1. Antimalarial drugs

2. Plasmodium species which
infect humans
Plasmodium vivax (tertian):
Plasmodium ovale (tertian)
Plasmodium falciparum (tertian)
Plasmodium malariae (quartan)
Plasmodium knowlesi:

3. Sir Ronald Ross

5. Life cycle of the malarial parasite
True causal prophylactics
Sporonticide Schizogony
Sporogeny (asexual)
(sexual)
Causal
prophylactics
Supressives
Man : Intermediate host
Mosquito : Definitive host Gametocidal

6. • Classification of antimalarial drugs
– Therapeutic classification
– Chemical classification

7. Therapeutic classification
• Causal prophylaxis: (Primary tissue
schizonticides)
– Destroy parasite in liver cells and prevent invasion of
erythrocytes
– Primaquine, proguanil
• Supressives Prophylaxis:
– Supress the erythrocytic phase and thus attack of
malarial fever can be used as prophylactics
– Chloroquine, proguanil, mefloquine, doxycycline

8. Therapeutic classification
• Clinical cure: erythrocytic schizonticides
– used to terminate an episode of malarial fever
• Fast acting high efficacy
– Chloroquine, quinine, mefloquine, atovaquone,
artemisinin
• Slow acting low efficacy drugs
– Proguanil, pyrimethamine, sulfonamides,
tetracyclines

9. Therapeutic classification
• Radical curatives:
– Eradicate all forms of P.vivax & P.ovale from the body
– Supressive drugs + hypnozoitocidal drugs
– For vivax: primaquine 15 mg daily for 14 days
• Gametocidal:
– Destroy gametocytes and prevent transmission
– Primaquine, artemisinin – against all plasmodia
– Chloroquine, quinine – Pl Vivax
– Proguanil ,pyrimethamine – prevent development
of sporozoites

10. Chemical classification
• 4 aminoquinolines:
– Chloroquine, Hydroxychloroquine, Amodiaquine, Pyronari
dine
• 8 aminoquinolines:
– Primaquine, Tafenoquine, Bulaquine
• Cinchona alkaloids:
– Quinine, Quinidine
• Quinoline methanol:
– Mefloquine
• Biguanides
– Proguanil, Chlorproguanil

11. Chemical classification
• Diaminopyrimidines
– Pyrimethamine
• Sulfonamides
– Sulfadoxine, dapsone
• Tetracyclines:
– tetracycline, doxycycline
• Naphthoquinone:
– Atovaquone
• Sesquiterpene lactones:
– Artesunate, artemether, arteether

12. • Chloroquine:
– Synthesized by Germans in 1934 ( resochin)
– d & l isomers, d isomer is less toxic
– Cl at position 7 confers maximal antimalarial
efficacy

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

14. Pharmacological actions
1. Antimalarial activity:
– High against erythrocytic forms of
vivax, ovale, malariae & sensitive strains of
falciparum
– Gametocytes of vivax
– No activity against tissue schizonts
– Resistance develops due to efflux mechanism
2. Other parasitic infections:
– Giardiasis, taeniasis, extrainstestinal amoebiasis
3. Other actions:
– Depressant action on myocardium, direct relaxant
effect on vascular smooth
muscles, antiinflammatory, antihistaminic , local

15. Pharmacokinetics
• Well absorbed, tmax 2-3 hrs , 60 % protein
bound
• Concentrated in liver , spleen, kidney, lungs ,
leucocytes
• Selective accumulation in retina: occular
toxicity
• T1/2 = 3-10 days increases from few days to
weeks

16. Adverse drug reactions
• Intolerance:
– Nausea, vomiting, anorexia
– skin rashes, angioneurotic edema,
photosensitivity, pigmentation, exfoliative
dermatititis
– Long term therapy may cause bleaching of hair
– Rarely thrombocytopenia, agranulocytosis,
pancytopenia

17. Adverse drug reactions
• Occular toxicity: High dose prolonged therapy
– Temporary loss of accommodation
– Lenticular opacities, subcapsular cataract
– Retinopathy: constriction of arteries, edema, blue
black pigmentation , constricted field of vision.
• CNS:
– Insomnia, transient depression seizures,
rarely neuromyopathy & ototoxicity
• CVS:
– ST & T wave abnormalities, abrupt fall in BP &
cardiac arrest in children reported

18. Dosage
• 600 mg of base stat
• 300 mg base after 8 hours
• 150 mg of base BD for 2 days
• 200 mg oral tablet of chloroquine phosphate
consists of 150 mg base

19. Chloroquine is administered in loading
dose in malaria
• Chloroquine is well absorbed after oral
administration. It is extensively tissue bound
and sequestrated by tissues particularly
liver, spleen, kidney it has got large apparent
volume of distribution
• So it is given in loading dose to rapidly achieve
the effective plasma conc.

