Lecture-06
Anti Malarial Drugs
BSN # 3rd Semister
IHS KMU
• Malaria is major health problem in Pakistan & tropics.
• Malaria caused by 4 species of plasmodium parasite :-
• -> Plasmodium vivax
• -> Plasmodium ovale
• -> Plasmodium falciparum (severe malaria)
• -> Plasmodium malariae
Life Cycle of Malaria
• Causative organism- Plasmodium (female anopheles mosquito)
• Intermediate host: human being i.e. a man.
• Life cycle occurs partly inside the mosquito (sexual sporogony ) & man
(asexual schizogony)
• Mosquito bites man, it transmits sporozoites to his blood.
• Sporozoites travel to liver where it reproduces asexually (tissue
schizogony) producing merozoites.
• Merozoites infect new RBCs and initiate asexual multiplication in RBC
(blood schizogony) leading to production of more merozoites.
• The RBC bursts and starts the infective cycle.
• Some merozoites develop into male and female gametes.
• Some merozoites remain dormant in the liver (hypnozoites) which can
cause a relapse of infection later (p. vivax & ovale)
• When mosquito bites infected person, gametes are taken up with the
blood.
• The gametocytes mature in the mosquito gut and fuse to form an
ookinate which develops into sporozoites.(Sexual sporogony)
• Sporozoites migrate to salivary glands and infect a new host
when mosquito bites the person.
• Recurrent malaria : Can be relapse(hypnozoites) or
recrudescence (parasites surviving in blood due to incomplete
treatment)
Plasmodium uses hemoglobin as a nutrient:
It is in the food vacuole that parasite digest the host cell’s hemoglobin to obtain
essential amino acids. However, this process releases large amounts of heme,
which is toxic to the parasite. To protect itself, the parasite ordinarily polymerizes the
heme to hemozine, which is nontoxic, with the use of heme polymerase. Some
drugs interfere with this process such as chloroquine.
Symptoms of malaria:
Fever, shivering, pain in the joints, headache, repeated vomiting, generalized
convulsions, and coma.
Drugs CLASSIFICATION
Classes Drugs
1. 4-aminoquinolines Chloroquine (CQ), amodiaquine (AQ),
Piperaquine
2. Quinoline-methanol Mefloquine
3. Cinchona alkaloid Quinine, quinidine
4. Biguanide Proguanil (chloroguanide)
5. Diaminopyrimidine Pyrimethamine
6. 8-aminoquinoline Primaquine, tafenoquine
7. Sulfonamides and sulfone Sulfadoxine, sulfamethopyrazine, dapsone
8. Amino alcohols Halofantrine, lumefantrine
9. Sesquiterpine lactones Artesunate, artemether, arteether, arterolane
10. Naphthyridine Pyronaridine
11. Naphthoquinone Atovaquone
12. Antibiotics Tetracycline, Doxycycline, Clindamycin
Target of Therapy Therapeutic Class Drug Examples
Artemisinin
To alleviate Blood schizontocidal drugs Chloroquine (in vivax
symptoms only)
Quinine (in pregnancy)
To prevent Relapses Tissue schizontocidal Primaquine
drugs
To prevent Spread Gametocidal drugs Primaquine
Chloroquine
• It has activity against the blood stages of plasmodium ovale, P. Malariae, and
susceptible strains of P. Vivax and P. Falciparum.
• Widespread resistance in most malaria-endemic countries has led to decline in
its use for the treatment of p. Falciparum, although it remains effective for
treatment of P. Ovale, P. Malariae and, in most regions, P. Vivax
Mechanism of Action
• Binds to and inhibits DNA and RNA polymerase; interferes with metabolism and
hemoglobin utilization by parasites; inhibits prostaglandin effects.
• The parasite digests the human hemoglobin in order to get amino acid, but the
problem here is that the Form complex with Hb-----deficiency of food material
• Chloroquine binds to heme to form what is known as the fp-
chloroquine complex, this complex is highly toxic to the cell and
disrupts membrane function. Action of the toxic compound results in
cell lysis and ultimately parasite cell auto-digestion.
