this ppt covers the pharmacologic classes of antimalarial drug as well as new analoge and recent advances of antimalrials. hope u ll like it.

1. Chemotherapy of Malaria
Faraza Javed
Mphil Pharmacology

2. Malaria
Malaria is caused by various species of
plasmodia, which are carried by the female
anopheline mosquito.
Four species of Plasmodium typically cause
human malaria.
Plasmodium falciparum
P. vivax
P. malariae
P. ovale

3. A 5th species, P. knowlesi, is primarily a
pathogen of monkeys, but has recently been
recognized to cause illness, including severe
disease, in humans in Asia.
Although all species may cause significant
illness, P. falciparum is responsible for the
majority of serious complications and death.

4. Pathophysiology

5. Sign & Symptoms
The signs and symptoms of malaria typically begin
8–25 days following infection.
Headache
Fever
Shivering
Joint pain
Vomiting
Hemolytic anemia

6. According to WHO, if any of these symptoms are
present, it is considered as complicated malaria.
Decreased Consciousness
Two or more convulsions
Low BP (less than 70mmHg)
Circulatory Shock
Pulmonary odema
Blood glucose less than 40mg/dl
Kidney failure or Hb in urine

7. Diagnosis
Different diagnostic test are available.
 Microscopy
 Rapid diagnostic antigen test (RDT)
 PCR

8. Aims of Treatment
Aims Causation Therapy Drugs
To alleviate
symptoms
Symptoms are
caused by blood
forms of the
parasite
Blood
schizonticidal
drugs
Chloroquine ,
quinine,
pyrimethamine/sul
phadoxine ,
artemisinin
Chloroquine,
sulphadoxine,
To prevent
relapses
Relapses are due
to hypnozoites of
P. vivax / P. ovale
Tissue
schizonticidal
drugs
Primaquine
To prevent
spread
Spread is through
the gametocytes
Gametocytocidal
drugs
Primaquine for P.
falciparum ,
Chloroquine for
all othes.

9. Classification of
Antimalarial Agents
Four Broad Groups Based on Mechanism of
Action:
Quinoline
Artemisinin
Antifolate
Antibacterial

10. Quinoline Derivatives
Quinoline derivatives include Chloroquine,
Amodiaquine, Quinine, Quinidine,
Mefloquine, Primaquine, Lumefantrine, and
Halofantrine. These drugs have activity
against the erythrocytic stage of infection;
Primaquine also kills intrahepatic forms and
gametocytes.

11. MOA: Parasite digest the host cell
hemoglobin to obtain essential amino acids
and releases large amount of heme which is
toxic to parasite. To protect itself parasite
parasite polymerize the heme to non toxic
hemozion. All Quinoline derivatives
prevent this polymerization and result in the
lysis of cell.

13. Chloroquine
Chloroquine, 4-aminoquinolines, has
activity against the blood stages of
Plasmodium ovale, P. malariae, and
susceptible strains of P. vivax and P.
falciparum.
Used in the treatment and
chemoprophylaxis of maleria.

14. Mutations in the gene encoding the
chloroquine resistance transporter protein
(PfCRT), located in the food vacuole, are
associated with chloroquine resistance both
in vitro and in vivo.

15. Quinine and Quinidine
Quinine is a derivative from the bark of the
South American Cinchona tree. In malaria-endemic
regions it is the most commonly used
parenteral antimalarial drug.
 Quinidine is a stereoisomer of quinine
available in parenteral formulation and is very
effective for treatment of severe malaria.

16. Primaquine
The only 8-aminoquinoline in clinical use.
It is largely used to prevent relapse of P.
ovale and P. vivax malaria by eliminating
dormant hypnozoites, and it also has activity
against the pre-erythrocytic stage and
gametocytes of P. falciparum.
Primaquine is used as radical cure and
chemoprophylaxis of infection with P.vivax
and P.ovale.

17. Halofantrine Hydrochloride, a phenanthrene
methanol, is effective against erythrocytic
stages of all four human malaria species. Its
mechanism of action is unknown.
Lumefantrine, an aryl alcohol related to
Halofantrin, is available only as a fixed dose
combination with artemether (Coartem) which
is now 1st line therapy for uncomplicated
falciparum malaria.

18. Adverse Effects:
Choloroquine is usually well tolerated.
Pruritis is common. Other side effects include
Nausea, Vomiting, Abdominal pain,
Headache, Anorexia and Urticaria. Dosing
after meal may reduce some effects.
Rare reactions include Hemolysis, Impaired
hearing, Hypotension, agranulocytosis,
Retinopathy and Peripheral Neuropathy.

19. Artemisinin
Artemisinin is a Sesquiterpine lactone extracted
from herb called sweet wormwood.
Most important of these analogs are:
Artesunate
Artemether
Dihydroartemisinin

20. MOA: Its antimalarial action involves the
production of free radicals within the
plasmodium food vacuole, following
cleavage of the drug's endoperoxide bridge
by heme iron in parasitized erythrocytes. It is
also believed to covalently bind to and
damage specific malarial proteins.

