2. Virology Overview
• Viruses are responsible for a large
proportion of morbidity and mortality
experienced worldwide
• They are infectious agents consisting of a
core genome of nucleic acid (nucleoid)
contained in a protein shell (capsid)
• The genetic material may be single or
double stranded DNA or RNA
• This arrangement is often surrounded by a
lipoprotein membrane (envelope)
3. Virology Overview
• Viruses can not replicate independently
• They must enter host cells and use their
cellular metabolic machinery (including
organelles, enzymes, biomolecules etc)
• Some viruses can integrate a copy of their
genetic material into hosts chromosome
(this is called a Provirus).
• This provirus achieves viral latency, a
condition in which clinical illness can recur
without re-exposure to the virus
4. • Since viruses always rely on the host’s
metabolic machinery to live and replicate, it
is not always easy to selectively target them.
This means that drug development has been
rather slow
• Most currently available drugs interfere with
viral nucleic acid synthesis/regulation
• Few agents work by blocking virus-cell
binding, interrupting virus uncoating or
stimulating host’s immune system
• A lot of knowledge of viral biochemistry has
only recently been known, it is hoped that
more effective drugs will result
5. • Because viruses generally take over host’s
nucleic acid/protein replication pathways
before clinical infection is discovered, most
antiviral drugs must penetrate cells
already infected in order to produce a
therapeutic antiviral response
• This requirement is often a source of
significant toxicity to healthy cells, limiting
the usefulness of antiviral drugs
6. Viral susceptibility testing
• In vitro susceptibility testing of antiviral
compounds differs significantly from that of
antibacterial agents. Here, cell cultures are
used (why?)
• In general, a greater than 50% reduction in
cell plaque formation at an achievable
serum concentration classifies a drug as
active on a given virus
• Many antiviral drugs have in-vitro activity
on many different viruses but are not
clinically effective
7. • Issues of drug distribution, administration
& timing of infection can limit usefulness of
many agents
• Several agents become converted in the
body to active compounds (Acyclovir,
Ganciclovir) or must be continuously
present to have an effect (Amantadine)
• Many antiviral agents inhibit single steps in
the viral replication cycle and are therefore
virustatic, they do not destroy the virus but
temporarily halt its replication
8. • Optimal antiviral effectiveness requires a
competent host immune system that can
eliminate viral particles
• Patients with immunosuppressive states like
leukemia, lymphoma, transplantation or AIDS
are prone to frequent and severe viral
infections that may occur when anti-viral
treatment is stopped. Prolonged suppressive
therapy is often necessary
• Viral resistance to specific drugs is also
known to occur
• Currently no antiviral eliminates viral latency
9. Viral infection & replication
• Virons must first come into contact with
an appropriate cell to initiate an infection
• The next steps follow host-cell contact:
1. Virus penetrates the cell
2. Disassembles
3. Initiates synthesis of virus components
by taking over host’s protein and nucleic
acid synthesis
4. Assembly of virons within host cell
5. Release of virons to enter other cells
10. Mechanism of antivirals
• Antiviral agents that interfere with several of
the steps in the virus reproductive cycle have
been developed
• Most are nucleic acid analogs that will
interfere with virus DNA/RNA production and
therefore inhibit virus replication
• Many viruses contain unique enzymes that
make them more susceptible to certain agents
(e.g. polymerase, transcriptase or HIV
protease)
11. • Single nucleotide changes leading to crucial
amino acid substitutions in protein is often
sufficient to cause antiviral drug resistance
• Combination antiviral therapy with multiple
agents has shown successful results in HIV
treatment but not in other conditions
• As antiviral agents are only virustatic, an
effective immune response is essential for
recovery from disease
• For this reason, clinical failures of antiviral
therapy may occur with drug sensitive virus
in highly immunocompromised patients.
12. Some DNA viruses
1. Pox viruses (small pox)
2. Herpes viruses (chicken pox, shingles,
herpetic ulcers oral & genital)
3. Adenoviruses (conjunctivitis, sore throat)
4. Hepadnaviruses (hepatitis B)
5. Papillomaviruses (warts)
• Typically DNA viruses enter into the host
cell nucleus where viral DNA is
transcribed into mRNA by host cell
mRNA polymerase
13. • Viral proteins follow in the usual fashion
• Poxvirus have own RNA polymerase and
therefore replicate in host cell cytoplasm
• RNA viruses may rely on contained viral
enzymes or serve as their own mRNA to
produce viral proteins
• The produced viral proteins may include
RNA polymerase which directs the
synthesis of more viral mRNA
15. Retroviruses
• Are a special group of RNA viruses
• Contain a reverse transcriptase enzyme
that makes a DNA copy of viral RNA
• This “Provirus” is then integrated into host
genome and transcribed into both genomic
RNA & mRNA for translation into proteins
• They include HIV and HTLV-1 that cause
AIDS and T-cell leukemias respectively
16. ANTI-HERPESVIRUS AGENTS
• Herpes simplex virus type 1 (HSV-1) will
cause infection in the mouth, face, skin,
esophagus & brain (encephalitis)
• Herpes simplex virus type 2 (HSV-2) will
cause infection in the genitals, rectum,
skin, hands & meninges
• In either case disease may be primary or
an activation of a latent infection
17. Acyclovir & Valacyclovir
• Acyclovir is an acyclic guanine nucleoside
analog that lacks the 3’-hydroxyl on the side
chain
• Valacyclovir is the L-valyl ester of Acyclovir
• Their clinical effectiveness is limited to only the
herpes virus family
• In-vitro, acyclovir is the most active against
HSV-1, it is twofold less sensitive against HSV-
2 and up to tenfold less sensitive on VZV and
Epstein-Barr virus
18. • It is least effective against Cytomegalovirus
(CMV) and Human Herpes virus (HHV-6)
Mechanism of action
• Acyclovir inhibits viral DNA synthesis
• It is converted to acyclovir monophosphate
(Acyclovir-MP) derivative by a viral enzyme
thymidine kinase.
