Microbiology Antiviral therapy Flashcards
(108 cards)
1
Q
Aciclovir:
Type of Drug
A
Nucleoside analogue of guanosine.
2
Q
Aciclovir: MOA
A
Competitive inhibitor of Viral DNA polymerase, an obligate DNA chain terminator.
3
Q
Aciclovir: Process
A
- Preferentially taken up by virally infected cells
- Monophosphorylated by virally encoded thymidine kinases
- 2nd and 3rd phosphate added by cellular kinases
- ACV-TP is the active moiety
- Competitive inhibitor of viral DNA polymerase
- Cellular DNA polymerases much les susceptible to inhibition
- Leads to viral DNA chain termination
4
Q
Aciclovir: Safety
A
• Remarkedly safe antiviral
5
Q
Aciclovir: Effective against
A
• HSV types 1 & 2, and VZV infections inhibitis CMV, and EBV but not clinically useful.
6
Q
Aciclovir: Main indications are
A
- Severe primary labial and genital herpes
- Ophthalmic HSV and VZV
- Eczema herpeticum
- Herpes zoster
- Chickenpox – adults require more aggressive
- Herpes encephalitis
- Prevention and treatment of disseminated herpetic disease in the immunocomprimised patient
7
Q
Aciclovir: Problems
A
• Limited oral bioavailability – 25% • Treatment needs to start within 24-72 hours • Intravenous • Topical therapy (creams) of limited value with exception of eye drops used in ophthalmic herpes ad ophthalmic zoster. • Toxicities → Headache, nausea →Renal → Neurological (encephalopathic)
8
Q
Aciclovir: Oral dosage
A
• Requires to be given 5x daily for 5-7 days.
9
Q
Aciclovir: Iv dosage
A
• Intravenous therapy substantially better at disease control in all compartments. Given 8 hourly
10
Q
Aciclovir: Renal concern
A
• Safe. Dose reduction with renal dysfunction
11
Q
Aciclovir Resistance
A
• Can be problematic in continuous use or in immunocomprimised
• Mediated by mutations in viral thymidine kinae and/or viral DNA polymerase genes
→TK-deficienct and TK altered virus can be produced
• Clinically significant infections can be caused by drug resistant HSV and VZV
12
Q
Anti-herpes Prodrugs
A
• Better absorption – both drugs improve bioavailability by 55% and 77% respectively for oral abministration
13
Q
Anti-herpes prodrugs example
A
- Valaciclovir
* Famciclovir
14
Q
Anti-cytomegalovirus drugs
A
Ganciclovir
Foscarnet
Cidofovir
15
Q
Ganciclovir
Activity against
A
CMV (10x better than acyclovir)
HSV/VZV (similar acyclovir)
HHV6
16
Q
Ganciclovir dosing
A
I.v.
17
Q
Cidofovir activity against
A
CMV HSV/VZV BKV Adenovirus Papillomavirus
18
Q
Cidofovir dosing
A
Oral version in development
19
Q
Ganciclovir and Foscarnet excretion
A
Renal Failure
20
Q
Ganciclovir and Foscarnet Indications
A
CMV infection and disease in the immunocomprimised-haematology-oncology and HIV patient
CMV pneumonitis retinitis, colitis, hepatitis and encephalitis
21
Q
Ganciclovir and Foscarnet used in the neonate with
A
Congenital infection to stop progression of hearing loss and other associated neurology
22
Q
Ganciclovir MOA
A
- Competes with deoxyguanosine triphosphate similar to acyclovir
- Howevere in CMV, viral-encoded phosphotransferase converts to ganciclovir triphosphate
- Competitive inhibitor of DNA polymerase, unlike acyclovir, ganciclovir contains a 3’-hydroxyl group, allowing for DNA to continue – short chain terminator
23
Q
Ganciclovir Adverse effects
A
- Reversible pancytopaenia (most common)
- Fever
- Rash
- Phlebitis
