ANTIVIRAL AGENTS

Dr. Roshna Sh. Aziz

Department of Pharmacology
School of medicine
University of sulaimani
VIRUSES, WHAT ARE THEY?

 Viruses are obligate intracellular parasites, i.e. they utilize:

􀂄 Host metabolic enzymes

􀂄 Host ribosome for protein synthesis

 They cannot make anything on their own, they use the
cell’s materials to build themselves
STRUCTURE OF VIRUSES

Virus particles (virions) consist of

following parts:

􀂄 Nucleic acid core: DNA or RNA

􀂄 Often contain virus-specific enzymes

􀂄 Surrounded by protein: “capsid”

􀂄 sometimes an outer lipid “envelope”

Classification of Viruses
DNA viruses RNA Viruses

 Contain an DNA genome.

 Contain an RNA genome.

 Virus replication:
 Virus replication:
 RNA-dependent RNA polymerase
 DNA polymerase  Reverse transcriptase
 Examples: (Retroviruses)
 Herpes Virus  Examples:
 Hepatitis B virus  Rubella virus
 Epstein-Barr virus  Dengue fever virus
 Hepatitis A virus
 Hepatitis C virus
 HIV
 Influenza virus
 The Life Cycle of Viruses

1. Attachment of the virus to receptors on the host cell surface;

2. Entry of the virus through the host cell membrane;
3. Uncoating of viral nucleic acid;
4. Replication
Synthesis of early regulatory proteins, eg, nucleic acid polymerases;
Synthesis of new viral RNA or DNA;
Synthesis of late, structural proteins;
5. Assembly (maturation) of viral particles;
6. Release from the cell
1
2 3

6
7
8
• Many viruses infect a specific host cell

• Many viral infections are self-limiting and require no medical

treatment—ex. Rhinoviruses that cause common cold.
• Common viral infections such as the influenza, mumps, or
chicken pox are usually overcome by the body’s immune
system.

 Other viruses cause serious and even fatal disease & require
aggressive therapy—ex. HIV that causes AIDS.
Virus Replication

The virus uses the cell mechanism to replicate itself

9
 Virus Groups of Clinical Importance
Virus Genera Nucleic Acid Clinical Illness
Adenovirus DNA URTIs, Eye infections

Hepadnaviridae DNA Hepatitis B, Cancer (?)

Herpesvirus DNA Genital herpes, Varicella, IM, Encephalitis, Retinitis

Papillomavirus DNA Papilloma, Cancer

Parvovirus DNA Erythema infectiosum

Arenavirus RNA Lymphocytic choriomeningitis

Bunyavirus RNA Encephalitis

Coronavirus RNA URTIs

Influenzavirus RNA Influenza

Paramyxovirus RNA Measles, URTIs

Picornavirus RNA Poliomyelitis, diarrhea, URTIs

Retrovirus RNA Leukemia, AIDS

Rhabdovirus RNA Rabies

Togavirus RNA Rubella, Yellow fever

 Antiviral Drugs
 Vaccines are often used to build up immunity before a
viral infection occurs.

 Common viral infections such as the influenza, mumps,

or chicken pox are usually overcome by the body’s
immune system.

 To be effective, antiviral agents must either block viral

entry into or exit from the cell or be active inside the
host cell.

11
 Antiviral drugs work by:

1. Altering the cell’s genetic material so that the virus cannot

use it to multiply, i.e. acyclovir (inhibiting Viral enzymes,
Host expression of viral proteins & Assembly of viral
proteins)

2. Preventing new virus formed from leaving the cell, i.e.

amatadine.
 Antiviral therapy challenging.
1. Rapid replication of viruses makes it difficult to develop
effective antiviral.
2. Viruses can rapidly mutate and drug becomes ineffective.
3. Difficulty for drug to find virus without injuring normal
cells.(Nonselective inhibitors of virus replication may
interfere with host cell function and result in toxicity.)

Antiviral drugs share the common property of being

virustatic; they are active only against replicating
viruses and do not affect latent virus.

