Antiviral Drugs

Prof. Alhaider, 1431 H

Definition:
What are the differences between bacterial and viral
infections?
Classification of Antiviral Drugs:

Note: To understand the classification of antiviral drugs, students

should remember the steps that are involved in viral replication

(See Figure 491). However, most antiviral agents interfere with

nucleic acid synthesis or late synthesis of viral proteins.

Furthermore, most of them act as antimetabolites.

 Classification of Antiviral Drugs
• Best Classification Based on 1) Type of Viral
Infections (Organisms) or 2) its site:
• I. Agents to Treat Herpes Simplex virus (HSV) and
Varicella Zoster Virus (VZV) infections.
• II. Agents To Treat Cytomegalovirus infection (CMV)
• III. Drugs Used for Rx of AIDS (Antiretroviral Agents)
• IV. Antihepatitis Agents
• V. Antiviral Used for Respiratory Tract Infections:
 Table 2: Types of Antiviral drugs

4
1) Agents to Treat Herpes Simplex virus (HSV)
and Varicella Zoster Virus (VZV) infections.
• Examples: Acyclovir (prototype); Valcyclovir;
Famiciclovir; Trifluridine (Topical)
• MOA: (49-2) They are guanosine analogs
without sugar moiety (so what?).
• Three phosphorylation Steps are required for
activation (one depends on viral thymidine
kinase), forming triphosphate form (1 in the
viral 2 on the host). This (acyclo-GTP), will
incorporate into viral DNA-causing premature
DNA-chain termination (irreversible binding to
viral DNA polymerase) and inhibition of DNA
snythesis.

• What is the effect of drugs on the host cells

(not infected)?
 Ganciclovir ,

)
P
• Resistance: Can be developed due to
deficient or alteration of thymidine kinase
and or alteration DNA polymerases.
• Cross resistance: to valcyclovir,
famiciclovir and gancyclovir
• but no cross resistance for cidofovir
(Cytomegalovirus drug)? Why (see Fig 49-2)
PK of Acyclovir :
–is available as oral (15-20%) (not affected by food),
topical and i.v.
–Does it have high or low oral bioavailability?
–Short t 3 hr (thus given 4-5 times daily) and
1l2
eliminated mainly by kidney (t1l2 prolonged in renal
impairment) t1l2 20 hr.
,
–Distribute in ALL parts of the body including CNS
(e.g: encephalitis) .
–What is Valacyclovir?.
–What is the meaning of a prodrug?

Clinical Uses (see Table 49-1)

HSV, Varicella-zoster VZV; Epstein-Barr virus mediated
.infection; HSV encephalitis; Genital herpes infection
Side Effects of Acyclovir
Generally speaking, acyclovir considers to be(
:save drug Why?, however, it may produce
1 . Transient Renal dysfunction at high dose or at i.v
(Crystalline Nephropathy). RX
2. GIT disturbances

How valcyclovir differs from acyclovir?

High oral bioavailability; long duration (almost five times the
plasma concentration)
Can replace i.v cyclivir
Effective even for CMV

Side Effects: Thrombotic thrombocytopenic purpura in

pts with AIDS
• II. Agents To Treat Cytomegalovirus infection (CMV)
• Ganciclovir: Analog of acyclovir
• Why Acyclovir is not active against CMV?

• MOA: Similar to acyclovir

• PK: How does it differ from acyclovir?

– What is valganciclovir?

