REPURPOSING DRUGS

FOR COVID-19:
INVESTIGATING THE DRUG ACTIONS AND
GENETIC IMPACT OF CHLOROQUINE AND
HYDROCHLOROQUINE.

BY
PHARMACOKINETICS AND PHARMACOGENOMICS
INTRODUCTION:

IT IS A PROCESS OF IDENTIFYING NEW

THERAPEUTIC USE(S) FOR
OLD/EXISTING/AVAILABLE DRUGS. IT IS AN
EFFECTIVE STRATEGY IN DISCOVERING OR
DEVELOPING DRUG MOLECULES WITH NEW
PHARMACOLOGICAL OR THERAPEUTIC
INDICATIONS.
 WHAT IS COVID-19?
• CORONAVIRUS DISEASE (COVID-19) IS AN INFECTIOUS DISEASE CAUSED BY
THE SARSCOV-2 VIRUS.
• IT WAS IDENTIFIED IN DECEMBER 2019.
• IT IS CAUSED RESPIRATORY ILLNESS.
• CORONAVIRUSES ARE NAMED FOR THE CROWN-LIKE SPIKES ON THEIR
SURFACE. (CORONA MEANS CROWN)
• THE CORONAVIRUS CAN BE SPREAD FROM PERSON TO PERSON. IT IS
DIAGNOSED WITH A TEST.
• AFTER THE FIRST CASES OF THIS PREDOMINANTLY RESPIRATORY VIRAL
ILLNESS WERE FIRST REPORTED IN WUHAN, HUBEI PROVINCE, CHINA, IN LATE
DECEMBER 2019, SARSCOV-2 RAPIDLY DISSEMINATED ACROSS THE WORLD IN
A SHORT SPAN OF TIME, COMPELLING THE WORLD HEALTH ORGANIZATION
(WHO) TO DECLARE IT AS A GLOBAL PANDEMIC ON MARCH 11, 2020.
CORONAVIRUSES ARE A FAMILY OF VIRUSES THAT CAUSE ILLNESS
SUCH AS RESPIRATORY DISEASES OR GASTROINTESTINAL
DISEASES. RESPIRATORY DISEASES CAN RANGE FROM THE COMMON
COLD TO MORE SEVERE DISEASES E.G.
 MIDDLE EAST RESPIRATORY SYNDROME (MERS-COV).
 SEVERE ACUTE RESPIRATORY SYNDROME (SARS-COV)[8].

CORONAVIRUSES ARE ZOONOTIC[9], MEANING THAT THE VIRUSES

ARE TRANSMITTED BETWEEN ANIMALS AND HUMANS. IT HAS BEEN
DETERMINED THAT MERS-COV WAS TRANSMITTED FROM
DROMEDARY CAMELS TO HUMANS AND SARS-COV FROM CIVET CATS
TO HUMANS[8]. THE SOURCE OF THE SARS-COV-2 (COVID-19) IS YET
TO BE DETERMINED, BUT INVESTIGATIONS ARE ONGOING TO
IDENTIFY THE ZOONOTIC SOURCE TO THE OUTBREAK[10].
SARS-COV-2 VIRUS:

 VIRUSES LIKE SARS-COV-2 CONTINUOUSLY EVOLVE AS CHANGES

IN THE GENETIC CODE (CAUSED BY GENETIC MUTATIONS OR
VIRAL RECOMBINATION) OCCUR DURING REPLICATION OF THE
GENOME.
 SARS-COV-2 HAS CONSISTENTLY MUTATED OVER THE COURSE OF
THE PANDEMIC, RESULTING IN VARIANTS THAT ARE DIFFERENT
FROM THE ORIGINAL SARS-COV-2 VIRUS.
 THROUGHOUT THE COVID-19 PANDEMIC, MANY VARIANTS OF
SARS-COV-2 HAVE BEEN FOUND IN THE UNITED STATES AND
GLOBALLY.
 SCIENTISTS USE MULTIPLE CLASSIFICATION SYSTEMS TO
DESCRIBE AND COMMUNICATE SIMILARITIES AND DIFFERENCES
BETWEEN SARS-COV-2 VIRUSES.
LIST OF VARIANTS OF SARS-COV-2 FOUND IN COVID-19 PATIENTS:
WHO LABELS Date of
Pango Lineage Current Status
(Variants) Designation

