PS01 - Antiviral Agents Flashcards

1
Q

What are the six stages of viral replication?

A
Attachment
Entry
Uncoating
Macromolecular Synthesis
Assembly
Release
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2
Q

What is the MoA of Aciclovir?

A

Aciclovir is an analogue of Deoxyguanosine, but without a 3’ hydroxyl group
Both a 5’ and a 3’ hydroxyl group are required for the replication of DNA
Without the 3’ group DNA synthesis comes to a halt

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3
Q

How is Aciclovir selectively toxic?

A

Aciclovir has to be triphosphorylated to have its DNA chain termination effect
The initial phosphorylation is performed by HSV-TK (thymidine kinase)
HSV-TK is present in viral cells but not eukaryotic cells

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4
Q

What determines the cellular uptake of Aciclovir into specifically viral cells?

A

Diffusion down a concentration gradient

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5
Q

What three factors determine the selective toxicity of Aciclovir?

A

Only active in viral cells (HSV-TK)
Concentrated in viral cells
Higher affinity for viral DNA polymerase

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6
Q

Describe the spectrum of activity of Aciclovir

A

Narrow, only targets HSV1/2 and VZV

Only these families possess HSV-TK

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7
Q

How does resistance to Aciclovir arise?

A

Absence of Thymidine Kinase (TK-ve)
Alteration of Thymidine Kinase
Exist pretreatment, appear during therapy
Alteration of DNA polymerase

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8
Q

Why is Aciclovir resistance due to TK absence not a clinical issue?

A

Because the absence of HSV-TK renders the variants non-pathogenic
Alteration strains are also attenuated

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9
Q

What Aciclovir resistance mechanism is clinically important?

A

Alteration of DNA polymerase, strain is fully virulent

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10
Q

In what population is Aciclovir resistance a huge clinical problem?

A

AIDS patients suffering from repeated HZV infections

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11
Q

What is Valaciclovir?

A

A variant of aciclovir joined to a valine ester

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12
Q

What is the key property of Valaciclovir?

A

Valaciclovir has a much higher oral bioavailability than aciclovir

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13
Q

What is Penciclovir?

A

An antiviral agent which acts as a viral DNA polymerase inhibitor but is not a chain terminator

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14
Q

How does primary oral herpes present?

A

Painful, white lesions on the tongue and soft/hard palate

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15
Q

Where does herpes virus lie dormant?

A

Trigeminal ganglion

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16
Q

How does recurrent oral herpes present?

A

Cold sores

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17
Q

In what situation is treatment of oral herpes clinically justifiable?

A

Treatment of primary oral herpes ONLY

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18
Q

How does primary genital herpes present?

A

Painful, white lesions on the genitalia

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19
Q

How does recurrent genital herpes present?

A

Fewer, less painful lesions

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20
Q

In what situation is treatment of genital herpes clinically justifiable?

A

Treatment of primary genital herpes

Prophylaxis for frequent, severe, atypical genital HSV

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21
Q

How is treatment of atypical recurrent genital herpes managed?

A

Long term therapy

Titration of dose down to eventual cessation

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22
Q

What is herpes simplex encephalitis?

A

Inflammation of the cerebral hemispheres due to infection with HSV

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23
Q

How is herpes simplex encephalitis treated?

A

Immediate administration of i.v. aciclovir

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24
Q

What other forms of HSV can be treated with Aciclovir?

A

Ocular herpes simplex

Eczema herpeticum

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25
Q

What diseases are caused by Varicella Zoster Virus?

A

Chickenpox

Shingles

26
Q

When is Aciclovir used to treat chickenpox?

A

In adults, often suffering from Varicella Pneumonia (i.v. aciclovir)

27
Q

What complications can chickenpox cause in pregnancy?

A

Increases risk of varicella pneumonia

28
Q

Should aciclovir be used in pregnancy?

A

In life threatening situations ONLY

Worries of teratogenesis as DNA synthesis inhibitor but safe record

29
Q

Where does VZV go latent?

A

Nerve cell bodies in the spinal cord and cranial nerves

30
Q

How should reactivated VZV (shingles) be treated?