• Acyclovir-MP is then phosphorylated to
Acyclovir-DP and subsequently Acyclovir-TP
by mammalian cellular enzymes
19. • Incorporation of acyclovir-MP (obtained from
acyclovir-TP) into primer strand of viral DNA
replication leads to chain termination and
formation of an inactive complex with viral
DNA polymerase
• Cellular uptake and first phosphorylation are
facilitated by viral thymidine kinase.
• The affinity of drug for viral enzyme is about
200X greater than mammalian thymidine
kinase (basis of selectivity)
• Acyclovir-TP is present in infected cells 40 -
100X the concentration in healthy cells
20. • Within the cell, they compete with dGTP a
substrate of viral DNA polymerase
• Acyclovir triphosphate (ATP) is also
incorporated into viral DNA, where it acts
as chain terminator because of lack of the
3’-hydroxyl group. (this is where normal
condensation occurs)
• The terminated DNA template containing
acyclovir binds the enzyme leading to
irreversible inactivation of the enzyme
• This is termed suicide inactivation
21. Pharmacokinetics
• Oral bioavailability ranges from 10-30%,
administration Valacyclovir increases this
to 50%
• The drug distributes widely in body fluids
including vesicular fluid, aqueous humor &
CSF. Salivary concentrations are low and
vaginal concentrations are variable
• Acyclovir is concentrated in breast milk,
amniotic fluid and placenta
• Percuteneous absorption following topical
application is low
22. • Plasma half-life averages 2.5 hrs in adults,
about 4 hrs in neonates and 20 hrs in
anuric patients
• Renal GF & TS are the main methods of
elimination from the body
• Acyclovir is available as capsules, as an
ointment and as powder for I.V use
23. Side effects
• Oral preparations may have the usual GI
disturbances (nausea, diarrhea
• Topical preparation may cause mucosal
irritation and transient burning when applied
to genital lesions
• Phlebitis may occur with extravasations into
tissues (I.V use)
• Rash, headache and rarely neurotoxicity or
renal insufficiency
• It has been found safe in long term use as
well as during pregnancy
24. Drug interactions
• Probenecid decreases renal clearance and
prolongs the plasma half-life of drug
• Acyclovir may decrease renal clearance of
other drugs eliminated by active renal
secretion such as Methotrexte (anticancer)
• Severe somnolence and lethargy may occur
in combination with Zidovudine
• Concomitant use with cyclosporine and other
nephrotoxic drugs enhances the risk of
nephrotoxicity
25. Therapeutic uses
• In immunocompetent patients, clinical benefit
of acyclovir is greater in initial HSV infection
than in recurrent ones (milder)
• Used in immunocompromised patients who
frequently suffer severe attacks of
mucocuteneous HSV or VZV
• Higher doses must be used in treating
varicella or zoster cases than HSV
• Oral Valacyclovir is preferred in VZV as it
requires less dosing frequency
26. • In primary infection, acyclovir 200mg X5/Day
for 10 days reduces symptoms (like vesicles,
pain), viral shedding and healing time
• I.V acyclovir 5mg/kg per 8 hrs is good in ISS
patients with mucocuteneous infection
• Frequently occurring genital herpes can be
suppressed with 400mg twice daily
• HSV transmission to sexual partners may
occur even during suppression
• Oral acyclovir is effective in primary herpetic
gingivostomatitis (600mg/m2 X4 for 10 days)
with modest benefit in recurrent orolabial d’se
27. • Topical ointment only effective in labial and
genital herpes simplex infections and to a
limited extent facial HSV infection
• Systemic acyclovir prophylaxis is highly
effective in seropositive patients undergoing
Immunosuppression therapy
• In HSV encephalitis, acyclovir 10mg/kg/8 hrs
for no less than 10 days reduces mortality by
over 50% and improves overall neurologic
outcome
• Acyclovir ophthalmic formulation may be used
in herpetic keratoconjunctivitis
28. Varicella-Zoster virus infection
• If acyclovir is begun within 24 hrs of rash
onset, it has therapeutic effects, reducing
overall disease process by 2 days. Later
treatment is not beneficial
• In ISS patients with herpes-zoster, I.V
acyclovir reduces viral shedding, healing
time and risk of cuteneous dissemination as
well as length of hospitalization
• No beneficial effect is seen on post-herpetic
neuralgia
29. Other viruses
• Acyclovir is ineffective in established CMV
infection but is used for prophylaxis in
seropositive transplant recipients
• In infectious mononucleosis, acyclovir is
associated with transient antiviral effects
but no clinical benefits
• Epstein-Barr Virus-related oral hairy
leukoplakia may improve with acyclovir
30. Penciclovir & Famciclovir
• Penciclovir is an acyclic guanine nucleoside
analog. It is similar to Acyclovir in its activity
spectrum and potency profile against HSV,
VZV
• It is however less potent than Acyclovir yet
with a better pharmacokinetic profile
• Famciclovir is the diacetyl ester prodrug of
Penciclovir.