13
 AGENTS TO TREAT
HERPES SIMPLEX VIRUS (HSV)
& VARICELLA-ZOSTER VIRUS
(VZV) INFECTIONS
Oral Agents Topical Agents
Acyclovir Acyclovir
Valacyclovir Docosanol
Famciclovir Penciclovir

Ophthalmic
Intravenous
Trifluridine Acyclovir
 Herpes simplex viruses (HSV)—cause repeated,
blister-like lesions on the skin, genitals, mucosal
surfaces.

 Some remain latent; activated by physical or

emotional stress
 HSV-type 1—non genital

 HSV type 2—genital infections

Acyclovir
 Valacyclovir is a prodrug, with
Will “normal”Acyclovir
better availability Herpes virus
specific
 (non-infected)
Acyclovir is Guanosine analog thymidine kinase

 host cells Acyclovir

mostly taken up by the virus
infected cells and has low monophosphate
be sensitive to
toxicity for host cells. Host kinase
acyclovir? Acyclovir
triphosphate

1. Incorporated into DNA and terminates synthesis

2. Inhibition of herpes virus DNA polymerase
Acyclovir.
Clinical Use
 Herpes simplex
 Herpes zoster
 Chickenpox
 Epstain-Barr virus
IV, oral, topical.
Can be used during pregnancy
 Adverse Reactions:
 Well tolerated
 Toxic effect occur in patients with renal failure.
 OTHER TOPICAL DRUGS FOR HSV
 Orolabialherpes
 Penciclovir
 similar to acyclovir
 Application site reactions

 Docosanol
 Active against a broad range of lipid-envelop viruses
 MOA: interferes with viral fusion to host cell

 HSV Keratoconjuctivitis
 Trifluridine Active against acyclovir resistant strains
 Also active against vaccinia virus and smallpox
HAVING TROUBLE REMEMBERING ALL OF THE
DRUGS FOR HERPES??
If gets to your conjunctava
 If you get the Herpes
I got just what you need
Have no Fear Its one heavy dose of TRIFLURIDINE
Doctors gonna give you some ACYCLOVIR
Put it right to your eye LIKE HEAD-ON
If it spreads to your eye please dont cry TRI FOR THE EYE
Doctors gonna give you another NUCLEOSIDE TRI FLURIDINE
Like GANCYCLOVIR
APPLY DIRECTLY TO THE EYE
Myelosuppressions severe with Gancyclovir TRIFLURIDE

FOSCARNETs a last resort IF these drugs dont work you better

Pyrophosphate analogue start to worry
FOMIVIRSENs an antisense CD4 count down and your DEAD in a
For CMV retinitis, yeaaaa HURRY
 AGENTS USED TO TREAT
CYTOMEGALOVIRUS (CMV)
INFECTIONS

Ganciclovir
Valganciclovir
Foscarnet
Cidofovir
Fomivirsen
CMV infections occur in advanced
immunosuppression, typically due to
reactivation of latent infection.
Dissemination results in end-organ disease:
retinitis, colitis, esophagitis, CNS disease,
and pneumonitis.
 GANCICLOVIR
Valganciclovir ( a prodrug)

 Mechanism like Acyclovir

 Active against all Herpes viruses & CMV
 Low oral bioavailability given I.V.
 Most common A/E: bone marrow suppression
(leukopenia, thrombocytopenia ) and CNS effects
(headache, psychosis, convulsions).
 1/3 of patients have to stop because of adverse effects
 FOSCARNET
 An inorganic pyrophosphate analog
 does not have to be phosphorylated

 Active against Herpes (I, II, Varicella , CMV), including

those resistant to Acyclovir and Ganciclovir.
 IV only

 Direct inhibition of DNA polymerase and RT

 A/E: Nephrotoxicity , electrolyte abnormalities, CNS

toxicity
 Foscarnet should only be given during pregnancy when
benefit outweighs risk.
Cidofovir

 Incorporation into viral DNA chain results in

reductions of the rate of viral DNA synthesis
 A/E: nephrotoxicity
 Must be administered with high-dose probenecid &
adequate hydration
ANTIHEPATITIS
AGENTS
 Treatment of Viral Hepatitis A

