Antivirals Flashcards
What is a virus
infectious, obligate intracellular parasite
aka can only replicate inside another cell
NOT CELLS
dependant on host cells to synthesise progeny virus particles
How do most viruses survive?
the viral genome is packaged inside particles
the genome contains all the information required to initiate and complete an infection within a susceptible and permissive cell
all successful viruses establish themselves in a host population
susceptible vs permissive
a susceptible cell has a functional receptor for a given virus (aka the virus can enter)
a permissive cell has the capacity to support virus replication
MUST BE BOTH SUSCEPTIBLE AND PERMISSIVE
a resistant cell means it is not susceptible, but not necessarily not permissive
Viral structure
nucleic acid surrounded by a capsid
+/- an envelope full of protiens surrounding the nucleocapsid
the genome of a virus can take many different forms such as
linear double strand DNA, circular ds DNA, circular ss DNA, ds RNA, + ss RNA, - ss RNA
negative sense RNA is complimentary to mRNA, and positive sense RNA is the same as mRNA and can be replicated directly
this genome does not code for membrane proteins or enzymes, but instead non-functional proteins that must be cleaved to make them functional
viral replication
the virus attaches to a cell, usually interacting via receptors
penetrates the membrane and injects nucleic acid into the cell
using the host machinery, the viral nucleic acid replicates
uses the host machinery to make non-functional proteins that are then cleaved by proteases to make the structural proteins and enzymes
the viral nucleic acids are packaged in viral proteins and burst from the cell, may or may not destroy the host
SARS-CoV-2 virus
severe acute respiratory syndrome
family: coronaviridae
enveloped virus, linear + ss RNA
receptor: angiotensin converting enzyme 2 (ACE2), respiratory epithelial cells
can enter to 2 ways: plasma membrane fusion, or endosomal membrane fusion. (interacts with ACE2, then injecting through the named membrane)
does not need to enter the nucleus to replicate, because it is compatible with mRNA.
transcription done by RNA dependant RNA polymerase
COVID-19 symptoms
incubation time: 2-14 days after contact, and generally take 5-6 days for symptoms to begin
fever, dry cough, fatigue, sputum production
first infects the upper respiratory system and inflames the lungs, then gets into the blood to infect other organs
main risk factors of severe COVID
over 75 years of age
obesity
cancer and treated with chemotherapy
immunocompromised
organ transplant
severe chronic diseases such as asthma, diabetes, end stage kidney disease
systemic corticosteroids in people with COVID-19
only for those who require respiratory support (or for other indications) like mechanical ventilation or supplemental oxygen
paxlovid
nirmatrelvir + ritonavir
nirmatrelivir inhibits the protease
ritonavir inhibits the metabolism of nirmatrelvir
Dose: 300mg nirmatrelvir and 100mg of ritonavir orally bid for 5 days (reduce for moderate renal impairment)
given as soon as possible after diagnosis, and within 5 days of symptom onset
indicated for those at risk of severe disease and are: unvaccinated, vaccinated but immunocompromised meaning it is likely to be unprotected, vaccinated adults at high risk (eg older 75, or 65 with additional risks)
limits: only for those with currently mild but risk of severe disease, not those with currently severe. not for prophylaxis for the prevention of COVID-19. not for paediatric patients. not for use over 5 days)
Remdesivir
pro-drug
IV administration
inhibits rna dependant rna polymerase
Indications: COVID-19 positive, but do not require oxygen with less than or equal to 7 days since symptom onset, for unvaccinated or immunocompromised patients at risk of progressing to severe infection. Dose: 200mg, 2 x 100mg
hospitalised patients older than 12 with pneumonia requiring supplemental oxygen. Dose: 200mg, 4 x 100mg
Tocilizumab
IV
recombinant anti-IL-6 receptor IgG antibody
covid causes high levels of Il-6, which could cause a “cytokine” storm
