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Antiviral Agents
1. Dr Htet Htet
MBBS, MMedSc
Lecturer
Faculty of Medicine
18th July, 2015
All rights reserved
2. • At the end of the lecture, students must be able to
– To classify major drug groups and specific examples of
drugs for the viral infections (Herpes, HIV, HBV, HCV
and influenza).
– To describe the mechanism of action of antiviral drugs
including their pharmacological actions, important
pharmacokinetic parameters, interactions and dosing.
– To outline the application of these drugs clinically (eg.
Antiretroviral therapy – ART)
3. 1. Introduction to viral replication (recall)
2. Drugs used for anti-herpes therapy
3. Drugs used for anti-HIV therapy
4. Drugs used for hepatitis B and C infection
5. Drugs used for influenza
4. Introduction
• Viruses are obligate intracellular microorganisms, drugs that
target viral processes must penetrate host cells.
• Therefore, drugs that negatively impact on a virus are also
likely to negatively impact normal pathways of the host.
5. Steps of viral replication
1. Attachment of the virus to receptors on the host cell surface;
2. Entry of the virus through the host cell membrane;
3. Uncoating of viral nucleic acid;
4. Synthesis of early regulatory proteins, eg, nucleic acid
polymerases;
5. Synthesis of new viral 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.
6.
7. 1. Introduction to viral replication (recall)
2. Drugs used for anti-herpes therapy
3. Drugs used for anti-HIV therapy
4. Drugs used for hepatitis B and C infection
5. Drugs used for influenza
9. Drugs used as anti-herpes agent
• Acyclovir
• Valacyclovir
• Famciclovir
• Penciclovir
• Docosanol
• Trifluridine
10. Acyclovir
• MOA
– Activation
– Inhibition of viral DNA synthesis
• Activation
• Acyclovir requires three phosphorylation steps for activation.
• It is converted first to the monophosphate derivative by the virus
specific thymidine kinase and then to the di- and triphosphate
compounds by host cell enzymes.
11. • Inhibition of viral DNA synthesis
• Two mechanisms:
– competition with deoxy GTP for the viral DNA polymerase, resulting
in binding to the DNA template as an irreversible complex; and chain
termination following incorporation into the viral DNA.
12. • Selective toxicity
• Because it requires the viral kinase for initial phosphorylation,
acyclovir is selectively activated—and the active metabolite
accumulates only in infected cells.
• Pharmacokinetics
• Bioavailability – low 15-20%
• T ½ - 2.5 – 3hrs
• Clearance – via glomerular filtration & tubular secretion
• 20 hrs in patient with anuria (anuria - Anuria means nonpassage of urine,
in practice is defined as passage of less than 50 milliliters of urine in a day.)
• Route – topical, oral and IV
13. Therapeutic uses
• Oral – genital herpes (recurrent, first episode), herpes labialis,
cutaneous zoster, ( decreases the total number of lesions,
duration of symptoms and viral shedding) also reduces the
post-herpetic neuralgia.
• Porphylactically – organ transplant patients to prevent HSV
reactivation.
• IV – HSV encephalitis (doc), neonatal HSV, serious HSV or VZV
• Topical – less effective than oral for primary HSV infection, not
benefit for recurrent genital HSV
14.
15. Adverse effects
• Well tolerated, nausea, diarrhoea may occur
• IVI – reversible renal toxicity (crystalline nephropathy)
• Can have neurologic effects (need adequate hydration and avoid rapid
infusion)
• Concurrent use of nephrotoxic agents – enhance potential of
nephrotoxicity.
17. Anti-herpes agents Route of
administration
Use Dose
Famciclovir Oral • Genital herpes
(first/recurrent)
• Orolabial herpes
(first/recurrent)
• Herpes zoster
Different
doses/duration and
frequency
Valaciclovir Oral
Foscarnet IV Acyclovir resistant
HSV and VZV
infection
Ganciclovir Topical Keratitis Every 3 hr while
awake
Docosanol Topical Recurrent herpes
labialis
Every 2 hr while
awake
Penciclovir Topical Herpes labialis or
herpes genitalis
Every 2 hr while
awake
Trifluridine Topical Acyclovir resistant
HSV infection
5 times a day
18.
19.
20.
21. Classification of anti-retroviral agents
• 1st agent – zidovudine (1987)
• “6” Classes of Anti-retroviral drugs nowadays
1. NRTI (nucleoside/nucleotide Reverse transcriptase
inhibitors)
2. NNRTI (non-nucleoside Reverse transcriptase
inhibitors)
3. PI (Protease inhibitors)
4. FI (Fusion inhibitors)
5. CCR5 co-receptor antagonists
6. II (HIV integrase strand transfer inhibitors)
23. • Mechanism of action
– NRTIs act by competitive inhibition of HIV-1 reverse
transcriptase
– Incorporation into growing viral DNA chain causes
premature chain termination due to inhibition of
binding with the incoming nucleotide
• Status of NRTIs
– Considered as “backbone” of the antiretroviral therapy
– Used with other agents (NNRTI, PI, or II)
– NRTI itself given in pairs but certain combinations
should be avoided due to drug interactions, similar
resistance patterns or overlapping toxicities
24. Adverse effects Comments
Zidov-
udine
AZT
Myelosuppression (most common)
Macrocytic anaemia or
neutropenia
• Avoid concurrent
stavudine
• Avoid other
myelosuppressive
drugs
AZT reduce the
phosphorylation of
stavudine.
