introduction to virus and pharmacotherapy of viral infections. *not including anti retrovirus

1. VIRAL INFECTIONS

2. INTRODUCTION
• Viruses are obligate intracellular parasites. They are inert in the
extracellular environment and depend on the intracellular machinery
of the living host cell for replication.
• Viruses are small particles of genetic material (either DNA or RNA)
that are surrounded by a protein coat. Some viruses also have a fatty
"envelope" covering. They are incapable of reproducing on their
own. Viruses depend on the organisms they infect (hosts) for their
survival.

3. VIRAL INFECTION
• A viral infection is a proliferation of a harmful virus inside the body.
Viruses cannot reproduce without the assistance of a host.
• Viruses infect a host by introducing their genetic material into the
cells and hijacking the cell’s internal machinery to make more virus
particles.
• With an active viral infection, a virus makes copies of itself and
bursts the host cell (killing it) to set the newly-formed virus particles
free. In other cases, virus particles “bud” off the host cell over a
period of time before killing the host cell. Either way, new virus
particles are then free to infect other cells.
• Symptoms of the viral illness occur as a result of cell damage, tissue
destruction, and the associated immune response.

5. VIRAL REPLICATION
5 steps: 1) attachment
2) entry and uncoating
3) biosynthesis
4) maturation
5) release

6. Virus Transmission
• Viruses can be transmitted in a variety of ways.
• Some viruses can spread through touch, saliva, or even the air.
• Other viruses can be transmitted through sexual contact or by sharing
contaminated needles.
• Insects including ticks and mosquitoes can act as "vectors,"
transmitting a virus from one host to another.
• Contaminated food and water are other potential sources of viral
infection.

7. VIRAL INFECTION TYPES
1) Respiratory Viral Infections
Respiratory viral infections affect the lungs, nose,
And throat. These viruses spread by inhaling
droplets containing virus particles.
Examples include:
Rhinovirus is the virus that most often causes the common cold, but there are more
than 200 different viruses that can cause colds. Cold symptoms like coughing,
sneezing, mild headache, and sore throat typically last for up to 2 weeks.
Seasonal influenza is an illness that affects about 5% to 20% of the population in the
US every year. Flu symptoms are more severe than cold symptoms and often include
body aches and severe fatigue. The flu also tends to come on more suddenly than a
cold.
Respiratory Syncytial Virus (RSV) is an infection that can cause both upper respiratory
infections (like colds) and lower respiratory infections (like pneumonia and
bronchiolitis). It can be very severe in infants, small children, and elderly adults.
Frequent hand-washing, covering the nose and mouth when coughing or sneezing, and
avoiding contact with infected individuals can all reduce the spread of respiratory
infections. Disinfecting hard surfaces and not touching the eyes, nose, and mouth can
help reduce transmission as well.

8. 2) Viral Skin Infections
• Viral skin infections can range from mild
to severe and often produce a rash.
Examples of viral skin infections include:
• Molluscum contagiosum causes small, flesh-colored bumps most often in children
ages 1 to 10 years old; however, people of any age can acquire the virus. The
bumps usually disappear without treatment, usually in 6 to 12 months.
• Herpes simplex virus-1 (HSV-1) is the common virus that causes cold sores. It’s
transmitted through saliva by kissing or sharing food or drink with an infected
individual. Sometimes, HSV-1 causes genital herpes. An estimated 85% of people in
the US have HSV-1 by the time they are in their 60s.
• Varicella-zoster virus (VZV) causes itchy, oozing blisters, fatigue, and high fever
characteristic of chickenpox. The chickenpox vaccine is 98% effective at preventing
infection.
• The best way to avoid viral skin infections is to avoid skin-to-skin contact (especially
areas that have a rash or sores) with an infected individual. Some viral skin
infections, such as varicella-zoster virus, are also transmitted by an airborne route.
Communal showers, swimming pools, and contaminated towels can also
potentially harbor certain viruses.

9. 3)Foodborne Viral Infections
• Viruses are one of the most common
causes of food poisoning. The symptoms
of these infections vary depending on the
virus involved.
• Hepatitis A is a virus that affects the liver for a few weeks up to several months.
Symptoms may include yellow skin, nausea, diarrhea, and vomiting. Up to 15% of
infected individuals experience recurrent illness within 6 months of infection.
• Norovirus has been reported to be responsible for outbreaks of severe
gastrointestinal illness that happen on cruise ships, but it causes disease in many
situations and locations.
• Rotavirus causes severe, watery diarrhea that can lead to dehydration. Anyone can
get rotavirus, but the illness occurs most often in babies and young children.
• Rotaviruses and noroviruses are responsible for many (but not all) cases of viral
gastroenteritis, which causes inflammation of the stomach and intestines. People
may use the terms “stomach virus” or “stomach flu” to refer to viral gastroenteritis,
which causes nausea, vomiting, diarrhea, and abdominal pain.
• Contaminated water and fecal-oral route are potential source of infection.