Indicated: ICU admission with severe pneumonia and requiring respiratory support, or recently hospitalised with significantly increased inflammation markers and requiring non-invasive ventilation or high-flow oxygen
single dose of 8mg/kg to a maximum of 800mg
Special populations and COVID-19
Pregnant women are no more or less likely to have a covid infection than the general population. prednisolone and hydrocortisone are preferred corticosteroids over dexamethasone due to crossing the placenta less. oral paxlovid is okay to give, and iv remdesivir has no evidence of causing harm, but its only based off of a case-study
children have lower risks of developing severe COVID than adults. vaccination is the safest option, as theres very little reseach on the effects in the paediatric population
Influenza structure
family: Orthomyxoviridae
enveloped virion with - ss RNA (aka requires the nucleus to replicate)
in the envelope there are two major proteins: haemagglutinin and neuraminidase
haemagglutinin binds to the sialic acid receptors in the human cells in the respiratory tract, neuraminidase cleaves the neuraminic acid molecules in infected cells
when finished replicating using the nucleus, the virus buds from the cell membrane, however this causes the sialic acid receptors to bind in again, requiring them to be cleaved
Influenza as a disease
spread by aerosol droplets, respiratory droplets, or contact with contaminated surfaces
incubation period: 1-5 days, infectious period: 5-7 days
symptoms: fever, headache, fatigue, cough, sore throat, runny or congested nose, aches, diarrhoea and vomiting (children, not as often adults)
antigen drift and shift
genetic changes to the virus
drift: minor changes in the haemagglutinin and neuraminidase antigens (happens annually)
shift: major change (30% or more) in haemagglutinin and/or neuraminidase antigens, creating a “new virus” that can start an epidemic or pandemic
compilations of influenza infection
respiratory is most common. eg pneumonia, croup, exasperation of COPD, bronchitis, otitis media
cardiovascular issues are not uncommon eg myocarditis and pericarditis
muscular: rhabdomyositis and rhabdomyolysis
neurological: Reye’s syndrome, encephalitis, transverse myelitis
systemic: toxic shock syndrome, sudden death
How to prevent the spread of influenza
VACCINATE (the exact virus changes from year to year, and therefore high risk people should
wash hands
cover nose and mouth when sneezing and coughing
don’t touch face
isolate when sick and avoid others who are sick
people at high risk of influenza complications
over 65
resident of chronic-care facilities
people with chronic diseases
pregnant people in the 2nd or 3rd trimester during flu season
treatment of influenza
rest, fluid intake, paracetamol, antivirals
NOT ANTIBIOTICS
neuraminidase inhibitors
zanamivir (powder for inhalation) and oseltamivir (oral preparation)
use within 48 (ideally 12) hours of symptoms starting up
exceptions can be made for critically ill people, and those who have been hospitalised due to the influenza
prevents the sialic acid receptors from being cleft, therefore the virion cannot be released from the host cell
side effects of zanamivir: allergic reaction, arrhythmia, seizure, infection, sinusitis, nausea
side effects of oseltamivir: aggravation of diabetes, pyrexia, seizure, unstable angina, nausea and vomiting
Herpes family
dna viruses
herpes simplex virus 1: orofacial herpes (cold sores)
herpes simplex virus 2: genital herpes
varicella zoster virus: chickenpox and shingles
epstein-barr virus: infectious mononucleosis
cytomegalovirus: flu-like syndrome, infectious mononucleosis-like syndrome, retinitis
herpes simplex
enveloped, linear ds DNA
replication and assembly occur in nucleus on infected cell
glycoproteins (envelope spikes) interact with a number of cell receptors
fuses with membrane of host cell, enters nucleus. in there the DNA replicates and mRNA is formed and sent outside the ribosomes for protein production. late proteins return to the nucleus and form the capsid and enzymes. early proteins form the envelope around the capsid as it exits the nucleus
blister and scab. can form around mouth, eye, or genitals. spread by direct contact with lesion fluid.
