Antivirals Flashcards
What is the process of viral replication
- Attachment - Haemaglutinin on virus with host cell surface receptor
- Uncoating - M2 ion channel H+ influx into virus allows nucleocapsid breakdown
- DNA/RNA replication
- Protein synthesis
- Assembly
- Release - Neuraminidase prevents virus adhesion to host cell membrane on release
What are features of antiviral agents
Few types of Antiviral agents
Virostatic, not virocidal
Not broad spectrum
Not given empirically
What are general mechanisms of action of antiviral agents
Virocidal:
Organic solvents, Non-organic solvents, Cryotherapy, Radiotherapy
Not given systematically
Virostatic:
Risk of resistance, not effective in latent infection, requires host immune response to clear existing virus
Immunomodulators:
Enhance host immune (interferons), replace depleted host immune (immunoglobulin)
What are the main groups of antiviral agents
Anti-herpes virus
Anti-hepatitis virus
Anti-retroviral
Anti-influenza
What are types of anti-herpes drugs
Aciclovir
Ganiclovir
Foscarnet
What is mechanism of action of Aciclovir
Enters virally infected cells Activated to nucleoside triophosphate by viral Thymidylate Kinase Incorporated into viral DNA Bind to and Inhibit DNA polymerase Act as chain terminator
What are indications of Aciclovir
Herpes simplex encephalitis
Cold sores (HSV1)
Genital ulcers (HSV2)
VZV (chicken pox, shingles >50)
What are types of resistance for Aciclovir
Viral strains that:
Lack thymidylate kinase
mutation in thymidylate kinase gene
Mutation in DNA polymerase gene that prevents binding with Aciclovir triphosphate
What are side effects of Aciclovir
Nephrotoxicity
CNS: lethargy, confusion, tremor, hallucination
What is mechanism of action of Ganciclovir
Same as Aciclovir
But phosphorylation also catalysed by host and viral enzyme (phosphotranserase)
Thus also activated in non infected host cell
What are indications for Ganciclovir
CMV infection: Colitis Retinitis Pneumonitis Pneumonia
What are side effects of Ganciclovir
Nephrotoxic
Neurotoxic: confusion, headache, behavioural change
What is mechanism of action of foscarnet
Inhibit binding of nucleoside triphosphate to viral DNA
(Thus does not need to be phosphorylated to be active)
Inhibit HIV reverse transcriptase
What are indications of Foscarnet
Aciclovir resistant HSV
Ganciclovir resistant CMV
HIV
What are side effects of Foscarnet
Narrow therapeutic index
GI: N+V, diarrhoea
Nephrotoxicity
CNS: headache, hallucination, tremor, seizure
What are types of anti-hepatitis drugs
Lamivudine Adefovir Entecavir Telbivudine Ribavirin IFN alpha
What is mechanism of action of Lamivudine
Nucleoside Reverse transcriptase inhibitor:
Nucleoside analogue
Gets activated by phosphorylation in cell by nucleoside kinase
Incorporated into viral DNA
Inhibits RT and acts as chain terminator
What are indications of Lamivudine
Chronic hepatitis B
HIV
What is resistance of Lamivudine
Common - 67% by 4 years
What are side effects of Lamivudine
Well tolerated
Raised liver enzymes
What is mechanism of action of Adefovir
Nucleoside Reverse Transcriptase Inhibitor
What are indications of Adefovir
Chronic hepatitis B
What is the resistance in Adefovir
Slow to develop
What are side effects of adefovir
Well tolerated
GI: nausea, diarrhoea, abdo discomfort
CNS: headache
What is mechanism of action of entecavir
Nucleoside RT inhibitor
What are indications of entecavir
Chronic hepatitis B
Lamivudine-resistant
What is resistance in entecavir
No reported resistance
What are side effects of Entecavir
GI: nausea, diarrhoea
CNS: headache, dizziness, photosensitivity
What is mechanism of action of Telbivudine
Potent NRTI
When is telbivudine indicated
Chronic hepatitis B
When other treatments failed
What is mechanism of action of Ribavirin
Inhibit RNA synthesis