20. Therapeutic uses
1. Hepatic amoebiasis:
2. Giardiasis
3. Clonorchis sinensis
4. Rheumatoid arthritis
5. Discoid Lupus Erythematosus
6. Control manifestation of lepra reaction
7. Infectious mononucleosis

21. • Hydroxy chloroquine:
– Less toxic, properties &uses similar
• Amodiaquine:
– As effective as chloroquine
– Pharmacological actions similar
– Chloroquine resistant strains may be effective
– Adverse events: GIT, headache
, photosensitivity, rarely agranulocytosis
– Not recommended for prophylaxis
• Pyronaridine: effective in resistant cases

22. Quinine
• 1820 Pelletier & caventou isolated quinine
from cinchona bark.
• Mechanism of action:
– Similar to chloroquine

23. Pharmacological actions
1. Antimalarial action:
– Erythrocytic forms of all malarial parasites including
resistant falciparum strains .
– Gametocidal for vivax & malariae
2. Local irritant effect:
– Local pain sterile abcess.
3. Cardiovascular:
– depresses myocardium, ↓ excitability, ↓ conductivity,
↑ refractory period, profound hypotension IV.
4. Miscellaneous actions:
– Mild analgesic, antipyretic activity , stimulation of
uterine smooth muscle, curaremimitic effect

24. Adverse drug reactions
Cinchonism:
• Tinnitus, nausea & vomiting
• Headache mental confusion, vertigo,
difficulty in hearing & visual disturbances
• Diarrhoea , flushing & marked perspiration
• Still higher doses , exagerated symptoms
with delirium , fever, tachypnoea,
respiratory depression , cyanosis.

25. Adverse drug reactions
• Idiosyncrasy : similar to cinchonism but
occurs in therapeutic doses
• Cardiovascular toxicity: cardiac
arrest, hypotension ,fatal arrhytmias
• Black water fever:
• Hypoglycemia:

26. Uses
• Malaria:
– uncomplicated resistant falciparum malaria
– Cerebral malarial
• Myotonia congenita: 300 to 600 mg BD/ TDS
• Nocturnal muscle cramps: 200 – 300 mg
before sleeping
• Spermicidal in vaginal creams
• Varicose veins: along with urethane causes
thrombosis & fibrosis of varicose vein mass

27. • Primaquine:
– Mechanism of action:
Primaquine
Converted to
electrophiles
Generates reactive
oxygen species
– Interferes with oxygen transport system

28. Antimalarial action
• Liver hypnozoites
• Weak action against erythrocytic stage of
vivax, so used with supressives in radical cure
• No action against erythrocytic stage of
falciparum
• Has gametocidal action and is most effective
antimalarial to prevent transmission disease
against all 4 species

29. Adverse effects
• Gastrointestinal:
– epigastric
distress, abdominal cramps ,
• Hemopoetic:
– mild
anemia, methaemoglobinem
ia, cyanosis, hemolytic
anemia in G6PD deficiency
• Avoided during
pregnancy, G6PD deficient

30. Uses
• Primary use is radical cure of relapsing malaria
15 mg daily for 14 days with dose of
chloroquine
• Falciparum malaria 45 mg of single dose with
chloroquine curative dose to kill gametes &
cut down transmission of malaria.

31. • Tafenoquine:
– More active slowly metabolized analog of
primaquine, has advantage that it can be given on
weekly basis.
• Bulaquine:
– Congener of primaquine developed in india
– Comparable antirelapse activity when used for 5
days
– Partly metabolized to primaquine
– Better tolerated in G6PD deficiency

32. Mefloquine
• Quinoline methanol derivative developed to
deal with chloroquine resistant malaria
• Rapidly acting erythrocytic schizonticide ,
slower than chloroquine & quinine
• Effective against chloroquine sensitive &
resistant plasmodia
• Mechanism of action similar to chloroquine

33. Pharmacokinetics
• Good but slow oral absorption
• High protein binding
• Concentrated in liver, lung, intestine
• Extensive metabolism in liver, primarily
secreted in bile , under goes enterohepatic
circulation
• Long t1/2 = 2 – 3 weeks

