ANTI-VIRAL DRUGS Flashcards Preview

PHARM MIDTERM2 > ANTI-VIRAL DRUGS > Flashcards

Flashcards in ANTI-VIRAL DRUGS Deck (30):
1

OSELTAMIVIR

ZANAMIVIR

 

NEURAMINIDASE INHIBITORS

• Effective against BOTH Type A and Type B Influenza

• Administered prior to exposure as prophylaxis

• Administered within 24 - 48h after infection drugs have modest effect on symptoms

2015-2016 Influenza Season

• Oseltamivir & zanamivir are the only TWO agents recommended for use

MOA: inhibit the RELEASE of virus by inhibiting SIALIC ACID SUBSTRATE

2

NEURAMINDIASE INHIBITORS

PK/AE

Resistance

Oseltamivir: orally active prodrug (hydrolyzed in liver)

• Zanamivir: NOT orally active (inhaled, intranasal)

Adverse Effects

• Oseltamivir: GI discomfort, nausea (alleviated when taken with food)

• Zanamivir: airway irritation (avoid in severe asthma, COPD)

RESISTANCE: 

• Less infective & virulent neuraminidase mutations identified

3

AMANTADINE

RIMANTADINE

ION CHANNEL BLOCKERS

EXCLUSIVELY ACTIVE ON INFLUENZA A VIRUS*****
• Equally effective in prophylaxis and treatment (70-90%)

Since 2006 not recommended as first-line treatments due to resistance

2015-2016 Influenza Season

• Amantadine & rimantadine are NOT effective for the treatment or prevention of the currently circulating strains of influenza A.

MOA: BLOCKS VIRAL M2 PROTEIN THEREBY INHIBITING FUSION/UNCOATING

• Block viral membrane protein, M2 (H+ channel)

• Channel is required for fusion of viral with cell membrane to endosome (requirement for viral uncoating)

PK: 

• Oral

Amantadine is widely distributed & crosses BBB (Rimantadine is NOT), not extensively metabolized & excreted into urine where it may accumulate (b/c a MAN = STRONG --> goes everywhere and can cross any barrier) 

Rimantadine IS metabolized before elimination in urine

4

AMANTADINE

RIMANTADINE

 

adverse effects + contraindications + resistance

AE 

• Amantadine: CNS (~10%) (insomnia, dizziness, ataxia leading to hallucinations, seizures)

• Rimantadine: fewer problems

• Both: GI intolerance

CONTRAINDICATIONS: 

• Amantadine should be monitored in psychiatric patients, cerebral atherosclerosis, renal impairment, epilepsy (b/c A MAN = MORE LIKELY TO BE CRAZY!) 

Pregnancy, nursing (FDA Category C)

RESISTANCE: 

Up to 50% individuals are naturally resistant

• Cross-resistance between drugs occurs

 

5

RIBAVIRIN

SYNTHETIC GUANOSINE ANALOG

RIB-A-VIRIN --> RIB A LIVIN with your girl. Think of going out for ribs with your GIRL (guanosine analog). She's a sweet girl so she likes any food --> broad spectrum (RNA + DNA) -->  and has many flavors Regular (RSV), Hot (HCV), and LAVA hot (lassa fever)

--> if you choose the Hot (HCV) means you're the ALPHA male (IFN-alpha used for HCV)

NOTE: at the restaurant you CANNOT WEAR A CAP!!! (b/c it's fancy) --> prevents RNA capping!!! 

--> also inhibits RNA dependent RNA pol (RRRRR for Ribs) 

• Active against broad spectrum of RNA & DNA viruses

--> (eg, RSV, HCV, Lassa fever)

• Commonly used in combination with interferon alpha for the treatment of HCV

MOA: 

1) Converted to ribavirin-triphosphate which inhibits guanosine triphosphate formation and PREVENTS VIRAL mRNA CAPPING!!! 

