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Class: Immuno Block > Anti-Viral (NON-HIV) Drugs > Flashcards

Anti-Viral (NON-HIV) Drugs Flashcards

1
Q

DRUG CLASS 1: anti-DNA viruses

What is the mechanism of the drug treatments for HSV and CMV?

A

Nucleoside analogs that competitively bind VIRAL DNA POLYMERASE -> Most are chain terminators and inhibit viral DNA replication

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2
Q

Which two anti-HSV and anti-CMV drugs are so toxic that they can ONLY be used as TOPICAL agents?

A

Trifluridine

Vidarabine

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3
Q

How do the nucleoside analog drugs get converted to its active form?

A

Pro-drug form needs to be phosphorylated by HOST PT kinases -> Triphosphorylated form = active form

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4
Q

What is the one exception among the anti-HSV and anti-CMV drugs requiring host kinase for active phosphorylation?

A

ACYCLOVIR - Requires VIRAL thymidine kinase (TK) for the first phosphorylation event

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5
Q

Mutations of developing resistance to ACYCLOVIR

A

1) Mutations in the binding site of VIRAL DNA POLYMERASE

2) Mutations in VIRAL THYMIDINE KINASE - necessary for first phosphorylation

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6
Q

What are the drug treatments for Herpes Simplex Virus (HSV) and Cytomegalovirus (CMV) - DNA VIRUSES?

A 
"-clovirs"
Acyclovir
Ganciclovir
Cidofovir
Famciclovir

“-idines”
Trifluridine
Vidarabine

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7
Q

What is the chemical composition of ACYCLOVIR?

A 
Guanosine analog 
COMPETITIVE substrate (against dGTP) for VIRAL DNA Polymerase
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8
Q

How does ACYCLOVIR specifically get concentrated inside PARTICULARLY in viral-infected cells?

A

1st phosphorylation event is by VIRAL thymidine kinase (HSV-TK)
Then the 2nd and 3rd phosphorylation events by host kinases -> Gets trapped inside the virus

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9
Q

What is the chemical composition of CIDOFOVIR?

A 
CMP analog 
Competitive substrate (against dCTP) for VIRAL DNA Polymerase
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10
Q

How does CIDOFOVIR get activated within BOTH virus-infected and non-infected cells?

A

ONLY 2 PHOSPHORYLATION events by host kinases

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11
Q

Mechanism of CIDOFOVIR

A

CMP analog that competitively binds (against dCTP) for VIRAL DNA polymerase -> No 3’OH elongation -> Chain termination

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12
Q

Mechanism of resistance development for CIDOFOVIR

A

Mutations in the VIRAL DNA Polymerase

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13
Q

What does the CMP analog state of CIDOFOVIR imply in terms of pharmacoDYNAMICS?

A

Low oral bioavailability - because it is a charged molecule

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14
Q

Which agent is given commonly with CIDOFOVIR to increase its levels in pt? Name two reasons why.

A

PROBENECID

REASON 1: Blocks tubular transport of cidofovir -> Reduces renal clearance
REASON 2: Reduces associated nephrotoxicity

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15
Q

Which is the most broad-spectrum anti-viral drug in that it blocks all 3: HIV RT + VIRAL DNA polymerase + VIRAL RNA polymerase

A

FOSCAVIR

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16
Q

What is the chemical composition of FOSCAVIR?

A

Phosphate + Carboxylate moieties

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17
Q

Mechanism of resistance development against FOSCAVIR

A

Mutations in VIRAL DNA Polymerase

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18
Q

Why is FOSCAVIR also preferred with regards to resistance?

A

Retains its anti-DNA pol activity against GANCICLOVIR/CIDOFOVIR resistant strains

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19
Q

What are the three toxicities associated with FOSCAVIR administration?

A

1) NEPHROTOXICITY: Due to its negative charge (3-)
2) PENILE ULCERS: High levels of ionized urine
3) CNS TOXICITIES: Headache, hallucinations, seizures

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20
Q

DRUG CLASS 2: anti-Influenza (RNA - strand virus, orthomyxovirus)
What are the two subclasses?

