Antiviral drugs

‫هﺬي اﻟﻨﻮﺗﺔ وﻻ ﻣﻮ ﻣﺘﺎآﺪة ﻣﺮة ﺑﺲ هﺬا اﻟﻠﻲ ﺟﻤﻌﺘﻪ ﻣﻌﺎهﺎ‬

Mechanism of action of antiviral drugs.
• DNA polymerase inhibitors:
– Purine analogues: acyclovir, ganciclovir.
– Pyrimidine analogues: trifluridine
• m RNA synthesis inhibitors: ribavarin.
• Inhibitors of viral penetration and uncoating : enfuvirtide, amantadine,
rimantadine.
• Neuraminidase inhibitors: zanamivir, oseltamivir
• Immunomodulators: interferons.

Discussion of drugs according to viral diseases

1. Agents to treat herpes simplex virus
(HSV) and varicella zoster (VZV)
infection.
• Acyclovir- oral or IV
• Trifluridine (topical)
2. Agents to treat cytomegalovirus
(CMV) infection
• Ganciclovir
3. Antihepatitis virus
• Interferon α
• Pegylated interferon α
• Ribavarin
4. Antiinfluenza agents
• Amantadine
• Rimantadine
• Zanamivir and oseltamivir
5. Anti retroviral drugs
• Nucleoside reverse transcriptase
inhibitors (NRTIs): zidovudine
• Nonnucleoside reverse
transcriptase inhibitors
(NNRTIs): nevirapine
• Protease inhibitors: nelfinavir.
• Fusion inhibitor: enfuvirtide

1. Agents to treat Herpes simplex virus (HSV) and varicella zoster (VZV)
infection.
i. Acyclovir
Mechanism of action
First converted to monophosphate by virus specific thymidine kinase and then to di and
triphosphate compounds by the host’s cellular enzymes. Acyclovir triphosphate inhibits
viral DNA synthesis by 2 mechanisms: competitive inhibition of viral DNA
polymerase and chain fragmentation following incorporation into viral DNA.

Kinetics: oral bioavailability is 15-20%. Excreted through GF and TS. Half life 3
hours, increased to 20 h in renal failure.

Uses:
– Genital herpes: first attack or recurrent episodes.
– Herpes encephalitis
– Neonatal HSV infection

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 – Mucocutaneous herpes in immunocompromised host.
– Varicella or zoster infection in immunocompromised host.
Adverse effects:
– Nausea, vomiting, diarrhea, headache,
– Renal dysfunction due to crystalline nephropathy.
– Neurotoxicity: tremor, delirium, seizures

ii. Trifluridine - topical agent

• A fluorinidated pyrimidine nucleoside that inhibits viral DNA synthesis.
• Applied as 1% solution for HSV 1 and 2 infection (keratoconjunctivitis, keratitis).
• Topically used in combination with INF α for acyclovir resistant HSV infection.

2. Agents to treat CMV infections

Ganciclovir
• an acyclic guanosine analog that requires triphosphorylation for activation prior to
inhibiting the viral DNA polymerase and termination of viral DNA elongation.
• 100 times more active than acyclovir for CMV.
Adm :oral or IV or intraocular implant. Excreted through kidney.

Uses
• To delay progression of CMV retinitis in patients with AIDS.
• For CMV colitis, esophagitis.
• CMV pneumonitis in immunocompromised .
• Prophylaxis in transplant recipients.

Adverse effects
• Myelosuppression- neutropenia (20-40%)
• CNS toxicity- headache, seizures
• Others: fever, rash, abnormal liver function.
• Mutagenic, carcinogenic and embryotoxic at high doses and causes
aspermatogenesis in animals.

3. Antihepatitis agents
• Hepatitis B: Chronic hepatitis B: interferon α2b. Newer drugs (lamivudine,
adefovir, entecavir not discussed).

