Class antimalarial drugs

this class is in brief for under graduate understanding and examination purpose

1. Dr. RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.

2. Protozoa are eukaryotes and unicellular organisms.
Most of the protozoal infections are due to unhygienic
conditions.
Less easily treated than bacterial infections and
antiprotozoal drugs are more toxic.
Protozoalinfections may be one or more infection
results from the following:
Amoebiasis, trypanosomiasis,giardiasis, leishmaniasis,
trichomoniasis, Malaria, toxoplasmosis.
PROTOZOAL INFECTIONS

3. Plasmodium specieswhich infect
humans
Plasmodium vivax (tertian):
Plasmodium ovale (tertian)
Plasmodium falciparum(M.tertian)
Plasmodium malariae (quartan)

4. Sporogeny
(sexual)
Schizogony
(asexual)
Man : Intermediate
host
Mosquito :
Definitive host
True causal prophylactics
CAUSAL
PROPHYLACTICS
SUPRESSIVES
GAMETOCIDAL
SPORONTICIDE

5. 5

6. 4 Aminoquinolines:
CHLOROQUINE, HYDROXYCHLOROQUINE,
AMODIAQUINE, PIPERAQUINE
8 Aminoquinolines:
PRIMAQUINE, TAFENOQUINE, BULAQUINE
Cinchona alkaloids:
QUININE, QUINIDINE
Quinoline methanol: MEFLOQUINE
Biguanides:PROGUANIL, CHLORPROGUANIL

7. Diaminopyrimidines:PYRIMETHAMINE
Sulfonamides: SULFADOXINE, DAPSONE
Antibiotics:TETRACYCLINE, DOXYCYCLINE,
CLINDAMYCIN
Naphthoquinone: ATOVAQUONE
Sesquiterpene lactones:ARTESUNATE, ARTEMETHER,
ARTEETHER, ARTEROLANE
Amino-alcohols:HALOFANTRINE, LUMIFANTRINE
Naphthyridine:PYRONARIDINE

8. Synthesized by Germans in 1934 ( resochin)
d & l isomers, d isomer is less toxic
Cl at position 7 confers maximal antimalarial efficacy
Antimalarial activity:
High against erythrocytic forms of vivax, ovale,
malariae & sensitive strains of falciparum
Gametocytes of vivax

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

10. Other parasitic infections:
Giardiasis, taeniasis, extrainstestinal amoebiasis
Other actions:
Depressant action on myocardium, direct relaxant effect
on vascular smooth muscles, anti-inflammatory,
antihistaminic , local anaesthetic
Resistancedevelops due to effluxmechanism
Well absorbed, tmax 2-3 hrs , 60 % protein bound
Concentrated in liver , spleen, kidney, lungs , leucocytes
Selective accumulation inretina:oculartoxicity
T1/2 = 3-10 days increases from few days to weeks

11. 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.
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

12. Intolerance:
Nausea, vomiting, anorexia
skin rashes, angioneurotic edema, photosensitivity,
pigmentation, exfoliative dermatitis's
Long term therapy may cause bleaching of hair
Rarely thrombocytopenia, agranulocytosis,
pancytopenia

13. Ocular toxicity: High dose prolonged therapy
Temporary loss of accommodation
Lenticular opacities, sub capsular 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. Hepatic Amoebiasis:
Giardiasis
Clonorchis sinensis
Rheumatoid arthritis
Discoid Lupus Erythematosus
Control manifestation of lepra reaction
Infectious mononucleosis

15. 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
4 AMINOQUINOLINES:

16. 1820 Pelletier & caventou isolated quinine from
cinchona bark.
Mechanism of action:
Similar to chloroquine
Pharmacokinetics-Administeredorally is completely
absorbed
Tmax = 1-3 hrs , crosses placental barrier
Metabolized in liver degradation products excreted in
urine t ½ = 10 hrs