Variants containing the

1 N/A VBM September 1,2023
F456L spike mutations

2 Omicron BA.2.86 VBM September 1,2023

3 Omicron XBB.1.9.1 VBM September 1,2023

4 Omicron XBB.1.9.2 VBM September 1,2023

5 Omicron XBB.2.3 VBM September 1,2023

6 Omicron XBB.1.16 VBM September 1,2023

7 Omicron XBB.1.5 VBM September 1,2023

 FEVER COLDNESS

SYMPTOMS
WEAKNESS COUGH
OF

SHORTNESS
COVID-19
OF
SNEEZE
BREATH
HIGH-RISK POPULATIONS
OLDER PEOPLE (PEOPLE OVER 70 YEARS OF AGE)
PEOPLE WITH SERIOUS CHRONIC ILLNESSES SUCH AS:
 DIABETES O CARDIOVASCULAR DISEASE
 CHRONIC RESPIRATORY DISEASE O CANCER O HYPERTENSION
 CHRONIC LIVER DISEASE
PEOPLE WHO ARE PHYSICALLY INACTIVE

THE WHO HAS ISSUED AND PUBLISHED ADVICE FOR HIGH-RISK

GROUPS (OLDER PEOPLE AND PEOPLE WITH SERIOUS CHRONIC
ILLNESS) AND COMMUNITY SUPPORT.
CAUSES OF CORONAVIRUS:
Through the coughing and sneezing of
infected people.
Touching an infected person’s hands
or face.
By touching things infected people
have touched.
Being in public spaces where there
might be infected people.

Not maintaining hand hygiene.

 GENES RELATED TO COVID-19:

TLR4 NLRP3 MBL2 IL6 IL1RN

CX3CR
IL1B CCR5 AGT ACE
1

F2

Polymorphisms of these genes may be predictors of susceptibility and

severity of COVID-19. Disease-related mutations genes are listed.
 METHODS USED FOR COVID-19
PATIENTS DETECTION:
THERE ARE TWO COMMON TYPES OF COVID-19
DIAGNOSTIC TESTS: MOLECULAR TESTS, SUCH AS
POLYMERASE CHAIN REACTION (PCR) AND OTHER
NUCLEIC ACID AMPLIFICATION TESTS (NAATS) TESTS,
WHICH DETECT GENETIC MATERIAL CALLED RNA FROM
THE VIRUS.
COMBINATIONS OF GENOME SEQUENCING, NUCLEIC ACID
MOLECULAR TESTING, CLUSTERED REGULARLY
INTERSPACED SHORT PALINDROMIC REPEATS EDITING
TECHNOLOGY, ANTIGEN/ANTIBODY DETECTION, AND
COMPUTED TOMOGRAPHY IMAGING HAVE BEEN
IMPLEMENTED TO IDENTIFY AND SCREEN COVID-19
 TREATMENTS FOR COVID-19
PATIENTS:

