5B: Antivirals Flashcards
1
Q
Antiviral targets
A
- Viral replication cycle is reliant on host cellular function so limited unique targets & increased toxicity
- Ideally unique viral targets not present in mammalian cells, & usefully therapeutic with minimal mammalian damage
Unique viral targets include:
- Viral penetration into host cells
- Replication of viral genome
- Translation of viral mRNA
- Assembly of viral components
- Release of new viruses from host cells
2
Q
Virology - mechanism
A
- Attachment
- Entry
- Replication & gene expression
- Assembly
- Release
Prevention is only with vaccination
3
Q
Antiviral PK/PD
A
- More (or less) complex than for bacteria or fungi
- In vitro testing involves complex tissue culture system
- Potency of antivirals is determined using 50% inhibitory dose (EC or IC50: Dose required to inhibit the growth of cell culture by 50%)
- MIC is conceptually similar to an EC90
- Limited to no studies for most drugs correlating efficacy with specific PKPD parameters
4
Q
Herpes virus
A
- HSV1 & 2, VSV, CMV, EBV
- Large core containing double stranded DNA genome in a capsid, protein coat & glycoprotein structure
- (Val)aciclovir, (val)ganciclovir, cidofovir, foscarnet
5
Q
- (Val)aciclovir
A
- Nucleotide analogue of guanine
- Must become tri-phosphorylated to become active
+ Largely (40 – 100x more) occurs in infected cells due to viral enzyme TK for step 1
+ Cellular kinases for step 2 & 3 - This tri-P form persists within cells at high concentrations as it cannot cross cellular membranes
- Inhibits DNA polymerase in HSV-1, HSV-2 & VZV – cellular DNA polymerase is inhibit to a significantly lower degree
- Inhibition of DNA polymerase occurs by stopping DNA synthesis as the chain cannot become elongated & the enzyme becomes bound
- Aciclovir has poor (20%) bioavailability (& topical penetration) & necessitates multiple (up to 5X) daily dosing
- Valaciclovir is a L-valyl ester that is rapidly (95%) converted to acyclovir following oral administration (BA 50%) (luminal, intestinal & hepatic esterases)
+ Has uptake via dipeptide transporter that aciclovir does not - Different dosing regimes for IV/PO & clinical condition
- ADRs include nephrotoxicity (precipitation of drug in nephron) which can be prevented by a slow infusion & hydration & reversible neurotoxicity
6
Q
- (Val)fanciclovir
A
- Also a guanine analogue requiring tri-phosphorylation
- Initial phosphorylation is achieved by a CMV UL97 gene encoded protein kinase
+ In HSV & VZV this step can be achieved by TK - High intracellular levels in infected cells 10-100x
- 35-50x more selective for viral polymerase than cellular polymerase
- Valganciclovir is also a L-valyl ester of ganciclovir with similar gains as valaciclovir
7
Q
- Cidofovir
A
- Nucleotide analogue of cytosine but already has a highly stable phosphate group
+ Still needs to be triphosphorylated to work but initial step is overcome so broad spectrum antiviral - As phosphonate needs active transport into cells but then has a very long intracellular t1/2 of up to 65 hours
- Competitive inhibition of many viral DNA polymerase with high affinity compared to cellular polymerase (80x for CMV & 600x for others)
- Poorly bioavailable so only used IV
- ADRs – nephrotoxicity 25%: Uptake by renal proximal tubules exceeds efflux into lumen causing accumulation (probenecid reduces renal clearance of cidofovir by inhibiting tubular secretion & decreases nephrotoxicity)
+ No haematological toxicity
+ Carcinogenic – handling precautions
8
Q
- Foscarnet
A
- Analogue of inorganic pyrophosphate
- Inhibits DNA polymerase by binding to a site where pyrophosphate has been removed in DNA chain stabilising the enzyme & chain in place blocking further production
