Malaria is caused by Plasmodium parasites transmitted through the bites of infected female Anopheles mosquitoes. The parasite has a complex life cycle alternating between human and mosquito hosts. In humans, it causes symptoms in the blood stage of infection which can be severe and life threatening in P. falciparum cases. Several classes of antimalarial drugs act on different stages of the parasite life cycle, including aminoquinolines, antifolates, and artemisinin derivatives. Artemisinin compounds like artesunate, artemether and artesunate are now first-line therapies for P. falciparum malaria due to their rapid action and effectiveness against multi-drug resistant strains.

1. ANTI-MALARIAL
DRUGS
MARIE JEANNE INGABIRE , SAFINA AKELLO
BEATRICE AGIK, SISTER REGINE RUTAYA

2. MALARIA
• It most important parasitic disease of humans, causing
hundreds of millions of illnesses and probably over a
million deaths each year(WHO,2017).

3. CAUSATIVE AGENT
• Plasmodium
4 species
P. vivax
P. falciparum
P. ovale
P. malariae

4. CAUSE AND TRANSMISSION OF MALARIA
Malaria caused by Plasmodium parasites
Spread by female Anopheles mosquitoes infected with parasites
Anopheles mosquitoes usually active at night
Infected mosquito bites a person
Malaria parasites reproduce in human blood
Mosquito bites infected person, and goes on to bite and infect
another person

5. PARASITE LIFE
CYCLE

6. PARASITE LIFE CYCLE
I. Asexual stage in human:
① Primary exoerythrocytic stage: sporozoites
invade liver cells → schizonts —— incubation
period
② Asexual erythrocytic stage: merozoites invade
erythrocytes, trophozoites → schizonts, rupture host
erythrocytes → repeated cycles —— cause
clinical illness
③ Secondary exoerythrocytic stage: In P vivax and
P ovale infections, a dormant hepatic stage,
hypnozoite → relapses

7. CON’T
11. Sexual stage in anopheline mosquito:
Sexual stage gametocytes also develop in erythrocytes
before being taken up by mosquitoes, where they
develop into infective sporozoites

8. Malaria is transmitted by the bite of infected female anopheles
mosquitoes.
During feeding, mosquitoes inject sporozoites, which circulate to
the liver, and rapidly infect hepatocytes, causing asymptomatic
liver infection (hepatic phase)(absent in falciparum; malariae)
Merozoites released from the liver, rapidly infect erythrocytes to
begin the asexual erythrocytic stage of infection that is
responsible for human disease
Multiple rounds of erythrocytic development, with production of
merozoites that invade additional erythrocytes, lead to large
numbers of circulating parasites and clinical illness

9. Release of merozoites subsequent to rupture of
erythrocytes causes the clinical attack of malaria.
Some erythrocytic parasites also develop into sexual
gametocytes, which are infectious to mosquitoes,
allowing completion of the life cycle and infection of
others
In P vivax and P ovale parasites also form dormant liver
hypnozoites, which are not killed by most drugs,
allowing subsequent relapses of illness after initial
elimination of erythrocytic infections

10. CON’T
The typical paroxysmal attack comprises of three distinct stages:
a) Cold stage- The onset is with lassitude, headache, nausea and chilly
sensation followed by rigors. The stage lasts for ¼ - 1 hour
b) Hot stage- The patient feels burning hot, the skin is hot and dry to touch.
Headache is intense. Pulse rate is high. The stage lasts for 2-6 hours
c) Sweating stage- Fever comes down with profuse sweating. The pulse rate
gets slower, patient feels relieved. The stage lasts 2-4 hours

11. Classification
1) 4-Aminoquinolines: Chloroquine
,Amodiaquine
2) Quinoline methanol: Mefloquine
3) Cinchona alkaloid: Quinine, Quinidine
4) Biguanides : Proguanil
(Chloroguanide)

