Antiviral Agents

Dr. Milcah Dhoro

Department of Clinical Pharmacology
Faculty of Health Sciences
New Health Sciences Building
4th Floor Office No. 38
Phone: +263 4 791 631 ext 2120
Email: milcah_dhoro@yahoo.com
 Viruses

• obligate intracellular parasites.

• UNABLE to grow and reproduce outside of a living
cell
• utilize:
– Host metabolic enzymes
– Host ribosome for protein synthesis
• Host range determined by;
– specific attachment site on host cell's surface
– availability of host cellular factors
• Helical, polyhedral, complex, enveloped
• Difficult to kill, drugs that kills virus kills host cells,
drug resistance
 Typical infectious cycle of a virus
• attachment,
• entry of the particle,
• decoding of genome information,
• translation of viral mRNA by host
ribosomes,
• genome replication,
• Assembly,
• release of new particles
• Viral diseases = consequences
of life cycle.
 Some Viral Diseases
• Chickenpox
• Flu
• Herpes Simplex
• HIV/AIDS
• Mumps
• Measles
• German Measles
• Herpes zoster
• Small Pox
 Antivirals
Key characteristics :
• Able to enter cells infected with virus.
• Interfere with viral nucleic acid synthesis and/or
regulation
– Inhibit viral attachment
– Prevent genetic copying of virus
– Prevent viral protein production
• Some agents interfere with ability of virus
to bind and infect cells.
• Some agents stimulate body’s immune system
 Anti-Herpesvirus Agents
• Over 130 herpesviruses
– Herpes Simplex Virus (HSV) 1 &2,
– Cytomegalovirus (CMV),
– Varicella zoster virus (VZV)
Antiherpes drugs:
– Acyclovir*
– Valacyclovir
– Famciclovir
– Penciclovir
– Ganciclovir
– Cidofovir
– Trifluridine
– Vidarabine
• All inhibit viral replication- serve as competitive
substrates for viral DNA polymerase
 Acyclovir
• guanosine derivative – competes with dGTP
for viral DNA polymerase
• Oral, IV, Topical formulations
• Uses: HSV 1 & 2, VZV
• Primary, recurrent genital HSV infection
• Phosphorylated by viral thymidine kinase (TK)
• Di-and tri-phosphorylated by host cellular
enzymes
• A/Es: nausea, diarrhea, headache, tremors,
nephrotoxicity
• Drug resistance, viral mutants deficient in TK,
altered DNA polymerase.
Acyclovir MOA
 Valacyclovir

