Antivirals Flashcards
Most antivirals are ….. (Type)
nucleoside analog; inhibit replication of viral nucleic acid
Selective toxicity comes from the advantage of differences …..?
in affinity of viral and host cell replicative enzymes for antiviral agents (we choose the antivirals that have more affinity to viruses replicative enzymes)
Most antivirals chemotherapies are? (Drugs or prodrugs)?
Prodrugs
How antivirals become active?
antivirals prodrugs must be phosphorylated (we must add phosphate) by viral or host cell enzymes in order to become active
why the therapeutic index of antiviral chemotherapies is more narrower than for antibacterial medications?
it’s difficult to interfere with the viral protein synthesis without disturbing the host cellular pathways
why it’s difficult to interfere with the viral protein synthesis without disturbing the host cellular pathways?
because viruses use the host cell metabolic machinery for replication and as a result host toxicity of antiviral agents is higher than antibacterial agents
Antiviral chemotherapies are predominantly (static or cidal)?
Virustatic
Because antiviral chemotherapies are predominantly virustatic; mention 3 results
- They do not eradicate the virus and only inhibit the replication of the virus (not curative)
- The current antiviral agents are ineffective to eliminate latent virus
- They restore the immune system homeostasis to clear the viral infection (for e.g. virus cells are 1milion, our immune system kills 800,000 so antivirals restore homeostasis to fight viruses)
increased risk of viral resistance is associated with ??
long-term antiviral treatment
what is the most effective way to prevent viral infection?
vaccination
why vaccination is not possible all times
either due to
- there’s no vaccine
or that
- the available vaccine is not useful (e.g. resistance)
because vaccine is not possible all the time, antivirals can be used as …?
chemoprophylaxis agent
Drug that prevents attachment?
Enfuvirtide
Vaccines
Drug that prevents uncoating?
Amantadine
Drug that prevents protein synthesis by host cell ribosome?
IFN-alpha2a
Drug that prevents the synthesis of viral DNA?
acyclovir
Drug that prevents budding?
Zanamivir
Influenza viruses are? (genome & mutations)
RNA viruses & undergo frequent mutations
Antiviral agents used to treat influenza viruses include:
Amantadine
Oseltamivir and Zanamivir (Neuraminidase inhibitors)
Amantadine (Symmetrel)
(Therapeutic uses)
- today use, what type of influenza it targets, time of giving the drug and effect, other use
- Very rare use today because of resistance (nearly 100%)
- prevent & treat influenza type A virus
- has no activity against type B (Type B should be given Neuraminidase inhibitors)
- Should be given within 48 hours of the onset of symptoms to be effective (after 48 hours it will be ineffective)
- decreases the duration of viral symptoms by about 2 days
- also used to treat Parkinson’s disease (PD); It reduces tremor & dyskinesia in about 70% of patients with PD but Amantadine effectiveness fades (sometimes quickly)
Amantadine (Symmetrel)
MOA
- not a nucleoside analog
- It blocks influenza A M2 ion channel protein so it reduces the influx of protons (H+) => ultimately inhibits viral capsule disassembly
- inhibits uncoating
- Does not bind to the influenza B M2 channel because of different amino acid sequence
Amantadine (Symmetrel)
Pharmacokinetics
- orally available & well absorbed from the GI tract
- Eliminated by the kidney (dose must be reduced in renal insufficiency)
How Amantadine is eliminated?
by the kidney (dose must be reduced in renal insufficiency)
Amantadine dose must be ____in renal insufficiency, becasue _____
reduced
it’s eliminated by the kidney
Amantadine (Symmetrel)
Adverse effects
- Common: Tremor, nervousness, confusion and dizziness
- Peripheral edema (Ankle edema)
- Livedo reticularis
Neuraminidase Inhibitors drugs
Oseltamivir (Tamiflu)
Zanamivir (Relenza)
Neuraminidase Inhibitors (Therapeutic uses); uses, types of influenza, time given, resistance
- used for the prevention and treatment of influenza caused by
influenza A and B virus within 2 days of the onset of flu symptoms - Oseltamivir-resistant is more common than zanamivir
Neuraminidase Inhibitors
Pharmacokinetics of Oseltamivir)(absorption, bioavailability, activation
- Well absorbed from GIT (bioavailability > 0.8)
- A prodrug & hydrolyzed by the liver enzymes to its active metabolite
Neuraminidase Inhibitors
Pharmacokinetics of Zanamivir)(absorption, availability
- Extremely poor absorption form GIT
- Available as a dry powder for oral inhalation
Neuraminidase Inhibitors
Adverse effects
- Well-tolerated (nausea/vomiting and headache)
- Bronchospasm
- They have less CNS adverse effects compared to amantadine
Neuraminidase Inhibitors
MOA
- not a nucleoside and interfere with replication
- Competitive inhibitor of neuraminidase enzyme
what happens when Neuraminidase inhibitors inhibits neuraminidase enzyme?
