MALARIA CHEMOTHERAPY

IBRAHIM OREAGBA PhD FPCPharm

Department of Pharmacology, Therapeutics

and Toxicology

College of Medicine, University of Lagos

Idi-Araba.
 LEARNING OBJECTIVES
• To understand the pathogenesis of
Malaria

• To understand the current concepts in

the management and therapy of malaria
 INTRODUCTION
MALARIA

Malaria is an acute infectious disease caused by 4

species of the protozoa genus plasmodia. P.
falciparum is the most dangerous species.
`P. malariae, P.ovale, P.vivax

• One fifth of the world population is at risk of

malaria more than 300 million cases each year.
(WHO 1998).

• Malaria kills more than a million people annually

most of whom need not die.
Majority are children under five who die cause they do
not receive treatment quickly enough. (Alnwick 2000).

Nigeria is a malaria-endemic area, and malaria is the

principal cause of childhood mortality.

At least 10% of all childhood deaths are due directly

to malaria (Salako 2000).

300 – 500 children die from malaria each day! (FMOH)

 WHO WORLD MALARIA
REPORT 2020
 Twenty-nine countries accounted for 95% of
malaria cases globally. Nigeria (27%), and 4
other countries accounted for about 51% of all
cases globally. Similar stats for death

 ■ The World Health Organization (WHO)

African Region, with an estimated 215 million
cases in 2019, accounted for about 94% of
cases
THE MALARIA SCOURGE
Malaria distribution in Nigeria
 Diagram of Life Cycle of Malaria Parasite

18/09/2023 G.N NTADOM, NMCP, FMOH 9

 SUMMARY OF LIFE CYCLE
• Infected mosquito inject sporozoites
• Sporozoites migrate to liver where they form
merozoites
• Merozoites are released and invade red blood
cells
• Rupture of red blood cells releases
merozoites, which can infect other red cells.
• Female mosquito picks up gametocytes from
infected individual
SIGNS AND SYMPTOMS
UNCOMPLICATED MALARIA
 Fever
 Headache
 Joint and body pains
 Weakness
 Malaise
 Vomiting
 Diarrhea
 Nightmares
 SEVERE MALARIA
 The presence of one or more of the following clinical or
laboratory features
 classifies the patient as suffering from severe malaria:
 Clinical features: (WHO)
 – impaired consciousness or unrousable coma
 – prostration, i.e. generalized weakness so that the patient is
unable walk
 or sit up without assistance
 – failure to feed
 – multiple convulsions – more than two episodes in 24 h
 – deep breathing, respiratory distress (acidotic breathing)
 SEVERE MALARIA
 circulatory collapse or shock, systolic blood
pressure < 70 mm Hg in adults
 and < 50 mm Hg in children
 – clinical jaundice plus evidence of other vital
organ dysfunction
 – haemoglobinuria
 – abnormal spontaneous bleeding
 – pulmonary oedema (radiological)
 SEVERE MALARIA
 Laboratory findings:
 – hypoglycaemia (blood glucose < 2.2 mmol/l or < 40 mg/dl)
 – metabolic acidosis (plasma bicarbonate < 15 mmol/l)
 – severe normocytic anaemia (Hb < 5 g/dl, packed cell volume
< 15%)
 – haemoglobinuria
 – hyperparasitaemia (> 2%/100 000/μl in low intensity
transmission areas or > 5%
 or 250 000/μl in areas of high stable malaria transmission
intensity)
 – hyperlactataemia (lactate > 5 mmol/l)
 – renal impairment (serum creatinine > 265 μmol/l).
 Malaria in Pregnancy
 Despite being clinically immune from P. falciparum malaria,
women living in endemic areas suddenly become susceptible to
the disease when they become pregnant.
 Malaria during pregnancy is characterised by very heavy
parasitization of the placenta.
 Protection against P. falciparum malaria acquired prior to the
first pregnancy for some reason does not work against the
parasites causing pregnancy-associated malaria.
 The severity and prevalence of parasitaemia both rapidly
decline with increasing parity

16
 The Available Antimalarial Medicines
 The Arylaminoalcohol
 4-Aminoquinolines
 8-Aminoquinolines
 Sulphones
 The Biguanides
 The Antibiotics
 The Naphthoquinolines
 The Peroxides
 The Arylaminoalcohols
- Quinoline methanols (Quinine, Quinidine, Mefloquine)
- Phenanthrene methanols (Halophanthrene, Lumefantrine)
 Mefloquine
 4-quinoline methanol
 Mode of Action
 Activity on the mid- to late trophozoite
 Alters the binding affinity of the parasite through the ATP-binding cassette
transporter.
 Blood schizonticide active against P.falciparum, P.malariae, P.vivax
 Adverse Effects
 Dizziness, nausea, vomiting, diarrhoea and abdominal pain.
 Major adverse effects include neuropsychiatric reactions and cardiovascular
abnormalities. However, these effects seem to be dose-related and possibly
associated with prophylactic use. Concurrent use with quinine can potentiate
the dose-related adverse reactions to mefloquine.

