05/01/2022

Antiviral Drugs
“Drug Therapy of COVID-19”

Pharmacology 3 (PHL423)

What is Virus?
-A virus is Nucleic acid (DNA or RNA), surrounded by a protein coat.
- A virus cannot replicate alone.
-Viruses must infect cells and use their components to Replicate.
Often, they kill the host cell and damage to the host organism.

Covid-19

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Types of viruses:
Viruses consist of nucleic acid (RNA or DNA) enclosed in a protein coat

1. DNA viruses : Herpes, HBV,

chicken pox, cytomegalovirus (CMV)…..
2. RNA viruses : Covid-19 ,
influenza, mumps, measles, HCV &
poliomyelitis
DNA virus RNA virus
3. RNA Retrovirus : HIV (contains
reverse transcriptase enzyme).

Steps of Virus replication & enzymes involved

(targets for drug therapy)

1. Adsorption- penetration & uncoating; viruses enter

host cell.

2. Early protein synthesis: e.g., synthesis of viral RNA

& DNA polymerases.

3. Synthesis of RNA & DNA & coat proteins: by RNA

& DNA polymerases

4. Late protein synthesis by viral protease→ viral protein synthesis & processing →
mature virion core.

5. Assembly of formed nucleic acid & coat proteins into new viral particles (mature virion)
6. Release of new virus from host cell; facilitated by neuroaminidase

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Example:
COVID-19

Neuroaminidase

release of
nucleocapsid
Mature
Virion

Or Assembly

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Drug Mechanism Indications

Acyclovir Inhibits DNA polymerase Herpes simplex. H. zoster – chicken pox.

Remdesivir Inhibits RNA polymerase - Covid-19

Remdesivir, prodrug, analogue of adenosine nucleotide (FDA approval 2020 for COVID-19)
Favipiravir Favipiravir, prodrug, analogue of guanosine nucleotide (Approved in Japan 2014 for INF.A) - Influenza A & B.

Ritonavir/ Inhibits protease → inhibition of viral protein processing Covid-19

Lopinavir
HIV (+zidovidine)
Oseltamivir Influenza A & B
Inhibit neuroaminidase → ↓viral release
Zanamivir

Ribavirin Inhibits RNA dependent polymerase & m - RNA synthesis - Influenza A & B.
- HCV

Zidovudine Inhibit reverse transcriptase → inhibition of replication HIV (AIDs).

Interferon-α Inhibit viral penetration , translation, transcription, protein

processing, maturation & release HCV, HBV, HPV

Amantadine Inhibits penetration & uncoating -Influenza A

-parkinsonism.

Rifampicin Inhibit viral particles assembly Vaccinia or Variola

Virus (SmallPox).

Adverse effects of some Antiviral Drugs

1. Acyclovir: N&V, headache, confusion, Seizures, renal Stones, eye Stinging.

2. Ribavirin : Anemia - upper airway irritation (with aerosol) – teratogenic.

3. Zidovudine: myelosupression -flu like syndrome - cholestatic hepatitis.

4. Zanamivir/ Oseltamivir: N& V – nose & throat irritation (inhaled zanamivir).

5. Interferon-α: Flu-like symptoms, Alopecia, Arrhythmia, Neutropenia, Confusion, Depression, .

6. Amantadine: Insomnia –nausea- hallucination - livido reticularis.

7. Ritonavir/Lopinavir : GIT upset, metallic taste, parasthesias, QT-prolongation &

CYP3A4 & CYP2D6 inhibitors → Drug interactions.

8. Remdesivir : ↑ liver transaminases, headache, nausea…

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Drug Therapy of COVID-19

Objectives
To answer the following questions:

1. What is COVID-19? And its Virus?

2. What is Pathophysiology of COVID-19?
3. What are the different classes of drug therapy of anti-
COVID-19?
4. What is the targeted mechanisms of actions of anti-
COVID-19 drugs?
5. What are the guidelines (NIH, IDSA & NICE “Dec.2021”)
Recommendations toward anti-COVID-19 drugs?
6. What are the possible side effects and drug interactions of
anti-COVID-19 drugs?
7. What is the Egyptian Ministry of Health (MOH) Algorithm
for management of COVID-19?