• Penciclovir is also inhibitory against Hepatitis
B virus (HBV)
31. Pharmacodynamics
• Penciclovir is an inhibitor of viral DNA synthesis
• It is initially phosphorylated by viral thymidine
kinase (only in infected cells), mammalian
enzymes then convert it to the triphosphate
• Penciclovir triphosphate then serves as a
competitive inhibitor of viral DNA polymerase
• Although it is less potent than Acyclovir, it is
present in higher concentrations and for a
longer time in infected cells than Acyclovir
(remember these are virustatic drugs)
32. • The prolonged intracellular half-life ranges
from 7-20 hrs and is associated with a
prolonged antiviral effect.
• Because it has a 3’hydroxyl group, the drug
is not a chain terminator unlike Acyclovir, but
it does inhibit DNA elongation
• Resistance may occur by alteration of the
key enzymes: thymidine kinase or viral DNA
polymerase.
• Cross resistance between Penciclovir and
Acyclovir occurs
33. Pharmacokinetics, S/E
• Oral Penciclovir has a bioavailability of 5%
• Given as Famciclovir, bioavailability is up to
75%
• Penciclovir has a half-life of 2 hrs and up to
90% is excreted unchanged in urine
• Drug is generally well tolerated although
headache and GI disturbances may occur
• May carry a mutagenic risk in high
concentrations
34. Therapeutic uses
• All oral preparations are available as
Famciclovir
• Used for treatment of localized herpes zoster
in immunocompetent adults, given as 500mg
3X daily for 7 days
• Topical and I.V preparations, undergoing
clinical trials for various herpesvirus infections
• May also be used in treatment of chronic
hepatitis B virus infection
35. Ganciclovir
• An acyclic guanine nucleoside analog similar
in structure to acyclovir
• It has an additional hydroxymethyl group on
the acyclic side chain
• It is active against all herpesviruses but is
especially active against CMV
• Inhibitory concentrations for progenitor bone
marrow cells (human) is similar to those of
CMV replication (this finding is predictive of
myelotoxicity during clinical use)
36. Pharmacodynamics
• It inhibits viral DNA synthesis
• It is monophosphorylated by viral enzyme (a
viral phosphotransferase in CMV & thymidine
kinase in HSV)
• The di- and triphosphates are eventually
formed by cellular enzymes
• The triphosphate is a competitive inhibitor of
deoxyguanosine triphosphate incorporation
into DNA. It preferentially inhibits viral rather
than host DNA polymerase
37. • It is incorporated into both viral & cellular DNA
causing termination of chain growth
• Intracellular Ganciclovir concentrations are
10X higher than those of acyclovir and decline
much more slowly with a t1/2 exceeding 24 hrs
• This difference may account for its greater
anti-CMV activity. It also provides the rationale
for a single daily dose when suppressing
Human CMV infections
• Drug resistance is due to point mutation in
viral enzymes. Cross resistance with acyclovir
may occur
38. Pharmacokinetics
• Oral bioavailability averages 6-9%, prodrug
not available so I.V route is recommended
• Aqueous and sub-retinal fluid levels are
similar to those of plasma
• Plasma half-life is 2-4 hrs in patients with
normal renal function but will increase in
those with renal insufficiency
• It is excreted 90% by renal mechanisms (TS,
GF)
39. Adverse effects
• Myelosuppression is the principal dose
limiting toxicity of Ganciclovir
• After 1 week of treatment, Neutropinea,
thrombocytopenia, lymphopinea will occur
in up to 40% of patients
• It is reversible within a week of drug stop
• CNS effects may occur in up to 15% of
patients (ranging from headache to coma)
• About one third of patients stop treatment
prematurely due to side effects
40. • Infusion related phlebitis, azotemia, anemia,
rash, fever and liver enzyme abnormalities,
eosinophilia occur
• Teratogenicity and embryo toxicity have
been observed in animal studies
• Zidovudine and other cytotoxic agents will
increase the risk of myelosuppression
• Probenecid and acyclovir reduce renal
clearance of Ganciclovir (is this desirable?)
41. Therapeutic uses
• Treatment and chronic suppression of CMV
retinitis in immunocompromised patients.
(5mg/kg every 12 hrs for up to 21 days).
• Oral Ganciclovir 1000mg 3X daily may also
be used for suppression of retinitis
• Relapses of retinitis despite suppressive
treatment are usually due to drug resistance
• Prevention of CMV disease in transplant pts.
