ANTIVIRAL DRUGS

1. ANTIVIRAL DRUGS

2. VIRUSES??? • Intracellular parasites. • They lack both a cell wall and a cell membrane • Do not carry out metabolic processes. • Viral reproduction uses much of the host's metabolic machinery • Few drugs are selective enough to prevent viral replication without injury to the host.

3. Viral replication • The viral particle attaches to the host cell membrane (adsorption) by linking its capsular glycoproteins to specific structures of the cell membrane. • The viralcoat fuses with the plasmalemma of the host cell and the nucleocapsid (nucleicacid plus capsule) enters the cell interior (penetration)). • The capsule opens (“uncoating”) near the nuclear pores and viral DNA moves into the cell nucleus.The genetic material of the virus can now direct the cell’s metabolic system. (4a) Nucleic acid synthesis: The genetic material (DNA in this instance) is replicated and RNA is produced for the purpose of protein synthesis. (4b) The proteins are used as “viral enzymes” catalyzing viral multiplication (e.g., DNA polymerase and thymidine kinase), as capsomers, or as coat components, or are incorporated into the host cellmembrane. (5) Individual components are assembled into new virus particles(maturation). (6) Release of daughter viruses results in spread of virus inside and outside the organism.

5. Description of Viral Infections CYTOMEGALOVIRUS (CMV) • virus of the herpes family, • common viral infection. Symptoms • malaise, fever, pneumonia, and superinfection. • Infants may acquire the virus from the mother while in the uterus, resulting in learning disabilities and mental retardation. • CMV can infect the eye, causing retinitis.

6. Description of Viral Infections • HERPES SIMPLEX VIRUS (HSV) • HSV is divided into HSV-1, which causes oral, ocular, or facial infections,and HSV-2, which causes genital infection. • HSV-1 causes painful vesicular lesions in the oral mucosa, face, or around the eyes. • HSV-2 or genital herpes is usually transmitted by sexual contact and causes painful vesicular lesions on the mucous membranes of the genitalia. • The lesions usually heal within 2 weeks.

7. Description of Viral Infections • HERPES ZOSTER • Herpes zoster (shingles) is caused by the varicella (chickenpox) virus. • Highly contagious. • The virus causes chickenpox in the child and is easily spread via the respiratory system. • Recovery from childhood chickenpox results in the infection lying dormant in the nerve cells. • The virus may become reactivated later in life as the older adult’s immune system weakens or the individual becomes ill with other disorders. • The lesions of herpes zoster appear as pustules along a sensory nerve route. • Pain often continues for several months after the lesions have healed.

8. Description of Viral Infections • HUMAN IMMUNODEFICIENCY VIRUS (HIV) • HIV or AIDS is a type of viral infection transmitted through an infected person’s bodily secretions, such as blood or semen. • HIV destroys the immune system, causing the body to develop opportunistic infections such as Kaposi’s sarcoma, Pneumocystis carinii pneumonia, or tuberculosis. • Symptoms include chills and fever, night sweats, dry productive cough, dyspnea, lethargy, malaise, fatigue, weight loss, and diarrhea.

9. Description of Viral Infections • INFLUENZA • Influenza, commonly called the “flu,” is an acute respiratory illness caused by influenza viruses A and B. • Symptoms include fever, cough, sore throat,runny or stuffy nose, headache, muscle aches, and extreme fatigue. • Most people recover within 1 to 2 weeks. • Influenza may cause severe complications such as pneumonia in children, the elderly, and other vulnerable groups. • The viruses causing influenza continually change over time, which enables them to evade the immune system of the host. These rapid changes in the most commonly circulating types of influenza virus necessitate annual changes in the composition of the “flu” vaccine.

10. Description of Viral Infections • RESPIRATORY SYNCYTIAL VIRUS (RSV) • RSV infection is highly contagious and infects mostly children, causing bronchiolitis and pneumonia. • Infants younger than 6 months are the most severely affected. • In adults, RSV causes colds and bronchitis, with fever, cough, and nasal congestion. • When RSV affects immunocompromised patients, the consequences can be severe and sometimes fatal

11. Antiviral drugsClassification

17. Acycloviracyclic guanosine derivativeclinical activity against HSV-1,HSV-2, & VZV. MOA Virus Thymidine kinase Acyclovir ↓ Acyclovir monophosphate ↓ ↓ Acyclovir triphosphate ↓ inhibits viral DNA synthesis Resistance can develop through alteration in the viral thymidine kinase Host Cellular kinases