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 Quinoline methanols (contd)
Quinine, Quinidine
 Mode of Action
 Acts like CQ
 Mid to late trophozoite stage of the parasite.
 Efficacy
 Blood schizonticide effective against P.f
 Adverse Effects
 Tinnitus, muffled hearing, sometimes vertigo or dizziness.
 Quinine can cause severe hypotension if injected too rapidly.
 May cause enhanced cardiac toxicity when administered to individuals who
have taken mefloquine.
 Hypoglycaemia
 Quinidine is cardiotoxic

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 4-Aminoquinolines
- Chloroquine, Amodiaquine, Piperaquine, Naphthoquinoline, Mepacrine (acridine),
Pyronaridine (benzonaphthyridine)
Mode of Action
 Activity on mid- to late trophozoite stage
 Prevents detoxification of haem by polymerization to haemozoin or malaria pigment.
Efficacy
 Marked and rapid schizonticidal activity against all infections of P.falciparum, P.malariae,
P.ovale and P.vivax in areas where Gametocytocidal against P.vivax, P.malariae and P.ovale
 Has both an antipyretic and anti inflammatory effect.
CQ Adverse Effects
 Nausea, vomiting, headache, GIT symptoms, visual disturbance and pruritus (commoner in dark-
skinned people). Irreversible visual impairment. Retinopathy has rarely, if ever, resulted from
doses recommended for malaria prophylaxis. Attacks of porphyria and psoriasis may be
precipitated in susceptible individuals.
AQ Adverse Effects
 Repeated and prolonged use of AQ has been associated with leucopaenia and
agranulocytosis. However, adverse reactions to standard doses of AQ used in the treatment
of malaria are generally similar to those of chloroquine. Itching is less common with AQ.
 Not recommended for chemoprophylaxis.

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 8-Aminoquinolines
Primaquine, Pamaquine,
Mode of Action
 The mechanism of action is unknown.
Efficacy
 Effective against intrahepatic forms of all types of malaria
parasite.
 For radical cure of P. V and P. O,
 Gametocytocidal against P. f and has significant blood
stage activity against P. vivax (and some against asexual
stages
 of P. falciparum).
Adverse Effect
 Haemolysis in individuals with G6PD Deficiency.

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 Sulfones
- Sulphonamides (sulphadoxine, sulphalene, co-trimoxazole),
Dapsone
Mode of Action
 Works synergistically with pyrimethamine against the parasite specific
enzymes, DHPS (acts as PABA analogues) and DHFR.
 Activity on mature trophozoite to early schizont stage.
 Inhibits parasite synthesis of folate, which is essential for pyrimidine synthesis

Adverse Effects
 Serious adverse reactions to sulfa drugs include severe cutaneous reactions,
such as Stevens Johnson syndrome and TEN.
 Commoner amongst the Europeans and North Americans taking the drug for
prophylaxis.
 TEN appears to be more common in HIV infected patients.
 Dapsone causes varying degree of haemolysis and methaemoglobinaemia

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 The Biguanides
Proguanil, Chlorproguanil, cycloguanil, chlorcycloguanil,
Pyrimethamine
Mode of Action
Also known as Type 2 Antifolate
 Cycloguanil inhibits DHFR
 Active against pre-erythrocytic forms of the parasite
 Sporontocidal activity, rendering the gametocytes non-infective
 In co-formulation with atovaquone:
 Pharmacokinetics

Adverse Effect
 Haematological changes (megaloblastic anaemia and pancytopenia) have been
reported in patients with severe renal impairment.
 Mild gastric intolerance, diarrhoea, occasional aphthous ulceration
 and hair loss, there are few adverse effects associated with usual doses of
 proguanil hydrochloride.

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 The Antibiotics
Tetracyclines, Doxycycline, clindamycin, fluoroquinolones)
Mode of Action
 Tetracyclines are inhibitors of aminoacyl-tRNA binding during protein
synthesis.

Adverse Effects
 GIT effects , Renal failure, Oesophageal ulceration, Diarrhoea etc.