12. Con’t
5) Diaminopyrimidines : Pyrimethamine
6) 8-Aminoquinoline : Primaquine ,Tafenoquine
7) Sulfonamides & sulfone :Sulfadoxine,
Sulfamethopyrazine ,Dapsone
8) Antibiotics: Tetracyclins ,Doxycycline

13. 9) Sesquiterpine lactones: Artesunate, Artemether
Arteether
10) Amino alcohols: Halofantrine, Lumefantrine

14. Mechanism of action: chroloquine
• It is actively concentrated by sensitive intra-
erythrocytic plasmodia by accumulating in the acidic
vesicles of the parasite and weakly basic nature it
raises the vesicular pH and thereby interferes with
degradation of haemoglobin by parasitic lysosomes
• Polymerization of toxic haeme to nontoxic parasite
pigment hemozoin is inhibited by formation of
chloroquine-heme complex

15. Con’t
• Haeme itself or its complex with chloroquine
then damages the plasmodial membranes.
Clumping of pigment and changes in parasite
membranes follow: death
• Other related anti-malarials like amodiaquine
quinine, mefloquine, lumefantrine act in an
analogous manner

16. RESISTANCE
• Reduced uptake and transport of chloroquine to food
vacuole of plasmodium.

17. PHARMACOKINETICS
• Oral
• Widely distributed & concentrated in tissues
like liver, spleen, kidney, lungs (several hundred-fold), skin,
leucocytes and some other tissues
• Its selective accumulation in retina is responsible for the
ocular toxicity seen with prolonged use

18. con’t
• metabolized by liver
• excreted in urine.
The early plasma t1/2 varies from 3-10 days. Because of
tight tissue binding, small amounts persist in the body
for longer time.

19. Adverse Effects
GI intolerance
Nausea, vomiting, abdominal pain, headache, anorexia,
malaise, and urticaria are common. Dosing after meals
may reduce some adverse effects.
 The long-term administration of high doses of
chloroquine for rheumatologic diseases can result in
loss of vision due to retinal damage.
• Corneal deposits may occur affect vision: reversible

20. Contraindications & Cautions
• Chloroquine is CI in patient with attacks of seizures,
psoriasis or porphyria
Cautious use
• Liver damage
• Severe GI, neurological, retinal & haematological
diseases
Safe in pregnancy and for young children

21. OTHER ACTIONS
• E. histolytica & Giardia lambia
• Anti-inflammatory
• Local irritant
• Local anaesthetic (on injection)
• Weak smooth muscle relaxant
• Anti-histaminic
• Anti-arrythmic properties

22. • Pharmacological Effect
• Antimalarial action:
blood schizonticide.
• Antiamebic –extra intestinal
amebiasis
• Antiinflammatory –Rheumatoid
arthritis
• Antiarrhythmia-Quinidine like the
activity on the heart

23. RESISTANCE
• Resistance to chloroquine is now very common among
strains of P falciparum and uncommon but increasing for
P vivax.
ACT IT IS first line for plasmodium falciparum cases
countrywide.

24. AMODIAQUINE
• This is another aminoquinorone similar to chloroquine .
• Its antimalarial activity and side effects are similar to
chloroquine .
• Prolonged use may result in the pigmentation of the
palate ,nail beds and the skin and high incidences of
hepatitis

25. PRIMAQUINE
• Synthetic 8-aminoquinoline.
• Pharmacological Effects
• Against hepatic stages of malaria parasites.
• The only available agent active against the dormant hypnozoite stages of P vivax and
P ovale.
• Also gametocidal against the four human malaria species.

26. Clinical Uses
• Chemoprophylaxis of Malaria: protection
against falciparum and vivax malaria. But
potential toxicities of long-term use limited its
routinely administration.
• Gametocidal Action: A single dose of
primaquine (45 mg base) can be used as a
control measure to render P falciparum
gametocytes non-infective to mosquitoes. This
therapy is of no clinical benefit to the patient
but will disrupt transmission

27. Adverse effect and cautions
• Nausea, epigastric pain, abdominal cramps, headache.
• Hemolysis or methemoglobinemia, especially in persons
with hereditary metabolic defects.

