COVID-19 Pharmacology

SARS-CoV-2

-Coronaviridae family

-Host cell entry via ACE2 receptors

-Enveloped ssRNA virus

-Droplet transmission (also contact, airborne)

pathogenesis of COVID-19

1) coronavirus infects lung cells

2) immune cells, including macrophages, identify the virus and produce cytokines

3) cytokines attract more immune cells, such as white blood cells, which in turn produce more cytokines, creating a cycle of inflammation that damages the lung cells

4) damage can occur through the formation of fibrin

5) weakened blood vessels allow fluid to sleep in and fill the lung cavities, leading to respiratory failure

early phase and pulmonary phase

-viral replication of SARS-CoV-2

-antivirals

stop viral replication

What is the goal in early phase and pulmonary phase of covid?

hyperinflammation phase

-dysregulated immune/inflammatory response to SARS-CoV-2 leads to tissue damage

-corticosteroids

-anti IL-6

-JAK/STAT inhibitors

immune suppressive/anti-inflammatory

What is the goal of hyperinflammation phase of covid?

antivirals

prevent viral replication

antiviral agents

-Nirmatrelvir/Ritonavir (Paxlovid)

-Remdesivir (Veklury)

-Molnupiravir

immunomodulatory agents

-corticosteroids

-IL-6 inhibitors

-JAK inhibitors

corticosteroids in covid

Dexamthasone

IL-6 inhibitors in covid

-Tocilizumab

-Sarilumab

JAK inhibitors

-Baricitinib

-Tofacitinib

Ritonavir-boosted Niramatrelvir (Paxlovid)

-oral

-within 5 days of symptom onset

-renal clearance

-DDIs (BBW)

Nirmatrelvir MOA

protease inhibitor that is active against MPRO, a viral protease (highly conserved) that is essential for viral replication by cleaving polyprotein precursors → inhibition of viral replication

Ritonavir MOA

strong CYP3A4 inhibitor → pharmacokinetic booster (increase nirmatrelvir half-life & concentrations to target therapeutic range)

AEs of Ritonavir-Boosted Nirmatrelvir (Paxlovid)

-Taste disturbances (dysgeusia)

-diarrhea

-Viral rebound?

Remdesivir (Veklury) MOA

Selective inhibitor of the viral RNA-dependent, RNA polymerase (RdRp)→chain termination → ↓ viral RNA production Broad-spectrum antiviral (in vitro activity against multiple RNA viruses, inc. SARS-CoV-1, Ebola)

PK of Remdesivir (Veklury)

-IV administration

-Long half-life, high barrier to viral resistance

AEs of Remdesivir (Veklury)

-GI symptoms (nausea), ↑ in prothrombin time, rash, ↑ serum glucose, ↑ SCr

-↑ LFT

-Bradycardia

-Hypersensitivity & infusion reactions

Molnupiravir (Lagevrio) MOA

nucleoside analog uptake by viral RNA-dependent RNA-polymerase → lethal mutagenesis→ inhibits viral replication

Molnupiravir (Lagevrio)

-Prodrug of cytidine nucleoside analogue → antimetabolite

-Reduces risk of hospitalization and death in people with mild or moderate COVID-19 at high risk for severe COVID.

-Clinical trial stopped early due to clear benefit. Risk of AE similar to placebo.

-First COVID-19 oral treatment, taken early in the course of infection to reduce severity. Now only if Paxlovid or remdesivir are not available

AEs of Molnupiravir (Lagevrio)

-Hypersensitivity reactions

-Diarrhea

-nausea

-dizziness

Dexamethasone MOA

mitigates COVID-19-induced systemic hyperinflammatory response that leads to lung injury and multisystem organ dysfunction

MOA of Tocilizumab (Actemra) and Sarilumab (Kevzara)

Anti-IL-6 receptor mAb

IL-6

-is a pleiotropic, pro-inflammatory cytokine produced by a variety of cell types, including lymphocytes, monocytes, and fibroblasts

-one of the MAIN drivers of cytokine storm

tocilizumab + dexamethasone

IV in hospitalized patients

Janus Kinase Inhibitors

Targeted synthetic oral small molecule that disrupts JAK-STAT signaling pathway →inhibition of inflammatory gene transcription

mAb cocktails anti-SARS-CoV-2-S protein

-Bind to SARS-CoV-2 spike protein →prevent virus attachment and entry

-activity depends on the circulating variant

Pemgarda (pemivibart)

-EUA 2024

-COVID-19 pre-exposure prophylaxis in immunocompromised individuals