Medical University of Sofia Faculty of Medicine Department

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)

QUINOLONES (inhibitors of DNA gyrase, resp. inhibitors of topomerases) • Nalidixic acid and its derivatives • Fluoroquinolones

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 thirdline oral treatment for Gram (-) urinary tract infections.

Gr (—): E. coli Salmonella Shigella P. aeruginosa • Nalidixic acid ® (Nelidix ) ® • Gramurin

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 -fluoroquinolones (or fluoroquinolones)

Bactericidal effect • Gr (+): topoisomerase IV • Gr (–): topoisomerase II (DNA gyrase) Ciprofloxacin

Bacterial DNA topoisomerase II and IV) (- ) Fluoroquinolones

• Bactericidal effect; very broad antibacterial sp • High activity against P. aeruginosa, Salmonella, Shigella, Neisseria Campylobacter, and Chlamydia • Beta-lactamase stability • Limited activity against streptococci

>70% F (p. o. ) DD/2 applications Good intracellular distribution 50– 80%/24 h urinary excretion

INDICATIONS (infections): • urinary • respiratory • GIT • genital (incl. gonorrhoea) • septicemia • ophthalmic (topically)

CIPROFLOXACIN ® • Ciprobay tabl. 500 mg/12 h (5– 10 days)

• Co-administration of ciprof xacin and theophylline cau eleveted plasma theophylli concentrations due to inhib tion of cytochrome P 450. • Both drugs are epileptogen

Moxifloxacin Tabl. 400 mg NB: 400 mg once daily

• Gatifloxacin • Levofloxacin (Tavanic®) – S-isomer of ofloxacin 500 mg/24 h p. o. 10 days • Norfloxacin • Lomefloxacin • Ofloxacin • Pefloxacin • Trovafloxacin, etc.

Fluoroquinolones Adapted from Bennett and Brown (2003)

ADVERSE EFFECTS • convulsions (in patients with epilepsy or comm • 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.

The mechanism of cartilage damage may be rela to chelation of magnesium in joints. Lesions have been documented in dogs given five times the re mended dose and occur within 1– 2 days of begin administration. It is recommended that fluoroquin lones be avoided in large breed dogs up to 18 m of age (12 months for medium breeds, 9 months small breeds). If a fluoroquinolone must be used because there is no suitable alternative, strict ex restriction (especially for large breed dogs) and u of chondroprotectives are advised.

Contraindications • pregnancy • old people • epilepsy • meningitis • children

OXIQUINOLONES They block RNA polymerase. TILBROQUINOL – enteroantiseptic with antiamoebic activity NITROXOLIN – broad spectrum uroantiseptic (p. o. )

NITROFURANS – broad spectrum antibacterial agents 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 Co. A synthes

Furazolidone

Nitrofurantoin ® (Furadantin ):

ANTIVIRAL AGENTS Viruses are composed of a core genome consisting o double-stranded or single-stranded DNA or RNA surr by a protein shell known as a capsid. Some viruses a further surrounded by a lipoprotein membrane or env Both the capsid and lipoprotein membrane may be a Viruses cannot replicate independently and must usu host’s metabolic machinery to replicate. Therefore vir are obligate intracellular parasites. The host’s pathwa energy generation, protein synthesis, and DNA or RN replication provide the virus with the means of viral re For some viruses, replication is initiated by viral enzy

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 subsequ infection), or the cell may be transformed such that hos control of cell growth is lost to viral activities. Viral replication occurs in five or six sequential step • cell entry, including host cell attachment, generally thr specific receptors, followed by host cell penetration; • disassembly or uncoating resulting in release of viral g • transcription of viral genome (or viral messenger RNA which is dependent on virus-specified enzyme; • translation of regulatory (early) or structural (late) vira • post-translation modifications (incl. proteolytic cleavag • assembly of virion components; and release of the vir generally by budding or cell lysis.

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. , penetratio intracellular stages (i. e. , replication, assembly, and 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 b viral-induced immunosuppression, pharmacologic immunomodulation (resp. immunostimulation) may help prevent viral penetration especially during the stages of infection, which are often missed because lack of clinical signs.

(Ag)

Cyclic amines inhibit influenza-A DNA replication. Rimantadine is from two to 8 -fold times more active than Amantadine.

Indications: prophylaxis and treatment of influenza A viral infection: А (H 5 N 1) (Flumadine ): • Rimantadine p. o. • Vitamin C • Esberitox N (immunostimulant)

Rimantadine adverse effects: • orthostatic hypotension • dizziness, confusion • headache, insomnia • vomiting, xerostomia • urinary retention

b) Neuraminidase inhibitors (active against virus A and B Zanamivir: • inhibits neuraminidase and prevents replication of influenza-A and B-virus • application: per inhalationem

Oseltamivir ® – Tamiflu against virus А, B A (H 5 N 1): bird or avian flu (influenza) – (2 s/78 °C) A (H 1 N 1): swine or pig flu (influenza) Treatment: 75 mg/12 h 5 days Prophylaxis: 75 mg/24 h about 30 days

Pig flu: Bird flu:

Symptomatic therapy

Paracetamol Metamizole

Please, give me something against influenz

Influenza Virus Vaccines (PRC Against virus А (H 5 N 1) Against virus – A (H 1 N 1) : • Fluarix ® • Celvapan • Fluogen ® • Focetria • Inflexal V ® • Pandemrix • Influvac ® • Prepandrix • Invivac • Vaxigrip • Vacciflu 0, 5 ml i. m. /deep s. c.

