Antiviral Pharmacology

Terriann Crisp, Ph.D.

tc@pharmprofessor.com
Crisp Enterprises: Pharmacology Instruction and Consultation, LLC
www.pharmprofessor.com
Confidential - International University of the Health Sciences

Antiviral
Pharmacology

Antiviral Drug Classification

1. Drugs for Herpesvirus Infections

Nucleoside Analogues- compounds (e.g., guanosine or adenosine)
that consists of a purine or pyrimidine base combined with
deoxyribose or ribose and found in DNA or RNA. These pro-drugs
MUST be phosphorylated by viral and host kinases.
Nucleotide any of several compounds that consist of a ribose or
deoxyribose sugar joined to a purine or pyrimidine base and a
phosphate group that are the basic structural units of RNA and DNA
Acyclovir
Ganciclovir
Cidofovir
Trifluridine
Pyrophosphate Derivative
Foscarnet
Terriann Crisp, Ph.D.

Antiviral
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2. Drugs Used to Treat HIV

A. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
Zidovudine
Lamivudine
Emtricitabine
Didanosine
Tenofovir
B. Nonnucleoside Reverse Transcriptase Inhibitors
Efavirenz
Nevirapine

Terriann Crisp, Ph.D.

Antiviral
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Drugs Used to Treat HIV, continued.

C. Protease Inhibitors
Ritonavir
Indinavir
Atazanavir
Fosamprenavir
D. Fusion and Entry Inhibitors
Enfuvirtide
Maraviroc
E. Integrase Strand Transfer Inhibitor
Raltegravir

Terriann Crisp, Ph.D.

Antiviral
Pharmacology

3. Drug treatment for influenza

Oseltamivir (TAMIFLU)
Zanamivir
Amantadine
Rimantadine

4. Drugs for Hepatitis

Ribavirin respiratory syncytial virus
Tenfovir - HBV
Lamivudine - HBV
Simeprevir HCV
Telaprevir - HCV
Interferon-
Interferon-
Terriann Crisp, Ph.D.

Antiviral
Pharmacology

Terriann Crisp, Ph.D.

Antiviral
Pharmacology

I. Antiviral Treatment Considerations

It is important to remember that viruses are obligate
intracellular parasites that always reproduce by using the host
cells metabolic machinery.
Antibacterial and antifungal drugs are not useful for treating
viral infections.
Effective antiviral drugs have been developed for the treatment
of herpesvirus infections, human immunodeficiency virus (HIV),
influenza and hepatitis.

Terriann Crisp, Ph.D.

Antiviral
Pharmacology

II. General Information on Herpesvirus Infections

Herpesviruses are DNA viruses, and the common types are
herpes simplex virus (HSV), varicella-zoster virus (VZV) and
cytomegalovirus (CMV).
HSV herpes genitalis, herpes labialis, herpetic
keratoconjunctivitis and herpetic encephalitis
VZV chickenpox (varicella) and shingles (herpes zoster)
CMV retinitis, esophagitis and colitis

Terriann Crisp, Ph.D.

Antiviral
Pharmacology

III. Drugs for Herpes Infections

A. Nucleoside Analogues
Acyclovir
Ganciclovir (CMV)
Cidofovir
Mechanism of action
These drugs contain purine or pyrimidine bases, and are
considered prodrugs.
They are phosphorylated by viral and host thymidine
kinases; the phosphorylated metabolites inhibit viral DNA
polymerase.
Resistance: involves loss of thymidine kinase activity
Terriann Crisp, Ph.D.

Antiviral
Pharmacology

Acyclovir and other nucleoside analogues are

converted to active nucleoside triphosphates
by viral and host cell kinases.
These active nucleoside triphosphates
compete with endogenous nucleoside
triphosphates and competitively inhibit viral
DNA polymerase.
Acyclovir and the Nucleoside Reverse
Transcriptase Inhibitors (NRTIs) are
incorporated into viral DNA and cause chain
termination.
The loss of an ability to produce viral
thymidine kinase is a major cause of
resistance to acyclovir and ganciclovir.
Terriann Crisp, Ph.D.

Brenner and Stevens Pharmacology 3rd Edition,

Copyright 2010 by Saunders, an imprint of
Elsevier Inc.

Antiviral
Pharmacology

Mechanism of Action:
Acyclovir is an antimetabolite
that is converted to an active
form by viral thymidine
kinase. The active
form interferes with viral DNA
polymerase and acts as a
chain terminator.

Special thanks to McGraw Hill for permission to use figures from Katzung, Masters and Trevor
Basic and Clinical Pharmacology, 11th Edition, Chapter 49, McGraw Hill, a Lange Medical Book.
Terriann Crisp, Ph.D.

