Antivirals Flashcards
Walk through the viral life cycle.
- receptor recognition
- attachment
- Penetration
- Entry
- Uncoating
- genome replication
- RNA+protein synthesis
- assembly and maturation
- Release
Drugs used in tx of respiratory viral infections? [in general]
Neuraminidase Inhibitors - Oseltamivir (Tamiflu), Zanamivir [preventing viral release] – used for prophylaxis and tx
Inhibitors of Viral uncoating - Amantadine, Rimantadine [ion channel blocker]
Synthetic Guanosine Analog - Ribavirin
Neuraminidase Inhibitors in tx of influenza?
Oseltamivir (Tamiflu) and Zanamivir
[-amivir = neuramidase inhibitor]
• 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 - reduce course and length of infecton
**these are the only drugs that work in preventing the flu
MOA - neuraminidase cleaves receptors to release virions from cell therefore if they are inhibited there is no virion release from the cell, neuraminidase also requires sialic acid substrate (on host cells) for neuraminidase and inhibitors block that sialic acid substrate. Replication and spread of the viron is halted.
Administration
• Oseltamivir: orally active prodrug (hydrolyzed in liver)
• Zanamivir: NOT orally active (inhaled, intranasal) [low Bioavailability when administered orally]
Adverse Effects
• Oseltamivir: GI discomfort, nausea (alleviated when taken with food) [better option in pts with asthma and COPD}
• Zanamivir: airway irritation (via route that it is administered -avoid in severe asthma, COPD)
*safe in children - Zanamivir is harder to give to younger children due to mode of administration, but if they can be given, both are safe
Ion channel blockers that work exclusively active to influenza A virus?
Inhibitors of Viral uncoating – Amantadine and Rimantadine
*not recommended as first-line treatment due to resistance and are not effective to the current circulating strains of influenza A - up to 50% of individuals are naturally resistant (have not been used since 2006, but the thought is that if not used for a long time then resistance will be diminished - currently, not the drug of choice], cross-resistance may also occur
MOA - block viral membrane protein M2 which is a H+ channel blocking. The channel activity is required for fusion of viral with cell membrane to endosome [requirement for viral uncoating]. Only works with influenza A because B does not have this protein.
• 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
AE:
• Amantadine: CNS effects occur within 10% (insomnia, dizziness, ataxia leading to hallucinations, seizures)
• Rimantadine: fewer problems : fewer problems
• Both: GI intolerance
Contraindication - Amantadine should be monitored in psychiatric patients, cerebral atherosclerosis, renal impairment, epilepsy, pregnant and nursing mothers (FDA category C)
Synthetic guanosine analogs to treat influenza?
Ribavirin - purine/pyrimidine analog that prevents RNA/DNA synthesis
Active against broad spectrum of RNA and DNA viruses and is commonly used in combination with interferon a for the tx of HCV – one of first line tx for Hep C.
MOA - converted to ribavirin-triphosphate which inhibits guanosine triphosphate formation - this is its major mechanism b/c if you replace guaninine in the virus you reverse action of the drug. It also prevents viral mRNA capping. Lastly it inhibits RNA-dependent RNA polymerase there is inhibition of viral synthesis.
- Oral IV & aerosolized Oral, IV, & aerosolized
- Distribution significantly prolonged in RBC (16-40 days)
Adverse Effects:
• Dose-dependent transient anemia (can bind to RBC) -reversible b/c it binds RBC
• GI (nausea, anorexia)
• CNS (fatigue, headache, insomnia)
**do not use in pregnancy (category X) – a negative pregnancy test is required prior to treatment and use – THE MOST TERATOGENIC DRUG
Drugs used in tx of hepatic viral infections? [in general]
• Hepatitis A, B, C, D & E
• HBV and HCV are most common causes of chronic
hepatitis, cirrhosis & hepatocellular carcinoma
HBV - cannot cure, but you can tx symptoms
HCV - tx more effectively compared to HBV
Interferon - Interferon alpha
Nucleotide / Nucleoside Analogs - Lamivudine, Entecavir, Ribavirin
Protease Inhibitors - Boceprevir, Telaprevir [newest drugs]
*most of these drugs work on RNA/DNA synthesis inhibition
Interferon to treat hepatitis?
Interferon - Interferon alpha
Interrupts RNA/DNA synthesis
IFN-a – this is a naturally occurring, inducible glycoprotein/cytokine
IFN-gamma - produced by immune cells (T cells)
MOA - used in innate immune response by inhibiting RNA and DNA synthesis by activating/inducing protein expression that inhibits viral infection - there is no directly targeting of the viral gene products directly
• Not orally active (IV, subcutaneously, intralesionally - parenterally)
• Cellular uptake and metabolism by liver & kidney
• Usually pegylated to improve PK profile – make it bigger prolonging action and improving pharmacokinetics (needs to be administered less often)
[natural proteins do not have a long half-life]
Adverse Effects –
• Flu-like (fever, chills, myalgias & GI disturbances)
• Fatigue & mental depression
• Interferes with hepatic drug metabolism. Can cause toxic
accumulation of theopyhylline. [theophylline has a small therapeutic window which is why it is of concern]
• May potentiate zidovudine induced myelosuppression
Clinical Applications
• HCV (in combination with RIBAVIRIN)
• HBV (administered alone)
• condyloma acuminata, hairy-cell leukemia, Kaposi’s sarcoma
Nucleoside/nucleotide analogs to treat Hepatitis?
