Influenza A virus

Inf virus replication

Virion attaches to siliac acid containing
receptors at the surface, the virus-receptor
complex is taken in to cell by endocytosis,
process by which cells takeup mol from
extracellur fluid.
As the endosomal vesicles that contain the virus
particles move towards the cell nucleus, their pH
drops.
This changes in pH accomplished by a cellurar
channel that pumps proton into the vesicle.

In inf virus RNA are not naked

Bound viral memb, M1 protein.
This protein form shell under the lipid memb
If virus RNA is bound to M1 protein when they are
released from the virion, they cannot enter the nucleus.
Inf virus has few copies in its memb of protein called M2.
This viral protein form a channel in the memb that
actively pump proton from endosome in to interior of the
virion.
These protons lower the pH in the interior of the virion,
releasing the viral RNA from M1.
N this way RNA enter the nucleus.

MOA of Amantadine

Amantadine block the channel and prevent it

from pumping proton into virion.
In the presence of amandadine viral RNA
remains bound to M1 memb and cannot enter
the nucleus. Therefore viral replication is
inhibbited.

Mechanism of Action of Neuraminidase Inhibitors. Panel

A shows the action of neuraminidase in the continued
replication of virions in influenza infection. The
replication is blocked by neuraminidase inhibitors (Panel
B), which prevent virions from being released from the
surface
of
infected
cells.

RIBAVIRIN

Synthetic guanosine analog.

Phosphorylated intracellularly by host cell enzymes
Effective against a broad spectrum of RNA & DNA viruses
included influenza A and B, HCV and HIV-1.
Used in treating infants & young children infected with severe
RSV (Respiratory Syncytial virus, lower respiratory tract infet ).

Ribavirin is effective in chronic hepatitus C infections when used

in combination with interferon --2b.

MOA

Ribavirin first converted to 3-phosphate derivative, major

product is ribavirin triphosphate (RTP), which then inhibit viral

mRNA capping and blocking RNA-dep RNA polymerase.

PHARMACOKINETICS

Given Orally, I/V , as an aerosol

PPL = 1 2 hrs
Drug & metabolites excreted in urine.

THERAPEUTIC USES
1.

2.
3.

An aerosol is used in certain respiratory viral cond,

treatment of RSV infection e.g Respiratory syncytial
viral pneumonia and broncholitis.
Aerosolized ribavirin used to treat influenza A & B
infection.
I/V Ribavirin mortality in lassa fever &
haemorrhagic fever.

ADVERSE EFFECTS

Dose dependent Anemia.

bilirubin levels
Aerosolized ribavirin cause conjunctival (clear
mucous membrane consisting of cells and
underlying basement membrane that covers the
sclera,white part of the eye) or bronchial
irritation (result from illnesses like bronchitis or
other respiratory infections) in infants so
monitoring is essential.

Treatment of hepatic viral infections

Hepatitis viruses identified are A, B, C, D and E

Each have a pathogenesis specifically involving
replication in & destruction of hepatocytes.
Hep B & C common cause of chronic hep, cirrhosis &
hepatocellular carcinoma
While A is infection
Chronic hep B treated with Inf-a or lamivudine
Combination therapy inf+lamivudine is not effective
than mono therapy
Chronic hep C responds to combination of inf a
+ribavirin

Hepatocelluar carcinoma

Cirrhosis

Immunomodulators
INTERFERON

Interferons (IFNs) are endogenous proteins

made and released by lymphocytes in response
to the presence of pathogens such as viruses,
bacteria, or parasites or tumor cells. They allow
communication between cells to trigger the
protective defenses of the immune system that
eradicate pathogens or tumors.

Family of naturally occuring inducible glycoproteins, synthesized

by mammalian cells, now produced by DNA Recombinant
technique.

Interfere ability of viruses to infect cells

There types, , , and IFN classified according to cell type from

which they were derived

Three vials filled with human leukocyte interferon

The molecular structure of human interferon-alpha
Right handed

IFN- - 2b one of the family of 15-proteins with similar activities,

approved for treatment of hep B&C, Condylomata acuminata (genital
warts, sexually tran, human papilloma) and cancers such as hairy cell
leukemia( type of cancer, bone marrow make too WBS), Chronic
myelogenous leukemia( cancer of WBC unregulated growth of myeloid
cell i.e bone marrow and spinal card cells) and Kaposi sarcoma (tumor
caused by Herpes virus, patches of abnormal tissue to grow under the
skin.
INF- effective in the treatment of multiple sclerosis ( nervous system
disease that effect brain and spinal card, damage myelin sheath which
surrounds nerve cells.