2) Inhibits RNA-dependent RNA polymerase resulting in INHIBITION OF VIRAL PROTEIN SYNTHESIS 

6

RIBAVIRIN

PK/AE + CONTRAINDICATIONS

 

Eat 16-40 wings --> means the dinner will be PROLONGED and DISTRUBUTED

--> WINGS are so hot they are toxic to the baby, so ***DON'T GIVE TO PREGNANT GF***

--> WINGS so hot they can cause HEMOLYTIC ANEMIA 

 

• Oral, IV, & aerosolized
Distribution significantly prolonged in RBC (16-40 days)

Adverse Effects

• Dose-dependent transient anemia (can bind to RBC)

• GI (nausea, anorexia)
• CNS (fatigue, headache, insomnia)

CONTRAINDICATIONS: 

• Pregnancy (FDA Category X)

• Negative pregnancy tests required before treatment and monthly during treatment of female patients or female partners of male patients

7

TREATMENT OF HEPATIC VIRAL INFECTIONS 

 

Hepatitis A, B, C, D & E
• HBV and HCV are most common causes of chronic hepatitis, cirrhosis & hepatocellular carcinoma

A) Interferon

􏰃--> INTERFERON ALPHA

B) Nucleotide / Nucleoside Analogs

--> Lamivudine, Entecavir, Ribavirin

C) Protease Inhibitors

--> Boceprevir, Telaprevir

8

INTERFERON ALPHA

ALPHA = ARRESTS RNA/DNA synthesis by ACTIVATING protein expression that inhibits viral infection

• Naturally occurring, inducible glycoproteins / cytokines

• 􏰃􏰃alpha and beta􏰄􏰄 produced by many cell types

--> gamma by immune cells (T cells)

MOA

Use innate immune response.

• DO NOT target viral gene products directly

• Inhibit RNA & DNA synthesis by activating / inducing protein expression that inhibit virus infection eg, PKR

PK: 

• Not orally active (IV, subcutaneously, intralesionally)

• Cellular uptake and metabolism by liver & kidney
• Usually pegylated to improve PK profile

Adverse Effects

• Flu-like (fever, chills, myalgias & GI disturbances)

• Fatigue & mental depression

 

9

INTERFERON ALPHA

DRUG INTERACTIONS

CLINICAL APPLICATIONS 

ALPHA --> the alpha male THEOPHYLLUS (theophylline) gets angry and accumulates!!!! 

--> think of theophyllus as a WARTY, HBV/HCV DRUG user that has KAPOSI dots everywhere, and is HAIRY!!! (hairy cell leukemia) 

• Interferes with hepatic drug metabolism.

--> Can cause toxic accumulation of theophylline.****

• May potentiate zidovudine induced myelosuppression

 

Clinical Applications

HCV (in combination with ribavirin)

HBV, condyloma acuminata, hairy-cell leukemia, Kaposi’s sarcoma

10

LAMIVUDINE

ENTECAVIR

NUCLEOSIDE/NUCLEOTIDE ANALOGUES

LAMB DINING ENTErs-CAVE  --> he's just going into cave because can't do much else ie he is just SUPRESSING what is actually going to happen (ie not curative) 

--> must be PHOSPHORLYATED to ACTIVE form 

• Must be phosphorylated by cellular enzymes to triphosphate (active) form

Actions are suppressive rather than curative

 

11

LAMIVUDINE

NUCLEOTIDE/NUCLEOSIDE ANALOG

LAMB DINING --> lamB dining for hep B, also HIV. Is what you get for getting a little LAMB on the SIDE (nucleotide/nucleoside analog) 

  • MONO --> gets incorporated into DNA
  • TRI --> inhibits reverse transcriptase 

• Effective against hepatitis B and HIV
• Triphosphate form inhibits HBV and HIV reverse transcriptase

• Monophosphate form is incorporated into DNA (by HBV polymerase) resulting in chain termination

• Well tolerated (headache, dizziness, GI complaints)

12

ENTECAVIR

NUCLEOTIDE/NUCLEOSIDE ANALOG

ENTER CAVE from the SIDE to avoid the TIDE (analogs) 

 

Effective against lamivudine-resistant strains of HBV & HIV

Phosphorylated form competes with natural substrates for viral polymerase.