When is Ribavirin indicated
Hepatitis C
What are side effects of Ribavirin
Anaemia (extravascular haemolysis) Myelosupression Myalgia Pruritus Rash Anxiety
What is mechanism of action of Interferons
Enhance cell-mediated immune response
Increased activation of NK cells, macrophages
IFNs are cytokines released by Th1 cells when infection by intracellular pathogen occurs
What are indications of IFN therapy
Hepatitis B
Hepatitis C
What are side effects of IFN therapy
Flu-like symptoms: Fever Chills Malaise Headache GI
What are types of anti-influenza drugs
M2 ion channel inhibitors
Neuraminidase inhibitors
Give examples of M2 ion channel inhibitors
Amantadine
Ramitidine
What is mechanism of action of M2 inhibitors
Inhibit proton influx into virus
Inhibit pH mediated uncoating of virus
Thus inhibit viral replication
What are indications of M2 ion channel inhibitors
Influenza A
What are side effects of M2 ion channel inhibitors
Low dose: nervousness, confusion, insomnia
High dose: delirium, hallucination, seizure
Give examples of neuraminidase inhibitors
Oseltavir (Tamiflu)
Zanamivir
What is mechanism of action of Neuraminidase inhibitors
Inhibit breaking of bond bw virus and host cell membrane
Inhibit release of virus from infected host cell
What are indications of neuraminidase inhibitors
Influenza A + B
Oseltavir: treatment and prophylaxis
Zanamivir: treatment only
What is process of HIV replication
- Attachment - to CD4+ on T cells
- Uncoating
- Reverse transcription - reverse transcriptase
- vDNA integration- integrase
- Transcription
- Replication
- Assembly + budding
- Maturation - proteases in new virion
What are types of antiretroviral drugs
Nucleoside Reverse Transcriptase Inhibitor
Non-Nucleoside Reverse Transcriptase inhibitor
Protease inhibitor
Fusion inhibitor
Give examples of NRTIs
Lamivudine
Zidovudine
What are indications of NRTIs
HIV 1
HIV 2
What is resistance in NRTIs
High
What are side effects of NRTIs
Hyperlactataemia
Lactic acidosis
Hepatomegaly
What are examples of NNRTIs
Nevirapine
Delavirdine
What is mechanism of action of NNRTI
Allosteric inhibition of RT
What are indications of NNRTI
HIV 1
Can be combined with NRTI (binding site on RT different )
What are side effects of NNRTI
Raised LFTs
Dizziness, sleep disturbance, headache
Rash
Erythematous maculopapular rash
Give examples of protease inhibitors
Saquinavir
Ritonavir
What is mechanism of action of protease inhibitors
Inhibit protease activity in new virion - cleavage of polyprotein into mature proteins
Inhibit maturation
What are indications of protease inhibitors
HIV 1
HIV 2
What are side effects of protease inhibitors
Inhibit CYP450 Hypercholesterolaemia Hyperglycaemia Increased risk of MI Osteoporosis, osteopenia, osteonecrosis
Give examples of fusion inhibitors
Enfuvirtide
What is mechanism of action of fusion inhibitor
Inhibit HIV binding to CD4 receptors on T cells
What are indications of Fusion inhibitors
HIV 1
When other combinations failed
What are side effects of Fusion inhibitors
Injection site reaction: pain, induration, erythema, cysts
Hypersensitivity rash
Fever
Hypotension
Why do you need to do antiviral resistance testing
Optimise patient outcomes
Save costs
Reduce pool of drug-resistant virus
When is antiviral resistance testing indicated
Rising viral load despite good compliance
Rising viral load in Poor compliance
Newly diagnosed patients
How is antiviral resistance testing carried out
Incubate suspected resistant viral strain with drug
Compare response with normal viral strain
What does low barrier to response mean
Only need few mutations to develop antiviral resistance
What does ‘unfit’ virus mean
Mutation that causes antiviral resistance also has negative impact on virus ability to replicate
Thus virus strain cannot survive