Chronic Hep C response to combination of IFN- with ribavirin

IFN- - 2b leads to loss of HBeAg, normalization of serum
aminotransferase, and sustained histologic improvement in appr. 1/3 of
patients with ch hep B, thus reducing the risk of progressive liver
disease.

Condylomata acuminata

Kaposi sarcoma.

leukemia chronic myelogenous

Pegylated interferon

Pegylated interferon alfa-2a and pegylated interferon alfa-2b have

been introduced for the treatment of patients with chronic hepatitus
C infection.

In these agents , a linear or branched polyethylene glyco (PEG)

moeity is attached to interferon by a covalent bond.

This attachment prolongs the half-life of interferon, so once-a-week

dosing employed.

The PEG molecule is a non toxic polymer that is readily excreted in

the urine.

MOA

IFN- induced in ribosomes of hosts cells causing

production of host cell enzymes (e. g. Protein kinase,
2 5 oligoadenylate synthase).

These enzymes then inhibits translation of viral

mRNA into viral proteins, thus stop the production of
viruses.

THERAPEUTIC USES
IFN- Used in
Chronic Hepatitis B & C
Genital warts, caused by papilloma virus.
Hairy cell Leukemia.
Kaposis Sarcoma.
IFN- Used in
Relapsing remitting multiple sclerosis
IFN- used in
Chronic granulomatous disease

Pharmacokinetics

Interferon is not active orally, it may be administered

intralesionally, subcutaneously or intravenously.
Dosage
Acute Hepatitus C 5 millions units daily for 3 weeks, then 5
million units three times weekly
Chronic Hep C 3 millions units three times weekly
PEG inf -2a
Chronic hep C 180g once weekly
PEG inf -2b Cronic hep C 40-150g once weekly
according to weight

Adverse Effects

Bone marrow depression.

Fever, Lethargy (fatigue), chronic malaise (severe
fatigue) and weight loss
Alopecia (hair loss)
Disturbance in Hepatic & Thyroid function

Flu like symptoms on injection, such as fever, chills,

gastrointestinal disturbance.
Other principle side effects are bone marrow
suppression are
Granulocytopenia ( dec in the no of granulocytes,
WBC,red body resistance), nausia, fatigue, weight loss,
autoimmune disorder such as thyroiditis (inflammation
of the thyroid gland)
Cardio Vas Prob such as congestive heart failure and
acute hypersensitivity reaction and hepatic failure are
rare

3. TREATMENT OF HERPESVIRUS INFECTIONS

(inhibitors of viral DNA synthesis)
Herpes viruses are associated with a broad spectrum of diseases
e.g cold sores, viral encephalitis and genital infections

ACYCLOVIR

Guanosine derivative.
Active against HSV & VZV.
HSV causes cold sores, conjunctivitis, mouth ulcers, genital
infections and rarely encephalitis (inflammation of the brain
parenchyma) in immunocompromised (having an immune
system that has been impaired by disease or treatment) pts.
VZV causes shingles (painful localized skin rash, usually with
blisters (fluid filled sacks) on top of the reddish skin , chicken
pox.

MOA
Inhibits viral replication by inhibiting viral DNA
Polymerase.
Acyclovir is phosphorylated to monophosphate
by herpes virus-encoded enzyme, thymidine
kinase.
Host cell kinases then convert monophosphate to
Di & triphosphate compounds.
Acyclovir triphosphate act as a substrate for
viral DNA polymerase and incorporated into viral
DNA causing premature DNA chain termination.
Less effective against the host enzyme.

Pharmakokinetic.
Given orally I/V or topically.
Oral B.A 15-20%.
PPL 1-2 hrs.
T = 3 hrs.
Distribution widely distributed, diffuses
tissues and body fluids and CSF.
Partially metabolize to inactive product.
Excreted by kidney by Glomerular Filtration
and partly by tubular secretion.

Therapeutic Uses
Oral Acylovir used in: Primary genital herpes, recurrent genital herpes.
Long term chronic suppression of genital
herpes.
Recurrent herpes labialis.
Decreases total no of lesion and duration of
varicella and cutaneous zoster.

I/V Acyclovir
Prophalactically before organ transplantation,
prevents reactivation of HSV.
Herpes simplex encephalitis.
Neonatal HSV infection.
Serious HSV or HZV infections.
In immunocompromised pts with zoster I/V
acyclovir reduces incidence of cutaneous and visceral
dissemination.

ADVERSE EFFECTS
Well tolerated, minimum adverse effects.
N, D, headache.
Local inflamm, during I/V inj, if there is
extravasation of solu.
I/V infusion reversible renal dysfunction, due
to crystalline nephropathy and neurological
toxicity (delirium, seizures (A seizure is the physical
changes in behavior that occur after an episode of
abnormal electrical activity in the brain).