Lamiv-
udine
(3TC)
Headache, dizziness,
GI side effects
Mild and infrequent
• Also has activity against HBV***
• One of the recommended ARTs in pregnant
women. ***
Stavu-
dine
Dose-related peripheral sensory
neuropathy
Pancreatitis, arthralgia,
aminotransferases,
Hepatic steatosis, lactic acidosis
• Avoid concurrent
administration of
neurotoxic drugs
• Avoid with ddI
(lactic acidosis and
pancreatitis)
• Avoid with AZT
Didan
osine
Dose-dependent pancreatitis
Peripheral distal sensory neuropathy
Avoid with stavudine
Avoid other neurotoxic
27. • Mechanism of action
– Bind directly to HIV-1 reverse transcriptase, resulting in
inhibition of RNA and DNA dependent polymerase
activity.
– The binding site of NNRTI is near but distinct from that
of NRTI.
• Status of NRTIs
– Unlike NRTI, NNRTIs do not compete with nucleoside or
do not require phosphorylation to be active.
28. • Adverse effects in general
– GI intolerance
– Skin rash ( infrequently – Steven-Johnson syndrome)
– NNRTIs – either enzyme inducer/inhibitor (potential
drug drug interactions) (one of the limitation factors)
29. Drug name Therapeutic usefullness Adverse effect
Nevirapine used for prevention of mother to child
transmission (PMCT)
200 mg single dose at the onset of labor fb
2mg/kg to neonate within 3 days of delivery
No evidence of human
teratogenicity
Maculopapular rash
SJ$
Enzyme inducer
Delavirdine Skin rash (rarely SJ$)
Enzyme inhibitor
Should be avoided in preg:
Efaviranz Skin rash (rarely life
threatening)
Both inducer and inhibitor
Should be avoided in preg:
Etravirine Skin rash (rarely life
threatening)
Both inducer and inhibitor
31. Mechanism of action
Function of HIV protease enzyme
• During the later stage of HIV growth cycle, the gene
products are translated into proteins, which become
immature budding particles.
• HIV protease is responsible for cleaving these precursor
molecules to produce the final structural proteins of
mature virion core.
Activity of PI
• PIs prevent the processing of viral proteins into functional
conformations, resulting immature, noninfectious viral
particles.
32. Adverse effects
• Redistribution of accumulation of body fat (resulting central
obesity, buffalo hump, Cushingnoid appearance.)
• Drug drug interactions (extensively metabolized by liver,
some are inhibitors and some are inducers).
• PI agents when given in combination, acting as
pharmacokinetic enhancer rather than antiretroviral agent.
• (Ritonavir boosted prolong drug half life.)
33. Enfuvirtide (Fusion inhibitor)
Mechanism of action
Enfuvirtide
• Fusion inhibitor that blocks HIV entry into the cell.
• Binds to GP41 subunit of the viral envelope glycoprotein
preventing the conformational change required for the
fusion of viral and cellular membranes.
• Must be administered SC.
• Adverse effect: - local injection site reactions.
34.
35. Mechanism of action
Maraviroc
• Binds to host protein CCR5, one of the two chemokine
receptors necessary for entrance of HIV into CD4+ cells.
• Is active against HIV that uses the CCR5 co-receptor
exclusively, not against HIV strains with CXCR4.
• CI in patients with severe or end stage Renal impairment.
Maraviroc (entry inhibitor)
36.
37. Integrase inhibitors
• Dolutegravir
• Elvitegravir
• Raltegravir
Mechanism of action
• INSTIs bind integrase, a viral enzyme essential to the
replication of both HIV-1 and HIV-2.
• It inhibits strand transfer.
• And interfering the integration of reverse-transcribed HIV
DNA into the chromosomes of the host cells.
38.
39. • The accepted standard for HIV treatment is that combination “highly active
anti-retroviraltherapy (HAART)” should be administered before substantial
immunodeficiency intervenes.
• The primary aim of treating patients with HIV infection is
– maximal suppression of HIV replication for as long as possible. To decrease viral load
– To improve survival.
42. • during pregnancy initiated at 14-34 weeks up to onset of
labour – oral AZT 600 mg/day in divided dose
• during labour IV. AZT 2mg/kg in 1 hr followed by 1 mg/kg/hr
till delivery
• infant AZT 2mg/kg 6 hrly up to 6 weeks
• Nevirapine 200 mg single oral dose at onset of labour and
2mg/kg single oral dose at 48-72 hrs after delivery (47% ↓)
43. • Individuals are eligible for HIV PEP if –
– The exposure occurred within the past 72 hours and
– The exposed individual is not infected with HIV and
– Non-intact skin or mucous membrane was significantly exposed to a potentially
infectious body fluid
– And the source is HIV infective or the HIV status is unknown.
