Antimalarial drugs made easy for medical students

1. Antimalarial drugs
Dr. Divya Krishnan
KMCT Medical College

2. Questions
• Classification of antimalarial drugs (chemical/therapeutic)
• Chloroquine
• Primaquine
• Quinine
• Artemisinin/sesquiterpine derivatives

3. Introduction
• Malaria is major health problem in India & tropics.
• Malaria caused by 4 species of plasmodium parasite :-
-> Plasmodium vivax (tertian)
-> Plasmodium ovale (tertian)
-> Plasmodium falciparum (tertian)(severe malaria)
-> Plasmodium malariae (quartan)
Sir Ronald Ross

5. Life cycle of the malarial parasite
Sporogeny
(sexual)
Schizogony
(asexual)
Man : Intermediate host
Mosquito : Definitive host

6. Life cycle (brief)
• Causative organism - Plasmodium vivax
• Vector/definitive host - female anopheles mosquito,
intermediate host - 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)

7. • 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)

8. Antimalarial drugs
Drugs for treatment/prophylaxis /prevention of
relapses of malaria.

9. Objectives of use of antimalarial
drugs/THERAPEUTIC CLASSIFICATION
1. To prevent clinical attack of malaria (prophylactic)
- Causal prophylactics attack the pre-erythrocytic phase in
liver which is the cause of malarial infection.(TISSUE
SCHIZONTOCIDE) E.g. Primaquine, proguanil
- Suppressive prophylactics suppress the erythrocytic
phase & prevents attack of malarial fever. E.g.
Chloroquine, proguanil, mefloquine
Prophylaxis adviced in:-
- Non immune travellers to endemic areas
- Non immune persons living in endemic areas for fixed
time (e.g.army units)
- Infants, children, pregnant women in endemic areas

10. 2. To treat clinical attack of malaria (clinical curatives)
- Attack the erythrocyte schizonts & terminates episode
of malarial fever.(ERYTHROCYTIC SCHIZONTOCIDE)
There are Fast acting high efficacy ones
(E.g.Chloroquine, quinine, artemisinin ) & Slow acting
low efficacy drugs (E.g.Proguanil, pyrimethamine,
sulfonamides)
3. To completeley eradicate the parasite from the body
(radical cure)
- Indicated only in P.vivax & P. ovale because they
produce relapsing malaria due to persistence of
hypnozoites. E.g. Primaquine

11. 4. Gametocidal drugs
- Helps in decreasing the transmission of malaria from
infected person to another.
- No use to the infected person
Eg. Primaquine, proguanil, pyrimethamine.

13. Chemical classification
• 4 aminoquinolines
– Chloroquine, Amodiaquine, Piperaquine
• Quinoline methanol
– Mefloquine
• Cinchona alkaloid
– Quinine, Quinidine
• Biguanides
– Proguanil
• Diaminopyrimidines
- Pyrimethamine
• Sulfonamides
– Sulfadoxine, dapsone

14. Chemical classification
• 8 aminoquinolines:
– Primaquine, Tafenoquine
• Antibiotics
– tetracycline, doxycycline, Clindamycin
• Naphthoquinone
- Atovaquone
• Naphthyridine
- Pyronaridine
• Amino alcohols
- Halofantrene, Lumefantrene
• Sesquiterpene lactones:
– Artesunate, artemether, arteether, Arterolane

15. Chloroquine
- Rapid action Erythrocytic schizontocide of all species
of Plasmodium.
- Controls clinical attacks in 1-2 days.

16. Mechanism of action
• Plasmodia digest hemoglobin to heme & globin in their
acidic vacuole. Globin is used by plasmodia for
nutrition. Heme being toxic to plasmodium is
converted to non toxic pigment hemazoin by heme
polymerase enzyme of the parasite.
• Chloroquine concentrates inside the acidic vacuole of
parasite & raises the pH of vacuole. Interferes with
conversion of toxic heme to non toxic hemazoin by
inhibiting heme polymerase.
CQ-Heme complex formed damages plasmodial
membranes.

17. Hemoglobin Globin utilized by
malarial parasite
Heme (highly toxic for malaria parasite)
Chloroquine
Quinine, (+) Heme Polymerase
mefloquine (-)
Hemozoin (Not toxic to plasmodium)
Mechanism of action

18. Chloroquine resistance
• Chloroquine resistance is fast developing in
P.falciparum & is a major problem because severe
cases of malaria are caused by this species.
• Resistance develops due to efflux mechanism

19. Pharmacological actions
1. Antimalarial activity
2. Other parasitic infections:
– Giardiasis, extrainstestinal amoebiasis
3. Other actions:
– Antiinflammatory, antihistaminic , local
anaesthetic , weak smooth muscle relaxant,
Antiarrhythmic activity .

