Antibiotic

Antiviral Agents

Presented by: Professor Dr. Imad A-J Thanoon

Viruses

Obligate intracellular parasites Consist of a core genome in a protein shell and some are surrounded by a lipoprotein lack a cell wall and cell membrane do not carry out metabolic processes Replication depends on the host cell machinery

Viruses

Steps for Viral Replication 1) adsorption and penetration into cell 2) uncoating of viral nucleic acid 3) synthesis of regulatory proteins 4) synthesis of RNA or DNA 5) synthesis of structural proteins 6) assembly of viral particles 7) release from host cell

Sites of Drug Action

Antiviral Agents
Block viral entry into the cell or must work inside the cell Most agents are pyrimidine or purine nucleoside analogs

Classification

1. Anti Herpes Virus Acyclovir 2 .Anti retrovirus Reverse transcriptase inhibitors--NRTI Non reverse transcriptase inhibitors-NNRTI Protease inhibitors Nucleotide inhibitors e.g tenofovir 3. Anti influenza virus -Amantadine 4. Non selective-ribavarin,interferons.

Antiherpes Agents

Acyclovir- prototype Valacyclovir Famciclovir Penciclovir Trifluridine Vidarabine

Mechanism of Action Acyclovir

an acyclic guanosine derivative Phosphorylated by viral thymidine kinase Di-and tri-phosphorylated by host cellular enzymes Inhibits viral DNA synthesis by:

Mechanism of Resistance Acyclovir

Alteration in viral thymidine kinase Alteration in viral DNA polymerase Cross-resistance with valacyclovir, famciclovir, and ganciclovir

Clinical Uses  Acyclovir

Oral, IV, and Topical formulations Cleared by glomerular filtration and tubular secretion Uses: Herpes Simplex Virus 1 and 2 (HSV) Varicella-zoster virus (VZV)

PHARMACOKINETICS

Oral bioavailability ranges from 10-30% and decreases with increasing dose Clearance thru GF and Tubular Secretion Half-life: 3 hrs in normal renal function and 20 hrs in anuria Distributes widely in body fluids including vesicular fluid, aqueous humor, and CSF Concentrated in breast milk, amniotic fluid, and placenta Percutaneous absorption is low

THERAPEUTIC USES

ACUTE HERPES ZOSTER (SHINGLES) SYSTEMIC ACYCLOVIR PROPHYLAXIS HSV ENCEPHALITIS ( IV form) VARICELLA ZOSTER VIRUS INFECTION CMV PROPHYLAXIS



SIDE EFFECTS
TOPICAL PREPARATIONS- mucosal irritation and transient burning to genital lesionsORAL – nausea, diarrhea, rash, headache, renal insufficiency, and neurotoxicityIV- renal insufficiency, CNS side effects

Anti-Cytomegalovirus Agents

Gancyclovir Valgancyclovir Cidofovir Foscarnet Fomivirsen

Ganciclovir

An acyclic guanosine analog requires triphosphorylation for activation monophosphorylation is catalyzed by a phosphotransferase in CMV and by thymidine kinase in HSV cells M.O.A.: same as acyclovir

PHARMACOKINETICS

Oral bioavailability is 6-9% following ingestion with food and less in the fasting state CSF concentration are approximately 50 % of those in serum

CLINICAL USES

Delay progression of CMV retinitis in AIDS CMV colitis & esophagitis CMV infection in transplant patient CMV pneumonitis CMV retinitis CMV, HSV1, HSV2, EBV

ADVERSE REACTIONS

Myelosuppression CNS toxicity Vitreous hemorrhage, retinal detachment Neutropenia (2nd wk) CNS (headache, behavioral changes, convulsions, coma) Infusion related phlebitis, anemia, rash, fever, liver function test abnormalities



Antiretroviral Agents
1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 2) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) 3) Nucleotide inhibitor 4)Protease inhibitors

Life cycle of HIV

When HIV infects a cell, reverse transcriptase copies the viral single stranded RNA genome into a double-stranded viral DNA

Reverse Transcriptase Inhibitors

Zidovudine (AZT) Didanosine- causes pancreatitis* Lamivudine- causes pancreatitis Zalcitabine- causes peripheral neuropathy* Stavudine- causes peripheral neuropathy* Abacavir

Mechanism of Action Zidovudine (AZT)

A deoxythymidine analog enters the cell via passive diffusion must be converted to the triphosphate form by mammalian thymidine kinase competitively inhibits deoxythymidine triphosphate for the reverse transcriptase enzyme causes chain termination

