ANTI-MALARIAL DRUGS

P HA R M ACO LO GY
Learning Objectives:
 To classify the Anti-Malarial drugs
 To explain schizonticide, gametocide, sporontocide, radical cure, suppressive
prophylaxis, terminal prophylaxis and causal prophylaxis with examples
 To describe mechanism of action of Anti-Malarial drugs
 To describe uses, adverse effects and contraindications of Anti-Malarial drugs
 To describe mechanism of action of Anti-Malarial drugs
 To describe uses, adverse effects and contraindications of Anti-Malarial drugs
Life Cycle Malarial Parasite
Symptoms Of Malaria
Cold Stage:
Feeling intense cold and shivering
(15-60 minutes)
Hot Stage:
High fever, dry burning skin,
throbbing headache (2-6 hours)
Sweating Stage:
Profuse sweating, decrease
temperature, feeling of exhaustion (2-4
hours)
Objectives Of Anti-Malarial Treatment
 Prevent clinical attack of malaria (prophylactic)

 Treat clinical attack of malaria (clinical curative)

 Completely eradicate the parasite from patient body (radical curative)
 Cutdown human-to-mosquito transmission (gametocidal)
Classification Of Anti-Malarial Drugs

ti c Ch
u em
a pe ica
e r l
Th
Therapeutic Classification

Causal Prophylaxis: (Tissue Schizonticides) Suppressive Prophylaxis:

Destroy parasite in liver cells and prevent Destroy merozoites released from liver
invasion of erythrocytes
Suppress the erythrocytic phase and protects
Primaquine, proguanil against clinical illness
Chloroquine, Proguanil, Mefloquine,
Doxycycline
Therapeutic Classification
Clinical Cure: (Erythrocytic schizonticides) Radical Curatives:
 Fast acting high efficacy Eradicate all forms malarial parasites
Chloroquine, Quinine, Mefloquine, Suppressive drugs + Hypnozoitocidal drugs
(that kill dormant stage of malarial parasite in
Atovaquone, Artemisinin liver)
 Slow acting low efficacy drugs  Primaquine
Proguanil, Pyrimethamine, Sulfonamides,
Tetracyclines
Therapeutic Classification
Gametocidal:
Destroy gametocytes and prevent transmission
Primaquine, Artemisinin – Against all
plasmodia
Chloroquine, Quinine – P. vivax
Proguanil, Pyrimethamine – Prevent development of sporozoites
Chemical Classification
4 Aminoquinolines: Chloroquine, Amodiaquine
8 Aminoquinolines: Primaquine
Quinoline methanol: Mefloquine
Cinchona alkaloids: Quinine, Quinidine
Folate antagonist combination: Sulfadoxine-Pyrimethamine (Fansidar)
Quinone – Folate antagonist combination: Atovaquone – proguanil (Malarone)
Tetracyclines: Doxycycline
Sesquiterpene lactones: Artesunate, Artemether
Phenanthrene methanol: Halofantrine
 SCHIZONTICIDES : Blood schizonticides are the first-line drugs for the treatment of
malaria
They must be started as soon as the diagnosis is made, or even suspected, in severe disease
They act on the asexual forms in the erythrocytes and interrupt clinical attacks
EXAMPLE : Chloroquine, Primaquinine

 GAMETOCIDE : An agent that destroys the gametocytes of a malaria parasite e.g. Quinine

 SPORONTOCIDE : Which has the property of killing or stopping the development of sexual
forms of the malaria parasite e.g. Proguanil
CHLOROQUINE
Mechanism of Action
 The major action of chloroquine is to inhibit
the formation of hemozoin (Hz) from the heme
released by the digestion of hemoglobin (Hb)

 The free heme then lyses membranes and

leads to parasite death

 RESISTANCE : Chloroquine resistance is due to

a decreased accumulation of chloroquine in the
food vacuole
Mechanism of Action of Chloroquine
Pharmacokinetics
 Rapidly and completely absorbed from small intestine
 Reaches maximum plasma concentration in 3 hours
 60% bound to plasma proteins and equally cleared by the kidney and liver
 Use of loading dose leads to achievement of peak levels earlier
 Have large Vd, extensively distributed 200 to 800 L/kg
 Terminal elimination half-life of 1 to 2 months

Dose: 1 g stat followed by 500mg after 6 hrs, 24 hrs & 48 hrs

( 4 Tab stat, 2 tab after 6 hrs, 1 Tab BD for 2 days )
Anti-Malarial Action
Blood schizonticidal against all forms of malaria
Not active against liver stage parasite
Eradication of P. Vivax and P. Ovale requires a course of Primaquine to clear the
hepatic stage
Active against gametocytes of P. vivax, P. ovale and P. malariae but not P.
falciparum
Also used for amoebic liver abscess
Therapeutic Uses
 Hepatic Amoebiasis

