The document discusses antimalarial drugs, including their mechanisms of action, classifications, and clinical uses. It covers quinine, chloroquine, primaquine, mefloquine, artemisinin derivatives, and combinations such as artemisinin-based combination therapies (ACTs). ACTs combine a fast-acting artemisinin drug with a long-acting partner drug to treat malaria infections more effectively and prevent drug resistance from developing. The classification of antimalarials is based on the stage of the malaria parasite life cycle they affect and their chemical structures. Adverse effects and guidelines for use are provided for many of the major antimalarial drugs.

1. Antimalarials

2. • Introduction:
– Most devastating parasitic infection
– 1-3 million deaths world wide each year
– India 8 lac deaths
• Etiology: Plasmodium
• Transmission : Female anopheles

3. • Clinical features:
a) Cold stage: onset with fatigue, headache, chills,
nausea, followed by rigors. Skin feels cold lasts
for 1 hr
b) Hot stage: feels, burning hot , casts off his
clothes , skin is hot & dry to touch, lasts for 2 to
6 hrs
c) Sweating stage: fever comes down with profuse
sweating & temperature drops rapidly to normal.
Skin is cool & moist. Pt feels relieved lasts for 2
to 4 hrs

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

5. • Classification of antimalarial drugs
– Based on stage of life cycle they affect
– Based on chemical structure

6. • Based on stage of parasite they affect:
– True causal prophylactics:
– Causal prophylactics: Primaquine,
Pyrimethamine,proguanil
– Supressives: quinine, 4-aminoquinolines,
mefloquine,artemisinin
– Radical curatives: primaquine,pyrimethamine
– Gametocidal:
• Supressives (Chloroquine, quinine, artesunate )
– Pl Vivax ,
• Primaquine – against all,
• Proguanil ,pyrimethamine – prevent development of
sporozoites

7. • Based on chemical structure:
– Cinchona alkaloids: quinine,quinidine
– 4 aminoquinolines: chloroquine,
hydroxychloroquine, amodiaquine, pyronaridine
– 8 aminoquinolines: primaquine, tafenoquine,
bulaquine
– quinoline methanol: mefloquine, halofantrine,
lumefantrine
– Antifolates:
• Diaminopyrimidine: pyrimethamine
• Biguanides: proguanil
• Sulfonamides: sulfadoxine

8. – Antibiotics: tetracycline, doxycycline, clindamycin
– Hydronaphthoquinone: Atovaquone
– Qinghaosu compounds: Artesunate, artemether,
arteether

9. • Chloroquine:
– Germans 1934 resochin
– closely resembles 8 amino quinolines
– d & l isomers, d isomer is less toxic
– Cl at position 7 confers maximal antimalarial
efficacy

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

11. • Pharmacological actions:
1. Antimalarial activity:
• Highly against erythrocytic forms of vivax, ovale,
malariae & sensitive strains of falciparum
• Gametocytes of vivax , ovale, malariae
• 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 anaesthetic

12. • Pharmacokinetics:
– Well absorbed, tmax 2-3 hrs , 55 % protein bound
– Conc in liver , spleen, kidney, lungs , leucocytes
– T1/2 = 3- 5 hrs increases from few days to weeks
• Adverse drug reaction:
– Intolerance:
• skin rashes, angioneurotic edema, photosensitivity,
pigmentation, exfoliative dermatititis
• Long term therapy may cause bleaching of hair
• Rarely thrombocytopenia, agranulocytosis,
pancytopenia

13. • 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.
These changes are reversible on stopping therapy
• CNS:
– Insomnia, transient depression seizures,
rarely neuromyopathy & ototoxicity
• CVS:
– ST & T wave abnormalities, abrupt fall in BP &
cardiac arrest in children reported

14. • Dosage:
• Therapeutic uses:
1. Hepatic amoebiasis:
2. Giardiasis
3. Clonorchis sinensis
4. Rheumatoid arthritis
5. DLE
6. Control manifestation of lepra reaction

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

16. • Quinine:
– 1820 Pelletier & caventou isolated quinine from
cinchona bark.
– Pharmacological actions:
1. Antimalarial action: primarily on erythrocytic
forms of all malarial parasites especially
resistant falciparum strains . gametocidal for
vivax & malariae
2. Local irritant effect: depresses variety of
enzymatic processes, reduces ciliary activity ,
inhibits phagacytosis & growth of protoplasm
so called general protoplasmic poison. Local
pain sterile abcess.