:Clinical Uses of Ganciclovir

i.v: (commonly used formulation)
to delay the progression of CMV retinitis in patients with -
)AIDS 2 weeks followed by oral form
.for CMV colitis, esophagitis and pneumonitis -
.to prevent CMV before trasplantation -
Oral: (Used for prophylaxis)
CMC prophylaxis in transplant patients -
.prevention of end organ CMV disease in AIDS patients -
.as maintenance therapy for CMV retinitis -
:Intraocularly (implant)
.Rx CMV retinitis
:Adverse Effects of Ganciclovir
Myelosuppression (neurtroprnia 20-30%) and increases if -
Zidovudine; azathioprime, mycophenolategiven with?
)mofetil
Vitreous hemorrhage and retinal detachment with -
.intraocular implant
- carcinogenic Mitogenicity in mammalian cells and -
in animals at high dose

What is valganciclovir and when it should be

?used
Simply it is an oral replacement for i.V
.Ganciclovir
• Cidofovir:
– Differs from acyclovir in its long t1/2 26 hr with active
metabolite.and MOA.
– Activity: CMC; HSV; VZV and in:
– MOA: phosophorylation does not depend on viral
enzyme, and works as inhibitor and alternative
substrate for viral DNA polymerase.
– Used for CMV retinitis, colitis, and esophagitis.
and for Acyclovir-resistant
PK: produce active metabolite, thus it has long t1/2,
eliminated in the kidney, Probenicid prolonged its
.action. but with poor CNS penetration
?Why acycliver is better than Cidofovir for encephalitis
Side effects: Dose-dependent nephrotoxicity (53%) and
uveitis and decrease IOP
• Note: Normally, RNA from DNA,
however,
• Reverse transcriptase = RNA-directed
DNA polymerase (DNA polymerase that
transcribes single- stranded RNA into
double-stranded DNA.
• III. Drugs Used for Rx of AIDS (Antiretroviral
Agents)
– AIDS are caused by HIV, and zidovudine was the first drug used
(1987).
– To understand drugs used for AIDS, the life cycle of HIV should
be utilized for drugs combination (See Figure 38-16)
– Drug combination or the so-called Highly Active Antiretriviral
Therapy (HAART) (Figure 38-17) as well as adherence to the
regimen, both are very essential.

Classification of Anti AIDS (Based on life cycle)

:)Table 2 and Figure 38-17

;.Nucleotide Reverse Transcriptase Inhibitors (NRTIS) e.g )1

;.Non Nucleotide Reverse Transcriptase Inhibitors (NNRTIS) e.g )2
Protease Inhibitors e.g. Saquinavir; Ritonavir; Indinavir )3
Viral Fusion Inhibitor e.g. Enfuvirtide )4
• Objectives of HIV Treatment:
– Suppression of viral replication (decrease the
viral load).

– Restoration of a degree of
immunocompetency to the host.

– Decrease incidence of opportunistic

infections.
– prolonged survival
Table 2: Types of Antiviral drugs
 1) Nucleotide Reverse Transcriptase Inhibitors
(NRTIS)
Chemistry (Figure 49-4): These are analogs of native
ribosides (nucleotide with side chain containing
.ribose) but lack the 3’-hydroxy group
MOA: Similar to most antiviral drugs, require
triphosphorylation but mainly by cellular enzyme.
Competitive inhibitor of HIV-1 reverse transcriptase.
The triphosphorylated analog (with no hydroxyl
group) incorporate into viral DNA by virus RT,
preventing DNA chain elongation (See Figure 38-
16)
NRTIS can be classified into group A (thymidine
Analoges) (Zidovudine and Stavudine) and group
B: (Didanosin; Zalcitabine and Lamovidin)
Group A
Group B
Zidovudine (AZT): 3-azido3deoxythymidine (AZT) (Pyrimidine
Analog) Important Discovery 1987 G
.MOA: Requires mammalian thymidine kinase for triphophorylation
.Resistance: Due to high rate of mutation at several code

• PK:
– Excellent oral absorption
– Penetrate well to CNS but has short t .(3 hrs 100 mg q 5 hr)
1/2
– Metabolized by liver to glucuronated AZT but eliminated by kidney,
therefore:
Its half life is affected in uremic and hepatic patients and by drugs that
.metabolized by glucoronidation. E.g

