Malaria is caused by a parasite called Plasmodium, which is transmitted via the bites of infected mosquitoes. In the human body, the parasites multiply in the liver, and then infect red blood cells.

1. 1

2. HISTORY OF ANTIMALARIAL DRUGS (I)
• Malaria has been affecting populations in tropical and temperate
regions of the world from time immemorial.
• Malaria is mentioned in early Chinese, Egyptian and Indian writings.
• Hippocrates described its full clinical symptoms in 400 B. C.
• In China, the powdered roots of Dichora febrifusa and leaves and
stem of Artemisia annua are in use for at least 2000 years.
• Cinchona (fever tree) ---- Linnaeus (1749).
• Development of synthetic antimalarials drugs form the basis of the
history of chemotherapy. 2

3. HISTORY OF ANTIMALARIAL DRUGS(II)
• C. F. A. Laveran 1880 – discovered malaria parasite Plasmodium falciparum
in human blood.
• Danilevsky – 10 years later found bird malaria parasites.
• At the same time Guttmann and Ehrlich – published beneficial effects of
methylene blue in malaria patients.
• Thirty years later these two seemingly unconnected findings converged.
• Roehl (1926) developed first methods for screening antimalarial compounds
using Plasmodium relictum in canaries; also compared the activities of new
compounds with that of quinine. Ehlrich’s observation of activity of methylene
blue provided the starting point; Roehl’s test provided a method for the
assessment of test compounds.
3

4. HISTORY OF ANTIMALARIAL DRUGS(III)
• Schonhoffer and Wingler (1920) synthesized thiazine derivatives of
methylene blue; compounds with a basic dialkylamino side chain were
found active.
• Combination of basic group with 6-methoxyquinoline – lead to first
synthetic 8- aminoquinoline Plasmochin (pamaquine).
• Andersag, 1934, synthesized two 4-aminoquinolines: Santochin and
Resochin.
• In 1944, USA, two 4-aminoquinolines, chloroquine and amodiaquine
under went extensive clinical trials. Chloroquine (corresponding to
Resochin) came out best.
4

5. HISTORY OF ANTIMALARIAL DRUGS(IV)
• The British chemists Curd, Davey and Rose in 1945 obtained
chloroguanil; proguanil discovered.
• 1948, Vincke, discovered P. berghei; it provided a simple and
convenient animal model for antimalarial testing.
• 1951, pyrimethamine developed by Falco and Hitchings, found
active against human malaria.
• 1960, Young and Moore, discovered P. falciparum resistance to
chloroquine in Colombia.
5

6. GLOBAL MALARIA INCIDENCE
• Thirty-six percent of world population (2020 million) in 90 countries is at risk.
• Kills one person every 12 seconds.
• Clinical cases per year – 300 – 500 million.
• Deaths per year – 1.5 – 2.7 million.
• Cases :- 219 million malaria estimated cases worldwide in 2017
 Number of malaria cases
• Incidence :- 18 % global decrease in malaria incidence between 2010 and 2017
 Progress report
• Mortality :- 28 % estimated decrease in global malaria deaths between 2010 and 2017
6

7. GLOBAL MALARIA INCIDENCE
• In 2017, it was estimated that 435 000 deaths due to malaria had
occurred globally, of which 403 000 deaths (approximately 93%) were
in the WHO African Region. Almost 80% of all deaths in 2017
occurred in 17 countries in the WHOAfrican Region and India.
7

8. INDIAN SCENE
• National Malaria Eradication Programme reports 2.5 – 2.8
million cases per year.
• Plasmodium vivax– 60 – 65 %
• Plasmodium falciparum – 30 – 50%
• Four epidemics in 3 years; Rajasthan, Manipur and Indo-Bhutan
borders.
8

9. INDIAN SCENE
9
Location Indicator Period FirstTooltip
India Estimated number of malaria deaths 2017 16733 [1200-31900]
India Estimated number of malaria deaths 2016 22786 [1580-45300]
India Estimated number of malaria deaths 2015 22326 [1520-42000]
India Estimated number of malaria deaths 2014 20647 [1410-39800]
India Estimated number of malaria deaths 2013 17086 [1530-32100]
India Estimated number of malaria deaths 2012 20722 [1980-39300]
India Estimated number of malaria deaths 2011 25990 [2360-49100]
India Estimated number of malaria deaths 2010 30930 [2770-58600]
Location Indicator Period FirstTooltip
India Estimated number of malaria cases 2017 9590000 [6965000-13260000]
India Estimated number of malaria cases 2016 12630000 [8993000-17830000]
India Estimated number of malaria cases 2015 12200000 [9175000-16200000]
India Estimated number of malaria cases 2014 11420000 [8506000-15510000]
India Estimated number of malaria cases 2013 11210000 [8306000-15110000]
India Estimated number of malaria cases 2012 14220000 [10490000-19450000]
India Estimated number of malaria cases 2011 17520000 [12760000-23930000]
India Estimated number of malaria cases 2010 20490000 [15080000-28300000]

