Fever Headache Stiff neck Seizures Partial paralysis Stupor Coma

Antivirals Flashcards by Quynh Tran

Viral

Host Cell Killing

Interfere w/ host cell macromolecular synthesis
Decline of plasma membrane function
Failure of lysosomal membranes
Cell lysis

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Antiviral

Targets

Goal to block viral replication only in infected cells.

Adsorption, penetration, uncoating
- Amantadine ⇒ ⊗ uncoating of influenza
- Gamma globulins against specific Ag on cell surface ⇒ modify infection
  - Ex. Measles
Replication of nucleic acids
- Catalyzed by enzymes not present in normal cells
- Nucleic acid analogues ⇒ ⊗ replication
  - Ex. Acyclovir
Integration of viral genome
- Viral integrase vs host integrase
- Target of HIV drugs, covered later
Viral mRNA synthesis
- Viral vs host RNA polymerases
- Some viral mRNA capped at 5’ end by viral enzymes
- Ribavirin ⇒ ⊗ this step
  - Nucleoside analogue
Translation of viral mRNA
- ⊗ by interferons
Viral morphogenesis
- Large precursor viral proteins cleaved by virus specific proteases
- ⊗ by HIV drugs
Viral escape
- ⊗ by Neuraminidase inhibitors
  - Ex. Zanamivir, Oseltamivir

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Influenza

Pathogenesis

Hemagglutinin ⇒ binds to sialic acid on target cell
- Faciliates endocytosis
- Binding on new virus after replication prevents virus from separating from parent cell
M2 protein ⇒ ion channel required for uncoating
Neuraminidase ⇒ cleaves sialic acid
- Allows new virus to be separated from target cell

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Uncoating Inhibitors

Amantadine & Rimantadine

⊗ M2 proton channel in viral envelope
- ⊗ uncoating
- ⊗ viral replication @ early stage

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Amantadine & Rimantadine

Indications

Treat influenza A
Can alleviate sx if given within first 48 hrs
Can be used prophylactically
Does not prevent Ab development w/ vaccine
No longer recommended in US d/t widespread resistance

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Amantadine

Pharmacokinetics

Is not metabolized ⇒ almost all excreted into urine changed

Dose adjustment needed for renal impairment

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Amantadine

Adverse Effects

Readily crosses BBB
- Causes release of dopamine from CNS neurons
Neurological side effects:
- Lightheadedness
- Difficulty concentrating
- Nervousness / anxiety
- Insomnia
May be used during initial therapy for Parkinson’s disease

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Rimantadine

Pharmacokinetics

Extensively metabolized before renal excretion

Dose adjustments not necessary until creatinine clearance

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Rimantadine

Adverse Effects

Lower risk of CNS adverse effects

May cause ataxia or livedo reticularis (netlike pattern of reddish-blue skin discoloration)

Is not used for Parkinson’s

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Release Inhibitors

Zanamivir (Relenza) & Oseltamivir (Tamiflu)

⊗ Neuraminidase
- ⊗ cleavage of sialic acid by newly synthesized virions
- ⊗ budding from target cell
- Virus remains tethered to parent cell

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Zanamivir & Oseltamivir

Indications

Active against influenza A and B
- Works best when given early
↓ time to improvement in sx by one day
↓ in influenza-related complications
Effective prophylactically
Oseltamivir ⇒ drug of choice for treatment and prevention of bird flu
- Resistant strains have been identified
- H1N1 epidemic in 2009

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Oseltamivir

Pharmacokinetics

Ethyl ester prodrug
Well-absorbed in GI tract
Bioavailability 80% after desterification
Excreted unchanged in the urine

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Oseltamivir

Adverse Effects

Nausea, vomiting, and headache in 15%

↑ risk of psychiatric disturbances and renal events

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Zanamivir

Pharmacokinetics

Poor oral bioavailability
Given as dry powder that is inhaled
< 20% absorbed systemically
90% excreted unchanged in urine

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Viral Replication

Inhibitors

Acyclovir, Valacyclovir, Famciclovir

Nucleoside analogues
- Mechanism similar for all 3 drugs
Phosphorylated by viral thymidine kinase
- 200x greater affinity for viral enzyme than mammalian enzyme
- Resistance d/t alterations in viral thymidine kinase
Acyclovir-monophosphate → acyclovir-triphosphate by cellular kinases
Acyclovir-℗₃
- Acts as substrate for viral DNA polymerase ⇒ ⊗ DNA polymerase
- Incorporated into DNA ⇒ terminates chain elongation

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Keratitis

Inflammation of the cornea.

Causes sudden and severe pain, blurred vision, or corneal lesions.

