This document discusses malaria, which is caused by Plasmodium parasites and transmitted through mosquito bites. It describes the symptoms and species of Plasmodium, including P. falciparum which causes severe malaria. Various antimalarial drugs are outlined, including chloroquine, quinine, mefloquine, primaquine, and artemisinin combinations. The mechanisms of action, pharmacokinetics, uses, resistance, adverse effects and contraindications are summarized for major antimalarial drugs. Treatment guidelines for different forms of malaria and radical cure using primaquine are also provided.

2.  Malaria - caused by sporozoites of Plasmodium
 Transmitted by infected female Anopheles
 Symptoms: chills, rigor, fever, headache,
sweating
 Chronic- progressive spleenomegaly
 Sym appear after 7-10 days of mosquito bite
 Incubation period 10-30 days.

4.  Clinically important species of plasmodium
P.falciparum, P.vivax, P.ovale, P.malariae
 Definitive host- female anapheles mosquito
 Intermediate host- human being
P.vivax:
 causes benign tertian malaria
 Relapse can occur due to hypnozoites in liver
P.ovale:
 Has periodicity & relapses, milder

5. P.falciparum:
 Malignant tertian malaria
 Forms RBC rosettes
 Blocks vital organs-renal failure &
encephalopathy
 Exo-erythrocytic stage absent
 Relapse do not occur, recrudescence can occur
P.malariae:
 Quartan malaria,Exo-erythrocytic stage absent
 relapse can occur, rare.

6. 1) 4-Aminoquinolines – Chloroquine
Amodiaquine
Piperaquine.
pyronaridine
2) Quinoline-methanol – Mefloquine.
3) Cinchona alkaloid - Quinine
Quinidine
4) Biguanides –------- Proguanil
Chlorproguanil
5) Diaminopyrimidines – Pyrimethamine
6) 8-Aminoqunilones–---- Primaquine
Bulaquine

7. 7) Sulfonamides and sulfones – Sulfadoxine
Sulfamethopyrizone
Dapsone
8) Tetracyclines –---------- Tetracycline
Doxycycline
9) Sesquiterpinelactones –----- Artesunate
Artemether
Arteether
10) Amino alcohols –------------ Halofantrine
Lumefantrine
11) Acridine –--------------- Mepacrine
Quinacrine
12) Naphthoquinone –-----------Atovaquone

8. Schizonticides
1)Tissue (Hepatic) schizonticides:
 Primary- proguanil & pyrimethamine
 Active against pre-erythrocytic state of P.Falc
 Secondary- primaquine
 Acts on both pre & exo erythrocytic cycle of all
Ps

9.  Destroy blood schizonts
 Prevent erythrocytic schizogony
1) Fast acting high efficacy-
 Chloroquine, quinine, mefloquine,
lumefantrine, atremisinin & atovaquone
 Used to terminate attack of malaria promptly
2) Slow acting low efficacy-
 Pyrimethamine+sulfadoxine, proguanil &
doxycycline.
 Used in combination to terminate clinical attack

10. Gametocides
 Destroy gametocytes so mosquito can’t transmit
 Primaquine for all species
 Chloroquine & quinine- except P.falciparum
Sporontocides
 Makes gametocytes ineffective in mosquito
 proguanil & pyrimethamine
 No clinical advantage

11. Causal prophylactics
 Prevent pre-erythrocytic phase
 proguanil & pyrimethamine – P.Falciparum only
 Primaquine- all Ps, toxic
 If G6PD levels are normal 0.5mg/Kg daily till
stay in endemic region.

12.  Blood schizonticides are used - kills merozoites
 Prevents erythrocytic phase
 No effect on hepatic phase
 Following drug regimens are used.
1) Areas with CQ-sensitive P. falc or P. viv only
 Tab.Chloroquine 300mg(free base)
[500mg chl. phosphate contains 300mg free base]
 Begin 1–2 weeks before travel to malarious
areas. Take weekly on the same day of the
week while in the malarious areas and for 4
weeks after leaving such areas.
 Primaquine 15mg/d X 14 days after leaving

13. 2) Areas with chloroquine-resistant P. falciparum
 T.Mefloquine 250 mg once weekly, 1 week
before and 4 weeks after travel.
3) Areas with chloroquine or mefloquine-resistant
Plasmodium falciparum
 Atovaquone/proguanil 1 adult tablet daily 1-2
days before & 7 days after travel
 An adult tablet contains 250 mg of atovaquone
and 100 mg of proguanil hydrochloride. (or)
 Doxycycline: 100mg daily, a day before travel
and taken till 4 weeks after return from endemic
area.