- Confusion
- Renal dysfunction
- Psychiatric disturbances
- Seizures
24
Q
Valganciclovir spectrum
A
Similar ganciclovir
25
Valganciclovir adverse effects
Similar to ganciclovir
26
(Val) ganciclovir resistance
1. Mutations in the viral protein kinase (UL97)
| 2. Mutations in the viral polymerase gene (UL54)
27
Viral protein kinase (UL97) responsible for and resistance
Responsible for monophosphorylation
| Confers resistance to ganciclovier alone
28
Viral polymerase gene (UL54)
May show cross resistance to similar antivirals
29
Foscarnet activity against
CMV
HSV/ VZV
HHV6
30
Foscarnet dosing
I.V only
31
Foscarnet excretion
Renally
32
Foscarnet Indications
CMV infection and disease in the immunocomprimised-haematology-oncology and HIV patient
CMV pneumonitis retinitis, colitis, hepatitis and encephalitis
33
Foscarnet used in the neonate with
Congenital infection to stop progression of hearing loss and other associated neurology
34
Foscarnet MOA
• Inorganic pyrophosphate analogue – trisodium phosphonoformate hexahydrate
• Does not require thymidine kinase – works on HSV strains deficient of this enzyme
Selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerase (100x cellular) – non-competitive inhibitor
35
Foscarnet resistance
• By alterations to viral DNA polymerase
→ Not caused by thymidine kinase alterations
→ Does not cause cross resistance to ganciclovir or cidofovir
36
Foscarnet adverse effects
* Renal dysfunction (common, can required dialysis)
| * NV, anaemia, CNS disturbance, electrolyte abnormalities, seizures, arrhythmias, neutropenias
37
Cidofovir MOA
• Acyclic nucleoside phosphate derivative (nucleotide analogue)
• Phosphorylation not dependent on viral kinases (TK)
• Selective inhibition of CMV DNA pol
→ Active drug as cidofovir diphosphate
• Incorporation into viral DNA chain results in reduction of the rate of viral DNA synthesis
38
Cidofovir adverse effects
* Nephrotoxicity: nephrotoxicity (dose-limiting), neutropenia, metabolic acidosis
* Must be given with adequate hydration and PO probenecid (protects against
39
PO probenecid combination with cidofovir why
Protects against renal toxicity
40
Cidofovir resistance
* Due to point mutations in viral DNA polymerase
* Can confer resistance to ganciclovir in CMV
* Foscarnet activity not affected by cidofovir resistance
* Still active against UL97 mutations induced by ganciclovir
41
CMV Antivirals – Recent Developments:
Maribavir
Letermovir
Brincidofovir
Leflunomide
42
Maribavir
Direct UL97 kinase gene competitive inhibitor
43
Letermovir
DNA processing gener UL56 inhibitor
44
Brincidofovir
Lipid conjugate of cidofocir – reduced toxicity , oral
45
Leflunomide
Immunosuppressive (!) – late stage viral assembly
46
Interferons → Three classes
* Alpha
* Beta
* Gamma
47
Interferons → Description
* INF – alpha and beta are produced by nearly all cells in response to infection
* INF – gamma only produced by T cells and NK cells
48
Interferons → MOA
• Not directly virucidal or virustic
• Induces changes in the infected or exposed cell to promote resistance to the virus
• Induces several enzyme activities that promote an antiviral state
→ Proteins that inhibit synthesis of RNA
→ Proteins that cleave viral DNA
→ Protein that inhibit mRNA
→ Alterations of the clel membrane that inhibit the release of replicated virions.