Clinical Uses  Zidovudine

Available in IV and oral formulations activity against HIV-1, HIV-2, and human T cell lymphotropic viruses mainly used for treatment of HIV, decreases rate of progression and prolongs survival prevents mother to newborn transmission of HIV

ADVERSE EFFECTS

Myelosuppression – most commonThrombocytopenia, hyperpigmentation of nails, myopathy, anxiety, confusion and tremulousnessFatal lactic acidosis & severe hepatomegaly


Other NRTIs
Didanosine- synthetic deoxy-adenosine analog; causes pancreatitis* Lamivudine- cytosine analog Zalcitabine- cytosine analog; causes peripheral neuropathy* Stavudine- thymidine analog;causes peripheral neuropathy* Abacavir- guanosine analog; more effective than the other agents; fatal hypersensitivity reactions can occur

Nucleotide Inhibitors

Tenofovir Adefovir

Tenofovir

An acyclic nucleoside phosphonate analog of adenosineM.O.A.- competively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNAUses – in combination with other antiretrovirals for HIV-1 suppression

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Nevirapine Delavirdine Efavirenz

Mechanism of Action NNRTIs

Bind to site on viral reverse transcriptase, different from NRTIs results in blockade of RNA and DNA dependent DNA polymerase activity do not require phosphorylation these drugs can not be given alone substrates and inhibitors of CYP3A4

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Nevirapine- prevents transmission of HIV from mother to newborn when given at onset of labor and to the neonate at delivery Delavirdine- teratogenic, therefore can not be given during pregnancy Efavirenz- teratogenic, therefore can not be given during pregnancy

Retroviral Protease Inhibitors (PIs)

Saquinavir (SQV), Nelfinavir (NFV), Indinavir (IDV), Ritonavir (RTV), Lopinavir and Amprenavir (AMP) MOA: In last stage of HIV growth cycle viral polyproteins are formed and then become immature budding particles Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of the mature virion core PIs bind to these proteins and inhibit formation of structural proteins

Protease Inhibitors

The protease enzyme cleaves precursor molecules to produce mature, infectious virions these agents inhibit protease and prevent the spread of infection These agents cause a syndrome of altered body fat distribution, insulin resistance, and hyperlipidemia

INDINAVIR

Specific inhibitor of HIV- 1 & HIV-2 proteases Higher CSF penetration Must be given on empty stomach for maximal absorption Most common adverse effects are indirect hyperbilirubinemia & nephrolithiasis due to crystalization

Anti-Hepatitis Agents

Lamivudine -Nucleoside Reverse Transcriptase Inhibitor (NRTI) Adefovir -Nucleotide Inhibitor Interferon Alfa Pegylated Interferon Alfa Ribavirin

INTERFERON ALFA

Endogenous proteins that exert complex antiviral immunomodulatory & antiproliferative activities through cellular metabolic process Enzyme induction, suppression of cell proliferation, immunomodulatory activities & inhibition of viral replication Inhibition of viral penetration & uncoating Treatment of both HBV & HCV Tx chronic hepatitis C in combination with ribavirin

INTERFERON ALPHA 2a

Approved for the treatment of chronic Hepatitis C, AIDS associated Kaposi’s sarcoma, hairy cell leukemia, chronic myelogenous leukemia


Anti-Influenza Agents
Amantadine Rimantadine Zanamivir

Amantadine and Rimantadine

cyclic amines inhibit the uncoating of viral RNA therefore inhibiting replication used in the prevention and treatment of Influenza A


Well absorbed orally. Large volumes of distribution and excreted in milk. Dose related G.I side effects. Higher conc.produce neurotoxic reactions. Toxicity increases with antihistamines,anticholinergic drugs. Teratogenic in animals and safety not established in pregnancy.

Oseltamivir75mgtwice daily for 5 days.

Inhibits the enzyme neuraminidase inhibit the replication of influenza A and Influenza B treats uncomplicated influenza infections administered intranasally


Select the true answer from the followings, regarding anti-TB ethionamide: A. mechanism of action static though inhibition of bacterial cell wall synthesis. B. mechanism of action static by inhibiting bacterial RNA synthesis. C. mechanism of action by making pores in the wall of bacteria. D. mechanism of action by inhibiting bacterial DNA-Gyrase. E. mechanism of action cidal by inhibiting bacterial cell wall synthesis