Antivirals Flashcards
Viruses overview and how they function?
Obligatory intracellular parasites
Uses host cell’s energy/ machinery to synthesize :
Proteins (structural, regulatory)
Nucleic acid (DNA, RNA)
Viral enzymes
Cannot replicate on its own
Must attach to & enter the host cell
Difficult to kill -
Live inside the host cells
Any drug that kills a virus may also kill the host cell
Challenges in Developing Effective Antiviral Drugs?
Lack of specific viral targets
Virus replicates intracellularly
Asymptomatic during rapid growth phase
Escape from immune surveillance
Persistence of latent reservoirs
Development of drug resistance
Viruses: General Structure
Genome > Capsid >Glycoprotein > Coat
With genome being the innermost
The central dogma of molecular biology?
Reverse transcrip
<—
DNA. —> RNA —>PROTEIN
Repli/ —Transcrip—Translation
Classification of viruses?
Non-enveloped and enveloped
RNA viruses and DNA viruses
Process of viral replication?
Adsorption > Entry> Translation > Replication > Assembly > Release
Targets of antiviral drugs with viruses?
Attachment - HIV. Parainfluenza viruses
Penetration and uncoating - influenza virus, HIV
MRNA synthesis - Influenza virus, CMV
Polyprotein processing - Hepatitis C virus, HIV-1
DNA/RNA replication - Herpesviruses, HIV-1, Hep B, Influenza virus, Hep C
Integration - HIV-1
Assembly - HIV-1, Hep B
Release - Influenza virus
What type of virus is Herpes virus?
Genome: dsDNA
DNA: DNA Polymerase
RNA: RNA Polymerase
ACYCLOVIR MOA
Activated by Viral thymidine kinase (TK) to a monophosphate form
Host enzyme then converts the monophosphate to Di- and then tri-phosphate (active) form
Which INHIBITS THE VIRAL DNA POLYMERASE causing chain termination
NOT EFFECTIVE AGAINST CMV because CMV-TK cannot activate the drug
MOR OF ACYCLOVIR
Lack (mutation ) of viral thymidine kinase
A/E of ACYCLOVIR
Nausea
Vomiting
Diarrhea
NEPHROTOXICITY
NEUROTOXICITY (tremors, confusion, convulsions)
Valacyclovir?
A prodrug that gets converted to acyclovir - has long plasma half life
Use of ACYCLOVIR
- HERPES SIMPLEX VIRUS INFECTION
HSV 1 - MUCOCUTANEOUS HERPES
Herpetic gingivostomatitis,
HSV 2 - HERPES PROCTITIS
B. KERATOCONJUCTIVITIS - topical .5x daily
C. SEVERE FORMS OF HERPES -
HERPES ENCEPHALITIS
NEONATAL HSV INFECTION
HERPES in IC pt.
D. PRIMARY GENITAL HERPES - HSV 2
E. RECURRENT GENITAL HERPES - HSV 2
Use of ACYCLOVIR
- VARICELLA ZOSTER
. COMPLICATED CASES
. HELPS IN REDUCING TIME OF ERUPTION
. CRUSTING
. FEVER DURATION
. PREVENTS VISCERAL COMPLICATION
- PROPHYLACTIC USE IN PT. RECEIVING IMMUNOSUPPRESSANTS
GANCICLOVIR MOA
Activated by vital thymidine kinase and host enzymes, which inhibits the viral DNA polymerase
Diff between GANCICLOVIR and ACYCLOVIR
GANCICLOVIR differs from ACYCLOVIR by a single carboxyl side chain. This confers 50x greater activity than acyclovir against CMV
GANCICLOVIR Activity
CMV (most important), HSV, VZV
USE OF GANCICLOVIR
CMV RETINITIS IN IMMUNOCOMPROMISED PT.
(Intravitreal injection or intraocular implant)
A/E of GANCICLOVIR
BONE MARROW SUPPRESSION - LEUKOPENIA, THROMBOCYTOPENIA, ANEMIA
MOA OF CIDOFOVIR
its Phosphorylation to active form inside the cell is independent of viral enzymes
INHIBITS DNA POLYMERASE
Active against HSV, CMV
Uses of CIDOFOVIR
CMV RENITIS IN IMMUNOCOMPROMISED PT.