• Prevent dissemination of CMV colitis, there is
no obvious symptomatic benefit
42. Foscarnet
• Foscarnet is trisodium phosphoformate
• It is an inorganic pyrophosphate analog that
is inhibitory to all herpesviruses & HIV
• It is effective in Acyclovir or Ganciclovir
resistant viruses
• A highly ionized compound at physiologic pH
making it a cause of metabolic abnormalities
(distortion of Ca2+ & PO4 levels in plasma)
43. Pharmacodynamics
• It inhibits viral nucleic acid synthesis by
interacting directly with herpesvirus DNA
polymerase and HIV reverse transcriptase
• It reversibly blocks the pyrophosphate
binding site of the viral polymerase, inhibiting
cleavage of pyrophosphate to form
deoxynucleotide triphosphates
• It has about 100X greater effects on viral
enzyme than mammalian one
44. Pharmacokinetics & S/E
• Oral bioavailability is poor, given via I.V route
• Poorly soluble in aqueous solution, requiring
large volumes for administration
• Over 80% of drug is excreted unchanged by
glomerular filtration
• The rest of the dose tends is sequestered in
bone (10-20%)
• Dose limiting toxicities are nephrotoxicity and
hypocalcaemia which are more likely with
rapid infusion or dehydration
45. • Acute tubular necrosis, crystaluria and
interstitial nephritis have also been reported
• Hypocalcaemia; which may cause
paresthsias, arrhythmias, tetany or seizures
• Painful genital ulcerations
• Abnormal liver function tests
• CNS effects: headache, tremor, irritability
• Leucopenia, anemia, fever and nausea are
other reported side effects
46. Therapeutic uses
• It is used in treatment of CMV retinitis and
acyclovir resistant HSV & VZV infections.
These are common in AIDS patients
• Also other types of CMV infections in
combination with other antiviral drugs
• Dose is 60mg/kg per 8hrs for 14-21 days
• Oral Foscarnet is under study for CMV
prophylaxis
47. Idoxuridine
• It is an iodinated thymidine analog
• It inhibits the in-vitro replication of various
DNA viruses including herpesviruses and
poxviruses
• Inhibitory concentrations for HSV-1 are 10X
higher than those of acyclovir
• It lacks selectivity in affecting the growth of
uninfected cells even in low concentration.
This makes it unfavorable for systemic use
48. Pharmacodynamics
• Antiviral mechanism is poorly understood
• The phosphorylated derivatives interfere with
various enzyme systems
• The triphosphate is incorporated into both viral
and cellular DNA
• Such altered DNA is more prone to breakage
and faulty transcription
• Resistance development occurs during use
49. Indications & S/E
• It is indicated for topical treatment of HSV
keratitis
• Idoxuridine in dimethyl sulfoxide is available
for treatment of herpes labialis, genitalis and
zoster
• Adverse reactions include pain, pruritus,
inflammation or edema
50. Sorivudine
• It is a pyrimidine nucleoside analog
• It has a potent and selective activity on VZV
• Inhibitory concentrations are over 1000X
lower for VZV than acyclovir
• It is also active in-vitro against HSV-1& EBV
but not HSV-2 or CMV
Pharmacodynamics
• Inhibits viral DNA synthesis
• Initial phosphorylation is by viral thymidine
kinase (concentrates more in infected cells)
51. • The triphosphate (STP) is a competitive
inhibitor of deoxythymidine triphosphate
• Unlike Acyclovir triphosphate, STP is not
incorporated into viral DNA
Pharmacokinetics
• It is well absorbed following oral administration
• Protein binding is high (98%), giving a plasma
half-life averaging 5-7 hrs.
• Eliminated unchanged via the renal route
• A well tolerated drug with GI disturbances and
headaches as only significant side effects
52. • Long-term use is associated with hepatic and
testicular neoplasms in animal studies
• Its metabolite will inhibit dihydropyrimidine
dehydrogenase which metabolizes the drug
5-fluorouracil (anti-cancer drug). Fatal
interactions have occurred in combination
Clinical indications
• A relatively new drug under clinical trials. It
appears to be superior to acyclovir in treating
VZV infection in HIV (40mg once daily)
• Available in both oral and intravenous
formulations
53. Vidarabine
• An adenosine analog (with altered sugar
arabinose instead of ribose)
• Activity against: Herpesviruses, Poxviruses
Hepadnaviruses, Rhabdoviruses and some
RNA tumor viruses
• Inhibitory concentrations are similar to those
of Acyclovir on HSV and VZV
• The triphosphate derivative competitively
inhibits deoxyadenosine triphosphate
• It is incorporated into both viral and cellular
DNA where it acts as a chain terminator
54. • Vidarabine also inhibits ribonuleoside
reductase, RNA polyadenylation & SAHH (S-
adenoslyhomocysteine)
• Following I.V infusion, it is deaminated to an
inactive metabolite hypoxanthine arabinoside
by adenosine deaminase. This lowers the
effective drug concentration by over 50%
• Both drug forms are excreted via the kidney
• Intravenous Vidarabine causes a dose related
G.I toxicity seen as anorexia, nausea,
vomiting, diarrhea & weight loss
• For solubility, large infusion volume is needed
55. • Infusion related phlebitis, hypokalemia, rash,
anemia, leucopenia, thrombocytopenia
• Neurotoxicities includes tremor and altered
mentation
• Vidarabine is Teratogenic and Oncogenic in
laboratory animals
• Allopurinol may interfere with Vidarabine
metabolism leading to increased toxicity
Clinical indications
• Used in HSV encephalitis, neonatal herpes,
VZV infections only second to acyclovir
• It is ineffective in acyclovir resistant strains
56. Trifluridine
• A fluorinated pyrimidine nucleoside
• Has in-vitro activity against HSV-1 & 2, CMV
vaccinia (small pox) and adenoviruses
• Has similar potency as acyclovir on herpes
viruses including drug resistant strains
• Trifluridine inhibits cellular DNA synthesis at
low concentrations, this does not favour its
systemic application
Pharmacodynamics
• It inhibits viral DNA synthesis
57. • The monophosphate irreversibly inhibits
thymidylate synthetase, the triphosphate is a
competitive inhibitor of thymidine triphosphate
incorporation into DNA by DNA polymerases
• Incorporated into both viral and cellular DNA.