• Prodrug, greater oral bioavailability

• Converted to acyclovir when ingested
• M.O.A.: same as acyclovir
• Uses:
– 1) recurrent genital herpes
– 2) herpes zoster infections
• A/Es: nausea, diarrhea, headaches
 Famciclovir
• Prodrug of penciclovir (guanosine analog)
• rapidly converted to active penciclovir by
deacetylation and oxidation.
• M.O.A.: same as acyclovir
• Uses: HSV-1, HSV-2, VZV, EBV,
• Also used for hepatitis B
• well tolerated
• A/Es: nausea, diarrhea, headaches, jaundice
 Trifluridine
• fluorinated pyrimidine – modified form of deoxyuridine
• phosphylated to triphosphate form by cellular kinase
• competitively inhibits viral DNA polymerase.
• Uses:
• primary and recurrent HSV infections of the eyes (cornea
and conjunctiva)
• treatment of persistent cutaneous ulcers due to acyclovir
resistant HSV infection in patients with AIDS
• A/Es: local irritation of eye following topical application,
edema of eyelids
 Vidarabine
• adenosine analog
• Phosphorylated by cellular kinases rather than viral TK
• incorporated into viral DNA
• inhibits viral DNA polymerase
• Anticancer properties
• active against herpes viruses, poxviruses (smallpox),
RNA tumour viruses
• ophthalmic solution for treating recurrent epithelial
keratitis
• A/Es: GI intolerance, myelosuppression, nausea,
vomiting, diarrhoea, tremors, ataxia seizures.
 Anti-Cytomegalovirus Agents
• Prophylaxis
– Valganciclovir*
– Ganciclovir
– Acyclovir
• Disseminated disease
– Ganciclovir
– Foscarnet
• Retinitis
– Formiversin
– Ganciclovir
 Ganciclovir
• acyclic guanosine analog
• requires triphosphorylation for activation
• Phosphorylated by viral enzymes
• M.O.A.: same as acyclovir
• Uses: CMV*, HSV, VZV, EBV
• A/Es: myelosuppression, reversible neutropenia
or thrombocytopenia
• Combination therapy with foscarnet
• Resistance in CMV isolates:
– Alteration in viral protein kinase
– Point mutations in viral polymerase
 Foscarnet
• Alternative when there is ganciclovir resistance
• inorganic pyrophosphate, nonnucleoside derivative
• Not orally bioavailable, given by IV
• selectively inhibits pyrophosphate binding site on viral
DNA polymerases - halts DNA chain elongation
• Effective for thymidine kinase deficient strains
• Other uses: HSV, VZV, EBV, HBV, HIV
• A/Es: hypo- or hypercalcemia , Nephrotoxicity*,
seizures, anemia
 Other antiherpes agents
• Sorivudine
– VZV, HSV1, EBV
– thymine analogue- chain termination
– Inhibits viral replication
– therapy is superior to acyclovir
– May cause headaches, GIT symptoms
• Cidofovir
– Injectable, primarily used for CMV retinitis, 2nd line option
– Indicated for ganciclovir-resistant CMV disease
– acyclovir-resistant HSV infections
– competitive inhibitor of viral DNA polymerase
– A/Es; nephrotoxicity, anaemia, nausea, vomiting, headache
 Antiviral Drugs For Influenza
• Amantadine, Rimantadine
• inhibit replication of influenza A virus by impairing function of
membrane protein M2
• M2 - ion channel required for nucleocapsid release
• rapid functional recovery, reduces duration of fever + other
symptoms by about 1 day, if given within 48 hours of disease onset
• prophylaxis for preventing symptomatic influenza A infection in
exposed persons
• Well tolerated
• mild neurologic symptoms: anxiety, disorientation, headache
• resistance, characterized by amino acid substitutions in M2 protein,
emerges within 2 to 4 days of treatment.
 Oseltamivir
• prodrug of oseltamivir carboxylate,
• Effective against influenza A and B
• selectively blocks viral neuraminidase, prevents release of
virus from infected cells
• Treatment should start within 48 hours of disease onset and
continue for 5 days
• Post exposure prophylaxis (up to 6 weeks during outbreak)
• Capsules, oral suspension
• second-line alternative : oseltamivir + rimantadine

• A/Es: nausea, vomiting, diarrhea, abdominal pain, insomnia,

and vertigo, neuropsychiatric adverse effects, including
delirium,
 Zanamivir
• inhaled neuraminidase inhibitor
• Treatment + prophylaxis of influenza A and B viruses
• not available orally, poorly absorbed
• given by inhalation twice daily for 5 days, with therapy
begun within 48 hours after symptom onset.
• can be given once daily for 10 days as post exposure
prophylaxis
• prophylaxis during community outbreaks may be given for
28 days.
• Occasionally given IV to treat critically ill patients with
influenza.
• Well tolerated
• A/Es: headaches,GI symptoms, hypersensitivity reactions,
neuropsychiatric adverse effects
 Anti-hepatitis Agents
• Interferons (IFNs)
• IFN α-2a or α-2b
• Available only in parenteral formulation (IM, SC)
• antiviral, antiproliferative, immunoregulatory functions.
• bind to receptors, initiate cascade of events:
– inhibition of virus replication,
– suppression of cell proliferation,
– enhancement of phagocytic activity of macrophages,
• commonly used for treating chronic viral hepatitis B, C & D
• not recommended in acute viral hepatitis
• Other uses: HSV1, 2, HPV, Infuenza

• A/Es: depression, confusion, seizures, neutropenia, aplastic

anemia, arrhythmias, thyroid disorders, dyspnea
 Adefovir
• An analog of adenosine monophosphate
• Phosphorylated by cellular kinases
• M.O.A. - Competitively inhibits HBV DNA
polymerase and results in chain termination
after incorporation into viral DNA
• Other Uses - HIV
• Side effects - nephrotoxicity
Antiretroviral Agents
Nucleoside/Nucleotide Reverse Transcriptase
Inhibitors (NRTIs)