HIGH-FLOW NASAL OXYGEN THERAPY (HFNO) MAY BE AN

ATTRACTIVE FIRST-LINE VENTILATORY SUPPORT IN COVID-
19 PATIENTS,ESPECIALLY IN THE TREATMENT OF MEDIUM
TO SEVERE ADULT RESPIRATORY DISTRESS SYNDROME
(ARDS). HOWEVER, HNFO USE FOR THE MANAGEMENT OF
COVID-19 PATIENTS AND RISK FACTORS FOR HFNC
FAILURE REMAIN TO BE DETERMINED.
 CONTROVERSY ABOUT COVID-19
PATIENTS TREATMENTS:
USE OF HIGH-FLOW NASAL OXYGEN
THERAPY:
MANY GUIDELINES INITIALLY PROHIBITED OR
DISCOURAGED USE OF HIGH-FLOW NASAL
OXYGEN (HFNO) THERAPY IN PATIENTS WITH
COVID-19, BASED ON THE POTENTIAL RISKS
OF AEROSOL GENERATION AND VIRAL
SPREAD. THE EXTENT OF THIS RISK REMAINS
LIST OF COVID-19 VACCINES APPROVED BY WHO:
 PFIZER–  SINOPHARM  QAZCOVID-IN  NOORA
BIONTECH. WIBP  FAKHRAVAC  SOBERANA PLUS
 JANSSEN  ABDALA  CHINESE  TURKOVAC
 MODERNA  CONVIDECIA ACADEMY OF  COVLP
 SINOPHARM  OXFORD– MEDICAL
SCIENCES  SINOPHARM
BIBP ASTRAZENECA. CNBG
 SPUTNIK V  EPIVACCORONA  ZYCOV-D  V-01
 CORONAVAC  COVIVAC  COVIRAN
BAREKAT  INCOVACC
 NOVAVAX  ZIFIVAX  SKYCOVIONE
 COVAX-19
 COVAXIN  SOBERANA 02  GEMCOVAC
 TURKOVAC
 VLA2001  CORBEVAX  WALVAX
 SINOPHARM
 SANOFI–GSK  MINHAI CNBG  INDO-VAC
 SPUTNIK LIGHT  MEDIGEN  RAZI COV PARS
VACCINES APPROVED IN PAKISTAN:

SINOPHARM, SINOVAC, CANSINO-BIO AND SPUTNIK DOSES

HAVE BEEN ADMINISTERED IN PAKISTAN SO FAR. THE 2.47
MILLION DOSES OF OXFORD-ASTRAZENECA COVID-19
VACCINE WILL BE USED TO IMMUNIZE ABOUT 1.24 MILLION
HIGH-RISK PEOPLE AGAINST THE VIRUS
 ELEVATED INTEREST IN HYDROCHLOROQUINE
AND CHLOROQUINE AS THERAPEUTIC
• CANDIDATES
WHILE AGAINST
THERE IS GROWING SARS-COV-2
SCIENTIFIC INFECTIONS:
DATA ON THE THERAPEUTIC EFFECT,
THERE IS ALSO CONCERN FOR TOXICITY OF THE MEDICATIONS.
• THE THERAPY OF COVID-19 BY HYDROXYCHLOROQUINE AND CHLOROQUINE
IS OFF-LABEL.
• FOR APPROXIMATELY 6000 IDENTIFIED MEDICAL CONDITIONS, ONLY 500 HAVE
APPROVED THERAPIES; A CRITICAL NEED CURRENTLY EXISTS FOR THE
AVAILABILITY OF DRUG THERAPIES.
• DRUG REPURPOSING IS BEING APPLIED TO FINDING A THERAPEUTIC
APPROACH FOR THE COVID-19 PANDEMIC. THIRTY-ONE POTENTIAL BROAD-
SPECTRUM ANTIVIRAL AGENTS (BSAAS) WERE RECENTLY IDENTIFIED AS
HAVING POTENTIAL FOR TREATING SARSCOV-2/COVID-19
• CHLOROQUINE (CQ) WAS FIRST DEVELOPED FOR THE TREATMENT OF
MALARIA.9 HYDROXYCHLOROQUINE (HCQ) IS Β-HYDROXYLATED ANALOGUE
OF CQ.
 ADVERSE REACTIONS OF CHLOROQUINE AND
HYDROXYCHLOROQUINE: QK

Life-Threatening Events: Both drugs can lead to severe, even fatal events if taken in excessive
amounts.

Cardiac Complications: Patients may experience heart-related issues.

Retinopathy: Chloroquine can cause irreversible damage to the retina.

Cutaneous Reactions: Hydroxychloroquine may result in severe skin reactions.