14. a)Vivax (ovale, malariae) malaria
1.Chloroquine 600mg stat followed by
300mg after 8 hrs and for next 2
days(total 25mg/kg over 3 days) +
Primaquine 15mg (0.25mg/kg daily) for 14 days
In chloroquine resistance
2) Quinine- 600mg 8 hourly x7 days+
Doxycycline- 100mg daily x 7days+
Primaquine- 15mg daily X 14 days

16. B) Chloroquine sensitive falciparum malaria
 Chloroqiuine as above +
Primaquine- 45 mg single dose as gametocide
C) Chloroquine resistant falciparum malaria
1.Artesunate- 100mgBD(4mg/kg daily) x 3 days+
Sulfadoxine-1500mg(25mg/kg)+
Pyrimethamine- 75mg(1.25mg/kg) single dose
 First line ACT
2.Artesunate- 100mgBD(4mg/kg daily) x 3 days+
Mefloquine- 750mg(15mg/kg)on 2nd day and
500mg(10mg/kg) on 3rd day

18. 3. Artemether- 80mg +
Lumefantrine- 480 mg B.D X 3days
4. Arterolane 150 mg +
Piperaquine 750mg od X3 days
5.Quinine 600mg 8hly X 7 days+
Doxycycline100mg daily X 7days or
Clindamycin 600mg 12hly X 7 days
 In India irrespective of CQ – resistance status
are treated with ACT.

19. 1. Artesunate- 2.4mg/kg i.v or i.m, f/b
2.4mg/kg after 12 and 24 hrs
Then OD for 7 days.
2. Artemether- 3.2mg/kg i.m on 1st day f/b
1.6mg/kg for next 7 days
3. Arteether- 3.2mg/kg on 1st day f/b
1.6mg/kg for next 4 days
Switch over to 3 day oral ACT in between
whenever the patient is able to take oral med

20. 4. Quinine diHCL-20mg/kg(loading dose) diluted
in 10ml/kg 5%dextrose/dextrose-saline and
infused i.v over 4 hours, f/b
10mg/kg(maintenance dose) i.v infusion over 4
hours(adults) or 2 hours (children) every 8
hours, until patient can swallow.
Switch over to oral quinine 10mg/kg 8hourly to
complete 7 day course.
Falciparum malaria during pregnancy
 Q 600mgTDS 7d+ clindamycin 300md 7d all tri
 3 day ACT regimen in 2nd & 3rd tri alt to above

21. Radical cure:
Drugs which attack the exo-erythrocytic stage
given together with a clinical curative achieve
total eradication of parasite.
 Drug of choice for vivax and ovale malaria is
Primaquine: 15mg daily for 14 days.
It should given with or immediately after
chloroquine or other schizonticide only to
persons who test negative to G6PD deficiency.
 Anti relapse treatment is restricted to:
a) Areas with low levels of transmission.
b) Patients treated during an epidemic along with
effective vector measures to cut down
transmission.

22. Chloroquine
 Available as Cl.Phosphate for oral use
PK
 A-almost completely absorbed from GIT.
 D-large aVd, extensively tissue bound.
 M- liver, initial t1/2- 3-4 days, terminal t1/2- 1-2mts
 E-urine
 ROA- oral/ I.M/ slow I.V infusion

23. MOA
 Preferentially accumulates in Parasitized RBC
 Being basic diffuses freely in to parasite
lysosome
 Gets ionized in acidic pH of lysosome
 Inhibits peptide formation & AA synthesis
 Inhibits parasite haem polymerase→
 Host haem is not converted to haemozoin
 Free haem is toxic to malarial parasite

24. Antimalarial action & clinical use
 It is rapidly acting erythrocytic schizonticide
against all species of plasmodia.
Uses
1) Drug of choice for clinical cure and prophylaxis
of all types of malaria.
2) Extra-intestinal amoebiasis
3) Rheumatoid arthritis
4) DLE- very effective. Less effective in SLE.
5) Lepra reactions.
6) Photogenic reactions
7) Infectious mononucleosis – symptomatic relief.

