Antiviral Drugs

• Viruses hijack many metabolic process in host cell itself so hard to find drugs just selective for pathogen -  but there are virus specific enzymes = drug target

• Most available antivirals only effective when the virus is replicating, initial phases of viral infections are asymptomatic, treatment isnt started until infection is well established 

• High rates of viral mutation = multiple strains which are drug resistant

• Virus incorporated in DNA can act as potential 'reservoirs' and replication can cause relapse following cessation of the therapy = need life long treatment 

• Each class of antivirals has the potential to cause toxicities

• Drug - drug interactions eg; induce or inhibit cytochrome P450 enzymes/metabolise other medications

• There is a limited availability of ARV drugs and safe alternatives in other countries that standards and supply may not be maintained = further problem

MOA: An attachment and entry inhibitor of HIV-1 virus fusion with CD4 cells. Binds to the gp41 subunit of viral envelope of glycoprotein preventing conformational changes needed for fusion of membranes at the final stage

GIVEN: Subcutaneous injection in combination with other retroviral drugs 

INDICATION: When resistance becomes a problem or the patient is intolerant of other anti-retrovirals

ADR: Flu like symptoms, central effects eg: headaches, dizziness, alterations in mood, GI effects, hypersensitivity reactions

Both CCR5 and CXCR4 are both chemokine receptors on the surface of host cells used by HIV for entry. 

INDICATION: In patients who are have previously been treated and are refractory/resistant to other antiretroviral drugs and have CCR5 strains Maraviroc is used.

MOA: CCR5 chemokine receptor antagonist drug (Pfizer) that is a reversible antagonist blocking HIV gp120 from binding to CCR5 receptor, so HIV cannot enter the host cell

ADR: Mainly GI distrubances and CNS disturbances 

A synthetic nucleoside similar in structure to guanosine 

MOA: Targets the Respiratory Syncytial Virus by either altering virus nucleotide pools or by interfering with the synthesis of viral mRNA. Inhibits a range of other DNA/RBA viruses too.

ADRs: fever, GI effects 

Disassembly of the coat allows the Influenza A virus to enter host cell to enter by endocytosis.

The endosome is acidified following influx of H+ through another viral protein the M2 ION CHANNEL. This channel facilitates disassembly of viral structure so RNA enters host nuclues and replicates 

AMATIDINE is an old drug that is hardly used today but

MOA: Blocks viral M2 ion channel so inhibits dissassembly 'uncoating', active only against influenza A virus

GIVEN: Orally; well absorbed high levels in secretions eg: saliva

EXCRETED: Kidneys 

ADRs: infrequent, insomnia, GI, dizziness

MOA: A guanosine derivative that is converted by thymidine kinase to its monophosphate form. In infected cells it is conveted to acyclovir triphosphate competitively inhibits viral DNA polymerase acting as a nucleotide chain terminator.

GIVEN: Orally, IV, topically wide distribution 

EXCRETED: Kidneys by glomerular filtration and by tubular secretion

ADRs: Mainly GI nausea and headaches. Local inflammation where given IV

First drug developed for treatment of HIV 

MOA:  Inhibits the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of its 5' trisphosphate form. It competes with the natural substrate dGTP and incorporates itself into viral DNA. 

GIVEN: Orally 2/3 times a day 

EXCRETED: Most is metabolised to its inactive glucuronide in liver, only 20% of the active form is excreted in the urine

ADRs: Nausea, vomitin, blood disorders, CNS effects - insomnia, dizziness and headaches 

MOA: Raltegravir targets and inhibits integrase enzyme

Integrase is a HIV enzyme that splices viral DNA to the host genome when forming the provirus. Used as part of combination therapy.

INDICATION: Reserved for cases of resistance to other antiretroviral agents. 

The mRNA transcribed from the provirus is translated into two inert polyproteins. A virus specific protease then cleaves and converts these polyprotesins into various structural and functional proteins eg: enzymes to go to maturing virus. 

RITONAVIR 

MOA: Binds to and inactivates the protease active site of HIV virus and is combined with other protease inhibitors or retrovirals

GIVEN: orally twice a day 

EXCRETION: 80% faecal and some 10% in urine 

ADRs: GI disturbances (nausea, vomiting, pain), blood disorders (anaemia), CNS effects (insomnia, dizziness)..

MOA: By binding and inhibiting the neuraminidase transmembrane protein coded by influenza genome, the drug renders the influenza virus unable to escape its host cell and infect others.

GIVEN: 

zanamivir - available as a power for inhalation ; unsually can lead to bronchospasm

Oseltamivir - available as oral preparation ; causes GI distrubances (nausea, vomiting, dirrhoea and headaches)