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 The Naphthoquinones

Atovaquone
Mode of Action
 Active against all Plasmodium species.
 Inhibits pre-erythrocytic development in the liver, and oocyst
development in the mosquito.
 Act in synergy with Proguanil
 Adverse Effects
 Skin rashes, headache, fever, insomnia, nausea, diarrhoea, vomiting,
raised liver enzymes, hyponatraemia, and, very rarely, haematological
disturbances, such as anaemia and neutropenia have all been reported.
 High affinity for plasmaproteins

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 The Peroxides
Artemisinin, Arthemeter, Artemotil, Artesunate, Artelinic acid, Dihydroartemisinin
 Artemisinin, also known as qinghaosu, is a sesquiterpene lactone extracted from the leaves of Artemisia annua
(sweet wormwood).
Mode of Action
 Inhibits an essential calcium adenosine triphosphatase, PfATPase 6 (29).
 Inhibits the conversion of haem to haemozoin, coverts haemozoin to haem
 Potent and rapidly acting blood schizontocide and is active against all Plasmodium species.
 It has an unusually broad activity against asexual parasites, killing all stages from young
rings to schizonts. In P. falciparum malaria, artemisinin
 Kills the gametocytes – including the stage 4 gametocytes, which are otherwise sensitive
only to primaquine.
 The elimination half-life of all Artemisinin is approximately 1 h
Adverse Effect
 Artemisinin and its derivatives are safe and remarkably well tolerated
 Mild GIT disturbances, dizziness, tinnitus, reticulocytopenia, neutropenia, elevated liver
enzyme values, and ECG abnormalities,
 The only potentially serious adverse effect reported with this class of drugs is type 1
hypersensitivity reactions in approximately 1 in 3000 patients
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 COMBINATION DRUGS

Artemisinin based Combinations

 Artesunate and SP
 Artesunate and Amodiaquine
 Co-artem(Artemeter and lumefantrine)
 Artesunate and Mefloquine

Non-Artemisinin based Combinations

 Malarone (Proguanil and Atovaquone)
 Maloprim( Dapsone and Pyrimethamine)
 LAPDAP ( Dapsone and Chlorproguanil)
 Mefloquine-SP
 Sulfalene –Pyrimethamine
 WHO WORLD MALARIA
REPORT 2020
 In the WHO African Region, the first-line
treatments for P. falciparum include
artemether-lumefantrine (AL), artesunate-
amodiaquine (AS-AQ) and
dihydroartemisinin-piperaquine
(DHA_x0002_PPQ).

 The overall average efficacy rates for P.

falciparum – 98.0% for AL, 98.4% for AS-AQ
and 99.4% for DHA-PPQ – remained
PROBLEMS WITH CHEMOTHERAPY AND
CHEMOPROPHYLAXIS

 Drug resistance
 Adverse drug reaction
 Cost
 Limited dosage forms
 Unfavorable pharmacokinetics e.g. poor
unpredictable oral bioavailability, unfavorable
t1/2and inconvenient dosage schedule
 Availability.
 RATIONAL USE OF ANTIMALARIAL DRUGS
 This refers to appropriate use of antimalarials for the right
indications and at the correct/adequate dosages.

 Antimalarial drugs will be needed for treatment of

uncomplicated malaria, severe malaria and chemoprophylaxis
for groups at risk.

 Appropriate use of antimalarial drug is determined by the goal

of treatment and the person responsible for taking the primary
decision on use of the drug either at home or at the different
health care levels.

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 Background to the Use of ACTs
 The drug therapeutic efficacy trial conducted on Chloroquine and
Sulphadoxine-Pyrimethamine in the six geopolitical zones

 High level of resistance was reported (ACPR of 39.2%

 and 56.7% for CQ and SP respectively)

 Inappropriate for use in the treatment of uncomplicated malaria

in Nigeria.

 In line with WHO recommendation, Nigeria embarked on drug

trial of some selected Artemisinin-based Combination Therapies
and found them to be very safe and effective.

 This lead to the change in the first line antimalarial drug in

Nigeria from Chloroquine to ACTs.
RATIONALE FOR USE OF ACTs
 Artemisinin
 One of the most novel discoveries in recent
medicinal plant research
 1967- extracts of Artemisia was found to have
antimalarial activity
 1972- artemisinin isolated from the plant
 1979- structure of artemisinin determined by
X-ray analysis
 Chemical Structure
Sesquiterpene Trioxane Lactone

Structure of Artemisinin Derivatives

Structure of Artemisinin
 UNIQUE QUALITIES OF ACTs
 Unique mode of action of the artemisinin
component which includes:
 Rapid and substantial reduction of the parasite
biomass,
 Rapid parasite clearance,
 Rapid resolution of clinical symptoms,
 Effective action against multidrug-resistant P.
falciparum,
 Reduction of gametocyte carriage, which
potentially reduces transmission of resistant
alleles.
 UNIQUE QUALITIES OF ACTs
 Artemisinin kills rapidly and substantially most of the
parasites.
 Remaining are then killed by a high conc of the
companion drug.
 The efficacy and short half life (< 1 hr) of the
artemisinins offer protection against resistance.
 The long half life companion drug kills the rest of the
parasites.
 In this way, the probability that mutant parasites survive
and emerge from these two drugs is low.
 Resistance
 Currently no evidence for clinically relevant
artemisinin resistance