:Uses
.The most important drug in HAART-
for Rx and prevention of neanate (transmission) 14-35 of gestation and -
i.v during labor then AZT syrup from birth till 6 weeks.(decrease vertical
.transmission)
?Does it decrease the severity of infection in mother

:Adverse effects
Pronounced bone marrow suppression as severe anemia & -
. leucopenia (increases if given with?); thrombocytopenia
.Headache, insomnia & seizure at higher doses -
• Stavudine:
– This is like AZT, a thymidine analogue
(activated by the same enzymes) therefore,
should not be combined with AZT
– Like AZT has good oral bioavailability
– Eliminated mainly by tubular secretion and
glomerular filtration.
– Major Side effect: sensory neuropathy and
Hyperlipedemia but no leucopenia
Note: MCQ on side effect of Stavudine specially
.that related to neuropathy
Tenofovir:
• (it has one phospahate group in its
structure) therefore requires only two
phosphorylation
• Has long t1/2 (once daily)
• Similar to AZT requires dose adjustment in
renal impairment.
• Unlike AZT has no myelosuppressive
effect.
• Didanosine (dideoxyinosine) With out the two hydroxyl group.
– Differ from Zidovudine:
• Low oral bioavailability and destroy by acid (given before meals),
but they change to chewable Tablets.
• Used for AZT resistance.
• Like AZT, Its elimination is dependent on kidney.
• However, It is a chelating agent (interaction with tetracyclins and
fluroquinoline (Two hour should be given before or after).
:Side Effects
• Pancreatitis (check serum amylase) increases in alcoholics
• Peripheral neuropathy (Dose related); hepatitis, but unlike AZT has
no leucopenia.
• Optic neuritis
• Hyperuricemia

.Note: should not be combined with AZT! Antagonize each other

• Zalcitabine:
– Similar to Didanosine
• Lamivudine:
– This cytosine analog is the most interesting anti viral
drug, because it can be used for HIV and HBV
infections.
:Advantages
Like AZT has good oral bioavailability with active -
metabolite.Safest drug among NRTI
Can be combined with AZT -
COMBIVIR (Lamovidine 150 mg + Zidovudine 300 mg)
No significant side effects because it does not affect -
mitochondrial DNA synthesis or bone marrow
precursor cells
:Disadvantages
has high rate of mutation if given alone, therefore
.)should be combined in case of AIDS and hepatitis

Is there any differences in the dose of Lamivudine for

?HIV and HBV patients
• Zalcitabine (dideoxycytidine ddc)
– Does it remind you with Didanosine?

This drug used as replacement for Lamivudine

:in HIV, but differ in the following
Oral bioavailability is dependent on food )1
(Why?)
Similar to didanosine, it produces dose )2
dependent neuropathy due to inhibition of
mammalian mitochondrial DNA
.polymerases
.Pancreatitis but less than didanosine )3
:Emtricitabine
This is fluoro-derivative of Lamuvidine; can
replaced the former in HBV and HIV pateints.
Which of the following drugs does not cause peripheral
neuropathy?
a) Lamivudine
b) Stavudine
c) Didanosine
d) Zalcitabine
Non Nucleotide Reverse Transcriptase Inhibitors )2
(NNRTIS) e.g.;Nevirapine; Efaverenz
MOA: Bind selectively and non-competitive way to HIV
reverse transcriptase at a side adjacent to that of
NRTIs, and from their names they are neither
nucleotide triphosphate nor require phosphorylation to
.be active
:Resistance
Rapid resistance can be developed but it is not cross
.resistance to NRTIs or protease inhibitor
:Main features
These drugs are lipophilic in nature with high degree of
protein binding and oral bioavailability. Also, some of
them either inhibit or enhance the liver metabolic
.enzymes
Hypersensitivity has been observed with their use as
serous rashes and Steves-Johnson syndrome. LFT
• Nevirapine:

