Download anti viral drugs

 Viruses are obligate intracellular parasites.
 They lack a cell wall and a cell membrane
 Do not carry out metabolic processes and uses
the host’s metabolic machinery for reproduction,
therefore antiviral drugs are capable of injury to
the host.
 Symptoms of viral illness appear late in the
course of the disease when most of the virus
particles have replicated. At this stage,
administration of antiviral drugs have limited
effectiveness though some are used as
prophylaxis
Viral Structure
Contains DNA or
RNA
Virus attaches to surface of host cell
Host cell’s proteolytic
enzymes break down
envelope.
Virus takes control of host
cell’s molecular
synthesizing capability to
begin making new viral
enzymes and proteins.
Making new viruses
New viruses are released
either by exocytosis or
lysis of host cell.
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Drugs for respiratory virus infections
Drugs for hepatic viral infections
Drugs for herpes and CMV infections
Drugs for HIV infections
 For influenza A and B
 Respiratory syncytial virus
 Antiviral drugs are used against influenza A for
those allergic to the vaccine, or when the
outbreak is due to a variant of the virus not
covered by the vaccine or when the outbreak
occurs among unvaccinated individuals at risk
who are in closed settings
oseltamivir, zanamavir
are sialic acid analogs
 MOA : inhibits neuraminidase, thereby inhibiting
the release of new virions and their spread from
cell to cell
 Spectrum : Influenza A & B—prior to exposure-good
 Route : Oral(oseltamivir),
inhalation/intranasal(zanamivr)
 Excretion : renal
 SE : GI disturbance(not zanamivir), ataxia,
dizziness
 CI : preg, lactating, zanamavir --asthmatics
 Due to mutations of the neuraminidase
 Amantadine, rimantadine—adamantine
derivatives
 Used in the treatment of influenza A infections
 MOA: Block viral membrane matrix protein, M2
preventing viral uncoating.
 Both absorbed well orally
 Amantadine crosses bbb. Can cause insomnia,
dizziness, hallucinations and seizures.
 Rimantadine does not efficiently cross the BBB, so
fewer CNS effects
 Resistance: change in an amino acid in the M2
protein
 Other uses: Amantadine is used in the
treatment of Parkinson disease.
 CI: pregnant, lactating patients, cerebral
atherosclerosis, renal impairment, epilepsy
 MECH : synthetic Guanosine analog converted
to its triphosphate derivate →inhibition of viral
RNA polymerase and mRNA capping.
 ROUTE – ORAL / IV, AEROSOL
 EXCRETION : RENAL
 SE: ANEMIA
 CI : Preg
 USES : CHILD RSV INFECTIONS, can also be
used for Hepatitis C, Influenza A & B, Lassa
fever
 HEPATITIS VIRUSES THUS FAR IDENTIFIED
 A,B,C,D and E.
 HEP B & C ARE MOST COMMON—chronic
hepatitis, cirrhosis and hepatocellular ca.
 Chronic hep B is treated with interferon alfa plus
lamivudine
 Chronic hep C responds to interferon alfa plus
ribavarin.
 MECH : induces host cell enzymes that INHIBIT
VIRAL RNA TRANSLATION→ degradation of viral
mRNA and tRNA
 ALPHA INTERFERON (α-INTERFERON) IS
USED FOR
 HEPATITIS B AND C
 PAPILLOMA VIRUS
 KAPOSI’S SARCOMA
 HAIRY CELL LEUKEMIA
 SE : BONE MARROW, neurotoxicity,
HYPERSENSITIVITY, flu-like symptoms (fever,
chills, myalgias, arthralgias)
 INTERFERON β: Treatment of multiple sclerosis
 INTERFERON γ: Treatment of chronic
granulomatous disease
 Lamivudine— a cytosine analog
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Converted to its triphosphate derivative
inhibitor of HBV & HIV-reverse transcriptase
Competitively inhibits HBV Dna polymerase
Well absorbed orally
T1/2 ---9 hrs
 Adefovir
 Nucleotide analog phosphorylated to its
diphosphate derivative and then incorporated
into viral DNA—termination of DNA synthesis
ACYCLOVIR, a guanosine analog
 MECH : phosphorylated by bacteria thymidine
kinase then host cell kinase to its triphosphate
derivative which competes with deoxyguanosine
triphosphate as a substrate for VIRAL DNA
POLYMERASE → incorporation into the viral DNA
causing premature chain termination
 SPECTUM:HSV 1, HSV 2, V-Z , EBV
 SPECIFIC – HSV
 USES : DOC – HS ENCEPHALITIS
 COMMON : GENITAL HERPES
 RESISTANT : CMV
 Oral, I.V., topical,, crosses BBB
 Exe: Renal
 SE: Headache, vomiting, diarrhea and also
renal dysfunction.
