Anti Viral drugs

(Part 1)

Presented by

• Dr. Amira El-Gazar

• PhD of Pharmacology
and Toxicology
Importance of virus ????
Environmental homeostasis
Viruses are able to infect humans, animals, plants
and even bacteria by invading the cells and
utilizing the cellular metabolic machinery of the
host.
Viruses are obligate intracellular parasites; their
replications depend primarily on synthetic
processes of the host cell.
Are viruses living or non-living???
 Steps of viral replication
1-Adsorption to and penetration into susceptible host cells
2- Un-coating of viral nucleic acid
(the capsid is removed and viral genes released)

3-Synthesis of early regulatory proteins e.g. nucleic acid polymerases.

4-Synthesis of RNA or DNA
5-Synthesis of late structural proteins (capsid).
6-Release from the cell
 Antiviral drugs

Specific characters for the antiviral agents

For any chemotherapeutic agent to have antiviral property, it should have
one or more of the following functions

1-Prevent invasion of the host cell (it is mostly).

2-Prevent penetration of the virus to nucleus.
3-Inhibit replication of the DNA and/or RNA inside the host cell.
4-Inhibit synthesis of the virus envelop
Herpes simplex virus (HSV)

Double stranded
DNA genome
HSV1
HSV2 Human herpes virus(HHV) 8 human HHV
VZV
CMV
 1-Herpes simplex virus (HSV)

The herpes simplex virus, also known as HSV, is an infection that

causes herpes. Herpes can appear in various parts of the body, most
commonly on the genitals or mouth.
There are two types of the HSV

HSV-1: primarily causes oral herpes HSV-2: primarily causes genital herpes
responsible for cold sores and fever responsible for genital herpes outbreaks.
blisters around the mouth and on the
face.
Entry by mucous membrane
or damaged Epithelium

viral multiplication
Central ganglia
Sensory
lysis of cells (lytic phase ) neurons

Vesicles and ulcers

neurotropic viruses
like neurons and establish latent infection
They are taken by sensory neurons to central ganglia
Latent virus can be activated (no definite reason )
 2-Varicella zoster virus (VZV)

Primary Secondary
infection infection

Chickenpox Zoster/Shingles

1-Distinct to an area Activation after being latent

1- flu like symptoms
2-Very painful (old age –immunocomprimised )
2- rash (very itchy)
3-Pain persists (up
to one year
I- Agents used to treat a)Herpes simplex virus (HSV)

b)Varicella zoster virus (VZV)

In-active Pro drugs

Acyclovir Valacyclovir

Pencyclovir Famcyclovir
In-active

Trifluridine
Acyclovir

Acyclovir triphosphate
inhibits HSV or VZV DNA
polymerase competitively
with deoxyguanosine
triphosphate
1-Mechanism of action
Acyclovir
It is converted into
active metabolite by
three phosphorylation
steps. It is converted
into monophosphate
derivative by the virus-
specified thymidine
kinase and then to di –
and triphosphate
compounds by the
hosts cellular enzymes.

competitive inhibition with

deoxyGTP for viral DNA
polymerase, resulting in binding
to the DNA template as an
irreversible complex
chain termination following
incorporation into the viral DNA.
 It is highly selective and accumulated
in the infected cells ????
Why

because it needs virus-specific thymidine kinase for initial phosphorylation.

2-Pharmacokinetics
1-It can be administered orally or I.V. and topically
2- It is excreted in urine

plasma t½ is 3 hours in patient 250 hours in patients

with normal renal function with anuria

3-Resistance
Resistance to acyclovir can be developing in HSV or
HZV through alteration in either the viral thymidine
kinase or DNA polymerase
4-Toxicity
•Extravasations with I.V. use cause severe local inflammation.
•Nausea, vomiting, headache and diarrhea.
•Neurologic toxicity e.g. tremors, delirium, seizures.
•High dose cause testicular atrophy in rats.
•Nephrotoxicity.