they prevent the cleave of sialic acid residues
on the surface of the infected host cell and thus prevents the release of progeny virions from infected cells
Herpes Simplex Virus (HSV)
Causes infection of the genitalia, mouth, skin,
meninges and brain
Varicella-Zoster Virus (VZV)
Causes chickenpox in children & herpes zoster (shingles) in adults
Cytomegalovirus (CMV)
- not common but life-threatening for the
immunocompromised patients (e.g HIV- patient) - It causes retinitis with extensive haemorrhage
Antiviral chemotherapies for herpesvirus (Nucleoside Analogs)
Acyclovir
Valacyclovir
Ganciclovir
Antiviral chemotherapies for herpesvirus (Non-Nucleoside Analogs)
Foscarnet
Acyclovir (Zovirax)
Therapeutic uses
- Routes: topical, oral and IV
- Antiviral spectrum of acyclovir: HSV»VZV»_space;»CMV (more potent to HSV)
- not used for CMV because high dose is required = increase the risk of side effects
Antiviral spectrum of acyclovir
HSV»VZV»_space;»CMV
why acyclovir is not used in cytomegalovirus?
because high dose is required = increase the risk of side effects
Acyclovir (Zovirax)
Pharmacokinetics
- Widely distributed in the body include CSF
- Metabolized by liver and eliminated by the kidneys
- Has low oral bioavailability
since acyclovir has low oral bioavailability, what was the solution?
producing valacyclovir, which is an L-valyl ester prodrug with 5-fold greater oral bioavailability compare to acyclovir and it is rapidly converted to acyclovir by liver
Acyclovir (Zovirax)
Adverse effects
- Reversible renal dysfunction due to acyclovir-induced crystalline nephropathy
- Neurotoxicity (tremor and seizure)
Acyclovir targets which nucleotide?
guanine
what’s the prodrug of acyclovir?
valacylovir
Acyclovir (Zovirax)
Structure
Acyclovir is acyclic nuecloside produrg, it lacks a 3’-OH group on side chain.
Acyclovir (Zovirax)
MOA
- when it enters an infected cell; it’s converted by viral thymidine kinase (TK) to acyclo-GMP
- host cell TK converts acyclo-GMP to acyclo- GDP and finally acyclo-GTP inside infected cell
- Acyclo-GTP inhibits replication of viral DNA by mechanisms:
3a. Acyclo-GTP is incorporated into viral DNA by viral DNA polymerase & causes
chain termination
3.b Acyclo-GTP inhibits viral DNA polymerase
explain acyclovir selective toxicity?
Affinity for viral TK is 200-fold greater than for mammalian TK
explain resistance to acyclovir?
viral thymidine kinase (TK) deficiency
Ganciclovir
Therapeutic uses)(Routes, target viruses, toxicity
- Routes: oral, IV and ocular insert
- Has activities against all herpesviruses
- Due to its toxicity is restricted for treatment of CMV retinitis in immunocompromised patients and prevention of CMV in transplant patients
Restrictions of Ganciclovir
- Treatment of CMV retinitis in immunocompromised patients (ocular insert)
- Prevention of CMV infection in transplant patients
Ganciclovir
Adverse effects
Myelosupression (dose-dependent)
Non-Nucleoside Analogs for Herpes
Foscarnet
Foscarnet
Therapeutic uses)(virus targets, common use
- Has activity against all herpesviruses and HIV
- used mostly to treat immunocompromised patients with CMV and acyclovir–resistant HSV infections
Foscarnet
Pharmacokinetic
- It is not well absorbed by GIT, thus Usually foscarnet is given IV
- 80% eliminated unchanged by the kidneys
Foscarnet
MOA
- It is phosphorylated analog of formic acid, thus, phosphorylation by viral or host cell kinases is not required
- It directly Inhibits herpesvirus DNA polymerase and HIV reverse transcriptase
drug that directly Inhibits herpesvirus DNA polymerase and HIV reverse transcriptase
Foscarnet
Foscarnet
Adverse effects
Nephrotoxicity & electrolyte disturbances