Antiviral
Pharmacology

Important Properties of Antiherpes Agents

1. Acyclovir and ganciclovir
Clinical Uses: herpes simplex, herpes genitalis, herpes zoster,
varicella zoster, cytomegalovirus (ganciclovir)
Resistance through changes in UL97 or TK
Acyclovir congeners: famciclovir, penciclovir, valacyclovir
Adverse effects: nephrotoxicity, confusion, coma, encephalopathy
2. Cidofovir
Clinical Uses: cytomegalovirus (CMV) retinitis or herpesvirus
infections.
Not dependent upon intracellular activation for its antiviral
activity.
Hepatotoxicity - major dose-limiting toxicity.
Terriann Crisp, Ph.D.

Antiviral
Pharmacology

B. Foscarnet
Mechanism of action
does NOT require activation by viral or host kinases.
Blocks binding sites on viral DNA polymerase and prevents
attachment of nucleotide precursors to DNA.
Numerous side effects renal impairment, hematologic
deficiencies, cardiac arrhythmias and heart failure.
Clinical Uses: cytomegalovirus, herpes simplex virus, varicella
zoster virus

Terriann Crisp, Ph.D.

Antiviral
Pharmacology

IV. Pharmacological Treatment for HIV

HIV is an RNA retrovirus

Combining the use of two or more drugs reduces viral loads
and improves survival in HIV-positive individuals.
This multidrug regimen has been termed highly active
antiretroviral therapy, or HAART.

Classes of Anti-HIV Drugs

A.
B.
C.
D.
E.
Terriann Crisp, Ph.D.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

Nonnucleoside Reverse Transcriptase Inhibitors
Protease Inhibitors
Fusion and Entry Inhibitors
Integrase Strand Transfer Inhibitors

Antiviral
Pharmacology

Treatment for HIV/Aids

There are five major types of medicines:
1. Reverse transcriptase (RT) inhibitors - interfere with a
critical step during the HIV life cycle and keep the virus from
making copies of itself
2. Protease inhibitors - interfere with a protein that HIV uses
to make infectious viral particles (P-450 inhibitors)
3. Fusion inhibitors - block the virus from entering the body's
cells
4. Integrase inhibitors - block an enzyme HIV needs to make
copies of itself
5. Multidrug combinations - combine two or more different
types of drugs into one (HAART)
NIH: National Institute of Allergy and Infectious Diseases
Terriann Crisp, Ph.D.

Antiviral
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MedlinePlus
A service of the U.S. National Library of Medicine
From the National Institutes of Health National Institutes of Health
Tuesday, September 10, 2013
TUESDAY, Sept. 10 (Health Day News) -- Antiretroviral drugs can provide a high level of protection against HIV for uninfected people in
heterosexual couples in which the other partner has HIV, according to a new study.
The study included more than 1,100 HIV-uninfected people in Uganda who had a partner with HIV, the virus that causes AIDS. The
participants were given antiretroviral drugs and received counseling support throughout the study to help them adhere to their drug
regimen.
The drug adherence rate was 97 percent to 99 percent in the study, which was published Sept. 10 in the journal PLoS Medicine.
After an average follow-up period of 11 months, just 14 of the participants became infected with HIV, according to a journal news release.
The findings provide further proof that strict adherence to what is called antiretroviral pre-exposure prophylaxis offers high levels of
protection to uninfected people, said Jessica Haberer, of Harvard Medical School, and colleagues.
The researchers said several previous studies in various groups (such as men who have sex with men, or women at high risk for HIV) have
shown that taking antiretroviral drugs provided uninfected people with varying levels of protection against HIV. One possible explanation for
the range of findings is different levels of adherence to the antiretroviral drugs, the researchers said.
"Proper support and assessment of adherence will be critical for determining efficacy of [pre-exposure prophylaxis] outside of clinical trials,"
the study authors wrote. "This data will be important for guiding ethical decisions about resource allocation for both prevention and
treatment of HIV."
The Bill & Melinda Gates Foundation funded the study.
HealthDay
Copyright (c) 2013 HealthDay. All rights reserved.
More Health News on:
HIV/AIDS Medicines
Terriann Crisp, Ph.D.

Antiviral
Pharmacology

HIV enters the CD4-positive cell and

viral RNA serves as a template to
produce a complementary doublestranded viral DNA (catalyzed by viral
reverse transcriptase; RNAdependent DNA polymerase).
Viral DNA is incorporated into the cell
nucleus by HIV integrase and
transcribed to RNA.
Viral RNA is incorporated into new
virions and translated to synthesize
polyproteins.
The polyproteins are cleaved into
viral proteins by HIV protease as the
new infectious virions are released
from the cell.
http://www.youtube.com/watch?feature=player_detailpage&v=7oyp1zIIWmM
Terriann Crisp, Ph.D.