25. Resistance
 Most common in P.falciparum
 Due to mutation in putative chloroquine
transporter (PfCRT).
Adverse effects
 Nausea, anorexia, uncontrollable vomiting,
epigastric pain, difficulty in accommodation, and
headache.
 Parenterally – hypotension, cardiac depression,
arrhythmias, convulsions
 Prolonged use: loss of vision due to retinal
damage.

26. CI
 Retinal & visual field abnormalities.
 Aggravates psoriasis & porphyria.
 G6PD deficiency- haemolytic anemia.
DI
 Antacids ↓ absorption
 C+ metoclopramide precipitates extra pyramidal
side effects.
 Safe in pregnancy and children >2yrs

27. Amodiaquine
 Similar to chloroquine
 Withdrawn-risk of agranulocytosis, hepatotoxic.
 Reintroduced in chloroquine resistant areas
 Resistant P.falciparum responds to
amodiaquine combination regimens
 Artesunate + amodiaquine or
 Pyrimethamine-sulfadoxine + amodiaquine.
 Toxicity is rare with combination.

28. Piperaquine
 Piperaquine is chloroquine analogue.
 Used for Rx of P.falciparum malaria in fixed dose
combination with dihydroartemisinin
 Longer t1/2- 35 days, reduces rate of relapse
Pyronaridine
 Amodiaquine analogue used in china.
 Combined with artesunate for chloroquine
resistant falciparum & vivax malaria
 Effective orally & has low toxicity.

29. Quinine
 Alkaloid derived from cinchona bark
 Rx and prevention of malaria since 1820
PK
 A- well absorbed from GIT.
 D-large aVd, extensively tissue bound.
 M- liver, t1/2- 10-11 hrs
 E- urine
 ROA- oral/ slow I.V infusion

30. MOA
 Not clear
 Like chloroq inhibits parasite haem polymerase.
 Acts as a protoplasmic poison to parasite &
hampers supply of AA & peptides.
Antimalarial action & clinical use
 Similar to chloroquine.
 No effect on pre-erythtocytic stages and on
hypnozoites of relapsing malaria, but kills vivax
gametes.
 Main drug for chloroquine resistant P.fal malaria

31. Other uses
 Nocturnal leg cramps- varicose veins
Diabetes mellitus
Arthritis
 Quinine + clindamycin- 1st line Rx of Babesiosis
Resistance
 To P.falciparum reported in Thailand.
 Due to ↑ expression of P-glycoprotein

32. Adverse effects
 Bitter taste- poor compliance
 Gastric irritant – nausea, vomiting
 Bolus I.V admin- hypotension & arrhythmias
 Stimulates insulin release- Hypoglycemia.
 Hence quinine usually infused with 5%dextrose.
 May lead to hypoglycemic coma in P.f malaria.
 Black water fever- erratic use in other fever.
 Leads to marked haemolysis & renal failure.

33. Cinchonism
 A syndrome due to intake of a large single dose
or higher therapeutic doses taken for a few
days.
 Characterized by
 Sweating
 Tinnitus
 Blurred vision
 Headache
 Diarrhoea
 Cardiac arrhythmias
 Neurotoxicity (higher doses)
 Hematological toxicity (hemolysis in G6PD def)

34. Contraindications (CI)
 Visual & auditory problems
 Cardiac abnormalities
Drug interactions (DI)
 Antacids ↓ absorption
 Quinine raises plasma levels of digoxin
 Shouldn’t be given concurrently with mefloquine
both effect cardiac conduction- arrhythmias

35. Mefloquine
PK
 A- orally well absorbed
 D- highly protein bound, extensively distributed
 M- liver, undergoes enterohepatic circulation.
 E- feces, t1/2- 20 days, weekly dosing in
chemoprophylaxis, single dose regimen for
clinical cure.
 ROA- oral, can’t give parenterally-pain, irritation
MOA & Resistance
 Similar to quinine

36. Antimalarial action & uses
 Blood schizonticide
 used for chemoprophylaxis and clinical cure
 Not useful in severe & complicated malaria
Adverse effects
 Nausea
 Vomiting
 Neuropsychiatric side effects in 0.5% patients
 Vertigo, Confusion, vivid dreams, seizures
 Abnormal AV conduction
 CI with quinine or halofantrine

37. Primaquine
PK
 A- orally well absorbed.
 D- wide, not extensively tissue bound.
 M- liver, active metabolites- toxic.
 E- urine, t1/2-3-6 hrs.
 ROA- oral
MOA
 Not clear
 Quinone metabolite inhibits coenzyme-Q in
parasite, also hemolysis in host.

