Antivirals and antiretrovirals Flashcards
Oseltamivir, Zanamivir
- Neuraminidase inhibitors - inhibit release of virus
- 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
PK
• Oseltamivir: orally active prodrug (hydrolyzed in liver)
• Zanamivir: NOT orally active (inhaled, intranasal)
SE
• Oseltamivir: GI discomfort, nausea (alleviated when taken with food)
• Zanamivir: airway irritation (avoid in severe asthma, COPD)
Amantadine, Rimantadine
- Ion channel blockers -> prevent viral uncoating
- 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
2012-2013 Influenza Season
• Amantadine & rimantadine are NOT effective for the treatment or prevention of the currently circulating strains of influenza A.
- 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
• Rimantadine IS metabolized before elimination in urine
SE
• Amantadine: CNS (~10%) (insomnia, dizziness, ataxia leading to hallucinations, seizures)
• Rimantadine: fewer problems
• Both: GI intolerance
CI
• Amantadine should be monitored in psychiatric patients, cerebral atherosclerosis, renal impairment, epilepsy
• Pregnancy, nursing (FDA Category C)
- Up to 50% individuals are naturally resistant
- Cross-resistance between drugs occurs
Ribavirin
- Synthetic guanosine analog
- Active against broad spectrum of RNA & DNA viruses (eg, RSV, HCV, Lassa fever)
- Commonly used in combination with interferon a for the treatment of HCV
- Converted to ribavirin-triphosphate which inhibits guanosine triphosphate formation and prevents viral mRNA capping.
- Inhibits RNA-dependent RNA polymerase resulting in inhibition of viral protein synthesis
PK
• Oral, IV, & aerosolized
• Distribution significantly prolonged in RBC (16-40 days)
SE
• Dose-dependent transient anemia (can bind to RBC)
• GI (nausea, anorexia)
• CNS (fatigue, headache, insomnia)
CI
• Pregnancy (FDA Category X)
• Negative pregnancy tests required before treatment and monthly during treatment of female patients or female partners of male patients
Interferon a
• a and B produced by many cell types, y by immune cells (T cells)
- 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
- Cellular uptake and metabolism by liver & kidney
- Usually pegylated to improve PK profile
SE
• Flu-like (fever, chills, myalgias & GI disturbances)
• Fatigue & mental depression
- Interferes with hepatic drug metabolism. Can cause toxic accumulation of theophylline.
- May potentiate zidovudine induced myelosuppression
Tx
• HCV (in combination with ribavirin)
• HBV, condyloma acuminata, hairy-cell leukemia, Kaposi’s sarcoma
Lamivudine, Entecavir
- Nucleoside/nucleotide analogs. Must be phosphorylated by cellular enzymes to triphosphate (active) form
- Actions are suppressive rather than curative
LAMIVUDINE
• 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
• 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
• Renal function must be assessed and drugs with renal toxicity avoided
• Monitor after discontinuation in case of exacerbation of severe hepatitis
Boceprevir, Telaprevir
- Used in the treatment of HCV in adult patients who have been previously untreated or failed treatment with interferon a and ribavirin
- Administered in combination with interferon a and ribavirin
• Bind reversibly to nonstructural protein 3 (NS3) serine protease and inhibit replication of HCV
SE • fatigue • anemia • nausea • headache • dysgeusia
Acyclovir
- 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
- CMV is resistant at clinically achievable levels (does not encode thymidine kinase)
- Valacyclovir = prodrug of acyclovir
- 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 resistance, PK
• Resistance is rare in immunocompetent host
• Cross resistance to other ‘cyclovirs’ does occur
Occurs by:
• Altered or deficient thymidine kinases
