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Quinolones Oxiquinolones Nitrofurans and Antiviral agents PowerPoint Presentation

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Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology Quinolones Oxiquinolones Nitrofurans Antiviral agents (Summary) Assoc. Prof. Ivan Lambev (www.medpharm-sofia.eu)
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(inhibitors of DNA gyrase, resp. inhibitors of topomerases) Nalidixic acid and its derivatives QUINOLONES Fluoroquinolones
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Nalidixic acid has been available for over 60 years but low activity poor tissue distribution, and adverse effects limited its use to being a second- and third- line oral treatment for Gram (-) urinary tract infections.
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Nalidixic acid (Nelidix®) Gramurin®  E. coli  Salmonella  Shigella  P. aeruginosa Gr (—):
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Changes to the basic quinolone structure such as the addition of fluorine and piperazine ring have dramatically increased antibacterial potency, particularly against P. aeruginosa. The new compounds are called 4-fluoro- quinolones (or fluoroquinolones)
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Ciprofloxacin Bactericidal effect Gr (+): topoisomerase IV Gr (–): topoisomerase II (DNA gyrase)
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Bacterial DNA topoisomerase II and IV) (-) Fluoroquinolones
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Bactericidal effect; very broad antibacterial spectrum High activity against P. aeruginosa, Salmonella, Shigella, Neisseria, Campylobacter, and Chlamydia Beta-lactamase stability Limited activity against streptococci
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>70% F (p.o.) DD/2 applications 50–80%/24 h urinary excretion Good intracellular distribution
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INDICATIONS (infections): urinary respiratory GIT genital (incl. gonorrhoea) septicemia ophthalmic (topically)
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CIPROFLOXACIN Ciprobay® tabl. 500 mg 500 mg/12 h (5–10 days)
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Co-administration of ciproflo- xacin and theophylline causes eleveted plasma theophylline concentrations due to inhibi- tion of cytochrome P450. Both drugs are epileptogenic
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Moxifloxacin Tabl. 400 mg NB: 400 mg once daily
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Gatifloxacin Levofloxacin (Tavanic®) – S-isomer of ofloxacin 500 mg/24 h p.o. 10 days Norfloxacin Lomefloxacin Ofloxacin Pefloxacin Trovafloxacin, etc.
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Fluoroquinolones Adapted from Bennett and Brown (2003)
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convulsions (in patients with epilepsy or commotion) arthritis (in growing animals) dizziness hepatic and renal damage ruptura tendinorum in old people crystallization (in excessively alkaline urine and dehydration) cartilage damage. The mechanism of cartilage damage may be related to chelation of magnesium in joints. ADVERSE EFFECTS
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The mechanism of cartilage damage may be related to chelation of magnesium in joints. Lesions have been documented in dogs given ﬁve times the recom- mended dose and occur within 1–2 days of beginning administration. It is recommended that ﬂuoroquino- lones be avoided in large breed dogs up to 18 months of age (12 months for medium breeds, 9 months for small breeds). If a ﬂuoroquinolone must be used because there is no suitable alternative, strict exercise restriction (especially for large breed dogs) and use of chondroprotectives are advised.
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Contraindications pregnancy old people epilepsy meningitis children
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TILBROQUINOL – enteroantiseptic with antiamoebic activity NITROXOLIN – broad spectrum uroantiseptic (p.o.) They block RNA polymerase. OXIQUINOLONES
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FURAZOLIDONE, NIFUROXAZIDE – enteroantiseptics (Salmonella etc.) NITROFURANTOIN (p.o.) – uroantiseptic: E. coli, Proteus mirabilis, Staph. aureus, Klebsiella, Serratia, Pseudomonas. It blocks carbohydrate metabolism by inhibiting its acetyl CoA synthesis. NITROFURANS – broad spectrum antibacterial agents
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Furazolidone
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Nitrofurantoin (Furadantin®):
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ANTIVIRAL AGENTS Viruses are composed of a core genome consisting of either double-stranded or single-stranded DNA or RNA surrounded by a protein shell known as a capsid. Some viruses are further surrounded by a lipoprotein membrane or envelope. Both the capsid and lipoprotein membrane may be antigenic. Viruses cannot replicate independently and must usurp the host’s metabolic machinery to replicate. Therefore viruses are obligate intracellular parasites. The host’s pathways of energy generation, protein synthesis, and DNA or RNA replication provide the virus with the means of viral replication. For some viruses, replication is initiated by viral enzymes.