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What is COVID-19?

- COVID-19 is COronaVirus Infectious Disease that emerged in

December 2019 and is caused by the SARS-CoV-2 virus (RNA virus).
- Most people infected with the virus will experience mild to moderate
respiratory illness and recover without requiring special treatment.
- However, some will become seriously ill & require medical attention.
- Older people and those with CVS disease, diabetes, chronic
respiratory disease, or cancer are more likely to develop serious
illness.
- Anyone can get sick with COVID-19 and become seriously ill or die at
any age (WHO, 2021).

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No. of people affected by COVID-19 worldwide is >263 Millions &

rapidly ↑ (WHO, Dec. 2021)
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COVID-19 Clinical Picture

Pulmonary

Cough
↓breath
Pneumonia
ARD, Fever

Nature Medicine , (2020)

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What is SARS-CoV-2 virus?

(RNA virus).

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What is Pathophysiology of COVID-19?

1. Antiviral
2.Immunomodulatory

3. Anti-inflammatory
4.Anticoagulants

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What are the different classes of drug

therapy of anti-COVID-19?

I. Antiviral Drugs

II. Immunomodulatory Drugs

III. Anti-inflammatory Drugs

IV. Anticoagulants Drugs

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• What is the targeted mechanisms of actions of anti-

COVID-19 drugs?
• What are the guidelines (NIH, IDSA & NICE “Dec.2021”)
Recommendations toward anti-COVID-19 drugs?
• What are the possible side effects and drug interactions
of anti-COVID-19 drugs?

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NIH, IDSA & NICE

Guidelines, Dec. 2021

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I. Antiviral Drugs

1.Remdesivir
2.Favipiravir
3.Ritonavir/Lopinavir
4.Antimicrobials with antiviral effect:
Chloroquine, Ivermectin, Nitazoxanide, Azithromycin
(Repurposing for Covid-19 treatment)

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Neuroaminidase

1
2. ↑endosomal pH
(endosome acidification
facilitates viral escape &
release of nucleocapsid)
2

3
Or Assembly

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Antiviral Drugs

Remdesivir Mechanism: Inhibits RNA polymerase

Remdesivir, prodrug, analogue of adenosine nucleotide (FDA approved)
Favipiravir, prodrug, analogue of guanosine nucleotide (NO FDA approveal)
Favipiravir
Use: Remdesivir is FDA approved to treat COVID-19 in hospitalized
adult and pediatric patients (aged ≥12 years and weighing ≥40 kg).
Side effects: (Both)↑ liver transaminases & ↑PT, Nausea, Hypersenstivity.
N.B. Favipiravir: muscle pain, edema, asthma attack, GIT upset, miscarriages.

Ritonavir/ Mechanism: Inhibits protease → ↓ viral protein processing

Lopinavir (Anti-HIV or AIDs)
Use:
NIH Guidelines recommends against the use of lopinavir/ritonavir for treatment of COVID-19 in
hospitalized (AI) and nonhospitalized patients (AIII).

Side effects: GIT upset, metallic taste, parasthesias, QT-prolongation &

Hepatotoxicity, CYP3A4 & CYP2D6 inhibitors → Drug interactions.

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Antimicrobial with antiviral effect

1. Chloroquine & hydroxychloroquine
Anti-malarial and Anti-ameabic

Mechanism in COVID-19:
(1) Interfere with ACE-2 receptor → inhibit viral entry
(2) ↑endosomal pH (endosome acidification facilitates viral escape & subsequent release of the nucleocapsid).
(3) ↓cytokine storm (Anti-inflammatory)

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Antimicrobial with antiviral effect

1. Chloroquine (CQ) & hydroxychloroquine (HCQ)
Mechanism and uses:
• Anti-amebic (tissue amoebicide in hepatic amoebiasis)
• Anti-malarial. (conc. in infected RBCs)
• Rheumatoid arthritis & SLE (Anti-inflammatory).
• Antiviral (Covid-19) see before………….

