Pharmacotherapy of

Malaria
Dr. Sumit Ourasang
Senior Resident
Department of Pharmacology
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 • Malaria is an acute febrile illness caused by Plasmodium parasites, which are
spread to people through the bites of infected female Anopheles mosquitoes.

• Incidence: 59 cases/1000 population at risk 2021

• 247 million cases and 619 000 deaths globally in 2021

Organization WH. World malaria report 2022. World Health Organization; 2022. 2
MAGNITUDE OF THE PROBLEM :: National Center for Vector Borne Diseases Control (NCVBDC) [Internet]. [cited 2021Oct19].. Available from:
https://ncvbdc.mohfw.gov.in/index4.php?lang=1&level=0&linkid=420&lid=3699
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 Life cycle

P.vivax 50%
P.falciparum >40%
P.malariae and P. ovale (rare)

Yellow Fever Vaccine & Malaria Prophylaxis Information, by

Country - Chapter 2 - 2020 Yellow Book | Travelers’ Health | CDC
[Internet]. [cited 2023 Apr 9]. Available from:
https://wwwnc.cdc.gov/travel/yellowbook/2020/preparing-inter
national-travelers/yellow-fever-vaccine-and-malaria-prophylaxis-i 5
nformation-by-country
 Clinical features
Severe malaria
Uncomplicated malaria
• Altered consciousness
• Tertian fever – P.falciparum, P.vivax, • Seizures
P.ovale (48 hrs)
• Severe anemia (eg massive intravascular
• Quartan fever – P.malariae (72 hrs) hemolysis)
• Lethargy • Hypoglycemia

• Pallor • Respiratory distress or acute respiratory distress

syndrome (ARDS)
• Jaundice
• Coagulopathy, with or without disseminated
• splenomegaly intravascular coagulation
• Metabolic acidosis
• Circulatory collapse
• Renal failure, hemoglobinuria ("blackwater
fever") 7
Diagnosis:
• Microscopy

• Thin & Thick smear

• Conventional method

• Species, quantification and the life cycle stage

• RDT(Rapid Diagnostic Test)

• Do not require laboratory skills/equipment

• Detection limit of 100-200 parasites/microlitre

• PCR

• Detects 1 parasite/microlitre
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 Mosquito (sexual phase)

sporozoite
PRIMAQUINE

PRIMAQUINE hypnozoite
PRIMAQUINE schizont
PROGUANIL
ARTEMISININ
derivatives PRE-ERYTHROCYTIC
STAGE
Gametocytes

Blood schizont

Merozoites
ERYTHROCYTIC STAGE
Late trophozoite
CHLOROQUINE SULFONAMIDES
ARTEMISININ TETRACYCLINES
LUMEFANTRINE CLINDAMYCIN RBC
MEFLOQUINE PYRIMETHAMINE
PROGUANIL Early trophozoite (ring form)
QUININE 9
 Anti-malarial agents
Erythrocyctic schizonticides Chloroquine
Artemisinin
Lumefantrine
Mefloquine
Proguanil
Quinine
Sulfonamides
Tetracyclines
Clindamycin
Pyrimethamine

Tissue schizonticides hypnozoites Primaquine

Tafenoquine
Primary liver forms Atovaquine
proguanil
Gametocides Primaquine
artemisinin

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Brunton LL, Knollmann BC, Hilal-Dandan R, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. Thirteenth edition. New York: McGraw Hill Medical; 2018. 1419 p. page no.973
 Principles of malaria management

1. Early diagnosis and prompt, effective treatment of malaria

2. Rational use of antimalarial agents

3. Combination therapy

4. Appropriate weight-based dosing

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1.WHO Guidelines for malaria, 14 March 2023. Geneva: World Health Organization; 2023 (WHO/UCN/GMP/ 2023.01).
 Objectives and use of antimalarial drugs

• To prevent clinical attack (prophylactic)

• To treat clinical attack (clinical cure)

• To completely eradicate the parasites (radical cure)

• To cut-down transmission (gametocidal)

Tripathi KD. Essentials of medical pharmacology. Eighth edition. New Delhi: Jaypee Brothers Medical Publishers; 2019. 1064 p. page no.874 12
Chloroquine
• 4-aminoquinoline
• Targeting the Food VacuolePrevents polymerization of
heme to hemozoinLysis

