Antimalarial drugs

 Identify drugs that target human ‘liver stage’ of malaria, i.e,

tissue stage, exo-erthrocytic stages, (few drugs target liver
stage)
 Drugs that affect active liver stages (tissue schizonts)
 Drugs that affect dormant/ hyponozoites/relapsing liver stages
(only two drugs: Primaquine and Tafenoquine)
 Distinguish drugs that target human ‘blood stage’ of malaria, i.e,
erthrocytic stage, blood schizonts (most drugs target blood
stage)
- NB, no dormant blood stage
 Drugs that affect gametocytes and inhibit transmission to
mosquito, and drugs that inhibit sporozoite formation in
mosquitoes, hence no transmission to other individuals
 Elaborate the side effect and mechanism of actions of
antimalarial drugs
 Discuss regimens used for prophylaxis and treatment of
 Drugs used in causal prophylaxis
-Drugs that can affect liver exo-erythrocytic stage
 Drugs used in clinical/suppressive prophylaxis (blood stage)
 Drugs used in radical cure (liver stage +blood stage)
- Needs drugs for dormant + drugs for blood stage
 Drugs used in clinical cure (acts on blood stage only)
distinguish the terms
-recrudescence (due to incomplete eradication of the parasite)
- Relapse (because of dormant parasites in the liver)
 Revise the malaria pathologic steps, and understand that
these steps are antimalarial drug target (the human two
stages, and the Anopheles mosquito stage)
 Antimalarial agents
Malaria: caused by protozoa of the genus plasmodium
 killing > 1/2 million each year
 Life cycle of malaria parasite: Takes place in two hosts
o In human (asexual reproduction) &
o Female anopheles (sexual reproduction), primary host
 Types of malaria
Caused by 5 different species of plasmodium [p.vivax, p.falciparum, p. ovale, p.
malariae, P. knowlesis]
• P. falciparum malaria (most common):
• Common parasite with P. vivax.
• On the top to severe malaria and death
• Resistant to most of the drugs
P. vivax malaria:
 P. vivax is the most widespread of the malaria species outside Africa.
 Developing severe malaria is lower than P. falciparum
 Resistance to antimalarials is also lower than the aformentioned
 Antimalarial Agents
 P. vivax and P. ovale
- Additionally, have dormant phase where they may develop later to disease.
- Also known as hypnotic phase
- Hides in the liver, after clearing the parasites from the circulation
- Long after treatment, the dormant parasites cause a new malaria disease (relapse)
This not due to new infection , but because of relapse from those hidden in liver
- So, relapse is characteristics of P. vivax and P. ovale

-To affect these dormant parasites, in addition to the treatment for the other parasites
Primaquine or Tafenoquine is added to the regimen.

 P. Knowles malaria
• Zoonotic disease (meaning it is transmitted from animals to human)
• Transmitted from monkey to humans through Anopheles mosquitoes
• Commonly found in Asia
• Can also cause severe malaria like that of P. falciparum
 Antimalarial agents
 Steps followed in malaria infection:
1. Anopheles mosquito pierces the skin, and injects sporozoite in to human
circulation

2. Through the circulation the malaria sporozoites of any type first arrive at the
liver (All the infective plasmodial species). The malaria stage in the liver is known as
tissue stage or exorythrocytic stage to mean the parasite is not in the circulation, it
is in the liver.

3. In the liver they start to multiply asexually to form schizonts. The schizonts form
meroziotes, the merozoites then move from the liver to blood. In .P vivax and P.
ovale, some of the schizonts may come to hide in the liver and stay dormant. The
dormant stage is known as hypnozoites.
In liver, so, we have two types of parasites: Active Schizonts and hypnozoites. As the
active schizonts do not stay in the liver, finally, they come to circulation, so drugs
that act in the blood may kill in blood (most scenario), or some drugs may act on
them before they arrive in the circulation.
The dormant parasites develop to disease after some months, or even years. So,
two drugs (Pramquine or Tafenoquine should used in addition to other drugs for
active malaria schizonts or blood stage, if P. vivax and P. ovale)