34. Adverse events
• GIT:
– bitter in taste, nausea, vomiting , abdominal pain ,
diarrhoea
• Neuropsychiatric disturbances:
– anxiety, hallucinations, sleep disturbances, psychosis,
errors in operating machinery, convulsions
• CVS:
– Bradycardia, sinus arhythmia, & QT prolongation
• Teratogenicity:
– Avoided in first trimester
• Miscellaneous:
– allergic skin reactions, hepatitis & blood dyscrasias

35. Uses
• Effective drug for MDR falciparum
1. T/t of uncomplicated falciparum in MDR malaria
should be used along with artesunate (ACT)
2. Prophylaxis in MDR areas 250 mg per week
started 2- 3 weeks before to asses side effects
• Due to fear of development of drug
resistance mefloquine should not be used as
drug for prophylaxis in residents of endemic
area

36. Halofantrine
• Quinoline methanol
• 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
• Adverse events; Nausea, vomiting, QT
prolongation , diarrhoea, itching , rashes
• C/I: along with
quinine, chloroquine, antidepressants, antips

37. Atovaquone
• Synthetic napthoquinone
• Rapidly acting erythrocytic schizonticide for
plasmodium falciparum & other plasmodia
• MOA: Collapses mitochondrial membrane &
interferes ATP production
• Proguanil potentiates action of atovaquone
and prevents development of resistance
• Also used in P. Jivoreci & Toxoplasma gondii
infections

38. Dihydrofolate reductase inhibitors
• Proguanil :
– Biguanide converted to cycloguanil active
compound
– Act slowly on erythrocytic stage of vivax &
falciparum
– Prevents development of gametes
 Adverse effects:
 Stomatitis, mouth ulcers, larger doses depression
of myocardium , megaloblastic anemia
 Not a drug for acute attack
 Causal prophylaxis: 100 – 200 mg daily

39. Pyrimethamine
• Diaminopyrimidine more potent than proguanil
& effective against erythrocytic forms of all
species.
• Tasteless so suitable for children
 Adverse events: megaloblastic
anemia, thrombocytopenia, agranulocytosis.

40. Sulfadoxine-pyrimethamine
• Sequential blockade
• sulfadoxine 500 mg + pyrimethamine 25 mg, 3
tablets once for acute attack
• Not recommended for prophylaxis
• Use:
– single dose treatment of uncomplicated
chloroquine resistant falciparum malaria
– patients intolerant to chloroquine
– First choice treatment for toxoplasmosis

41. Artemisinin
• Artemisinin is the active principle of the plant
artimisia annua
• Sesquiterpine lactone derivative
• Most potent and rapid acting blood
schizonticides
• Short duration of action
• high recrudescence rate
• Poorly soluble in water & oil

42. Artemisinin derivatives
• Artesunate
• Artemether
• Arteether

43. PLANT- ARTEMISIA ANNUA

44. Mechanism of action
• These compounds have presence of endoperoxide
bridge
• Endoperoxide bridge interacts with heme in parasite
• Heme iron cleaves this endoperoxide bridge
• There is generation of highly reactive free radicals which
damage parasite membrane by covalently binding to
membrane proteins

45. Antimalarial action
Artemisinin
Conventional
Treatment
Artemisinin

46. Artesunate
• Water soluble ester of dihydroartemisinin
• Dose: can be given oral, IM,IV, rectal
– Oral
• 100 mg BD on day 1
• 50 mg BD day 2 to day 5
– Parenteral
• 120 mg on day 1 (2.4 mg/kg BD )
• 60 mg OD ( 2.4 mg/kg) for 7 days

47. Artemether
• Methyl ether of dihydroartemisinin
• Dose:
• Oral & IM
• 80 mg BD on day 1 (3.2 mg/kg)
• 80 mg OD (1.6 mg/kg) for 7 days

48. Arteether
• Ethyl ether of dihydroartemisinin
• Therapeutically equivalent to quinine in
cerebral malaria
• A longer t1/2 & more lipophilic than
artemether favouring accumulation in brain
• Dose:3.2 mg/kg on day1 followed by 1.6
mg/kg daily for next 4 days

49. Adverse events
• Leucopenia
• Hypersensitivity: Drug fever, itching
• GIT: nausea, vomiting, abdominal pain
(common)
• ECG changes: ST-T changes, QT prolongation
• Abnormal bleeding, dark urine
• Reticulocytopenia

