Virology

ANTIVIRAL AGENTS

The Life Cycle of Viruses Attachment of the virus to receptors on the host cell surface; Entry of the virus through the host cell membrane; Uncoating of viral nucleic acid; Replication Synthesis of early regulatory proteins, eg, nucleic acid polymerases; Synthesis of new viral RNA or DNA; Synthesis of late, structural proteins; 5. Assembly (maturation) of viral particles; 6. Release from the cell


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AGENTS TO TREAT HERPES SIMPLEX VIRUS (HSV) & VARICELLA-ZOSTER VIRUS (VZV) INFECTIONS

Oral Agents Acyclovir Valacyclovir Famciclovir Ophthalmic Trifluridine
Topical Agents Acyclovir Docosanol Penciclovir Intravenous Acyclovir

Acyclovir

Valacyclovir is a prodrug, with better availability Acyclovir is Guanosine analog mostly taken up by the virus infected cells and has low toxicity for host cells.

Acyclovir

Acyclovir monophosphate
Herpes virus specific thymidine kinase
Acyclovir triphosphate
Host kinase
Incorporated into DNA and terminates synthesis Inhibition of herpes virus DNA polymerase

Acyclovir. Clinical Use

Herpes simplex Herpes zoster Chickenpox Epstain-Barr virus IV, oral, topical. Can be used during pregnancy Adverse Reactions: Well tolerated Toxic effect occur in patients with renal failure.

OTHER TOPICAL DRUGS FOR HSV

Orolabial herpes Penciclovir similar to acyclovir Application site reactions Docosanol Active against a broad range of lipid-envelop viruses MOA: interferes with viral fusion to host cell HSV Keratoconjuctivitis Trifluridine Active against acyclovir resistant strains Also active against vaccinia virus and smallpox

 AGENTS USED TO TREAT CYTOMEGALOVIRUS (CMV) INFECTIONS

Ganciclovir Valganciclovir Foscarnet Cidofovir Fomivirsen

CMV infections occur in advanced immunosuppression, typically due to reactivation of latent infection. Dissemination results in end-organ disease: retinitis, colitis, esophagitis, CNS disease, and pneumonitis.


GANCICLOVIR
Valganciclovir ( a prodrug) Mechanism like Acyclovir Active against all Herpes viruses & CMV Low oral bioavailability given I.V. Most common A/E: bone marrow suppression (leukopenia, thrombocytopenia ) and CNS effects (headache, psychosis, convulsions). 1/3 of patients have to stop because of adverse effects

FOSCARNET

An inorganic pyrophosphate analog does not have to be phosphorylated Active against Herpes (I, II, Varicella , CMV), including those resistant to Acyclovir and Ganciclovir. IV only Direct inhibition of DNA polymerase and RT A/E: Nephrotoxicity , electrolyte abnormalities, CNS toxicity Foscarnet should only be given during pregnancy when benefit outweighs risk.

Cidofovir

Incorporation into viral DNA chain results in reductions of the rate of viral DNA synthesis A/E: nephrotoxicity Must be administered with high-dose probenecid & adequate hydration

ANTIHEPATITIS AGENTS

Treatment of Viral Hepatitis A
There is no specific hepatitis A treatment. Fortunately, the disease usually gets better on its own. Most people who get hepatitis A recover in several weeks or months. Persons acutely infected with HAV should avoid hepatotoxic medications until they have fully recovered.

Viral Hepatitis B

Acute hepatitis B infection does not usually require antiviral drug treatment. Early antiviral treatment may only be required in patients, with a very aggressive "fulminant hepatitis" or who are immunocompromised. For people with chronic hepatitis B, antiviral drug therapy used to slow down liver damage and prevent complications (cirrhosis and liver cancer). Alpha interferon Pegylated alpha interferon Lamivudine

INTERFERONs

A family of small antiviral proteins produced as earliest response of body to viral infectionsBoth DNA and RNA viruses induce interferon but RNA viruses tend to induce higher levels. currently grouped into : IFN-α, IFN-β, and IFN-γ.α and β are produced by all body cells in response to various stimuli: viruses, bacteria, parasites and tumor cells γ produced by T-lymphocytes and natural killer cells, has less anti-viral activity.


Administered Intralesionally, S.C, and I.V Distribution in all body tissues, except CNS and eye.

Pegylated interferons are modified interferons with improved pharmacokinetic properties

INTERFERON ALFA
Acts by : Binding to membrane receptors on cell surface induction host cell enzymes that inhibit viral RNA translation and cause degradation of viral mRNA and tRNA May also inhibit viral penetration, uncoating, mRNA synthesis, and translation, and virion assembly and release Enhancement of phagocytic activity of macrophages, Augmentation of the proliferation and survival of cytotoxic T cells.

Clinical UseChronic hepatitis B and CHerpes virusesInfluenza virusesSome types of cancer: Kidney cancer, Malignant melanoma, Lymphomas, LeukemiaAIDS-related Kaposi’s sarcoma. Side effects: Flu-like symptoms (within few hours after administration) Neurotoxicity (depression, seizures). Myelosuppression (neutropenia) elevation of hepatic enzymes. Mild hair loss
C/I: Hepatic failure, Autoimmune diseases, Pregnancy

OTHER TREATMENT OF HEPATITIS B VIRUS INFECTION

Competitively inhibit HBV DNA polymerase to result in chain termination after incorporation into the viral DNA. Adefovir Entecavir Lamivudine Telbivudine Tenofovir

