Chemotherapy (Antiviral Drugs) Flashcards
List the steps in viral replication
- Adsorption and penetration into cell
- Uncoating of viral nucleus acid
- Synthesis of regulatory proteins
- Synthesis of RNA/DNA
- Synthesis of structural proteins
- Assembly of viral particles
- Release from host cell
State the major sites of antiviral drug action and the drugs that act on them
- Viral attachment + entry : enfurvitide; maraviroc; docosanol; palivizumab
- Penetration : interferon-alfa
- Uncoating : amantadine; rimantadine
- Nuclei acid synthesis : NRTIs; NNRTIs; acyclovir; foscarnet; entecavir
- Late protein synthesis : protease inhibitors
- Packaging + assembly for viral release : neuraminidase inhibitors
State the classification of antiviral drugs according to MoA
NRTIs
NNRTIs
Protease inhibitors
DNA polymerase inhibitors
Neuraminidase inhibitors
Inhibitors of viral coat assembly
Integrate inhibitors
Entry inhibitors
Biological agents + immunomodulators
List the NRTIs used to treat HIV
abacavir
emtricitabine
lamuvidine
stavudine
tenofovir
zidovudine
List the NRTIs used to treat hepatitis B
lamuvidine
tenofovir
adefovir dipivoxil
entecavir
telbivudine
Describe the mechanism of action of NRTIs
Competitive inhibitors of reverse transcriptase
Phosporylated by host cell enzymes to give 5’-triphosphates which compete with equivalent host cellular triphosphates for incorporation into viral DNA which causes premature termination of viral DNA synthesis
Inhibit viral replication
What mechanisms are involved in the resistance to NRTIs
- Impairment of the incorporation of the analogue into DNA
- Removal of the analogue from the prematurely terminated DNA chain
(occur as a result of mutations leading to a change in the structure of reverse transcriptase)
What are the general adverse effects of NRTIs?
GI disturbances
CNS and related effects
Musculoskeletal
Dermatological effects
Blood disorders
Liver damage
Pancreatitis
Metabolic effects including lactic acidosis and lipodystrophy
List the NRTIs used in HIV treatment and state their specific adverse effects
- Zidovudine: Bone marrow depression, GI intolerance, cardiomyopathy, myopathy
- Stavudine: Peripheral neuropathy, lipodystrophy, hepatotoxicity
- Abacavir: Hypersensitivity reactions (predisposing factor: presence of HLA-B5701 gene), increase in myocardial infarction
- Tenofovir: Nephrotoxicity, osteoporosis, exacerbation of hepatitis B with discontinuation
- Lamivudine: Pancreatitis
- Emtricitabine: Hyperpigmentation
How are NNRTIs classified?
- First generation: Efavirenz (EFV) and nevirapine (NVP)
- Second generation: Etravirine and rilpivirine
Describe the MoA of NNRTIs
Bind to reverse transcriptase near the catalytic site and denature it.
They are non-competitive inhibitors of HIV-1 RT i.e. do not compete with nucleoside triphosphates and do not require phosphorylation
They do not inhibit HIV-2 reverse transcriptase
Differentiate the action of NNRTIs in drug sensitive vs drug resistant viruses
In drug-sensitive viruses, NNRTIs bind to a pocket next to the active site and block the polymerization of DNA by reverse transcriptase
In drug-resistant viruses, mutations prevent the binding of NNRTIs to their binding site, allowing DNA polymerization to proceed normally
What are the side effects and contraindications of efavirine?
Neuropsychiatric effects (insomnia, somnolence, dizziness, amnesia, nightmares, neuropathy, anxiety, psychosis, seizures etc.), hepatotoxicity, skin reactions and gynaecomastia. Contra-indicated in patients with seizure disorders, neurological disorders and psychiatric disorders
What are the side effects and contraindications of nevirapine?
Hepatotoxicity and skin reactions (including Steven-Johnson syndrome and toxic epidermal necrolysis); more frequent and more severe than with EFV. Contraindicated in patients with hepatic impairment
State the general contraindications of first gen NNRTIs
Hypersensitivity
Concurrent administration of drugs that depend on cytochrome P450 for metabolism, and those that induce or inhibit cytochrome P450
Concomitant use of NNRTIs is not recommended
Describe the first gen NNRTIs drug-drug interactions
- NVP induces CYP3A: increases metabolism of protease inhibitors (PIs), oestrogens, ketoconazole, rifampicin (reduced efficacy)
- EFV induces CYP3A4: increases metabolism of drugs metabolised by these enzymes e.g. some PIs (reduced efficacy)
- Cytochrome P450 inducers (e.g. rifampicin) increase metabolism of NNRTIs (reduced efficacy)
- Cytochrome P450 inhibitors (e.g. ketoconazole, cimetidine) reduce metabolism of NVP (increased toxicity)
What are the side effects of second gen NNRTIs?
Etravirine adverse effects: Hypersensitivity reactions that include skin reactions and hepatitis
Rilpivirine adverse effects: Rash, depression, headache, insomnia, increased serum aminotransferases and QTc prolongation
What is the mechanism of action of protease inhibitors in HIV?
Protease inhibitors prevent viral replication by selectively binding to viral proteases and blocking proteolytic cleavage of the polyproteins into functional and structural proteins that are necessary for the production of infectious viral particles
Describe protease inhibitor drug resistence
Resistance to PIs is the consequence of amino acid substitutions on proteases. These amino acid changes modify the number and the nature of the points of contact between the PIs and the proteases, thereby reducing their affinity for the enzymes.
