ANTIMALARIAL DRUGS

GROUP 1
ELVIN MBUGUA NGUGI 1047069
TITUS MAKAU KISILU 1046819
MARY AYIEKO AKOYI 1036684
MARY BRENDA NGIMA 1046837
DIANA CHEPNGENO 1046830
ANITA LOPOKOIYIT 1046813
TED MWITI 1031155
 What is Malaria?
• Acute infectious disease caused by four
species of the protozoa Plasmodium. It is
transmitted to humans through the bite of the
female anopheles mosquito.
• 4 species:
 P. falciparum
 P. vivax
 P. malariae
 P. ovale
 P. knowlesi (uncommon)
 TYPES OF MALARIA
a) Falciparum malaria – caused by p. falciparum. Most
dangerous and is the primary cause of severe malaria
e.g. cerebral malaria. It causes hemolysis of RBC
resulting in anemia and weakness. Haemoglobin
released from these cells causes the urine to darken
giving rise to the term black water fever. When
treated immediately, responds well to treatment. If
not leads to irreversible shock and death. Once
eliminated the patient is free of the disease as p.
falciparum does not form hypnozoites that remain
dormant in the liver. Drug resistance is common.
b) Vivax malaria – the most common form of malaria. Caused
by p. vivax. Drug resistance is uncommon. Relapse is
common as dormant parasites, hypnozoites, remain in the
liver.

Malaria may be “uncomplicated” or “severe”.

• Uncomplicated – A patient who presents with symptoms of
malaria and a positive parasitological test (microscopy or RDT)
but with no features of severe malaria. Symptoms: fever,
chills, sweats, headache, muscle ache, nausea vomiting
• Severe (complicated) – symptoms: confusion, coma, severe
anemia, respiratory difficulty, hypoglycemia, jaundice,
pulmonary edema

