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