Antiviral drugs

Question 1

Broad steps of managing viral infections

Answer 1

1) vaccination (most effective method if possible)

2) pharmacotherapeutic treatment via antiviral drugs
- narrow spectrum drugs and specific for one virus
- also includes palliative care

3) immune response stimulation (very controversial)

Question 2

General consideration for antiviral drugs

Answer 2

Most viral infections resolve spontaneously unless immunosuppressive

Therapy primary aim is to minimize symptoms and infectivity

Drugs act by arresting the viral replication cycle
- do not kill

Almost impossible to not harm host cells due to viruses being obligate intracellular parasites

24-48 hrs after symptom onset is the best time to administer antivirals

Viral load must be monitored during treatment if symptoms are still present

Question 3

5 Stages of the viral life cycle

Answer 3

Attachment and penetration of virus to host cell

Unloading of viral genome

Synthesis of viral components within the host cell

Assembly of viral particles

Release of virus from host cells

Question 4

Antivirals against herpes

Answer 4

Target inhibition of DNA replication since they are DsDNA

• Analogs are phosphorylated to mimic nucleotides
• nucleotides are then incorporated into replicating DNA virus strand and inhibits DNA poly.
• results in truncated viral DNA that has little/no effect on host cells

Includes nucleoside analogs, DNA/RNA polymerase inhibitors

All strands are affected by all drugs but to varying efficacies

Question 5

Types of herpes strands

Answer 5

HSV-1 = oral, skin,bran, lungs

HSV-2 = genitalia, rectum, meninges

HSV-3 = VZV, chicken pox, shingles

HSV-4 = Epstein Barr, infectious mono

HSV-5 = Cytomegalovirus (CMV)

Question 6

Why do herpes viral drugs work more towards viral thymine kinase vs host thymine kinase to be phosphorylated?

Answer 6

Viral thymine kinase affinity for the “clovir” drugs is roughly 200-300x high than host cell thymine kinases

Question 7

Acyclovir and valacyclovir

Answer 7

Acyclovir (IV, topical)
- is the ONLY herpes antiviral that can be IV administered

Valacyclovir (PO)

• more common since it can be taken PO
• is a prodrug of acyclovir (will be cleaved into acyclovir

Both of these work as guanosine analogs

Good vs HSV-1:4

Acyclovir (t1/2 =. 2.5-3 hrs) renal excretion

Question 8

How does herpes viruses gain resistance to acyclovir?

Answer 8

Alter their thymine kinases or the DNA polymerases

Question 9

Acyclovir ADRs

Answer 9

Nephrotoxicity: usually only in high doses without infusion
- High chance if on diuretics

Nausea, diarrhea, vomiting

Neurotoxicity: very rare

TTP occurs in patients that are HIV+

probencid and cimetidine decrease acyclovir clearance

Question 10

Penciclovir and famciclovir

Answer 10

Penciclovir (topical) famciclovir (PO)

• similar MOA as acyclovir except does not cause DNA chain termination
• used for HSV-1/2 and VZV

Famciclovir is a prodrug of penciclovir so super high PO bioavailability

No major ADRs

Question 11

Ganciclovir and valganciclovir

Answer 11

Ganciclovir = IV drug that is an analog of acyclovir
- same MOA and distribution as acyclovir

VERY potent against cytomegalovirus (CMV) and helps immunocompromised patients and a prophlayxis for transplant patients as well.

Renally excreted with t1/2 = 4 hrs

valganciclovir is the prodrug of ganciclovir

Question 12

Ganciclovir and valganciclovir ADRs

Answer 12

Myelosuppression (major issues)
- can cause neutropenia and thrombocytopenia as well

Neurotoxicity

Teratogen since it is not as selective for viral DNA polymerases and thymine kinases

Question 13

Foscarnet

Answer 13

IV drug that is apyrophosphate derivative that directly binds to DNA polymerase, skipping thymine kinase since it is already phosphorylated.
- prevents cleavage of pyrophosphate to triphosphates used to build viral DNA

Used for HSV infections that are resistant to acyclovir/ganciclovir
- also CMV in immunocompromised hosts

Renally excreted and t1/2 = 3-7 hrs

super broad so resistance is occurring, use sparingly

Question 14

Foscarnet ADRs

Answer 14

Nephrotoxicity

Electrolyte imbalances (hypocalcemia, hypomagnesemia, hypokelmia)