Lamivudine, Entecavir
These medications are phosphorylated by cellular enzymes to triphosphate (active) form which then acts as a suppressive agent rather than curative agent.
Lamivudine - effective against hep B and HIV, the triphosphate form inhibits HBV and HIV RT. The monophosphate form is incorporated into DNA (by HBV polymerase) resulting in chain termination. This medication is well tolerated with side effects including headache, dizziness, and GI complaints. – but not given if pt has both HBV and hep b?
Entecavir - effective against lamivudine-resistant strains of HBV and HIV. The phosphorylated form competes with natural substrates for viral polymerase thereby blocking RT activity. Pt needs to be monitored after discontinuation in case of hepatitis exacerbation as the infection cannot be cured, but rather symptoms are just controlled.
Protease inhibitors used for hepatitis?
Broceprevir or Telaprevir
Used in tx of HCV in adult patients who have been previously untreated or failed tx with IFN-a and Ribavirin. Administered in combination with IFN-a and Ribavirin.
MOA - binds reversibly to nonstructural protein 3 (NS3) serine protease and inhibit replication of HCV
AE - fatigue, anemia, nausea, headache, dysgeusia
General tx of herpes?
- Purine / Pyrimidine Analogs [Acyclovir, Valacyclovir, Cidofovir, Gancicl Ganciclovir, Valganciclovir, Penciclovir, Trifluridine]
- Foscarnet
Acyclovir
Go to drug for tx of Herpes that treats every form of herpes (with an exception of CMV). CMV is resistant as it does not encode thymidine kinase.
Treatment of choice for HSV encephalitis.
Commonly used for genital herpes infections (frequent cold sores) and prophylaxis for immunocompromised and transplant pts.
Valacyclovir = prodrug of acyclovir with better bioavailability
MOA - requires triple phosphorylation via the viral enzyme, so mutations in the viral enzyme there is no phosphorylation and resistance is present to acyclovir. [1st phosphate is added by herpes virus-encoded thymidine kinase, then host cell adds the 2nd and 3rd phosphate] Once all 3 phosphates are present, it competes with dGTP causing chain termination and inhibition of viral DNA polymerase.
Resistance - via altered/deficient thymidine kinase and altered viral DNA polymerase with decreased affinity for acyclovir
Given via IV, oral or topical. Valacyclovir has greater oral bioavailability than acyclovir itself. Partially metbaolized thus can accumulate with renal failure.
AE dependson route of administration –
IV administration - acute renal failure
Oral administration - headache, diarrhea, nausea, vomiting
Topical administration - local irritation
Ganciclovir
2nd line drug to Acyclovir, but the DRUG OF CHOICE for CMV retinitis and prophylaxis in immunocompromised
Uses viral enzyme [UL97] for 1st phosphorylation then host kinases for 2nd and 3rd phosphorylations. IT has the same action of Acyclovir where it acts as a DNA chain terminator and DNA polymerase inhibitor.
Ganciclovir - IV admin
Valganciclovir - oral admin that undergoes rapid hydrolysis in intestines and liver to ganciclovir
Excretion via urine
AE - myelosuppression and severe dose-dependent neutropenia – problematic when pt when is immunocompromised
*do not use in pregnancy - category C
Cidofovir
Major drug used in tx of CMV-induced retinitis and HIV/AIDS. Unlike Acyclovir and ganciclovir, it is not phosphorylated by viral kinases rather needs activation by host cell kinases. IT is also effective against HSV and ganciclovir resitsant HSV
Resistance - mtuations in viral DNA polymerase
PK - IV, intravitreal and topical admin, co-administered with probenecid which blocks renal tubular secretion
AE - nephrotoxicity
Penciclovir
Topical agent against herpes cold sores - most commonly used agent against HSV-1, 2, VZV
Needs viral thymidine kinase to be activated then 2nd and 3rd phosphorylations comes from the cell. It inhibits HSV DNA polymerase/chain terminator. It has low resistance as it is only used topically.
AE - only associated with topical administration (mild erythema)
Trifuridine
Effective against HSV-1, 2, vaccina virus.
DOC - HSV keratoconjunctivitis and recurrent epithelial keratitis
MOA - triphosphate form incorporated into viral DNA causing fragmentation
This is a TOPICAL OINTMENT (too toxic for system) with a half life of abotu 12 minutes therefore needs to be applied frequently.
AE - transient irritation fo eye and palpebral (eyelid) edema