• Hepatitis C:
• Acute hepatitis C: interferon α2b,
• Chronic hepatitis C:
• interferon α2a, interferon α2b
• pegylated interferon α2a, α2b
• Ribavirin.
• Treatment is supportive rather than curative
.
i. Interferon α

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 • Endogenous proteins that exert antiviral, immunomodulatory and
antiproliferative activities.
• Used for chronic hepatitis B infection.
• Combination with ribavirin is more effective in chronic hepatitis C infection
than monotherapy with either drug (maximum effect 6-12 months).
• Given SC or IM, thrice weekly. Filtered at glomeruli and undergoes rapid
proteolytic degradation in tubules.

Adverse effects
• Flu like syndrome (headache, fever, chills, myalgias, malaise) within 6 hr-
resolves on continued administration.
• Transient increased transaminases.
• During chronic therapy:
– Neurotoxicities (mood disorders, depression, somnolence, confusion,
seizures).
– Myelosuppression- thrombocytopenia
– Profound fatigue, weight loss, rash, cough, myalgia, alopecia, tinnitus,
reversible hearing loss, retinopathy, pneumonia, cardiotoxicity,
hypotension, edema.
– Induction of autoantibodies
Contraindications
• Hepatic decompensation
• Autoimmune disease.
• Psychiatric illness, epilepsy.
• Pregnancy – abortifacient

ii. Pegylated interferon α :

• pegINF α 2a and α 2b - used in hepatic C infection.
• Polyethylene glycol (PEG) moiety is attached to INF by a covalent bond which
leads to reduced clearance and sustained absorption and increased half life
and steadier drug concentration, allowing less frequent dosing (once a week).
• Efficacy better than nonpegylated INF.
• Combination with ribavirin better than monotherapy.

iii Ribavirin
•
A guanosine analog- phosphorylated intracellularly - inhibits synthesis of
guanosine triphosphate, inhibit viral mRNA and RNA polymerase.
• Inhibits replication of many DNA and RNA viruses (influenza A and B,
parainfluenza, respiratory syncytial virus, paramyxoviruses, HCV and HIV-1).
• Adm orally, IV, or as nebuliser; excreted through kidney.
Therapeutic uses:
• Used with INF α 2b in compensated hepatitis C infection.
• For severe respiratory syncytial virus bronchitis or pneumonia in infants and
children, used as nebuliser
• Influenza A and B, parainfluenza.
• Lassa fever, other viral hemorrhagic fever, severe measles pneumonitis.

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Adverse effects:
• Dose dependent hemolytic anemia.
• Dose related GI (nausea) and CNS complaints(fatigue, irritation, depression,
insomnia)
• Rash, pruritus, cough.
• Teratogenic, embryotoxic, oncogenic and gonadotoxic in animals and
mutagenic in mammalian cells.

Contraindications: end stage renal failure, pregnancy and advise not to conceive for 6
months after treatment.

4. Antiinfluenza drugs
• i. Amantadine and rimantadine Amantadine and rimantadine (α methyl
derivative of amantadine)- are cyclic amines. Used only for influenza A
infection.

• Mechanism of action: These inhibit uncoating of viral RNA of influenza A

within infected host cells, thus prevent its replication.

Uses
• For prevention and treatment of influenza A esp in elderly.
• Post exposure prophylaxis.
• Parkinsonism.

Adverse effects
• GIT intolerance.
• CNS- nervousness, difficulty in concentration, lightheadedness, toxicity
increases with antihistaminic, anticholinergic agents.
• Teratogenic in humans.
Comparison between amantadine and rimantadine
Amantadine Rimantadine
• Half life- 12-18 H • 4-10 times more active than amantadine.
• Exc. In urine • Half life:24-36 H
• More CNS toxicity. • Metabolised (hydroxy, glucuronide) in liver,
• Dose to be reduced in reduce dose in hepatic insufficiency.
elderly. • Less CNS toxicity
• Administered twice daily. • Dose to be reduced in elderly.
• Administered once daily.

ii. Zanamivir and oseltamivir (neuraminidase inhibitors)

Neuraminidase is an essential viral glycoprotein for virus replication and release.
These drugs inhibit release of virus from infected cells, reduce spread of virus within
respiratory tract. Used for prevention and treatment of influenza.
Effective for both influenza A and B.