4. Merozoites move to blood because they are in search for Red blood cells like
hyena is searching for donkeys or a cat hunting rats. (to mean they feed RBCs)
 Antimalarial agents
 Steps followed in malaria infection:
5. In blood, they invade red blood cells. After on, the parasite is said be blood schizonts/
Erythrocytic stage/blood stage. Inside RBCs, the schizonts feed hemoglobin, multiply and
form merozoites. After multiplying multiple times in RBCs, they fill the RBCs and causes
the RBCs to burst. The Bursting RBCs release the contents in side them to circulation
including lysosomes and toxic compounds in them. This occurs at regular intervals
causing regular symptoms.

The release of these toxic chemicals in to the blood induces our immune system to
produce inflammatory mediators causing inflammation. It is this RBCs bursting and
releasing their toxic components to the circulation that is responsible to the signs and
symptoms seen in malaria infection. (Chills, raise in temperature, etc .). Hence, it is the
blood stage of the parasite which is responsible for clinical sign and symptoms of malaria,
not tissue (liver stage).

The merozoites released in to circulation after bursting of RBCs, again infect other RBCs
causing further damages and depleting RBCs from the circulation. As malaria affects the
RBCs, i. e, causes their hemolysis, malaria leads to a type of anemia which is known as
hemolytic anemia. So, cells cannot get O2, a condition known as ischemia. Hence, cells
including brain cells do not get sufficient O2, and die. The severity is very high in P.
falciparum.
 Antimalarial agents
 Steps followed in malaria infection:
 Some of the schizonts in the blood develops to gametes (male and female), instead
of infecting RBCs again and again. These gametes are not causing harm to the
infected individuals. Instead, they are taken by the mosquitoes and form zygotes in
mosquitoes, which develops to sporozoites that infect normal individual when the
mosquito bite him/her. So, if we kill gametes in the blood of the an individual
infected with Plasmodium, then we can inhibit transmission to the other individuals.
(gametocidal drugs: transmission inhibitors)

 The reason why the malaria parasites invade RBCs is to digest and eat hemoglobin.
The parasite takes hemoglobin in to its food vacuole, and digest it. Hemoglobin is
an important component of RBCs that transports O2 to tissues. Hemoglobin is
digested to Heme and amino acids by plasmodium. Amino acids are used as food by
the parasite while heme formed is toxic to the parasite. Hence, the parasite converts
heme to a nontoxic molecule which is known as hemozoin. This reaction is catalyzed
by the enzyme which is known as heme polymerase.

 The digestive process and the detofication of heme occurs in the acidic environment
of the parasite food vacuole. Hence, most antimalarial drugs act by raising the PH
inside the food vacuole of the parasite inhibiting hemoglobin digestion, disrupts the
activity of enzymes such hemepolymerase leading to heme accumulation and death
of the malaria parasite.
8
2/23/2024 9

Life cycle of the malarial parasite:

Exoerythrocytic
stage
1.
2.
Erythrocyt
ic stage

1
 Cont’d Antimalarial agents
• Chemotherapy of malaria
– Considered in relation to the biology of infection/steps of replication
1. Drugs active against sporozoites: (acting on mature sporozoites)
– True causal prophylaxis, on sporozoites released after mosquito bite.
– No drug is yet available
2. Drugs active against pre or primary exo-erythrocytic stage
– Causal prophylaxis [primary tissue schizonticides]=active liver stager
– Proguanil & pyrimethamine
o Kill the parasites before RBCs are invaded
o Primaquine has causal prophylaxis activity especially against p.falciparum but its
use is unsafe
3. Drugs active against the secondary exo-erythrocytic stage [persistent liver cycle,
hypnozoite]=dormant liver stage
o Secondary tissue schizonticide
o Primaquine, Tafenoquine act on hypnotic of p.vivax
4. Drugs active against the erythrocytic stage [blood schizonticides]
a. Suppression or clinical prophylaxis
- Chloroquine, proguanil, mefloquine
Used for temporary prevention of clinical symptoms
 Cont’d Antimalarial agents
• - Kill blood schizonts, but the tissue schizonts are not destroyed
• - Falciparum promptly cured
• b. Clinical cure
• i. 4-aminoquinolines
– Cholorquine, Amodiaquine
• ii. Quinoline methanol
– Quinine, Quinidine, Mefloquine
• iii. Artemisinin compounds
• Dihyddroartemisinin, Artemether,
•  Interrupt the erythrocytic cycle of the malaria parasite
5. Drugs active against the sexual stage
• A. Gametocidal: primaquine
• B. Sporontocides: proguanil & pyrimethamine
•  gamates become incapable of forming sporozoite
 Cont’d Antimalarial agents
THERAPEUTIC OBJECTIVE
- P. falciparum is almost resistant to Chloroquine every
where, P. vivax is sensitive to Chloroquine in most areas.
Drugs for prophylactic of malaria in
travellers