10. 4)Sexually Transmitted Viral Infections
• Sexually transmitted viral infections spread
through contact with bodily fluids. Some sexually
transmitted infections can also be transmitted
via the blood (blood-borne transmission).
• Human papillomavirus (HPV) is the most common sexually-transmitted infection in the US.
There are many different types of HPV. Some cause genital warts while others increase the
risk of cervical cancer.
• Hepatitis B is a virus that causes inflammation in the liver. It’s transmitted through
contaminated blood and bodily fluids. Some people with the virus don’t have any symptoms
while others feel like they have the flu. The hepatitis B vaccine is more than 90% effective at
preventing infection.
• Genital herpes is a common sexually-transmitted infection caused by herpes simplex virus-2
(HSV-2). Herpes simplex virus-1 (HSV-1), the virus responsible for cold sores, can also
sometimes cause genital herpes. There’s no cure for genital herpes. Painful sores often occur
during outbreaks. Antiviral medications can decrease both the number and length of
outbreaks.
• Human immunodeficiency virus (HIV) is a virus that affects certain types of T cells of the
immune system. Progression of the infection decreases the body’s ability to fight disease
and infection, leading to acquired immune deficiency syndrome (AIDS). HIV is transmitted by
coming into contact with blood or bodily fluids of an infected person.
• People can reduce the risk of getting a sexually-transmitted viral infection by abstaining from
sex or only having sex while in a monogamous relationship with someone who does not
have a sexually-transmitted infection. Using a condom decreases, but doesn’t entirely
eliminate, the risk of acquiring a sexually-transmitted infection.

11. 5)Other Viral Infections
• Viruses are abundant in the
world and cause many other
infections ranging from mild
to life-threatening.
• Epstein-Barr virus (EBV) is a type of herpes virus that’s associated
with fever, fatigue, swollen lymph nodes, and an enlarged spleen.
EBV is a very common virus that causes mononucleosis (abnormally high
proportion of monocytes in the blood).More than 90% of adults have been
infected with this “kissing disease” that is spread primarily through
saliva.
• West Nile virus (WNV) is a virus that’s most commonly transmitted
by infected mosquitos.Less than 1% of people with WNV develop
inflammation of the brain (encephalitis) or inflammation of the tissue
surrounding the brain and spinal cord (meningitis).
• Viral meningitis is an inflammation of the lining of the brain and
spinal cord that causes headache, fever, stiff neck, and other
symptoms. Many viruses can cause viral meningitis, but a group of
viruses called enteroviruses are most often to blame.

12. SOME VIRAL INFECTIONS
1) COMMON COLD:
• The common cold is caused by many different viruses.
• The common cold is transmitted by infected airborne droplets or by direct contact
with infected secretions.
• The common cold is medically referred to as a viral upper respiratory tract
infection
• Being in cold weather does not cause the common cold.
• Symptoms of the common cold include
– cough
– sore throat
– sneezing
– runny nose
• Over-the-counter medications may be used for treatment of the common cold.
• Antibiotics are not necessary for the common cold.
• More than 200 different types of viruses are known to cause the common cold,
with rhinovirus causing approximately 10%-40% of all adult colds.
• Other commonly implicated viruses include coronavirus, adenovirus,respiratory
syncytial virus,and parainfluenza virus.

13. 2)INFLUENZA
• Influenza is a viral infection that affects mainly the nose, throat,
bronchi and occasionally lungs. Infection usually lasts for about a
week, and is characterized by sudden onset of high fever, aching
muscles, headache and severe malaise, non-productive cough, sore
throat and rhinitis.
• The virus(influenza A and B) is transmitted easily from person to
person via droplets and small particles produced when infected
people cough or sneeze. Influenza tends to spread rapidly in seasonal
epidemics.
• Most infected people recover within one to two weeks without
requiring medical treatment. However, in the very young, the elderly,
and those with other serious medical conditions, infection can lead to
severe complications of the underlying condition, pneumonia and
death.