Adverse effects
1. GIT: nausea, vomiting, dyspepsia & abdominal pain.
2. Skin: pruritis, rash & discoloration. (CI. in psoriasis).
3. Eye: retinal degeneration – corneal opacities.
4. C.V.S.: quinidine like action & ↑QT interval
5. Hemolytic anemia: in G6PD-deficient subjects.
6. Drug interaction: CQ & HCQ are CYP2D6 inhibitors
and → ↓ antiviral Activity of Remdesivir

NIH Guidelines recommends against the use of chloroquine or hydroxychloroquine and/or

azithromycin for treatment of COVID-19 in hospitalized (AI) and nonhospitalized patients
(AIIa).

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Antimicrobial with antiviral effect

2. Nitazoxanide
Anti-protozoal

Mechanism:
(1)↓virus/cell fusion , (2)↓ Virus replication, (3)↓ RNA sensing, (4)↓IFN pathway →
↓cytokine storm , (5) inhibits oxidative phosphorylation ↓ATP → viral protein misfolding

NIH recommends against use of nitazoxanide for COVID-19, except in a clinical trial (BIIa).

3. Ivermectin
Mechanism:
(1)↓virus/cell fusion, (2) Interfere with ACE-2 Receptors,
(3) block importin receptor → inhibit import of viral protein
to host nucleus receptor → ↓ Virus replication
N. B. Ivermectin (Antifilarial):  GABA transmission (↑Cl- influx ) →worm paralysis

NIH:NO sufficient evidence to recommend either for or against its use COVID-19

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4. Azithromycin (AZ) “unique pharmacokinetic”

Mechanism in COVID-19:
1- AZ is a macrolide antibiotic protein synthesis inhibitor (50S)
with a broad G+ve & G-ve → ↓ risk of bacterial co-infection
2- AZ has anti-inflammatory & immunoregulatory effects
3- AZ accumulates within phagocytic cells that mostly migrate to the site of infection
/inflammation (e.g. lung) → modulate monocyte & macrophage action → ↓ inflammatory
damage, ↓ fibrosis and vascular remodelling (↓cytokine storm)
4- AZ has Antiviral effect : interfere with S-protein/ACE2 R binding, ↑endosomal pH as
CQ. &↑ antiviral genes & IFN →↑cellular antiviral response mediated by the IFN pathway.

RCTs for Non-hospitalized patients with mild-to-moderate COVID-19 managed

with azithromycin it did not reduce the risk of subsequent hospital admission or
death. The LANCET & JAMA. 2021 & Guidelines do not support the use of
azithromycin in patients with mild-to-moderate COVID-19. (Removed from
Egyptian MOH Algorithms)
inappropriate use of antibiotics leads to increased antimicrobial resistance

Adverse Effects: GIT upset, allergy, Hepatotoxic, ↑QT interval

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Drug interactions with Antiviral Drugs

Ritonavir/
Lopinavir
Ritonavir/Lopinavir
Chloroquine (CQ)
Chloroquine (CQ) & hydroxychloroquine
hydroxychloroquine (HCQ)
Azithromycin

May interact together or with other Also, CQ & HCQ → ↓ antiviral Activity
drugs ↑QT e.g. TCA, Antipsychotics, of Remdesivir (↓its conversion from
Azoles ………….. prodrug to active form ) ??!!

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II. Immunomodulatory Drugs

(To ↓ viral load)

1. Monoclonal Antibodies (Anti-CoV-2)

2. Convalescent plasma (CP)

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1. Anti-SARS-CoV-2 Monoclonal Antibodies

Monoclonal Antibodies (mAbs) against S-protein CoVid-19

“NEW TARGETs”

Casirivimab/Imdevimab
Double

Sotrovimab
Single

•Not renally excreted or metabolized by CYP450 enzymes→ No drug interactions

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Casirivimab/Imdevimab

Mechanism :
- Casirivimab/imdevimab are double recombinant human
monoclonal Antibodies (mAbs) to the spike (S) protein
of SARS-CoV-2. They bind to epitopes of the spike
protein Receptor Binding Domain (RBD) of SARS-CoV-2,
and thereby block binding to human ACE2 receptor.
→ ↓ Viral Load
- Also Bamlanivimab/ etesevimab have same mechnism.