Dx of malaria: blood smear test

LIFE CYCLE OF MALARIA PARASITE
The cycle takes place in two hosts: humans and female
anopheles mosquito. Asexual reproduction occurs in
humans while sexual reproduction occurs in the
mosquito.
Pre-erythrocytic/exo erythrocytic phase of the life cycle
1. Begins when sporozoites are injected into the
bloodstream by an infected female aopheles
mosquito.
2. Sporozoites migrate to the liver, invade the
hepatocytes.
 They either multiply and transform into merozoites
 Transform into hypnozoites and remain dormant
(months to years)
Erythrocytic phase
3. Merozoites are released infect the RBCs, there they
transform into trophozoites then to schizonts. The
RBC rupture releasing the schizonts and pyrogens.
The schizonts develop into new merozoites which
infect new RBCs, and the cycle of RBC invasion and
lysis continues.
The three steps above are part of asexual reproduction.
4. Sexual reproduction begins with formation of
gametocytes which differentiate from merozoites.
5. Gametocytes enter the female anopheles mosquito
when it ingests blood when feeding.
6. In the mosquito, the gametocytes
differentiate into mature forms, fertilization
occurs, the resulting zygote produces
sporozoites.
The cycle then repeats itself.
 Principles of Antimalarial therapy
Malaria treatment should not be initiated, until the diagnosis has been
established by laboratory testing. “Presumptive treatment”, i.e.,
without prior laboratory confirmation, should be initiated only in
extreme circumstances, such as strong clinical suspicion of severe
disease in a setting where prompt laboratory diagnosis is not available.
Anti-malarial therapy should be guided by the following four main
factors:
• The infecting Plasmodium species,
• The clinical status of the patient,
• Expected drug susceptibility of the infecting parasite as determined
by the geographic area where the infection was acquired; and
• Previous use of antimalarials, including those taken for malaria
chemoprophylaxis.
• The infecting Plasmodium species – Plasmodium
falciparum and P. knowlesi infections can cause
rapidly progressive severe illness or death, while the
other species, P. vivax, P. ovale, and P. malariae, are
less likely to cause severe disease. Secondly, P. vivax
and P. ovale infections also require treatment for the
hypnozoites, which remain dormant in the liver and
can cause relapsing episodes. Thirdly, P. falciparum
and P. vivax species have different drug resistance
patterns in different geographic regions of the world.
Finally, for P. falciparum and P. knowlesi infections,
the urgent initiation of appropriate therapy is
especially critical.
• The clinical status of the patient - Patients
diagnosed with uncomplicated malaria can be
effectively treated with oral antimalarials. However,
patients with severe malaria should be treated
aggressively with intravenous antimalarial therapy
• Expected drug susceptibility of the infecting
parasite as determined by the geographic area
where the infection was acquired; provides
information on the likelihood of drug resistance of
the infecting parasite and enables the treating
clinician to choose an appropriate drug or drug
combination.
• Previous use of antimalarials, including those
taken for malaria chemoprophylaxis- It is
important to consider if malaria occurred
while an individual was taking a drug for
malaria chemoprophylaxis. In this case, the
treatment regimen should not include the
drug or drug combination used for prophylaxis
unless no other options are available.
 Aim of Antimalarial Therapy
1. Treatment of an acute attack (clinical cure): eliminate
parasites from RBC, therefore the erythrocytic cycle is
stopped.
2. Prevention of relapse – pts infected with p.vivax and p. ovale
harbor hypnozoites in the liver. The use of drugs to completely
eradicate parasite from the body is called radical cure.
3. Prophylaxis – prevention of malaria. Used by people travelling
to malaria endemic areas. Two types of prophylaxis:
– Casual prophylaxis: these are directed against the
preerythrocytic phase of the malaria parasite
– Suppressive prophylaxis: these drugs cannot prevent primary
infection of the liver but prevent infection of the RBCs
(erythrocytic phase).
 PROPHYLAXIS FOR MALARIA
• Recommendations for drugs to prevent malaria differ by
country of travel and can be found in Malaria Information by
Country. Recommended drugs for each country have
comparable efficacy in that country
• No antimalarial drug is 100% protective and must be
combined with the use of personal protective measures, (i.e.,
insect repellent, long sleeves, long pants, sleeping in a
mosquito-free setting or using an insecticide-treated bednet).
• For all medicines, also consider the possibility of drug-drug
interactions with other medicines that the person might be
taking as well as other medical contraindications, such as drug
allergies.
 PROPHYLAXIS FOR MALARIA
• Atovaquone – proguanil combinations (malarone):
(PO). Start 1 day before departure and continue for 7
days after return. Contraindicated: pregnancy,
breastfeeding mothers, children < 11 kg. (Casual
prophylaxis)
• Mefloquine(PO): Start at least 1 week ( preferably 2
to 3 weeks) before departure and continue for 4
weeks after return. Use in special groups: pregnancy-
not recommended in first trimester, safe for breast
feeding mothers. Children: not recommended if <
5kg (suppressive prophylaxis)
• Doxycycline (PO) - start 1 day before departure and
continue for 4 weeks after return. C/I: pregnant,
breastfeeding, children <8kg, liver dysfunction,
hypersensitivity. (suppressive prophylaxis)
• Proguanil (PO) - start one day before departure and
continue for 4 weeks after return. Safe: pregnant,
breastfeeding and children. (casual prophylaxis)
• Chloroquine (PO)- Start at least 1 week before
departure and continue for 4 weeks after return.
(suppressive prophylaxis)
NB: Chloroquine is not used as a prophylaxis in areas
where chloroquine resistant falciparum has developed
e.g. Kenya
• In areas of moderate to high malaria transmission,
Intermittent Preventive Treatment in Pregnancy (IPTp)
with sulfadoxine and pyrimethamine is recommended for
pregnant women. IPTp-SP should start as early as possible
in the second trimester and not before week 13 of
pregnancy.
• Seasonal malaria chemoprevention - In areas of seasonal
malaria transmission, children belonging to age groups at
high risk of severe malaria should be given antimalarial
medicines during peak malaria transmission seasons -
Monthly cycles of sulfadoxine-pyrimethamine plus
amodiaquine (SP+AQ) have been widely used for SMC in
African children under 5 years old.
• Malaria vaccine – RTS, S vaccine , GSK vaccine
 TREATMENT OF UNCOMPLICATED MALARIA
TYPE OF MALARIA DRUG
P. falciparum malaria Treat children and adults with uncomplicated P. falciparum
Chloroquine resistant malaria (except pregnant women in their first trimester) with
one of the following ACTs:
Artemisinin-based combination therapies:
• 1st line treatment in Kenya - Artemether + Lumefantrine,
twice daily for 3 dys PO
• 2nd line treatment in Kenya – Dihydroarmetisinin- piperaquine
3 days PO
Other combinations:
• Artesunate + Amodiaquine 3 days PO
• Artesunate + Mefloquine 3 days PO
• artesunate + sulfadoxine–pyrimethamine (SP) 3 days PO
In case of no response to ACT (clinically and parasitologically) -
7-day treatment regimens (with artesunate or quinine) both of
which should be co-administered with + tetracycline, or
doxycycline or clindamycin)
Chloroquine-resistant P. ACTs containing piperaquine, mefloquine or
vivax lumefantrine are the recommended treatment

