This document discusses drug therapy for malaria. It defines malaria and describes the life cycle and species of Plasmodium that cause malaria in humans. It then discusses the clinical presentation of malaria and diagnosis. The bulk of the document categorizes and describes various classes of antimalarial drugs, including quinine, chloroquine, primaquine, atovaquone, lumefantrine, and artemisinin derivatives. It provides details on the mechanisms of action, pharmacokinetics, uses, and adverse effects of many common antimalarial medications.

1. DRUG THERAPY FOR
MALARIA
PRESENT BY,
DR.Chintan Doshi

2. INTRODUCTION
DEFINITION:--
• Protozoal disease
• Caused by infection with parasites of the
genus Plasmodium.
• Transmitted to man by certain species of
infected female anopheline mosquito.

3. Problem statement
• At present malaria is a major public health
in the tropical developing world.
• Those at greatest risk of dying from the
disease are:
• Children under age 5 years in malaria
endemic areas,
• Pregnant women,
• Travelers who visit endemic countries and
return home with the disease.

4. AGENT FACTORS
common & severe
• Plasmodium falciparum
• Plasmodium vivax
• Plasmodium ovale
• Plasmodium malariae
rare & mild

5. • A fifth species, P. knowlesi is primarily a
pathogen of monkeys, but has recently
been recognized to cause illness in
humans in Asia.

6. CLINICAL PRESENTATION
• c/f:-high spiking fevers, chills, headache, myalgia,
malaise, and gastrointestinal symptoms
• Malarial Paroxysm—3 distinct stages
– Cold stage
– Hot stage
– Sweating stage

8. • Each Plasmodium species causes a distinct
illness:
• (1) P. falciparum is the most dangerous---
invading erythrocytes of any age---
sequestering in the vasculature, and
producing vasoactive products--- cause an
overwhelming parasitemia, hypoglycemia,
and shock with multiorgan failure, including
cerebral malaria.
• Treatment delay may lead to death.

9. • If treated early, the infection usually
responds within 48 hours.
• If treatment is inadequate, recrudescence
of infection may result.

10. MANIFESTATIONS OF SEVERE FALCIPARUM
MALARIA
• Signs Manifestations
• Unarousable coma/cerebral malaria
• Acidemia/acidosis
• Severe normochromic,Normocytic anemia.
• Renal failure
• Pulmonary edema/
• adult respiratory distress syndrome
• Hypoglycemia
• Hypotension/shock
• Bleeding/disseminated Intravascular coagulation
• Hemoglobinuria
• Impaired consciousness/arousable
• Jaundice

11. Diagnosis
• Thick and thin blood smears are gold standard
– Identify species and quantify density.
• Rapid diagnostic tests for detection of parasites:-
• Combo Test targeting the Plasmodium falciparum
specific antigen histidine-rich protein (HRP-2) and
the pan-Plasmodium antigen lactate
dehydrogenase (pLDH)
• Microtube concentration methods with acridine
orange staining using fluorescence microscopy.

12. DRUG THERAPY FOR MALARIA
• ANTIMALARIALS DRUGS CLASSIFY
BASED ON ATTACKING PARASITES AT
ITS VARIOUS STAGES OF LIFE CYCLE IN
THE HUMAN HOST.
• Erythrocytic schizontocides:- act on
erythrocytic schizogony;
• Tisuue schizontocides :- act on
preerythrocytic and exoerythrocytic stages in
liver.
• Gametocides.:-kill gametocytes in blood.

13. ANTIMALARIAL DRUGS
CLASSIFICATION
• 4-Aminoquinolines:-
chloroquine,amodiaquine,piperaquine.
• Quinoline-methanol:- mefloquine
• Cinchona alkaloid:- quinine, quinidine
• Biguanides:- proguanil, chlorproguanil
• Diamiopyrimidines:-pyrimethamine
• 8-Aminoquinoline:-primaquine,Tafenoquine.

14. • Sulfonamides and sulfone:-sulfadoxine,
sulfamethopyrazine, dapsone
• Tetracyclines:-tetracycline, doxycycline
• Sesquiterpine lactones :-artesunate,
artemether,arteether,arterolane.
• Amino alcohols :- halofantrine, lumefantrine
• Naphthyridine:- pyronaridine
• Naphthoquinone :-atovaquone.

