ANTIVIRAL AGENTS

2017

ANTIVIRALS AND ARVS;2016 1

Introduction
 Viruses are obligate intracellular parasites;
their replication depends primarily on
synthetic/metabolic processes of the host
cell
 To be effective, antiviral agents must either

block viral entry into or exit from the cell

or be active inside the host cell

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Introduction ct.
 Viral replication consists of several steps
(1) Attachment of the virus to the host cell
(2) Entry of the virus through the host cell
membrane
(3) Un-coating of viral nucleic acid
(4) Synthesis of early regulatory proteins, eg,
nucleic acid polymerases

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Introd ct.
(5) Synthesis of RNA or DNA
(6) Synthesis of late, structural proteins
(7) Assembly (maturation) of viral particles;
and
(8) Release from the cell
 Antiviral agents can potentially target any
of these steps

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Most common viruses
 Flu
 Herpes simplex virus (hsv)
 Varicella-zoster virus (vzv) infections
 HIV

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AGENTS TO TREAT HERPES SIMPLEX
VIRUS (HSV) & VARICELLA-ZOSTER
VIRUS (VZV) INFECTIONS
 Include: acyclovir, gancyclovir, valacyclovir,
and famciclovir
 All have similar mechanisms of action and

similar indications for clinical use

 All are well tolerated

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1.ACYCLOVIR
 An acyclic guanosine derivative with clinical
activity against HSV-1, HSV-2, and VZV
 It a pro-drug (inactive) and must be activated
in the body
 Require 3 phosphorylation steps for activation
 Step I is by virus specified thymidine kinase
 Step II and & III is by host cell enzyme
 Selectively activated and active metabolite
accumulate only in infected cells

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MOA

 Inhibit viral DNA synthesis by 2 mechanism

◦ Compete for viral DNA polymerase with deoxy
GTP therefore bind to DNA template
◦ Chain termination following its incorporation into
viral DNA

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PK

 Formulations : IV, Oral, and topical

 Topical preparations produce high

concentration in herpetic lessions

 15-20% bioavailability after oral

administration
 Absorption not affected by food

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 Elimination: Glomerular filtration and
tubular secretions
 Readily cleared by haemodialysis( not

peritoneal dialysis)
 t1/2- 3hrs
 Cross to most fluids, with 50% serum

concentration achieved in CSF

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 Treatment does not reduce frequency or
severity of subsequent infections- long term
treatment does
 Vericella zozter is less susceptible

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ADR
 Reversible renal dysfunction secondary to
crystalline nephropathy
 Neurologic toxicity- seizures, delirium

tremors

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VALCYCLOVIR
 L-valyl ester of acyclovir
 Rapidly converted to acyclovir after oral

administration via intestinal and hepatic

first-pass metabolism,
 Result in serum levels that are three to five

times greater than those achieved with oral

acyclovir and approximate those achieved
with intravenous acyclovir administration

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Pk
 Has an oral bioavailability of 54%
 CSF concentration is 50% that in serum
 Elimination half-life is 2.5-3.3 hours

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CLINICAL USES
 Approved uses of valacyclovir include
◦ Rx of first or recurrent genital herpes
◦ Suppression of frequently recurring genital
herpes
◦ As a 1-day treatment for orolabial herpes
◦ Once-daily dosing of valacyclovir (500 mg) for
chronic suppression in persons with recurrent
genital herpes has been shown to markedly
decrease the risk of sexual transmission
◦ Effective in preventing cytomegalovirus
disease after organ transplantation

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ADRs
 well tolerated
 Occasionally may cause nausea, vomiting, or
rash
 Rare ADRs: Agitation, dizziness, headache,
liver enzyme elevation, anemia, and
neutropenia
 At high doses, confusion, hallucinations, and
seizures
 High doses may cause GIT intolerance as well
as thrombotic microangiopathies in HIV
patients
ANTIVIRALS AND ARVS;2016 16
FAMCICLOVIR