20. Pharmacokinetics
• Good oral absorption.
• Concentrated in liver , spleen, kidney, lungs ,skin,
leucocytes
• Selective accumulation in retina: ocular toxicity
on prolonged use.
• Metabolized in liver, excreted in urine.
• T1/2 = 3-10 days. Due to tissue binding, small
amounts persist in body with terminal t1/2 of 1-2
months.

21. Adverse drug reactions
Occuring at low dose/ short duration use
– Nausea, vomiting, anorexia, epigastric pain
– uneasiness
– Uncontrollable itching
– Headache, difficulty in accommodation
Occuring at high doses/prolonged use
- Loss of vision(retinal damage)/, corneal deposits
leading to diminished vision
- Loss of hearing
- Mental disturbances
- Graying of hair
- Rashes, photoallergy

22. Contraindication
• Liver damage
• Severe GIT, neurological, retinal , hematological
diseases.
• Should not be co-administered with mefloquine,
amiodarone, antiarrhythmics.
• CAN BE GIVEN IN PREGNANCY
• 250 mg oral tablet of chloroquine phosphate consists of 150
mg base

23. Therapeutic uses
1. Malaria : Used for clinical cure against P. ovale,
P.malariae, P.ovale & some P. falciparum that are
still sensitive.
2. Giardiasis
3. Extraintestinal amoebiasis
4. Rheumatoid arthritis
5. Discoid Lupus Erythematosus
6. Lepra reaction
7. Infectious mononucleosis
8. Photogenic reactions

24. Amodiaquine
– Identical properties to chloroquine
– Even Chloroquine resistant strains may be
effective.
Piperaquine
Appears effective in resistant cases

25. Mefloquine (Quinoline methanol)
• Developed to deal with chloroquine resistant P.falciparum
• Rapidly acting Erythrocytic schizonticide of chloroquine
sensitive & resistant plasmodia (clinical curative).
Also effective suppressive prophylactic for multidrug
resistant P.falciparum.
• Mechanism of action similar to Chloroquine.
• Adverse effects : Nausea, vomiting, diarrhoea, QT
prolongation, neuropsychiatric reactions (ataxia, anxiety,
hallucinations)
• Contraindicated in psychiatric disorders, cardiac conduction
defects, 1st trimester of pregnancy.

26. Quinine
• L-isomer alkaloid isolated from cinchona bark.
(Quinidine is d-isomer used as antiarrhythmic(mainly) &
as antimalarial)
• Erythrocyte schizontocide against all plasmodium
(including CQ &MDR P.falciparum) but more toxic than
CQ.
Also kills gametes of P.vivax
• Mechanism of action: Similar to chloroquine

27. Adverse drug reactions
Cinchonism ( large single dose/higher therapeutic doses
for longer period)
• Tinnitus, nausea & vomiting
• Headache, mental confusion, vertigo, difficulty in hearing &
visual disturbances
• Diarrhoea , flushing & marked perspiration
• Still higher doses : exaggerated symptoms with delirium ,
fever, tachypnoea, respiratory depression , pulmonary
edema, hypoglycemia.
- Idiosyncrasy in some individuals: cinchonism develops at
therapeutic doses itself
- Occasional hemolysis in pregnant women & patients with P.
falciparumhemoglobinuria (black water fever)&kidney
damage

28. Uses
• Malaria:
– uncomplicated resistant falciparum malaria – oral
quinine given.
– Complicated & severe malaria including cerebral
malarial – IV quinine used
• Nocturnal muscle cramps

29. Proguanil
– Not a popular drug for acute attack (slow action)
Pyrimethamine
- Used only in combination with sulfonamides for
malariaa treatment.

30. Sulfadoxine-pyrimethamine
• Long acting sulfonamides (Sulfadoxine) are not effective
antimalarial but combination with Pyrimethamine
causes sequential blockade of folic acid synthesis in
plasmodia.
• Effective against erythrocytic stage of P.falciparum.
• Combination acts faster &prevents development of
resistance.
• Risk of hypersensitivity reactions due to sulfonamide
component.

31. Primaquine
• Most active against Liver hypnozoites (pre-erythrocytic
phase).
• Weak action against erythrocytic stage of vivax. No
action against erythrocytic stage of falciparum
• Has gametocidal action against all species.

32. Mechanism of action:
Primaquine
Converted to electrophiles
Generates reactive oxygen
species

33. Adverse effects
• Gastrointestinal
– epigastric distress, abdominal cramps ,
• Hemopoetic:
– mild anemia, methaemoglobinemia, cyanosis,
hemolytic anemia in G6PD deficiency.
• Avoided during pregnancy, G6PD patients

34. Use
• Primary use is radical cure of relapsing malaria in P.
vivax . ( 15 mg daily for 14 days with dose of
chloroquine)
• Gametocidal in Falciparum malaria(45 mg of single
dose with chloroquine ) & cut down transmission of
malaria.