10. Cycle of development of malaria parasites in anopheline mosquito and in man.
Action of various groups of antimalarial
drugs on different parts of each cycle
10

11. ANOPHELES HUMAN HOST (blood) HUMAN HOST (tissue)
SPOROGONY
OOCYST
SPOROZOITES
ERYTHROCYTIC
SCHIZOGONY
SCHIZONTOCIDAL
DRUGS
LATENT
EXOERYTHROCYTIC
SCHIZOGONY
E. E.
MEROZOITES
PRIMARY
EXOERYTHROCYTIC
SCHIZOGONY
MEROZOITES P. E. MEROZOITES
CASUAL
PROPHYLATIC DRUGS
GAMETOCYTES
SCHIZONTS
TROPHOZOITES
SPORONTOCIDAL DRUGS GAMETOCYTOCIDAL DRUGS ANTIRELAPSE DRUGS
11

12. Drug Sporozoites Tissue phase
during the
incubation
period
Erythrocytic phase Latent tissue
phase
(responsible for
relapses
Developmen
t of
gametocytes
in the
mosquito
(sporontoci
dal action)
Chemical class of
relevantantimalari
al compound
Asexual
stages
Sexual stages
Quinine No action No action Fast action Active against
P. vivax& P.
malariae, no
action on
P. falciporum
No action No action Cinchona
alkanoids
Mepacri-ne No action No action Fast action As quinine No action No action 9-aminoacridines
Chloroquin
e,
amodiaquin
e
No action No action Fast action As quinine No action No action 4-aminoquinolines
Primaquine No action Active , not used
for prophylaxis
Active but
only in toxic
dose
Direct & fast
action, but
particularly
on P.
falciporum
Highly active Highlyascti
ve
8-aminoquinolines
Proguanil No action active, but
particularly on
P. falciporum
Active but
relatively
slow
No direct
action
No action Highly
active
Biguanides
Pyrimetha
mine
No action As proguanil As proguanil No evidence Some action on
P. vivax
Little
evidence
Diaminopyrimidin
es
Sulfones &
sulfonamide
s
No action Possible action Moderate
action when
given alone
As
pyrimethamin
e
Little evidence These drug
comprose a large
no. of short& long
acting compounds
12

13. Drug resistance in malaria
• The state of drug resistance:
The parasite becomes adapted to the altered chemical
microenvironment and, by surviving and multiplying in the presence
of drug has entered the state of drug resistance.
• Definition:
WHO 1965/1973 “ability of the parasite strain to survive/multiply
despite administration and absorption of drug given in doses equal
to or higher than those usually recommended but within the limit of
tolerance of the subject.”
13

14. Drug resistance to Plasmodium falciparum
• FIRST DOCUMENTATION
CHLOROQUINE - 1960
AMODIAQUINE - 1961
PROGUANIL - 1963
PYRIMETHAMINE - 1963
MEPACRINE - 1963
QUININE - 1964 (1908-1911 Brazil ?)
QUININE + TETRACYCLINE - 1974
MEFLOQIUNE - 1981
METAKELFIN - 1981
FANSIDAR - 1981
PYRINARIDINE - 1982
FANSIMEF - 1985
Chloroquine resistance to P. vivax - 1989 14

15. Response to field test for sensitivity of falciparum
malaria to chloroquine*
15
Days after start of treatment on day 0
Sensitivity (S)
STANDARD TEST
7 Day Observation
EXTENDED TEST
28 day observation
* Chloroquine administered during the first 3 days.
-- -- -- -- Patent parasitaemia may reappear by day 5; in sensitive (S) strain, however it is
absent on and after day 6.
Note that it is not possible to distinguish between S and RI in the standard
(7 day) test.
AsexualP.falciparum
parasitaemia

16. 16
Days after start of treatment on day 0
STANDARD TEST
7 Day Observation
EXTENDED TEST
28 day observation
- - - - - Patent parasitaemia may reappear by day 5; in sensitive (S) strain, however it is absent
on and after day 6.
R I Resistance, delayed recrudescence
Asexual
P.falciparum
parasitaemia