Use: in mild-to-moderate COVID-19 patients aged ≥12 years

with positive SARS-CoV-2 who are at high risk for
progressing to severe COVID-19. Casirivimab 600 mg and
imdevimab 600 mg as a single IV infusion or SC.

Adverse Effects
SC Injection site reactions (12%) , IV Infusion-related reactions (1.5%), Pneumonia,
Hyperglycemia, Nausea, Vomiting, Dyspnea, Anaphylactic reactions.

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Sotrovimab
Single monoclonal Antibodies to the spike (S) protein of SARS-CoV-2.

Mechanism :
It binds to a conserved epitope on the spike protein receptor binding domain of SARS-
CoV-2 but does not compete with ACE2 receptor binding. It inhibits an undefined step
that occurs after virus attachment and before fusion of the viral and cell membranes

-MHRA approves Xevudy (sotrovimab), a COVID-19 treatment found to cut

hospitalisation and death by 79%
Use: Sotrovimab is the second to be authorised by the Medicines and
Healthcare products Regulatory Agency (MHRA) – is for people with mild to
moderate COVID-19 who are at high risk of developing severe disease. (2
December 2021)
-Among high-risk patients with mild-to-moderate Covid-19, sotrovimab
reduced the risk of disease progression. No safety signals were identified
N ENGL J MED 385;21 , November 18, 2021 500 mg IV
infusion.
Adverse Effects: Hypersensitivity, anaphylaxis (infusion-related reactions)

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2. Convalescent plasma
Previously used In epidemics of Influenza A (H1N1), SARS-CoV and MERS-CoV,
Mechanism:
- Transfusing convalescent plasma collected from patients who have recovered from a viral
illness, to transfer virus-neutralizing antibodies (NAbs) & confer passive immunity.
- Also, the immunomodulatory effects of plasma components could have benefits.

1. Antiviral effects of NAbs.

IgM and IgG against S-protein

2. Immunomodulatory:
-NAbs →↓autoantibodies,
cytokine storm, Th1/Th17 ratio, DCs
complement……..
-NAbs →↓ DCs→↑ IL-10 ….
3. Regulate coagulation& ↓Clot
(Neutralize COVID-19 induced↑APA)

NIH Guidelines: insufficient evidence to recommend either for or against the use
of high-titer COVID-19 convalescent plasma for the treatment of COVID-19
Side effects: (SAFE)
- Mild allergic reaction, nausea, skin erythema, and fever…. .
- V Rare, problems with the heart or lungs, or infection. JAMA. 2020;324(5):524.
CP did not reduce the risk of intubation or death in COVID-19. CP Transfusion with unfavorable antibody is
associated with worse clinical outcomes compared to standard care. Nature Medicine , 2021

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II. Anti-inflammatory Drugs

To ↓ Cytokine storm

1. Corticosteroids

2. Colchicine

3. Interleukin-6 Inhibitors

4. Interleukin-1 Inhibitors

5. JAK Inhibitors

N.B. in some guidelines No. 3, 4, & 5 classified as immunomodulators

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1. Corticosteroids
Mechanism in COVID-19 :
-to address both ARDS and systemic inflammation

Use in COVID-19:
NIH & IDSA guideline panel recommends dexamethasone in hospitalized +
Need O2 critically ill* or with severe illness**, patients with COVID-19.
Dexamethasone 6 mg IV or PO for 10 days (or until discharge) or equivalent G dose

Systemic corticosteroids in combination with antivirals and immunomodulators,

such as tocilizumab (IL-6 Inhibitors) or baricitinib (JAK Inhibitors), have
demonstrated clinical benefit in subsets of hospitalized patients with COVID-19.

Side effects:
hyperglycemia, neuropsychiatric symptoms, secondary infections ………
↑risk of opportunistic fungal infections (e.g., mucormycosis, aspergillosis) and
reactivation of latent infections (e.g., HBV, herpesvirus infections, tuberculosis).

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2. Colchicine
Mechanism in COVID-19:
- It prevents microtubule assembly → disrupts inflammasome
activation, ↓ microtubule-based inflammatory cell chemotaxis,
↓ leukotrienes, cytokines (IL-6 &1 β, and phagocytosis.
- Colchicine is an anti-inflammatory drug treats gout, recurrent
pericarditis, and familial Mediterranean fever.

