lecture 7 Flashcards
(40 cards)
Antiviral Agents
Viruses have no independent metabolic activity.
Only replicates within a cell of its host.
Simpler than bacteria.
Contain either DNA or RNA (we know more RNA ones)
Cause much of the morbidity and mortality in populations worldwide.
*we used to think we could get HIV the same way as getting a cold, now we know that isn’t true
Viruses
The number of drugs available to treat viruses is low, but antiviral drug development has greatly increased because of AIDS epidemic.
Several viral diseases are prevented by vaccines: measles, mumps, rubella, polio, chickenpox, smallpox, hepatitis A and B, rabies and Influenza.
!!Antivirals are only really used for serious illnesses (they are highly chemical) so I will lose points if you give an antiviral for a cold!!!
Innate and Humeral responses
pathogen –> natural barriers –> contact with the immune system
–> no immune response (tolerance)
–> immune response
–> innate (nonspecific, phagocytosis, inflammatory response)
–> adaptive (specific, humoral, cell mediated, immune memory)
*Memory cells don’t last forever, which is why we need booster shots for things like tetanus
*SEE OTHER PARTS OF IMAGE!!
HIV pathophysiology
Basis of how antivirals were created, IMPORTANT!!! KNOW THIS!!
After entry, reverse transcriptase converts RNA to DNA (reverse from the usual DNA to RNA)
Integrate into cell genome to make copies
Once you have copies you make
RNA for the virus (transcribe DNA to viral RNA)
RNA makes proteins (translation to viral proteins)
Need to package it all and the genome together (assembly into virus particles)
Budding and release to then infect others
(!!IMAGE IS REALLY IMPORTANT FOR THIS!!)
Different mechanisms of antiretroviral drugs (KNOW ALL THESE AND THEIR MECHANISMS)
- Entry inhibitors
- Fusion inhibitors (FIs) - HIV
- Chemokine receptor 5 antagonists (CRAs) - HIV - Nucleoside reverse transcriptase inhibitors (NRTIs)- HIV, HEP-B
- Non-nucleoside reverse transcriptase inhibitors (NNRTI)-HIV
- Protease inhibitors (PI) – HIV, HEP C
- Integrase strand transfer inhibitors (ISTIs) -HIV
- Polymerase Inhibitors – Herpes, HEP C
- Neuraminidase Inhibitors - Influenza
- Interferons
- Monoclonal antibodies
transcriptases are similar to polymerases?
HIV Infections
Caused by HIV1 and HIV2.
Most medications are against HIV1.
Infect helper T lymphocytes (CD4+ cells). (CD4 is a protein found on the surface of certain immune cells (CD4+ T cells))
Not everybody develops AIDS (immunosuppressed) but they can be carriers.
Most patients die of SECONDARY INFECTIONS (the ones you couldn’t fight off because you had HIV)
HIV pathophysiology
HIV single stranded RNA.
Requires the enzyme reverse transcriptase to synthesize DNA.
Attaches to the CD4 proteins on the surface of the cells.
Cells die in about 30 hours.
Can also infect macrophages and microglial cells which carry CD4 proteins.
*HIV infects CD4+ T cells by binding to the CD4 receptor (along with a co-receptor like CCR5 or CXCR4). The virus then enters the cell, integrates into its DNA, and hijacks it to produce more HIV particles.
HIV transmission + prevention
In all body fluids of infected patients (blood, semen, vaginal secretions).
Prevention can be achieved by using condoms, limiting partners, abstinence, and certain medications.
Infection can occur after 1 exposure, risk increases with increased fluid exposure.
Antiretroviral drugs can greatly reduce risk of HIV transmission.
Antiretroviral drugs
HAART (Highly Active Antiretroviral Therapy)
Combination of 3 or more medications (nucleoside analogues and protease inhibitors). (because you won’t be able to do it with one?)
Has harsh side effects and potential for drug resistance.
Reduce morbidity and mortality
Improve the quality of life
!!Reduce plasma viral RNA load
Prevent transmission to others (sex partners, needle-sharing partners, mother to infant)
Prevent drug resistance
Improve immune function
- Fusion Inhibitors; FI’s
Block fusion of the viral membrane with the lipid bilayer of the plasma membrane.
Administered subcutaneously.
Only 1 available
- Enfuvirtide (Fuzeon)
- Expensive to manufacture
- Generally well tolerated but
may cause hypersensitivity,
nephrotoxicity, neutropenia
and thrombocytopenia.
*Need CD4 and CCR5 to properly bind
- CCR5 antagonists
CCR5 antagonists selectively and reversibly block entry into the CD4 T-cells by preventing interaction between CD4 cells and the gp120 subunit of the viral envelope glycoprotein.