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Cells respond to viral infection in three ways: infection may have no impact on the cell or its function, cellular death may occur (which may preclude subsequent infection), or the cell may be transformed such that host control of cell growth is lost to viral activities. Viral replication occurs in five or six sequential steps: cell entry, including host cell attachment, generally through specific receptors, followed by host cell penetration; disassembly or uncoating resulting in release of viral genome; transcription of viral genome (or viral messenger RNA), which is dependent on virus-specified enzyme; translation of regulatory (early) or structural (late) viral proteins; post-translation modifications (incl. proteolytic cleavage); assembly of virion components; and release of the virus, generally by budding or cell lysis.
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TARGETS OF ANTIVIRAL THERAPY Potential targets in the viral life cycle that might be pharmacologically inhibited are expressed during extracellular stages of viral infection (i.e., penetration), intracellular stages (i.e., replication, assembly, and viral release), and dissemination. Antivirals that diminish penetration of host cells by the virus are more viral specific and less toxic from those that prevent viral replication. Because cell penetration is enhanced by viral-induced immunosuppression, pharmacologic immunomodulation (resp. immunostimulation) may also help prevent viral penetration especially during the early stages of infection, which are often missed because of the lack of clinical signs.
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(Ag) (Ag)
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Cyclic amines inhibit influenza-A DNA replication. Rimantadine is from two to 8-fold times more active than Amantadine.
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Rimantadine (Flumadine): p.o. Vitamin C Esberitox N (immunostimulant) Indications: prophylaxis and treatment of influenza A viral infection: А (H5N1)
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Rimantadine - adverse effects: orthostatic hypotension dizziness, confusion headache, insomnia vomiting, xerostomia urinary retention
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inhibits neuraminidase and prevents replication of influenza-A and B-virus application: per inhalationem b) Neuraminidase inhibitors (active against virus A and B Zanamivir:
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Oseltamivir – Tamiflu® against virus А, B A (H5N1): bird or avian flu (influenza) – (2 s/78 °C) A (H1N1): swine or pig flu (influenza) Treatment: 75 mg/12 h 5 days Prophylaxis: 75 mg/24 h about 30 days
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Pig flu: Bird flu:
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Symptomatic therapy
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Paracetamol Metamizole
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Please, give me something against influenza.
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Influenza Virus Vaccines (PRC C) Against virus А (H5N1) Fluarix Fluogen Inflexal V Influvac Invivac Vaxigrip Vacciflu Against virus – A (H1N1) : Celvapan® Focetria® Pandemrix® Prepandrix® 0,5 ml i.m./deep s.c.
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It is time to get vaccinated against influenza virus A (H1N1)
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William Osler (1849-1919) ,,Good humor helps enormously both in the study and practice of medicine.”
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2. INTERFERONS (IFNs) They are cytokines (mediators of cell growth and function). They are glycoproteins secreted by cells infected with viruses or foreign DNA.
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Interferons are active against a wide range of viruses. Main types of IFNs: α – produced by leukocytes β – produced by fibroblasts γ – produced by lymphocytes
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IFN gamma has significant immunoregulatory function. Interferon alfa-2b (Intron) is used in chronic hepatitis, Kaposi’s sarcoma in AIDS, multiple myeloma, etc. Interferon beta-1b (Betaferon) used s.c. in multiple sclerosis (MS).
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Adverse effects of IFNs fever (influenza-like syndrome) lympho- and thrombocytopenia anorexia and weight loss alopecia confusion, tremor, and fits transient hypotension cardiac arrhythmias hypothyroidism
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3. Antiherpetic Drugs They are prodrugs – nucleoside analogues. H. simplex
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After phosphorylation nucleoside analogs convert into active metabolites, which inhibit viral DNA polymerase (reverse transcriptase) and block viral replication.
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Indications: H. simplex and varicella-zoster infections aciclovir ganciclovir valaciclovir brivudine
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Herpes zoster infection Treatment of postherpetic neuralgia: ●Anticonvulsants Gabapentin, Pregabalin ●Antidepressants Nortriptyline, Duloxetine ●Opioid painkillers Tramadol
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Acyclovir and Valacyclovir Acyclovir is is structurally similar to guanosine (purine nucleoside). Valacyclovir is an L-valyl ester prodrug of acyclovir. Efficacy of acyclovir depends on activation of the drug to its monophosphate derivative by viral thymidine kinase. Subsequent phosphorylation to the diphosphate and then triphosphate form is mediated selectively by cells infected with herpesvirus. The formation of acyclovir-GTP results in the inhibition of viral DNA polymerase and incorporation of acyclovir-GTP into viral DNA, which terminates viral DNA synthesis. The drug has a greater affinity for viral (versus host) thymidine synthetase. Antiviral activity of acyclovir is limited essentially to herpesviruses. The in vitro activity of acyclovir is 100 times than of vidarabine.