 Reasons for delay of artemisinin resistance:

 Short half-life
 Reduces transmission potential

 Used in combination with other antimalarial drugs

 Combination Therapy
 Use of artemisinin-based combined therapies would
help delay antimalarial drug resistance
 Summary
 Artemisinin induce rapid killing of parasites
 Fast clearance rate
 Very few side effects
 Artemsinin-resistant parasites have not been
identified
 Should be used in combination with other
antimalarial drugs
MECHANISM OF ACTION
Site of Action

Artemisinin

Conventional
Treatment

Artemisinin
 Mechanism of Action
 Killing of malaria parasite is mediated by
production free radicals
 Artemisinin derivatives lacking endoperoxide
bridge are devoid of antimalarial activity
 Addition of free radical generating compounds
enhances antimalarial activity
 Antioxidants block antimalarial activity
 Mechanism of Action
 Heme/iron mediates breakage of endoperoxide
bridge
 Chloroquine antagonizes the antimalarial activity
 Iron chelators antagonize antiparasitic effect of
artemisinin

 Artemisinin-derived free radicals bind to

protein through alkylation
Mechanism of Action
 Mechanism of Action
 Inhibit hemozoin biosynthesis or cause
hemozoin degradation
 Inhibit hemoglobin digestion by malaria
parasites
 Forms covalent adducts with malarial proteins
ADVERSE DRUG REACTIONS
 Adverse Reactions
 Very few adverse reactions
 Common side effects include
 Nausea
 Vomiting
 Anorexia
 dizziness
 Safe for pregnant women
 A trial conducted in northwest Thailand has found that it is
safe to use artemisinin combination therapy (ACT) to treat
pregnant women (2nd or 3rd trimester) with malaria, but that
efficacy is inferior to single-drug artesunate treatment.
 Science Daily (Dec. 22, 2008)
DOSAGE REGIMEN
 DOSAGE REGIMEN
 The following ACTs are currently recommended:
 Artemether-lumefantrine,
 Artesunate + amodiaquine,
 Artesunate + mefloquine,
 Artesunate + sulfadoxine-pyrimethamine.

 Officially adopted ACT for uncomplicated malaria in

Nigeria is Artemether-Lumefantrine (AL)
 DOSAGE REGIMEN
 The partner medicines of all other
ACTs have been previously used as
monotherapies

 Lumefantrine absorption is enhanced with fat

hence the need to take AL with milk or fat-
containing food – particularly on the second
and third days of treatment.
 DOSAGE REGIMEN
 This is currently available as co-formulated
tablets containing 20 mg of artemether and
120 mg of lumefantrine.

 The total recommended treatment is a 6-dose

regimen of artemether-lumefantrine twice a
day for 3 days.
 DOSAGE REGIMEN
Artemether/Lumefantrin
 Weight (Age group) Number of tablets/dose
5-14kg (6mths-3yrs) 1 tab twice daily x 3days

15-24kg (4-8yrs) 2 tabs twice daily x 3days

25-34kg (9-14yrs) 3 tabs twice daily x 3days

>35kg (>14yrs) 4 tabs twice daily x 3days

 DOSAGE REGIMEN
 Artesunate (4mg/kg) + amodiaquine (10mg
base/kg) daily for 3 days.

 Artesunate (4mg/kg) once daily for 3 days +

mefloquine 25mg base/kg (15mg/kg on day 2,
10mg/kg on day 3).
 Artesunate + Amodiaquine
Artesunate (50 mg) Amodiaquine(153mg)
Day 1 Day 2 Day 3 Day 1 Day 2 Day 3
5-11 25 (1/2) 25 25 76 (1/2) 76 76

1-6 50 (1) 50 50 153 (1) 153 153

7-13 100 (2) 100 100 306 (2) 306 306

14&A 200 (4) 200 200 612 (4) 612 612

 SEVERE MALARIA
 For severe malaria:

 Artesunate 2.4 mg/kg bw i.v. or i.m. given on admission

(time = 0), then at 12 h and 24 h, then once a day;

 Artemether 3.2 mg/kg bw i.m. given on admission then

1.6 mg/kg bw per day;

 Quinine 20 mg salt/kg bw on admission (i.v. infusion or

divided i.m. injection), then 10 mg/kg bw every 8 h; infusion
rate should not exceed 5 mg salt/kg bw per hour.
 PREGNANCY

 For severe malaria in full doses. Where

available, artesunate is the first, and artemether
the second option in the second and third
trimesters.

 In the first trimester, until more evidence

becomes available, both artesunate
and quinine may be considered as options.