:PK
Lipophilic drug with high oral bioavailability.(not food dependent)
t1/2 of someMetabolized by liver and it is enzyme inducer, may decrease the
.drugs including anti AIDS, contraceptives and warfarin
:Uses
.In AIDS, it is only used together with other antiretrovirals
newbornSingle dose (200 mg) for transmission of HIV from mother to
A single dose of nevirapine to the mother, with or without a dose of nevirapine to the infant, added to
oral zidovudine prophylaxis starting at 28 weeks' gestation, is highly effective in reducing mother-
to-child transmission of HIV. N Engl J Med. 2004 Jul 15;351(3):217-28. Epub 2004 Jul 9

;Disadvantages
Life threatening skin rashes including Stevens-Johnson Syndrome and toxic
.epidermal necrolysis (can be reduced by Starting with low dose)

Fulminant hepatitis

:Delaviridine

It is unlike nevirapine, it inhibits CYP3A, with rash but not to the

.degree of Stavens Johnson Syndrome
• Efaverenz (commonly used NNRTI Safest):

Drug with long t1/2 (40-55 hrs) with high albumin

binding; metabolized in the liver with some
.enzyme induction
Side Effects: Occur only in the beginning of
therapy, mainly in CNS (agitation, delusion;
nightmares; euphoria)
Note: Unlike, nevirapine, efaverenz should not
be used in pregnancy (fetal abnormalities)
Note: Enzyme inhibitors and inducers affects ALL
.NNRTI to the same level
• HIV Protease Inhibitors:
• Very good Discovery 1995, make significant Decline
– MOA:
• Reversible inhibitors of the HIV aspartyl protease
• What is aspartyl protease?
• Are these drugs specific for HIV protease as
compared to human? (Thousand)
– PK:
• In contrast to NNRTIs, most protease inhibitors
have poor oral bioavailability and affected by by
meal.
• All are metabolized in the liver CYP3A4 isozyme of
Cyto P450, and some of them like Ritonavir is
CYP3A4 inhibitor.
• High protein binding and pass blood BB.
• What is the pharmacokinetic enhancer?
Drug Interaction: Pharmacokinetic Type
Since they are inhibitors of CYP isozyme
(Ritonavir (strong) while Saquinavir is the least)
Drug interaction so common e.g: Statins;
Benzodiazepines; Fentanyl; warfarin; phenytion
:Side Effects
• Common: Parasthesias, N/V and Diarrhea.
Hyperglycemia, Hypertriglyeridemia, LDL.
Chronic use gives rise to Buflo hump and breast
enlargement.(Similar to steriods but
 Ritonavir
– Is not uesd alone as a single protease inhibitorm but it is used as
pharmacokinetic enhancer.
– Side effects: GIT; paresthesia; hypertriglycemia; elevated AST

• Indinavir:
– Well absorbed orally with lowest protein binding among this
group and high penetration to the CNS; but should be given in
empty stomach.
– Enzyme inhibitor
– It is given together with Ritonavir as Trade name
:Side Effects
Indirect hyperbilirubinemia,thrombocytopenia and nephrolithiasis -
due to crystallization of the drug (good hydration). Fat
.disribution
• Lopinavir/Ritonavir (Common and prefered
combination)
– Here, Ritonavir is used to suppress CYP3A4 .
– What are the drugs that decrease the level of Lopinavir?
Lopinavir 100mg /ritonavir 400 mg
(continue…)
- Advantages
- potent antiretroviral activity
- co-formulated as Kaletra(R)
- once daily dosing is an option for treatment-naive patients
- no food restriction with oral tablet formulation
- Disadvantages
- GI intolerance (once daily associated with a
higher incidence compared with twice daily)
- hyperlipidemia
- possibly lower drug exposure in pregnant women