14. 3)CHICKEN POX
• Chickenpox (varicella), a viral illness characterised by a very itchy
red rash, is one of the most common infectious diseases of childhood.
It is usually mild in children,but there is a risk of serious
complications, such as bacterial pneumonia.
• People who have had chickenpox almost always develop lifetime
immunity However, the virus remains dormant in the body and it can
reactivate later in life and cause shingles.
• Chickenpox is caused by the herpes varicella-zoster virus. It is spread
by droplets from a sneeze or cough, or by contact with the clothing,
bed linens or oozing blisters of an infected person. The onset of
symptoms is 10 to 21 days after exposure.

15. 4)MEASLES
• Measles is caused by a measles virus and it is normally passed
through direct contact and through the air (airborne disease).The
virus infects the mucous membranes, then spreads throughout the
body. Measles is a human disease and is not known to occur in
animals.
• The highly contagious virus is spread by coughing and sneezing, close
personal contact or direct contact with infected nasal or throat
secretions.
• The virus remains active and contagious in the air or on infected
surfaces for up to 2 hours.

16. 5)POLIO
• Poliomyelitis (polio) is a highly infectious viral disease, which mainly
affects young children. The virus(poliovirus) is transmitted by person-
to-person spread mainly through the faecal-oral route or, less
frequently, by a common vehicle (e.g. contaminated water or food)
and multiplies in the intestine, from where it can invade the nervous
system and can cause paralysis.
• Initial symptoms of polio include fever, fatigue, headache, vomiting,
stiffness in the neck, and pain in the limbs. In a small proportion of
cases, the disease causes paralysis, which is often permanent. There
is no cure for polio, it can only be prevented by immunization.

17. 6)DENGUE FEVER
• Dengue is a painful, debilitating mosquito-borne disease caused by
any one of four closely related dengue viruses. These viruses are
related to the viruses that cause West Nile infection and yellow fever.
• Dengue virus is transmitted by female mosquitoes mainly of the
species Aedes aegypti and, to a lesser extent, A. albopictus.
• Mild dengue fever causes high fever, rash, and muscle and joint pain.
A severe form of dengue fever, also called dengue hemorrhagic fever,
can cause severe bleeding, a sudden drop in blood pressure (shock)
and death.

18. 7)RABIES
• Rabies is an infectious viral disease that is almost always fatal
following the onset of clinical signs. In more than 99% of human
cases, the rabies virus is transmitted by domestic dogs. Rabies affects
domestic and wild animals, and is spread to people through bites or
scratches, usually via saliva.
• The rabies virus infects the central nervous system, ultimately causing
disease in the brain and death.

19. 8)HEPATITIS
• Hepatitis is an inflammation of the liver. The condition can be self-
limiting or can progress to fibrosis (scarring), cirrhosis or liver cancer.
Hepatitis viruses are the most common cause of hepatitis in the
world but other infections, toxic substances (e.g. alcohol, certain
drugs), and autoimmune diseases can also cause hepatitis.

20. 9) AIDS
• AIDS is a syndrome caused by the HIV virus (RNA ritrovirus).
• AIDS occur when a person’s immune system is too weak to fight off
many infections, and develops when the HIV infection is very
advanced. This is the last stage of HIV infection where the body can
no longer defend itself and may develop various diseases, infections
and if left untreated, death.
• There is currently no cure for HIV or AIDS. However, with the right
treatment and support, people can live long and healthy lives with
HIV.
• HIV is a virus that gradually attacks the immune system, which is our
body’s natural defence against illness.
• The virus destroys a type of white blood cell called a T-helper cell and
makes copies of itself inside them. T-helper cells are also referred to
as CD4 cells.

21. 10)MUMPS
• Mumps is a viral infection that primarily affects the parotid glands —
one of three pairs of saliva-producing (salivary) glands, situated
below and in front of your ears.
• The hallmark symptom of mumps is swelling of the salivary glands.
• Symptoms of mumps usually appear within two weeks of exposure to
the virus. Flu-like symptoms may be the first to appear, including:
-fatigue
-body aches
-headache
-loss of appetite
-low-grade fever

22. Viral Illness Prevention
• Vaccines can reduce the risk of acquiring some viral illnesses.
Vaccines are available to help protect against the flu, hepatitis A,
hepatitis B, chickenpox, herpes zoster (shingles), cancer-causing
strains of human papillomavirus (HPV), measles/mumps/rubella
(MMR), polio, rabies, rotavirus, and other viruses.
• Vaccines vary in effectiveness and in the number of doses required to
confer protection. Some vaccines require booster shots to maintain
immunity.

23. ANTIVIRAL AGENTS
Antivirals treat viral infections by affecting viral replication.
Because viruses lack independent metabolic activity and can replicate
only within host cells, Antiviral tend to injure host as well as viral cells.
Although most antiviral drugs are active against either DNA or RNA
viruses, some (eg: adefovir,ribavirin)are active against both.