Subsequent inhibition of polymerase blocks reverse transcriptase activity

Monitor after discontinuation in case of exacerbation of severe hepatitis

13

BOCEPREVIR

TELAPREVIR

PROTEASE INHIBITORS = "PREVIR" 

TELA BOCCE PREVIR ---> tell a bocce player to BIND RIVERSIBLY to the NS3 serine protease --> inhibits HCV for NS3

Used in the treatment of HCV in adult patients who have been previously untreated or failed treatment with interferon 􏰃and ribavirin

• Administered in combination with 1) interferon 􏰃􏰃 and 2) ribavirin

MOA

• Bind reversibly to nonstructural protein 3 (NS3) serine protease and inhibit replication of HCV

AE: 

The most commonly reported adverse reactions in adult subjects are:

• fatigue
• anemia
• nausea
• headache

dysgeusia: is an abnormal taste or change in taste that won't go away. It can be described as bad, metallic, salty, foul or rancid.

 

14

TREATMENT OF HERPES VIRAL INFECTIONS 

 

eg, cold sores, viral encephalitis, genital infections etc

• Herpes can form latent infection. Available drugs are for replicating virus only.

Purine / Pyrimidine Analogs
Acyclovir, Valacyclovir, Cidofovir, Ganciclovir, Valganciclovir, Penciclovir, Trifluridine

• Foscarnet

15

ACYCLOVIR

PURINE/PYRIMIDINE ANALOG

KNOW THIS SLIDE WELL

• Prototypic antiherpetic therapeutic agent

• Activity against: herpes simplex virus (HSV) Types 1 and 2, varicella-zoster virus (VZV) & some Epstein- Barr (HSV4) infections

TREATMENT OF CHOICE IN HSV ENCEPHALITIS*****

• Commonly used for genital herpes infections & prophylactically in immunocompromised and transplant patients

16

TREATMENT OF CHOICE FOR HSV ENCEPHALITIS?

ACYCLOVIR 

17

ACYCOVIR

CAN'T USE FOR WHAT? 

MOA? 

competes with dGTP because it's a GREAT drug 

CMV is resistant at clinically achievable levels (does not encode thymidine kinase)

Valacyclovir = prodrug of acyclovir

MOA: 

• Requires 3 phosphorylation steps for activation
• Monophosphorylated by herpes virus-encoded enzyme (thymidine kinase)

Host cell enzymes complete phosphorylation to di- and triphosphate forms

Competes with dGTP; once incorporated into DNA causes chain termination & inhibition of viral DNA polymerase

18

ACYCLOVIR

PK 

AE

PK: 

• IV, oral or topical

Valacyclovir has greater oral bioavailability than acyclovir

• Partially metabolized thus can accumulate with renal failure

AE: 

Depends on route of admin. eg,
• topical = local irritation
• oral = headache, diarrhea, nausea & vomiting

• IV = acute renal failure. Risk can be minimized by slow infusion and prior hydration of patient

19

GANCICLOVIR

Valganciclovir = pro-drug with greater oral bioavailability

• Analog of acyclovir (8-20 x activity against CMV)
• *********Drug of choice for CMV retinitis & CMV prophylaxis in

immunocompromised******

MOA

• Phosphorylated by viral (UL97) and cell kinases

• DNA chain terminator & DNA polymerase inhibitor

20

DOC FOR 

1) CMV RETINITIS

2) CMV PROPHYLAXIS IN IMMUNOCOMPROMISED

GANCYCLOVIR 

21

GANCYCLOVIR

RESISTANCE/PK

GREEN CYLOVIR --> green think of RIV --> b/c he has so much money. Riv is #97 in hockey. DOC for CMV retinintis b/c he's the one that oversees the grocery stores (sketchy) that he owns!!! 

