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![Anti-hepatitis virus drugs
• Hepatitis B virus (HBV) DNA virus [integrates into
host chromosomal DNA to establish permanent
infection]
• Hepatitis C virus (HCV) RNA virus [does not
integrate into chromosomal DNA, does not establish
non curable infection, but frequently causes chronic
hepatitis]](https://image.slidesharecdn.com/anti-viraldrugs8-230402115719-f4485830/75/Anti-viral-drugs-16-2048.jpg)
![Highly active antiretroviral therapy
(HAART)
• WHO guidelines for ART (2016)
1. When to start All HIV +ve pts. regardless of WHO
clinical stage & at any CD4 cell
• For pts. With TB & HIV, t/t of TB should be started 1st
foll. By ART asap within 1st 8 weeks of t/t
2. What to start 2 NRTI + 1 NNRTI (Tenofovir +
Lamivudine[or Emtricitabine] + Efavirenz)
3. Post exposure prophylaxis (For 28 days; start within
72 hrs) Tenofovir + Lamivudine + Protease inhib.](https://image.slidesharecdn.com/anti-viraldrugs8-230402115719-f4485830/75/Anti-viral-drugs-47-2048.jpg)
Uploaded byKarun Kumar
Anti-viral drugs
This document summarizes various anti-viral drugs used to treat viral infections like herpes, influenza, hepatitis, HIV, and their mechanisms of action and clinical applications. It discusses nucleoside and nucleotide reverse transcriptase inhibitors like acyclovir, valacyclovir, famciclovir for herpes; oseltamivir and zanamivir for influenza; lamivudine for hepatitis B; and protease inhibitors and integrase inhibitors for HIV treatment. It also covers classification, uses, advantages, resistance and adverse effects of these anti-viral medications.
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Anti-viral drugs
- 1. Anti-viral drugs Dr. KarunKumar Senior Lecturer Dept. of Pharmacology
- 2. • The applicationof antiviral drugs in dentistry is restr. to T/t of orophar. herpes simplex & herpes labialis that occur in immunocompromised pts.
- 3.
- 4. Anti-viral drugs • Actat any step of viral replication • Viral replic. inv. fusion of virus to host cell membrane & penetration inside the cell • This is foll. by uncoating & synth. of early proteins like DNAP • This is foll. by DNA & RNA synth. • After that final func. prot. are synth. & processed • After packaging & assembly, viral particles are rel. (with the help of neuram.) & inf. other cells
- 5. Anti-herpes virus drugs •These are drugs active against the Herpes group of DNA viruses which include Herpes simplex virus-1 (HSV-1), Herpes simplex virus-2 (HSV-2), Varicella- Zoster virus (VZV), Epstein Barr virus (EBV) and Cytomegalovirus (CMV)
- 6. Acyclovir • Requires avirus specific enzyme for conversion to the active metabolite that inhibits DNA synthesis and viral replication. Active against HSV-1 & 2, VZV
- 7. • Acyclovir ispreferentially taken up by the virus infected cells • Due to selective generation of the active inhibitor in the virus infected cell and its greater inhibitory effect on viral DNA synthesis, acyclovir has low toxicity for host cells • Acyclovir is active only against herpes group of viruses; HSV-1 is most sensitive followed by HSV-2 > VZV=EBV, while CMV is practically not affected
- 8. Uses 1. Genital Herpessimplex 2. Mucocutaneous H. simplex 3. H. simplex encephalitis 4. H. simplex (type I) keratitis 5. Herpes zoster 6. Chickenpox
- 9. Adverse effects • Topical Stinging and burning sensation after each application • Oral The drug is well tolerated; headache, nausea, malaise and some CNS effects are reported • Intravenous Rashes, sweating, emesis and fall in BP occur only in few patients • Dose-dependent decrease in g.f.r. is the most important toxicity; occurs especially in those with kidney disease; normalises on discontin. of the drug