GANCICLOVIR, an analog of acyclovir (IV)
MOA: Converted to triphosphate derivative by
another route cos CMV lacks thymidine kinase
 SPECTRUM : CMV
 USE : CMV RETINITIS
 SE: NEUTROPENIA
 CI: Pregnancy
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FAMCICLOVIR (oral) , penciclovir (topically)
famciclovir : ACUTE HERPES ZOSTER
Pencicovir:HSV-1, HSV-2 and VZV
MOA: triple phosphorylation →incorporation into
viral DNA causing premature chain termination
→inhibition of viral DNA polymerase
CIDOFOVIR, analog of cytosine
 MOA: triple phosphorylation not dependent
on viral thymidine kinase → inhibition of
viral DNA synthesis
 CMV – Retinitis in HIV/AIDS patients
 I.V route
 SE: Nephrotoxic, Neutropenia, Metabolic
acidosis
VIDARABINE (IV, TOPICAL)
 IMMUNO COMPROMISED PATIENTS WITH
HS KERATITIS, ENCEPHALITIS, VZV
TRIFLURIDINE, IDOXURIDINE
 TOPICAL – HS KERATO CONJUCTIVITIS
FOSCARNET(IV) – not purine or
pyrimidine analog
MOA: INHIBIT VIRAL RNA & DNA
POLYMERASES→termination of chain elongation
 FOR CMV retinitis in immunocompromised host
 Acyclovir RESISTANT HSV and VZV infections.
 SE : NEPHROTOXICITY,ANEMIA, ELECTROLYTE
IMBALANCE( hypokalemia, hypocalcemia,
hypomagnesemia, hypo and hyper phosphatemia)
Life Cycle of HIV
1. attachment: Virus binds to surface
molecule (CD4) of T helper cells and
macrophages.
 Coreceptors: Required for HIV infection.
 CXCR4 and CCR5 mutants are resistant
to infection.
2. fusion: Viral envelope fuses with
host cell membrane,
3. Penetration and uncoating:
penetrates host cell releasing
contents into the cell.
Life Cycle of HIV
4. Reverse Transcription: Viral RNA is
converted into DNA by unique enzyme
reverse transcriptase.
Reverse transcriptase
RNA ---------------------> DNA
Reverse transcriptase is the target of
several HIV drugs: AZT, ddI, and ddC.
Life Cycle of HIV
5. Integration: Viral DNA is inserted into host cell
chromosome by unique enzyme integrase.
Integrated viral DNA may remain latent for years and
is called a provirus.
6. Replication: Viral DNA is transcribed and RNA is
translated, making viral proteins.
Viral genome is replicated.
7. Release: New virus RNA and precursor polyprotein
bud through the cell membrane.
8. Assembly & maturation: virion protease is activated
and cleaves the precursor polyprotein into
component protein(attachment protein & fusion
protein) which then assemble into the mature
virion.New viruses are made.
Transmission of AIDS (Worldwide)
1. Sexual contact with infected individual: All
forms of sexual intercourse (homosexual and
heterosexual). 75% of transmission.
2. Sharing of unsterilized needles by intravenous
drug users and unsafe medical practices: 5-10%
of transmission.
3. Transfusions and Blood Products: Hemophiliac
population was decimated in 1980s. Risk is low
today. 3-5% of transmission.
4. Mother to Infant (Perinatal): 25% of children
become infected in utero, during delivery, or by
breast-feeding (with AZT only 3%). 5-10% of
transmission.
AIDS Associated Disease Categories
1. Gastrointestinal: Cause most of illness and death
of late AIDS.
Symptoms:
 Diarrhea
 Wasting (extreme weight loss)
 Abdominal pain
 Infections of the mouth and esophagus.
Pathogens: Candida albicans, cytomegalovirus, Microsporidia,
and Cryptosporidia.
AIDS Associated Disease Categories
2. Respiratory: 70% of AIDS patients develop serious
respiratory problems.
Partial list of respiratory problems associated with AIDS:
 Bronchitis
 Pneumonia
 Tuberculosis
 Lung cancer
 Sinusitis
 Pneumonitis
AIDS Associated Disease Categories
3. Neurological: Opportunistic diseases and tumors
of central nervous system.
Symptoms may include: Headaches, peripheral
nerve problems, and AIDS dementia complex
(Memory loss, motor problems, difficulty
concentration, and paralysis).