Lamivudine

Lamivudine is a potent nucleoside analog Lamivudine inhibits HBV DNA polymerase and both types (1 and 2) of HIV reverse transcriptase. It is prodrug. It is needs to be phosphorylated to its triphosphate form before it is active. Clinical Use: Chronic hepatitis B HIV Adverse Effects: CNS: paresthesias and peripheral neuropathies Pancreatitis

Treatment of Chronic Viral Hepatitis C

Interferon alpha Pegylated interferon alpha Ribavirin

Ribavirin

Guanosine analog Mechanism: Phosphorylated to triphosphate by host enzymes, and inhibits RNA-dependent RNA polymerase, viral RNA synthesis, and viral replication. A/E: Hemolytic anemia, Conjunctival and bronchial irritation

ANTIRETROVIRAL AGENTS

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CURRENT CLASSES OF ANTIRETROVIRAL DRUGS INCLUDE:

Three main enzymatic targets: Reverse Transcriptase, Protease, Integrase six drug classes Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Protease inhibitors (PIs) Entery inhibitors CCR5 receptor antagonists Integrase inhibitors

CURRENT ARV MEDICATIONS

NRTI Abacavir Didanosine Lamivudine Stavudine Tenofovir Zidovudine NNRTI Efavirenz Etravirine Nevirapine
PI Atazanavir Darunavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir Fusion Inhibitor Enfuvirtide

CCR5 Antagonist Maraviroc

Integrase Inhibitor Raltegravir

HIV DRUG REGIMENS

Always combine multiple agents. Usually 2 NRTIs along with: A PI An NNRTI An integrase inhibitor An entery inhibitor HAART Taking 3 or more antiretroviral drugs at the same time vastly reduces the rate at which resistance develops, the approach is known as highly active antiretroviral therapy, or HAART.

NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS

These were the first type of drug available to treat HIV infection . NRTIs interfere with the action of an HIV protein called reverse transcriptase, which the virus needs to make new copies of itself. Most regimens contain at least two of these drugs (Reverse transcriptase changes viral RNA to DNA)


Act by competitive inhibition of HIV reverse transcriptase; incorporation into the growing viral DNA chain results in premature chain termination due to inhibition of binding with the incoming nucleotide . Require intracytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form.

NON NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI)

Bind directly to HIV reverse transcriptase, prevents viral RNA from conversion to the viral DNA that infects healthy cells, by causing conformational changes in the enzyme. The binding site of NNRTIS is near to but distinct from that of NRTIS. Do not require phosphorylation to be active.

Drug resistance develops quickly if NNRTIs are administered as monotherapy and therefore NNRTIs are always given as part of combination therapy, (HAART). Etravirine Efavirenz Nevirapine

PROTEASE INHIBITORS

Prevent the processing of viral proteins into functional conformations, resulting in the production of immature, noninfectious viral particles . Do not need intracellular activation.

Atazanavir Indinavir Lopinavir Nelfinavir Saquinavir Ritonavir Darunavir Fosamprenavir Tipranavir
contain sulfonamide

ENTRY INHIBITORS

Binds to the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes Enfuvirtide By subcutaneous injection Toxicity Injection site reactions Nausea, diarrhea, fatigue, hypersensitivity

CCR5 RECEPTOR ANTAGONISTS 

They are inhibitors of the human CCR5 receptor, a receptor that is found on several host defense cells (T-cells and killer cells). The act of the CCR5 antagonist binding to the CCR5 receptor is thought to alter the conformational state of the CCR5 receptor. Maraviroc A/E: Abdominal pain, Upper respiratory tract infections, Cough, Hepatotoxicity, Musculoskeletal symptoms, Rash

INTEGRASE INHIBITORS Bind integrase, a viral enzyme essential to the replication of HIV, Inhibits strand transfer, the final step of the provirus integration, thus interfering with the integration of reverse-transcribed HIV DNA into the chromosomes of host cells. Raltegravir A/E: Nausea, Headache, Diarrhea


ANTI-INFLUENZA AGENTS


Influenza virus strains are classified by : Their core proteins (i.e., A, B, or C), Species of origin (eg, avian, swine), Geographic site of isolation.

CLASSES OF INFLUENZA ANTIVIRAL DRUGS

M2 ion channel inhibitors Amantadine Rimantadine Neuraminidase inhibitors Oseltamivir Zanamivir

Amantadine & Rimantadine

Block the M2 ion channel of the virus particle and inhibit Uncoating of the viral RNA within infected host cells, thus preventing its replication. Activity: influenza A only. Rimantadine is 4 to 10 times more active than amantadine in vitro. A/E GI disturbance, nervousness, insomnia.

Oseltamivir & Zanamivir

Neuraminidase inhibitors, 1999 Chemically related, but have different routes of administration Interfere with release of influenza virus from infected to new host cells. Competitively and reversibly interact with the active enzyme site to inhibit neuraminidase activity and destroy the receptors found on normal host cells recognized by viral hemagglutinin.

Activity: both influenza A and influenza B viruses. Early administration is crucial because replication of influenza virus peaks at 24–72 hours after the onset of illness. Oseltamivir is FDA-approved for patients 1 year and older, whereas zanamivir is approved in patients 7 years or older.

Oseltamivir

Administered orally Prodrug that is activated by hepatic esterases Widely distributed throughout the body. A/E: N/V/D, Abd. Pain, Headache, Fatigue, Rash. Rates of resistance to oseltamivir among H1N1 viruses have risen abruptly and dramatically worldwide. It may be associated with point mutations in the viral hemagglutinin or neuraminidase genes.

Zanamivir

Administered by inhalation. 10 to 20 % of the active compound reaches the lungs, and the remainder is deposited in the oropharynx. A/E: cough, bronchospasm, reversible decrease in pulmonary function, and transient nasal and throat discomfort.