1. Antimalarial drugs can be classified based on their mechanism of action and targets in the parasite lifecycle. Chloroquine is a widely used antimalarial that is effective against sensitive strains of Plasmodium. 2. Artemisinin derivatives like artesunate are the most rapidly acting antimalarials currently available. They are recommended in combination therapies to reduce the risk of resistance developing. 3. Severe and complicated malaria requires parenteral administration of artesunate, artemether, or quinine along with supportive care. Oral antimalarials are used once the patient can tolerate them.

1. ANTIMALARIAL DRUGS
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2. CLASSIFICATION OF ANTIMALARIAL
DRUGS -p1

3. CLASSIFICATION OF ANTIMALARIAL DRUGS-p2

4. Antimalarial therapy P1

5. Antimalarial therapy P2

6. Antimalarial therapy P3

9. Plasmodium species

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

17. 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

18. 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.

19. 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

20. • 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

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

22. 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

23. 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.

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

25. 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

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

27. 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

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

29. 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.

30. • 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

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

39. 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

40. 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

41. Artemisinin derivatives
• Artesunate
• Artemether
• Arteether

42. PLANT- ARTEMISIA ANNUA

43. 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

44. Antimalarial action
Artemisinin
Artemisinin
Conventional
Treatment

45. 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

46. 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

47. 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

48. 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

49. 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

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

51. 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

52. 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

53. 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

54. Management of Malaria

55. 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

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

57. • 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)
Acute attack of chloroquine
sensitive malaria:

58. 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

59. • 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

60. 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

61. 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

62. 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

63. 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

64. • 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

65. 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

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