- ACYCLOVIR - RESISTANT HSV
A/E of CIDOFOVIR
NEPHROTOXICITY, NEUTROPENIA
MOA of Foscarnet
Does not require phosphorylation for antiviral activity
INHIBIT DNA POLYMERASE
INHIBITS VIRAL RNA POLYMERASE AND HIV REVERSE TRANSCRIPTASE
MOR of Foscarnet
Point mutation in viral DNA Polymerase and HIV reverse transcriptase
Uses of Foscarnet
CMV retinitis
*Colitis
*Esophagitis
Acyclovir-resistant strains of HSV
A/E of Foscarnet
NEPHROTOXICITY
*ELECTROLYTE IMBALANCE
*HYPOCALCAEMIA
INFLUENZA VIRUS overview
Genome:8 single-stranded -ve sense RNA
Viral hemagglutinin (HA) binds to sialic acid receptors on cell
Receptor-mediated endocytosis,
M2 proton channel allows proton influx into virions ;
Acidification triggers uncoating & release of ribonucleoprotein (RNP) complex into cytoplasm
Viral RNA enters host nuclei, viral replication and viral protein synthesis
Neuraminidase (NA) cleaves and removes sialic acid receptors from the surface of the cell, allowing release and spread of virus to new cells
Drugs for INFLUENZA VIRUS
Amantadine and Rimantadine inhibit the influx of proton through M2
Drugs for INFLUENZA VIRUS
Viral neuraminidase cleaves terminal NEURAMINIC ACID (also called SIALIC ACID) residues from GLYCAN structures on the surface of the infected cell
This promotes the release of progeny viruses
Neuraminidase also cleaves SIALIC ACID residues from viral proteins, preventing aggregation of viruses
Drugs for INFLUENZA VIRUS
What are the Neuraminidase Inhibitors?
ZANAMIVIR - Inhalation
OSELTAMIVIR - Orally
Drugs for either INFLUENZA A or B VIRUS
Amantadine - Influenza A only
Zanamivir, Oseltamivir - both Influenza A and B
MOA of Amantadine and Rimantidine
Inhibits replication of influenza viruses
Acts on M2 ion channel and INHIBIT VIRAL UNCOATING (early stage) and VIRAL ASSEMBLY (late step)
Amantadine vs Rimantidine
AMANTADINE:
Excretion - unchanged
A/E - Cross BBB. CNS effects. Insomnia. Dizziness. Light headedness
RIMANTIDINE:
Excretion - Metabolite formed
A/E - Fewer CNS disturbance
Uses of Amantadine
Prophylaxis and txt of influenza A
Parkinsonism
A/E of Amantadine
Nausea
Anorexia
Insomnia
Dizziness
*Nightmares
Rarely hallucinations
*Ankle edema
Moa of Zanamivir and Oseltamivir
Neuraminidase inhibitors - inhibit Neuraminidase, which is essential for viral replication and release
Interfere with release of progeny influenza virus from infected to new host cells
Halt the spread of infection within the respiratory tract
Use of Zanamivir and Oseltamivir
Influenza A & B
Oseltamivir - DOC for?
H5N1 & H1N1
A/E of Zanamivir and Oseltamivir
Abdominal pain & GI dysfunction - Oseltamivir
Bronchospasm, headache, and dizziness - Zanamivir
Drugs for HBV
Adefovir
Lamivudine
Interferon alfa
Entecavir
A LIE
Moa of Interferon alfa
Activate host cell Ribonuclease which preferentially degrades viral mRNA
Uses of IFN alfa
Hepatitis B (alone or with Lamivudine)
Hepatitis C (with Ribavirin)
Toxicity or A/E of IFN
GI irritation
Flu-like syndrome
Moa of ADEFOVIR
Nucleotide analog that is phosphorylated to its active metabolite
Interferes was th HBV viral RNA-dependent DNA polymerase to inhibit replication
Indication/Use of ADEFOVIR
HBV
ADR or A/E of ADEFOVIR
Dose-related nephrotoxicity
Moa of Entecavir
Inhibits HBV DNA polymerase.
