antivirals Flashcards
what is the aim, how, effectiveness and objectives?
Aim : Treat infection/diseases caused by viruses
How : Target steps in viral replication with minimal effect on host cell function
Effectiveness: Only small number of viruses respond (only a small number of targets on virus)
Objectives:
At the end of this section, you should be able to describe
1. Mechanisms of action
2. Pharmacokinetics
3. Clinicaluses
4. Resistance
5. Adverseeffects
of specific examples of antiviral drugs used clinically
what is a virus?
- Latin word meaning toxin or poison
- Definition: sub-microscopic infectious agent that cannot grow or reproduce outside a host cell - need to have host cell environment to replicate
~100 X smaller bacteria - Structure: RNA or DNA, protein coat (capsid), lipid-rich envelope (some viruses)
how does viral replication happen?
- Adsorption/entry
- Uncoating
- Transcription/mRNA synthesis
- DNA/RNA replication
- Protein synthesis
- Assembly
- Release
- antiviral drugs target these steps
what is the classification of viruses
how are viruses transmitted and treated? what are examples of types of viral infection?
- Viruses are transmitted to host via Imany routes (bodily fluid contact, skin-skin contact, airborne etc.)
- not all viruses cause disease
Prevention/treatment = ↓ exposure risk, healthy immune system, vaccines, antiviral drugs
Examples of types of infection
Acute: Smallpox, Influenza, Rhinovirus, Ebola, SARS
Chronic: Hepatitis B & C
Latent: Herpesviruses → remain dormant/latent for prolonged periods of time and then cause symptoms at a random time
Progressive: HIV → progresses to AIDS
Cancer: HPV, Epstein-Barr
what is SARS-CoV-2 and what is it caused by?
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
- Coronavirus disease caused by SARS-CoV-2 first identified in 2019 (COVID-19)
SARS-CoV-2 believed origin and route of transmission
believed to have zoonotic origins (bats)
- human-human transmission confirmed January 2020
- main routes of transmission: respiratory droplets and aerosols
how do covid-19 treatments work?
Antivirals:
- virus particles multiply inside the body
- antiviral drug prevents virus from multiplying
Anti-inflammatories:
- immune system dangerously overreacts to virus
- anti-inflammatory drug calms immune response
Antibody treatments:
- antibody specific to coronavirus binds to it and makes it harmless
What do antiviral drugs target and how are they administered?
- Specifically target viral entry or replication with limited effects on host cells.
- Limited number of drug targets.
- Viruses highly adaptive; mutations could result in increased infectivity or development of resistance to previously effective drugs or vaccines. (ex. flu vaccine on virus mutations)
- Remdesivir: First approved antiviral for COVID-19 July 2020: authorized with conditions in Canada.
- Administered IV within 7 days of infection: patients hospitalized with severe COVID-19 or non-hospitalized patients at risk of severe COVID-19
how is Remdesivir metabolized and how does it work as a drug?
- metabolized to nucleoside
monophosphate - triple phosphorylated
- adenosine triphosphate (ATP) analog is incorporation into the newly synthesized RNA strand
- premature termination of the RNA product
what is Paxlovid?
- combo of two drugs
- Ritonavir-boosted nirmatrelvir
how do Ritonavir and Nirmatrelvir work to treat COVID-19?