- 10. Valacyclovir • Ester prodrugof Acyclovir with improved oral bioavailability (55–70%) due to active transport by peptide transporters in the intestine • It is comp. conv. to Acyclovir & higher plasma levels of Acyclovir are obtained improving clinical efficacy in certain conditions (DOC in herpes zoster) • Dose Orolabial herpes 2 g BD × 1 day • In immunocompromised pt. 1 g BD × 5 days • For herpes zoster 1 g TDS × 7 days
- 11. Famciclovir • Ester prodrugof Penciclovir, which has good oral bioavailability and prolonged intracellular t½ of the active triphosphate metabolite • Like Acyclovir, it needs viral thymidine kinase for generation of the active DNA polymerase inhibitor • Used as an alternative to acyclovir for genital or orolabial herpes and herpes zoster • Side effects are headache, nausea, loose motions, itching, rashes and mental confusion
- 12. Anti-influenza virus drugs •Amantadine Inhibits replication of influenza A virus (a myxovirus) • Antiviral activity is strain specific; influenza B, H5N1 (avian influenza/bird flu) and H1N1 (swine flu) strains of influenza A are resistant • Acts at an early step (possibly uncoating) as well as at a late step (viral assembly) in viral replication • Target of action M2 protein (ion channel)
- 13. • Uses Prophylaxis of influenza A2, T/t of infl. A2, Parkinsonism • A/E Nausea, anorexia, insomnia, dizziness, nightmares, lack of mental conc., rarely hallucinations. Ankle edema occurs due to local vasoconstriction • Rimantadine More potent, longer acting, better tolerated, fewer s/e, higher oral bioavailability than Amantadine. Dose and clinical application is similar.
- 14. Oseltamivir • Broad spectrumactivity covering influenza A (amantadine sensitive as well as resistant), H5N1 (bird flu), H1N1 (swine flu) strains and influenza B • Ester prodrug conv. to Oseltamivir carboxylate which acts by inh. Viral NA enzyme • S/E Nausea and abdominal pain due to gastric irritation (reduced by taking the drug with food), headache, weakness, sadness, diarrhoea, cough and insomnia. Skin reactions have been reported
- 15. Zanamivir • Influenza A(including amantadine resistant, H1N1, H5N1 strains) & influenza B virus neuraminidase inhibitor • Administered by inhalation as a powder (low oral bioavailability) • Mechanism of action, clinical utility and efficacy Similar to Oseltamivir
- 16. Anti-hepatitis virus drugs •Hepatitis B virus (HBV) DNA virus [integrates into host chromosomal DNA to establish permanent infection] • Hepatitis C virus (HCV) RNA virus [does not integrate into chromosomal DNA, does not establish non curable infection, but frequently causes chronic hepatitis]
- 17. Drugs for hepatitisB • Combination therapy not superior • Drugs used sequentially • Lamivudine, Tenofovir, Entecavir, Adefovir and Telbivudine • Entacavir Most active 1st line option for treating chr. hepatitis B
- 18. Drugs for hepatitisC • Aim SVR (Undetectable HCV-RNA in blood for at least 6 mths. after therapy completion) • Oral Ribavirin + Peg-INFα Standard therapy • Achieves SVR in 50-80% cases (given for 6-12 mths.) • Ribavirin Activity against influenza A, B, RSV, other DNA & RNA viruses • IFNs Low mol. wt. glycoprotein cytokines produced by host cells in response to viral infections • IFNRs JAK-STAT tyrosine protein kinase receptors
- 19. Interferons • Bind tospecific cell surface receptors & affect viral replication at multiple steps 1. Viral penetration 2. Synthesis of viral mRNA 3. Assembly of viral particles 4. Release of viral particles 5. Direct or indirect suppression of viral protein synthesis
- 20. Uses of IFNα 1. Chronic hepatitis B and C 2. AIDS-related Kaposi’s sarcoma 3. Condyloma acuminata (HPV) refractory to podophyllin 4. H. simplex, H. zoster and CMV infections in immunocompromised patients as adjuvant to acyclovir/ganciclovir
- 21. Adverse effects 1. Flu-likesymptoms Fatigue, aches and pains, malaise, fever, dizziness, anorexia, taste and visual disturbances (a few hours after each injection) 2. Neurotoxicity—numbness, neuropathy, tremor 3. Myelosuppression (dose limiting); neutropenia, thrombocytopenia
