Antivirals Flashcards
1
Q
**Antiviral nucleosides **- mechanism of action
A
- Mimic natural nucleosides - deoxy derivatives of Adenosine, Cysteine, Thymidine and Guanine
- Need to be phosphorylated to be substrate for DNA polymerase enzymes
- Virion polymerase is less specific and doesn’t recognise the false nucleotides –> they are incorporated into viral DNA –> nonsense genes
- Also act as competitive inhibitors and DNA chain terminators
- Thus antiviral is targeted to affected cells and is not incorporated into human DNA
2
Q
**Aciclovir **- mechanism of action
A
- Nucleoside analogue of guanosine
- Competitive inhibitor of Viral DNA polymerase - an obligate DNA chain terminator
- Requires initial monophosphorylation with viral thymidine kinase
- Incorporated as aciclovir triphosphate into viral DNA by viral DNA polymerase
- Resistance associated with both thymidine kinase deficient and DNA polymerase mutants
3
Q
**Aciclovir **- pharmacokinetics
A
- Limited oral bioavailability –> 5-10%
- Must be given 5x daily for 5-7 days
- Treatment must start within 24-72 hours
- IV therapy substatially better at disaese control in all compartments
- Given 8 hourly
- Topical therapy (creams) of limited value except eye drops used in opthalmic herpes and opthalmic zoster
- Very safe. Reduced dose used in patients with renal dysfunction as accumulation can –> encephalopathy
4
Q
**Aciclovir **- indications
A
- Effective against: HSV types 1 and 2, VZV
- Inhibits CMV and EBV but not clinically useful
- Main indications are:
- Severe primary bilabial and genital herpes
- Opthalmic HSV and VZV
- Eczema herpeticum
- Herpes zoster
- Chickenpox
- Herpes encephalitis
- Prevention/treatment of disseminated herpetic disease in the immunocompromised
5
Q
**Valaciclovir **- anti-herpes prodrug
A
- Valine ester of acyclovir
- Improved bioavailability of 55%
- Orally absorped - delivers aciclovir after deamination in the liver
- Used as an alternative to aciclovir for similar indications - reduced dosing schedule of 2/3 times day vs. 5
- Similar safety profile to aciclovir
- Used for better blood levels of aciclovir after GI disturbance seen in immunocompromised patients or when better antiviral control is required
6
Q
**Famciclovir **- anti-herpes prodrug
A
- Di-acetyl ester of penciclovir
- Penciclovir = a short chain terminator allowing limited incorporation before DNA chain dissociation
- 77% bioavailability
- Delivers penciclovir after deacetylation in the liver
- Used in patients >50 years with herpes zoster to significantly reduce the duration of acute and chronic pain including post-herpetic neuralgia
- Once daily dosing of 750mgs for 7 days
- Similar activity and safety profile to aciclovir
7
Q
Ganciclovir - anti-CMV drug
A
- Available as IV oral and prodrug formulation (valganciclovir)
- Nucleoside analogue (guanosine)
- Competitor for guanosine and DNA polymerase inhibitor
- Short chain terminator allowing limited incorporation before DNA chain dissociation
- Activated by monophosphorylation by viral kinase UL97
- Resistance (UL97 and polymerase mutants) produced after polonged therapy of >3 months in the immunocompromised
- Usefulness often limited by tendancy to induce neutropaenia
8
Q
**Foscarnet **- anti-CMV drug
A
- Available in IV formation
- Doesn’t require phosphorylation and therefore useful in UL97 resistance after ganciclovir therapy
- DNA polymerase blocker - not nucleoside competitor
- Limited usefullness due to SEs of renal toxicity and biochemical disturbances
9
Q
**Anti-CMV antivirals **- indications
A
- Ganciclovir and foscarnet used in similar situations
- Very potent
- Renally excreted - dose must be reduced in renal failure
- Indications