RESISTANCE

• Reduced intracellular phosphorylation

• Mutations in phosphotranferase (UL97), or viral DNA polymerase

Pharmacokinetics

• Ganciclovir (IV)

Valganciclovir (oral) undergoes rapid hydrolysis in intestine & liver to ganciclovir

• Excretion via urine

22

GANCICLOVIR

AE/CONTRAINDICATIONS

GREEN CYCLOVIR --> think of riv... MYLOW times are when i go there and get suppressed, as well as NEUTROPENIA --> because he always has NEW PENS 

--> def does not want a kid, is contraindicated in pregnancy 

 

AE:

• Myelosuppression + NEUTROPENIA 
• Severe dose-dependent neutropenia

CONTRAINDICATIONS:

-PREGNANCY (FDA Category C) 

23

CIDOFOVIR

CIDOFOVIR --> C --> think of CAM --> CMV retinitis, also remember that it is nOT phosphorylated by viral kinases, it requires acitvation by HOST CELL KINASE (b/c i DO THINGS MYSELF)

--> I'M BETTER, so use when the others don't work, like Green (riv) 

--> can use for CMV RETINIITIS, or HSV 

Major use is treatment of CMV-induced retinitis in HIV/AIDS

Not phosphorylated by viral kinases****
• Requires activation by host cell kinases****
Effective against HSV & ganciclovir resistant HSV

 

MOA

• DNA chain terminator & DNA polymerase inhibitor

24

CIDOFOVIR

RESISTANCE

PHARMACOKINETICS

AE

I must be coadministered with a PROBE to block renal secretion 

 

Resistance

• Mutations in viral DNA polymerase

Pharmacokinetics

• IV, intravitreal & topical

Must be co-administered with probenecid*** (blocks renal tubular secretion)

--> 

Adverse effects

• Nephrotoxicity

25

PENCICLOVIR

Pencil on the cold sore treatement!!! 

--> normal mech, needs to us VIRAL THYMIDINE KINASE 

 

• Active against HSV-1, 2 and VZV
• Used for the TOPICAL TREATMENT  of HSV (cold sores)

MOA: 

• Monophosphorylated by viral thymidine kinase
• Further phosphorylation occurs to give active triphosphate form
• Inhibit HSV DNA polymerase / chain terminator

Resistance

• Low occurrence clinically

PK: topically only

AE: dermatologic (Mild erythema) 

26

TRIFLURIDINE

TRIFLURIDINE --> like TRIFLE while ur DINING --> get shot when youre dying --> HSV keratoconjunctivits (can't believe what you just saw) and recurrent EPITHELIAL KERATITIS (from rifle gunshot burn) --> triphosphate (tripple bullet in barrel) causes DNA FRAGMENTATION 

--> only used as OPTHALMIC OINTMENT, can cause PALPEBRAL EDEMA

 

• Effective against HSV-1, 2, and vaccina virus

Drug of choice for

  • ***1) HSV keratoconjunctivitis*** AND
  • 2) recurrent epithelial keratitis

MOA

• Triphosphate form incorporated into viral DNA causing fragmentation

PK: 

Ophthalmic ointment (too toxic for systemic)

• t1/2 = ~12 min (apply frequently)

Adverse Effects

• Transient irritation of eye & palpebral (eyelid) edema

27

Drug of choice for

1) HSV keratoconjunctivitis AND

2) recurrent epithelial keratitis

TRIFLURIDINE

28

FOSCARNET

IS FAST --> DOES NOT REQUIRE PHOSHORYLATOIN TO BE ACTIVE 

--> how does the FAST CAR NET WORK? it selectively inhibits the PYROPHOSPHATE (the care has FLAMES ON THE SIDE) binding site on viral DNA polymerase 

What do you put into the car? ELECTROLYTES for fuel --> is what can go wrong --> can cause NEPHROTOXICITY 

• Organic analog of inorganic pyrophosphate

• DOES NOT require phosphorylation to be active!!!!***

• Used for (KNOW THIS SHIT!!!) 

  1. CMV retinitis in immunocompromised patients****
  2. acyclovir-resistant HSV & CMV retinitis &
  3. ganciclovir-resistant CMV & VZV

MOA: Structural analog of the anion pyrophosphate that selectively inhibits the pyrophosphate binding site on viral DNA polymerases

Resistance

• Point mutations in polymerase

PK: --> IV only

Adverse Effects

Nephrotoxicity
• Electrolyte disturbances (Ca2+, Mg2+, K+, PO43-)

• Anemia,
• Genital ulceration (mainly men)
• CNS: hallucinations, seizures, headache (25%)

29

DOC FOR CMV RETINITIS IN IMMUNOCOMPROMISED 

FOSCARNET

30