Common Side Effects: Nausea, vomiting, and diarrhea are common side effects. Other
complications include hypoglycemia in diabetics and hemolytic anemia in certain patients.
METHODS:
1. RESEARCHERS SEARCHED DATABASES LIKE MEDLINE
AND PUBMED FOR ARTICLES ABOUT CHLOROQUINE,
HYDROXYCHLOROQUINE, COVID-19, AND RELATED
TOPICS FROM 1947 TO JULY 2020.
2. THEY USED KEYWORDS TO FIND RELEVANT PAPERS AND
GOT 126 RESULTS.
3. TWO INVESTIGATORS INDEPENDENTLY REVIEWED AND
EXTRACTED DATA FROM THESE PUBLICATIONS.
4. THEY FOCUSED ON ENGLISH LANGUAGE AND HUMAN
STUDIES, AND ALSO LOOKED AT REFERENCES IN THE
ARTICLES FOR MORE INFORMATION TO SUPPORT
EXISTING IDEAS AND PLAN FUTURE RESEARCH.
 RESULTS:
1. CYP3A IS INVOLVED IN THE METABOLISM OF BOTH CHLOROQUINE AND
HYDROXYCHLOROQUINE.
2. CYP3A4’S ROLE IN DRUG METABOLISM CAN LEAD TO VARIATIONS IN BLOOD
CONCENTRATIONS AMONG INDIVIDUALS AND CAN ALSO INFLUENCE DRUG-DRUG
INTERACTIONS.
3. CYP2C8 AND CYP3A4 PRIMARILY METABOLIZE CHLOROQUINE.
4. CYP3A4 METABOLIZES HYDROXYCHLOROQUINE.
5. CYP3A5 AND CYP2D6 PLAY SMALLER ROLES IN CHLOROQUINE METABOLISM.
6. THESE ENZYMES CAN INFLUENCE DRUG LEVELS, LEADING TO VARIATIONS IN BLOOD
CONCENTRATIONS AND POTENTIAL DRUG INTERACTIONS.
7. GENETIC DIFFERENCES AMONG INDIVIDUALS INFLUENCE VARIATIONS IN DRUG BLOOD
LEVELS.
8. THESE GENETIC FACTORS AFFECT HOW THE BODY METABOLIZES DRUGS LIKE
CHLOROQUINE AND HYDROXYCHLOROQUINE.
9. THESE DRUGS ARE MAINLY ELIMINATED THROUGH URINE.
10. CHLOROQUINE: 50% UNCHANGED IN URINE, 10% AS ACTIVE METABOLITE, 19% IN FECES,
5% THROUGH SKIN, 45% IN LEAN TISSUES.
11. HYDROXYCHLOROQUINE: 16-21% UNCHANGED IN URINE, 24-25% IN FECES, 5% THROUGH
SKIN, 45% IN LEAN TISSUES.
 PHARMACOGENOMICS OF CHLOROQUINE
AND HYDROXYCHLOROQUINE:
 DRUG RESPONSE VARIES WIDELY AMONG INDIVIDUALS, WITH 40-70%
EXPERIENCING EITHER LACK OF EFFECTIVENESS OR ADVERSE
REACTIONS.
 UP TO 30% OF THIS VARIABILITY IS DUE TO GENETIC DIFFERENCES,
INCLUDING SNPS (SINGLE-NUCLEOTIDE POLYMORPHISMS).
 CYTOCHROME P450 (CYP) ENZYMES, PARTICULARLY CYP2D6, 2C9, 2C8,
3A4, AND 3A5, ARE CRUCIAL IN DRUG METABOLISM AND CLEARANCE.
 THESE GENES ARE HIGHLY VARIABLE, WITH NUMEROUS SNPS AND COPY
NUMBER VARIATIONS.
 RENAL EXCRETION, INFLUENCED BY THE SLC47A1 GENE, ALSO AFFECTS
DRUG PHARMACOKINETICS.
 UNDERSTANDING GENETIC VARIATIONS HELPS PREDICT HOW
INDIVIDUALS WILL RESPOND TO THESE DRUGS AND CAN GUIDE
 CONCLUSION:
LIMITED STUDIES ON GENETIC VARIATIONS IN CHLOROQUINE
AND HYDROXYCHLOROQUINE RESPONSES, ESPECIALLY IN
MALARIA AND LUPUS PATIENTS.
DATA SUPPORTING THEIR USE FOR COVID-19 ARE
INSUFFICIENT AND INCONCLUSIVE.
CAUTION IS NEEDED DUE TO POTENTIAL TOXICITIES,
INCLUDING HEART, EYE, AND SKIN PROBLEMS.
URGENT, WELL-DESIGNED TRIALS WITH PHARMACOGENOMIC
INSIGHTS ARE NECESSARY FOR SAFER AND MORE
EFFECTIVE DOSING AND TO MINIMIZE ADVERSE EFFECTS.
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