132
5
 CHLOROQUINE

Mechanism: remains controversial; probably acts

• - On heme disposal by preventing digestion of heamoglobin by the
parasite and thus reducing the supply of amino acid necessary for
parasite viability.
• - Also inhibits heme polymerase
• - Alkalization (PH increased) of food vacuole
Therapeutic uses
• - Malaria
• Rx of malaria caused by: p.vivax, p.ovale, p.malarae
• Chloroquine sensitive p.falciparum
• Chemoprophylaxis
• - Amebic liver abscess: given combined with metronidazole
• - Rheumatoid arthritis
• - Discoid lupus erythromatous
 Cont’d CHLOROQUINE
Adverse effects
– CVS (parenteral dose): vasodilation, hypotension, decrease
myocardial infarction, ECG changes
– Oral route can cause (high dose)
• Visual disturbance
• Urticaria
• Headache
• GI upset
– Rare reaction include hemolysis in pts with G6PD deficient
– High daily doses of chloroquine :Irreversible ototoxicity &
retinopathy
– Chloroquine is safest drug in pregnancy
CONTRAINDICATION
– Psoriasis
– porphyria cutanea tarda
 QUININE & QUINIDINE

• Derived from the bark of cinchona bark

• Mechanism: increases PH in the vacoule, then heme not detoxified
• Pharmacological effects
– Quinine acts primarily as blood schizonticidal
• Gametocidal for p.vivax, p.ovale, p.malarae
• Not effective liver stage parasite
– Quinine is the drug of choice for severe illness due to chloroquine
resistant & MDR strains of p.falciparum
– Used in severe malaria in first trimester of pregnancy. Otherwise,
the drug of choice in severe malaria is artisunate injection except
in first trimester of pregnancy.
– Potentiation of neuromuscular blocking drugs
• Therapeutic use
– Rx malaria
• Cure of chloroquine resistant & MDR p.falciparum
• Reserved for severe P. falciparum in pregnancy (1 trimester)
st

