17. Antiviral Agents

Question 1

Are antivirals virostatic or virucidal?

Answer 1

They are virostatic i.e. they do not kill existing viruses they just stop the replication of new viruses.

Question 2

Describe the structure of viruses

Answer 2

• obligate intracellular parasites
• no cell wall or cell membrane
• genome consists of DNA or RNA
• viral replication uses the hosts machinery as they dont have their own mitchondria/Golgi etc

Question 3

Describe the 6 steps of viral replication

Mnemonic: APURAR

Answer 3

1) Attachment - the virions attach to specific receptors on the surface of the host cell
2) Penetration - the virus can then fuse directly with cell membrane of host or through endocytosis/pH mediated fusion
3) Uncoating - virion disassembles, freeing nucleic acid and viral proteins needed for replication
4) Replication/protein synthesis
5) Assembly: new virions containing viral nucleic acid are formed
6) release: new virions are released from the cell via lysis of the cell

Question 4

Name some drugs that can be used for Influenza A and B and how do they work?

Answer 4

• Oseltamivir (Tamiflu): oral
• Zanamivir: inhaled/intranasally

These are neuraminidase inhibitors which block the release of newly assembled influenza virions from the host cell.

There are yearly vaccinations available for those at risk (elderly, respiratory disease, immunocompromised)

Question 5

Give some examples of drugs for herpes virus 1/2 and what is the mechanism of action?

Answer 5

Aciclovir - IV, oral or topical.

Herpes virus is associated with cold sores, encephalitis and genital infections.

The drug inhibits viral DNA synthesis - Aciclovir is converted by viral thymidine kinase to aciclovir monophosphate, which is then converted by host cell kinases to aciclovir triphosphate (ACV-TP).

ACV-TP, in turn, competitively inhibits and inactivates HSV-specified DNA polymerases preventing further viral DNA synthesis without affecting the normal cellular process

Question 6

What are some ADRs for Aciclovir and how can resistance develop?

Answer 6

ADRs: some nephrotoxicity, may show CNS symptoms (lethargy, confusion, extra pyramidal signs)

Resistance occurs due to thymidine kinase enzyme mutations in the virus which prevents binding to acyclovir so it cant act as a false substrate in DNA replication anymore.

Question 7

When does aciclovir work?

Answer 7

• Only works during acute phase of viral infection
• when the patient is symptomatic
• helps to control time/severity

Question 8

Which drug can be used for cytomegalovirus and what is the mechanism of action?

Answer 8

Ganciclovir (IV, crosses the blood brain barrier)

It is an analogue of Aciclovir and acts in the same way but is phosphorylated by a different enzyme, not thymidine kinase.

Question 9

What is CMV retinitis?

Answer 9

• can cause blindness
• transplant rejection
• hepatitis
• encephalitis

This can be treated with ganciclovir or foscarnet initially and cidofovir can be used for resistant cases.

Question 10

Name the ADRS for Ganciclovir

Answer 10

• myelosuppressive (severe dose dependent neutropenia)
• carcinogenic/teratogenic
• renal cleared so accumulates in renal failure

Question 11

What is lamivudine?

Answer 11

Used for HIV/Hep B

• reverse transcriptase inhibitor
• acts as a false substrate and chain terminator of reverse transcriptase enzyme in viral replication

Question 12

What is sofosbuvir?

Answer 12

• blocks the action of HCV polymerase

- to prevent production of new virus

Question 13

What is interferon alpha? How does it work and what are the ADRS?

Answer 13

• used for Hep B/C
• IM injection
• immunomodulatory effect: not directly antiviral but stimulates proteins to enhance cellular resistance to viral infection

ADRs: In the first few hours to days, flu like illness, fever, chills, headache, malaise, myalgia, nausea/vomiting, diarrhoea

Question 14

What is Ribavirin, how does it work and what are the ADRs?

Answer 14

Given oral or IV.

• used in treatment of chronic Hepatitis C
• in combination with interferon alpha
• and treatment of infants with RSV

Mechanism: guanosine analogue: inhibits guanosine triphosphate formation, preventing viral mRNA capping. Essentially prevents assembly of the viral genome/DNA

ADR: transient anaemia, teratogenic

Question 15

Name 6 classes of antiretroviral drugs and give an example of each.

Mnemonic: NNPRIF

Answer 15

Nucleoside reverse transcriptase inhibitors e.g. Zidovudine

Non-nucleoside reverse transcriptase inhibitors e.g. nevirapine

Protease inhibitors e.g. ritonavir

Receptor inhibitors

Integrase inhibitors e.g. Raltegravir

Fusion inhibitors e.g. enfuvirtide

Question 16

How do NRTIs work?

Answer 16

-inhibit DNA polymerase so cant replicate DNA

ADRs:

• hyperlactataemia
• lactic acidosis
• hepatomegaly + steatosis (possibly fatal)

Question 17

How do NNRTIs work?

Answer 17

• active without further phosphorylation
• non competitive inhibitors of HIV reverse transcriptase
• bind at a different site to the NRTI but have same effect
• therefore can be used as combination therapy
• only works on HIV

Question 18

How do protease inhibitors work?

Answer 18

• block the cleavage of viral polyproteins
• by HIV protease enzymes
• preventing the production of viral proteins for the formation of final mature virions

Question 19

How do fusion inhibitors work?

Answer 19

Salvage therapy if other treatments haven’t worked

Question 20

How do integrase inhibitors work?

Answer 20

Prevent integration of HIV DNA provirus into host cell genome