15. OBJECTIVES AND USE OF
ANTIMALARIALS
• AIMS OF TREATMENT:-
1. To prevent and treat clinical attack of
malaria.
2. To completely eradicate the parasite from the
patient’s body.
3. To reduce the human reservoir of infection –
cut down transmission to mosquito.

16. • Antimalarial therapy is given in the following
forms:-
1.Causal prophylaxis:- covers the preerythrocytic
phase in liver.
2.Suppressive prophylaxis:-covers the
erythrocytic phase and attack of malarial fever.
3.Clinical cure:-terminates the episode of
malarial fever.

17. 4.Radical cure:- needed in relapsing malaria
to covers the exoerythrocytic
stage(hypnozoites)
5.Gametocidal:- cover male and female
gametes of plasmodia formed in the
patient’s blood.

18. Chloroquine
 4-amino quinoline
 Rapidly acting erythrocytic schizontocide
 No effect on pre and exo-erythrocytic phases
of the parasite- does not prevent relapses in
vivax and ovale malaria.
 P/K:-oral absorption excellent.
plasma t1/2:-3-10 days
highly concentrated in liver,spleen,
kidney,retina,lung etc.

19. Mechanism

20. Adverse Effects
• Nausea, vomiting, headache, blurred
vision
• Prolonged use of high doses cause loss of
vision due to retinal damage.
• Iv use causes hypotension, cardiac
depression
• safe for children and in pregnancy

21. Other actions
• Anti-inflammatory, local irritant
• Local anaesthetic (on injection),
• Weak smooth muscle relaxant,
• Antihistaminic
• Antiarrhythmic

22. Uses
 Drug of choice for clinical cure and suppressive
prophylaxis of all types of malaria, except
resistant p. falciparum
 Extra intestinal amoebiasis
 Rheumatoid arthritis
• Discoid lupus erythematosus
• Lepra reaction
• Photogenic reactions.
• Infectious mononucleosis

23. MEFLOQUINE
Relatively fast acting erythrocytic
schizontocide.
P/K:-
 Good but slow oral absorption
 Highly protein bound and concentrated in
liver, lung etc.
 Enterohepatic circulation
 Tissue binding ---longer t1/2 of 2-3 weeks.

24. Adrs.:-
 Nausea,
 Vomiting,
 Dizziness,
 Sinus tachycardia,
 Abdominal pain.
 Neuropsychiatric reactions

25. • Contraindication:-h/o seizure and acute
neuropsychiatric disorders.
• Safe in children and pregnancy except the
first trimester
• Drug interaction:- not given with
halofantrine and quinine—prolonged QTc
interval-cardiac arrests.

26. Use:-
1)Along with the artemisinin derivatives for
uncomplicated chloroquine as well as s/p
resistant falciparum malaria.
2)for prophylaxis of malaria among travellers
to areas with multidrug resistance

27. QUININE
• Derived from the bark of the cinchona tree.
• Erythrocytic schizontocide for all species of
plasmodia.
• No effect on preerythrocytic stage and on
hypnozoites of relapsing malaria but kills
vivax gametes.
• P/K:-rapidly and completely absorbed orally.
70% bound to alfa-1 acid glycoprotein.
metabolised in liver by CYP3A4.
t1/2:- 10-12 hours.

28. CINCHONA PUBESCENS

29. • ADRs:-toxicity of quinine –high and dose related .
- Cinchonism:- at large single dose .
-ringing in ear
-nausea, vomiting
-headache
-mental confusion
-Difficulty in hearing and vision
-vertigo etc.
- hypoglycemia.
- idiosyncratic/hypersensitive reaction-Purpura,
rashes, itching, angioedema of face and
bronchoconstriction
- hypotension and cardiac arrhythmias on rapid i.v.
injection

30. • Safe in pregnancy.
• Uses:-
- uncomplicated resistant falciparum malaria:-
quinine given orally.
- complicated and severe malaria including
cerebral malaria:- i.v. quinine with 5%
dextrose infusion.(to prevent hypoglycemia)
- Nocturnal muscle cramps
• Amplification of the pfmdr1 gene is
associated with resistance to quinine.