Clinical uses
• Used topically against keratoconjunctivitis and
epithelial keratitis due to HSV-1 & 2
• It is more effective than Idoxuridine and as
good as Vidarabine in HSV ocular infections
• Side effects include: irritation, edema and
occasional hypersensitivity reactions
58. Anti Influenza Agents
• AMANTADINE and its methyl derivative
RIMANTADINE are tricyclic amines
• Both inhibit the replication of influenza A
viruses at low concentrations
• Rimantadine is 4-10 fold more active than
Amantadine depending on viral strain
• Both drugs share two pharmacodynamic
mechanisms:
1. They inhibit viral uncoating by binding to a
viral membrane integral protein M2
59. 2. M2 is an ion channel, its blockade will also
inhibit the acid mediated dissociation of the
ribonucleoprotein complex preventing an
early event in replication
Pharmacokinetics
• Both drugs are well absorbed after oral
administration with very large Vd
• Drug levels in salivary and nasal secretions
approximate those in plasma
• Plasma half-life of amantadine is 12-18 hrs
• Amantadine is excreted largely unchanged
in urine via GF and TS mechanisms
60. • Rimantadine is largely metabolized with less
than 15% of dose excreted unchanged
• Plasma half-life ranges between 24-36hrs
• Most common side effects of the two drugs
are dose related gastrointestinal and CNS
complaints. These include loss of appetite,
nausea, lightheadedness, insomnia, lack of
concentration & nervousness
• Side effects will occur less with Rimantadine
• Amantadine dose reductions are needed in
elderly patients due to decreased renal fcn.
• Amantadine is teratogenic in animal studies
61. Therapeutic uses
• Used for the prevention and treatment of
Influenza A virus infections. As a treatment, it
reduces duration of fever & other complaints,
this speeds functional recovery
• Seasonal prophylaxis with 200mg/day may
be up to 90% protective against influenza
• Used in curtailing nosocomial influenza A
• Post-exposure prophylaxis (PEP)
• Amantadine is also useful in Parkinsonism
(please find out how)
62. Interferons
• These are potent cytokines possessing
antiviral, immunomodulating & antiproliferative
properties
• They are proteins made by cells in response
to various inducers, they cause biochemical
changes leading to an antiviral state
• Three major classes of human Interferons
have significant antiviral activity: Alpha, Beta
and Gamma
• Preparations of natural and recombinant
Interferons are available for clinical use
63. • All body cells will produce Interferons Alpha &
Beta in response to viral infection or other
stimuli like double stranded RNA, Interleukin-1
Interleukin-2, & tumor necrosis factor (TNF)
• Interferon Gamma production is restricted to T
lymphocytes and NK cells following stimuli like
antigens, mitogens or specific cytokines
• Interferon Gamma has less antiviral activity but
more immunomodulatory effects than the other
two (esp. macrophage activation, MHC antigen
expression and inflammatory responses)
• Many DNA viruses are relatively not sensitive
to Interferons, unlike the RNA types
64. Interferon pharmacodynamics
• Following binding to specific receptors, they
trigger synthesis of many antiviral proteins
• These have the effect of inhibiting many viral
processes including; penetration, uncoating,
transcription, translation, assembly & release
• Some such proteins include Kinases & 2’-5’-
oligoadenylate synthetase both of which can
inhibit protein synthesis in the presence of
double stranded RNA.
65. • 2-5 oligoadenylate synthetase produces
adenylate oligomers that activate a latent
cellular endoribonuclease which will cleave
both cellular and viral RNA
• Interferons also induce a phosphodiesterse,
which cleaves a portion of transfer RNA thus
preventing peptide elongation
• A particular virus may be inhibited at any of
several steps above
• Some viruses are able to counter interferon
effects by blocking production or activity of
selected interferon-inducible proteins
66. Other mechanisms
• Interferon-induced expression of MHC
antigens may contribute to the antiviral actions
of Interferons by enhancing the cytolytic
effects of cytotoxic T lymphocytes
• In addition to controlling infection, Interferons
may mediate some systemic symptoms
associated with viral infections and contribute
to immunologically mediated tissue damage in
some viral diseases
67. Pharmacokinetics
• They are administered I.M or subcutaneously
• Absorption exceeds 80% with dose related
plasma levels peaking at 4-8hrs. Interferon β
results in negligible plasma levels yet effects
may be detectable
• Increased levels of 2-5 oligoadenylate synth.