• Saquinavir:
– Available as hard gel capsule or soft. However, this drug has
very short t1/2 and low bioavailability (12% and decreases of
taken with fatty meal); therefore, it is combined with ritonavir.
Why?
– Side Effects: Headache and nausea.
MCQs
• Which of the following are protease inhibitors:
1) Nelfinavir
2) Saquinavir
3) Abacavir
4) Ritonavir
5) Tenofovir
Nevirapine is a
Protease inhibitor )1
NRTI )2
NNRTI )3
Fusion inhibitor )4
Regarding Ritonavir in AIDS
should not be used alone )1
contraindicated in renal failure )2
GIT symptoms can be seen )3
may decrease the level of warfarin )4
.Regimens for RX of AIDS patients
Highly Active Antiretriviral Therapy (HAART) •
:(Figure 38-17) consists of
:Two NRTIs (why) plus –
One NNRTI or protease inhibitor
However, now aday most regimens use protease inhibitors
What should be done if some one working in the medical
field is exposed accidentally to AIV virus?

How to decrease the development of mutation to HIV

medications?
1) Drugs combination
2) Adherence to medication (missing 6 doses/year)
Regimens
- Preferred: (One NNRTIs Plus Two NRTIs)
- Efavirenz (NNRTI) plus (lamivudine or emtricitabine)
Plus (zidovudine or tenofovir (NRTI)) (except in first
trimester of pregnancy or women with high
pregnancy potential)
- Alternative:
- Efavirenz plus (lamivudine or emtricitabine) plus
(abacavir or didanosine or stavudine*) (except in
first trimester of pregnancy or women with high
pregnancy potential)
: - Alternative
Nevirapine**(NNRTI) plus (lamivudine or emtricitabine) -
plus (didanosine or zidovudine or stavudine* or
abacavir or tenofovir)
- * Stavudine has higher incidence of lipoatrophy,
hyperlipidemia, and mitochondrial toxicities than
other NRTIs
Protease Inhibitor-based •
Regimens (2 NRTI plus
prorease inhibitor)
- Prefered
- Indinavir/ritonavir (Kaletral) * plus
(lamivudine or
emtricitabine) plus (zidovudine or
stavudine** or
abacavir or tenofovir or didanosine)
- Alternative:
- Lopinavir/ritonavir plus (lamivudine or
emtricitabine) plus (stavudine** or
abacavir or
tenofovir or didanosine)

However, there are too many protocols for •

this type of treatment
3) Viral Fusion Inhibitor):
Enfuvirtide
MOA: Block entry into the cell.
Use: not orally but SC for resistance HIV-1 patients.
Regimens for RX of AIDS patients (HAART) (see Fig. 38-
17).
• IV. Antihepatitis Agents:
• Like in AIDS, they are suppressive rather than
curative. Among many hepatitis viruses, HBV
and HCV are the most common cause of chronic
hepatitis, cirrhosis, and HCC.
• Drugs for Hepatitis B (see Table )
– Lamivudine:
– MOA: inhibit HBV DNA polymerase and HIV reverse
transcriptase, resulting in chain termination.
• This safest NRTI antiretroviral drug, shows prolonged
intracellular t1/2 in HBV cell lines (17-19 Hr), than in HIV-
infected cell line. So What?.
:Effectiveness
Achieves almost universal HBV DNA suppression, with
decrease in viral replication; and decrease progression to
.liver fibrosis
.Response is more rapid than using interferon alone
• Resisitance:
– 20 % can occur after 8-9 months of therapy.
– What is the evidence of resistance?

• 2. Aldefovir:
– This nucleotide (NRTIs) analog is also HBV
infection especially in lamivudine resistance
cases.
– Is there any cross resistance between lamivudine and Aldefovir?
– Side effects:
• Eliminated by glomerular fil.and tubular
secretion, thus it is nephrotoxic.
• Lactic acidosis and hepatomegaly with
steotosis may occur.
• 3. Interferon Alfa:
– Endogenous glycoprotein or cytokine that
produced in human leukocytes and exert anitviral,
immunomodulatory and antiproliferative
activities.
:Commercially available as
• Interferon alfa-2b: Licensed for Rx of HBV and
acute hepatitis C.