Adverse Effects
• Nausea, vomiting, anorexia, skin rashes, angioneurotic edema, photosensitivity,
pigmentation, exfoliative dermatititis
• Long term therapy may cause bleaching of hair
• Rarely thrombocytopenia, agranulocytosis, pancytopenia
• Ocular Toxicity- Temporary loss of accommodation
• Retinopathy- Constriction of arteries, edema, blue black pigmentation, constricted field of
vision
• CNS- Insomnia, transient depression seizures, rarely neuromyopathy & ototoxicity
• CVS-abrupt fall in bp & cardiac arrest in children reported
2. Quinine
• Quinine is a l-isomer of alkaloid obtained from cinchona bark and quinidine
(antiarrhythmic) is its d-isomer.
• An effective erythrocytic schizontocide as suppressive and used to prevent or
terminate attacks of vivax, ovale, malariae, sensitive falciparum. less effective and
more toxic than chloroquine.
• Moderately effective against hepatic form (pre-exoerythrocyte and gametocytes).
MOA + Resistance mechanism:
Same as chloroquine
Other Actions:
•Antiarrhythmic as well = quinidine like action.
•Mild oxytoxic effect on pregnant uterus
•Slight neuromuscular blocking action
•Weak antipyretic action
Major ADRs:
•In therapeutic does:
•Bitter taste => poor compliance “patient may not take it regulatory or stop because of its tastes”
•In Higher doses:
Cinchonism (tinnitus, deafness, headaches, nausea & visual disturbances) “it’s called cinchonism
reffering to its origin plant cinchona bark.”
•Abdominal pain & diarrhea Oxytoxic effect: stimulate uterus
contraction to deliver the fetus. In
•Rashes, fever, hypersensitivity reactions late pregnancy , it has a similar
•Hypotension & arrhythmias action to the natural the oxytocin
hormone in the body.
•Blood dyscarasis; anaemia, thrombocytopenic purpura & hypoprothrombinaemia
•Blackwater fever, a fatal condition in which acute haemolytic anaemia is associated with renal failure.
If given IV => neurotoxicity => tremor of the lips and limbs, delirium, fits, stimulation followed by
Cinchonism: a syndrome causing
depression of respiration & coma. nausea and vomiting, tinnitus,
and vertigo
Contraindications:
•Prolonged QT Interval.
•Glucose-‐6-‐Phosphate Dehydrogenase Deficiency.
•Myasthenia Gravis. “because of neuromuscular blocking action”
•Hypersensitivity.
•Optic Neuritis, auditory problems.
•Dose should be reduced in renal insufficiency.
Interactions
•Antacids: Antacids containing aluminum &/or magnesium may delay or decrease absorption of quinine.
•Erythromycin (CYP3A4 inhibitor)
Cimetidine, Mefloquine. Quinine can raise, plasma levels. of warfarin and digoxin. *** Less
resistance than chloroquine
QUINOLINE-METHANOL Mefloquine
• Mefloquine, is marketed as the R,S-isomer.
• Mefloquine's effectiveness in the treatment and prophylaxis of malaria is due to the
destruction of the asexual blood forms of the malarial pathogens that affect humans,
Plasmodium falciparum, P. vivax, P. malariae, P. ovale.
• Used in chloroquine-resistant strains of P. falciparum and other species.
• Has strong blood schizonticidal activity against P. falciparum and P. vivax, it is not
active against hepatic stages or gametocytes.
Adverse effects
1. Mefloquine is bitter in taste
2. At high doses: Nausea, vomiting, diarrhea, abdominal pain, bradycardia, ataxia,
hallucinations, depression.
3. Mefloquine is safe in pregnancy
Atremisinin:
Important drug because plasmodium have not developed resistance to it yet. Another preparations are available
with better solubility: Artensuate, and artemether.
Halif Life of Drugs
• Artemisinin$(4hrs)
• Artesunate$(45min)
• Artemether$(4Q11hrs)
Mechanism of Action:
By production of free radicals within the plasmodium vacuole, following cleavage of the drug’s endoperoxide
bridge by heme iron in parasitized erythrocyte.
These free radicals will attack the lipids, membranes and the structures of the organism, and inhibit its growth
by inhibiting enzyme called sarco endoplasmic reticulum Ca ++ ATPas (SERCA)
Why quinine can be given in 1st trimester only?
Because of the oxytoxic effect.
Chloroquine is safe in pregnancy, but yet not given. Why? Because if I give it and the
pregnant lady has P.falciparum infection, she will die from the infection not the drug. So we
must give another drug that is both safe and can attack all parasites whether sensitive or
resistance.