A

SUBCLASS 1: Neuraminidase Inhibitors (Prevents viral escape)

SUBCLASS 2: Adamantanes - M2 protein Inhibitors (Prevents viral uncoating/unsheathing -> Prevents viral entry)

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21
Q

What are the 3 Neuraminidase inhibitors and routes of administration?

A

OSELTAMIVIR (Tamiflu) - Oral
ZANAMIVIR - Inhaled
PERAMIVIR - IV (single IV dose versus 5 days of oseltamivir)

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22
Q

What is the chemical composition of OSELTAMIVIR + ZANAMVIR + PERAMIVIR?

A

Sialic acid transition state analogs that INHIBIT viral neuraminidase activity

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23
Q

Mechanisms of resistance development in OSELTAMIVIR + ZANAMIVIR + PERAMIVIR

A

Mutations in neuraminidase gene OR hemagglutinin (HA)

24
Q

Describe the prodrug -> activated drug conversion of OSELTAMIVIR

A

Prodrug taken orally -> Activated by ESTERASES (GI/liver)

25
Q

Name the 2 Adamantane drugs that prevent M2 protein and thus Influenza viral entry

A

Amantadine

Rimantadine

26
Q

What is the specific mechanism of action of AMANTADINE + RIMANTADINE?

A

Binds and inhibits by clogging the M2 protein (H+/ion pore) -> Inhibits viral uncoating/unsheathing for its entry into host cell

27
Q

What is the mechanism of developing resistance against AMANTADINE + RIMANTADINE?

A

Mutation in viral M2 protein

  • Currently most circulating strains are all resistant to this and currently waiting for a strain to emerge for which we can use the adamantanes *
28
Q

DRUG CLASS 3: anti-Hepatitis C (RNA virus, + sense)

What is the overall goal/benchmark for anti-hepatitis therapy?

A

SUSTAINED virologic response (SVR)

  • Often times, the virologic response may be suppressed only temporarily due to a small pool of infected cells that emerges thereafter *
29
Q

Does a vaccine exist for Hepatitis C? How about Hepatitis B?

A

Hep B- YES

Hep C - NO

30
Q

HBV is responsible for the majority of which cases of cancer?

A

Hepatocellular carcinoma (one of the most common cancers)

31
Q

What was the first ALL ORAL TREATMENT for Hepatitis C virus (HCV)?

A

SOFOSBUVIR/ RIBAVARIN

32
Q

What is the chemical composition of SOFOSBUVIR and its mechanism of action?

A

UMP analog - NUCLEOTIDE pro-drug bec it carries one phosphate
Terminates chain elongation of HCV RNA-dependent RNA polymerase

33
Q

What drugs do you have to be careful administering together with SOFOSBUVIR? Hint: Think [drug]

A

Drugs that induce the p-glycoprotein drug efflux pump
SOFOSBUVIR is a substrate for this pump

SOFOSBUVIR + pump-inducing drugs -> Increases drug efflux -> Lowers [SOFOSBUVIR]

34
Q

What is the chemical composition of RIBAVARIN

A 
Guanosine analog (similar to acyclovir in this sense) 
DIFFERENCE from Acyclovir: Acyclovir requires VIRAL thymidine kinase for first phosphorylation event followed by host kinases for the other phosphorylations. Ribavarin is phosphorylated 3x all by host kinases
35
Q

What are the targets of RIBAVARIN? (3)

A
  1. GTP-synthesis enzymes: LOWERS cellular GTP
  2. Inhibits mRNA capping
  3. Inhibits VIRAL RNA-dependent RNA polymerase -> Inhibits RNA virus replication
36
Q

What is the main difference between the 2 nucleoside analogs: SOFOBUVIR + RIBAVARIN

A

Sofobuvir - UMP analog that TERMINATES chain elongation of HCV RNA-dependent RNA polymerase
Ribavarin - Guanosine analog that does NOT terminate chain elongation. Rather targets the 3 specific enzymes

37
Q

What drug is the latest HCV NS3 protease inhibitor?