31. PROGUANIL
• Slow acting erythrocytic schizontocide
• Inhibits DHFRase
• Use :-prophylaxis of malaria in combination
with chloroquine in areas of low level
chloroquine resistance among p.falciparum
• Safe in pregnancy
• Resistance due to mutations in plasmodial
dihydrofolate reductase

32. Primaquine
-Poor erythrocytic schizontocide
-it is only available agent active against the
dormant hypnozoite stages of P. vivax and P.
ovale.
- P/K:-readily absorbed after oral ingestion.
plasma t1/2:-3-6 hours
-Dose:- 15 mg (children 0.25 mg/kg ) daily for 2
weeks with full curative dose of choloquine.

33. • Adrs.:-g.i. upset ,abdominal pain
haemolysis,methaemoglobinaemia,
tachypnoea and cyanosis.(G6PD
deficient patient)
• Avoid during pregnancy .
• Use:-1) radical cure (therapy) and terminal
prophylaxis of vivax and oval malaria.
2) chemoprophylaxis of malaria.

34. PYRIMETHAMINE
• Slowly acting blood schizontocide
• Pyrimethamine resistance results from
mutations in dihydrofolate reductase–
thymidylate synthetase.
• S/E:occasional nausea and rashes.
• Folate deficiency is rare

35. Sulfonamide-pyrimethamine
(S/P)
• Supra-additive synergistic combination with
pyrimethamine due to sequential block
• Sulfadoxine 1500 mg + pyrimethamine 75 mg
• Use:efficacy against CQ-resistant P. falciparum.
• Decrease resistance

36. ATOVAQUONE
• Malarone, a fixed combination of
atovaquone and proquanil , is highly
effective for both the treatment and
chemoprophylaxis of falciparum malaria.

37. ANTIBIOTICS
• Act by inhibiting protein synthesis in a
plasmodial prokaryote like organelle,
apicoplast.
• These groups includes:-
-tetracycline
-doxycycline
-clindamycin
-azithromycin

38. • Tetracycline and doxycycline are active
against erythrocytic schizonts of all human
malaria parasites.---no active against liver
stages.
• Use:- 1) treatment of falciparum malaria in
conjunction with quinine.
2) To complete treatment courses of 1 week
after initial treatment of severe malaria
with i.v. quinine or artesunate.

39. • Clindamycin is slowly active against
erythrocytic schizonts and be used after
treatment courses of quinine or artesunate
in those for whom doxycycline is not
recommended ( i.e. children and pregnant
women)
• Azithromycin – under study as an
antimalarial agent.
• Fluoroquinolones – efficacy as a
antimalarial is suboptimal.

40. HALOFANTRINE
• Effective against P.falciparum and P.vivax
resistant to chloroquine
• Prolongation of QTc interval at therapeutic
doses and few cases of serious ventricular
arrhythmia.
• Not approved in india.

41. LUMEFANTRINE
• Orally active, high efficacy,long acting
erythrocytic schizontocide
• P/K:-plasma protein binding -99%
metabolised predominantly by CYP3A4
• Use:-only in combination with artemether
and is the only ACT currently available as
fixed dose combination tablets.
• High cure rate >95%
• Active against multidrug resistant areas
including mefloquine resistant.

42. • Well tolerated with minimum side effects.
• Contraindicated in first trimester of
pregnancy and during breastfeeding.

43. ARTEMISININ DERIVATIVES
• Active principle of the plant artemisia
annua used in chinese traditional medicine
as ‘QUINGHAOSU’
• Active against P. falciparum resistant to all
other antimalarial drugs as well as
sensitive strains.
• Potent and rapid blood schizontocide
action – quicker defervescence and
parasitaemia clearance < 48 hours than
chloroquine or any other drug.

44. ARTEMISININ PLANT

45. • Artemisinins of 3 types are:-
-artemether prodrugs
-artesunate
-arteether
-arterolane –developed in india

46. Mechanism of Action

47. • Use:-
oral therapy:- for the treatment of
uncomplicated chloroquine/multidrug
resistant falciparum malaria.
parenterally:- severe and complicated
falciparum malaria.
rectally:-artesunate and artemether both
use for severe falciparum malaria when
parenteral therapy is not available.