17. 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 on skeletal muscles
• Pharmacokinetics:
• administered orally is completely absorbed
• Tmax = 1-3 hrs , crosses placental barrier
• Metabolized in liver degradation products
excreted in urine t ½ = 10 hrs

18. • Adverse drug reactions:
• Cinchonism:
– Mild: Nausea, headache visual impairment
– 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.

19. • Idiosyncrasy : similar to cinchonism but occurs
in therapeutic doses
• Cardiovascular toxicity: cardiac arrest,
hypotension ,fatal arrhytmias
• Black water fever:
– Triad of hemolysis, hemoglobinemia, hemoglobinuria
with fever
– Rare type of hypersensitivity to quinine therapy
having immunological basis. Presence of
incompletely supressed falciparum malaria.
• Hypoglycemia:

20. • Uses:
– Malaria:
• uncomplicated resistant falciparum malaria
• Cerebral malarial
– Myotonia congenita: heriditory myopathy
characterized by tonic spasm of skeletal muscle,
benefitted by 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

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

22. • 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
• Pharmacokinetics:
– Readily absorbed, t1/2 = 3-6 hrs
– Oxidised in liver, excreted in urine

23. • Adverse effects:
– Gastrointestinal: epigastric distress, abdominal
cramps , can be minimised by taking drug with or
after food , or with antacids
– Hemopoetic: mild anemia, methemoglobinemia,
cyanosis, hemolytic anemia in G6PD deficiency
– Avoided during pregnancy, G6PD deficient
• Uses:
– Primary use is radical cure of relapsing malaria 15
mg daily for 14 days with dose of chloroquine
– India 5 day therapy
– Falciparum malaria 45 mg of single dose with
chloroquine curative dose to kill gametes & cut
down transmission of malaria.

24. • 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

25. • 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
• 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

26. • Adverse events:
1. GIT: bitter in taste, nausea, vomiting , abdominal
pain , diarrhoea
2. neuropsychiatric disturbances: disturbed sense of
balance, anxiety, hallucinations, sleep
disturbances, psychosis, errors in operating
machinery, convulsions
3. CVS: Bradycardia, sinus arhythmia, & QT
prolongation
4. Teratogenicity: avoided in first trimester
5. Miscellaneous: allergic skin reactions, hepatitis &
blood dyscrasias

27. • Uses:
– Effective drug for MDR falciparum
1. T/t of uncomplicated falciparum in MDR malaria
25 mg/kg (1.5 gm) in 2 divided doses taken on
same day
2. Prophylaxis in MDR areas 5 mg/kg (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
single drug for prophylaxis.

28. • 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, antipsychotics.

29. Drugs affecting synthesis &
utilisation of folate:

30. PABA +
Dihydropterine
+ Glutamic acid
Di hydrofolic
acid
Tetra hydrofolic
acid
Dihydrofolate
reductase
Ѳ
sulfonamides
Ѳ
DHFR
inhibitors

31. Sulfonamides:
Sulfanilamide moeity structural analog
of PABA,
PABA essential for folate synthesis
Sulfonamides compete with PABA for
folate synthetase
Weak effect , potentiate action of DHFR
inhibitors ,hence used in combination
Advantages of combination
Supradditive , sequential block
Combination faster acting

32. Dihydrofolate reductase inhibitors:
• Proguanil :
– Biguanide converted to cycloguanil active compound
– Act slowly on erythtocytic stage of vivax & falciparum
– Sporonticidal & also 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

33. • Pyrimethamine:
– Diaminopyrimidine more potent than proguanil &
effective against erythrocytic forms of all species.
– Tasteless so suitable for children
 Adverse events: megaloblastic anemia,
thrombocytopenia, agranulocytosis.
– Generally combined with sulfadoxine 500 mg +
pyrimethamine 25 mg, 3 tablets once for acute
attack
– Not recommended for prophylaxis due to severe
cutaneous reactions like exfoliative dermatitis &
stevenson johnson syndrome.