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Ointment or cream ophthalmicum 5% 5 g Aciclovir (INN)
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Aciclovir Vials (fl.) 250 mg i.v. In herpes simplex encefalitis: 10–12.5 mg/kg/8 h i.v. inf. 10 days
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Ganciclovir Ganciclovir is structurally similar to acyclovir. Its spectrum includes herpesvirus, with particular efficacy against cytomegalovirus. Resistance most commonly reflects point mutations or deletions in viral DNA, resulting in reduced formation of viral phosphotransferase. The primary ARs is myelosuppression, with neutropenia occurring in up to 40% and thrombocytopenia in 5–20% of patients. Myelosuppression more commonly occurs with i.v. administration and is generally reversible by 1 week after discontinuation of therapy. Therapeutic use of ganciclovir includes cytomegalovirus retinitis, particularly in humans with AIDS. Ganciclovir is also used for treatment of any infection or prevention of infection (particularly in transplant recipients) associated with cytomegalovirus.
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4. Antiretroviral Drugs Indications: AIDS a) Nucleoside analogues (prodrugs – DNA polymerase inhibitors) Abacavir, Didanozine, Inosine (?) Lamivudine, Stavudine, Zalcitabine Zidovudine (AZT)
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Blood Blood products Sexual secretions HIV infections
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The HIV lifecycle
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Retrovir® caps. 100 mg Zidovudine analogue of thymidine AZT (azidothymidine - USA)
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AZT AZT-MP AZT-TP (-) Viral DNA polymerase MP - monophosphate TP - 3-phosphate ...
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Bone marrow suppression (anaemia in 15%) vomiting, fatigue, headache, insomnia Unwanted reactions
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Zalcitabine Oral bioavailabilty 86% Urinary excretion 70%
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Unwanted reactions peripheral neuropathies in 23% of patients stomatitis aftosa skin rash myopathy
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CombivirТМ – Lamivudine – Zidovudine Trizivir™ – Abacavir – Lamivudine – Zidovudine
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Inosine Inosine (Isoprinosine) is a nucleoside analog which can inhibit cytopathic effects of several viruses in culture. The mechanism of antiviral activity appears to involve specific suppression of viral mRNA. Inosine does not appear to be as efficacious as several antimetabolite antiviral compounds. Inosine can also induce T-cell differentiation similar to that induced by thymic hormones, apparently by augmenting RNA synthesis. Thus Inosine may be more useful as an immunostimulant in immunodeficient patients.
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b) Non-nucleoside analogues used in AIDS: Еfavirenz Nevirapine
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c) HIV-protease inhibitors Amprenavir, Indinavir, Nelfinavir, Ritonavir They prevent cleavage of protein precursors essential for HIV infection of new cells and viral replication.
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Indinavir Ritonavir
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ENFUVIRITIDE (Fuzeon®) – s.c. e) Integrase inhibitors – act on the gene level RALTEGRAVIR d) Drugs, inhibiting HIV with target membrane of human cells
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g) Infective complications of HIV-infections Pneumocystis carinii pneumonia high dose co-trimoxazole (21 days i.v./p.o. is first-line standard therapy Oropharyngeal candidiasis fluconazole (14 days p.o.) Tbc: M. avium complex (with Rifabutin)
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Feline Immunodeficiency Virus (FIV)
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FIV can attack the immune system of cats, much like the HIV can attack the immune system of human beings. FIV infects many cell types in its host, including CD4+ and CD8+ T lymphocytes, B lymphocytes, and macrophages. FIV can be tolerated well by cats, but can eventually lead to debilitation of the immune system in its feline hosts by the infection and exhaustion of T-helper (CD4+) cells. FIV and HIV are both lentiviruses; however, neither can infect the other's usual host: humans cannot be infected by FIV nor can cats be infected by HIV. FIV is transmitted primarily by way of saliva and blood throwgh bite wounds during territorial battles between males. Cats housed exclusively indoors are much less likely to be infected.
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5. HPV vaccines: SILGARD®: 0, 2, and 6 month i.m. (from 9 to 26 years old) CERVARIX® Cervarix® HPV
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HPV vaccines: SILGARD®: 0, 2, and 6 month i.m. (from 9 to 26 years old) CERVARIX® Cervarix® HPV may causes cancer…
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Prof. G. Gorchev, MD, DSc, oncogynecologist, Medical University – Pleven