21. Clinical Significance:
Artemisinin monotherapy for uncomplicated
malaria treatment is now strongly
discouraged. Combination therapy is now the
standard for the treatment of uncomplicated
falciparum malaria.
Artemisinin are also proving to have
outstanding efficacy in the treatment of
complicated falciparum malaria.

22. Artesunate and Artemether have also been
effective in treatment of severe malaria
when administered rectally, offering
valuable treatment modality when
parenteral therapy is not available.

23. Adverse Effects:
No clinical toxicity seen in thousands of
people.
Irreversible Neurotoxicity has been seen in
animals.
Rare toxicities include Neutropenia,
Hemolysis and Allergic Reactions.

24. Antifolate Drugs
MOA: Inhibit DNA synthesis by inhibiting
enzymes involved in folate metabolism.
Agents in this class are:
Pyrimethamine
Sulfadoxine

25. Clinical Significance:
Fansidar, a fixed combination of
sulphonamide sulphadoxine (500mg/tab)
and pyrimethamine (25mg/tab) is widely
used in the treatment of malaria but
resistance limits the efficacy of this
combination in the treatment of malaria.

26. Antibiotics
A no. of antibiotics in addition to folate
antagonist and sulfonamides are modestly
active antimalarial.
MOA: Antibiotics that are bacterial protein
synthesis inhibitors appears to act against
malaria by inhibiting protein synthesis in
Plasmodial prokaryote like organelle, the
Apicoplast.

27. None of the antibiotic should be used as single
agent in the treatment of malaria because their
action is much slower than that of standard
antimalarial.
Antibiotics used as antimalarial include:
Doxycycline
Clindamycin
Azithromycin

28. Clinical Significance:
Doxycycline is useful in combination therapy
with quinine for multiple-resistant organisms.
Also useful for chemoprophylaxis in areas
with multiresistant Plasmodium.
Clindamycin treats mild malaria and can work
against quinoline-resistant strains.

29. Drug Resistant Malaria
Ability of parasite species to survive and/or
multiply despite the administration or
absorption of a drug given in doses equal to or
higher than those usually recommended.
MDR Malaria: Resistance to 3 or more
antimalarials of different chemical classes of
which two are 4-aminquinoline and
diaminopyridine.

30. Mechanism of Resistance
Efflux of drug by active pump mechanism.
Decrease concentration of drug in vacuole.
Crt-chloroquine resistant transporter and
mutation in Pfmdr transporter.
Binding of chloroquine with hemoglobin
breakdown product to form toxic complexes
prevented.

31. Treatment of Malaria

32. Uncomplicated Malaria
1. P.vivax:
P.Vivax cases should be treated with
chloroquine for three days and Primaquine
for 14 days.
Primaquine is used to prevent relapse but is
contraindicated in pregnant women and
individuals with G6PD deficiency.

33. 2. P. falciparum:
P. Falciparum cases should be treated with ACT
accompanied by single dose primaquine preferably on
day 2.
• Artemether/lumefantrine
• Artesunate + amodiaquine
• Artesunate + SP
• Artesunate + mefloquine
ACTs
Combination Therapies Recommended by WHO
FDC

34. 3. Pregnant women with uncomplicated P.
falciparum should be treated as follows:
1st Trimester: Quinine
2nd & 3rd Trimester: ACT
Primaquine is contraindicated in pregnant
woman .
All mixed infections should be treated with
ACT and Primaquine therapy for 14 days.

35. Severe Malaria
Administration of parenteral Artemisnin
therapy.
After parenteral artemisinin therapy, patients
will receive a full course of oral ACT for 3
days. OR
Combination of Quinine+Doxycycline

36. Development of Analogs of
Existing Drugs
1. Pyronaridine
Related to chloroquine developed in china.
2. Tefanoquine
More active slowly metabolized analogue of primaquine,
has advantage that it can be given on weekly basis.
3. Bulaquine
 Congener of primaquine developed in india
 Better tolerated in G6PD deficiency
 Comparable antirelapse activity when used for
5 days.

37. New Chemosensitizing
Agent
Tricyclic Acridone molecules could make chloroquine
resistant parasites susceptible to the drug again. This
action is attributed to blocking the PfCRT pump
protein, meaning that chloroquine can reach its
target.
This new class of antimalarial drug have dual role that
is reserve the malaria parasite resistance to existing
drugs and also have an antimalarial action.

38. Vaccine for Malaria
RTS,S/ASO1 Vaccine
 Hybrid construct of the Hepatitis B surface
antigen fused with the recombinant antigen
derived from part of circum sporozoite protein.
 This vaccine is now in Phase III clinical trials.
WHO has already taken the unusual step of
indicating that it would recommend this 1st
malaria vaccine fore use in some African
countries as early as 2015.

39. References
 Katzung Pharmacology, 12th Edition.
 Lippincott Pharmacology, 6th Edition.
 Diagnosis and treatment of malaria by National vector borne
disease control programe, 2013.
 WHO global database on drug resistance 1996-2004.
 The National Antimalarial Drug Policy, 2010.