It is nucleoside analog that is phosphorylated to its active metabolite
Selectively blocks HBV polymerase (has a 300-1300-fold higher affinity for HBV vs human DNA polymerase
Moa of Lamivudine
Discuss with Anti-HIV drugs
Moa of Interferon alfa mediated Antiviral Activity
IFN Effects
- INHIBITION OF TRANSCRIPTION
Activates Mx protein
Block mRNA synthesis - INHIBITION OF TRANSLATION
Activates methylase, reducing the mRNA cap methylation
Activates 2’5’ oligoadenylate synthetase ->2’5’A ->inhibits mRNA splicing and activates RNaseL -> cleaves viral RNA
Activates protein kinase P1 -> blocks eIL-2a function -> inhibits initiation of mRNA translation
Activates phosphodiesterase -> blocks tRNA function
THE WHOLE OF POINT 2. IS THE MAJOR MECHANISM
(pto)
Moa of Interferon alfa mediated Antiviral Activity
IFN Effects
- INHIBITION OF POST-TRANSLATIONAL PROCESSING
Inhibits glycosyltransferase, reducing protein glycosylation - INHIBITION OF VIRUS MATURATION
Inhibits glycosyltransferase, reducing glycoprotein maturation - INHIBITION OF VIRUS RELEASE
causes membrane changes -> blocks budding
Drugs for HCV
Simeprevir
Sofosbuvir
IFN alfa
Ribavirin
SSIR
Moa of RIBAVIRIN
Inhibits viral RNA polymerase
Indication/use of RIBAVIRIN
Respiratory Syncytial Virus (RSV) in hospitalized infants (aerosol)
Hepatitis C virus infection (combined with IFN alpha)
Some success against Influenza A & B
Moa of SOFOSBUVIR
Inhibits the Hepatitis C NS5B protein
(Nonstructural protein 5B is an RNA-dependent RNA polymerase that plays a critical role in HCV replication)
CONTRAINDICATIONS of HCV DRUGS
PREGNANCY category x
SIDE EFFECTS of HCV DRUGS
Sudden deterioration of respiratory function (esp in infants)
Hemolytic Anemia
HIV Structural Biology
Structural Proteins?
Matrix P
Envelope P
Core/Capsid P
MEC
HIV Structural Biology
Viral Enzymes?
Reverse T
Integrate
Protease
RIP
HIV Structural Biology
Viral Genome?
2 identical
ssRNA
9700 nucleotides long
Life cycle of HIV
- Binding
- Fusion
- Reverse Transcription
- Integration
- Replication
- Assembly
- Budding
Drug targets of Anti-HIV
CHEMOKINE RECEPTOR ANTAGONIST
PROTEASE INHIBITORS
REVERSE TRANSCRIPTASE INHIBITORS
INHIBITORS OF VIRAL FUSION
INHIBITORS OF VIRAL INTEGRASE
Anti-HIV drug classes, moa and drugs?
Nucleoside reverse transcriptase inhibitors (NRTI)
Blocks reverse transcriptase, an enzyme HIV needs to make copies of itself
Zidovudine
Lamivudine
Abacavir
Tenofovir disoproxil fumarate
Emtricitabine
Moa of NRTI
NNRTIs & NTRIs - block the conversion of HIV RNA to HIV DNA
Because NRTIs lack a 3’-HYDROXYL GROUP on the ribose ring, attachment of the next nucleotide is impossible
Thus they interrupt DNA chain elongation
Zidovudine, drug class?