- Approved for patients with mild-moderate symptoms at risk of severe COVID-19; FDA – December 2021;
Canada – January 2022. - Ritonavir = proteas inhibitor (high dose) or booster (low dose)
- Nirmatrelvir = inhibitor of M^PRO a viral proteases in all coronaviruses known to affect humans
adverse effects of Remdesivir and Nirmatrelvir/ritonavir
Remdesivir: infusion site reactions, low blood pressure, nausea, vomiting, chest tightness → someone on ventilator should not use this drug, respiratory failure, altered liver enzymes, back impairment
- also bad for people with pre-existing cardio and renal diseases
Nirmatrelvir/ritonavir: change in taste, muscle aches, swollen joints, headache, blurred vision, changes in heart-rate
Remdesivir and Nirmatrelvir resistance
Remdesivir: mutations in viral RNA-dependent RNA polymerase (RdRP) → drug cant bind as readily anymore once triple phosphorylated
- ATP analogue not incorporated into RNA
Nirmatrelavir: multiple mutations identified in SARS-CoV-2 MPRO near nirmatrelavir binding site therefore drug cant bind
overview of covid 19 phases
how is influenza caused and its treatment
- Caused by variety of viral species and strains
- New viruses constantly appearing due to mutations
- Antiviral drugs:
Neuraminidase inhibitors (ie. oseltamivir) - M2 (ion channel) inhibitors (ie. amantadine)
what is Oseltamivir (Tamiflu), its MOA, adverse effects and pharmacokinetics
Sialic acid analog (competes with sialic acid)
Mechanism: inhibits neuraminidase (sialidase)
Neuraminidase cleaves sialic acid on surface of infected host cell to promote release of newly synthesized virus
Pharmacokinetics: administered as pro-drug, metabolized to active form in liver and GI tract
Adverse Effects: nausea, GI discomfort
Oseltamivir (Tamiflu) clinical uses and resistance
Clinical uses: prevention and treatment of early infection by many influenza A & B sub-types.
H1N1 = subtype of influenza A: caused 2009 pandemic. Most variants protected against by vaccine and responsive to oseltamivir.
Clinical trials: treatment results in alleviation of symptoms ~ 1 day sooner than without treatment
Resistance: mutation in neuraminidase, however mutant strains often less virulent
Amantadine MOA
Mechanism: inhibits proton ion channel (M2) in viral envelope of influenza A → inhibits uncoating of virus→ inhibits release of viral RNA-protein complex
during viral protein synthesis – inhibits H+ transport necessary for proper protein synthesis
Amantadine pharmacokinetics, adverse effects, clinical uses and resistance
Pharmacokinetics: distributed throughout the body, including CNS, excreted unchanged by kidney
Adverse Effects: GI disturbances, CNS disturbances (nervousness, insomnia, difficulty concentrating) and renal damage in patients with renal insufficiency
Clinical uses: treatment of early infection by influenza A (not H1N1)
Resistance: mutation in M2 (resistance rate ~ 50 %)
what are the two cases of herpes and the lytic and latent phase
Herpes simplex 1: cold sores Herpes simplex 2: genital herpes
how do you treat herpes?
infection cycles between active phase and remission
Currently no cure or vaccine is available
Antiviral agents: inhibit viral DNA synthesis ie. acyclovir
-activation of drug requires 3 step phosphorylation, first step by viral thymidine kinase
acyclovir mechanism of action, pk, adverse effects, clinical uses and resistance
Mechanism: guanosine analogue, activated by viral thymidine kinase therefore infected cells most susceptible; tri-phosphate acyclovir competes with dGTP during DNA synthesis → DNA chain termination
Pharmacokinetics: oral, IV or topical formulations, distributed throughout the body, including CNS
Adverse Effects: nausea, vomiting, diarrhea, headache, renal damage (high doses or dehydrated patients, accumulates in patients with renal failure)
Clinical uses: treatment of active herpes infection
Resistance: altered or deficient thymidine kinase
what is HIV/AIDS
HIV = human immunodeficiency virus
AIDS = acquired immune deficiency syndrome, disease caused by infection with HIV
HIV positive
-infected with virus -generally symptom free -without treatment: clinical latency of 2 to 10 years
AIDS
-symptoms (opportunistic infections)
-life-span without treatment 1 to 2 years
how does HIV invade host cell?
what cells does HIV infect?
HIV infects immune cells (CD4+ T cells, macrophages, and dendritic cells) via CD4 and co-receptor
The majority (up to 90%) of newly transmitted HIV uses the CCR5 co-receptor (R5-tropic).
X4-tropic virus emerges in ~ 50-60% of infected individuals; average time to emergence = 5 years
what is the treatment of HIV?