34. ARTEMISININ DERIVATIVATIVES:
• Mechanism of action:
• Antimalarial action:
Shorter acting drugs, so recrudescence
Prevented by combining with long acting drugs
• Dose: Artesunate, arteether, artemether
• Adverse events:
– No serious adverse events
– Most common GIT , Itching & fever
– Abnormal bleeding, dark urine , ST-T changes,
QT prolongation
– Transient reticulocytopenia & leucopenia
• Use:

35. Artemisinin based combination therapy:
• WHO: acute uncomplicated Pl Falciparum be
treated only by combining one Artemisinin with
other effective erythrocytic schizonticide?
• 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

36. • Artemether & lumefantrine:
– Lumefantrine is highly effective , long acting oral
erythrocytic schizonticide related to mefloquine
– Same mechanism of action
– Highly lipophilic onset delayed , peak 6 hrs
– Slower acting than chloroquine, 99 % bound ,
metabolized by CYP3A4, T1/2= 2-3 days
– Available as fixed dose combination
– Adverse events: headache, dizziness, sleep
disturbances, abdominal pain, arthralgia, pruritis &
rash
– 80 mg artemether BD WITH 480 mg lumefantrine
BD for 3 days
• DHA – Piperaquine, Artesunate- pyronaridine

37. • 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
• Atovaquone:
– Synthetic napthoquinone derivative, rapidly
acting erythrocytic schizonticide for
plasmodium falciparum & other plasmodia
– Pnemocystis carinnii & toxoplasma gondii
– Mechanism of action:
– Combined with proguanil
– 250 mg of atovaquone + 100 mg proguanil

38. Management of malaria:
• Prophylaxis;
– Indication
– Duration :
– Drug regimens:
• Chloroquine sensitive malaria: 300 mg / week
• Chloroquine resistant malaria: mefloquine, doxy,
malarone
• Drugs not allowed for prophylaxis: quinine,
artemisinin, pyrimethamine, sulfadoxine,
amodiaquine
– Other measures
– Causal prophylaxis
– Supressive prophylaxis

39. Treatment of acute attack
• Diagnosis , thick & thin smear
• Acute clinical attack of chloroquine
sensitive malaria:
– Chloroquine /
– Amodiaquine: 600 mg base followed by 200
mg base on day1 then 400 mg OD on day 2 &
day3/
– Quinine
– Patients who cannot take orally
• 2.5 mg/kg IM every 4 hrs or 3.5 mg/kg IM every 6
hrs
• 10 mg/kg IV over 4 hrs then 5 mg/kg over 2 hrs BD
– Role of primaquine
– Precautions:

40. • Treatment of chloroquine resistant malaria acute
attack
A. Pts who can take orally:
– Pyrimethamine sulfadoxine 3 tabs , quinine for 2 days
or
– Quinine 3 days with doxy 7 days or
– Quinine 3 days with mefloquine
– (Atovaquone 250 mg + proguanil 100 mg) 4 tab 3 days
– Sodium artesunate 100 mg BD day1 , 50 mg BD for 4
days

41. • 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 pt able to swallow
– Then quinine 600 mg TDS for 7 days &
tetracycline/ doxycycline
– Or artemether / arteether injection
• 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 / Complicated / cerebral malaria
– CNS symptoms, convulsions, coma
– Hypoglycemia, metabolic acidosis, renal failure
or other complications
– Quinine is drug of choice IV dose
– S-P , doxycycline added with oral therapy
– BP, blood sugar, ECG Monitored during quinine
therapy.
– Supportive measures:
• ICU administration
• Good nursing care,Tepid sponging, Na bicarbonate
• Hypoglycemia, anemia, BP , Increase ICT
– GC, urea, mannitol not used now a days

43. • Malaria in children:
– Quinine parenteral high toxicity / oral well tolerated
– Chloroquine convulsions in infants & small children
– Primaquine avoided in neonates
– Mefloquine not used in children below 15 kg weight
• Acute malaria in pregnant women
– Chloroqune, quinine, S-P in usual doses
– Mefloquine C/I in first trimester
– Primaquine/ tetracycline avoided
– Anemia: folic acid & iron

44. • Vaccines for malaria:
– Pre-erythrocytic stage vaccines
• RTS VACCINE designed to prevent invasion of
hepatocytes by sporozoites
– Erythrocytic stage vaccine:
• Aim is to reduce or eliminate number of blood stage
parasites
• Malarial surface protein 1 (MSP1) vaccine
• Apical merozoite antigen 1 (AMA1) vaccine
– Transmission blocking vaccines:
• Designed to prevent mosquitoes that feed on
vaccinated individuals from becoming infected &
reduce transmission (indirect prevention)
– Multicomponent vaccines: combination
vaccines
• Combination vaccine of 3 blood stage antigens