begin to rise at 6hrs lasting thru 4 days with
only a single injection
• An antiviral state peaks at 24 hrs, slowly
decreasing to baseline levels in 6 days
68. Clinical uses
• Specific Alpha Interferons are used in
treatment of Condyloma acuminatum (warts),
chronic hepatitis B & C, Kaposi’s Sarcoma in
HIV patients & multiple sclerosis
• Prolonged use may be required in hepatitis
• Intralesional inj. are used in genital warts
• Interferon alpha is effective in treatment of
HIV-related thrombocytopenia resistant to
Zidovudine therapy
70. ANTIRETROVIRAL AGENTS
• An ever increasing number of antiretroviral
agents are becoming available on the market
for treating HIV infection
• There are three major categories of such drugs
and these include:
1. Nucleoside reverse transcriptase inhibitors
(NRTIs)
2. non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
3. Protease inhibitors (PIs)
71. • The first 2 groups are inhibitors of viral
reverse transcriptase
• The last group inhibit protease, a viral enzyme
required for viral maturation
• Nucleoside reverse transcriptase inhibitors
were the first group of drugs to be used in HIV
therapy include: Zidovudine, Didanosine,
Lamivudine, Zalcitabine, Stavudine & Abacavir
• They act by competitive inhibition of reverse
transcriptase and can also be incorporated into
a growing viral DNA causing chain termination
72. • They require intracytoplasmic activation via
phosphorylation by cellular enzymes
• Nuclear DNA polymerase is resistant to NRTIs
while mitochondria enzyme is fairly sensitive
• Lactic acidosis and severe hepatotoxicity are
side effects general to all NRTIs (may occur)
• The non-nucleoside reverse transcriptase
inhibitors include: Nevirapine, Delavirdine &
Efavirenz. Their general side-effects include
allergic reactions and a risk of teratogenicity,
they are contraindicated in pregnancy
73. • The protease inhibitors include: Indinavir,
Saquinavir, Ritonavir, Nelfinavir & Amprenavir
• the enzyme protease is responsible for cleaving
precursor molecules (products of HIV genes-
Gag & Pol) to produce the final structural
proteins of the mature virion core
• Protease inhibitors thus prevent new waves of
infection by rendering the particle noninfectious.
• Group adverse effects include a syndrome of
altered body fat distribution (buffalo hump &
truncal obesity with facial & peripheral atrophy),
insulin resistance & hyperlipidemia
74. HAART
• A combination of antiretroviral drugs has
demonstrated good efficacy on inhibiting viral
replication. Highly Active anti-Retroviral
Therapy (HAART) is currently recommended
• A typical HAART combination contains two
NRTIs with either one NNRTI or one PI
• Good management of HAART can reduce viral
levels to virtually undetectable levels, however
regimens are complex with many side effects
and adherence problems as they have to be life
long (this is not a cure!)
75. • Most drugs are well absorbed following oral
administration. Penetration into CSF is crucial
as drugs which poorly penetrate may lead to
viral proliferation in the brain
• When considering HAART initiation, it is vital
to start therapy before Immunosuppression
with at least 3 drugs, monitor plasma viral load
& CD4 cell count and change combination
when viral load seems to be stagnant or
increasing
76. ZIDOVUDINE
• A deoxythymidine analog
• Well absorbed & distributed to body tissues
and fluids including CSF (60% of plasma)
• Serum t1/2 averages 1 hr (35% protein binding)
while & intracellular half-life is 3.3 hrs
• Eliminated mainly by renal excretion following
glucuronidation in the liver (20% unchanged)
• A useful drug in treatment of HIV associated
dementia and thrombocytopenia
• Also reduces mother to child transmission by
over 23% (PMTCT)
77. • Most common S/E is myelosuppression
resulting in anemia and neutropenia
• Zidovudine may be withdrawn in patients with
a rise in serum liver enzymes, progressive
hepatomegaly & lactic acidosis of unknown
cause (these are signs of toxicity)
• Probenecid will increase serum levels of drug
as will Lamivudine, Fluconazole, Phenytion &
other drugs
• Hematologic toxicity may increase during co-
administration of myelosuppressive drugs like
ganciclovir or cytotoxic agents
78. DIDANOSINE
• A deoxyadenosine analog
• Following oral administration, bioavailability is
poor (40%) owing to instability in acid pH.
• Taken on empty stomach as food significantly
retards absorption
• CSF levels are only 20% of serum values
• Plasma t1/2 is 0.6-1.5hrs while intracellular t1/2
is as long as 12-24 hrs
• Elimination is by glomerular filtration and
active tubular secretion
79. • Fluoroquinolones and tetracyclines should be
given 2 hrs before or after in order to avoid
chelation with Didanosine
• Resistance to didanosine may confer cross-
resistance to other drugs in this group except
zidovudine (may restore partial susceptibility)
• Dose dependent pancreatitis is major S/E
whose risk is increased in alcoholism
• Peripheral neuropathy, cardiomyopathy and
esophageal ulceration are other S/E
• Lactic acidosis, Hepatotoxicity & pancreatitis
are also grounds for drug withdrawal
80. LAMIVUDINE
• A cytosine analog
• Bioavailability exceeds 80% and is not food
dependent (CSF levels about 20% of serum)
• Plasma t1/2 is 2.5 hrs while intracellular is 10-
15hrs in HIV & 17-19hrs in HBV infected cells
• Most of drug is eliminated unchanged in urine
• Resistance to Lamivudine may confer cross-
resistance to other NRTIs while restoring
partial susceptibility to Zidovudine.