AIDS Associated Disease Categories
4. Skin Disorders: 90% of AIDS patients develop skin
or mucous membrane disorders.
 Kaposi’s sarcoma
 1/3 male AIDS patients develop KS
 Most common type of cancer in AIDS patients
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Herpes zoster (shingles)
Herpes simplex
Thrush
Invasive cervical carcinoma
5. Eye Infections: 50-75% patients develop eye
conditions.
 CMV retinitis
 Conjunctivitis
 Dry eye syndrome
 Uses combination of drugs to suppress
replication of HIV and restore a degree of
immunocompetency to the host
 The multidrug regimen is commonly referred to
as “highly active antiretroviral therapy” or
HAART
 There are three classes of antiretroviral drugs,
each of which targets one of two viral processes
(reverse transcriptase, protease)
 Nucleoside and nucleotide reverse transcriptase
inhibitors (NRTIs)
 Non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
 Protease inhibitors (PIs)
 Current recommendation: 2NRTIs plus either a
PI or a NNRTI.
 Reason for multidrug therapy: maximize the
inhibition of viral replication and minimize drug
toxicities
Drugs Against HIV
 Reverse Transcriptase Inhibitors:
Competitive enzyme inhibitors.
Example: AZT, ddI, ddC.
 Protease Inhibitors: Inhibit the viral
proteases. Prevent viral maturation.
 Problem with individual drug
treatments: Resistance.
 Are nucleosides or nucleotides
containing ribose which all lack
a 3′-hydroxyl group.
 Once they enter cells, they are
converted to corresponding
triphosphate analog by
mammalian thymidine kinase
which is incorporated into the viral
DNA by virus reverse transcriptase
and DNA chain elongation is
terminated.
ZIDOVUDINE / AZT ( Thymidine analog)
Approved for use in children and adults and to
prevent prenatal infection in pregnancy.
It is also used as prophylaxis in individuals
exposed to HIV infection
 ORAL ABSORPTION
 Pharmacokinetics: AZT is glucuronylated by the
liver
 Excretion: kidney in urine
 SE : BONE MARROW toxicity, HEADACHE ,
SEIZURES
 Toxicity is potentiated if glucuronylation is decreased
by co-administration of drugs probenecid,
indomethacine, cimetidine, lorazepam
DIDANOSINE ( Adenosine) :
RESISTANT HIV
 SE : PANCREATITIS, PERIPHERAL
NEUROPATHY
ZALCITABINE ( Cytosine):
- SE-PERIPHERAL NEUROPATHY
OTHER DRUGS: STAVUDINE (Thymidine),
LAMIVUDINE (Cytosine) also used for Hep - B
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NEVIRAPINE
DELAVIRDINE
EFAVIRENZ
MOA: are selective noncompetitive inhibitors of
HIV-1 reverse transcriptase
- They do not require activation to triphosphate
derivatives by cellular enzymes
- Advantage: their lack of effect on host blood
forming cells
 Used for treatment HIV-1 infections in adults and
children
 Effective in reducing vertical transmission during
pregnancy and may be used as a substitute for
AZT for this purpose
 Oral route
 Renal exe.
 SE: Rash, fever, Stevens – Johnson Syndrome
and Toxic epidermal necrolysis, elevated serum
transaminases, Fatal heptotoxicity.
DELAVIRDINE
 Oral route
 Bile and renal exe.
 SE: nausea, rash, dizziness
EFAVIRENZ
 Good increase in CD4+ count, decreases viral
load
 SE: Mostly CNS effects, vivid dreams
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SAQUINAVIR
RITONAVIR
INDINAVIR:
NELFINAVIR
AMPRENAVIR
 MOA: inhibit viral protease preventing the
formation of new mature virions
SE; Important are lipodystrophy & hyperglycemia,
hypertriacylglycerolemia, fat redistribution
including loss of fat from the extremities
and its accum in the abdomen and the base
of the neck “buffalo hump”(indanavir) &
breast enlargement, nephrolithiasis &
hyperbilirubinemia (indanavir)
CI : with many drugs
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Antiarrhythmic’s
Antihistamines
Ergot derivatives
Antimycobacterial drugs
Benzodiazepines
GI drugs such as cisapride
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VIRAL FUSION INHIBITOR
ENFUVIRTIDE
new class of anti retroviral drug
in order to gain entry into the host cell it must
fuse its membrane with that of host cell. This is
accomplished by changes in the conformation of
viral transmembrane glycoprotein gp41.
Enfuvirtide binds to gp41 preventing the
conformational change.
 Given subcutaneously.