50. 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 3-5 day
regimen of artemisin compounds with one long
acting drug like mefloquine 15 mg/kg single
dose
• Indicated by WHO in acute uncomplicated
resistant falciparum malaria

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

52. ACT Regimens in use
• Artesunate – Sulfadoxine, pyrimethamine:
– Adopted as first line in india under NMP
– ARTESUNATE 100 mg BD for 3 days with S-P, 3
tablets
• Artesunate Mefloquine:
– By combining artesunate further spread of
mefloquine resistance can be prevented
– Artesunate 100 mg BD for 3 days, + mefloquine
750 mg on second day & 500 mg on third day

53. Artemether & lumefantrine
• Lumefantrine is highly effective , long acting
oral erythrocytic schizonticide related to
mefloquine
• Highly lipophilic onset delayed , peak 6 hrs
• Available as fixed dose combination
• 80 mg artemether BD WITH 480 mg
lumefantrine BD for 3 days
Other ACTs:
– DHA – Piperaquine, Artesunate- pyronaridine

54. Tetracyclines
• Slow but potent action on erythrocytic stage
of all MP & Pre-erythrocytic stage of
falciparum
• Always used in combination with quinine or S-
P for treatment of chloroquine resistant
malaria

55. Management of Malaria

56. Prophylaxis of malaria
• Indication:
• Duration :1-2 weeks before to 4 weeks
after returning from endemic area
• Drug regimens:
– Chloroquine sensitive malaria: 300 mg / week
– Chloroquine resistant malaria:
• Mefloquine 250 mg once a week ,
• Doxycycline 100 mg daily ,
• Atovaquone + proguanil daily

57. Drugs not allowed for prophylaxis
• Quinine , artemisinin compounds
– Shorter acting, higher toxicity
• Pyrimethamine sulfadoxine
• Amodiaquine

58. Acute attack of chloroquine sensitive
malaria:
• Tab. 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
• Patients who cannot take orally
– 3.5 mg/kg IM every 6 hrs for 3 days
• Tab primaquine 15 mg OD for 14 days in
Plasmodium vivax, ovale
• Primaqine 45 mg single dose for falciparum
after chloroquine (gametocidal)

59. Acute attack of chloroquine resistant
malaria
A. Pts who can take orally:
– 3 tablets of (Pyrimethamine + sulfadoxine) single
dose followed by quinine 600 mg TDS for 2 days
or
– Tab Quinine 600 mg TDS X 3 days with Cap
doxycycline 100 mg BD for 7 days or
– Quinine 3 days with mefloquine or
– (Atovaquone 250 mg + proguanil 100 mg) 4
tab(Single dose ) for 3 days or
– artesunate 100 mg BD x 3 days with Sulfadoxine-
pyrimethamine or mefloquine

60. • 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

61. When should resistance be suspected
• All pts with complication
• Any pt who has already received chloroquine
last 1 month
• Hb continues to fall in absence of bleeding &
asexual forms persist along with symptoms
after 48 hrs of treatment

62. Severe and complicated falciparum
malaria
• Hyperparasitaemia
• Hyperpyrexia
• Fluid electrolyte disturbances, acidosis
• Hypoglycemia
• Cardiovascular collapse
• Jaundice, severe anaemia
• Spontaneous bleeding
• Pulmonary edema
• Renal failure
• Hemoglobinuria, black water fever
• Cerebral malaria

63. 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
– Switchover to 3 Day oral ACT in between
whenever patient can take oral medication

64. 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

65. • Malaria in children:
– Quinine parenteral high toxicity / oral well
tolerated
– Primaquine avoided in neonates
– Mefloquine not used in children below 15 kg
weight
• Acute malaria in pregnant women
– Chloroqune in usual doses
– Mefloquine C/I in first trimester
– Primaquine/ tetracycline avoided
– Anemia: folic acid & iron

66. Practice points
• Most antimalarials are bitter in taste give
along with milk or fruit juice
• If vomiting occurs within hour of drug repeat
full dose, in case of mefloquine repeat half
dose
• If vomiting after 1 hour no need to repeat
• Postural hypotension : quinine, chloroquine

67. Drugs used in chloroquine resistant
malaria
• Mefloquine
• Quinine
• Sulfadoxine pyrimethamine
• Artemisinin compounds