38. Antimalarial action & uses
 Tissue schizonticide, gametocidal.
 Effective on both pre & exo erythrocytic state
 Not effective on erythrocytic state.
 Mainly used for radical cure and to prevent
relapse in P.vivax & P.ovale
 Other use- primaquine + clindamycin in
Pneumocystis jiroveci pneumonia
 Improved tolerance over cotrimoxazole

39. Adverse effects
 Git distress, nausea
 Head ache
 Pruritis
 Leukopenia
 G6PD def pt- fatal haemolytic anemia
 CI in pregnancy
 Other congeners-
 Bulaquine, etaquine, tafenoquine

40.  Bulaquine : developed in India,
 Prodrug for primaquine
 Dose- 25mg/d starting on 2nd day of chloroquine
therapy
 primaquine or bulaquine not given parenterally
 Produces marked hypotension
 Etaquine & tafenoquine more potent and longer
acting
 Tafenoquine –orally once weekly.

41. Pyrimethamine-sulfonamide/dapsone
 Pyrimethamine selectively inhibits plasmodial
folate reductase enzyme.
 Slow acting erythrocytic schizonticide
 Sulfonamides are added to prevent resistance.
 Sulfadoxine/sulphamethopyrazine/dapsone
 Inhibit dihydropteroate synthase enzyme
 Used for clinical cure of P.falciparum malaria.
 Q+Sd+P- chloroquine resistant P.falc .
 Other uses:
 Toxoplasmosis : in immunodeficient P(50-
75mg/d)+sulfadiazine(2-4g/d) 1-3 wk 1st line
therapy.

42. Adverse effects
 Pyrimethamine -megaloblastic anemia
 Folinic acid is added to therapy to prevent this
 Anorexia, vomiting, atrophic glossitis, seizures
 P+Sd- exfoliative dermatitis
stevens johnson syndrome.
Allergic alveolitis, blood dyscrasias
 P+D- Haemolytic anemia,
Agranulocytosis
Eosinophilic alveolotis

43. Tetracycline & Doxycycline
 Slow acting & weak erythrocytic schizonticides
 Effective against all species.
 Use – combination with quinine for CQ resistant
falciparum & vivax malaria.
 Dose: Tetracycline- 250mg QID
Doxycycline- 100mg OD
 Doxycycline 100mg/day is 2nd line prophylactic
treatment for travellers to chloroquine resistant
P.falciparum areas.

44. Proguanil (Chloroguanide)
 Inhibitor of plasmodial dihydrofolate reductase
PK
 A- rapid, t1/2 16hrs, administered OD.
Antimalarial action
 Slow acting erythrocytic schizonticide for all Ps.
 Acts on pre-erythrocytic stage of P.vivax
 No effect on exoerythrocytic cycle & gametes
 Resistance develops rapidly when used alone
 Hence used in combination

45.  250 mg Atovaquone + Prouguanil 100mg OD X
2days prior to & 7 days after exposure for
chemoprophylaxis of P.falciparum malaria.
 AQ 1000mg + PG 400 mg OD X3 days
preferred for Rx of CQ R P.viv & MDR P.fal
 Combined formulations should be taken with
food
 AE: less severe

46. Atovaquone
 Used in combination with proguanil
 FDC prevent resistance & better tolerated
MOA
 Not clear, disrupts plasmodial mitochondrial
electron transport
 Inhibits pyrimidine & ATP synthesis
PK
 A-BA poor & erratic, ↑ with fatty meal
 D- PB-99%
 M- long t1/2 (2-3 d) partly due to EH recycling
 E- feces

47. Uses
 Chemoprophylaxis & Rx of P.fal with PG
 Other- mild to mod Pneumocystis.carinii
pneumonia in pt intolerant to cotrimoazole
 Rx or suppression of Toxoplasma gondii
encephalitis
AE
 Abd pain, N, V, Headache, rash
 Reversible elevation in liver enzymes
DI
 Metoclopramide, tetracycline, rifampicin ↓AQ
plasma levels