28. QUININE
 Quinine and quinidine remain first-line therapies for
falciparum malaria——especially severe disease.
 Quinine is an alkaloid derived from the bark of the cinchona
tree, a traditional remedy for intermittent fevers from South
America.
 Quinine is the levorotatory stereoisomer of quinidine.
 Rapidly absorbed after oral administration.
 Metabolized in the liver and excreted in the urine.

29. PHARMACOLOGICAL ACTION OF QUININE
• Antimalarial
• Quinidine –like action on the heart
• Mild oxytocic effect on the uterus
• Blocking action on the neuromuscular junction
• Weak antipyretic

30. Pharmacological Effects
• Highly effective blood schizonticide against the four
species of human malaria parasites.
• Gametocidal against P vivax and P ovale but not P
falciparum.
• Not active against liver stage parasites.
• Depressing cardiac contractility and conduction,
lengthening refractory period, exciting uterine smooth
muscle, depressing central nervous system, little
antipyretic-analgesic effect.

31. CURRENT USES OF QUININE
• Antimalrial agent
• a) Acts primarily as a blood schizontocide.To treat severe
forms of multidrug resistant falciparum malaria .Slow i.v
administration of quinine is a must.
• B) Cerebral malaria

32. • Clinical Uses: mainly for chloroquine-resistant falciparum
malaria, especially for cerebral malaria.
• Parenteral treatment of severe falciparum malaria
• Oral treatment of falciparum malaria
• Malarial chemoprophylaxis
Current uses of quinine

33. Adverse Effects and Cautions
1. Cinchonism: tinnitus, headache, nausea,
dizziness, flushing, visual disturbances
2. Cardiovascular effects: severe hypotension and
arrhythmia can follow too-rapid intravenous
infusion.
3. Idiosyncrasy: hemolysis with G6PD deficiency.
4. Others: hypoglycemia through stimulation of
insulin release, stimulate uterine contractions

34. MEFLOQUINE
• A synthetic 4-quinoline methanol that is chemically related to quinine.
• Pharmacokinetics
• Only be given orally because severe local irritation occurs with
parenteral use.
• Well absorbed.
• Highly protein-bound, extensively distributed in tissues, and eliminated
slowly. t1/2 is 20 days.
• Pharmacological Effects:
• Strong blood schizonticidal activity against P falciparum and P vivax,
but not active against hepatic stages or gametocytes.

35. Clinical Uses
• Chemoprophylaxis:
• Treatment: mainly for chloroquine-resistant
falciparum malaria.
• Adverse Effects and Cautions
• Nausea, vomiting, diarrhea, abdominal pain——
dose-dependent
• Neuropsychiatric toxicities: dizziness, headache,
behavioral disturbances, psychosis, seizures.

36. POTENTAILLY NEW ANTIMALARIALS
• Halofantrine – effective against multidrug resistant P.
falciparum malaria.
• Its antimalarial drug used as an alternative to quinine and
mefloquine for acute attacks for chloroquine reisitant P.
Falciparum.

37. ANTIBACTERIALS USED IN MALARIA
• Sulphonamides –sulfadiazine, sulfadoxine,
Sulphamethopyrazine
• Sulfone-dapsone
• Tetracyclines-doxyclines
• Clindamycin,ciprofloxacin,norfloxacin

38. ARTEMISININ
• Artemisinin and its derivatives has a significant effect on
gametocytogenesis, thus reducing transmission and consequently the
spread of resistant strains
• They prevent gametocyte development by their action on the ring stages
and on the early (stage I-III) gametocytes

39. CON’T
In studies including over 5000 patients in Thailand, it was
shown that gametocyte carriage was significantly less frequent
after treatment with artemisinin derivatives than after treatment
with mefloquine.
The fast parasite killing is probably an important factor for
reduction of gametocyte development.

40. CHEMISTRY
• Artemisinin is a so-called sesquiterpene with a
molecular weight of 282
• It is a tetracyclic structure with a trioxane ring and a lactone ring.
• The trioxane ring contains a peroxide bridge, the
active moiety of the molecule.

