ANTIMALERIAL DRUGS

1. Antimalarial drugs

2. POINTS TO BE COVERED
Chloroquine*,
Amodiaquine,
 Primaquine,
Proguanil,
Pyrimethamine*,
Quinine,
Trimethoprim

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

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

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

7. Chemical classification
• 4 aminoquinolines:
– Chloroquine,, Amodiaquine,
• 8 aminoquinolines:
– Primaquine,
• Cinchona alkaloids:
– Quinine, Quinidine
• Biguanides
– Proguanil, Chlorproguanil
• Diaminopyrimidines
– Pyrimethamine

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

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

10. 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
1. Other parasitic infections:
– Giardiasis, taeniasis, extrainstestinal amoebiasis
2. Other actions:
– Depressant action on myocardium, direct relaxant
effect on vascular smooth
muscles, antiinflammatory, antihistaminic , local

11. 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

12. 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

13. 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

14. 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

15. 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.

16. 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

17. • 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

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

19. 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

20. 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.

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

22. 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

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

24. 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

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

26. 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.

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

28. 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

29. 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

30. Artemisinin derivatives
• Artesunate
• Artemether
• Arteether

31. PLANT- ARTEMISIA ANNUA

32. 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

33. Antimalarial action
Artemisinin
Artemisinin
Conventional
Treatment

34. 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

35. Management of Malaria

36. 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

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

38. • 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:

39. 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

40. • 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

41. 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

42. 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

43. 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

44. 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

45. • 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

46. 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

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