List the protease inhibitors used in HIV treatment
amprenavir
atazanavir
darunavir
lopinavir
ritonavir
What are the adverse effects of protease inhibitors?
fatigue
GI disturbances
CNS and related effects, musculoskeletal and dermatological effects, blood disorders, and metabolic effects including pancreatitis, liver damage and lipodystrophy
These agents cause a syndrome of altered body fat distribution, insulin resistance and hyperlipidemia (metabolic syndrome)
What is the function of NS3/4A serine protease?
involved in post-translational processing in hepatitis C (HCV)
List the NS3/4A protease inhibitors and state their mechanism of action
grazoprevir,
paritaprevir and
simeprevir
are inhibitors of the NS3/4A serine protease, an enzyme involved in post-translational processing in hepatitis C (HCV)
List the entry inhibitors used to treat HIV
enfuvirtide and maraviroc
What is the general mechanism of action of entry inhibitors?
Entry inhibitors prevent HIV from entering human cells by inhibiting key proteins involved in the entry process
Describe how enfuvirtide works
Inhibits gp41, an HIV glycoprotein, resulting in prevention of fusion of the viral and cellular membranes, and thereby inhibits entry of HIV into the human cell
What are the adverse effects of enfuvirtide?
Local injection site reactions,
hypersensitivity reactions,
headache,
insomnia,
anorexia,
asthenia,
peripheral neuropathy,
depression,
pancreatitis
Describe how maraviroc works
binds to the CCR5 receptor on the membrane of human cells such as CD4 cells. This binding prevents the interaction of the HIV glycoprotein, gp120, and human CCR5 which is necessary for HIV entry into the cell.
What are the limitations of maraviroc?
HIV can also use another co-receptor on human cells, CXCR4, which maraviroc does not affect. Maraviroc does not prevent HIV entry into CXCR4-tropic or dual-tropic cells.
A tropism test must therefore be performed to determine if the drug will be effective
What are the adverse effects of maraviroc?
Hepatotoxicity (may be preceded by a systemic allergic reaction, pruritic rash and eosinophilia),
dizziness,
postural hypotension,
increased risk of cardiac ischaemic events (e.g. myocardial infarction)
List the integrase strand transfer inhibitors
raltegravir,
dolutegravir and
elvitegravir
What is the mechanism of action of integrase strand transfer inhibitors?
Bind they viral enzyme integrase, thereby inhibiting strand transfer, the final step of provirus integration, thus interfering with the integration of HIV DNA into the DNA of host cells
State the adverse effects for each of the specific ISTIs
Raltegravir
Rash, hypersensitivity reactions, myopathy and rhabdomyolysis
Dolutegravir
Headache, insomnia, anxiety, depression, increased serum aminotransferase levels, and hypersensitivity reactions
Elvitegravir
Diarrhea, rash, and elevation in serum aminotransferases
List the DNA polymerase inhibitors used to treat cytomegalovirus (CMV) infections
Cidofovir,
foscarnet,
ganciclovir,
valganciclovir
List the DNA polymerase inhibitors used to treat of herpes infections
Aciclovir,
famciclovir,
penciclovir,
valaciclovir,
idoxuridine,
trifluridine and
vidarabine
What is the MoA of aciclovir, valaciclovir, famciclovir and penciclovir ?
Phosphorylated by viral thymidine kinase then metabolised by host cell kinases to a nucleotide analogue. The nucleotide analogue then inhibits viral DNA synthesis by inhibiting DNA polymerase.
What could cause viral resistance to aciclovir?
(a) Decreased production of thymidine kinase
(b) Altered thymidine kinase substrate specificity
(c) Altered viral DNA polymerase
Cross-resistance occurs with valaciclovir, famciclovir and ganciclovir
What are the adverse effects of aciclovir?
Nausea,
diarrhea,
headache,
tremors and
delirium
What are the adverse effects of Valaciclovir, famciclovir and penciclovir?
Nausea, diarrhea and headache
State the MoA of Idoxuridine and trifluridine
converted by cellular enzymes to their triphosphate analogs which inhibit viral DNA polymerase
What are the adverse effects of idoxuridine and trifluridine?
Pain,
pruritus,
edema involving the eye or lids and
allergic reactions (rare)
State the MoA of vidarabine
Converted by cellular enzymes to its triphosphate analog which inhibits viral DNA polymerase
What are the adverse effects of vidarabine?
Neurotoxicity, GI intolerance and myelosuppression, syndrome of inappropriate secretion of ADH
What is the mechanism of action of ganciclovir?
Requires triphosphorylation for activation monophosphorylation is catalyzed by a phosphotransferase in CMV and by thymidine kinase in HSV cells
Phosphorylated ganciclovir inhibits DNA polymerase
How does ganciclovir resistance occur?
Results from impaired phosphorylation due to a point mutation or a deletion in the viral phosphotransferase
What are the contraindications of etravirine and rilprivirine?
Etravirine is a very potent inducer of CYP3A4 thus it should not be given with other NNRTIs, unboosted protease inhibitors and atazanavir/ritonavir
Rilpivirine is primarily metabolized by CYP3A4, and drugs that induce or inhibit CYP3A4 may thus affect the clearance of rilpivirine