It is time to get vaccinated against influenza virus A (H 1 N 1)

, , Good humor helps enormously both in the study and practice of William Osler (1849 -1919) medicine. ”

2. INTERFERONS (IFNs) They are cytokines (mediators of cell growth and function). They are glycoproteins secreted by cells infected with viruses or foreign DNA.

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

• IFN gamma has significant immunoregulatory function. • Interferon alfa-2 b (Intron ) is used in chronic hepatitis, Kaposi’s sarcoma in AIDS, multiple myeloma, etc. • Interferon beta-1 b (Betaferon ) used s. c. in multiple sclerosis (MS)

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

3. Antiherpetic Drugs H. simplex They are prodrugs nucleoside analogues.

After phosphorylation nucleoside analogs conv into active metabolites, which inhibit viral DNA polymerase (reverse transcriptase) and block viral replication.

Indications: H. simplex and varicella-zoster infections • aciclovir • ganciclovir • valaciclovir • brivudine

Treatment of postherpetic neuralgi ●Anticonvulsants Gabapentin, Pregabalin ●Antidepressants Nortriptyline, Duloxetine Herpes zoster infection ●Opioid painkillers Tramadol

Acyclovir and Valacyclovir Acyclovir is is structurally similar to guanosine (purine nucleoside). Valacyclovir is an L-valyl ester prodrug of Efficacy of acyclovir depends on activation of the drug t monophosphate derivative by viral thymidine kinase. Su phosphorylation to the diphosphate and then triphospha mediated selectively by cells infected with herpesvirus. The formation of acyclovir-GTP results in the inhibition DNA polymerase and incorporation of acyclovir-GTP in DNA, which terminates viral DNA synthesis. The drug h greater affinity for viral (versus host) thymidine syntheta Antiviral activity of acyclovir is limited essentially to herpesviruses. The in vitro activity of acyclovir is 100 tim than of vidarabine.

Aciclovir (INN) Ointment or cream ophthalmicum 5% 5 g

Aciclovir Vials (fl. ) 250 mg i. v. In herpes simplex encefalitis: 10– 12. 5 mg/kg/8 h i. v. inf. 10 days

Ganciclovir is structurally similar to acyclovir. Its spectrum herpesvirus, with particular efficacy against cytomegalovi Resistance most commonly reflects point mutations or de in viral DNA, resulting in reduced formation of viral phosphotransferase. The primary ARs is myelosuppressi with neutropenia occurring in up to 40% and thrombocyto 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.

4. Antiretroviral Drugs Indications: AIDS a) Nucleoside analogues (prodrugs – DNA polymerase inhibitors) • Abacavir, Didanozine, Inosine (? ) • Lamivudine, Stavudine, Zalcitabin • Zidovudine (AZT)

HIV infections • Blood products • Sexual secretions

The HIV lifecycle

Zidovudine analogue of thymidine AZT (azidothymidine - USA) ® • Retrovir caps. 100 mg

AZT-MP . . . AZT-TP MP - monophosphate TP - 3 -phosphate AZT (-) Viral DNA polymeras

Unwanted reactions Bone marrow suppression (anaemia in 15%) vomiting, fatigue, headache, insomnia

Zalcitabine • Oral bioavailabilty 86% • Urinary excretion 70%

Unwanted reactions • peripheral neuropathies in 23% of patients • stomatitis aftosa • skin rash • myopathy

ТМ Combivir – Lamivudine – Zidovudine Trizivir™ – Abacavir – Lamivudine – Zidovudine

Inosine (Isoprinosine) is a nucleoside analog which ca cytopathic effects of several viruses in culture. The me of antiviral activity appears to involve specific suppres viral m. RNA. Inosine does not appear to be as efficacio several antimetabolite antiviral compounds. Inosine ca induce T-cell differentiation similar to that induced by hormones, apparently by augmenting RNA synthesis. Thus Inosine may be more useful as an immunostimulant in immunodeficient patients.

b) Non-nucleoside analogues used in AIDS: • Еfavirenz • Nevirapine

c) HIV-protease inhibitors They prevent cleavage of protein precursors essential for HIV infection of new cells and viral replication. • Amprenavir, Indinavir, Nelfinavir, Ritonavir

Indinavir Ritonavir

d) Drugs, inhibiting HIV with target membrane of human cells ENFUVIRITIDE (Fuzeon®) – s. c. e) Integrase inhibitors – act on the gene lev RALTEGRAVIR

g) Infective complication of HIV-infections • Pneumocystis carinii pneumonia high dose co-trimoxazole (21 days i. v. is first-line standard therapy • Oropharyngeal candidiasis fluconazole (14 days p. o. ) • Tbc: M. avium complex (with Rifab

Feline Immunodeficiency Virus (FIV)

FIV can attack the immune system of cats, much like HIV can attack the immune system of human beings. FIV infects many cell types in its host, including CD 4+ and CD 8+ T lymphocytes, B lymphocytes, and macro FIV can be tolerated well by cats, but can eventually l debilitation of the immune system in its feline hosts by infection and exhaustion of T-helper (CD 4+) cells. FIV are both lentiviruses; however, neither can infect the usual host: humans cannot be infected by FIV nor can infected by HIV. FIV is transmitted primarily by way o and blood throwgh bite wounds during territorial battle between males. Cats housed exclusively indoors are less likely to be infected.

5. HPV vaccines: SILGARD®: 0, 2, and 6 month i. m. (from 9 to 26 years old) CERVARIX® HPV Cervarix®

HPV vaccines: SILGARD®: 0, 2, and 6 month i. m. (from 9 to 26 years old) CERVARIX® HPV may causes cance Cervarix®

Prof. G. Gorchev, MD, DSc, oncogynecologist, Medical University – Pleven