. Intravenous administration is used for severe herpes disease, including encephalitis, and for neonatal HSV infection. Toxic effects with parenteral administration include delirium, tremor, seizures, hypotension, and nephrotoxicity.

9. 4. Other drugs for HSV and VSV infections .

10. B. Ganciclovir • Mechanisms Ganciclovir, a guanine derivative, is triphosphorylated to form a nucleotide that inhibits DNA polymerases of cytomegalovirus (CMV), and HSV and causes chain termination. The first phosphorylation step is catalyzed by virus-specific enzymes in both CMV-infected and HSV-infected cells. CMV resistance mechanisms involve 1- mutations in the genes that code for the activating viral phosphotransferase and the viral DNA polymerase. 2- Thymidine kinase-deficient

11. B. Ganciclovir 2.Pharmacokinetics Gancicloviris usually given IV. and penetrates well into tissues, including the eye and CNS. The drug undergoes renal elimination. Oral bioavailability is less than 10%. An intraocular implant form of ganciclovir can be used in CMV retinitis. Valganciclovir, a prodrug of ganciclovir, has high oral bioavailability and has decreased the use of intravenous forms of ganciclovir (and also of intravenous cidofovir and foscarnet) in CMV disease.

12. 3. Clinical uses and toxicity Gancicloviris used for the 1- prophylaxis and treatment of CMV retinitis 2- other CMV infections in immunocompromised patients. Systemic toxic effects include leukopenia, thrombocytopenia, mucositis, hepatic dysfunction, and seizures. The drug may cause severe neutropenia when used with zidovudine or other myelosuppressive agents.

13. C. Cidofovir • Mechanisms and pharmacokinetics Cidofoviris activated exclusively by host cell kinases and the active diphosphate, which inhibits DNA polymerases of HSV, CMV, adenovirus, and papillomavirus (HPV). Because phosphorylation does not require viral kinase, cidofovir is active against many acyclovir and ganciclovir resistant strains. Resistance is due to mutations in the DNA polymerase gene. The drug is given intravenously and undergoes renal elimination. Dosage should be adjusted in proportion to creatinine clearance and full hydration maintained.

14. C. Cidofovir 2. Clinical uses and toxicity 1- Cidofovir is effective in CMV retinitis 2- in mucocutaneous HSV infections, including those resistant to acyclovir, and in genital warts. 3- Nephrotoxicity is the major dose-limiting toxicity of cidofovir, additive with other nephrotoxic drugs including amphotericin B and aminoglycoside antibiotics.

15. D. Foscarnet • Mechanisms Foscarnetis a phosphonoformatederivative that does not require phosphorylation for antiviral activity. Although it is not an antimetabolite, foscarnet inhibits viral RNA polymerase, DNA polymerase, and HIV reverse transcriptase. Resistance involves point mutations in the DNA polymerase gene. 2. Pharmacokinetics Foscarnetis given intravenously and penetrates well into tissues, including the CNS. The drug undergoes renal elimination in direct proportion to creatinine clearance.

16. D. Foscarnet 3. Clinical uses and toxicity 1- The drug is an alternative for prophylaxis and treatment of CMV infections, including CMV retinitis 2- has activity against ganciclovir-resistant strains of this virus. 3- Foscarnetinhibits herpes DNA polymerase in acyclovir-resistant strains that are thymidine kinase–deficient. Adverse effects are severe and include 1- nephrotoxicity (30% incidence) 2- disturbances in electrolyte balance (especially hypocalcemia), 3- genitourinary ulceration 4- CNS effects (headache, hallucinations, seizures).

17. E. Other Antiherpes Drugs 1. Vidarabineis an adenine analog and has activity against HSV, Varicella zoster virus VZV, and CMV. Its use for systemic infections is limited by and marked toxic potential. Vidarabine is used topically for herpes keratitis Toxic effects with systemic use include GI irritation, paresthesias, tremor, convulsions, and hepatic dysfunction. Vidarabine is teratogenic in animals.

18. 2. Idoxuridine and trifluridine These pyrimidine analogs are used topically in herpes keratitis (HSV-1). They are too toxic for systemic use. 3. Fomivirsen is an antisense oligonucleotide that binds to mRNA of CMV, inhibiting early protein synthesis. The drug is injected intra-vitreally for treatment of CMV retinitis.