Antiviral
Pharmacology

A. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

(NRTIs)
Zidovudine insulin resistance
Didanosine insulin resistance
Emtricitabine
Tenofovir also used to treat hepatitis B infections
Included in most combination drug regimens
Two NRTIs are used together with a protease inhibitor (PI).
HAART decreases viral RNA, reverses CD4 count decline and
decreases opportunistic infections.
Zidovudine can induce bone marrow suppression (causing
anemia and neutropenia).

Terriann Crisp, Ph.D.

Antiviral
Pharmacology

B. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz
Nevirapine

The NNRTIs directly inhibit reverse transcriptase.

Efavirenz used in pregnancy
These drugs do not require metabolic activation.
Are not myelosuppressive (like zidovudine)
Potentially life threatening Stevens-Johnson syndrome
serious side effect

http://www.youtube.com/watch?feature=player_detailpage&v=7oyp1zIIWmM
Terriann Crisp, Ph.D.

Antiviral
Pharmacology

C. Protease Inhibitors (PIs)

Ritonavir
Indinavir
Fosamprenavir

HIV protease is a viral enzyme that cleaves precursor

polypeptides in HIV buds to form the proteins of the mature
virus core.
PIs inhibit proteolytic activity, resulting in the production of
immature non-infectious viral particles.
Terriann Crisp, Ph.D.

Antiviral
Pharmacology

Protease Inhibitors continued.

Use PIs in combination regimens with two NRTIs.
PIs inhibit of P450 enzymes (CYP3A4 isoform) and increase
plasma concentrations of numerous drugs.
Ritonavir and Indinavir may induce insulin resistance.
All PIs can cause lipid accumulation in tissues (lipodystrophy).
fluid intake to avoid nephrolithiasis and crystalluria.

Terriann Crisp, Ph.D.

Antiviral
Pharmacology

D. Integrase Inhibitors
Raltegravir is an integrase inhibitor
Blocks integrase, a viral enzyme that inserts the viral
genome into the DNA of the host cell
Raltegravir is well tolerated

Terriann Crisp, Ph.D.

Antiviral
Pharmacology

E. Fusion and Entry Inhibitors

Maraviroc
Enfuvirtide

These drugs inhibit fusion and entry of HIV and are

Approved for infections from drug-resistant strains of HIV.
Maraviroc is an antagonist of chemokine co-receptor 5
(CCR5)
Enfuvirtid - inhibits the conformational change of gp41 that
is necessary for fusion of HIV virus to host cells
Terriann Crisp, Ph.D.

Antiviral
Pharmacology

Some HIV medicines (Nucleoside Reverse Transcriptase Inhibitors;

NRTIs) and Protease Inhibitors (PIs) may increase the risk of
diabetes.
NRTIs:
Didanosine
Stavudine
Zidovudine
PIs:
Indinavir
Lopinavir/Ritonavir
These HIV medicines seem to lessen the bodys ability to respond to
and use insulin (insulin resistance), which leads to high blood glucose
levels, which can result in type 2 diabetes.
Terriann Crisp, Ph.D.

Antiviral
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Terriann Crisp, Ph.D.

Antiviral
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V. Drugs for Influenza

Amantadine
Rimantadine
Block the fusion, penetration and uncoating of influenza A
virus into the host cytoplasm.
Block the M2 proton channel, preventing acidification of
influenza type A virus.
Not used much anymore due to emergence of resistant
strains.
No longer recommended for prophylaxis and treatment of
influenza in the U.S.

Terriann Crisp, Ph.D.

Antiviral
Pharmacology

The proton channels of viruses must function for viral replication

to occur.
Viruses enter the infected cell by endocytosis, and the interior of
the virion must become acidified while it is contained in the
endosome as a prerequisite for uncoating (release of genetic
material to the cytoplasm). The proton channels serve this
acidification function.

The life cycle and role of the M2

protein are similar for both strains
of influenza virus.
The M2 proton channels function
while the virion is contained in the
endosome (step 3) to permit
subsequent uncoating.
Terriann Crisp, Ph.D.