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Herpes Encephalitis

Fever
Headache
Stiff neck
Seizures
Partial paralysis
Stupor
Coma

Acyclovir, Valacyclovir, Famciclovir

Indications

Herpes keratitis
- Topical acyclovir mostly
- May be given PO if eye is sensitive
- Trifluridine also used topically
  - Unacceptable toxicity if used systemically
Herpes encephalitis
- Begin Acyclovir therapy immediately after biopsy
- Discontinue if biopsy negative for Herpes
Primary and recurrent genital herpes
- Herpes simplex type 2 most common cause
- Topical used for mild disease
  - Not effective for recurrent herpes
- PO used for more serious disease
  - Can prevent recurrence for up to 1 year
  - Protective effect disappears when drug is stopped
Mucocutaneous infections
- Acyclovir IV used in immunocompromised pts
Varicella-zoster
- Used in immunocompromised pts

Acyclovir

Pharmacokinetics

Given IV, PO, or topically
- Systemic absorption minimal w/ topical
15-30% bioavailability w/ PO
- Prodrug valacyclovir has greater bioavailability
Widely distributed in tissues
Metabolized to a small extent
Eliminated by glomerular filtration and tubular secretion

Acyclovir, Valacyclovir, Famciclovir

Adverse Effects

Obstructive crystallin nephropathy if not properly hydrated

Cytomegalovirus Retinitis

Treatments

Ganciclovir
Foscarnet
Cidofovir

Ganciclovir

MOA

Similar structure to acyclovir w/ additional hydroxymethyl group
Same MOA as acyclovir
100x more active against CMV than acyclovir

Ganciclovir

Indications

CMV retinitis & other viral manifestations

Ganciclovir + anti-CMV Ab ⇒ CMV PNA in renal transplant pts on immunosuppressants
- Significant improvement in survival rate

Ganciclovir

Pharmacokinetics

Oral availability very low
- Used for maintenance treatment
- Valganciclovir ⇒ prodrug that can be used PO
IV used for acute treatment
Ocular implant used for retinitis

Ganciclovir Adverse Effects

* **Bone marrow suppression** ⇒ most common * **CNS effects** ⇒ 5-15% * **Renal toxicity** * Only used to treat serious CMV infections

Foscarnet MOA

* **Phosphonate derivative** * **⊗ DNA polymerase & HIV reverse transcriptase** * Binds pyrophosphate site on enzymes

Foscarnet Indications

* **Cytomegalovirus retinitis** * In ganciclovir resistant disease * In pts unable to tolerate ganciclovir * **Some activity against Herpes**

Foscarnet Adverse Effects

* **Reduced renal function** * More expensive and generally less well tolerated than ganciclovir

Cidofovir MOA

* Nucleotide analogue that **mimics deoxycytidine monophosphate** * Does not require viral kinases for phosphorylation

Cidofovir Indications

* Alternative for CMV retinitis * Herpes infections resistant to acyclovir

Cidofovir Adverse Effects

**Nephrotoxicity** Must be given IV w/ probenecid (⊗ renal uric acid tubular transport)

SARS-CoV-2

* **⊕-sense ssRNA virus** * Codes for a **RNA replicase** (RNA-dependent RNA polymerase) * Makes a complementary ⊖ strand of RNA * Reads ⊖ RNA to make ⊕-sense RNA copy & small pieces of ⊕-sense mRNA for viral structural proteins

Remdesivir MOA

* **Adenosine analogue** * Inserts into RNA chain resulting in conformational changes * Prevents RNA from entering RNA dependent RNA polymerase

Remdesivir Indications

* Approved by FDA for emergency use * **Treat COVID-19, including all hospitalized pts** * Median recovery time decreased by 5 days * Overall odds of clinical improvement at day 15 greater in treated group

Remdesivir Adverse Effects

* **↑ Liver enzymes** * **Infusion related reaction** * Low BP * N/V * Sweating * Shivering

Ribavirin MOA

_Mixed mechanism of action:_ * **Competes with GTP and ATP** ⇒ ⊗ RNA polymerase * **⊗ inosine monophosphate dehydrogenase** ⇒ depletes virally infected cell of GTP * **⊗ N7 methyl transferase** ⇒ ⊗ capping of mRNA Development of resistant strains less likely.

Ribavirin Indications

* Active in tissue culture against 85% of all animal viruses studies * Is not toxic to cells * Uses * Used as an aerosol for **RSV** * In combo w/ interferon for **Hep C** * **Influenza**

Ribavirin Adverse Effects

* Aerosol for RSV ⇒ **upper airway irritation** * Combo w/ IFN for Hep C ⇒ **hemolytic anemia** * **Teratogenic**

Fomivirsen

* Second-line treatment for **CMV retinitis** * An **anti-sense mRNA** for a protein necessary for viral replication

Interferons Overview

* Viral nucleic acids ⇒ de-repression of host genes ⇒ induction of IFN production * IFN released into extracellular space ⇒ binds to receptors on nearby cells * _IFN induces proteins that ⊗ viral replication_ * Induces a protein kinase ⇒ ⊗ initiation factor ⇒ **⊗ viral protein synthesis** * Activates cellular endonuclease ⇒ **degrades viral mRNA** * Activates phosphodiesterase ⇒ degrades terminal nucleotides of tRNA ⇒ **⊗ peptide elongation**

Interferon Treatment

* Glycoprotein ⇒ give SubQ or IM * Indications: * **Chronic Hep B and C** ⇒ most common * Combo w/ ribavirin for Hep C ⇒ synergistic effects w/ decreased replapse * **Hairy cell leukemia** * **Kaposi's sarcoma 2/2 AIDS** * **Genital warts** (condyloma acuminatum) * **Prevent dissemination of herpes zoster** in cancer pts * Topical admin in combo w/ other antivirals for **herpes keratoconjunctivitis**

Interferons Adverse Effects

**Neutropenia** Results in flu-like sx, fever, chills, fatigue.