P. vivax malaria Oral chloroquine at a total dose of 25 mg base/kg

(chloroquine-sensitive)

P. falciparum malaria • First trimester: Quinine for 7 days. Quinine is

uncomplicated usually administered in combination with
in pregnancy doxycycline, tetracycline, or clindamycin.
• Second and third trimesters: ACT as above

Mixed infection (P. vivax + P. To be treated as P. falciparum

falciparum) case

Treatment of P. ovale and P. Treat P. ovale as P. vivax and P. malariae as P.

malariae cases falciparum
 TREATMENT OF COMPLICATED/SEVERE MALARIA
TYPE OF MALARIA DRUG
SEVERE MALARIA Treat adults and children with severe malaria (including
infants, pregnant women in all trimesters and lactating
women) with intravenous or intramuscular Artesunate:
given on admission (time = 0 hour); then at 12 hours and
24 hours and then once a day. Once a patient has
received at least 24 h of parenteral therapy and can
tolerate oral therapy, complete treatment with 3 days of
ACT. Quinine can be used if Artesunate is not available.

Artesunate is dispensed as a powder of artesunic acid,

which is dissolved in sodium bicarbonate (5%) to form
sodium artesunate. The solution is then diluted in
approximately 5 mL of 5% dextrose and given by
intravenous injection or by intramuscular injection into
the anterior thigh.