• Interferon alfa-2a: can be used for HCV (Either

alone or better with oral Ribaverin (quanosine
analog).
Note: Both types can be used for HCV

:MOA
Unclear but may be via the induction of host
cell enzymes that inhibit viral RNA translation
.and thus degradation of viral mRNA and tRNA
• PK of interferons:
– Both types could be administered either
S.C or I.M. with short t1/2.(4-7 hrs)
– Filtered unchanged in the glomeruli with
protolytic degradation in the tubule.

– What are the differences between interferon

and pegelated interferon Alfa?
Strucure: Peg Interferon alfa-2a and 2b )1
represent the corresponding interferons with
branched polyethylene moiety is attached by
,covalent bind. Thus

Peg has longer t1/2 as compared to normal )2

interferon. (80 Hr vs 5.1 for alfa-2b) and
.increase in renal impairment

Efficacy is superior to non-pegelated )3

.interferon
Other Uses of Interferon:
1) Cancers such as hairy-cell leukemia and Kaposi
sarcoma related to AIDS.
2) Multiple Sclerosis
3) topically for genital warts.
4) prevent dissemination of herpes zoster in cancer
patients or immunocompromised patients
5) Multiple myeloma
Side Effects of interferons:
-Since they are endogenous types of proteins, they may
produce Flu-like symptoms within 6 hr in more than 30%, with
N/V and anorexia; fatigue; rash; alopecia.

- Thrombocytopenia: granulocytopenia and elevation in

aminotransferase level mainly in responders. Induction of
autoantibodies.
- Mental depression and Neurotoxicity (somnolence)

Contraindications:
Psychosis; neutropenia; thrombocytopenia; dermatomyositis
(why).; organ transplanted patients.
:Ribavirin
Guanosine analog requires
phosporylation; and inhibits the replication
of wide range of DNA and RNA viruses,
including HCV; HIV; influenza A & B and
.respiratory syncytial virus (RSV)
:Uses
Orally: together with interferons for HCV.
Inhaled: For (RSV).
RRRibaverin
ii
bb
aa
vv
• V. Antiviral Used for Respiratory Tract Infections:
Inhibitors of viral coating (e,g: Amantadine* and )1
:Rimantadine
MOA: will Inhibit uncoating of viral RNA of influenza to the infected
host cell, via blocking the viral membrane matrix M2 protein,
.thus it inhibits the replication of viral RNA
?Note: M2 protein only present in Influenza A? So What
:PK
Amantadine eliminated unchanged in kidney, while rimantadine is
metabolized in the liver. Both drugs can pass BBB and available
.in Tablet forms
?Which one is preferred in a patient with renal failure
:Uses
For prophylactic and treatment of Influenza A
.)Influenza B has different protein in the membrane(
:Side Effects
CNS: Nervousness, difficulty in concentration, lightheadness
:GIT
Note: Amantadine is also used for management of Parkinson *
.disease
• 2. Neuraminidase Inhibitors:
?What is neuraminidase
Viruses that cause infuenza like orthomyxovirus contain
the neuraminidase; which can be selectively inhibited
.by Zanamavir and Oseltamivir
:MOA
theVia inhibition of neuraminidase these drugs inhibit -
release of new virions (Influenza viruses employ
specific neuroaminidase that is inserted into the host
cell membrane for the purpose of releasing newly
formed virions. Thus virions accumulate at the internal
. .infected cell surface
.Active against both Influenza A and B -
What is the difference between Amantadine and
?Zanamavir
What are the differences between Zanamavir (Inhaled)
?and Oseltamivir (Oral)
Why Zanamavir should not be given for patients with B.
• 4. Palivizumab:
– Huminized monoclonal antibody directed
against the F glycoprotein on the surface of
RSV
– Uses: only for prevention of high- risk infants