ANTI-VIRAL DRUGS Flashcards
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
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
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
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
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
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
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
INTERFERON ALPHA
ALPHA = _A_RRESTS 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
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
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
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)
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
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.
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
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
TREATMENT OF CHOICE FOR HSV ENCEPHALITIS?
ACYCLOVIR
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
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
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
DOC FOR
1) CMV RETINITIS
2) CMV PROPHYLAXIS IN IMMUNOCOMPROMISED
GANCYCLOVIR
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
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)
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
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
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)
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
Drug of choice for
1) HSV keratoconjunctivitis AND
2) recurrent epithelial keratitis
TRIFLURIDINE
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!!!)
- _CMV retinitis in immunocompromised patients****_
- acyclovir-resistant HSV & CMV retinitis &
- 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%)
DOC FOR CMV RETINITIS IN IMMUNOCOMPROMISED
FOSCARNET