First-line treatment = combination of 3 antiviral agents Typically begins with 2 NRTIs + 1 of NNRTI/INI/PI
Originally called HAART = highly active antiretroviral therapy Now more commonly: ART or combined ART (cART)
Antiviral drugs:
(1) Nucleoside reverse transcriptase inhibitors (NRTIs)
eg. azidothymidine (AZT; also known as zidovudine (ZDV))
(2) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) eg nevirapine
(3) Integrase inhibitors (INIs) eg. raltegravir
(4) Protease inhibitors (PIs) eg. ritonavir
(5) Viral fusion/entry inhibitors eg. maraviroc
Azidothymidine (AZT)
Mechanism:
Thymidine analogue activated (phosphorylated) by mammalian kinases
Viral reverse transcriptase (RT) not selective therefore competes with dTTP during DNA synthesis → DNA chain termination
Can affect human DNA polymerase at very high doses
Azidothymidine pk, adverse effects and resistance
Pharmacokinetics:
AZT well absorbed and distributed (even in CNS), metabolized in liver (glucuronidation)
Adverse Effects:
Bone marrow: anemia, leukopenia
CNS: headaches, seizures
Drug interactions: drugs that compete for glucuronidation eg. acetaminophen, benzodiazepines
Resistance:
Reverse transcriptase mutation, inefficient kinase activation – 1/3 of patients develop resistance with AZT monotherapy
Nevirapine moa, pk, adverse effects and resistance
Mechanism: Binds to non-catalytic site and inhibits viral reverse transcriptase
Pharmacokinetics: Well-absorbed and distributed (CNS, fetus, maternal milk), metabolized in liver [oxidation(CYP3A4 and CYP2B6) →glucuronidation]
Adverse Effects: Rash, hepatotoxicity Drug interactions: ↑CYP3A4 → ↑ metabolism of certain drugs eg. itself, oral contraceptives, azoles, methadone, protease inhibitors; metabolism affected by drugs that ↑ or ↓ CYP3A4 or CYP2B6
Resistance: reverse transcriptase mutation
Raltegravir moa, clinical trials and resistance
Mechanism: inhibits viral integrase therefore ↓ transfer of viral DNA into host genome
Initially approved by Health Canada in November 2007 for patients with ART resistant HIV, now approved for all patients
Clinical Trials:
↓ viral load earlier in patients taking raltegravir + ART drugs compared to those taking ART drugs alone
Effect of raltegravir as preventative treatment currently under investigation
Resistance: viral integrase mutation
what is an example of a fixed dose drug combination?
Eg. Biktarvy (2 NRTI + INI)
Ritonavir moa, pk, adverse effects, resistance
Mechanism: inhibits HIV aspartyl protease (cleaves viral polyprotein into specific proteins: Phe-Pro)
Inhibits CYP3A4 therefore given at low doses as enhancer of other antivirals, including other PIs
Pharmacokinetics: Good bioavailability. Metabolized by CYP3A4
Adverse Effects: GI disturbances, insomnia, hyperglycemia, metabolic abnormalities (lipid levels, liver enzymes). Drug interactions (↑half-life/concentration of drugs metabolized by CYP3A4).
Resistance: mutations in viral protease
maraviroc moa, clinical trials, adverse effects
Mechanism: CCR5 receptor antagonist blocks binding of viral gp120 to CCR5 therefore prevents viral entry
Approved in 2007
Clinical Trials:
↓ viral load in patients
with maraviroc compared
to placebo (participants all received optimized ART)
Now indicated for use in individuals with R5-tropic virus.
Adverse Effects: Muscle/joint pain, cold symptoms, dizziness, GI disturbances, rare but potentially serious liver damage and allergic reactions
what is a new method that might combat HIV?
A natural chemical in bananas may help protect women against sexual transmission of HIV.
In laboratory tests, they found that a lectin called BanLec was as potent as two current HIV drugs. Lectins – sugar- binding proteins found in plants – can identify and attach to foreign invaders. By binding to the sugar-rich HIV-1 envelope protein gp120, BanLec blocks HIV’s entry into the body.
BanLec could become a less expensive and highly effective new component of vaginal microbicides,
what might be a new method to defeat HIV latency?
increased crotonylation, an epigenetic mechanism that governs gene expression, might be the key to making HIV come out of hiding and become susceptible to anti-HIV drugs
This is the first study to identify histone crotonylation as a driver for HIV transcription and de-crotonylation of histone as an epigenetic marker for HIV silencing.