A

SIMEPREVIR

* Note photosensitivity w/ drug use *

38
Q

Name the 2 HCV protease inhibitor drugs.

A

SIMEPREVIR + PARITAPREVIR

39
Q

Name the two anti-HCV NS5A protein inhibitors.

A

LEDIPASAVIR + OMBITSAVIR

40
Q

What do LEDIPASAVIR + OMBITSAVIR target?

A

Block NS5A protein (DIMER) that is conserved among HCV genotypes - HCV structural protein with NO inherent enzymatic activity
BUT this inhibition blocks viral RNA replication + packaging

41
Q

What is the importance of LEDIPISAVIR binding and inhibiting the DIMER form of NS5A protein?

A

Ledipisavir binds the dimer form VERY tightly that it leads to inactivation within picomolar ranges

42
Q

What confers specificity of LEDIPASAVIR to HCV?

A

Viral NS5A has no human homolog

43
Q

ALL/ORAL Combo Pill: LEDIPISAVIR + SOFOSBUVIR

A

HARVONI - 96% success rate

44
Q

Most important precaution with taking SOFOSBUVIR or other SOFOSBUVIR-based drugs (e.g. HARVONI) with regards to drug/drug interaction

A

Should not take AMIODARONE (heart drug) + SOFOSBUVIR-base -> Results in slower heartbeat
Worry about CV issues

45
Q

What is the name of the non-nucleoside inhibitor of HCV RNA-dependent RNA polymerase?

A

DASABUVIR

46
Q

ALL ORAL HCV treatment: DASABUVIR + OMBITSAVIR + PARITAPREVIR + RITONAVIR (paritaprevir booster)

A

VIEKIRA PAK

47
Q

VIEKIRA PAK contains which drugs?

A

DASABUVIR (Non-nucleoside inhibitor of RNA pol)
OMBITSAVIR (NS5A inhibitor)
PARITAPREVIR (NS3 protease inhibitor)
RITONAVIR (NS3 booster)

48
Q

Precaution with drug-drug interactions with VIEKIRA PAK

A

DASABUVIR - metabolized by CYP2C8
PARITAPREVIR - metabolized by CYP3A4
RITONAVIR - CYP3A4 INHIBITOR

49
Q

Why is pegylated-Interferon NOT a first-line drug of treatment for HCV?

A

1) Long course of treatment that only works for 50% of HCV patients
2) SO SO MANY ADVERSE EFFECTS

50
Q

DRUG CLASS 4: anti-Hepatitis B (DNA virus that replicates via RNA intermediate)
Name the two drugs used for anti-HBV treatment.

A

ENTECAVIR

TENOFOVIR

51
Q

What are the first line-treatments of HBV?

A

1) INTERFERONS (really unfortunate bec there’s so many side effects such as reduced P450 metabolism, neurotoxicity, autoimmunity, hepatotoxicity)
2) NUCLEOSIDE ANALOG RNA pol Inhibitors: TENOFOVIR + ENTECAVIR

52
Q

How does ENTECAVIR get activated?

A

ENTECAVIR (guanosine analog) gets phosphorylated 3x by HOST kinases

53
Q

Mechanism of action of ENTECAVIR

A

Entecavir gets incorporated into first or second strand DNA synthesis -> Has 3’OH for elongation -> Additional bases are added BUT DNA is DISTORTED -> Blocks further synthesis

  • Chain terminator by causing DNA distortion *
54
Q

How long does a pt have to be on ENTECAVIR? Why?

A

For their LIFETIME

ENTECAVIR only SUPPRESSES HBV. If off treatment, REBOUNDING can occur

55
Q

Resistance properties of ENTECAVIR

A
  1. Emerged slowly - BEC resistance requires 2 mutations
  2. Cross-resistance to Lamivudine (anti-HIV) - If pt is taking lamivudine and develops resistance against this as well, ENTECAVIR resistance accelerates

Class: Immuno Block (13 decks)

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