Only one available
Maraviroc (Selzentry)
*Won’t be able to enter unless it binds to all the necessary things
- Nucleoside reverse transcriptase inhibitor NRTIs
They competitively bind to reverse transcriptase and cause premature DNA chain termination.
Require intracellular phosphorylation via host enzymes before they can inhibit viral replication.
(In HIV, reverse transcriptase converts RNA to DNA for replication?)
- Nucleoside reverse transcriptase inhibitor NRTIs examples
abacavir
didanosine
zidovudine
Abacavir
Analogue of the pyridine, guanine
83% bioavailability and penetrates cerebrospinal fluid well.
Gets converted to active form which causes CHAIN TERMINATION AND COMPETES FOR BINDING TO REVERSE TRANSCRIPTASE
Adverse effects include fatigue, nausea and vomiting, abdominal pain, diarrhea, headache, rash, dyspepsia, and hypersensitivity reactions.
(SEE IMAGE)
- Non-nucleoside reverse transcriptase inhibitors; NNRTIs
Delavirdine
- These agents cause a STEREOCHEMICAL CHANGE WITHIN REVERSE TRANSCRIPTASE, thus INHIBITING NUCLEOSIDE BINDING AND INHIBITION OF DNA POLYMERASE
Must be used in combinations with other antiretroviral drugs.
May cause rashes and hypersensitivity reactions.
(SEE IMAGE)
- Integrase Strand Transfer Inhibitors; INSTI’s AND EXAMPLES
Interfere with the INTEGRASE ENZYME, which HIV needs to INSERT its GENETIC MATERIAL into human cells.
Also called integrase inhibitors.
5 are available
!!Raltegravir (Isentress)
!!Dolutegravir (Tivicay)
!!Elvitegravir (Vitekta)
(SEE IMAGE)
- Protease Inhibitors; PI’s
Restrain ENZYMES needed for HIV REPLICATION
One of the most effective antiretroviral drugs, used with NRTI’s
They are used to treat HIV/AIDS, hepatitis C, and COVID-19
May cause GI disturbances, fat distribution, diabetes, decreased bone density, elevated triglycerides.
INHIBIT CYTOCHROME P450 ENZYMES possibly causing drug interactions.
- Protease Inhibitors; PI’s EXAMPLES
atazanavir
ritonavir
Atazanavir
HIV-1 protease inhibitor, used with ritonavir.
Disrupts the function of HIV PROTEASE.
May cause arrhythmias, rashes, hyperbilirubinemia, nephrolithasis, nausea, jaundice.
*Uses proteases to assemble itself, so the protease inhibitor can slow that down
(SEE IMAGE)
Overview of antiviral mechanisms
(VERY IMPORTANT TO KNOW THE IMAGE!!!)
*Pathogenesis of where the enzymes work (learn the process, and the rest should make sense)
fusion inhibitors are for binding
Cytomegalovirus (Human herpes virus 5)
Common virus 60-90% of adults have had CMV infections.
Once infected, your body retains the virus for life.
Most people don’t know they have cytomegalovirus (CMV) because it rarely causes problems in healthy people.
Transmitted through blood, body fluids or transplanted organs.
Can also pass through the placenta, risk for fetus
Congenital CMV may be asymptomatic but can cause abortion, still birth or postnatal death.
(CMV is more of an issue for women who are pregnant, you could pass it on to fetus)
GANCICLOVIR, VALGANCICLOVIR, FOSCARNET and CIDOFOVIR, which target VIRAL POLYMERASES, are used to treat immunocompromised individuals or affected newborns.
Valganciclovir
A synthetic purine nucleotide.
Inhibit viral replication by chain termination.
The L-valyl ester is cleaved by esterases in the intestines and the liver, leaving ganciclovir to be absorbed by the virus-infected cells.
Incorporates into viral DNA and inhibits viral DNA polymerase.
Used for prophylaxis and treatment of systemic CMV infections in immunocompromised patients.
Used to prevent CMV disease in patients who have received an organ transplant
Can cause neutropenia, thrombocytopenia and anemia as well as headaches, fever, ataxia, confusion, tremor and edema.
Herpes Zoster (Shingles)
Caused by varicella zoster virus (chickenpox)
The chickenpox virus doesn’t leave your body after you have chickenpox.
- Instead, the virus stays in a portion of your spinal nerve root called the dorsal root ganglion.
Shingles manifests as blisters and severe pain
The most common complication of shingles is long-term nerve pain called postherpetic neuralgia
ACYCLOVIR, VALCYCLOVIR and FAMCICLOVIR are used to shorten the length and severity of the illness.
*Rashes, painful (shingrix to help prevent shingles, especially if you’ve had chickenpox)
**Chicken pox increases risk of shingles because they both are caused by the same virus VZV
Acyclovir
!!Interfere with DNA synthesis and inhibits viral multiplication