35. Tafenoquine: single dose antirelapse therapy
for vivax malaria.

36. Antibiotics
• Slow but potent action on erythrocytic stage of all
malarial parasites including multidrug resistant ones.
• Always used in combination with quinine or S-P for
treatment of chloroquine resistant malaria.

37. Halofantrine & Lumefantrine
• Amino alcohols
• Used in chloroquine resistant malaria since 1980
• Erratic bioavailabilty, lethal cardiotoxicity & cross
resistance to mefloquine limited its use
• Now a days used only when no other alternative
available

38. Atovaquone
• Not used in India

39. Artemisinin
• Artemisinin is the active principle of the plant
artimisia annua .
• Sesquiterpine lactone derivative.
• Most potent and rapid acting against blood
schizonticides of P.falciparum resistant to all other
drugs.
• Due to short duration of action high
recrudescence rate .

40. PLANT- ARTEMISIA ANNUA

41. Artemisinin derivatives
• Artesunate
• Artemether
• Arteether
• Arterolane

42. Mechanism of action
• These compounds have endoperoxide bridge.
• Heme iron cleaves this endoperoxide bridge to form
highly reactive free radicals which damage parasite
membrane by covalently binding to membrane proteins

43. Artesunate
• Water soluble ester
• Can be given oral, IM,IV, rectal
Artemether
• Lipid soluble ester.
• Oral & IM
Arteether
• Ethyl ester
• Available for IM use.
Arterolane
• Used in combination therapy only
• Oral use

44. Adverse effects
• Mild adverse effects like nausea, vomiting, abdominal
pain, drug fever, itching (common)
• Tinnitus, dizziness, bleeding, dark urine, ECG changes ,
QT prolongation, leucopenia are rare.

45. Use
• Uncomplicated P.falciparum(CQ sensitive & resistant)
• Severe & complicated malaria : given parenterally.

46. Artemisinin based combination therapy (ACT)
• Artemisinin compunds are shorter acting drugs.
• Monotherapy needs to be extended beyond
disappearance of parasite to prevent recrudescence.
This can be prevented by combining artemisin
compounds with one long acting drug like mefloquine
etc.

47. Why combination therapy ?
• Rapid clinical & parasitological cure.
• High cure rates and low relapse rates.
• Absence of resistance.
• Good tolerability profile.

48. ACT Regimens in use
• Artesunate – Sulfadoxine- pyrimethamine
• Artesunate -Mefloquine
• Aretemether -lumefantrine
• Artesunate- amodiaquine
• Arterolane- piperaquine

49. Tu You You
Received Nobel prize in Physiology/Medicine in
December 2015 for discovery of Artemisinin

50. Management of Malaria

51. • Chloroquine phosphate 250 mg
– Contains 150 mg of base
– Give 4 tablets stat , 2 tablets after 8 hours and , 1
tablet BD for 2 days
• Tab primaquine 15 mg OD for 14 days in Plasmodium
vivax, ovale
• Primaqine 45 mg single dose for falciparum after
chloroquine (gametocidal)
Acute attack of chloroquine sensitive malaria:

52. Acute attack of chloroquine resistant malaria
– (Pyrimethamine + sulfadoxine)
– Quinine
– Atovaquone +proguanil
– ACT

53. • Pts who cannot take orally
– Inj Quinine Hcl 20 mg/kg in 500 ml dextrose saline
over 4 hrs then
– 10 mg/kg in dextrose saline over 2 hrs every 8 hrly
till patient is able to swallow
– Then quinine 600 mg TDS for 7 days &
tetracycline/ doxycycline
Or
– artemether / arteether injection

54. Treatment of severe and complicated
falciparum malaria
• Artesunate 2.4 mg/kg IV/IM, BD on day1 then 2.4
mg/kg daily for 7 days OR
• Artemether 3.2 mg/kg IM on day 1 then 1.6
mg/kg daily for 7 days OR
• Arteether 3.2 mg/kg IM on day1, followed by 1.6
mg/kg daily for next 4 days

55. OR
• Quinine: 20 mg quinine salt/kg on admission (i.v.
infusion in 5% dextrose/dextrose saline over a period
of 4 hours) followed by maintenance dose of 10
mg/kg body weight 8 hourly.
– When ever patient can swallow orally switch over
to oral quinine 10 mg/kg 8 hrly and complete 7
days course

56. THANK YOU