Thymidine analogue, prototype of NTRIs
Uses of Zidovudine
Prophylaxis - following needlestick injury (Post-exposure prophylaxis)
Prevention of mother to child transmission
A/E of Zidovudine
Bone marrow suppression
Neutropenia
Hepatotoxicity
Myopathy
Drug interactions of Zidovudine
DO NOT co-administer with STAVUDINE since zidovudine reduce the phosphorylation of stavudine
Zidovudine + Azoles/ Paracetamol - toxicity of Zidovudine
Moa of Didanosine
Synthetic analog of deoxyadenosine
Given orally, food decreases its absorption
Uses of Didanosine
Zidovudine-resistant HIV infection
A/E of Didanosine
Dose-dependent pancreatitis
Peripheral neuropathy
Stavudine A/E
Causes dose-limiting peripheral neuropathy
Lactic acidosis (mitochondrial toxicity)
Associated with LIPODYSTROPHY SYNDROME
Lamivudine & Emtricitabine Uses
Both are effective against hepatitis B
Side effects of NRTIs
- MITOCHONDRIAL TOXICITY - affects the normal mitochondrial conversion of pyruvate to acetyl-CoA, resulting in
- Increased CONVERSION OF PYRUVATE TO LACTATE leading to LACTIC ACIDOSIS
- Accumulation of KETONE BODIES & TRIGLYCERIDES. Esterification of high levels of triglycerides in the liver contributes to the development of non-alcoholic HEPATIC STEATOSIS (fatty liver), which can evolve into cirrhosis
Side effects of NRTIs
- PERIPHERAL NEUROPATHY (STAVUDINE)
- MYELOSUPPRESSION including NEUTROPENIA SEVERE & ANEMIA can be reversed with G-CSF & erythropoietin
Side effects of NRTIs
- MYOPATHY
- PANCREATITIS (common with DIDANOSINE)
- SEVERE HYPERSENSITIVITY REACTIONS seem with ABACAVIR - OCCASIONALLY FATAL
Side effects of NRTIs
GI DISTURBANCE
- Nausea
- Vomiting
- Abdominal pain
BONE MARROW SUPPRESSION
- Anemia
- Neutropenia
CNS TOXICITY
- Insomnia
- Headaches
- Peripheral neuropathy
METABOLIC EFFECTS
- Lactic acidosis
-Lactic Acid builds up
- Decrease blood pH
Non- Nucleoside RT Inhibitors, moa and drugs?
NNRTIs bind to and later alter reverse transcriptase, an enzyme HIV needs to make copies of itself
NEVIRAPINE
EFAVIRENZ
ETRAVIRINE
RILPIVIRINE
DORAVIRINE
NEERD
MOA OF NNRTIs
NNRTIs & NRTIs - block the conversion of HIV RNA to HIV DNA
NNRTI common Characteristics
- NNRTIs bind directly to a site on the HIV-1 RT, resulting in blockade of RNA & DNA-dependent DNA polymerase activities
- The binding site is near to, but distant from that of the NRTIs
- Unlike the NRTIs, NNRTIs do not compete with nucleoside triphosphate or require intracellular phosphorylation to be active
- Resistance to NNRTI is generally rapid if given as a monotherapy
- There is NO cross-resistance between NNRTIs, NRIs & protease inhibitors
NEVIRAPINE MOA
Crosses BBB and Placental barrier
Secreted in breast milk
NEVIRAPINE A/E?
Rashes
Hepatotoxicity
EFAVIRENZ MOA
Long duration of action - once daily dosing
Taken on empty stomach
EFAVIRENZ side effects
CNS side effects
TERATOGENIC
NEVIRAPINE USE
USED during PREGNANCY to PREVENT VERTICAL TRANSMISSION
- EASILY CROSSES the PLACENTA
ELTRAVIRINE & DELAVIRDINE A/E
CONTRAINDICATED DURING PREGNANCY
- CAUSE CONGENITAL MALFORMATIONS
Side effects of NNRTIs
DRUG HYPERSENSITIVITY - SKIN RASHES (potentially life-threatening), including STEVEN JOHNSON- SYNDROME
LIVER TOXICITY (NEVIRAPINE)
CNS symptoms (dizziness, drowsiness, insomnia, headache, nightmares) (EFAVIRENZ)
Protease Inhibitors moa and drugs
Block HIV PROTEASE, an enzyme HIV needs to make copies of itself
Darunavir
Ritonavir
Atazanavir
Fosamprenavir
Tipranavir
Saquinavir
DRAFTS
Protease Inhibitors moa
Block the action of HIV PROTEASE enzyme, thus preventing cleavage of viral polyproteins into active proteins needed for the Assembly of new viral particles
Side effects of Protease Inhibitors
REDISTRIBUTION AND ACCUMULATION OF BODY FAT, including BUFFALO HUMP, CENTRAL OBESITY, PERIPHERAL & FACIAL WASTING, BREAST ENLARGEMENT
HYPERGLYCEMIA DUE TO INSULIN RESISTANCE
HYPERLIPIDEMIA
Protease Inhibitors ARE INHIBITORS OF CYP3A4 and cause decreased clearance of other drugs leading to toxicity
INDINAVIR - NEPHROPATHY (RENAL STONES), HEMATURIA, THROMBOCYTOPENIA
Moa of Fusion Inhibitors
Entry inhibitors include fusion inhibitors & attachment inhibitors
They are used in combination therapy for the treatment of HIV
ENFUVIRTIDE MOA
Binds to gp41 & prevents the conformational changes required for the fusion of viral and cellular membranes
A FUSION INHIBITOR
Administer SC
A/E of ENFUVIRTIDE
Pain at the site of injection
Eosinophilia
Hypersensitivity reactions
Moa of Fusion Inhibitors
Blocks HIV envelope from fusing with CD4 cell membrane
Attachment Inhibitors moa and drugs
CCR5 Antagonists - block CCR5 coreceptors on the surface of certain immune cells that HIV needs to enter the cells
MARAVIROC
IBALIZUMAB - monoclonal antibody moa
Binds to CD4 receptor - leads to conformational changes which prevents gp120-CD4 complex from interaction with CCR5/CCR4 receptor — inhibits the viral entry and fusion
Attachment Inhibitors moa
CCR5 Antagonists - blocks HIV from entering CD4 cells
Integrase Inhibitors moa and drugs?