81. • A combination of Lamivudine and Zidovudine
is therefore beneficial
• Side effects include headache, insomnia,
fatigue or gastrointestinal discomfort
• Co-administration with Septrin increases its
bioavailability
• Lamivudine is also used in hepatitis B infection
82. ZALCITABINE
• Also a cytosine analog
• Bioavailability exceeds 80% with a plasma t1/2
of 2 hrs and intracellular t1/2 of 10hrs
• CSF levels are about 20% of serum levels
• Dose dependent neuropathy limits treatment
in some patients, its use is contraindicated
with other drugs causing neuropathy like
stavudine, didanosine and isoniazid.
• Drug is excreted by renal mechanisms which
may be decreased by aminoglycosides,
amphotericin B or foscarnet
83. STAVUDINE
• A thymidine analog like zidovudine
• Has a high oral bioavailability (86%) which is
independent of food
• Plasma t1/2 is 1.22hrs (with negligible protein
binding) while intracellular t1/2 is 3.5 hrs. CSF
levels are about 55% of serum values.
• Elimination is by glomerular filtration and
tubular secretion
• Limiting S/E is a dose-related neuropathy
which is increased when given with zalcitabine
or didanosine (also cause neuropathy)
84. • Other adverse effects may include: arthralgia,
pancreatitis & elevation of liver enzymes
• Stavudine & Zidovudine can not be given
together as they are similar analogs and can
reduce each others phosphorylation
85. ABACAVIR
• A guanosine analog that appears to be more
effective than other agents in this class
• Absorption is good (83%) being unaffected by
food. Protein binding is about 50%
• Half-life is about 1.5 hrs in plasma with a CSF
concentration about 30% of plasma
• It is metabolized by alcohol dehydrogenase &
glucuronosyltransferase to inactive metabolites
which are eliminated via urine
• Co-administration with alcohol decreases
Abacavir’s AUC by up to 40%
86. • Resistance appears to require at least 2
concomitant mutations (develops very slowly)
• Rare but fatal hypersensitivity reactions have
been reported with Abacavir
• Within first few weeks of therapy malaise, fever
skin rash & gastrointestinal upsets may occur.
• These symptoms disappear promptly on drug
discontinuation. Re-challenge with Abacavir
leads to immediate return of symptoms which
may be fatal
• Other adverse effects incl. hypertriglyceridemia
hyperglycemia, pancreatitis, & lactic acidosis
87. NNRTIs
• NNRTIs bind to a site on reverse transcriptase
that is near to but distinct from binding site of
NRTIs, they therefore do not compete with or
interfere with each other’s activity
• They do not require prior phosphorylation to be
active (they denature the enzyme with loss of
function of enzyme)
• Cross resistance within this group may occur
but not with NRTIs or protease inhibitors
• Most are inducers/inhibitors of P450 enzymes
88. NEVIRAPINE
• Oral bioavailability is over 90% and not food
dependent (highly lipophilic molecule)
• About 60% is protein bound with a CSF level of
45% of serum level
• It is extensively metabolized by CYP3A to
hydroxylated derivatives before renal excretion.
It also induces these cytochrome enzymes
• Generally used in combination therapy, a single
dose of Nevirapine (200mg) given to mother &
followed by 2mg/kg to neonate has been shown
to be superior to Zidovudine in PMTCT
89. • Life-threatening allergic reactions may occur
with Nevirapine incl. Steven-Johnson syndrome
and toxic epidermal necrolysis (Leyll’s disease)
• Nevirapine therapy should be discontinued in
patients who develop a rash accompanied by
constitutional symptoms
• When initiating therapy, dose escalation over 2
weeks is recommended to decrease frequency
of rash development
• Fulminant hepatitis has occurred with drug and
this calls for monitoring of liver function during
treatment
90. • Nevirapine induces drug metabolism of itself
as well as other NNRTI & oral contraceptives
• Nevirapine levels may increase when given
with enzyme inhibitors like cimetidine and
Macrolides and decrease with inducers like
Rifampicin & Rifabutin (caution required)
• Nevirapine decreases Ketoconazole levels
during co-administration which should be
avoided
•
91. DELAVIRDINE
• Has oral bioavailability of about 83% with
extensive protein binding (over 98%). CSF
levels are consequently low 0.4% of plasma
levels.