•Abacavir (ABC)
•Didanosine (ddI)
•Emtricitabine (FTC)
•Lamivudine (3TC)
•Tenofovir (TDF)
•Zidovudine (ZDV)
•Adefovir
 MOA NRTIs
• competitive inhibition of HIV reverse transcriptase
• Reverse transcriptase (RT)
• HIV-specific DNA polymerase
• Transcription of HIV RNA to proviral DNA
• Drugs act as "false building blocks” causes chain termination,

Adverse effects of NRTIs

•lactic acidosis
•hepatic steatosis (didanosine, zidovudine)
•body fat redistribution (lipodystrophy)
•anemia, neutropenia (Zidovudine)
 Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
• First-generation 2nd generation
– Delavirdine(DLV) - Etravirine (ETR)
– Efavirenz (EFV) - Rilpivirine (RPV)
– Nevirapine (NVP)

– Also block RT activity, bind to site away from active site

– induces conformational change in enzyme
– greater risk for resistance with failure or treatment interruption
– Transmitted resistance more common, but 2nd generation drugs
more flexible, resist mutations.
– potential for drug-drug interactions (substrates and inhibitors of
CYP3A4)
 NNRTIs Adverse effects
• Skin rash*, in some cases Stevens-Johnson
syndrome (NVP)
• toxic epidermal necrolysis
• CNS effects (EFV)
• Hepatotoxicity
• Teratogenic (EFV, Delavirdine)
 Protease Inhibitors (PIs)
•Atazanavir (ATV)
•Darunavir
•Fosamprenavir (FOS-APV)
•Indinavir (IDV)
•Lopinavir (LPV)
•Nelfinavir (NFV)
•Ritonavir (RTV)
•Saquinavir (SQV)
•Tipranavir (TPV)
• Block protease enzyme that cuts long protein
strands into small functional proteins + enzymes
needed to assemble mature virus
• Prevent maturation of new viral particles
 A/Es OF PIs

• Liver toxicity
• metabolic abnormalities;
– dyslipidemia,
– hyperglycemia,
– insulin resistance,
– lipodystrophy.
• may increase the risk of bleeding in hemophiliacs.
• significant interactions with other drugs
• inhibitor/substrate for CPY3A4, do not give with
antifungal azoles
 Entry Inhibitors
• Fusion Inhibitors
– Enfuvirtide
– binds to gp41 preventing creation of an entry pore for
capsid of virus
– Block fusion of HIV with cell membrane of CD4
cell
– Salvage therapy, patients with multi-drug resistant
HIV
– Subcutaneous administration
• ADRs:
– Injection-site reactions (eg, pain, erythema)
– diarrhea, nausea, fatigue,
– hypersensitivity reactions,
– increased rate of bacterial pneumonia
 Entry Inhibitors

• CCR5 Antagonists
– Maraviroc
– Bind to and block the CCR5 co-receptor of the
immune cell, thereby preventing HIV from entering
and infecting the cell
– works specifically against CCR5tropic HIV, not
CXCR4
• A/Es:
• Abdominal pain
• Upper respiratory tract infections
• Cough, Hepatotoxicity, Rash
 Integrase Inhibitors

• Raltegravir
• Elvitegravir
• Dolutegravir
• MOA:
– Prevent integration of HIV DNA into nucleus of
infected cells
• Side effects:
– Nausea
– Headache
– Diarrhea
 First - line ART
• combination regimens for treatment-naïve patients:
– two NRTIs + one NNRTI, or
– two NRTIs + a PI (with or without ritonavir boosting- for infants ≤
3yrs).
• preferred first-line regimen for adults, adolescents:
– Tenofovir + Lamivudine + Efavirenz
• Alternatives:
– TDF + 3TC + NVP
– AZT + 3TC + EFV/NVP
– TDF + FTC + EFV/NVP
• Avoid EFV in pregnant women
• TDF/3TC/ATV/r for adults and adolescents for PEP
 2ND LINE OPTIONS

3RD LINE OPTION

In adults, raltegravir (400mg) twice a day + darunavir
(800mg)/ritonavir (100mg) once daily
 HIV Drug Resistance
• changes/mutations in genetic information in
virus
• Partial HIV suppression
• Resistance to one drug can cause resistance to
others of the same class
• Drug resistant virus usually grows faster and
better than drug susceptible virus
Minimize Emergence of Viral Resistance

• Never prescribe ARVs in absence of adherence

counseling and support
• Never prescribe monotherapy or dual therapy
• Ensure optimal serum drug concentrations
• Avoid drug interactions
• Strict monitoring on discontinuation of
medications