49
```
Interferons → Pharmacology
Dosage
Excretion
Half-life
Structural changes
```
* Injected IM or SC
* Renal excretion and inactivation in body fluids/issues
* Pegylated – a linear or branched polyethylene glycol (PEG) moiety is attached to covalently to interferon
* Increased half-life and steady drug concentrations
50
Interferons → Toxicities
* Flu-like symptoms
* Haematological effects 0leukopaenia and thrombocytopaenia
* Neuropsychiatric effects
51
Interferons →Antiviral indications
* HBV
* HCV
* Papillomavirus (intalesional), respiraoty viruses? (SARS)
52
Interferons → Hepatitis B Agents
* Interferon alfa-2b/2a
* Peginterferon alfa-2a/2b
* Entecavir
* Adefovir
* Telbivudine
* Lamivudine/Emtricitabine
* Tenofovir
53
HBV – Who to treat
* All HBV carriers are potential treatment candidates
| * Based on risk of developing cirrhosis and liver cancer – active inflammation evidence by raised ALT or high viral load
54
Hepatiitis B Antiviral Therapy
```
Nucleosides (nucleotides)
• Lamivudine
• Adefovir
• Entecavir
• Tenofovir
Effective rapid reduction in HBV DNA
```
55
Antiviral therapy for Hep B resistance
```
May develop
• Especially to lamivudine
• 20% at one yr, 60% at 5 yrs
• Consider combination therapy/sequential therapy
Prolonged or life long therapy
```
56
Hepatitis C
```
Ribavirin
Pegylated interferon
Protease inhibitors
Polymerase inhibitors
NS5 gene inhibitors
```
57
Ribavirin I Description
Synthetic guanosine (nucleoside) analogue
58
Ribavirin I Active against
Active vs. broad range of RNA and DNA viruses
| → Flavi, paramyxo-, bunya-, arena-,retro-,herpes-,adeno-, and poxviruses
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Ribavirin II pharmacology
Aerosol, oral, i.v. administration
| Hepatically metabolizsed and renally excreted
60
Ribavirin II toxicity
Anaemia
61
MOA
Triphosphorylated by host cell enzymes
62
For influenza
Ribavirin – TP interferes with capping and elongation of mRNA and may inhibit viral RNA polymerase
63
For other agents
Ribavirin-MP inhibits inosine-5’- monophosphate dehydrogenase depleting intracellular nucleotide pools, particularly GTP
64
Chronic Hepatitis C
Goal is to clear HCV RNA
A sustained virological response (SVR) is associated with greatly rediced progression to cirrhosis
Combination antiviral therapy
• Standard therapy
• Interferon alpha and ribavirin
• Pegyylated interferon and ribavirin can clear virus in up to 80% genotype 2,3 and 50% genotype 1
• New agents highly effective
65
Influenza A antivirals
Amantidine
Rimantidine
Zanamivir
Oseltamir
66
Influenza B antivirals
Zanamivir
| Oseltamivir
67
Amantidine and Rimantidine: Description
Non-nucleosides
68
Amantidine and Rimantidine: MOA
Act on the early phase of virus un-coating by blocking the function of the matrix protein.
Ion channel blockers
69
Amantidine and Rimantidine: Active against
Influenza A strains only
70
Amantidine and Rimantidine: Dosing
Taken as 100 or 200mg o.d. for up to 2 weeks
71
Amantidine and Rimantidine:Amantidine in elderly
Not well tolerated in the elderly. Parkinsonian and extra-pyramidal signs are occasionally seen
72
Amantidine and Rimantidine: Side effects
Nausea, dizziness are frequent. Rimantidine has fewer side effects
73
Amantidine and Rimantidine: Resistance
Generated easily – most circulating strains resistant
74
Neuraminidase Inhibitors: Action
Inhibition of virues maturation and release at the level of the cell membrane
75
Neuraminidase Inhibitors: Use
Extreme conditions
76
Neuraminidase Inhibitors: Example
Relena (Zanamivir)
| Tamiflu (Oseltamivir)
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Neuraminidase Inhibitors: Relena Treatment and prevention of
Influenza A (inc avian) and B
78
Neuraminidase Inhibitors: Relena Delivery as
An aerosol of powder from blister pack inhaled as 10mg x b.d. for 5 days
79
Neuraminidase Inhibitors: Tamiflu (Oseltamivir)
Oral formulation (75 mg capsule) b.dd for 5 days and oral suspension for the treatment of influenza A and B (and prevention-o.d. regimen)
80
Neuraminidase Inhibitors: With these drugs
Needs to be taken within 48 hours of first symptoms for maximum benefit but should be given later if severely unwell/ high risk group
81
Zanamivir and Oseltamivir resistance
Oseltamivir
• H275Y in neuraminidase gene
• Rare de novo but can be induced, esp immunocomprimised
Zanamivir – occurs but rare, not cross-resistant
82
HAART
Highly active anti-retroviral therapy. Combination therapy made up of 2-5 classes of antiviral drug
83
The aim of treatment
Is not to cure but to suppress HIV VL and improve CD4 count, giving a longerCD4 count, giving a longer and better quality of life while reducing the incidence of opportunistic disease and lowering transmission potential (functional cure not eradication).