NB. Dosage of antimalarial drugs is based on weight

 CLASSIFICATION OF ANTIMALARIAL DRUGS

• Blood schizontocides– act on erythrocytic

forms of malaria parasite: Chloroquine,
Amodiaquine, Quinine, Mefloquine,
Pyrimethamine, Lumefantrine, Artemisinin,
Atovaquone
• Casual prophylactics- act on preerythrocytic
forms of malaria parasite: Proguanil,
Primaquine, Pyrimethamine
• Tissue schizontocides (radical curatives) –
drugs effective against hypnozoite forms of p.
vivax and p. ovale. Primaquine
• Gametocytocidal drugs-act on sexual
erythrocytic forms. For vivax: Chloroquine and
Quinine. For falciparum : Primaquine
• Sporontocides: inhibit life cycle of malaria
parasite in mosquito. Primaquine and
Proguanil
 Chloroquine
Is an antimalarial and amoebicidal drug
MOA - Chloroquine accumulates in the food vacuole of
plasmodia and prevents polymerization of the
hemoglobin breakdown product heme into hemozoin.
The accumulation of heme results in lysis of both the
parasite and the red blood cell.
Indication - Prophylaxis and treatment in areas without
chloroquine resistant P falciparum; treatment of P
vivax and P ovale malaria. Use is now limited due to P.
falciparum resistance. Other uses: rheumatoid arthritis,
SLE, Amoebic liver abscess
• PK - Rapidly absorbed following oral administration. The drug
has a large volume of distribution and concentrates in
erythrocytes, liver and spleen. It persists in erythrocytes. The
drug also penetrates the central nervous system (CNS) and
traverses the placenta. Metabolism – dealkylated in liver,
excretion – urine
• Resistance: mutation in transporter protein PfCRT. Reduces
chloroquine accumulation in the food vacuole of the pathogen.
• Adverse effects - GI distress, rash, headache; auditory
dysfunction and retinal dysfunction (high dose), Discoloration
of the nail beds and mucous membranes may be seen on
chronic administration. Hemolysis in G6PD deficient pts
• C/I: Patients with psoriasis or porphyria. Hypersensitivity 4-
aminoquinoline compounds. Long term therapy in children
• Drug Interaction:
Chloroquine can prolong the QT interval, and use
of other drugs that also cause QT prolongation
should be avoided if possible.
Digoxin: Plasma digoxin levels may increase
Antacids: Absorption of chloroquine may be
reduced
Ampicillin: Choloroquine reduces its bioavailability
therefore should be given at intervals of at least 2
hours.
Cyclosporin: Increase in serum cyclosporine
level,requires close monitoring.
 Quinine
• MOA - interferes with heme polymerization, resulting in death of the
erythrocytic form of the plasmodial parasite.
• Indication - It is reserved for severe infections and for chloroquine-
resistant malarial strains. P. falciparum malaria uncomplicated in pregnancy
• PK: Rapidly and completely absorbed from GITquinine is well distributed
throughout the body. Excreted in urine
• Adverse effects:
 The major adverse effect of quinine is cinchonism, a syndrome causing
nausea, vomiting, tinnitus, and vertigo. These effects are reversible and are
not reasons for suspending therapy. However, quinine treatment should be
suspended if hemolytic anemia occurs.
 Hypoglycaemia can occur in pregnant women.
 Less common but more severe side effects include – Asthma, Skin lesions,
hrombocytopenia, Liver damage, Psychotic episodes
• C/I:
 Hypersensitivity to toquinine,melfoquine,
Quinidine
 Optic neuritis
 Hemoglobinemia
 Primaquine
• MOA: act as oxidants that severely disrupt the metabolic processes
of plasmodial mitochondria. Also limits malaria transmission by acting
as a gametocide
• Indication:
 Sporontocide: inhibit life cycle of malaria parasite in mosquito
 Effective against hypnozoite forms of p. vivax and p. ovale
 Act on sexual erythrocytic forms of p. falciparum
• PK - Well absorbed after oral administration and is not concentrated
in tissues. It is rapidly oxidized to many compounds, primarily the
deaminated drug. Excretion: urine
• Adverse effects: GI distress, methemoglobinemia, drug-induced
hemolytic anemia in patients with G6PD deficiency,
• C/I: Primaquine should not be used during pregnancy or in patients
with G6PD deficiency.
 Mefloquine
• MOA: is not completely understood. Some studies suggest
that mefloquine specifically targets the 80S ribosome of
the Plasmodium falciparum, inhibiting protein synthesis
and causing subsequent schizonticidal effects
• PK: It is readily absorbed from the gastrointestinal tract;
food significantly increases absorption. Wide distribution.
Metabolism – liver by CYP450 enzymes. Excretion: bile
and feaces.
• Indications:
 Prophylaxis from all plasmodia and for treatment when
 used in combination with an artemisinin derivative for
infections caused by multidrug-resistant forms of P. falciparum.
• Adverse effects: nausea, vomiting, and
dizziness to disorientation, hallucinations, and
depression. Because of the potential for
neuropsychiatric reactions, Mefloquine is
usually reserved for treatment of malaria
when other agents cannot be used.
• Drug interactions: ECG abnormalities and
cardiac arrest are possible if mefloquine is
taken concurrently with quinine or quinidine.
 Sulphonamide-Pyrimethamine