- Very broadly antiviral including some effect on HIV, Hep B & Influenza (not clinically useful tho)
- Poor bioavailability (<10%)
- ADRs – nephrotoxicity 25% (crystallisation without hydration)
+ Electrolyte changes (Ca2+, Mg2+, PO4-)
+ Rarely haematological toxicity but anaemia more common
9
Q
Viral hepatitis
A
Hepatitis A, B, C, D & E
- A & B vaccinated
- A, B & C most common
- Different kinds of viruses & clinical syndromes
- Ideally all oral drug regimens for a chronic disease needing suppression or prolonged treatment
Hep B – DNA virus replicating with reverse transcriptase
- Treated with lamivudine, tenofovir, adefovir, entercavir
Hep C – RNA virus single stranded similar to flavivirus e.g. dengue or zika virus
- Treated with glecaprevir & pilbrentasvir, sofoxbuvir & ledipasvir
10
Q
NRTIs (for Hep B) (Lamivudine, tenofovir, adefovir, entecavi)
A
Nucleoside or nucleotide analogies inhibiting reverse transcriptase that terminates chain when incorporated:
- Lamivudine =cytidine
- Tenofovir = adenosine
- Entecavir = guanosine
- Adefovir = adenosine
- Entecavir only useful for Hep B, resistance rapidly develops when treating HIV
- Adefovir IC90 doses for HIV have dose limiting nephrotoxicity
Few ADRs seen but often some GI upset & treatment specific e.g. tenofovir & chronic renal toxicity & osteopenia
11
Q
Other direct acting antivirals (DAAs for Hep C) (Sofosbuvir, pibrentasvir, glecaprevir, ledipasvir)
A
- Sofosbuvir & pibrentasvir inhibit RNA dependent NS5B RNA polymerase required for coping HCV genome & transcribing mRNA
- Glecaprevir targets NS3/4A protease involved in post translational processing of HCV proteins
- Ledipasvir inhibits NS5A which has an unclear enzymatic role but interactions with other proteins in HCV working as a regulator of host cell function
- Relatively new treatments for Hep C with very high success rates of ‘cure’ (95%)
12
Q
Interferon
A
- Naturally occurring proteins with a wide variety of effects
- Interferon has been used to treat a variety of viral infections but predominately Hep C & less Hep B
- Gene inserted into E.coli to express interferon alpha
+ Alpha 2a & 2b are 1 amino acid different - Pegylated interferon (PEG-) by attaching polyethylene glycol which has low immunogenicity & toxicity & extends t1/2 through slowing degradation
+ Dosing changes from daily to weekly SC injections - Indirect antiviral activity by inducing/activating cytokine response pathway including up-regulated NK & T cells
- Possible direct activity on viral proteins & DNA production
- Almost all patients will have ADRs inc fatigue (65%), flu like illness (65%), anxiety (45%), depression (30%), neutropenia (30%)
13
Q
Ribarvirin
A
Very broad spectrum antiviral including Hep C, RSV, Measles, Lassa virus, influenza, herpes viruses
Analogue of guanosine that is tri-phosphorylated intracellularly but has multiple proposed actions:
- Direct inhibition of RNA polymerase
- RNA mutagenic effect
- Enhances T helper cell cytokine response
- Inhibits IMPDH enzyme that synthesises guanosine triphosphate promoting inclusion of ribavirin
ADRs – LFT changes & anaemia 15-20%
- Ribavirin has an active uptake into enterocytes & accumulation due to lack of phosphatases – is reversible on cessation
14
Q
HIV - mechanism
A
- Binding
- Fusion
- Reverse transcription
- DNA into nucleus
- Integration
- Viral DNA maintained
- Replication
- Protein production
- gp 120 produce on surface
- Assembly & budding
- Protease cleaving proteins
- Mature virus
15
Q
HIV - HAART
A
1987 – 1993: NRTI monotherapy 1993 – 1996: Dual NRTI 1996 - : HAART = Dural NRTI + PI 1998 - : PI -> NNRTI 2006 - : Single tablet combination (Atripla) 2011 - : Treatment as prevention 2012 - : PrEP
Multiple agents are now standard of care to reduce resistance development & increased efficacy of viral suppression