 Giardiasis

 Rheumatoid Arthritis

 Discoid Lupus erythematous

 Control manifestation of lepra reaction

 Infectious mononucleosis
Adverse Effects
 GIT: Nausea, vomiting, abdominal pain
 CNS: Headache, blurring of vision, malaise, dizziness
 Skin: Pruritis
 Others: Hemolysis in G6PD deficient patient, impaired
hearing, confusion, psychosis
 Long term high doses for rheumatological diseases
causes irreversible ototoxicity, retinopathy, myopathy
and peripheral neuropathy
Contraindications Drug Interactions
Psoriasis or porphyria Antidiarrheal agent kaolin , Ca & Mg
Retinal or visual field abnormalities or containing antacids interfere with the
absorption of chloroquine
myopathy
Neurological or Hematological
disorders

Safe in pregnancy and in young

children
PRIMAQUINE
Well absorbed orally, widely distributed, rapidly metabolized and excreted in urine
 Active against hepatic stages of all parasites
Only available agent active against the dormant hypnozoites stages of P. vivax & P. ovale
Gametocidal against the four human malarial species

USES
Used for radical cure of acute vivax and ovale malaria
Chloroquine is given to eradicate erythrocytic forms and primaquine to eradicate liver
hypnozoites and prevent a relapse
Also used with clindamycin as alternative regimen
for pneumocystosis jiroveci
 Adverse Effects &
Contraindications
Git: Nausea, abdominal cramps

CNS: Headache

CVS: Marked hypotension if given parenterally

Hematological: Hemolysis or methemoglobinemia

esp in pts with G6PD deficiency , due to oxidant action of metabolites

Rare: Leucopenia, agranulocytosis, leucocytosis

Pregnant women and people with glucose-6-phosphate dehydrogenase (or G6PD) deficiency
FOLATE SYNTHESIS INHIBITOR
Pyrimethamine & Proguanil
Pharmacokinetics
Slowly but adequately absorbed from Git
Bound to plasma proteins
Extensively metabolized
Fansidar – a combination of the sulfadoxine (500mg) & pyrimethamine (25mg)

MOA
 PYRIMETHAMINE : Inhibit plasmodial dihydrofolate reductase, key enzyme in
pathway of folate synthesis
PROGUANIL : antifolate that is commonly used for prophylaxis against Plasmodium
falciparum malaria and is metabolized to its active form of cycloguanil
Anti-Malarial Action
Acts slowly against erythrocytic forms of all four malarial parasites
Fansidar is used for chloroquine resistant P. falciparum malaria
Also use to treat toxoplasmosis

Adverse Effects
Git symptoms, skin rashes, cutaneous reactions like
erythema multiforme, SJ syndrome, epidermal nacrolysis
Artemisinin & its derivatives
Pharmacokinetics
Artemisinin is insoluble and can only be used orally
Analogs have been synthesized to increase solubility and improve antimalarial
efficacy
Artesunate and artemether used orally, I/M and rectally
They are all absorbed rapidly and metabolized to active metabolite
dihydroartemisinin
Half Life: Artesunate & Dihydroartemisinin = 30—60 min
Arthemether = 2—3 hours
MOA Anti-Malarial Action
The endoperoxide bridge of Very rapidly acting blood
artemisinin & its derivatives is cleaved schizonticides against all malarial
by the parasite in its food vacuole parasites but not effective against
which results in the production of free hepatic stages of parasite
radicals that kills the parasite Artemisinin based combination
therapy is standard for treatment of
uncomplicated falciparum malaria in
all endemic areas
 Highly efficacious, safe & well
tolerated
Artemisinin based combination therapy

Artesunate-sulfadoxine-pyrimethamine
Artesunate-mefloquine
Artesunate-amodiaquine or arthemether-lumefantrine
Dihydroartemisinin-piperaquine
Artesunate-pyronaridine (Pyramax)
Adverse Effects

 Nausea, vomiting & diarrhea

 Avoided in pregnancy due to teratogenicity reported in animals
Quinine & Quinidine
Pharmacokinetics
Quinine is derived from bark of cinchona tree and quinidine is the
dextrorotatory isomer of quinine
Rapidly absorbed after oral administration and widely distributed in body
tissues
Quinidine is less plasma protein bound and have shorter half life than quinine
Anti-Malarial Action
Blood schizoticidal agent against all four forms of malaria
Not active against liver stage parasite
Gametocidal against P. vivax and P. ovale but not P. falciparum
Drug of choice for severe falciparum malaria
Quinine in combination with clindamycin is used for Babesiosis caused by
babesia microti
Adverse Effects
Git: Nausea, vomiting
Cinchonism: Constellation of symptoms including tinnitus, headache, nausea, dizziness & visual
disturbances
Hypersensitivity reactions: Skin rashs, urticaria, angioedema & bronchospasm
Hematological abnormalities: Hemolysis in G6PD deficient patient, leucopenia, agranulocytosis
and thrombocytopenia
Severe hypotension can occur after too rapid I/V infusions of quinine or quinidine (QT
prolongation)
Hypoglycemia through stimulation of insulin release
Black water fever (intravascular hemolysis, hemoglobinuria, dark urine, uremia and renal failure)
Mefloquine
USES
Adverse effects
Treatment Of Malaria
Prevention of Malaria in Travelers
SUMMARY