Valacyclovir & Famicyclovir

Have similar MOA and clinical uses and are well

tolerated.

Agents used to treat CMV

Ganciclovir
Cidofovir
Formivirsen
Foscarnet
Valganciclovir

GANCICLOVIR

Synthetic guanosine analog.

Drug of choice for CMV.

MOA

Drug activated by phosphorylation.

Initial phosphorylation catalyzed by virus specified protein
kinase phosphotransferase UL97 in CMV infected cells.
Phosphorylated active drug competitively inhibits viral
DNA polymerase thus causing termination of viral DNA
elongation.
100 times more potent than acylovir for CMV.

Ph. K

Can be given orally, I/V or via intraocular implant.

t = 2-4 hrs
B.A = poor 6-9 %
CSF conc approx .50% of those in serum.

Clinical Uses
I/V administration use

To delay progression of CMV retnitis in AIDS pt.

CMV colitis and esophagitis.
To reduce risk of CMV infection in transplant pt.
To treat CMV pneumonitis in immunocompromised pt,
alongwith CMV immunoglobulin.

Oral Administration, use in

CMV prophylaxis
CMV retinitis treatment as maintenance therapy.
Intraocular Implants use
To treat CMV retinitis.
Adverse Effects
Myelosuppression particularly neutropenia.
CNS toxicity headache, changes in mental status,
seizures.
Fever, rash, abnormal liver function, retinal detachment
in pt with CMV retinitis.
Vitreous hemorrhage and retinal detachment with
intraocular implant.

ANTI RETROVIRAL AGENTS

(Reverse Transcriptase Inhibitor)
ZIDOVUDINE:One of most effective drug for the treatment of HIV infections and AIDS.
Is a deoxythymidine analog (Azidothymidine AZT)
MOA
Drug is an active inhibitor of viral reverse transcripase.
Drug is phosphorylated by cellular enzy into its active triphosphate form,
which is incorporated into growing viral DNA chain to cause its
termination.
Mammalian alpha DNA polymerase is relatively resistant to effect. Howver
gamma DNA polymerase in the host cell mitochondria is fairly sensitive to
the compound and may be the basis of unwanted effects.

Ph. K

Given orally, well absorbed

B.A = 60-80 %
Distribution wide to body fluids and tissues
including CSF.
PPB-35%
T hrs
Metabolized in liver by glucorindation
Metabolites are exereted in urine by kidney

Clinical Uses
Decreases rate of disease progression and prolongs
survival in HIV infected individuals.
Adverse Effects
Most common Myelosuppression resulting in
Anemia, neutropenia
GIT intolerance, headache, insomnia
Less frequent thrombocytopenia, hyperpigmentation
of nails, myopathy.
At higher doses: - Anxiety, confusion, tremulousness.

DIDANOSINE

Dideoxyinosine (ddI)
Synthetic analog of deoxyadenosine.
Second drug approved to treat HIV infection
not recommended for initial treatment of HIV
disease.
Used for Zidovudine resistant HIV infection.

MOA
Drug is phosphorylated in the host cells to triphosphate,
dideoxyadenosine in which form it act as DNA chain
terminator and inhibitor of the viral reverse transcriptase.
Adverse Effects
Dose dependent pancreatitis.
Dose related peripheral painful distal neuropathy.
Diarrhea, hepatitis, esophageal ulceration, cardiomyophthy.
CNS toxicity headache, irritability, insomnia.
Asymptomatic hyperuricemia, may precipitate attack of gout
in susceptible individuals.
Retinal changes and optic neuritis.

HIV PROTEASE INHIBITORS

Examples of current protease inhibitors are:
Saquinavir
Ritonavir
Indinavir
Nelfinavir

MOA

Host mRNAs Coded directly for functional proteins.

But in HIV, RNA are coded into biochemically inert

polyproteins, which are converted into various structural &
functional polyproteins by cleavage at appropriate postions
with viral specific protease. So cleavage is essential step of
viral proliferation.

These drugs inhibit protease enzyme, thus preventing cleavage

of viral polyproteins, resulting in production of immature,

non-infectious viral particles.

PHARMACOKINETICS

Given orally

Metabolized by hepatic cytochrome P450 &

function as a P450 inhibitor also, so these drugs
interact with other drugs metabolized by this
system.

ADVERSE EFFECTS

N,V,D

Elevated hepatic Aminotransferase & triglycerides, along with

glucose in tolerance & insulin resistance.

Paresthesia around the mouth.

Redistribution of cutaneous fat causing central obesity,

dorsocervical fat enlargment (baffalo hump), Peripheral &

facial wasting, breast enlargement & cushingoid appearance.

Latest viral infections and antiviral

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