A

Immediately w/ i.v. aciclovir in immunocompromised and most other patients

31
Q

What is disseminated voster?

A

Unusually widespread herpes zoster in immunocompromised patients

32
Q

What is the main problem with Aciclovir/Aciclovir like drugs?

A

They have a very narrow spectrum of use

33
Q

Why can Aciclovir not be used in Cytomegalovirus?

A

CMV does not posses HSV-TK so cannot phosphorylate aciclovir

34
Q

What antiviral can be used to treat CMV?

A

Ganciclovir, a drug with a similar MoA to aciclovir but that is initially phosphorylated by UL97

35
Q

Against which herpesviruses is Ganciclovir active?

A

All herpesviruses

36
Q

What are the disadvantages of Ganciclovir?

A

Poorly absorbed orally (use valganciclovir)

Toxic, often in bone marrow (less selective for viral cells)

37
Q

What is Cidofovir?

A

An acyclic phosphanate nucleotide analogue used as an antiviral to treat CMV retinitis

38
Q

What is the MoA of Cidofovir?

A

Same as Aciclovir (DNA chain terminator) but with the first phosphate already added

39
Q

What is the disadvantage of Cidofovir?

A

Less selective for virally infected cells

Leads to greater toxicity (nephrotoxic)

40
Q

What is the advantage of Cidofovir?

A

Can inhibit any viral DNA polymerase (potentially)

41
Q

What is Adefovir?

A

An analogue of Cidofovir used to treat chronic Hep-B infection

42
Q

What is Foscarnet?

A

A pyrophosphate analogue used as an antiviral agent

43
Q

What is the MoA of Foscarnet?

A

Inhibits DNA polymerase as it forms phosphodiester linkages in the DNA chain

44
Q

What are the disadvantages of Foscarnet?

A

Poor oral availability

Nephrotoxic

45
Q

What are the three CMV antiviral agents?

A

Cidofovir
Ganciclovir
Foscarnet

46
Q

What is Ribavirin?

A

A nucleotide analogue used as an antiviral agent

47
Q

What is the MoA of Ribavirin?

A

Not entirely known
Possibly interferes w/ mRNA processing
Possibly acts as a mutagen

48
Q

For what viruses is Ribavirin effective?

A

Severe RSV infection (inhalation)
Lassa fever
Chronic hepatitis C (w/ IFN)

49
Q

How do Uncoating Inhibitors work?

A

They inhibit the uncoating of the viral nucleic acid from its protective nuclear capsid

50
Q

Give two examples of Uncoating Inhibitors

A

Amantadine

Rimantadine

51
Q

What viruses is Amantadine treatment effective for?

A

Influenza A only

52
Q

What is the MoA of Amantadine?

A

Amantadine acts to block an ion channel created by one of the matrix proteins of Influenza A, preventing uncoating

53
Q

What are the disadvantages of Amantadine treatment?

A

Only effective in Influenza A
Poorly tolerated (CNS stimulation)
Resistance rapidly emerges

54
Q

How does resistance to Amantadine arise?

A

A SNP in the matrix protein, preventing Amantadine binding

55
Q

What two glycoproteins are studded throughout the viral lipid envelope?

A

Haemagluttinin

Neuraminidase

56
Q

What is the function of Neuramindase?

A

Cleaves the glycosidic linkages of neuraminic acids, allowing for the release of virions from infected cells

57
Q

What is the MoA of Neuramindase Inhibitors?

A

Compounds that bind to the active site of Neuramindase and inhibit it, preventing the release of virions from infected cells

58
Q

Give two examples of Neuramindase Inhibitors

A

Zanamavir (inhaled)

Oseltamivir/Camiflu (oral)

59
Q

What are Neuraminidase Inhibitors used to treat?

A

Severe influenza infection

Influenza infection in high risk individuals

60
Q

What is the advantage of Neuraminidase Inhibitors?

A

Work against all known influenza NA

61
Q

In which strain of influenza has resistance to Neuraminidase Inhibitors been demonstrated?

A

H5N1 (avian) w/ H274Y mutation