• Fixed dose combination. The synergistic

combination of long-acting sulfonamides enhances
the antimalarial action.
• MOA of sulphonamides: Bactericidal. Inhibit the
enzyme dihydropteroate synthetase which is an
enzyme necessary in the conversion of PABA to folic
acid. As folic acid is vital to the synthesis, repair,
and methylation of DNA which is vital to cell growth
in Plasmodium falciparum. With this vital nutrient
lacking, the parasite has difficulty in reproducing.
• MOA of pyrimethamine: inhibits plasmodial dihydrofolate
reductase required for the synthesis of tetrahydrofolate (a
cofactor needed for synthesis of nucleic acids).
• PK: Well absorbed in GIT. Metabolism: liver. Excretion:
urine
• Resistance to this combination has developed, so it is
usually administered with other agents, such as
artemisinin derivatives.
• Indications:
 In areas of moderate to high malaria transmission, Intermittent
Preventive Treatment in Pregnancy (IPTp)
 P. falciparum malaria - Chloroquine resistant
 This combination is also used in toxoplasmosis.
• Adverse effects: Due to sulfonamide moiety,
adverse effects such as exfoliative dermatitis
and Stevens-Johnson syndrome are observed.
Megaloblastic anaemia
 Artemisinin and derivatives
• Artemisinin and its derivatives are recommended first-line
agents for the treatment of P. falciparum malaria. It causes
more rapid clearance of the parasite and clinical improvement.
• MOA: its active metabolite DHA reacts with haem generating
free radicals which inhibit protein and nucleic acid synthesis of
the plasmodium
• PK: Oral, rectal, intramuscular (IM), and intravenous (IV)
preparations are available, but the short half-lives prevent their
use in prophylaxis. Metabolism: liver
• Addition of another antimalarial agent, or artemisinin-based
combination therapy (ACT), is recommended to prevent the
development of resistance.
• Derivatives: Artemether, Artesunate,
Dihydroxyartemisinin
• ACT combinations:
Dihydroartemisinin–piperaquine (superior)
Artemether + lumefantrine,
Artesunate + sulfadoxine–pyrimethamine,
Artesunate + amodiaquine
• Adverse effects – nausea, vomiting, abdominal pain,
diarrhea, prolongation of QT interval and cardiac
arrythmias. Hypersensitivity reactions and rash.
Benefits of ACT therapy
High efficacy
Fast action
Reduced likelihood of resistance developing
 Amodiaquine
It is an orally active 4- ominoquinoline derivative
with antimalarial and anti-inflammatory
properties. It is not widely used.
• MOA: not been fully established, it is likely to
inhibit heme polymerase activity in the body
resulting in accumulation of free heme which is
toxic to parasites
• Indications: Used in combination with
artesunate against some chloroquine- resistant
stains especially Plasmodium falciparum
• PK: Oral administration. Metabolism: liver (prodrug
converted to its active metabolite by enzymes in the liver).
Elimination: renal
• Adverse effects- Severe liver impairment and
hypersensitivity, irregular heartbeat, Nausea and vomiting,
diarrhoea, dizziness, rash.
• C/I:
 Not recommended for use in pregnant women unless
absolutely necessary, women who are breastfeeding.
 Should not be given to patients with liver impairment due
to increased risk of adverse effects
 Should be used with caution in patients with kidney
impairment
 Lumefantrine
• It is used for the treatment of uncomplicated
malaria due to P. falciparum and chloroquine-
resistant strains. It is effective against the
erythrocytic phase of Plasmodium species. It is
administered in combination with artemether
for improved efficacy and for the treatment of
chloroquine-resistant species.
 Atovaquone & Proguanil
• Indications: The combination of atovaquone
plus proguanil, available as Malarone, is
highly effective for both the prophylaxis and
treatment of malaria caused by chloroquine-
resistant plasmodia. Both drugs are active
against erythrocytic and exoerythrocytic
plasmodial forms, including strains that are
resistant to chloroquine, mefloquine, and
pyrimethamine/sulfadoxine.
• MOA Atovaquone: disruption of mitochondrial
electron transport.
• MOA Proguanil: It is inactive as administered,
but gets converted to cycloguanil, its active
form. It inhibits plasmodial dihydrofolate
reductase, preventing activation of folic acid.
In the absence of usable folic acid, the
parasite is unable to make DNA, RNA, and
proteins.
• PK: Absorption of atovaquone is low and variable,
but can be greatly enhanced by fatty foods. It
undergoes excretion unchanged in the feces.
Proguanil is extensively absorbed, both in the
presence and absence of food. The drug
concentrates in erythrocytes and undergoes
hepatic metabolism followed by renal excretion.
The combination should be taken with food or
milk to enhance absorption.
• Common adverse effects include nausea,
vomiting, abdominal pain, headache, diarrhea,
anorexia, and dizziness.
 Other Antibiotics
Tetracyclines
• Two members of the tetracycline family—doxycycline
and tetracycline—are used against chloroquine-
resistant malaria. Both drugs kill the erythrocytic forms
of the malaria parasite, although the rate of kill is slow.
• Doxycycline is used for prophylaxis and for acute
attacks, whereas tetracycline is used for acute attacks
only. To treat acute attacks, these drugs are combined
with quinine, which acts more quickly than the
tetracyclines
 REFERENCES
• Whalen, K. (2019). Lippincott Illustrated
Reviews: Pharmacology. Wolters Kluwer: New
Delhi, India
• WHO Guidelines for Malaria 3rd June 2022.
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