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Flashcards in Antivirals Deck (19):
1

what is the only way viruses can exist?

viruses can only exist as OBLIGATE INTRACELLULAR PARASITES

2

describe a viruses metabolism?

Viruses are metabolically inert

3

what are the major classes of viruses?

RNA viruses
-orthomyxoviruses (influenza)
-paramyxoviruses (measkes, mumps)
-rubella virus
-picornaviruses (colds, poliomyelitis, meningitis)
-retrovirus (HIV, T-cell leukaemia)
-Arboviruses (yellow fever)

DNA viruses
-Pox viruses (small pox)
-Herpes viruses (chicken pox, (varicella zoster, HHV-3), shingles, cols sores glandular fever (EBV/HHV-4))
-adenoviruses (tonsilitis, conjunctivitis)
-Papilloma virus (warts)

4

List the current drugs licensed for HIV treatment?

-Nucleoside reverse transcriptase inhibitors (NRTIs)
-Non-Nucleoside Reverse transcriptase inhibitors (NNRTIs)
-protease inhibitors
-Fusion inhibitors
-entry inhibitors
-HIV integrase strand transfer inhibitors

5

discuss HIV treatment?

-Treatment aims to reduce viral load as much as possible and for as long as possible
-drugs are toxic and expensive
-HAART: highly active anti-retroviral therapy used
1)combination of at least 3 drugs used
2)enhance efficacy of a single agent
3)minimise toxicicty by reducing individual doses
4)drug resistance is prevented or delayed
-BHIVA guidelines
1)when to start treatment
2)what drugs to start with
3)resistance testing

6

Discuss when to start HIV treatment, switching therapy and salvage therapy?

when to start:
-before immune system is irreversibly damaged
-BHIVA guidelines- CD4 <350 cells/mm3 (primary HIV infection)
-OR patients with diagnosis of AIDS or with clinical symptoms of underlying immunosuppresion

switching therapy:
-when viral load becomes detectable

salvage therapy:
-used in patients who have failed at least 2 anti-retroviral regimens

7

what are the 2 types of reverse transcriptase inhibitors?

-Nucleoside reverse transcriptase inhibitors (NRTI)
-Non-nucleoside reverse transcriptase inhibitors (NNRTI)

8

define NRTIs MOA?

-Act as competitive substrates for reverse transcriptase
-become incorporated into proviral DNA
-Malformed DNA transcript containing nucleoside analogues cannot be integrated into the host cell genome

9

Name nucleoside analogue drugs acting on reverse transcriptase?

-zidovudine/Retrovir (AZT,ZDV)
-didanosine/videx, videx EC (ddI)
-zalcitabine/HIVID (ddC)
-stavudine/zerit (d4T)
-Iamivudine/Epivir (3TC)
-abacavir/Ziagen (ABC)

10

What is the BHIVA guideline 3 point rationale?

treatment aim: prevent the mortality and morbidity associated with chronic HIV infection whilst minimising drug toxicity

rationale for treating with antiretroviral drugs in primary HIV infections:
1) preservation of specific anti-HIV immune responses that would otherwise lost, and which are associated with long-term non-progression in untreated individuals
2) Reduction in morbidity associated with high viraemia and CD4 depletion during acute infection
3) reduction in risk of onward transmission of HIV

11

Discuss NRTI Zidovine/retrovir (AZT, ZDV)?

Zidovudine/Retrovir (AZT, ZDV)
-thymidine analogue
-first HIV drug approved , first NRTI
-treatment of HIV when CD4 cell count is < 500/mm3 OR symptomatic
-also approved for use in HIV infected pregnant women in 2nd and 3rd trimesters, along with IV ZDV during labour and delivery, and ZDV syrup to newborn for 6 weeks
-toxicity issues neutropenia, anaemia, leucopoenia

12

Discuss the MOA of NNRTI

Non-nucleoside reverse transcriptase inhibitors
-act at the same point in HIV replication as NRTIs
-Bind to hydrophobic pocket in RT when the enzyme is complexed to DNA
-Good antiviral activity in vitro but associated with rapid development of resistance.

13

Name 2 NNRTI therapies currently in use?

-nevirapine
-Efavirenz

14

Discuss protease MOA and then explain Protease inhibitors MOA?

proteases (peptide bond hydrolases)
-catalyse the hydrolysis of peptide bonds in protein/peptide substrates
-highly specific due to geometry of active site
-cleave after certain sequences of AA
-expression and activity are highly regulated

HIV Protease inhibitors
-prevent cleavage of gag and gag-pol protein precursors (should be cleaved at 9 discreet points to yield functional proteins)
-2 GagPol polyproteins must dimerise to yield active HIV-1 Protease
-HIV-1 protease is a novel aspartyl protease with a unique cleavage specificity, it cleaves peptide bonds after phenylalanine/tyrosine and proline: no mammalian protease exhibits this specificity which makes this a unique target!

15

Name HIV protease inhibitors?

1)ritonavir/Norvvir
2)Indinavir/crixivan
3)saquinavir/Invirase,Fortovase
4)nelfinavir/viracept
5)amprenavir/agenerase
6)Iopinavir/ritonavir(low dose),kaletra

16

Discuss the use of protease inhibitors?

-usually in combination with other anti-retroviral drugs
-give rise to serious side effects as metabolised by cytochrome P450: drug-drug interactions such as ketoconazole, low doses of ritonavir boost activity of other protease inhibitors.
risk of lipodystrophy syndrome (fat redistribution, insulin resistance, dyslipidaemia)
-expensive

17

Discuss the use of Fusion inhibtors including MOA?

-Enfuviritde
-biomimetic peptide
-Binds viral gp41 surface protein
-Prevents HIV from binding to the surface of CD4 lymphocytes
-Given by SC injection, 90mg bd
-expensive
-useful when patients unresponsive to other anti-retroviral therapies and for salvage therapy

18

Discuss the use of entry inhibitors and MOA?

-Maraviroc
-Potent, orally bioavailable
-blocks binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry
-300mg bd

19

Discuss the use of integrase inhibitors and MOA?

-raltegravir (1st in class)
-target viral enzyme integrase which catalyses an essential process in the replication cycle of HIV- insertion of HIV-1 proviral DNA into hosts cellular genome
-good activity against broad panel of HIV isolates, isolates resistant to: PIs,NRTIs and NNRTIs