if spread congenitally (from mother to baby) 30% of babies will develop encephalitis (brain inflammation)
varicella-zoster virus
enveloped with ds linear dna
interacts with unknown receptors
causes a primary infection of chickenpox, coughing and skin lesions
for most people the virus is removed from the body’s system after infection, however for others it stays in the nerve ganglia. when it reactivates it travels down the nerves and causes shingles (rash) which is very painful
cytomegalovirus
in healthy people: flu-like syndrome, infectious mononucleosis-like syndrome (does not need to be treated)
in severely immunocompromised (such as those with aids): can cause retinitis
aciclovir
guanosine derivative
valaciclovir is an aciclovir pro-drug
most to least effective: herpes simplex > varicella zoster > epstein-barr > cytomegalovirus
treats: orofacial herpes, genital herpes, herpes-simplex associated encephalitis, chickenpox in immunocompromised patients, shingles
administered topically for genitals and mouth, orally for eyes and shingles, iv for complications
has a poor bioavailability, but valaciclovir improves it
side effects: nausea, headache, when given iv can cause local inflammation or renal dysfunction (risk reduced by a slow infusion and good hydration)
Ganciclovir
guanosine analogue
valganciclovir (prodrug)
high specificity for cytomegalovirus
available orally or by iv, but bioavailability is very low so usually iv.
half life of 4 hr
excreted in urine
side effects: carcinogenic, teratogenic, bone marrow suppression (therefore its considered cytotoxic)
penciclovir
guanine analogue
prodrug is called famciclovir
specific for herpes simplex and varicella zoster
treats: herpes simplex labialis (lips), genital herpes simplex, shingles
topical for herpes infections, given as the prodrug famciclovir to treat shingles
hepatically metabolism and excreted renally
half-life: 2-2.5 hours
foscarnet
phosphonic acid derivative
specific for herpes simplex and cytomegalovirus
has loads of side effects making not the first choice
for herpes simplex infections in immunocompromised patients that don’t respond to aciclovir, cytomegalovirus in AIDS
HIV as a virus
retrovirus
human immunodeficiency virus
enveloped virus with + ss RNA with reversed transcriptase
glycoproteins (especially gp 120) interact with the CD4 receptor, and have a coreceptor of CCR5 and CXCR4
HIV-1 is worldwide and causes 95% of infections, while HIV-2 is only in west Africa and spreads less well but causes worse symptoms and is resistant to some antiretrovirals
how HIV replicates
glycoprotein 120 binds to the CD4 receptor in CD4 t cells
cell and virus membrane fuse
virus enters cell and releases RNA and reverse transcriptase
reverse transcriptase turns the RNA into DNA in the cytoplasm
the DNA enters the nucleus, and integrase adds it to the host DNA for replication
Transcription occurs, and some of the mRNA is used as viral RNA and others is used to make polypeptides which viral proteases use to make the viral membrane and enzymes
Transmission of HIV
unprotected sex (semen and vaginal fluids)
sharing needles or syringes that have been contaminated with blood that is HIV positive
blood transfusion (lives in blood)
mother-to-child during pregnancy, delivery, or breastfeeding (can cross the placenta, cervical fluids, or breastmilk)
How AIDS presents
Acquired Immunodeficiency syndrome
when the patient gets infected initially, they have flu-like symptoms for a few weeks. headaches and fever
then for the next 6-7 years there are no symptoms, but the virus is replicating in the lymph nodes
after about 7 years the immune system starts to fail and stops being able to fight the disease
they also will not be able to fight opportunistic infections that immunocompetent people are not susceptible to, and AIDS related cancers
common opportunistic diseases
TB, candida, cytomegalovirus
oesophagus fungal infections
toxoplasmosis
retinitis
pneumocystis pneumonia
lymphoma and corporis sarcoma (cancer of the lymph nodes and a type of skin cancer)
Diagnosis of AIDS
based on clinical symptoms
test to see if there’s lymphopenia
pcr of blood for viral RNA
ELISA or western blot test
Highly active antiretroviral therapy
ART
generally consists of two nucleoside analogue reverse transcriptase inhibitors plus a protease inhibitor/a non-nucleoside reverse transcriptase inhibitor/integrase strand transfer inhibitor
3 drugs increase CD4 count more than 2, and reduce the copies of HIV RNA copies floating around
Enfuvirtide
inhibits HIV fusion