Don’t co-administer with cidofivir

produces synergistic effect when given with ganciclovir

Question 15

Cidofovir

Answer 15

IV durg that is A cytosine nucleotide analogy that is already phosphorylated
- Targets viral DNA polymerases and is used primarily for ganciclovir resistant CMV

• super potent for CMV in patients with AIDS*

Renally excreted and t1/2 = 2.6 hrs

Question 16

Cidofovir ADRs

Answer 16

Nephrotoxicity: so bad that renal impaired patients cant take this drug
- administered with IV saline to reduce concentration of cidofovir in renal tubules to try and combat nephrotoxicity

Neutropenia

Embryotoxicty/gonadotoxicity (contraindicated in pregnancy)

Question 17

Influenza and RSV infections with 4 types of drugs

Answer 17

Different from herpes since it uses RNA cycle to replicate

4 types:
amantadine antivirals 
Neuraminidase inhibitors
Viral replication inhibition 
RNA translation inhibition

Question 18

Amantadine and rimantadine

Answer 18

PO drugs that Prevent and treat only influenza A types
- (70-90% effective, but 0% effective against influenza B or RSV)

MOA = prevent virus from uncoating and releasing genetic material

• specifically block M2 channels which are used to trigger dissociation of the virus capsid once it has been endocytosis via host cells.
• if M2 channels are open, then RNP proteins are released and initiate transcription
• Amantadine is also used against Parkinson’s disease but is the primary agent*
• is not recommended all the time since resistance develops very quickly*

Question 19

Amantadine and rimantadine Pharmacokinetics and ADRs

Answer 19

Amantadine = renally cleared with half life of 12-18 hrs

Rimantadine = hepatically metabolized with renal clearance and a half life of 24-36 hrs.
- doses for both must be adjusted in renal impaired function patients

minor ADRs nothing serious

• do NOT take with antihistamines, psychotropics or anticholinergic drugs since it increases neurotoxicity*

Contraindicated in patients with seizure and/or psychiatric symptom history

Question 20

Neuraminidase

Answer 20

viral enzyme with 3 \main functions

1) cleaves Salic acid form host cell receptors which allows for controlling of viral adhesion to host cells
2) promotes fusion of viral envelope with host cell membrane
3) aids in releasing of newly formed virus particles form infected cells
- again cleaving Sialic acid prevents aggregation of the virus on the host cell membrane

• primary job is to cleave sialic acid from host cells so hemagglutinin cant bind to host cells and prevent both entrance and exit of viral particles*

Question 21

Neuraminidase inhibitors

Answer 21

Oseltamivir (PO), zanamivir (inhalation), peramivir (IV)

Bind to neuroaminidase and inhibit all actions

Treats influenza A/B and RSV types
- also is a prophylaxis for patients that cant take normal flu vaccine

Must be used within 24-48 hrs otherwise does not work anymore

ADRs are not severe, however must be careful with asthma or COPD patients especially if using zanamivir (can cause bronchospasms)

resistance is very common since it is such a broad agent

Question 22

Ribavirin

Answer 22

Broad spectrum antiviral agent that is used only to kill RSV infections

• guanosine nucleoside analogue but mechanisms is not well known, does kill viral replication though.
• is hypothesized to inhibit viral RNA polymerase and deplete GTP as well as increase host immune system*

Resistance already exists for this drug so you have to test for it (primarily in influenza A/B though)

Question 23

Ribavirin pharmacokinetics and ADRs

Answer 23

Ribavirin can be both PO and inhalation

• PO only for Hep C virus treatment though
• inhalation used for RSV infections

Renally cleared

ADR:

• hemolytic anemia that is dose dependent
• elevated bilirubin
• teratogen

Question 24

Palivizumab

Answer 24

IM drug that acts on the RSV fusion protein and inhibits it at the A antigenic site
- prevents adhesion and entrance into host cells

ONLY use in high-risk pediatric patients
- must take monthly for a year and is also super expensive

ADRs = hypersensitivity, thrombocytopenia fever and rash

Metabolized through liver

Question 25

Are antivirals cidal or static

Answer 25

Static (don’t kill just prevent load)