- CMV infection and disease in immunocompromised
- haemato-oncology
- HIV
- CMV pneumonitis, retinitis, colitis, hepatitis, encephalitis
- Used in neonates with congenital infection to stop progression of hearing loss and other associated neurology
- CMV infection and disease in immunocompromised
10
Q
Nucleoside reverse transcriptase inhibitors (NRTIs) + Nucleotide reverse transciptase inhibitors (phosphorylated NRTIs) - HIV antivirals
A
- Reverse transcriptase inhibitors and obligate chain terminators
- In HAART used as the backbone supplemented with other antivirals e.g. NNRTIs, PI or integrase/entry inhibitors
- Drugs:
- Zidovudine (AZT)
- Lamivudine (3TC)
- Emtricitabine (FTC)
- Abacavir (ABC)
- Tenofovir (TDF)
- Stavudine (d4T)
- Didanosine (ddI)
11
Q
Non-reverse transcriptase inhibitors (NNRTIs) - HIV antivirals
A
- Act as reverse transcriptase blocking agents but not as competitors
- Less potent than NRTIs
- Resistance more likely over time (1-3 years)
- Always used in combination with a NRTI/pNRTI agent
- Examples:
- Nevirapine (NVP)
- Efavirenz (EFV)
- Delaviridine (DLV)
- Relpivirine (RPV)
- Etravirine (ETV)
12
Q
Protease Inhibitors (PIs) - HIV antivirals
A
- Act as protease blockers thereby preventing maturation of the HIV virion following release from the cell
- Very potent when virus is susceptible but resistance common when unprotected
- Therefore always used with a NRTI/pNRTI agent
- Metabolised by the cytochrome p450 pathway
- p450 inducer/inhibitor drug interactions must be avoided
- Dual PI’s use low dose ritonavir to inhibit cytochrome p450 –< higher leverls of main PI
- Examples:
- Ritonavir (RTV)
- Nelfinavir (NFV)
- Tipranavir (TPV)
- Lopinavir (LPV)
- Darunavir (DRV)
- Atazanavir (ATV)
- Dual PI - lopinavir/rionavir (rLPV)
13
Q
**HAART **- Highly active anti-retroviral therapy
A
- Combination therapy of 2-5 classes of HIV antivirals
- NRTI e.g. tenfovir/entricitabine
- Phosphorylated NRTIS
- Non-nucloside reverse transcriptase inhibitor (NNRTI) e.g. nefirapine/efavirenz
- Protease inhibitor e.g. nelfinavir
- Fusion inhibitor e.g. enfuvirtide
- Co-receptor (CCR5) inhibitor e.g. maravir
- For starting therapy usually:
- Tenfovir/entricitabine (NRTIs) plus efavirenz (NNRTI) or atazanavir/ritonavir (PIs) or raltegravir (Integrase inhibitor)
- To overcome primary resistance:
- Switch NNRTI to a PI
- Switch current PI for newer one e.g. darunavir/ritonavir
14
Q
HAART - Goals
A
- Goal is not cure but to suppress HIV viral load and improve CD4 count to improve quality of life, avoid opportunistic infections and lower transmission.
- Initiation of therapy is delayed until the CD4 cell count is <350/ml blood
- For most patients with wild-type naiive HIV - Viral load will decrease from >500,000 copies to undetectable (<50 copies) with a signifcant rise in CD4 count within 6 weeks of beginning therapy
- Maintenance of an undetectable viral load requires >80% of the dose with >80% adherence >80% of the time.
- Adherence issues are usually caused be adverse effects and the tolerability of the drug combination
15
Q
**HAART **- Failure and resistance
A
- Failure occurs in 10% at one year for those on current 1st line treatments
- Treatment failure is defined as not maintaining an undetectable viral load of <50 copies/ml of blood
- Viral resistance - revealed by a fall in CD4 count and an significant (>1 log) increase in VL whilst on therapy
- Choice of second line drug combination determined by:
- Review of drug adherence
- Drug therapeutic monitoring to measure absorbance
- Sequencing of reverse transcriptase and protease genes to determine genotypic resistance
- __More than one drug is changed at once, often the entire regimen