 Thereis no specific hepatitis A treatment. Fortunately, the

disease usually gets better on its own. Most people who
get hepatitis A recover in several weeks or months.
 Personsacutely infected with HAV should avoid alcohol
and other hepatotoxic medications until they have fully
recovered.
 Viral Hepatitis B
 Acute hepatitis B infection does not usually require antiviral drug
treatment. Early antiviral treatment may only be required in
patients, with a very aggressive "fulminant hepatitis" or who are
immunocompromised.
For people with chronic hepatitis B, antiviral drug therapy used to
slow down liver damage and prevent complications (cirrhosis and
liver cancer).
Alpha interferon
Pegylated alpha interferon
Lamivudine
 INTERFERONs
 A family of small antiviral proteins produced as earliest response of
body to viral infections
 Both DNA and RNA viruses induce interferon but RNA viruses tend to
induce higher levels.
 currently grouped into : IFN-α, IFN-β, and IFN-γ.
α and β are produced by all body cells in response to various stimuli:
viruses, bacteria, parasites and tumor cells
γ produced by T-lymphocytes and natural killer cells, has less anti-
viral activity.

 Administered Intralesionally, S.C, and I.V

 Distribution in all body tissues, except CNS and eye.

 Pegylated
interferons are modified interferons with
improved pharmacokinetic properties
 INTERFERON ALFA
Acts by :
 Binding to membrane receptors on cell surface
 induction host cell enzymes that inhibit viral RNA translation and
cause degradation of viral mRNA and tRNA
 May also inhibit viral penetration, uncoating, mRNA synthesis, and
translation, and virion assembly and release
 Enhancement of phagocytic activity of macrophages,
 Augmentation of the proliferation and survival of cytotoxic T cells.
Clinical Use Side effects:

 Chronic hepatitis B and C  Flu-like symptoms (within

few hours after
 Herpes viruses
administration)
 Influenza viruses  Neurotoxicity (depression,
 Some types of cancer: Kidney seizures).
cancer, Malignant melanoma,  Myelosuppression
Lymphomas, Leukemia
(neutropenia)
 AIDS-related Kaposi’s  elevation of hepatic enzymes.
sarcoma.
 Mild hair loss

C/I: Hepatic failure, Autoimmune diseases, Pregnancy

OTHER TREATMENT OF HEPATITIS B VIRUS
INFECTION

Competitively inhibit HBV DNA polymerase to result in chain

termination after incorporation into the viral DNA.

Adefovir dipivoxil

Entecavir

Lamivudine

Telbivudine

Tenofovir
 Lamivudine
 Lamivudine is a potent nucleoside analog
 Lamivudine inhibits HBV DNA polymerase and both types (1
and 2) of HIV reverse transcriptase.
 It is prodrug. It is needs to be phosphorylated to its triphosphate
form before it is active.
 Clinical Use:
Chronic hepatitis B HIV
 Adverse Effects:
 CNS: paresthesias and peripheral neuropathies
 Pancreatitis
Treatment of Chronic Viral Hepatitis C

 Interferon alpha
 Pegylated interferon alpha
 Ribavirin
 Ribavirin
 Guanosine analog
 Mechanism: Phosphorylated to triphosphate by host enzymes,
and inhibits RNA-dependent RNA polymerase, viral RNA
synthesis, and viral replication.
 A/E: Hemolytic anemia, Conjunctival and bronchial irritation
ANTIRETROVIRAL AGENTS
 Retroviruses are enveloped, single stranded RNA
viruses that replicate through a DNA intermediate
using Reverse Transcriptase.

 This enzyme converts the RNA genome into DNA,

which then integrates into the host chromosomal
DNA by the enzyme Integrase.

 This large and diverse family includes members

that are oncogenic, are associated with a variety of
immune system disorders, and cause degenerative
and neurological syndromes.
CURRENT CLASSES OF ANTIRETROVIRAL
DRUGS INCLUDE:
Three main enzymatic targets:
 Reverse Transcriptase,
 Protease,
 Integrase