48. • i.v. artesunate now become a drug of
choice for severe complicated resistant P.
falciparum malaria because of
• i.v artesunate offers several advantages.:-
1. faster parasite clearance than i.v. quinine
2. safer and better tolerated than i.v. quinine.
3. simple dosing schedule
4. higher efficacy and lower mortality.

49. Adverse Effects
• Nausea, vomiting, abdominal pain, itching
and drug fever.
• Headache, tinnitus, dizziness, bleeding,
dark urine,
• S-T segment changes, Q-T prolongation,
• First degree A-V block,
• Transient reticulopenia
• Leucopenia are rare

50. Artemisinin based
combination therapy(ACT)
• WHO has recommended that acute
uncomplicated resistant falciparum malaria
should be treated only by combining one
of the artemisinin compounds(short acting)
with another effective long acting
erythrocytic schizontocide.

51. • Advantages of ACT over other
antimalarials are:-
a)Rapid clinical and parasitological cure.
b)High cure rates(>95%) and low
recrudescence rate.
c)Absence of parasite resistance (the
components prevent development of
resistance to each other.)
d)Good tolerability profile.

53. Causal prophylaxis:
• Primaquine is a causal prophylactic for all
species of malaria
• Proguanil is a causal prophylactic, primarily for
P.f
• Atovaquone (250 mg) + proguanil (100 mg) is
commonly used as a prophylactic by Americans
and other western travelers visiting malaria
endemic areas

54. Suppressive prophylaxis
• Mefloquine 250 mg started 1–2 weeks before
and taken weekly till 4 weeks after return from
endemic area
• Chloroquine (CQ) 300 mg weekly:
• Start one week before with a loading dose of 10
mg/kg and continue till one month after return
from endemic area.

55. Contd.
• Doxycycline 100 mg daily:
• Starting day before travel
• Taken till 4 weeks after return from
endemic area for CQ-resistant P.f.,

56. • Chemoprophylaxis of malaria limited to
short-term use in special risk groups
• Nonimmune travelers
• Nonimmune Persons living in endemic areas for
fixed periods(army units, labour forces)
• Infants, children and pregnant women

57. Radical cure
• Primaquine 15 mg daily for 14 days

58. Gametocidal
• Primaquine is gametocidal to all species of
Plasmodia
• Single 45 mg (0.75 mg/kg) dose of
primaquine

59. Treatment of Malaria:
Vivax (also ovale, malariae) malaria
• Chloroquine + Primaquine 15 mg (0.25
mg/kg) daily × 14 days
Chloroquine-sensitive falciparum
malaria
• Chloroquine + Primaquine 45 mg (0.75
mg/kg) single dose (as gametocidal)

60. Chloroquine-resistant
falciparum malaria
• Artesunate 100 mg BD (4 mg/kg/day) × 3 days
+
• Sulfadoxine 1500 mg (25 mg/kg) +
Pyrimethamine 75 mg (1.25 mg/kg) single dose

61. • Artesunate 100 mg BD (4 mg/kg/day) × 3 days
+
• Mefloquine 750 mg (15 mg/kg) on 2nd day and
500 mg (10 mg/kg) on 3rd day.

62. • Arterolane (as maleate) 150 mg +
Piperaquine 750 mg once daily × 3 days

63. • Quinine 600 mg (10 mg/kg) 8 hourly × 7
days
+
• Doxycycline 100 mg daily × 7 days or +
Clindamycin 600 12 hourly × 7 days

64. Treatment of severe and complicated
falciparum malaria
• Artesunate: 2.4 mg/kg i.v. or i.m., followed
by 2.4 mg/kg after 12 and 24 hours, and
then once daily for 7 days

65. Contd.
• Artemether: 3.2 mg/kg i.m. on the 1st day,
followed by 1.6 mg/kg daily for 7 days.

66. Contd.
• Quinine diHCl: 20 mg/kg (loading dose) diluted
in 10 ml/kg 5% dextrose/dextrose-saline
• Infused i.v. over 4 hours, followed by 10 mg/kg
(maintenance dose) i.v. infusion over 4 hours (in
adults) or 2 hours (in children) every 8 hours

67. THANK YOU