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Zanamivir
• Effective against
amantadine resistant
virus.
• Used as oral inhaler.
• Adverse reaction: nasal
and throat discomfort,
bronchospasm.
Oseltamivir:
• Effective against amantadine and zanamivir
resistant virus
• Oral adm.
• Is a prodrug - activated in gut and liver.
• Excreted in urine.
• Adverse effects: nausea, vomiting, abdominal
discomfort, headache.

5. Antretroviral drugs
I. Nucleoside reverse transcriptase inhibitors (NRTIs) : e.g zidovudine.
Zidovudine (AZT, ZDV, Azidothymidine)
• It is a thymidine analog with antiviral activity against HIV-1 and HIV-2.
• It gets converted to triphosphate form which competitively inhibits reverse
transcriptase (RNA dependent DNA) and also inhibits cellular DNA polymerase α
and mitochondrial polymerase gamma. It causes DNA chain termination.

ADME: well absorbed, widely distributed, including CSF, metablised by

glucuronidation, and partly exc unchanged in urine both by GF and TS.

Therapeutic uses.
• To treat adults and children with HIV infection either as monotherapy or in
combination with other antiretroviral agents.
• To prevent prenatal transmission of virus in pregnant women with HIV
infection. Given during pregnancy (beginning at 14 weeks with IV dosing during
intrapartum period) and continuation of administration to the newborns for first 6
weeks of life- reduces the risk of neonatal transmission of HIV by 80%.
• Also for post exposure chemoprophylaxis in HIV exposed health-care workers

Adverse effects
• Major toxicity: myelosuppression: granulocytopenia and anemia,
thrombocytopenia, megaloblastic anemia- toxicity increased with paracetamol,
aspirin, indomethacin (competition for glucuronidation).
GI intolerance- nausea, vomiting.
• Less common: hyperpigmentation of nails and myopathy- pain, increased
CPK
• Very high doses: Severe headache, insomnia, anxiety, confusion, tremors,
seizures. Severe lactic acidosis, hepatomegaly and steatosis. Stop the drug on if
rapid increase of transaminases.
• It is mutagenic, tumor promoting and embryotoxic.

Contraindications:
• Hypersensitive patients
• First 14 weeks of pregnancy.

II. NNRTIs (nonnucleoside reverse transcriptase inhibitors) eg. nevirapine

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 •
Mechanism of action- It binds directly to reverse transcriptase and blocks RNA
and DNA polymerase activities.
• ADME: absorbed well, widely distributed, crosses BBB, placenta and enters
breast milk.
• Inducer of hepatic cytochrome P450. Extremely metabolized, drug and it
metabolites are excreted in urine.
Therapeutic uses
• Part of multidrug regimens in both for naïve and experienced patients.
• A single oral intrapartum dose followed by a single dose to the new born -
superior to more complicated zidovudine therapy in preventing vertical
transmission of HIV.

Adverse effects
• GI intolerance- nausea, vomiting, abdominal pain.
• Skin rash- maculopapular rash, pruritus, and life threatening skin reactions
(Stevens-Johnson syndrome), toxic epidermal necrolysis
• Fever, headache, somnolence, paresthesia
• Increased hepatic enzymes, hepatitis.
Drug interactions
• It is an enzyme inducer- many drug drug interactions may occur.
Contraindications and precautions: pregnancy, patient with hepatic or renal
insufficiency

III. Protease inhibitors: nelfinavir

Most potent antiretroviral drugs.
Mechanism of action
• Inhibition of protease leads to formation of immature, noninfectious viral
particles.

Adverse effects:
• Nausea, vomiting, diarrhea, flatulence
• Glucose intolerance, diabetes, hypercholesterolemia and
hypertriglyceridemia.
• Prolonged use – leads to fat redistribution: Cushingoid appearance.

4. Fusion inhibitor
Enfuviride
• Is a peptide which binds to gp 41 of viral envelop glycoprotein preventing the
conformation changes required for fusion of viral and cellular membrane
• Blocks entry of virus into cell.
• Given SC.
• No cross resistance seen with other, no interaction with other antiretroviral drugs.
Adverse reactions:
• Injection site reactions
• Hypersensitivity reaction
• Eosinophilia.