Antiinfectives 2024 - BMS2047 PDF

Drugs of interest & Antibiotic resistance Lecture bite 1 Others drugs of interest POLYMIXINS: – Topical application, not absorbed by GI tract – high systemic toxicity BACITRACIN: – Topical application – Mainly used for superficial infections VANCOMYCIN: – Oral and injection – Bacteriocidal – Main us...

Drugs of interest & Antibiotic resistance Lecture bite 1 Others drugs of interest POLYMIXINS: – Topical application, not absorbed by GI tract – high systemic toxicity BACITRACIN: – Topical application – Mainly used for superficial infections VANCOMYCIN: – Oral and injection – Bacteriocidal – Main use is against multiresistant Staphylococci (MRSA) infection Figure 50.3 Rang & Dales Pharmacology (2016) 8th Edition https://www.who.int/medicines/publications/essentialmedicines/en/ ANTIBIOTIC RESISTANCE https://www.theguardian.com/society/2019/apr/29/antibiotic -resistance-as-big-threat-climate-change-chief-medic-sallydavies https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance Anti-Virals Lecture bite 2 Anti-Viral Therapy VIRUSES: Originally described as ‘mobile genes’ Consist of DNA or RNA in a protein coat – DNA virus example = Herpes Simplex Virus (HSV) – RNA virus example = Human Immunodeficiency Virus (HIV) Parasitic mode of action Preventing entry Prevent viral “uncoating” and release of vRNA genome. E.g. amantadine – Virus enters via endocytosis (low pH environment) – Inhibits M2 ion channel, raising the pH of endosome – May just delay entry (HIV) Prevent budding of new virions E.g. oseltamivir (Tamiflu) – Inhibits activity of viral neuraminidase enzyme Amarelle et al (2017) Arch Bronconeumol. Influenza clinical trial drugs Koszalka (2017) Influenza Other Respir Viruses Inhibition of DNA synthesis acyclovir, valomaciclovir and valacyclovir – Inhibits viral DNA polymerase Topical application (Acyclovir) against Herpes simplex/zoster, varicella zoster Oral administration (valaciclovir and ganciclovir) against Epstein Barr-Virus Minimal side effects Inhibition of DNA synthesis acyclovir, valomaciclovir and valacyclovir – Inhibits viral DNA polymerase Topical application (Acyclovir) against Herpes simplex/zoster, varicella zoster Oral administration (valaciclovir and ganciclovir) against Epstein Barr-Virus Minimal side effects Preventing a hostage situation Targeting genomic integration: – Inhibition of reverse transcription – E.g. Zidovudine (AZT) – Thymidine analogue – Inhibits viral reverse transcriptase – Relatively effective in the treatment of HIV – Common side effects: Nausea, insomnia, bone marrow depression, migraines Circumventing host defences: Immunomodulators Interferons Induce enzymes that inhibit translation of viral mRNA into protein Anti-virals 2 HIV: a case in point Lecture Bite 3 HIV Human Immunodeficiency virus (HIV) is an RNA retrovirus. CD4+ T lymphocytes are infected (CXCR5/CD4 complex is required for entry) Mainly cytotoxic T lymphocytes (CD8+ T cells) and CD4+ helper T lymphocytes (CD4+ cells) are involved, other immune cells may be affected & play a role in its pathogenesis. HIV treatment Blocking entry: Targeting cell surface receptors CXCR5/4, which is required for virus entry Preventing fusion of viral capsid with plasma membrane: – E.g. Enfurvitide – SIDE EFFECTS: CNS, metabolic and GI effects Figure 52.1 Rang & Dales Pharmacology (2016) 8th Edition Figure 52.3 Rang & Dales Pharmacology (2016) 8th Edition HIV treatment Blocking entry: Targeting cell surface receptors CXCR5/4, which is required for virus entry Preventing fusion of viral capsid with plasma membrane: – E.g. Enfurvitide – SIDE EFFECTS: CNS, metabolic and GI effects Figure 52.1 Rang & Dales Pharmacology (2016) 8th Edition HIV treatment Blocking entry: Targeting cell surface receptors CXCR5/4, which is required for virus entry Preventing fusion of viral capsid with plasma membrane: – E.g. Enfurvitide – SIDE EFFECTS: CNS, metabolic and GI effects Figure 52.3 Rang & Dales Pharmacology (2016) 8th Edition HIV treatment Preventing hostile take-over: Preventing conversion of RNA into cDNA through inhibition of reverse transcriptase. – E.g. Abacavir (nucleoside) or Efavirenz (non-nucleoside) – SIDE EFFECTS: GI disturbances, musculoskeletal and dermatological effects, blood disorders, liver damage. Inhibition of integration into host genome Figure 52.3 Rang & Dales Pharmacology (2016) 8th Edition HIV treatment Preventing further transmission: Disrupting new capsid assembly through protease inhibition: – E.g. timpranavir – SIDE EFFECTS: GI disturbances, musculoskeletal and dermatological effects, blood disorders, liver damage. Figure 52.3 Rang & Dales Pharmacology (2016) 8th Edition “Remission from HIV” Two cases of “recovery” from HIV https://www.nature.com/articles/d41586-019-00989y?utm_source=twitter&utm_medium=social&utm_content=organic&utm_campaign=NGMT_2_JAL_Nature SUMMARY: AntiVirals Neal (2016) Medical Pharmacology at a Glance 8th Edn To post on the discussion board click here References GENERAL: Rang & Dales Pharmacology (2016) 8th Edition, Elsevier. Neal (2016) Medical Pharmacology at a Glance 8th Edn (especially for revision) IN MORE DETAIL: WHO ESSENTIAL MEDICINES LIST: https://apps.who.int/iris/bitstream/handle/10665/273826/EML-20-eng.pdf?ua=1 British National Formulary(BNF) for info on drug:drug interactions, side effects and use for combinations: https://bnf.nice.org.uk/drug/ Fernandes, P., & Martens, E. (2017) Antibiotics in late clinical development. Biochemical Pharmacology 133:152–163 Bryan-Marrugo, O.L. (2015) History and progress of antiviral drugs: From acyclovir to direct-acting antiviral agents (DAAs) for Hepatitis C. Medicina Universitaria. 17(68):165-174 Amarelle, L., Lecuona, E., & Sznajdera, J.I.(2017) Anti-Influenza Treatment: Drugs Currently Used and Under Development. Arch Bronconeumol. 53(1):19–26 Ventola, C.L. (2015) The Antibiotic Resistance Crisis: Part 1: Causes and Threats P T 40(4): 277–283.