Other agents used to treat HSV and VZV

Valacyclovir Trifluridine
Famcyclovir and
It is a pro-drug (ester) it inhibits DNA synthesis +
of acyclovir, i.e. after Pencyclovir
Famcyclovir is a pro- It is phosphorylated in the
administration, the intracellular space into its
parent acyclovir is drug of pencyclovir,
which is similar to active metabolite by
released cellular enzymes
acyclovir
 3-Cytomegaloviurs (CMV) infections
Clinical presentation

1-Mononucleosis 1-Fever
2-Pharynigitis
EPV is the main cause of mononucleosis 3-Lymphadenopathy (cervical)
CMV causes 7-10% mononucleosis 4-Fatigue that increase by time
5-Atypical lymphocytosis
2-Congenital infection (Mononuclear cells )
6-Splenomegaly
Mother-to-child infection
Very common (transplacental)

Symptoms of CMV
congenital infection
At birth Long term complications
1-Premature birth with low birth weight 1- Hearing + vision problems
2- Microcephaly + seizures 2- seizures
3- Hepatosplenomegaly 3- weakness
4- Purpuric rash 5- Jaundice 4- low co-ordination
6- Respiratory disorders
 3-Immunocompromised Patients

Transplantation Advanced HIV

CMV is one of the most CD4 count < 50

frequently encountered
opportunistic viral pathogens 1- Retinitis blindness
kidney transplant recipient
2- Colitis
3- Esophagitis
1- Fever (flu like symptoms)
2- Pneumonitis
3- Hepatitis
4- Colitis
5-rejection
I- Agents used to treat
Cytomegaloviurs (CMV) infections

Gancilovir Valganciclovir

Foscarnet

Cidovir
 1- Mechanism

It is similar to acyclovir in its mode of action

but is much more toxic.

Initial phosphorylation is catalyzed by the virus specific protein

kinase phosphotransferase UL97 in CMV infected cells

The triphosphate metabolite is the active form, which acts by

inhibition of DNA polymerase and causes termination of viral DNA
elongation.
used in the treatment of
Retinitis
Colitis
1- CMV Esophagitis
Pneumonitis

2- Prevention of end-organ CMV disease in

AIDs patients

3- Prevention of CMV infection in organ

transplant recipients
2-pharmacokinetics:
It is given orally or I.V. and is eliminated mainly unchanged in
the urine, plasma t½is 4 hours with normal renal function.

3-Resistance:
Resistance can develop through mutation of phosphotransferase
UL97.
4-Toxicity and drug interaction:
•Neutropenia, thrombocytopenia. So, the use of bone-marrow
depressants in the same time e.g. Co-Trimoxazole, amphotericin
and zidovudine should be avoided.

•CNS toxicity as headache, changes in mental status, seizures.

•Other toxic effects include, fever, rash, abnormal liver function

 Valganciclovir

It is the pro-drug of ganciclovir

rapidly hydrolyzed after administeration into the

active form ganciclovir by intestinal and hepatic
esterase enzyme when given orally.
 Foscarnet
It acts by inhibition of DNA polymerase and RNA polymerase
directly without phosphorylation.

Uses
1-It is used I.V. for CMV retinitis in patients with HIV infection
when ganciclovir is contraindicated.
2-It can also be used to treat acyclovir-resistant HSV infection.

Toxicity
Nausea, vomiting, neurological reactions and bone marrow
depression.
 Cidovir
Cidovir is given by I.V. infusion (ACTIVE)

p Di-p p Tri-p

inhibition to viral DNA polymerase after phosphorylation

Toxicity
Nephrotoxicity, bone-marrow depression, nausea, vomiting and
uveitis.
Why
Influenza A Pathogenesis
 Anti-influenza agents (influenza A)
l 1-Amantadine and Rimantadine
h a n ne
M2 c kers MOA
bloc
They act by interfering with the uncoating
and release of viral genome into the host cell.

No protons will enter

Prevent un coating
M2: Ion channel No Release of viral genome

No new virus will be

formed by the host cell
Amantadine and Rimantadine MOA
Pharmacokinetics
They are well absorbed from GIT (t½ 3 h).

•Rimantadine excreted in the metabolized •Amantadine is eliminated

form (hydroxylation, conjugation) in urine. unchanged in the urine
Dose Dose
reduced reduced
renal and hepatic insufficiency in patient with renal insufficiency

Adverse reactions
dizziness insomnia drowsiness
nervousness hallucination delirium
convulsion coma