 Active against HSV-1, HSV-2, VZV, Ebstei

bar virus (EBV), and HBV
 After oral administration, famciclovir is

rapidly converted by first-pass metabolism

to penciclovir
 Penciclovir then require activation by

phosphorylation; catalyzed by the virus-

specified thymidine kinase in infected cells
 MOA: Competitively inhibit viral DNA

polymerase to block DNA synthesis

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PK
 Has an oral bioavailability of famciclovir is
70%
 Has an intracellular half-life of 10 hours in

HSV-1-infected cells, 20 hours in HSV-2-

infected cells, and 7 hours in VZV-infected
cells
 Penciclovir is excreted primarily in the urine

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Clinical uses
 Oral famciclovir is effective for the
treatment of first and recurrent genital
herpes,
 For chronic daily suppression of genital

herpes, and
 For the treatment of acute zoster
 An active metabolite of famciclovir

(penciclovir), is also available for topical use

ANTIVIRALS AND ARVS;2016 19

ADRs
 Generally well tolerated, although
headache, diarrhea, and nausea may occur
 Testicular toxicity has been demonstrated in

animals receiving repeated doses but no

changes in sperm morphology or motility

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2.Gancyclovir
 Also inactive, and activated by
triphosphorylation
 Step I by viral specified protein kinase

phospho-transferase in MV infected cells

 MOA- competitively inhibit DNA polymerase

Therefore terminating viral DNA elongation

ANTIVIRALS AND ARVS;2016 21

ADR
 Myolosupression- additive in patients
receiving concurrent zidovudine,
azathrioprine, mycophenolate mofetil
 Peripheral neuropathy
 Retinol detachment in patients with CMV

retinitis
 CNS toxicities
 Aspermatogenesis

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Drug interaction
 Levels increased in patients taking
probenacid and trimethoprim

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Antiretroviral Therapy

ANTIVIRALS AND ARVS;2016 24

Introduction
ARVs act on the HIV by interfering with its
viral life cycle to slow down viral activities
at various points :
1. Viral growth
2. Viral replication

ANTIVIRALS AND ARVS;2016 25

 Currently available ARVs interfere with a
critical viral enzyme, either:
1. Reverse transcriptase or
2. Protease

 A combination of 3 ARVs used together is

called HAART
 HAART-Highly Active Antiretroviral Therapy

ANTIVIRALS AND ARVS;2016 26

 Types:
1. NRTIs – Nucleoside Reverse transcriptase
Inhibitors
2. Nucleotide reverse transcriptase inhibitor (NtRTI)
3. NNRTIs – Non-Nucleoside Reverse
transcriptase Inhibitors
4. PIs –Protease Inhibitors
5. Fusion Inhibitors

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Approved ARV Agents Included
in WHO’s ARV Guidelines
Nucleoside reverse Nucleotide reverse Non-nucleoside Protease inhibitors
transcriptase transcriptase reverse (PIs)
inhibitors (NsRTIs) inhibitor (NtRTI) transcriptase
inhibitors
(NNRTIs)

zivodine (ZDV, AZT) tenofovir disoproxil Nevirapine (NVP) Saquinavir (SQV)

didanosine (ddI) fumarate (TDF) Efavirenz (EFZ) Ritonavir (RTV)
(pharmacoenhancer)
stavudine (d4T)
lamiduvine (3TC) Indinavir (IDV)
abacavir (ABC) Nelfinavir (NFV)
Lopinavir/ritonavir
(LPV/r)

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Recommended First-line ARV Regimens

Regimen Pregnancy Major Toxicities

Considerations
Zidovudine Substitute NVP for ZDV-related anemia
Lamivudine & EFZ in pregnant EFZ-associated CNS symptoms
Efavirenz / women for whom
effective contraception Possible teratogenicity of EFZ
Nevirapine
cannot be assured NVP-associated hepatotoxicity and
(ZDV/3TC/EFZ) severe rash
or NsRTI-related metabolic side effects
ZDV/3TC/NVP)