• Rx nocturnal leg cramps

 Cont’d QUININE & QUINIDINE
• Toxicities & side effects
– Commonly causes:
• tinnitus
• Nausea
• Head ache Cinchonism
• Dizziness
• Flushing
– Hyperinsulinema- severe hypoglycemia, enhances insulin secretion
– Stimulate uterine contraction,
– Black water fever
• marked hemolysis & hemoglobinuria
• Due to hypersensitivity reaction to the drug
• Contraindications
– Hypersensitivity reaction to quinine
– Severe cinchonism
• Drug interactions
– Absorption blocked by aluminum containing antacids
– Should not be given concurrently with mefloquine (cardiac arrest)
 Cont’d QUININE & QUINIDINE
MEFLOQUINE
• Antimicrobial action
– Effective blood schizonticidal
• Therapeutic use
– Chemoprophylaxis: nonimmune travelers
– Treatment: for malaria caused by chloroquine resistant & MDR p.
falciparum
• For severe or complicated malaria: quinine or quinidine are selected
• Adverse effects
– NVD; Abdominal pain, dizziness, dysphoria
– Higher doses cause
• Neuropsychiatric toxicity [disorientation, seizure, encephalopathy]
• Alter cardiac conduction, arrhythemias & bradycaridia
• Contraindications
– History of seizure & neuropsychiatry
– Combination with quinine & quinidine  Arrhythmia
 Primaquine and Tafenoquine
• Chemistry: synthetic 8-aminoquinoline
• Antimalarial action
– Active against hepatic stages of all human malarial parasite
– Gametocidal
• Therapeutic uses:
– Reserved primarily for radical cure of vivax & ovale malarias
– Used occasionally to interrupt malarial transmission by rendering plasmodial
gametocytes noninfectious to mosquitos
– Primaquine +Clindamycin: an alternative regimen for PCP
• Adverse effects: generally tolerated
– Infrequently causes
• Nausea
• Epigastric pain
• Abdominal cramp
• Head ache
– Hemolysis & methehemoglobinemia especially in persons with G6PD deficiency
 Cont’d PRIMAQUINE
• Contraindication to primaquine
– Granulocytopenia
– Methemoglobinemia
– Pregnancy as the fetus is deficient in G6PD

ARTEMISININ & ITS DERIVATIVE

• Artemisinin or Guinghaosu was isolated in 1972 from Artemisia
annua L. (discovered by Pharmacologist, Prof. Tu)
• The most active drugs we have today for malaria Rx
• Has been used in traditional Chinese medicine
• Derivatives: Artemether, Arteether, Artesunate, Artlinic acid
Adverse effect: Safe & well tolerated
• NVD (nausea, vomiting, darrhoea)
• Avoided in pregnancy if possible, but, except first trimester, it is the
drug of choice.
 Cont’d ARTEMISININ & ITS DERIVATIVE

• Mechanism: Act by interacting with heme to produce carbon-

centered free radicals that alkylate protein & damage
microorganelle & membranes of the parasites
• In contrast to other antimalarials:
– Artemisinins have very fast action
– Parasite clearance times are short
Therapeutic uses
• Active against all plasmodium species
• Should be administered in combination in order to:
– Reduce recrudescence
– Prevent or slow development of resistance
• uncomplicated malaria
• Due to short t1/2, they are not useful for chemoprophylaxis
 INHIBITORS OF FOLATE SYNTHESIS
Pyrimethamine
• Mechanism: Inhibit dihydrofolate reductase of plasmodia
• Therapeutic uses
– with sulphonamide
– not 1st line because it is slow to act
• suppressive Rx of chloroquine resistant p.falciparum
• Given concurrently with sulfadiazine for Rx of toxoplasmosis
• Adverse effect
– Erythema multiform
– Stevens’s Johnson syndrome
– Toxic epidermal necrosis
Proguanil: Inhibits dihydrofolate reductase
• prodrug metabolized to an active metabolite, cycloguanil
– Inhibition of DNA synthesis (folic acid inhibition).
– Depletion of folate co-factors (folic acid inhibition).
• Slow antimalarial action
• Therapeutic uses:
– With chloroquine used as alternative to Mefloquine for prophylaxis
– Not suitable for acute attack
– Considered safe for use during pregnancy
HALOFANTRINE & LUMEFANTRINE

• Halofantrine:
– Effective against erythrocytic stages of all for human malaria species
– Oral absorption is variable & is enhanced with food
– Plasma t 1/2  4 days
– Is generally well tolerated
• Abdominal pain
• Diarrhea
• Vomiting
• Cough, rash & head ache
• Altered cardiac conduction
• Lumefantrine:
– Availabe in fixed dose combination with artemether as Coartem
– T 1/2  4.5 hrs
• Coartem is very effective for Rx of p.falciparum
• Sulfonamides, tetracyclines, clindamycin