19. ANTI-HIV DRUGS The current approach to treatment of infection with HIV is the initiation of treatment with 3 or more antiretroviral drugs, if possible, before symptoms appear. Such combinations usually include nucleoside reverse transcriptase inhibitors (NRTIs) together with inhibitors of HIV protease (PI). Highly active antiretroviral therapy (HAART) involving drug combinations can slow progression of disease or reverses the decline in CD4 cells and decreases the incidence of opportunistic infections.

20. Nucleoside Reverse Transcriptase Inhibitors(NRTIs) 1. Abacavir—A guanosine analog, has good oral bioavailability and half-life of 12–24 h. HIV resistance requires several concomitant mutations and tends to develop slowly. Hypersensitivity reactions, occasionally fatal,occurin 5% of HIV patients. 2. Didanosine(ddI)—Oral bioavailability of ddI is reduced by food and by chelating agents. The drug is eliminated by the kidney, and the dose must be reduced in patients with renal dysfunction. Pancreatitis is dose-limiting and occurs more frequently in alcoholic patients and those with hypertriglyceridemia. Other adverse effects include peripheral neuropathy, diarrhea, hepatic dysfunction, hyperuricemia, and CNS effects.

21. 3-Zidovudine: *It inhibit reverse transcriptase which is responsible for conversion of viral single-stranded RNA to double –stranded DNA , so there will be premature chain termination and inability to incorporate into host DNA. *Well absorbed orally and rapidly cleared from plasma, concentration in CSF is half that of plasma, metabolically inactive and 20% is excreted unchanged by the kidney. ( half life 1 hour).

22. 3-Zidovudine: *Indicated for serious manifestations of HIV infection in patient with acquired AIDS or AIDS-related complex i.e.; opportunistic infection, constitutional or neurological symptoms, or with low CD4 counts. *It is also indicated alone for pregnant women and their offspring for prevention of maternal-fetal HIV transmission. *Adverse reactions :- -Early : anorexia ,N and V, headache, dizziness, malaise and myalgia -Long term: A toxic myopathy. -Rarely hepatic necrosis with lactic acidosis(also occur with other reverse transcriptase)

23. 4. Lamivudine Is 80% bioavailable by the oral route and is eliminated almost exclusively by the kidney. In addition to its use in Highly active antiretroviral therapy (HAART) regimens for HIV, lamivudine is also effective in hepatitis B infections. Dosage adjustment is needed in patients with renal insufficiency. Adverse effects of lamivudine are usually mild and include GI distress, headache, insomnia, and fatigue.

24. 5. Zalcitabine Has a high oral bioavailability. Dosage adjustment is needed in patients with renal insufficiency and nephrotoxic drugs (eg, amphotericin B, aminoglycosides) increase toxic potential. Dose-limiting peripheral neuropathy is the major adverse effect. Pancreatitis, esophageal ulceration, stomatitis, and arthralgias may also occur.

25. 6. Tenofovir • Although it is a nucleotide, tenofovir acts like NRTIs to competitively inhibit reverse transcript and cause chain termination after incorporation into DNA. Tenofovir also has activity against HBV. • Oral bioavailability of tenofovir is in the range 25–40%, the intracellular half-life is more than 60 h, and the drug undergoes renal elimination. Tenofovir may impede the renal elimination of acyclovir and ganciclovir. • Adverse effects include GI distress,, and headache; rare cases of acute renal failure and Fanconi’s syndrome have been reported.

26. B-Non-Nucleoside Reverse Transcriptase Inhibitors(NNRTIs) Efavirenz, Delavirdine, Nevirapine *NNRTIs bind directly to HIV-1 reverse transcriptase resulting in blockade of RNA and DNA-dependant DNA polymerase. The binding site of NNRTIs is near but distinct from that of NRTIs. *Unlike the NRTIs agents,NNRTIs neither compete with nucleoside triphosphate nor require phosphorylation to be active.

27. *NNRTIs are highly selective, with no effects on host blood-forming elements and there is no cross-resistant with NRTIs. *NNRTIs adverse effects include, GI intolerance and skin rash (infrequently steven-johnson syndrome) *NNRTIs agents are all substrate for CYP3A4 and can act as inducers (nevirapine), inhibitors(delavirdine), or mixed inducer and inhibitor(efavirenz) so drug-drug interaction must be expected.