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 Chloroquine
 Extensive tissue binding A loading dose is required to achieve
effective concentrations in plasma
 Complex pharmacokinetics Plasma levels of the drug are
determined primarily by the rate of distribution rather than the rate
of elimination
 Narrow safety margin
 Peak plasma levels ~3-5 hours after oral dose
 ADR – Oral therapy GI upset, headache, visual disturbances,
and urticaria
High cumulative doses - irreversible retinopathy and
ototoxicity
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 Quinine

 Chief alkaloid of cinchona

 Mechanism of action Binds heme and prevent its detoxification.
 Acts against erythrocytic forms
 Triad of dose-related toxicities cinchonism, hypoglycemia, and
hypotension
 Others- visual and auditory effects, GI symptoms
 Blackwater fever- triad of massive hemolysis, hemoglobinemia,
and hemoglobinuria
 Safe in pregnancy
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Primaquine
 Acts on exoerythrocytic tissue stages and gametocytes

 Forms intermediates that generate reactive oxygen species or

by interfering with mitochondrial electron transport

 Absorption from GI – 100%, t1/2 - 7 hours

 ADR- mild to moderate abdominal distress, High doses cause

some degree of methemoglobinemia

 G6PD deficiency Acute hemolysis and hemolytic anemia

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 Artemisinin
Endoperoxide bridge of
artemisininCleaved by
hemeRadicalsInhibit ER
based Ca ATPase of parasite

Generate free
radicals that alkylate
and oxidize proteins
and lipids in
parasitized
erythrocytes
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 Artemisinin
 Potent and fast-acting antimalarials  rapid parasite clearance
and fever resolution

 Blood schizonticide

 Semisynthetic  Dihydroartemisinin, Artesunate, Artemether

 To be used only in combination therapy

 Oral Bioavailability – <=30%

 Short t1/2
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Rationale for ACT(Artemisinin Combination
Therapy)
 Enhanced efficacy and reduced likelihood of resistance.

 Very short t1/2 of artemisinin derivatives Monotherapy requires a

multiple dose regimen of 7 days duration

 Combination with a longer half-life “partner” antimalarial drug

allows a reduction in the duration of artemisinin treatment

Monotherapy of Oral Artemisinin is banned.

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Advantages of ACT
The advantages of ACT relate to the unique properties and mode of
action of the artemisinin component –

 Rapid substantial reduction of the parasite biomass

 Rapid resolution of clinical symptoms
 Effective action against multidrug-resistant P. falciparum
 Reduction of gametocyte carriage
 No parasite resistance documented as yet
 Few reported adverse events

World Health Organization [WHO]. Antimalarial Drug Combination Therapy . Report of a WHO Technical Consultation. 2001.
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Other anti-malarials
Drug MOA/Class Use

Mefloquine Unclear, prev thought Chemoprophylaxis and treatment

similar to chloroquine of infections with P falciparum

Piperaquine Bisquinoline, similar to CQ Treatment of P falciparum

infection in fixed combination with
dihydroartemisinin

Atovaquone- Inhibition of Treatment and chemoprophylaxis

Proguanil Mitochondrial ETC- of P falciparum infection
Folate antagonist
combination
Lumefantrine Unclear Treatment of P falciparum malaria
in fixed combination with
artemether
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Drug MOA/Class Use

Sulphonamides PABA inhibition treatment of infections with

Plasmodia in fixed combination with
artesunate

Pyrimethamine DHFR inhibition Treatment of Plasmodia malaria in

fixed combination with artesunate

Clindamycin 50s Ribosomal subunit- Alternative to ACT regimen in

Protein synthesis inhibitor combination with quinine

Tetracyclines Protein synthesis inhibitors- Short term chemoprophylaxis &

30s ribosomal subunit alternative to ACT regimen in
combination with quinine

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25
26
 CHLOROQUINE
No of tablets
Age Day1 (10mg/kg) Day 2 (10mg/kg) Day 3 (5 mg/kg)
<1 ½ ½ ¼
1-4 1 1 ½
5-8 2 2 1
9-14 3 3 1½
>15 4 4 2

Quinine 600 mg (10 mg/kg) 8 hourly × 7 days +

Doxycycline 100 mg daily × 7 days or
Clindamycin 600 mg 12 hourly × 7 days

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Treatment of Uncomplicated malaria

Non-falciparum P.falciparum

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Non-falciparum malaria treatment (uncomplicated)

Erythrocytic asexual Chloroquine sensitive chloroquine

stage
Chloroquine resistant ACT

Atovaquone-proguanil
Quinine sulfate +
Doxycycline/
tetracycline/ clindamycin
mefloquine