48.  Artemether, Artesunate, Arteether are
Sesquiterpinelactone endoperoxidases
 Artemisinin is active principle of the plant
Artemisia annua used in Chinese traditional
medicine as” Quinghaosu.”
 Active against P.falciparum resistant to all
drugs as well as sensitive strains.
 Artemether, Artesunate, Arteether
semisynthetic derivatives of Artemisinin with
improved potency better BA

49. Pk
 Artemisinin is poorly soluble in water & oil,
 Artemether is soluble in oil , given orally, i.m, t1/2
4-11 hrs.
 Artesunate is water soluble , given orally, i.m, i.v
t1/2<1 hr . Both are prodrugs.
 Active metabolite Dihydroartemisinin also used
orally
 Arteether (i.m in oil) was produced in India in
1990. longer t1/2 23 hrs
 Arterolane –synthetic compound given orally.

50. Antimalarial action
 Potent and rapid blood schizonticide and
parasitemia clearance is<48 hrs.
 Action on a wide range of forms – from ring
forms to early schizonts, thus have the broadest
time window of anti-malarial action.
 Do not kill hypnozoites but some action on
gametes.
 Recrudescence depends on dose, duration, as
well as severity of disease.

51. MOA
 Involves two steps
 Initially intraparasitic protoporphyrin –IV
catalyses break down of endoperoxide bridge
(-O-O-) of artemisinin molecule
 Generation of highly reactive free radicals ->
 Damage parasite membrane by covalently
binding to proteins
 Free radicals specifically inhibit plasmodial
sarcoplasmic-endoplasmic Ca ATPase labelled
PfATP6

52. AE:
 N, V, Abd pain, itching
 Temp QT prolongation may occur
 Transient reticulopenia and leucopenia are rare
Halofantrine
 Potent blood schizonticide
 A- erratic, ↑with food
 MOA possible inhibition of proton pump
 Manifests lethal cardiotoxicity & cross
resistance with mefloquine
 USE: restricted for MDR P.fal 500mg QID X 1 d
repeated after 1wk

53. AE:
 Abd pain, Vomiting cough, rash, prutitis
 Transient elevation in liver enzymes
 Cardiotoxicity: prolong QT & PR interval, dose
related defects in cardiac conduction
 Worsens with mefloquine
 Embryotoxic in animals avoided in pregnancy
Lumefantrine
Used in combination with Artemether for MDR P.fa
BD X 3days
Combination not cardiotoxic
 Given with fatty meal ↑ BA

54. Artemisinin based combination therapy (ACT)
 WHO recommended that acute uncomplicated
resistant falciparum malaria should be treated
by combining artemisinin compounds with
another erythrocytic schizonticide.
 Most important consideration for companion
drug is elimination half life as effective
concentrations in blood must be maintained for
at least 3asexual cycles.
 Short half life drugs Ad. for 7 days.
 Long half life drugs Ad. for 1-3days.

55.  Advantages of ACT over other drugs:
 Rapid clinical and parasitological cure.
 High cure rates(>95%) and low recrudescence
rate.
 Absence of parasitic resistance.
 Good tolerability profile.
ACT regimens in use are:
1.Artesunate- 100mgBD(4mg/kg daily) x 3 days+
Sulfadoxine-1500mg(25mg/kg)+
Pyrimethamine- 75mg(1.25mg/kg) single dose
 First line ACT
 But not effective against multidrug resistant
strains.

56. 2.Artesunate- 100mgBD(4mg/kg daily) x 3 days+
Mefloquine- 750mg(15mg/kg)on 2nd day and
500mg(10mg/kg) on 3rd day
 First line treatment for uncomplicated falciparum
malaria in S-E Asia.
 Further spread of mefloquine resistance is
prevented.
3. Artemether- 80mg +
Lumefantrine- 480 mg B.D X 3days
components protect each other from plasmodial
resistance.
Active in multidrug resistance areas.
Artemether reduces symptoms and lumefantrine
prevents recrudescence.

57. 4. Arterolane 150 mg +
Piperaquine 750mg od X3 days
5. Dihydroartemisinin 120mg +piperaquine 750mg
daily X 3days
 Well tolerated even in children
6. Artesunate 200mg + Amodiaquine 600mg/day X
3days.
7. Artesunate 100-200mg + pyronaridine 300 -
600mg/day X 3days.

58. Thank you