Antiviral Pharmacology
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Antiviral Pharmacology
PHSC-1613 (Pharmacological Basis of Therapeutics I)
Steve Phipps, PharmD, PhD
______________________________________________________________________________________________________
Learning Objectives
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•
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Know/explain class (of antiviral) and mechanism of action
Know the “big items” that are identified -&- specified
Explain/characterize the key concepts from the following figures
– Katzung: 49-1
– G -&- G: 62-1
/
/
49-4(*)
64-1 /
63-1
/
58-5 [12th ed.]
Required Reading
•
Safrin S. Antiviral Agents (Chapter 49). In: Katzung BG, ed. Basic and Clinical Pharmacology, 14th ed. New York, NY: McGraw-Hill; 2015:863-893.
o AccessPharmacy:
– Chapter 49: Antiviral Agents
Recommended Reading
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•
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Acosta EP. Antiviral Agents [Nonretroviral] (Chapter 62). In: Brunton LL, Hilal-Dandan, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of
Therapeutics, 13th ed. New York, NY: McGraw-Hill; 2018:1105-1115.
Kiser JJ, Flexner CW. Treatment of Viral Hepatitis [HBV/HCV] (Chapter 63). In: Brunton LL, Hilal-Dandan, Knollmann BC, eds. Goodman & Gilman’s The
Pharmacological Basis of Therapeutics, 13th ed. New York, NY: McGraw-Hill; 2018:1119-1133.
Flexner CW. Antiretroviral Agents and Treatment of HIV Infection (Chapter 64). In: Brunton LL, Hilal-Dan R, Knollmann BC, eds. Goodman & Gilman’s The
Pharmacological Basis of Therapeutics, 13th ed. New York, NY: McGraw-Hill; 2018:1137-1154.
AccessPharmacy:
– Chapters 62, 63, and 64 [for the above chapters]
Antiviral Pharmacology
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Comments -&- A Different Approach
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Why a different approach? Well ... there are ~63-65 drugs on the following pages. Yes – that’s a lot! But it is doable ... and we have 4 lectures in which to do it.
It is a significant challenge to find the balance between equipping you with the core knowledge -and- not overwhelming you with the volume of information.
I’m endeavoring to accomplish both ... and it will require our best efforts. Work diligently with me in order to make this as effective and efficient as possible. 
Virus Particle Components
Overview of Antiviral Drug Action
[from ‘Life Cycle’ perspective]
Figure 49-1
Antiviral Pharmacology
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Viral Replication – DNA Viruses
Figure 62-1A; Example of HSV
Viral Replication – RNA Viruses
Figure 62-1B; Example of Influenza
Antiviral Pharmacology
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Categorization of the antiviral agents can take various forms. For organizational consistency and clarity, the following pages list the antiviral classes (including the
corresponding antiviral agents) similarly to how they are outlined in the Katzung textbook. (Please refer to the above ‘Required Readings’.)
Herpes Simplex Virus (HSV)
Drug
-&-
Varicella-Zoster Virus (VZV)
Class / Mechanism
Katzung: pp. 864-867
“Big” Items
Acyclovir
Valacyclovir
Famciclovir
Penciclovir
Docosanol
Trifluridine
Cytomegalovirus (CMV)
Drug
Class / Mechanism
Katzung: pp. 867-869
“Big” Items
Ganciclovir
Valganciclovir
Foscarnet
CMV -&- HSV
Antiviral Pharmacology
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Cidofovir
Letermovir
Inhibits CMV replication (targets CMV DNA terminase complex
– necessary for DNA packaging/processing)
CMV prophylaxis – hematopoietic stem cell transplant / po/IV / substrate of CYP2D6 and CYP3A4
Replication Cycle of HIV-1
Figure 64-1
Antiviral Pharmacology
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Antiretroviral Agents -- Nucleoside -&- Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Comments / Content / Items -- to know about this group of agents:
Drug
Class / Mechanism
“Big” Items
Abacavir
Emtricitabine
Lamivudine
HBV and HIV
Tenofovir disoproxil
fumarate
HBV and HIV
Zidovudine
Nucleoside: pentose + base
Nucleotide: pentose + base + phosphate
group(s)
Katzung: pp. 870-876
Antiviral Pharmacology
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Antiretroviral Agents -- Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Katzung: pp. 876-879
Comments / Content / Items -- to know about this group of agents:
Drug
Class / Mechanism
“Big” Items
NNRTI