• Altered viral DNA polymerase with decreased affinity for acyclovir
PK
• IV, oral or topical
• Valacyclovir has greater oral bioavailability than acyclovir
• Partially metabolized thus can accumulate with renal failure
SE
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
- Phosphorylated by viral (UL97) and cell kinases
- DNA chain terminator & DNA polymerase inhibitor
RESISTANCE
• Reduced intracellular phosphorylation
• Mutations in phosphotranferase (UL97), or viral DNA polymerase
PK
• Ganciclovir (IV)
• Valganciclovir (oral) undergoes rapid hydrolysis in intestine & liver to ganciclovir
• Excretion via urine
SE
• Myelosuppression
• Severe dose-dependent neutropenia
CI
• Pregnancy (FDA Category C)
Cidofovir
- 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
• DNA chain terminator & DNA polymerase inhibitor
RESISTANCE
• Mutations in viral DNA polymerase
PK
• IV, intravitreal & topical
• Must be co-administered with probenecid (blocks renal tubular secretion)
SE
• Nephrotoxicity
Penciclovir
- Active against HSV-1, 2 and VZV
- Used for the topical treatment of HSV (cold sores)
- Monophosphorylated by viral thymidine kinase
- Further phosphorylation occurs to give active triphosphate form
- Inhibit HSV DNA polymerase / chain terminator
RESISTANCE
• Low occurrence clinically
PK
• Topical only
SE
• Dermatologic: mild erythema
Trifluridine
• Effective against HSV-1, 2, and vaccina virus
• Drug of choice for HSV keratoconjunctivitis and
recurrent epithelial keratitis
• Triphosphate form incorporated into viral DNA causing fragmentation
PK
• Ophthalmic ointment (too toxic for systemic)
• t1/2 = ~12 min (apply frequently)
SE
• Transient irritation of eye & palpebral (eyelid) edema
Foscarnet
- Organic analog of inorganic pyrophosphate
- DOES NOT require phosphorylation!!
- Used for CMV retinitis in immunocompromised patients, acyclovir-resistant HSV & CMV retinitis & ganciclovir-resistant CMV & VZV
• 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
SE
• Nephrotoxicity
• Electrolyte disturbances (Ca2+, Mg2+, K+, PO43-)
• Anemia,
• Genital ulceration (mainly men)
• CNS: hallucinations, seizures, headache (25%)
NRTIs
• Analogs of native ribosides (lack 3’OH)
• Phosphorylated by cellular enzymes and incorporated into viral DNA by reverse transcriptase
• Lack of 3’OH terminates DNA elongation
ie. they are competitive inhibitors of reverse transcriptase
• Most have activity against HIV-2 as well as HIV-1
RESISTANCE
• Emerges rapidly if used alone
• Most common mutation at viral codon 184: lamivudine (restores sensitivity to zidovudine & tenofovir)
• Cross-resistance between agents of same analog class can occur
PK
• Dosage adjustments required with renal insufficiency
SE
• If more than one NRTI given toxicities may overlap
• AE mainly due to inhibition of mitochondrial DNA polymerase: peripheral neuropathy, myopathy, lipoatrophy & lactic acidosis
• Pancreatitis, myelosuppression & cardiomyopathy can also occur
• Liver toxicity is rare but fatal (lactic acidosis, hepatomegaly with steatosis).
• Zidovudine & stavudine may be particularly associated with dyslipidemia & insulin resistance
DRUG INTERACTIONS
Didanosine & tenofovir
• Tenofovir increases plasma didanosine levels ~60%.
• Doses of didanosine have to be reduced.
• NRTIs are not generally metabolized by cytochrome enzymes
Zidovudine (ZDV, AZT)
- Thymidine analog. Oral
- Penetrates well across BBB
- Dosage adjustments required in patients with cirrhosis
SE
• Bone marrow suppression (neutropenia, anemia)
• GI intolerance, headaches, insomnia
CI
• Toxicity potentiated by coadmin. of probenecid, acetaminophen, lorazepam, indomethacin & cimetidine.
• Stavudine & ribavirin activated by same pathways (might reduce active levels of zidovudine)