18. Oral First episode genital herpes 400 mg tid or 200 mg five times daily Recurrent genital herpes 400 mg tid or 200 mg five times daily Genital herpes suppression 400 mg bid Herpes proctitis 400 mg five times daily Mucocutaneous herpes 400 mg five times daily Varicella 20 mg/kg four times daily Zoster 800 mg five times daily IV Severe HSV infection 5 mg/kg Herpes encephalitis 10–15 mg/kg Neonatal HSV infection 20 mg/kg Varicella or zoster in the - immunosuppressed host 10 mg/kg Topical Herpes keratitis (ointment) Acyclovir

19. Adverse effects • Acyclovir is generally well tolerated. • Nausea, diarrhea, and headache have occasionally been reported. Intravenous infusion • reversible renal dysfunction • neurologic toxicity (eg, tremors, delirium, seizures)

20. Ganciclovir • Acyclic guanosine analog MOA • requires triphosphorylation for activation prior to inhibiting the viral DNA polymerase. • Initial phosphorylation is catalyzed by the virus-specified protein kinase phosphotransferase in CMV-infected cells. • The activated compound competitively inhibits viral DNA polymerase and causes termination of viral DNA elongation. • Active against CMV, HSV, VZV, EBV. RESISTANCE • The most common mechanisms of resistance is mutation in virus-specified protein kinase phosphotransferase , resulting in decreased levels of the triphosphorylated (ie, active) form of ganciclovir;

21. Adverse ReactionsGanciclovir • Neutropenia • Headache , changes in mental status, seizures • Fever , rash • Abnormal liver function • Retinal detachment

22. Clinical UsesGanciclovir • CMV retinitis in AIDS patients • To prevent CMV infections in transplant recipients. • CMV colitis • CMV esophagitis

23. Antiretroviral Agentsclassification Nucleoside Reverse transcriptase inhibitors (NRTIs): Abacavir, Didanosine, Lamivudine, Stavudine, Zalcitabine, Zidovudine Non-Nucleoside Reverse transcriptase inhibitors (NNRTIs): Delavirdine, Efavirenz, Nevirapine Nucleotide inhibitors: Tenofovir Protease Inhibitors: Amprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir Fusion Inhibitors: Enfuvirtide

24. Antiretroviral Agents

25. Zidovudine • Nucleoside Reverse Transcriptase Inhibitors (NRTIs) • Deoxythymidine analog MECHAMISM OF ACTION • The NRTIs act by competitive inhibition of HIV reverse transcriptase and can also be incorporated into the growing viral DNA chain to cause termination. • Each requires intracytoplasmic activation as a result of phosphorylation by cellular enzymes to the triphosphate form.

26. Zidovudine PHARMACOKINETICS • Well absorbed from the gut. • Distributed to most body tissues and fluids. • Plasma protein binding is ≈ 35% • Liver  Glucuronidation • Renal elimination ADVERSE EFFECTS • Anemia /Neutropenia • Gastrointestinal intolerance • headaches, and insomnia • Hyperpigmentation of the nails, • Myopathy . • Anxiety , confusion, and tremors.

27. Nevirapine • Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) MECHANISM OF ACTION • The NNRTIs bind directly to a site on the HIV reverse transcriptase, resulting in blockade of RNA- and DNA-dependent DNA polymerase activities. • The binding site is near to but distinct from that of the NRTIs. • Unlike the NRTIs, the NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active.

28. Nevirapine PHARMACOKINETICS • Oral bioavailability > 90% • The drug is highly lipophilic, • ≈ 60% protein-bound • Liver Hydroxylation • Excretion  urine. ADVERSE EFFECTS • Skin rashes (Stevens-Johnson syndrome) • Hepatitis • Fever, nausea, headache, and somnolence

29. Saquinavir • PROTEASE INHIBITORS • Protease is responsible for cleaving precursor polyproteins molecules to produce the final structural proteins of the mature virion core. • By preventing cleavage of the polyprotein, protease inhibitors result in the production of immature, Noninfectious viral particles.

31. Saquinavir PHARMACOKINETICS • Poor oral bioavailability. • Large volume of distribution. • Excretion  feces. ADVERSE EFFECTS • Nausea , diarrhea, abdominal discomfort, dyspepsia • Rhinitis . • Cushingoid appearance • Insulin resistance • Spontaneous bleeding

33. Interferon • Naturally occurring glycoproteins Mechanism of action • Interfere with the ability of viruses to infect cells. Induction of host cell enzymes (e.g., proteinkinase,phosphodiesterase) ↓ Inhibit viral RNAtranslation, ↓ Degradation of viral mRNA and tRNA.

34. Interferon

35. Interferon • Interferon is given intravenously Adverse effects • fever, lethargy, • bone marrow depression, • congestive heart failure, • acute hypersensitivity reactions. • Hepatic failure

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