• PEP treatment with 2 NRTIs –
– A regimen with 2 NRTIs is recommended if
• HIV status of the source person is unknown and
• The background prevalence of resistance to ART is <15% and
• the source person has never used ART or
• the source person is unlikely to have ART resistance based on ART therapy.
• Recommended two-drug combination therapy for HIV PEP ( given for 28 days)
– AZT + 3 TC
– Alternative is TDF + 3TC
– NVP and ddI are not used due to their relatively higher risk of potentially serious side
effects.
44.
45. What is boosted regimen?
• Pharmacologic enhancer
• Ritonavir is the ideal
• It inhibits two key stages of metabolism
– First pass metabolism
– Inhibit CYP3A4 in the hepatic metabolism
• Result
– Less drug is transported back out of the cell, thereby
increasing the drug’s half life.
46.
47. The goals of chronic HBV therapy
• To sustain suppression of HBV replication, resulting in slowing
of progression of hepatic disease(with retardation of hepatic
fibrosis and even reversal of cirrhosis),
• To prevent complications (ie, cirrhosis, hepatic failure, and
hepatocellular carcinoma), and
• To reduce the need for liver transplantation.
48. • Suppression of HBV DNA to undetectable levels,
• Seroconversion of HBeAg (or more rarely, HBsAg)
from positive to negative, and
• Reduction in elevated hepatic transaminase levels.
How does it carry out?
49. Indication in chronic hepatitis B Route of administration
NNRTI
ADEFOVIR + Oral
ENTECAVIR + Oral
LAMIVUDINE + Oral
TENOFOVIR + Oral
TELBIVUDINE + Oral
INTERFERON
INTERFERON-ALPHA-2b + SC or IM
PERGYLATED INTERFERON-
ALPHA-2a
+ SC
Drugs used for HBV infection, 7 drugs (2013)
50. What is pergylated interferon?
• Use of polyethylene glycol-complexed interferon
alfa-2a and alfa-2b
• Results in
– Slower clearance
– Longer terminal half-lives
– Steadier plasma drug concentrations
– Allowing for less frequesnt dosing
51. Pharmacology of interferon
• What is interferon?
Interferons are host cytokines that exert complex
antiviral, immunomodulatory and antiproliferative
actions and some has proven to be useful for both
HBV and HCV.
52. Pharmacology of interferon
• MOA
– Interferons appear to functions by Induce intracellular
signals following binding to specific cell membrane
receptors, resulting inhibition of viral penetration,
translation, transcription, protein processing,
maturation and release as well as increased host
expression of MHC, enhanced phagocytic activity of
macrophages, augmentation of the proliferation and
survival of cytotoxic T cells.
53. • Adverse effects
– Ful like syndrome within 6hrs of dosing.
– Transient hepatic enzyme elevations
– Neurotoxicities
• CI
– Hepatic decompensation
– Autoimmune disease
– History of cardiac arrhythmia
55. • Primary goal of therapy
– Viral eradication
• Drugs used for treatment of hepatitis C infection
– Polymerase inhibitors (sofosbuvir)
– Protease inhibitors (boceprevir, simeprevir, telaprevir)
– Ribavirin
56.
57. MOA
Polymerase inhibitors
(sofosbuvir)
inhibits the HCV RNA dependent DNA polymerase.
Protease inhibitors
(Boceprevir
Simeprevir
Telaprevir)
Inhibit HCV replication directly by binding to the protease that cleaves
the HCV encoded polyproteins.
Ribavirin Inhibit viral messanger RNA.
Inhibit viral RNA dependent DNA polymerase.
Inhibit replication of a wide range of RNA and DNA viruses – influenza
A, B, parainfluenza, respiratory syncytial virus, paramyxoviruses, HCV
and HIV-1.
58.
59. Oseltamivir & Zanamivir Amantidine & rimantidine
MOA • Neuriminidase inhibitors
• Interfere with release of progeny
influenza virus from infected host
cells
• Halting the spread of infection within
the respiratory tract
• blocks M2 proton ion channel
of the virus particle and inhibit
the uncoating of viral RNA
within infected host cells plus
preventing its replication.
Route of
administration
O – oral
Z – inh
Oral
Activity Active against Influenza A and B Only against influenza A
Dosing and
benefits
• Early administration is crucial because
replication of influenza virus peaks at
24-72 hours after the onset of illness.
• Initiation of 5 day course of therapy
within 48 hours after the onset of
illness decreases the duration of
symptoms, viral shedding and
transmission, and rate of
complications such as pneumonia,
asthma, hospitalization and mortality.
• When begun within 1-2 days
after the onset of illness, the
duration of fever and systemic
symptoms is reduced by 1-2
days.