Hypnozoites Chloroquine sensitive Primaquine (14 days)

and resistant Tefenoquine
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• Before giving primaquine always asses G6PD status

• Warning signs to stop primaquine

• Dark coloured urine

• Yellow conjunctiva

• Bluish discoloration of lips

• Abdominal pain

• Nausea

• Vomiting

• Breathlessness

• Evaluated on day 7 for adverse effects

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Anti-relapse:Eradicate dormant hypnozoites (liver stages)
Hypnozoiticidal Exclusion Blood G6PD activity
agent criteria schizonticidal
agent >70% 30-70% <30% unavailable

primaquine • Pregnant Chloroquine/ 0.5 mg base/kg 0.5 mg base/kg 0.75 mg 0.25 mg

• Lactating ACT once daily once daily base/kg base/kg
• ≤6 months 14 days 14 days once weekly once daily
of age (total dose 7 (total dose 7 8 weeks 14 days (total
mg/kg) mg/kg) (total dose 6 dose 3.5 mg/kg)
mg/kg)

Tefanoquine • Pregnant Chloroquine Adult dosing (>16 years): Not Not Not
300 mg single dose
• Lactating recommended recommended recommended
• ≤2 years of Pediatric dosing:
age
Children >2 years of age
and >10 kg to 20 kg: 100
mg (two 50 mg
dispersible tablets)

Children >2 years of age

and >20 to ≤35 kg: 200
mg (four 50 mg
dispersible tablets)
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Falciparum malaria treatment (uncomplicated)

Chloroquine sensitive ACT > Chloroquine

Chloroquine resistant
alternative regimens
ACT
Atovaquone-proguanil
Quinine sulfate +
Doxycycline/tetracycline/ clindamycin
mefloquine

Transmission reduction Primaquine (single dose on day 2)

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 Falciparum malaria

North-eastern states
All over India except North eastern states
Artemether- Lumefantrine
• Artesunate 4mg/kg for 3 days
• Sulfadoxine (25mg/kg) +
pyrimethamine (1.25mg/kg) on day 0

National Vector Borne Disease Control Programme (NVBDCP): Guidelines – Malaria.2013 35

Treatment of Severe malaria
• Mostly due to P.falciparum

• Mortality 100% if left untreated (cerebral malaria)

• Severe anemia – low mortality rate

• Acidosis- high mortality rates

• Diagnosis of severe malaria

• Mostly clinical

• Microscopy mostly shows negative due to sequestration and partial treatment

• RDT or repeat microscopy

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 Principles of management
• Supportive measures

• Parenteral antimalarial treatment – after lab/presumptive diagnosis

• Achieve anti-malarial drug therapeutic concentration asap

• Empirical broad spectrum antibiotics before blood culture reports

• Parenteral route for minimum 24 hrs or up till oral becomes tolerable

1.WHO Guidelines for malaria, 14 March 2023. Geneva: World Health Organization; 2023 (WHO/UCN/GMP/ 2023.01). 38
Principles of management
• ACT more preferable than quinine

• Dose calculation based on mg/kg

• Pre-referral management in case of resource limited setting

• Management of complications

• Avoid mefloquine due to risk of neuropsychiatric effects

• Anti-emetics causes sedation which should be distinguished from the patient progressing towards
severe malaria

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Pre-referral treatment

Artesunate IV> IM> rectal (for children < 6years)

If NA

Artemether IM (loading dose)

If NA

Quinine IM (loading dose)

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Management in tertiary centre IV artesunate
Evalaute after 4 weeks for
2.4mg/kg
Delayed hemolytic anemia
0,12,24 hrs
If NA

Artemether IM
3.2mg/kg,
Followed by 1.6mg/kg x 3 days

If NA

Quinine IV IV infusion
20mg/kg in 5% dextrose over 4 hours No bolus
Cardiac monitoring
Followed by 10mg/kg IV over 4 hours at 8-12 hrs interval Glucose monitoring
Once patient
tolerate orally
Oral regimen
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• Monitoring with parasite density
• Every 12hrs

• Artemisinin clears in 72 hrs

• Quinine clears 90% in 48 hrs

• Indicator for treatment failure/resistance

• Completing therapy
• If parasite density ≤ 1 % plan for oral regimen

• If parasite density > 1 % continue parenteral treatment for 6 more days

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 Malaria in Pregnancy
• High risk group

• Due to sequestration of parasites in the maternal blood spaces of placenta

• VAR2CSA

• protein on the surface of infected RBC

• Sticks to placental receptor chondroitin sulphate A (CSA)