- 22. New specific anti-HCVdrugs • Target specific NS (non str.) viral proteins • Achieved SVR of 99% • Shortened duration of therapy (12-24 weeks) • Less toxic than Ribavirin or IFNα 1. NS5B polymerase inh. Sofosbuvir 2. NS3/4A protease inh. Simeprevir 3. NS5A inh. Daclatasvir, Ledipasvir, Velpatasvir
- 24. Anti-retrovirus drugs • Drugsactive against HIV • Useful in prolonging and improving the QOL & postponing complications of AIDS or ARC • Do not cure the infection • Dentists run the risk of accidental exp. to HIV inf. • 1st line drugs NRTIs, NNRTIs, IIs, Pis • Reserve drugs Entry inh. & CCR5 rec. inhibitor • In India, t/t under NACP & implemented by NACO
- 25.
- 26. Reverse transcriptase inhibitors 1.Competitive inhibitors 1. Nucleoside reverse transcriptase inhibitors (NRTIs) 2. Nucleotide reverse transcriptase inhibitors 2. Non-competitive inhibitors 1. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) 2. Non-nucleotide reverse transcriptase inhibitors
- 27. NRTI • Prodrugs activatedby host cell kinases to form triphosphates • Competitively inhibit reverse transcriptase & act as chain terminators by incorporation into the DNA chain • Resistance to these drugs emerges rapidly if used alone
- 28. Zidovudine (AZT) • Afterphosphorylation in the host cell—zidovudine triphosphate selectively inhibits viral reverse transcriptase in preference to cellular DNA polymerase
- 29. • Zidovudine preventsinfection of new cells by HIV, but has no effect on proviral DNA that has already integrated into the host chromosome • It is effective only against retroviruses • Zidovudine itself gets incorporated into the proviral DNA and terminates chain elongation
- 30. Uses • In HIVinfected patients only in combination with at least 2 other ARV drugs • One of the 2 optional NRTIs used by NACO for its first line triple drug ARV regimen • There is a sense of well-being and patients gain weight • However, beneficial effects are limited from a few months to a couple of years after which progressively non-responsiveness develops
- 31. Adverse effects • Anaemiaand neutropenia are the most important and dose-related adverse effects • Nausea, anorexia, abdominal pain, headache, insomnia and myalgia are common at the start of therapy, but diminish later • Myopathy, pigmentation of nails, lactic acidosis, hepatomegaly, convulsions and encephalopathy are infrequent
- 32. Interactions • Paracetamol increasestoxicity, probably by competing for glucuronidation • Azole antifungals also inhibit metabolism • Stavudine and Zidovudine exhibit mutual antagonism by competing for the same activation pathway
- 33. Didanosine • It isa purine nucleoside analogue which after intracellular conversion to didanosine triphosphate competes with ATP for incorporation into viral DNA, inhibits HIV reverse transcriptase and terminates proviral DNA • Its use has declined due to higher toxicity than other NRTIs
- 34. Stavudine • It isalso a thymidine analogue which acts in the same way as AZT • By utilizing the same thymidine kinase for activation, AZT antagonises the effect of stavudine and the two should not be used together • It should also not be combined with didanosine, because both cause peripheral neuropathy • Resistance to Stavudine develops as for other NRTIs
- 35. Lamivudine • It isphosphorylated intracellularly and inhibits HIV reverse transcriptase as well as HBV DNA polymerase • Its incorporation into viral DNA results in chain termination • Most human DNA polymerases are not affected and systemic toxicity is low • Uses In combination with other anti-HIV drugs, HB • S/E Headache, fatigue, rashes, nausea, anorexia, abdominal pain