subcutaneous injection when resistance becomes a problem or if they’re intolerant of other antiretrovirals
side effects: flu-like symptoms, headache, mood alterations, gastrointestinal effects, dizziness, hypersensitivity
Reverse transcriptase inhibitors
nucleoside analogue: analogue of the naturally occurring nucleosides that make up viral DNA that compete to bind to the active sites of reverse transcriptase eg. zidovudine, didanosine
non-nucleoside analogues: non competitively bind near the catalytic site and denature it. eg nevirapine
protease inhibitors in art
prevents the useless polypeptides from being broken up into viral proteins
given orally
also treat chronic hepatitis c
eg. saquinavir, ritonavir
integrase strand transfer inhibitors
work by preventing the viral dna from being added to the host dna
film-covered tablets
eg. bictegravir
Goals of ART
provide maximum suppression of viral load (if there’s less virus, the immune system doesn’t spend all its time fighting it. also reduces chance of spreading)
restore and preserve immune function
reduce morbidity, and HIV-related infections
prevent onward transmission of HIV
minimise adverse affects (for compliance as they will be taking these drugs for the rest of their life)
liver functions
synthesis (bile, albumin, coagulation factors, prothrombin, cholesterol. meaning when hepatocytes are not working properly blood proteins will be low and prothrombin times will be unusually long)
metabolising
detoxifying (carcinogens and ammonia)
release of enzymes from hepatocytes
injury to cells means their contents leak out. electrolytes especially K+, and enzymes
elevations of aspartate aminotransferase and alanine aminotransferase greater than 10 times the normal means there’s severe hepatocyte damage
bilirubin
final part of the breakdown of haemoglobin
must be metabolised by liver and released in the bile
when it cannot be metabolised it collects in the skin and eyes causing jaundice
Types of viral hepatitis
acute: acute inflammation with necrosis for 6 months or less
variety of symptoms, from asymptomatic to liver failure but usually weakness, nausea and vomiting, fever, jaundice
chronic hepatitis: continued inflammation and necrosis that leads to fibrosis and cirrhosis and irreversible damage
asymptomatic or mild symptoms, abnormal blood tests the only manifestation, jaundice, fluid retention
infections caused by different hepatitis viruses
HAV - always acute, normally mild. 0.1% liver failure. just treat symptoms. inactivated vaccine. faecal-oral route
HBV: 1-10% chance of becoming chronic. 0.1-1% liver failure. 6-in-1 vaccine. antivirals to treat chronic infection. spread the same way as HIV
HCV: nearly always causes chronic infection, and 60% of patients get cirrhosis. 0.1% have liver failure. drugs to treat very well, but no vaccine. parenteral route
HDV: often chronic. 5-20% have liver failure. treated with interferon, uses the same vaccine as HBV. same routes as HBV
HEV: always acute. 1-2% liver failure. no drugs that work, no vaccine. faecal-oral route
Pegylated interferon-alpha
subcutaneous and intermuscular
monotherapy for Hep b, in combination with ribavirin for hep c that is not responding to directly acting antivirals
binds to receptors that release interferon alpha in the cell, making a non-virus specific antiviral state in the cell
injected once weekly
taken for one year, as opposed to nucleoside analogues which have to be taken for the rest of the patients life
absence of resistance and
frequent side effects (depression anxiety) and sc injection
nucleoside analogues in treating hepatitis B
oral route
inhibit reverse transcriptase, but the virus replicates again after stopping treatment
lamivudine
analogue of cytidine
inhibits rt and dna polymerase
treats HBV, and HIV
for those that cannot take interferon with mild liver damage
high levels of resistance in long-term therapy
entecavir/tenofovir
potent hbv inhibitors with high barrier to resistance
oral rt inhibitors
dosage needs to be adjusted for those with kidney impairment
adefovir
virus unlikely to develop resistance than lamivudine
less efficacious and more expensive than entecavir, and tenofovir
kidney damage
DAA
direct acting-antivirals
cures HCV after about 2-3 months orally
protease inhibitors, NS5A inhibitors, polymerase inhibitors
Ribavirin
oral route
prodrug that is activated by kinases into a 5’-triphosphate nucleotide
incorporated into the viral RNA and induces mutations
side effects: teratogenic, and collects in rbc who cannot eliminate it so it remains in the system for 6 months as the RBCs turn over