41. ARTEMISININ
Artemisinin is not very soluble either in water or oil.
This and its short elimination half life led to the search for the derivatives
that had improved pharmacological properties as well as better
antimalarial activity
Converted to dihydroartemisinin, which is a potent antimalarial compound
 Available for oral and rectal use in several countries in Asia, especially in
Vietnam

42. DERIVATIVES OF ARTEMISININ USED IN TREATMENT OF
MALARIA
1. Artemether
2. Arteether
3. Artesunate

43. CHEMICAL STRUCTURE

44. KEY FEATURES
• Rapid onset of actions
• Effective against severe malaria
• Rapid clearance rate
• Slow development of artemisinin resistance
• Frequent recurrence of infections

45. MECHANISM OF ACTION
• Exerts antimalarial activity by iron-mediated cleavage of
the peroxide bridge and generation of an organic free
radical.
• The artemisinin radical binds subsequently to membrane
proteins, and alkylation reactions eventually cause
destruction of the parasite.

46. ANTIMALARIAL EFFICACY
• Rapidly acting blood schizontocidal antimalarials
against chloroquine sensitive and chloroquine resistant falciparum
as well as vivax malaria
• They quickly arrest the ring or the trophozoite
development and also prevent pathological sequelae

47. CON’T
• Fever subsides and parasites are cleared rapidly
• Defervescence occurs within 2-3 days after drug
administration
• Ninety percent clearance of asexual erythrocytic
parasitaemia is usually observed within 4 hours

48. ARTEMETHER
Methyl ether of dihydroartemisinin
Superior to intravenous quinine with respect to
survival and parasite clearance
 Available as tablets, capsules and as IM injectable form
 In India, available as 40mg capsules and 80mg/ml ampoule

49. EFFICACY OVER OTHER ANTIMALARIALS
Artesunate and artemether have been shown to clear
parasitaemias more effectively than chloroquine and
sulfadoxine/pyrimethamine
Meta analysis of mortality in trials indicated that a patient
treated with artemether had at least an equal chance of
survival as a patient treated with quinine

50. CON’T
Artemisinin drugs cleared parasites faster than quinine in
patients with severe malaria but fever clearance was
similar
Parenteral artemether and artesunate are easier to use
than quinine and do not induce hypoglycaemia

51. PHARMACOKINETICS
• Absorption of orally administered artemisinin or its
derivatives seems to be rapid but incomplete
Substantial hydrolysis of artesunate (probable
complete) and artemether into dihydroartemisinin
probably occurs even before absorption

52. CON’T
• Elimination is mainly by hepatic metabolism.
• Arteether has much slower elimination
• Artesunate, artemether, arteether and probably also
artemisinin itself are transformed into dihydro- artemisinin,
which is subsequently converted into inactive metabolites

53. ARTEETHER
Ethyl ether of dihydroartemisinin
Therapeutically equivalent to quinine in cerebral malaria
Available as  arteether and / arteether
 arteether developed by WHO and The Special
Programme for Research and Training in Tropical Diseases (TDR)
/ arteether developed by CDRI

54. ARTEETHER
• A longer t1/2 beta and more lipophilic properties than
artemether favouring accumulation in brain tissue and
thus the treatment of cerebral malaria were regarded as
advantages over the other compounds.
• Available as 150mg per 2ml ampoule

55. ARTESUNATE
Water soluble hemisuccinate derivative
Used for oral, rectal, intravenous and
intramuscular administration.
Available as tablets and as powder with separate
vial.