six drug classes

1. Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
2. Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
3. Protease inhibitors (PIs)
4. Entery inhibitors
5. CCR5 receptor antagonists
6. Integrase inhibitors
 CURRENT ARV MEDICATIONS
NRTI PI
• Abacavir • Atazanavir
CCR5 Antagonist
• Maraviroc
• Didanosine • Darunavir
• Emtricitabine • Fosamprenavir Integrase Inhibitor
• Lamivudine • Indinavir • Raltegravir
• Stavudine • Lopinavir
Fixed-dose Combinations
• Tenofovir • Nelfinavir
•Zidovudine/ lamivudine
• Zidovudine • Ritonavir
•Zidovudine/lamivudine/abacavir
NNRTI • Saquinavir
•Abacavir/lamivudine
• Efavirenz • Tipranavir
•Emtricitabine/tenofovir
• Etravirine Fusion Inhibitor •Efavirenz/emtricitabine
• Nevirapine • Enfuvirtide
/tenofovir
•
HIV DRUG REGIMENS
 Always combine multiple agents.
 Usually 2 NRTIs along with:
 A PI enhanced with a low dose of a second PI,
 An NNRTI
 An integrase inhibitor
 An entery inhibitor

HAART
 Taking 3 or more antiretroviral drugs at the same time vastly reduces
the rate at which resistance develops, the approach is known as highly
active antiretroviral therapy, or HAART.
HIV DRUG TOXICITY
 HIV drugs have side effects that are either drug or drug class specific
(but distinguishing them from effects of prolonged infection are
challenging)
 Severe, life-threatening, and essentially irreversible

HIV DRUG RESISTANCE

 HIV mutates readily
 If virus replicates in presence of drug, mutations that allow faster
replication (drug resistance) will be selected
 Selection of drug resistance mutations will allow higher levels of
viremia and progression of immunologic disease unless drugs
changed and replication again controlled
 Drug resistance can be transmitted
 NUCLEOSIDE/NUCLEOTIDE
REVERSE TRANSCRIPTASE
INHIBITORS
 These were the first type of drug available to treat HIV
infection .
 NRTIs interfere with the action of an HIV protein called
reverse transcriptase, which the virus needs to make
new copies of itself.
 Most regimens contain at least two of these drugs

(Reverse transcriptase changes viral RNA to

DNA)
 Act by competitive inhibition of HIV reverse
transcriptase; incorporation into the growing viral DNA
chain results in premature chain termination due to
inhibition of binding with the incoming nucleotide .
 Require intracytoplasmic activation via phosphorylation
by cellular enzymes to the triphosphate form.
NRTIS COMMON ADVERSE
EFFECTS

 Zidovudine  Abacavir : N/V/D, perioral

 N/V, fatigue, bone marrow paresthesias, hypersensitivity
suppression
 Tenofovir , Lamivudine :
 Didanosine, Zalcitabine
(generally well-tolerated)
Stavudine:
N/Vvomiting, flatulence

peripheral neuropathy,
pancreatitis
 All NRTIs may be associated with mitochondrial
toxicity, lactic acidosis with fatty liver may occur,
which can be fatal.
 Zidovudine and Stavudine : dyslipidemia and insulin
resistance.
 Increased risk of myocardial infarction in : Abacavir or
Didanosine.
NON NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS (NNRTI)

 Bind directly to HIV reverse transcriptase, prevents viral RNA

from conversion to the viral DNA that infects healthy cells, by
causing conformational changes in the enzyme.
 The binding site of NNRTIS is near to but distinct from that of
NRTIS.
 Do not require phosphorylation to be active.
Drug resistance develops quickly if NNRTIs are administered as
monotherapy and therefore NNRTIs are always given as part
of combination therapy, (HAART).
Delavirdine

Efavirenz

Nevirapine
NNRTI’S: ADVERSE EFFECTS
Side effects are worst during the first 1 to 2 weeks of
therapy.
NNRTI agents are associated with varying levels of GI
intolerance and skin rash.

 elevated LFT
 CNS effects (e.g. sedation, insomnia, dizziness,
confusion)
 PROTEASE INHIBITORS
 Prevent the processing of viral proteins into functional
conformations, resulting in the production of immature,
noninfectious viral particles .
 Do not need intracellular activation.
Atazanavir Indinavir
Lopinavir Nelfinavir
Saquinavir Ritonavir

Darunavir
contain sulfonamide
Fosamprenavir
Tipranavir
PI CLASS SIDE EFFECTS
 Metabolic Disorders
 Hepatotoxicity
 Hyperglycemia, insulin resistance
 Lipid abnormalities (increases in triglyceride and
LDL levels)
 Fat redistribution
 Bone Disorders

 GI Intolerance

54
ENTRY INHIBITORS

Binds to the viral envelope glycoprotein, preventing

the conformational changes required for the fusion
of the viral and cellular membranes
Enfuvirtide
By subcutaneous injection
 Toxicity
 Injection site reactions
 Nausea, diarrhea, fatigue, hypersensitivity
CCR5 RECEPTOR ANTAGONISTS

 They are inhibitors of the human CCR5 receptor, a receptor that

is found on several host defense cells (T-cells and killer cells).
The act of the CCR5 antagonist binding to the CCR5 receptor is
thought to alter the conformational state of the CCR5 receptor.