28. C-Protease Inhibitors: Amprenavir,indinavir,lopinavir,nelfinavir,ritonavirand saquinavir: *They inhibit viral protease which is responsible for cleavage of viral protein so there will be disruption of collecting of viral protein in to virus particle and failure of viral replication. *They are extensively metabolized by cytochrom P450 isoenzymes notably by CYP3A4 which involved in the metabolism of many drugs. *Plasma half life for each of these is in the range of 2-4 h.

29. *Adverse effects include GI disturbances, headache, sleep disturbance, raised liver enzymes, neutropenia and pancreatitis. *Enzyme P450 inducers eg; rifampicin accelerate protease inhibitors metabolism and reduced their plasma concentration. *Enzyme P450 inhibitors e.g.; ketoconazole raise the plasma concentration of protease inhibitors. *Ritonavir itself a powerful inhibitor of CYP3A4 and CYP2D6. Ritonavir in small quantity is combined with lopinavir to inhibit its metabolism and increase its therapeutic efficacy .

30. Anti-Influenza Agents 1-Amantadine and Rimantadine *They inhibit an early step in replication of influenza A. They prevent uncoating by binding to protein M2. *These drugs are prophylactic against influenza A and can reduce the duration of symptoms if given within 48 h after contact. *Rimantadine has longer half-life, and safer in renal failure.

31. Anti-Influenza Agents 2-Oseltamivir and Zanamivir *They inhibit neuraminidases produced by influenza A and B which lead to impeding of viral spread; and are currently active against both H3N2 and H1N1 strains. *They decreases the time to improvement of influenza symptoms and they are more effective if used within 24 h after onset of symptoms.

32. Agents Used in Viral Hepatitis 1-IFN-α *IFN-α is a cytokine that act through host cell surface receptors increasing the activity of Janus kinases(this enzyme increase the formation of antiviral proteins). *IFN-α also promotes formation of natural killer cells that destroy infected liver cells. *There are several forms of IFN-α with minor differences in AA composition. Elimination is mainly via proteolytic hydrolysis in kidney.

33. *IFN-αis used in chronic HBV as an individual agent or in combination with Lamivudine. When used with ribavirine, the progression of acute HCV to chronic HCV is reduced. *Other uses include Kaposi's sarcoma, papillomatosis, topically for genital warts, H zoster in cancer patients and in CMV after renal transplantation. *IFN-αadverse effects include GI irritation, aflulike syndrome, fatigue and myalgia, alopeciareversible hearing loss, thyroid dysfunction, mental confusion and depression.

34. 2-Adefovir Dipivoxil *Prodrug of adefovir, competitively inhibits HBV DNA polymerase and result in chain termination after incorporation into viral DNA. *It suppress HBV replication and improve liver histology and fibrosis. *Adverse effects include nephrotoxicity, lactic acidosis and hepatomegaly.

35. 3-Lamivudine *Nucleoside inhibitor of HIV reverse transcriptase , active in chronic HBV infection(lower doses than in HIV). *Used as monotherapy, the drug rapidly suppress HBV replication and is remarkably nontoxic. 4-Entecavir A guanosine nucleoside that inhibit HBV DNA polymerase with similar efficacy to that of Lamivudine.

36. 5-Ribavirin *Inhibit the replication of a wide range of DNA and RNA viruses include influenza A and B, Para influenza, respiratory syncytial virus (RSV), paramyxoviruses, HCV and HIV. *Used with IFN-α in chronic HCV and also used in viral hemorrhagic fevers. *Adverse effects include hemolytic anemia, conjunctival and bronchial irritation and it is absolutely teratogenic.

37. 6. Newer Drugs for HBV Telbivudine, a nucleoside analog, is phosphorylated by cellular kinases to the triphosphate form, which inhibits HBV DNA polymerase. The drug is as effective as lamivudine in chronic HBV infections and is similar in terms of its safety profile. Tenofovir, an antiretroviral drug, is also approved for chronic HBV infection and is active against lamivudine- and entacavir-resistant strains.