56. CON’T
• containing 5% sodium bicarbonate
• In India, available as 50mg tablets and 60mg/ml injection
• In China also available as 100mg suppository and in
• Switzerland available as 200mg rectocap

57. COMBINATION THERAPY
• Chloroquine and pyrimethamine may antagonise the
activity of artemisinin whereas mefloquine, quinine,
primaquine and tetracycline potentiate artemisinin.
• The combination of artemisinin derivatives and
mefloquine improves parasite clearance compared with
either drug alone

58. CON’T
• The above combination slows down the development of
resistance to mefloquine, since the residuum of parasites
remaining after the action of artesunate is exposed to
more slowly eliminated mefloquine.
• There is little published data on combination therapy with
drugs other than mefloquine

59. ARTEMISININ AS ANTIGAMETOCYTE DRUG
• Artemisinin and its derivatives has a significant effect on
gametocytogenesis, thus reducing transmission and
consequently the spread of resistant strains
• They prevent gametocyte development by their action on
the ring stages and on the early (stage I-III) gametocytes

60. CON’T
• In studies including over 5000 patients in Thailand, it was
shown that gametocyte carriage was significantly less
frequent after treatment with artemisinin derivatives than
after treatment with mefloquine(Price R. N. et al., Lancet,
1996).
• The fast parasite killing is probably an important factor for
reduction of gametocyte development

61. SAFETY OF ARTEMISININ DERIVATIVES
The artemisinins are extremely well tolerated and virtually without
adverse effects
Toxicological studies in animals have shown that the toxicity of
artemisinin, artemether and artesunate is much less than that of
chloroquine.
Significant adverse effects or signs of toxicity of the artemisinins
have not been reported in human patients treated with therapeutic
dosages

62. COMBINATION THERAPY
• Artemether-lumefantrine
• Amodiaquine-artesunate (areas where AQ efficacy is
high)
• SP- artesunate (areas where SP efficacy is high)
• Mefloquine- artesunate (not for high transmission areas,
e.g., Africa)

63. ARTEMISININ DERIVATIVES
IN PREGNANCY
• Very limited data on the use of artemisinin group in pregnant women.
• Artemisinin and derivatives should be avoided during first trimester of
pregnancy, but in case of severe malaria the risks have to be balanced
against the benefits.
• No congenital malformations were detected in six children born to
mothers who received intramuscular
artemisinin or artemether at 17 to 27 weeks of gestation.

64. THE UGANDA NATIONAL MALARIA
TREATMENT POLICY
3. Intermittent preventive treatment (IPT) of malaria in pregnancy:
• Sulfadoxine/Pyrimethamine (SP) is the recommended medicine for IPT.

65. PROPHYLAXIS
• Pregnancy
• One dose every month from 13 WOA up to delivery
• 1 month interval
• Pyrimethamine(75 mg)+ sulphadoxine(1500mg)
• In areas with high P.f endemicity

66. THE UGANDA NATIONAL MALARIA
TREATMENT POLICY
1.Treatment of uncomplicated malaria:
• The recommended first line medicine is
• Artemether/ Lumefantrine.
• Any other ACT that has been recommended by WHO and MOH
and registered with the National Drugs Authority (NDA) will be the
alternative first line.
• The recommended second line medicine is oral quinine for
all patients

67. THE UGANDA NATIONAL MALARIA
TREATMENT POLICY
2.Treatment of severe and complicated malaria:
• Parenteral quinine is the recommended treatment for
the management of severe malaria for all patients.
• Parenteral Artesunate or artemether are the alternatives.
• Rectal artesunate shall be used as pre‐referral treatment
for severe malaria.

68. THE UGANDA NATIONAL MALARIA
TREATMENT POLICY
• Children below 4 months of age:
• Artemether/Lumefantrine or other ACTs are not
recommended for children below 4 months of age or
5kg body weight.
• Such children should be treated with quinine.

69. REFERENCE LIST
• Qaseem, A., Vijan, S., Snow, V., Cross, J. T., & Weiss, K. B. (2007). Clinical
Guidelines. Annals of Internal Medicine (Vol. 151). https://doi.org/10.1055/s-
0031-1275837
• Royal college. (2010). The diagnosis and treatment of malaria in pregnancy,
(54).
• Noguchi, L. (2017). Implementing Malaria in Pregnancy Programs in the
Context of WHO Recommendations on Antenatal Care for a Positive
Pregnancy Experience, (June).