– Used in combination with antimalarials to increase

protozoacidal effects
 Dosage Recommendations for Prevention and Treatment of
Malaria
• Primary Prophylaxis
• For Travel To Chloroquine-Sensitive Areas:
• Chloroquine once weekly.
Start 1–2 weeks before leaving, take weekly while away, and then take
once weekly for 4 weeks after returning home
• Atovaquone/proguanil once daily started 1–2 days before travel, for
duration of stay, and then for 1 week after returning home
• Doxycycline by mouth once daily. Must be taken 1-2 days before
travel, daily while away, and then up to 4 weeks after returning.
• Mefloquine orally given once weekly
• For Areas with Mainly P. Vivax:
• Primaquine phosphate once daily by mouth. Starting 1 day before
leaving, taken daily, and for 3–7 days after return
 Dosage Recommendations for Prevention and Treatment of
Malaria
• Primary Prophylaxis
• For Travel to Chloroquine-Resistant Areas:
• Atovaquone/proguanil (Malarone) once daily, started 1–2 days
before travel, for duration of stay, and then for 1 week after
returning home
• Doxycycline by mouth once daily. Must be taken 1–2 days before
travel, daily while away, and then up to 4 weeks after returning
• Mefloquine orally given once weekly (maximum 250 mg)
 Dosage Recommendations for Prevention and Treatment of
Malaria…
• Secondary Prophylaxis
• For P. vivax or P. ovale:
• Primaquine dose orally, daily for 14 days after departure from the
malarious area
 Dosage Recommendations for Prevention and Treatment of
Malaria…
• Treatment
 Uncomplicated P. falciparum from Chloroquine-Sensitive Region
• Chloroquine phosphate: 16.6 mg/kg body weight (10 mg/kg body
weight chloroquine base) (maximum 1000 mg) by mouth once, then 8.3
mg/kg body weight (maximum 500 mg) by mouth at 6, 24, and 48
hours (total dose = 41.6 mg/kg body weight chloroquine phosphate
[maximum 2500 mg] = 25 mg/kg body weight chloroquine base)
• Same above dose for other Chloroquine sensitive malaria species, but
to inhibit relapsing species, Pramaquine daily for 14 days could be used.
 Dosage Recommendations for Prevention and Treatment of
Malaria…
• Treatment
 Uncomplicated P. falciparum from Chloroquine-resistant Region
• Mefloquine (250-mg tablets only): 15 mg/kg body weight (maximum 750 mg) by
mouth once, then 10 mg/kg body weight (maximum 500 mg) by mouth given 12
hours later
• Quinine sulfate 10 mg/kg body weight (maximum 650 mg) per dose by mouth every 8
hours for 3 to 7 days, plus Clindamycin 7 mg/kg body weight per dose by mouth
every 8 hours for 7 days, or doxycycline: 2.2 mg/kg body weight per dose (maximum
100 mg) given by mouth every 12 hours, or tetracycline 6–12.5 mg/kg body weight
per dose by mouth given every 6 hours (maximum dose: 500 mg per dose given 4
times daily) for 7 days.
• Artemether-lumefantrine: 1 tablet=20 mg Artemether and 120 mg lumefantrine, a 3-
day treatment schedule for a total of 6 doses. 4 tabs after fatty food bid for 3 days..
 Dosage Recommendations for Prevention and Treatment of
• Treatment Malaria
 Severe malaria (usually caused by P.falcuparum)
 Quinidine IV infusion for 3-7 days (1st trimester pregnancy)
PLUS One of the Following:
Doxycycline 100 mg per dose by mouth every 12 hours for 7 days; OR
Clindamycin 7 mg/kg body weight per dose by mouth given every 8 hours for 7 days.
OR
Tetracycline 6–12.5 mg/kg body weight per dose every 6 hours (maximum dose 500
mg per dose given 4 times daily) for 7 days
 Artesunate 2.4 mg/kg body weight IV bolus at 0, 12, 24, and 48 hours
PLUS One of the Following:
-Doxycycline (treatment dosing as above), or Atovaquone-proguanil (treatment dosing
as above), or
Mefloquine 15 mg/kg body weight (maximum 750 mg) by mouth once, then 10 mg/kg
body weight (maximum 500 mg) by mouth once given 12 hours later, or
-Clindamycin (dosing as above