Treatment of Viral PN

Question 1

Factors suggesting BACTERIAL cause of PN

Answer 1

**Age: **Adults

**History of illness: **Rapid onset

**Clinical Profile: **High fever, tachypnea

**Total WBC count: **> 15 X 10⁹ cells per L

**[CRP] in serum: **> 60 mg/L

**[Pro-calcitonin]: **> 0.5 ug/L

**CXR: **Lobar alvelar infiltrates

**Response to ABX: **Rapid

Question 2

Factors suggesting VIRAL cause of PN

Answer 2

• **Age: **<5
• **Epidemic situation: **ongoing viral epidemic
• **History of illness: **slow onset
• **Clinical profile: **rhinitis, wheezing
• **Total WBC count: **<10 X 10⁹ cells per L
• **[CRP] in serum: **<20 mg/L
• **[Pro-calcitonin] in serum: **<0.1 ug/L
• **CXR findings: **Sole interstital infiltrates, bilaterally
• **Response to ABX: **Slow or non-response

Question 3

Describe the influenza virus replication process

Answer 3

• Virus protein hemagglutinin binds to sialylated glycoprotein receptors on host-cell surface, and the virus enters the cell by receptor-mediated endocytosis
• Internalization and endosomal acidification permit fusion of the host and viral membranes by altering the conformation of hemagglutinin
• Viral ribonucleotides (RNPs) are released into cytoplasm
• In the nucleus, viral RNAs are transcribed into mRNA and replicted by viral RNA-dependent RNa polymerase
• Newly synthesized viral RNPs exported to cytoplasm, and after assembly, mature virions bud from cell surface

Question 4

Describe Influenza Viral Entry/Uncoating

Answer 4

• Virus enters via receptor-mediated endocytosis and contained within an early endosome
• Early endosome contains H+ ATPase that acidifies endosome
• Low-pH dependetn conformational change in viral envelope hemagglutinin (HA) protein triggers fusion of viral membrane with endosomal membrane.
• Protons from low-pH endosome must enter the virus through M2, a pH gated proton channel in the viral envelope
• Dissociation of matrix protein from influenza virus ribonucleoprotein (RNP), releasing RNP into cytosol.

Question 5

What is the treatment of Influenza A and B viruses?

Answer 5

Oseltamivir (PO)

Zanamivir (Inhalation)

These drugs target neuraminidase, which is required for release of progeny. They are selective sialic acid analogue inhibitors that produce conformational changes in the active site of Influenza A and B neuraminidases. Use of these drugs leads to viral aggregation at the cell surface and reduced virus spread within the respiratory tract.

Prevention: vaccines (inactivated; live)

Question 6

What are other treatments for Influenza A virus?

Answer 6

Amantadine (PO) or Rimantadine (PO)

Block action of viral M2 ion channel protein during uncoating of virus. Thus, they inhibit acidification of the interior of the virion, dissociation of matrix protein, and uncoating.

Question 7

What is the treatment for RSV?

Answer 7

Ribavirin (inhalation, IV)

Prevention: Palivizumab (IM)

Question 8

What is the treatment of Adenovirus?

Answer 8

Cidofovir (IV)

Prevention: vaccine for types 4 and 7

Question 9

What is the treatment of Rhinovirus?

Answer 9

NO TREATMENT

Prevention: alfa interferon (intranasal), Ribavirin (off-label)

Question 10

What is the treatment for Enteroviruses?

Answer 10

NO TREATMENT OR PREVENTION METHODS

Question 11

What is the treatment for Human metapneumovirus

Answer 11

Ribavirin (IV)

Question 12

What is the treatment for Hantavirus?

Answer 12

Ribavirin (IV)

Question 13

What is the treatment for Varicella-zoster virus?

Answer 13

Acyclovir (IV)

Valacyclovir (PO)

Prevention: vaccine available

Question 14

Acyclovir

Answer 14

MOA: inhibition of viral DNA synthesis (DNA polymerase inhibition)

• Nucleoside analogue that targets nucleic acid synthesis.
• Require metabolic activation, usually to a triphosphate form, before incorporation of the deoxyribonucleoside triphosphate into the growing DNA chain. Their incorporation leads to termination of chain elongation.

Metabolism:

• viral cells transform acyclovir to its active triphosphate form.
• systemic elimination unchanged by glomerular filtraiton adn tubular secretion

**Toxicity: **

• headache, nausea, elevated hepatic enzymes, nasopharyngitis, neutropenia
• maintain hydration to prevent renal precipitation
• use catuiously in renal impairment or with reno-toxic drugs

Question 15

Amantadine

Answer 15

**MOA: **inhibition of viral entry or uncoating

**Metabolism: **systemic elimination unchanged by glomerular filtraiton and tubular secretion

**Toxicity: **

• multiple adverse effects inclduign neurologic, nausea, and orthostatic hypotension
• contraindicated in narrow angle glaucoma and with breastfeeding

Question 16

Cidofovir

Answer 16

**MOA: **inhibition of viral DNA synthesis (DNA polymerase inhibition)

**Metabolism: **

• metabolized via pyrimidine nucleoside monophosphate kinase to mono- and then to diphosphate analogs and finally to the monophosphate-choline
• systemic elimination by glomerular filatration adn tubular secretion

**Toxicity: **

• multiple adverse effects including neurologic, hematologic and tubular damage
• BLACK BOX WARNING for renal impairment/toxicity

Question 17

Osteltamavir

Answer 17

**MOA: **Inhibition of release of influenza virus from infeceted cell

**Mechanism: **

• hepatically metabolized to teh carboxylate active form of the drug.
• systemic elimination by glomerular filtration and tubular secretion

Toxicity:

• minimal adverse effects
• potential for fatal neuropsychiatric adverse effects in flu patients; serious skin reaction reported rarely

Question 18

Ribavirin

Answer 18

**MOA: **Inhibition of viral nucleic acid synthesis

**Metabolism: **undergoes non-CYP metabolism in nucleated cells with systemic elimination of drug and products in the urine

**Toxicity: **

• Many common adverse effects, most commonly fatigue, headache, myalgia, nausea, fever
• **BLACK BOX WARNINGS for hemolytic anemia and M/F teratogenicity **

Question 19

Rimantadine

Answer 19

MOA: inhibition of viral entry or uncoating

**Metabolism: **extensive hepatic metabolism with renal elimination of drug and metabolites

**Toxicity: **minimal adverse effects

Question 20

Valacyclovir

Answer 20

**MOA: **pro-drug for acyclovir

**Metabolism: **

• converted to acyclovir (and L-valine) by first-pass metabolism
• systemic elimination (acyclovir) by glomerular filtration and tubular secretion

Toxicity:

• headache, nausea, elevated hepatic enzymes, nasopharyngitis, neutropenia
• maintain hydration to prevent renal precipitation
• use cautiously in renal impairemetn or with reno-toxic drugs

Question 21

Zanamivir

Answer 21

**MOA: **inhibition of release of influenza virus from infected cell

**Metabolism: **renally eliminated unchanged

**Toxicity: **

• headache, throat/tonsil pain, cough, viral infection
• NOT to be used with underlying pulmonary disease - fatal bronchospasm !