24. Antiviral drugs have been developed to target virus specific steps like, cell
penetration,uncoating, reverse transcription, virus assembly or maturation,
etc.
-In majority of acute infections, viral replication is already at its peak when
symptoms appear. To be effective , therefore therapy has to be started in
the incubation peroid .ie, has to be prophylactic.
-> CLASSIFICATION
1) ANTI-HERPES VIRUS
2)ANTI-INFLUENZA VIRUS
3)ANTI-HEPATITIS/NONSELECTIVE ANTIVIRAL DRUGS
4)ANTI-RETROVIRUS

25. 1) ANTI-HERPES VIRUS
a)ACYCLOVIR: synthetic acyclic analog of guanosine.
spectrum of activity: HSV-1,HSV-2,VZV,EBV(some).
 Mechanism of action:
Acyclovir
Herpes virus specific thymidine kinase
Acyclovir monophosphate
Cellular kinases
Acyclovir triphosphate Inhibits herpes virus DNA
polymerase
Gets incorporated in viral DNA and stops lengthening of DNA
strand; the terminated DNA inhibits DNA-polymerase irreversibly
-KINETICS: available in iv, oral & topical forms
well absorbed and cross BBB.
-DOSE : GENITAL HERPES: 200mg for days/ 400 mg for 5 days
chicken pox : 800 mg 5 time for 7-10 days.

26.  Uses:
• Genital Herpes simplex
(Primary disease &
Recurrent disease)
• Mucocutaneous H. simplex
• H. simplex encephalitis (type-1
virus)(iv)
• H. simplex keratitis(ointment)
• Herpes zoster
• Chickenpox
 Adverse effects:
• Topical: stinging and burning
sensation after each application
• Oral: Headache, nausea,
malaise and some CNS effects
• Intravenous: Rashes, sweating,
emesis, and fall in BP(in few)
• Dose dependent decrease in
GFR (in renal failure)
-Resistance : altered / deficient thymidine kinase & DNA polymerase
-Contraindication: hypersensitivity, glaucoma, psychiatric disease,depression.

27. b)CIDOFOVIR:synthetic acyclic purine nucleoside phosphonate derivative
-approved for the treatment of CMV retinitis in AIDS patients
-M.O.A: cidofovir
phosphorylation
cidofovir diphospahte
selective inhibition of viral DNA synthesis.(replication process)
-available only in i.v form.(probenecid must be given before and after
each dose )
-contraindication: renal impairement , along with nephrotoxic drugs
-ADR: ACUTR RENAL FAILURE leading to dialysis or death.(patient must
be hydrated with 1 L of normal saline before infusing)

28. c)FAMCICLOVIR & PENCICLOVIR:
- Famciclovir is the prodrug of antiviral drug penciclovir.
- Penciclovir is acyclic guanosine nucleoside.
- Spectrum ofactivity : HSV-1,HSV-2,VZV
- DOSE: 500 mg every 8hr for 7 days.
- M.O.A: famiclovir
viral thymidine kinase
penciclovir monophospahte
competitive inhibition of viral DNA polymerase and thus
inhibit synthesis of viral DNA.
- FAMICLOVIR : oral
- PENCICLOVIR: topical

29. d)FOSCARNET: Unlike others foscarnet is not purine or pyrimidine
analog. It is pyrophosphate derivative & don’t require activation by
viral / cellular kinases.
- M.O.A: > Reversibly inhibit viral DNA nad RNA polymerase
> Active against HIV , inhibit HIV reverse transcriptase.
- Iv administration and crosses BBB
- Use : CMV retinitis in AIDS patients, acylovir-resistant HSV infection.
- ADR: iv foscarnet is highly nephrotoxic.causes acute tubular necrosis.
electrolyte abnormalities, anemia,fever ,seizures, headache etc
-given as iv infusion for 1.5-2 hrs.Do not administer as iv bolus.

30. e)GANCICLOVIR: synthetic purine nucleoside analog
- M.O.A: ganciclovir
viral /cellular enzymes
ganciclovir monophosphate.
inhibit DNA polymerase & inhibit viral DNA synthesis.
- Use: CMV retinitis in AIDS patients & for CMV prophylaxis in transplant patients.
- ADR: dose dependent neutropenia
fever , rash , GI disturbance
- Ganciclovir is extremly alkaline ,avoid direct contact with skin.
f)TRIFLURIDINE & IDOXURIDINE: trifluridine is a fluorinated pyrimidine nucleoisde
analog. And structurally similar to thymidine.
- trifluridine and idoxuridine have same action.
- they convert into triphosphate and competes with thymidine and inhibit thymidine
triphospahte incorporation into viral DNA.Thus faulty DNA is formed and destroyed.
- routes: topical , ophthalmic (iv is not used because it may cause cellualr DNA damage)
- use: HSV-1,HSV-2,HSV keratoconjuctivitis , recurrent epithelial keratitis .