CYP3A metabolism / CNS ADRs / skin rash / GI (N/D)
Efavirenz
Etravirine
Nevirapine
Riplivirine
Doravirine
Antiviral Pharmacology
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Recall:
Katzung: pp. 879-882
Antiretroviral Agents -- Protease Inhibitors (PIs)
Comments / Content / Items -- to know about this group of agents:
Drug
Atazanavir
Atazanavir
+ cobicistat
Darunavir
Fosamprenavir
Class / Mechanism
“Big” Items
Antiviral Pharmacology
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Lopinavir
+ ritonavir
Ritonavir
D/C’d -- as the individual agent
Tipranavir
Antiretroviral Agents -- Entry Inhibitors
Katzung: pp. 882-883
Drug
Class / Mechanism
Enfuvirti
de
Fusion Inhibitor
Maravir
oc
CC5R Antagonist
“Big” Items
Antiviral Pharmacology
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Antiretroviral Agents -- Integrase Strand Transfer Inhibitors (INSTIs) ~ “Integrase Inhibitors”
Drug
Class / Mechanism
“Big” Items
Dolutegravir
Must be given in combination
Raltegravir
Must be given in combination
Cabotegravir
Katzung: pp. 883-884
Antiviral Pharmacology
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Antihepatitis Agents -- Hepatitis B Virus (HBV)
Drug
Class / Mechanism
Katzung: pp. 884-887
“Big” Items
Peginterferon Alfa-2a
Interferon Alfa-2b
Adefovir dipivoxil
HBV
Entecavir
Lamivudine
[See above]
Tenofovir alafenamide
[See above]
[See above]
HBV and HIV
[See above]
Figure 58-5
Figure 49-1
Antiviral Pharmacology
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Hepatitis C Virus – Important Proteins « Drug Targets
•
NS5A
•
NS3/4A -- nonstructural protein 3 -- a protease ® essential for HCV replication
-- nonstructural protein 4A -- cofactor for NS3
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NS5B
-- nonstructural protein 5A -- essential for HCV replication
-- nonstructural protein 5B -- an RNA-dependent RNA polymerase ® essential for HCV replication
Antiviral Pharmacology
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Figure 49-4*
o
NS5A Inhibitors:
Elbasvir / Pibrentasvir / Ledipasvir / Ombitasvir / Velpatasvir
o
NS3/4A Inhibitors:
Grazoprevir / Glecaprevir / Paritaprevir / Voxilaprevir
o
NS5B Inhibitors:
Sofosbuvir / Dasabuvir
Antihepatitis Agents -- Hepatitis C Virus (HCV)
Trade
ZEPATIER
MAVYRET
Agents
Class / Mechanism
Elbasvir
NS5A Inhibitor
Grazoprevir
NS3/4 Protease Inhibitor
Pibrentasvir
NS5A Inhibitor
Glecaprevir
NS3/4 Protease Inhibitor
Katzung: pp. 887-891
“Big” Items
Antiviral Pharmacology
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HARVONI
VIEKIRA Pak
VIEKIRA XR
EPCLUSA
VOSEVI
Ledipasvir
NS5A Inhibitor
Sofosbuvir
NS5B Polymerase Inhibitor
Ombitasvir
NS5A Inhibitor
Paritaprevir
NS3/4 Protease Inhibitor
Dasabuvir
NS5B Polymerase Inhibitor
Ritonavir
CYP3A Inhibitor
Velpatasvir
NS5A Inhibitor
Sofosbuvir
NS5B Polymerase Inhibitor
Velpatasvir
NS5A Inhibitor
Sofosbuvir
NS5B Polymerase Inhibitor
Voxilaprevir
NS3/4 Protease Inhibitor
Also: Ribavirin
®
Antiinfluenza Agents
Drug
Oseltamivir
Class /
Mechanism
Katzung: pp. 891-892
“Big” Items
Antiviral Pharmacology
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Zanamivir
Peramivir
Baloxivir
marboxil
Amantadine
Rimantadine
Other Antiviral Agents
Katzung: p. 893
Drug
Class /
Mechanism
“Big” Items
Palivizumab
Imiquimod
Other Antiviral Agents
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Remdesivir
-- COVID-19 [hospitalized patients]
•
Bamlanivimab
-- COVID-19 [mild- to moderate-]
•
Bamlanivimab + etesevimab
//
//
inhibits RNA-dependent RNA polymerase [essential for replication]
mAb directed against SARS-CoV-2 spike protein [\ blocks viral attachment]
-- COVID-19 [mild- to moderate-]
//
both directed against SARS-CoV-2 spike protein [\ blocks viral attachment]
Antiviral Pharmacology
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(adjacent/overlapping sites)
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Casirivimab + imdevimab
-- COVID-19 [mild- to moderate-]
//
both directed against SARS-CoV-2 spike protein [\ blocks viral attachment]
(at nonoverlapping sites)
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Ribavirin
-- Broad spectrum // inhibits viral replication by inhibiting viral RNA polymerase; also inhibits capping of viral mRNA
-- HCV // off-label: hepatitis E; RSV; viral hemorrhagic fever
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Tecovirimat
-- Treatment of small pox
//
inhibits an orthopoxvirus wrapping protein ® inhibits the exit/egress of virions from infected cells