- 36. Tenofovir • Only nucleotideanalogue used as anti-HIV drug • Also active against HBV • Preferentially inhibits HBV DNA polymerase and HIV- reverse transcriptase • NACO includes tenofovir in its first line 3 drug regimen as an alternative • Due to its high efficacy, good tolerability and low risk of resistance, tenofovir is being preferred for HBV infection, especially lamivudine resistant cases
- 37. NNRTIs • Inh. Rtby acting at an allosteric site diff. from NRTIs • Resistance to these drugs develops very rapidly • Directly inhibit HIV reverse transcriptase without the need for intracellular phosphorylation • Indicated in combination regimens for HIV • Either NVP or EFV is included in the first line triple drug regimen used by NACO
- 38. Retroviral Protease Inhibitors(PIs) • An aspartic protease enzyme encoded by HIV is involved in the production of structural proteins and enzymes (including rt and integrase) of the virus from the large viral polyprotein synthesized in the infected cell • The polyprotein is broken into various functional components by this protease enzyme
- 39. • 6 proteaseinhibitors—Atazanavir (ATV), Indinavir (IDV), Nelfinavir (NFV), Saquinavir (SQV), Ritonavir (RTV) and Lopinavir (in combination with ritonavir LPV/r) have been marketed in India for use against HIV • They bind to the active site of protease molecule, interfere with its cleaving function, and are more effective viral inhibitors than AZT
- 40. • As theyact at a late step of viral cycle, they are effective in both newly as well as chr. infected cells • Under their influence, HIV-infected cells produce immature noninfectious viral progeny—hence prevent further rounds of infection • All PIs (especially ritonavir and lopinavir) are potent inhibitors of CYP3A4
- 41. • In dentistry,the drugs level ↑ in +nce of PIs are Metronidazole, Lidocaine, Midazolam & CBMZ • PIs are avoided in 1st line regimens, because their use in initial regimens markedly restricts second line regimen options • Most guidelines, including that of NACO, reserve them for failure cases
- 42. Boosted PI regimen •Used nowadays • A protease inhibitor taken with a low dose of ritonavir (100 mg) • Ritonavir boosts levels of the PI by – ↑ BA – ↓ FPM – ↓ CL – Of companion PI • Permits ↓ in no. or freq. of tablets taken
- 43. Integrase inhibitors 1. Raltegravir Active against both HIV-1 and HIV-2. • Component of 1st line triple drug regimen along with two NRTIs in some countries • In India, 2nd line regimen (higher cost) 2. Dolutegravir 2nd gen. Int. inh. • Activity similar to Raltegravir • Yielded sup. results than Raltegravir in triple drug • Can be used in Raltegravir resistant cases
- 44. Entry (fusion) inhibitor •Enfuvirtide Acts by binding to HIV-1 envelope glycoprotein 'gp41' (fusion of viral and cellular membranes) • Entry of the virus into the cell is blocked • Not active against HIV-2 • Reserve drug for multi resistant HIV
- 45. CCR5 receptor inhibitor •Maraviroc Anti-HIV drug which blocks the host CD4 cell receptor labelled CCR5 • Chemokine receptor of host CD4 cells anchors the the HIV through its glycoprotein gp120 • Entry of the viral genome into the CD4 cell is interfered with
- 46. Treatment of HIVinfection • Complex, lifelong, needs expertise, strong motivation & commitment of the patient, resources, expensive • In India, ARV provided free under NACO • HAART Combination of ≥ 3 ARV drugs belonging to at least two major classes mandatory for t/t • 1st line regimen 2 NRTIs + 1 NNRTI • NRTIs Lamivudine, Abacavir, Tenofovir • NNRTI Efavirenz pref. over Nevirapine
- 47. Highly active antiretroviraltherapy (HAART) • WHO guidelines for ART (2016) 1. When to start All HIV +ve pts. regardless of WHO clinical stage & at any CD4 cell • For pts. With TB & HIV, t/t of TB should be started 1st foll. By ART asap within 1st 8 weeks of t/t 2. What to start 2 NRTI + 1 NNRTI (Tenofovir + Lamivudine[or Emtricitabine] + Efavirenz) 3. Post exposure prophylaxis (For 28 days; start within 72 hrs) Tenofovir + Lamivudine + Protease inhib.