- NIH guidelines panel recommends against the use of colchicine for

hospitalized patients with COVID-19 (AI).
- NIH: Insufficient evidence to recommend either for or against the use
of colchicine to treat nonhospitalized patients with COVID-19.

Adverse effects: (serious)

1-Common: GIT (diarrhea, ANV, abdominal cramping & bloating), Alopecia
2- In rare cases, neuromyotoxicity and bone marrow suppression
3 - Fatal colchicine toxicity has been reported in renal or hepatic patients who received
colchicine in conjunction with strong CYP3A4 inhibitors e.g. Antiviral Protease inhibitors,
Antifungal Azoles, Macrolides

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3. Interleukin-6 inhibitors
Tocilizumab and Sarilumab

Mechanism: (to early BLOCK Cytokine storm)

Tocilizumab and Sarilumab are a monoclonal antibody
that competitively inhibits the binding of interleukin-6 (IL-6) to its
receptor (IL-6R). Inhibiting the entire receptor complex prevents IL-6
signal transduction to inflammatory mediators that summon B and T
cells → ↓ Cytokine storm

interleukin-6
(IL-6)

Tocilizumab
Sarilumab

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Tocilizumab
“Interleukin-6 inhibitor”

Use in COVID-19
IDSA and NIH guidelines recommend tocilizumab combination with dexamethasone
in hospitalized adults with COVID-19 who have elevated markers of systemic
inflammation and exhibiting rapid respiratory decompensation caused by COVID-19.

N.B. It is originally used to treat Rheumatoid and giant cell arteritis.

Side effects:
-Runny nose, sore throat, sinus infection, headache, high blood pressure and injection
site reactions. V Rarely, infections and GIT perforations.

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4. Interleukin-1 inhibitors
Anakinra
Mechanism: (to early BLOCK Cytokine storm)
It is a monoclonal antibody that inhibits the
binding of interleukin-1 (IL-1) to its receptor.
-IL-1 receptor blockers (e.g., anakinra) or IL-1
signaling blockers (e.g., canakinumab) can
potentially interrupt the autoinflammatory loop
→ ↓ Cytokine storm

NIH Guidelines Panel: insufficient evidence to recommend either

for or against the use of anakinra for the treatment of COVID-19.

Side effects:
-Headache, nausea, vomiting, and liver enzyme elevations .

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5. JAK inhibitors
(Baricitinib)
Mechanism
- Janus kinase (JAK) inhibitors inhibit phosphorylation
of signal transducer and activator of transcription
(STAT) proteins, key proteins involved in immune
activation and inflammation (e.g., response to IL-6)
→ ↓ Cytokine storm
- Baricitinib, has direct antiviral activity →↓ viral
endocytosis → ↓SARS-CoV-2 entering and infecting
susceptible cells.

NIH Guidelines Panel’s recommend use of baricitinib for hospitalized

patients who require high-flow oxygen or noninvasive ventilation.
- Baricitinib oral tablets were used to treat autoimmune diseases

Adverse effects:
1-infections (respiratory & urinary tract infections), reactivation of herpes viruses,
myelosuppression, transaminase elevations.
2- Baricitinib is CYP3A4 substrate → drug interaction with CYP3A4 inducers & inhibitors
Also, Need dose adjustment in Renal patients.

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IV. Anticoagulants Drugs

COVID-19, is associated with inflammation and a

prothrombotic state, with increases in fibrin, fibrin
degradation products, fibrinogen, and D-dimers.

NIH Guidelines recommends: Prophylactic dose

anticoagulation dose of LMWH for hospitalized
COVID-19, patients unless contraindicated (e.g., a
active hemorrhage or severe thrombocytopenia)

NIH recommends: Hospitalized patients with COVID-19 who are taking anticoagulant or
antiplatelet therapy for underlying medical conditions should continue this treatment unless
significant bleeding develops, or other contraindications are present (AIII).

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What is the Egyptian Ministry of

Health (MOH) Protocol or Algorithm
for management of COVID-19?

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