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ART GUIDELINES 2016

ANTIVIRALS AND ARVS;2016 30

Nucleoside reverse
transcriptase inhibitors (NRTIs)
• Lead to premature termination of the
production of the HIV DNA chain
• Are active against both HIV 1 and HIV 2
• Resistance rapidly develops if given as
single drugs alone (monotherapy
• zidovudine (AZT) and stavudine (d4T)
are structurally similar and should not
be used together

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ADRs


• Anemia (AZT)
• Nausea and vomiting
• Neutropenia
• Peripheral neuropathy (d4T, ddl, ddC)
• Pancreatitis (ddl, ddC, d4T, 3TC)

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 Non-nucleoside reverse transcriptase
inhibitors (NNRTIs)

• Are active only against HIV-1

• Delavirdine and Nevirapine are
antagonistic in action on the HIV
reverse transcriptase activity and,
therefore, should not be used together
• Interaction with some drugs occur due
to induction and/or inhibition of
cytochrome P450 enzymes

ANTIVIRALS AND ARVS;2016 33

Efavirenz
 High fat meal increase their bioavailability
 Should be taken on an empty stomach
 Highly bound to albumin
 Un-metabolised drug excreted in feces

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ADRS:
 CNS symptoms- dizziness, drowsiness etc. that
tend to resolve after 1st month of treatment
 Skin rashes early in therapy
 Crystaluria
 Elevated liver enzymes
 Elevated serum cholesterol by 10-20 %
 Avoided in pregnancy- cause congenital
anomalies
 An inducer and inhibitor of cytochrome p3A4-
and it induce its own metabolism and interact
with metabolism of other drugs

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Nevirapine
 Has excellent oral bioavailability (>90%)
 Bioavailability not dependent on food
 Achieve high CSF levels(45% that of plasma)
 Extensively metabolized and excreted in urine
 Rash occur in 17% of patients in the 1st 4-6 wks
of treatment and is dose limiting in some
patients
 Gradual dose escalation over 14 days is
recommended to decrease the incidence of
rash
 A moderate enzyme inducer

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ADRs of NNRTIs
 Adverse effects include:
◦ diffuse maculopapular rash,
◦ hepatitis,
◦ headache, and
◦ nausea

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Protease inhibitors (PIs)
 HIV protease enzyme is responsible for cleaving
various polyproteins in the process of producing
mature infectious virons. Interference with this
enzyme by PIs leads to significant reduction of the
virus in the body to undetectable levels
 Rapid resistance will develop if PIs are used as
single agents
 PIs are associated with multiple drug interactions
because of their inhibition of cytochrome P450
enzymes

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ADRs of PIs
 GI problems, i.e., nausea and
vomiting
 Redistribution and accumulation of
body fat that result in central
obesity, dorsocervical fat
enlargement( buffalo hump)
 Peripheral and facial wasting
 Breast enlargement
 Glucose intolerance and insulin
resistance
 Indinavir should be taken with plenty of water to
prevent kidney stones

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Drug Interactions
• Drugs of NNRTI and PI classes interact with the
cytochrome P450 enzyme system resulting in
either inhibition or induction of these enzymes
• When co-administered with other drugs
metabolized by the cytochrome P450 enzyme
system, increases or decreases in the given
NNRTI or PI and/or concomitant medication
may occur
• This can result in increased toxicity due to
elevated drug concentrations or drug failure
due to sub therapeutic drug concentrations

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Summary of ARV associated toxicities

 NRTIs  Rash
 PeripheralNeuropath  Fever

y  Nausea
 Pancreatitis  Diarrhea
 Lipoatrophy  Hepatoxicity
 Hepatitis
 Lactic acidosis
 Mitochondrial

toxicity
 NNRTIs

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PIs

 Lipodystrophy
 GI Intolerance
 Hyperglycaemia
 Lipid abnormalities

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Common Adverse Effects

 Peripheral Neuropathy – d4T,ddI

 Hematotoxicity – AZT
 Hepatotoxicity – NVP
 Diarrhea – NFV
 Skin rash –NVP
 Lipodystrophy – PIs, NRTIs
 CNS disturbance – EFV
 Hypersensitivity – ABC
 Hyperlipidemia-PIs, d4T

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