- 48. 1st line regimens(NACO, 2018) ART regimens Recommended for Tenofovir + Lamivudine + Efavirenz Age > 10 yrs., Body wt. >30 kg Abacavir + Lamivudine + Efavirenz Abn. Serum creatinine or Body wt. <30 kg
- 49. 2nd line regimen •All 3 drugs of regimen changed “Switch” of the entire regimen • Lamivudine may be contd. (Exerts residual antiviral activity & ↓ viral fitness) • Boosted PI + 2 NRTIs (Lamivudine + 1 NRTI not used earlier) OR • Boosted PI + Integrase inhibitor (Ralte./Dolute.)
Editor's Notes
- #3 Herpes labialis, commonly known as cold sores, is a type of infection by the herpes simplex virus that affects primarily the lip. Symptoms typically include a burning pain followed by small blisters or sores. oropharyngeal HSV-1 infection causes pharyngitis and tonsillitis more often than gingivostomatitis. Fever, malaise, headache, and sore throat are presenting features. The vesicles rupture to form ulcerative lesions with grayish exudates on the tonsils and the posterior pharynx
- #9 Herpes zoster is infection that results when varicella-zoster virus reactivates from its latent state in a posterior dorsal root ganglion. Symptoms usually begin with pain along the affected dermatome, followed in 2 to 3 days by a vesicular eruption that is usually diagnostic. A dermatome is an area of skin that is mainly supplied by afferent nerve fibers from a single dorsal root of spinal nerve which forms a part of a spinal nerve.
- #19 Therapy completion; Sustained viral response; Polyethylene glycol is added to make interferon last longer in the body
- #21 Interferon is not effective orally. Clinical utility of s.c. or i.m. injected interferon is limited by substantial adverse effects.
- #25 Virion, an entire virus particle, consisting of an outer protein shell called a capsid and an inner core of nucleic acid (either ribonucleic or deoxyribonucleic acid—RNA or DNA). The core confers infectivity, and the capsid provides specificity to the virus.; AIDS related complex
- #27 Nucleosides are made of a nitrogenous base, usually either a purine or pyrimidine, and a five-carbon carbohydrate ribose. A nucleotide is simply a nucleoside with an additional phosphate group or groups
- #29 Sugar + Base. A nucleoside consists of a nitrogenous base covalently attached to a sugar (ribose or deoxyribose) + po4 (nucleotide)
- #47 highly active antiretroviral therapy’ (HAART). (hepatotoxic)
- #49 Efavirenz is the pref. NNRTI over Nevirapine because Nevirapine is potentially hepatotoxic
- #51 CD4 cells are white blood cells that play an important role in the immune system. CD4 cells are sometimes also called T-cells, T-lymphocytes, or helper cells.; On the template of single-stranded RNA genome of HIV, a double-stranded DNA copy is produced by viral reverse transcriptase. This proviral DNA translocates to the nucleus and is integrated with chromosomal DNA of the host cell (by viral integrase enzyme) which then starts transcribing viral genomic RNA as well as viral mRNA. Under the direction of viral mRNA, viral regulatory and structural proteins are produced in the form of a polyprotein. Finally, viral particles are assembled and matured after fractionation of the polyprotein by viral protease. put (thoughts, speech, or data) into written or printed form Transcribe; move from one place to another Translocate