Maraviroc
 A/E: Abdominal pain, Upper respiratory tract infections,
Cough, Hepatotoxicity, Musculoskeletal symptoms, Rash
INTEGRASE INHIBITORS

Bind integrase, a viral enzyme essential to the replication of

HIV, Inhibits strand transfer, the final step of the provirus
integration, thus interfering with the integration of reverse-
transcribed HIV DNA into the chromosomes of host cells.

Raltegravir
A/E: Nausea, Headache, Diarrhea
ANTI-INFLUENZA AGENTS
 Influenza virus strains are classified by :
 Their core proteins (i.e., A, B, or C),
 Species of origin (eg, avian, swine),
 Geographic site of isolation.
INFLUENZA A

 Is the only strain that causes pandemics.

 Is classified into 16 H (hemagglutinin) and 9 N
(neuraminidase) known subtypes based on surface proteins.
 Can infect a variety of animal hosts.
 Avian influenza subtypes are highly species-specific, but they
can also on rare occasions crossed the species barrier to infect
humans and cats.
 Viruses of the H5 and H7 subtypes (eg, H5N1, H7N7, and H7N3)
may:
 Rapidly mutate within poultry
 Have recently expanded their host range to cause both avian and
human disease.
H5N1 virus
 First caused human infection (including severe disease and death)
in 1997 and has become endemic in some areas since 2003. It is
feared that the virus will become transmissible from person to
person rather than solely from poultry to human.
CLASSES OF INFLUENZA ANTIVIRAL
DRUGS
M2 ion channel inhibitors
Amantadine
Rimantadine

Neuraminidase inhibitors
Oseltamivir
Zanamivir
Amantadine & Rimantadine

 Block the M2 ion channel of the virus particle and inhibit

Uncoating of the viral RNA within infected host cells, thus
preventing its replication.
 Activity: influenza A only.
 Rimantadine is 4 to 10 times more active than amantadine in
vitro.
 A/E

GI disturbance, nervousness, insomnia.

 The marked increase in the prevalence of resistance
to both agents in clinical isolates over the last
decade, in influenza A H1N1 as well as H3N2, has
limited the usefulness of these agents for either the
treatment or the prevention of influenza.
 Oseltamivir & Zanamivir
• Neuraminidase inhibitors, 1999
• Chemically related, but have different routes of administration
 Interfere with release of influenza virus from infected to new
host cells.
 Competitively and reversibly interact with the active enzyme
site to inhibit neuraminidase activity and destroy the receptors

found on normal host cells recognized by viral hemagglutinin.

 Activity: both influenza A and influenza B viruses.
 Early administration is crucial because replication of
influenza virus peaks at 24–72 hours after the onset of
illness.
 Oseltamivir is FDA-approved for patients 1 year
and older, whereas zanamivir is approved in patients 7
years or older.
Oseltamivir
 Administered orally

 Prodrug that is activated by hepatic esterases

 Widely distributed throughout the body.

 A/E: N/V/D, Abd. Pain, Headache, Fatigue, Rash.

 Rates of resistance to oseltamivir among H1N1 viruses have risen abruptly

and dramatically worldwide. It may be associated with point mutations in

the viral hemagglutinin or neuraminidase genes.

Zanamivir

 Administered by inhalation.
 10 to 20 % of the active compound reaches the lungs,
and the remainder is deposited in the oropharynx.
 A/E: cough, bronchospasm, reversible decrease in
pulmonary function, and transient nasal and throat
discomfort.
 RESISTANCE
Resistance to any antiviral drug must be anticipated :
 viruses replicate so efficiently

 have modest to high mutation frequencies

THANKS