17. 17
STANDARD TEST
7 Day Observation
Days after start of treatment on day 0
EXTENDED TEST
28 day observation
R I Resistance, Early recrudescence
Asexual
P.falciparum
parasitaemia

18. 18
STANDARD TEST
7 Day Observation
Days after start of treatment on day 0
EXTENDED TEST
28 day observation
R II Resistance
Asexual
P.falciparum
parasitaemia

19. STANDARD TEST
7 Day Observation
Days after start of treatment on day 0
EXTENDED TEST
28 day observation
_._._._._ There may be an increase in parasitaemia in RIII resistance
RIII Resistance
Asexual
P.falciparum
parasitaemia
19

20. Spectrum of response of malaria to drugs
Between complete sensitivity and resistance there is a gradation in the response of P.
falciparum to antimalarials, ranging from a loss of effect demonstrated only by
occasional recrudescence to a level of resistance at which the drug apparently has no
effect on severe infections.
There is, thus, a spectrum of drug response. The WHO scientific group on
chemotherapy of malaria in 1967 proposed a grading system.
Grading of resistance of asexual parasite (P. falciparum) to schizonticidal drugs (4-
aminoquinoline).
20

21. 21
Response
Recommende
d symbol
Evidence
Sensitivity S
Clearance of asexual parasitaemia within 7 days of
initiation of treatment, without subsequent recrudescence
Resistance
R I
Clearance of asexual parasitaemia as in sensitivity,
followed by recrudescence
R II Marked reduction of asexual parasitaemia, but no clearance
R III No marked reduction of asexual parasitaemia

22. PROPOSED MECHANISM OF ACTION OF
QUINOLINES/CHLOROQUINE
A. OLD
1. INTERCALATION INTO DNA
2. ALKALINIZATION OF FOOD VACUOLES AFTER
ACCUMULATION BASED ON WEAK BASE
EFFECTS
3. BINDING TO HEME TO FORM A TOXIC COMPLEX
22

23. B. NEW
4. Inhibition of heme dependent protein synthesis.
5. Prevention of iron release from hemoglobin.
6. Inhibition of cysteine protease activity.
7. Blocking of the enzymatically-mediated formation of hemozoin.
8. Blocking of the non-enzymatically-mediated formation of
Hemozoin.
9. Formation of quinoline-heme complex and its subsequent
attachment to the elongation sites of hemozoin resulting in the
accumulation of toxic unpolymerised heme.
23

24. Diagrametic representation of the potentiating action of sulfonamides and inhibitors of
dihydrofolate reductase on malaria parasites
24
PTERIDINE
+
PABA
+
GLUTAMATE
FAH2
FAH4
COENZYMES
PRECURSORS
NUCLEIC
ACIDS,PROTEINS
FOLATES FROM
FOOD
PLASMODIUM HUMAN
PYRIMETHAMINE
SULFONAMIDE
- PABA is incorporated with co-enzyme folic acid.
- Inhibition of folic acid synthesis by sulfonamides is well known via tetrahydropteric acid synthase.
- From precursor bacteria/ plasmodia construct tetrahydrofolate for formation of purine precursors.
- For this tetrahydrofolate are oxidized to dihydrofolate, and must be generated by reduction.
- This is brought about by enzyme DHFR.
- 2, 4 diaminopyridines inhibit DHFR.
- Plasmodial DHFR is thousand times more susceptible to infection than mammalian DHFR.
Interfernce by sulfonamides

25. Artemisinin : mechanism of action
• P. berghei -infected mice
8 h – trophozoites showed swelling and spiral deformation of membranes of the food
vacuole.
12-14 h – trophozoites showed which of blood vacuoles and limiting membranes.
– Swelling of outer mitochondrial and nuclear membranes.
20-24 h – trophozoites showed extensive degeneration of their inner structures
• P. falciparum , in vitro
- All changes as above except no alteration in mitochondrial membranes.
- Minimum conc. of drug required to effect changes in vitro - 1x 10-7 µg
25

26. cont…
• Qinghosu (QHS) inhibits 50% of chloroquine-induced pigment clumping suggesting difference in mode and site of
action
QHS affect polyamine metabolism in P. falciparum , in vitro
Putreoscine - decrease
Spermine - increase
Spermidine - increase
• P. berghei :
PABA did not suppress the action of QHS, suggesting it did not interfere with folic acid metabolism of the parasite.
26

27. 27