Antiviral
Pharmacology

Drugs for Influenza continued

Neuraminidase Inhibitors (NIs)

Oseltamivir (TAMIFLU)
Zanamivir

Neuraminidase promotes viral spreading and infection by breaking

the bond between the newly form virus and the host cell following
viral replication.
For the virus to be released from the cell, neuraminidase must
enzymatically cleave the sialic acid groups from host glycoproteins.
Blocking the function of neuraminidase is an effective way to
prevent the spreading of virions in influenza A and B viruses.
Zanamivir is administered intranasally.

Terriann Crisp, Ph.D.

Antiviral
Pharmacology

Terriann Crisp, Ph.D.

Antiviral
Pharmacology

VI. Drugs for Hepatitis

Lamivudine (also inhibits the replication of HIV; NRTI)
Ribavirin
Tenfovir
Ribavirin is a synthetic guanosine analogue that disrupts cellular purine
metabolism and inhibits the synthesis of viral nucleic acids.
Ribavirin is approved by the FDA for the management of severe
respiratory syncytial virus.
Neonates are treated with aerosolized ribavirin.
Adverse effects (ribavirin) apnea, pneumothorax, cardiac arrest and
seizures (if administered IV).
Ribavirin is teratogenic in animals and contraindicated in pregnant or
lactating women.
Lamivudine prevents the replication of hepatitis B virus (which relies on
reverse transcription of RNA).
Terriann Crisp, Ph.D.

Antiviral
Pharmacology

Tenofovir reverse transcriptase inhibitor used to treat hepatitis B.

The FDA has recently approved 2 new drugs for treatment of chronic
hepatitis C virus (HCV) infection.
Simeprevir is the third oral protease inhibitor to be approved for use in
combination with peginterferon and ribavirin for treatment of chronic
HCV genotype 1 infection in adults with compensated liver disease.
Telaprevir and boceprevir were approved for the same indication.

-----------------STANDARD THERAPY For many years, the standard therapy for chronic HCV
genotype 1 infection (the most common genotype in the US and Europe) was
48 weeks of subcutaneously-injected pegylated interferon- and ribavirin. This
combination usually produces a sustained virologic response (SVR;
undetectable HCV RNA 24 weeks after stopping treatment) in 40-50% of
patients with HCV genotype 1 infection. Addition of telaprevir or boceprevir
to peginterferon and ribavirin increases SVR rates to 60-75% and has become
the standard of care for patients with HCV genotype 1 infection.
(Reference: The Medical Letter: Volume 56 (Issue 1433) January 6, 2014
www.medicalletter.org)

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Antiviral
Pharmacology

VII. Interferons
Interferon-
Interferon-
Mechanism: The interferons inhibit viral penetration and uncoating,
and prevent viral peptide elongation.
Systemic Interferon- is active against chronic hepatitis B and
C, hairy-cell leukemia, AIDS-related Kaposi's sarcoma,
condyloma acuminatum (genital warts) and some
papillomaviruses (anogenital warts).
Interferon- is effective at relieving the symptoms of multiple
sclerosis.
Adverse effects: neutropenia, cardiac arrhythmias, anemia and
influenza symptoms
Terriann Crisp, Ph.D.

Antiviral
Pharmacology

Sofusbivir-Ledipasvir

Sofusbivir-ledipasvir is a recently approved oral medication which

inhibits HCV replication.
It represents an alternative to interferon-based therapy and has
demonstrated distinct advantages of higher sustained virologic
response rates, decreased treatment duration, and fewer adverse
effects.
Sofosbuvir is a nucleotide analog inhibitor of hepatitis C virus
NS5B polymerasethe key enzyme mediating HCV RNA
replication.
Ledipasvir is a potent inhibitor of HCV NS5A, a viral
phosphoprotein that plays an important role in viral replication,
assembly, and secretion.
Patients who are not able to tolerate the effects of interferonbased therapy can benefit from this new option.
Sofosbuvir-ledipasvir treatment is, however, expensive at $1125
per day.

Terriann Crisp, Ph.D.

Antiviral
Pharmacology

Reference Material Used for this Lecture

1. Brenner and Stevens Pharmacology, 3rd Edition, Copyright 2010 by

Saunders, an imprint of Elsevier Inc.
2. www.studentconsult.com
3. The Medical Letter: Volume 56 (Issue 1433) January 6, 2014
www.medicalletter.org)
4. Special appreciation to McGraw-Hill for permission to use PowerPoint
slides from Katzung, Masters and Trevor Basic and Clinical Pharmacology,
11th Edition, McGraw Hill, a Lange Medical Book.
5. Student Consult: Rapid Review Pharmacology 2E (on 30 November 2011)
2011 Elsevier
6. YouTube video of HIV replication:
http://www.youtube.com/watch?feature=player_detailpage&v=7oyp1zII
WmM

Terriann Crisp, Ph.D.