• High transmission area – anemia

• Low transmission area – acute lung injury, severe hypoglycemia, coma, pregnancy loss

Rogerson SJ. Management of malaria in pregnancy. Indian J Med Res. 2017 Sep;146(3):328–33.
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Treatment
Uncomplicated P.falciparum 1st AM-L
Chloroquine-resistant trimester ACT (without antifolates)
Quinine + Clindamycin
2nd & 3rd ACT
trimester Quinine + Clindamycin
Chloroquine-sensitive Any Chloroquine/HCQ
P.falciparum trimester

Uncomplicated non-falciparum 1st AM-L

Chloroquine-resistant trimester ACT (without antifolates)
Quinine
2nd & 3rd ACT
trimester Quinine
Chloroquine-sensitive non- Any Chloroquine/HCQ
falciparum trimester

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• ACTs in Pregnancy
• Artemether- Lumefantrine

• Artesunate-amodiaquine

• Artesunate- mefloquine

• Dihydroartemisinin- piperaquine

• Tetracycline & doxycycline – not advisable

• Primaquine & Tafenoquine - CI

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 • Anti-relapse therapy (non-falciparum)
• Primaquine/tafenoquine are CI in pregnant women

• Chloroquine once weekly should be used

• If chloroquine failure – then DP

• Following delivery after G6PD status (mother and infant) initiate primaquine

• In 1st trimester – AM-L can be used rather than quinine based regimen
(DP) -Dihydroartemisinin-piperaquine

Saito M, McGready R, Tinto H, Rouamba T, Mosha D, Rulisa S, et al. Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials:
a systematic review and individual patient data meta-analysis. Lancet. 2023 Jan 14;401(10371):118–30.
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• Severe malaria
• IV artesunate

• Artemether > quinine

• Quinine – causes hypoglycaemia

• As per guidelines NVBDCP

P.falciparum 1st trimester Quinine
2nd & 3rd trimester ACT
P.vivax All trimesters chloroquine

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 Algorithm for diagnosis and treatment
Clinically suspected malaria

Prepare slide for microscopy

P. vivax P. falciparum negative

CQ 3 days ACT 3 days Needs further evaluation
PQ 14 days PQ day 2
0.25mg/kg 0.75mg/kg

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National Vector Borne Disease Control Programme (NVBDCP): Guidelines – Malaria.2013
 When microscopy not available

Perform RDT

Pf RDT, also prepare blood smear

Bivalent RDT

Positive Negative
Pf RDT positive Pf RDT negative
Treat acc. to
ACT 3 days CQ 3 days and wait species
for microscopy
PQ day 2

If microscopy (+) for P.f

If microscopy (+) for P.v
ACT 3 days +
PQ x 14 days
PQ 2nd day
0.25mg/kg
0.75mg/kg
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National Vector Borne Disease Control Programme (NVBDCP): Guidelines – Malaria.2013
 Chemoprophylaxis
• Short-term
• Less than 6 weeks

• Doxycycline 100 mg/day in adults & 1.5mg/kg/day in >8yrs

• From 2 days before travel & continued for 4 weeks

• Long-term
• More than 6 weeks

• Mefloquine 5 mg/kg weekly

• Two weeks before, during and four weeks after

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National Vector Borne Disease Control Programme (NVBDCP): Guidelines – Malaria.2013
 vaccine

• RTS,S/AS01
• Pre-erythrocytic recombinant protein vaccine

• 0.5ml IM

• Five-dose strategy from five months of age

• R21/MatrixM – PfCSP protein (circumsporozoite protein)

• Attenuated whole sporozoite vaccine PfSPZ

• Pfs25 and Pfs230 - sexual stages

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1.WHO Guidelines for malaria, 14 March 2023. Geneva: World Health Organization; 2023 (WHO/UCN/GMP/ 2023.01).
Summary

• >40% P.falciparum and 50% vivax

• Early diagnosis and treatment improves treatment outcome

• Combination therapy preferred over monotherapy

• Completion of the proper regimen to avoid resistance

• Oral treatment for uncomplicated malaria

• Clinical cure + radical cure

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• G6PD assessment before primaquine is needed

• Anti-malarials act against blood schizonts, liver schizonts and gametocytes

• Non-falciparum malaria requires radical cure

• Primaquine is contraindicated in pregnancy, infants, lactating mothers

• In case of mixed infection/presumptive treatment , falciparum has to be treated

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Thank
You

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