84
Classes of antiretroviral drugs
* NRTI-pNRTI – zidovudine/tenofovir
* NNRTI-nevirapine
* Protease inhibitors – Iopinavir
* Fusion Inhibitor-enfuvirtide
* Co-receptor (CCR5) – maraviroc
* Integrase inhibitor-raltegravir
85
NNRTIs action
* Acts as reverse transcriptase blocking agents not as competitors
* Less poten than NRTIs
86
NNRTIs resistance
• More likely over time 1-3 years
87
NNRTIs in combination
• With an NRTI agents
88
NNRTI examples
* Nevirapine (NVP)
* Efavirenz (EFV)
* Rilpivirine (RPV)
* Etravirine (ETV)
89
Protease Inhibitors – Pis action
* Act as protease blockers disabling maturation of the HIV virion on release from the cell
* Potent
90
PI drug problems
• Drug interactions problematic
91
Dosage
• Dual Pi’s utilised low dose ritonavir to inhibit cutochroe P450 allowing high levels of the main PI in the dual formulation
92
Examples
* Ritonavir (RTV)
* Nelfinavir (NFV)
* Tipranavir (TPV)
* Lopinavir (LPV)
* Darunavir (DRv)
* Atazanavir (ATV)
93
Treating with HAART (HIV1)
• Combination therapy is used for potency and prevention of drug resistance.
94
HAART for starting therapy
Two nucelo (t)ide reverse transcriptase inhibitor (NRTIs) plus one of the following: a ritonavir – boosted protease inhibitor (Pl/r), an NNRTI or an integrase inhibitor (INI)
95
HAART examples
```
Tenfovir
Emtricitabine with
Atazanavir
Ritonavir or
Efavirenz or
Raltegravir
```
96
HAART response
Most patients with a naïve wild-type HIV infection respond to HAART with a reduction in HIV viral load (V), >500,000 copies to undetectable (<50 copies), with a significant rise in CD4 count within 6 weeks of treatment initiation.
97
Maintenance of an undectable viral load requires
Good adherence >80% of the dose, >80% of the time.
98
Treatment Failure
Is defined as persistent detectable viral as persistent detectable viral load >50 copies/mL blood
99
Signals that show development of resistance
Viral rebound and fall in CD4 count on therapy
100
HAART Adverse Effects
Modern combinations very good
Early NRTIs limited by serious toxicities including anaemia and neutropenia (ZDV) and peripheral neuropathies (d4T), lipodystrophy, mitochondrial toxicity and lactic acidosis are serious consequences of NRTI therapy
101
Abacavir sensitivity
Is rare (4%) but can be life threatening
102
Lamivudine (3TC)
Rare significant toxicities
103
NNRTIs are limited by
Tendency to cause rash, fever, myalgia, hepatitis and diarrhoea (NVP) and Depression (EFV)
104
PIS were often difficult to tolerate due to a wide
Range of GI symptoms. Lipid changes can significantly increase risk of heart disease and stroke, as well as altering body shape (buffalo hump, midriff deposition, facial and thigh fat pad loss).
105
Ribavirin for RSV
Nebulied, oral,iv
| Immunocomprimised
106
Papillomavirus drug
Interferon inducer – imiquimod
107
HSV keratoconjunctivitis treatment
Trifluridine or idoxuridine
108
CMV treatment
Fomivirisen – antisense oligonucleotide, intra-ocular