• It is extensively metabolized by CYP3A and
CYP2D6 enzymes. It also inhibits CYP3A
thus inhibiting its own metabolism. This drug
shown interaction with many other ARVs,
antibiotics, antifungal & Benzodiazepines
• Skin rash may occur in the first weeks of
therapy but does not preclude re-challenge
92. EFAVIRENZ
• Bioavailability is about 45% following oral
administration, this is increased (65%) when
taken with a fat-rich meal
• Can be given once daily owing to a long serum
half-life (40-50hrs). Protein binding is nearly
99% with CSF levels of between 0.3 to 1.2%.
• Metabolized by CYP3A & CYP2B6, the same
as delavirdine, some drug is eliminated intact
• Principal S/E are of CNS: dizziness, insomnia,
depression, confusion, headache, amnesia,
they are common at the beginning of therapy
93. • Skin rash has also occurred in up to 28% of
patients receiving this drug
• Efavirenz induces CYP3A enzymes, inducing
its own metabolism as well as altering that of
many other drugs
• Levels of Ritonavir and Nelfinavir will increase
in the presence of Efavirenz while those of
Saquinavir, Amprenavir, indinavir as well as
clarithromycin are reduced when co-
administered (increase will be required)
94. PROTEASE INHIBITORS
• Are a very efficacious group of ARVs as they
prevent new waves of infection
• They are however considerably more costly
than the other two groups
• Problems of absorption/bioavailability are
common and require careful instruction to
enhance bioavailability, hence performance
• This group also contains some of the most
complex pharmacokinetic drug interactions as
some members are enzymes inhibitors while
others inducers
95. INDINAVIR
• It must be taken on an empty stomach like
didanosine for maximal absorption
• Drug is metabolized in the liver but primarily
excreted via the fecal route
• Indinavir has the highest CSF penetration of
all ARVs being over 75% of serum levels
• Adverse effects include hyperbilirubinemia &
nephrolithiasis due to crystallization of drug
• These can be prevented by consuming
plenty of water to maintain good hydration
96. • Thrombocytopenia, hemolytic anemia, nausea,
diarrhea & elevation of liver enzymes reported
• Co-administration with Rifampicin decreases its
AUC while co-administration with Zidovudine or
Clarithromycin increases AUC of both drugs
• Indinavir’s AUC increases with Clarithromycin,
Ritonavir, Nelfinavir, Delavirdine, Ketoconazole
• Indinavir inhibits metabolism of Stavudine,
Amprenavir & Isoniazid increasing their AUC
97. SAQUINAVIR
• Should be taken with food or within 2 hrs of a
fat-rich meal to enhance absorption
• Protein binding is very high (98%), just like for
Delavirdine. CSF concentrations are negligible
• Also eliminated via fecal route with a plasma t1/2
of 12 hrs
• They have a short shelf-life (3 months) which is
improved by refrigeration storage
• Saquinavir undergoes extensive first pass
metabolism. Enzyme inhibitors like Riton, Nelf,
Delav, Indin & Ketoc. improve its bioavailability
98. • Co-administration of Ritonavir with Saquinavir
has been adopted by clinicians since inhibition
of first pass metabolism of Saq. by Riton.
results in higher (efficacious) levels of Saq.
• Saquinavir levels are decreased in presence of
Efavirenz, Nevirapine & Rifampicin (inducers)
• Saquinavir itself is an inhibitor of CYP3A and
may lead to increased serum levels of other
drugs. Caution is necessary
99. RITONAVIR
• Unlike other Protease Inhibitors, Ritonavir has a
high bioavailability (75%) which further
increases when administered with food
• A gradual dose increase over 1 week reduces
incidents of gastrointestinal side effects
• Excretion is primarily via fecal route
• Other side effects include peripheral & peri-oral
paresthesias, altered taste, hypertriglyceridemia
• Ritonavir shows numerous drug interactions
which make it difficult to administer, as it inhibits
both CYP3A and CYP2D isoforms
100. • Ritonavir can produce large increases in
serum levels of many drugs. Co-administration
is specifically contraindicated with piroxicam,
antiarrythmic drugs, benzodiazepines and
some antidepressants
• Will also increase AUC of Saq. Indin. Ampren.
Ketoconazole and Clarithromycin
• Because Ritonavir contains alcohol, Disulfiram
and disulfiram-like drugs (Metronidazole,
Chlorpropamide ) are contraindicated
101. NELFINAVIR
• Bioavailability improves with food, is highly
protein bound (like Saq. Delav.)
• Also excreted primarily in faeces following
hepatic metabolism
• The most common side effects are diarrhea &
flatulence which are dose-related
• Nelfinavir is both an inducer and inhibitor of
cytochrome enzymes, multiple drug interactions
may occur
102. AMPRENAVIR
• Well absorbed with or without food, fat-rich
foods may appear to decrease absorption
• Didanosine, antacids interfere with absorption
and should be taken 1 hrs before
• Plasma t1/2 ranges from 7-10hrs
• Shows the least likelihood of cross-resistance
with other drugs in this class of drugs (PIs)
• Gastrointestinal effects, paresthesias & rash
(S-J.syndr.) are the most common side effects
• Numerous drug interactions as noted above
103. Future prospects
• Additional drugs in the 3 traditional classes
above are under investigation and may
appear on the market in the future
• New approaches to treatment also under
study include:
1. Nucleotide reverse transcriptase inhibitors
2. Integrase inhibitors
3. Fusion inhibitors