31. 2) ANTI-INFLUENZA VIRUS
a) AMANTADINE & RIMANTADINE:
-These are adamantane derivatives.
-Rimantadine is alpha-methyl derivative of amantadine. More potent, longer acting (t½ 30
hours) and better tolerated.
-amantadine is synthetic tricyclic amine. Structure similar to rimantadine .
-effective against influenza A viral infection.
-inflenza B,H5N1,H1N1,is not affected.
-M.O.A: action on early step (uncoating) as well as last step (viral assembly).
interfere with M2 protein function in virus.
(Blocks the viral membrane matrix protein, M2, which functions as a channel for hydrogen ion
 This channel is required for the fusion of the viral membrane with the cell membrane that ultimately
forms the endosome (during internalization of the virus by endocytosis))
-USE: influenza A infection,
parkinsonism.(dopamine release and anticholinergic activity)
-ADR: ataxia,nightmare ,insomnia,depression,confusion,dizziness, snticholinergic reaction
(dry mouth ,blurred vision)
-only amantadine cross BBB
-DOSE: 10mg BD

32. b) OSELTAMIVIR & ZANAMIVIR :
-oseltamivir is pharmacologically similar to zanamivir but structurally different
-M.O.A: oseltamivir undego hydrolysis and form oseltamivir carboxylate and it will
selectively inhibit influenza virus enzyme neuraminidase.(thus virions releaseto
host cell is prevented.)
-USE: active against both influenza A & B virus,
prophylaxis of influenza infection
H5N1,H1N1 infections.
oseltamivir : 75mg BD 5days
zanamivir: 5 mg /actuation powder
inhalation
--Oseltamivir
 Side effects:
• Nausea and abdominal pain
(gastric irritation)
• Headache, weakness, sadness,
diarrhoea, cough, and
insomnia
• Skin reactions
--zanamivir
• Low oral bioavailability; t½ of
2–5 hours
Containdication: Asthmatics (
bronchospasms)

33. 3) ANTI-HEPATIC VIRUS
FOR HEPATITIS B FOR HEPATITIS C
*ADEFOVIR DIPIVOXIL
*LAMIVUDINE
*TENOFOVIR
->Hepatitis B virus is DNA virus ,it will
integrate into host chromosomal DNA
&cause permanent infection.
*RIBAVIRIN
*INTERFERON ALPHA
->Hepatitis C virus is a RNA virus , it will
not integrate into host chromosomal
DNA & do not cause non curable
infection. But may cause chronic
hepatitis.
a) ADEFOVIR DIPIVOXIL : phosphonate nucleotide analog
-M.O.A: adefovir dipivoxil undergo phosphorylation by cellular kinase enzymes
and become active disphosphate form. It will then incorporate into viral DNA
and leads to termination of replication.
-use: HBV, Herpes virus,HIV
-dose: 10 mg / day
-ADR: nephrotoxicity,rashes,GI disturbance,acute hepatitis when discontinue
therapy, dose adjustment for renal insufficiency.

34. b) RIBAVIRIN: synthetic nucleotide analog
-M.O.A: ribavirin on administration will deplete intracellular nucleotide reserve. Thus
inhibit DNA & RNA synthesis.
-use: HCV,Herpes virus,influenza A ,B
-ADR: hemolytic anemia , GI disturbance
c) INTERFERON α: interferones are naturally occuring ,inducible gycoproteins
that interfere with the ability of virus to infect cells.
-synthesized by recombinent DNA technology.
- There are alpha beta & gamma interferons
- M.O.A: interferone bind to specific cell receptor & affect viral replication at
multiple steps.( viral penetration,synthesis of mRNA,assembly ,release).ie , direct
and indirect suppression of viral multiplication.
- Interferons are not active orally . (iv,sc)
- USE: chronic hepatitis B virus infection, AIDS related kaposis sarcoma,Herpes
simple virus , H.zoster ,CMV infection.
- ADR: flu like symptoms, bone marrow suppression, weight loss,
neurotoxicity,hypotension,myelosuppression,thyroid dysfunction.