Blocks HIV integrase, an enzyme HIV needs to make copies of itself
DOLUTEGRAVIR
RALTEGRAVIR
DR
Integrase Inhibitors moa
Prevents HIV from integrating its genetic material into the host cell DNA by specifically blocking the action of the viral integrase enzyme
HAART INDICATION
PATIENTS PRESENTING WITH AIDS-DEFINING ILLNESS, LOW CD4+ cell counts (<500 cells/mm3) or HIGH VIRAL LOAD
USE 3 DRUG COMBINATION
2 NRTIs + a PI (+|- Ritonavir) or a NNRTI or INSTIs
HAART AIM
Suppressing HIV load
Minimizing drug toxicity
Minimizing the likelihood of viral resistance
Reducing HIV-related morbidity and mortality
HIV Prophylaxis?
PrEP (pre-exposure prophylaxis) vs PEP (post-exposure prophylaxis)
When is PrEP taken
Before HIV exposure
Everyday before possible exposure
When is PEP taken
After HIV exposure
In emergency situations, PEP is taken within 72hrs (3 days) after possible exposure
Who is PrEP for
People who don’t have HIV and are
- at risk of getting HIV from sex
- at risk of getting HIV from injection drug use
Who is PEP for
People who don’t have HIV but may have been exposed
-during sex
-by sharing injection drug equipment
- sexual assault
- at work through a needlestick or other injury
HIV Prophylaxis
PEP (post-exposure prophylaxis) drugs?
Low viral load: zidovudine + Lamivudine for 1 month
High Viral load: zidovudine + Lamivudine + Indinavir
HIV Prophylaxis
HIV in Pregnancy
2 Regimens available
- Oral ZIDOVUDINE beginning 14&34 weeks of gestation
IV ZIDOVUDINE during LABOR, and ZIDOVUDINE SYRUP to the NEONATE from BIRTH THROUGH to 6 Weeks of age
- NEVIRAPINE as a SINGLE DOSE DURING THE ONSET OF LABOR for the PREVENTION OF HIV TRANSMISSION FROM MOTHER TO NEWBORN, followed by SINGLE DOSE TO THE NEWBORN AFTER DELIVERY
HIV OPPORTUNISTIC INFECTIONS, cd4 <100 and drug of txt
CD4 < 100 :
ESOPHAGEAL CANDIDIASIS - FLUCONAZOLE
HISTOPLAMOSIS -ITRACONAZOLE TOXOPLASMOSIS - SULFADIAZINE + PYRIMETHAMINE
HIV OPPORTUNISTIC INFECTIONS, cd4 <200 and drug of txt
CD4 < 200 :
CRYPTOSPORIDIUM DIARRHEA - HAART
PNEUMOCYSTIS JIROVECI PNEUMONIA - TMP- SMX
HIV OPPORTUNISTIC INFECTIONS, cd4 <50 and drug of txt
CD4 < 50 :
CMV RENITIS - GANCICLOVIR, CIDOFOVIR
CRYPTOCOCCAL MENINGITIS - FLUCONAZOLE +/- FLUCYTOSINE MYCOBACTERIUM AVIUM - AZITHROMYCIN, RIFABUTIN