17. Antimalarial action:
Erythrocytic forms of all malarial parasites including
resistant falciparum strains .
Gametocidal for vivax & malariae
Local irritant effect: Local pain sterile abscess.
3. Cardiovascular: depresses myocardium, ↓ excitability,
↓ conducvity, ↑ refractory period, profound
hypotension IV.
4. Miscellaneous actions: Mild analgesic, antipyretic
activity , stimulation of uterine smooth muscle, curare
mimetic effect

18. 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

19. Cinchonism:
Tinnitus, nausea & vomiting
Headache mental confusion, vertigo, difficulty in
hearing & visual disturbances
Diarrhoea , flushing & marked perspiration
Still higher doses , exaggerated symptoms with
delirium, fever, tachypnoea, respiratory depression ,
cyanosis.

20. Idiosyncrasy : similar to Cinchonism but occurs in
therapeutic doses
Cardiovascular toxicity: cardiac arrest, hypotension
fatal arrhythmias
Black water fever
Hypoglycemia

21. Primaquine-Converted toelectrophilesGenerates
reactive oxygen species
Liver Hypnozoites
Weak action against erythrocytic stage of vivax, so
used with suppressive 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

22. Readilyabsorbed,
t1/2=3-6hrs
Oxidizedinliver
excretedinurine
Uses-Primaryuse 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.

23. Gastrointestinal:
epigastric distress, abdominal
cramps ,
Hemopoetic:
mild anemia,
methaemoglobinemia,
cyanosis, hemolytic anemia in
G6PD deficiency
Avoided during pregnancy, G6PD
deficient

24. Tafenoquine:
More active slowly metabolized analog of
primaquine, has advantage that it can be given on
weekly basis.
Bulaquine:
Congener of primaquine developed inIndia
Comparable antirelapse activity when used for 5
days
Partly metabolized to primaquine
Better tolerated in G6PD deficiency
Tafenoquine and Bulaquine

25. 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
Neither gametocidal, nor kills Hypnozoites

26. 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

27. Effective drug for MDR falciparum
T/t of uncomplicated falciparum in MDR malaria
should be used along with Artesunate (ACT)
Prophylaxis in MDR areas 250 mg per week started 2-
3 weeks before to assess side effects
Due to fear of drug resistance mefloquine should not
be used as drug for prophylaxis in residents of endemic
area

28. GIT: bitter in taste, nausea, vomiting , abdominal pain ,
diarrhoea
Neuropsychiatric disturbances: anxiety, hallucinations,
sleep disturbances, psychosis, errors in operating
machinery, convulsions
CVS: Bradycardia, sinus arrhythmia, & QT prolongation
Teratogenicity: Avoided in first trimester
Miscellaneous: allergic skin reactions, hepatitis & blood
dyscrasias

29. 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.

30. Synthetic naphthoquinone
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. Jiroveci & Toxoplasma gondi infections

31. 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 cause
depression ofmyocardium,megaloblastic anemia
Not a drug for acute attack
Causal prophylaxis: 100–200 mg daily

32. Pyrimethamine isdiaminopyrimidinemore potent than
proguanil & effective against erythrocytic forms of all
species
Inhibitsdihydrofolatereductase enzyme
Tasteless so suitable forchildren
Used in uncomplicated chloroquine resistant malaria
Sulfadoxine(1500mg)+ Pyrimethamine(75mg)-single dose
Adverse events:sulfa related
megaloblasticanemia, thrombocytopenia,
agranulocytosis.

33. Artemisinin is the active principle of the plant
Artemisia annua
Sesquiterpene lactone derivative
Most potent and rapid acting blood schizonticides
Short duration of action
Poorly soluble in water & oil
Artesunate
Artemether
Arteether
Arterolane

34. 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

35. MOA-
2) Artemisinin free radicals specifically inhibit a plasmodial
sarcoplasmic-endoplasmic calcium ATPase
Watersoluble ester of dihydroartemisinin
Dose: can be givenoral, IM,IV, rectalt1/2-1-2hrs
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
Artemisinin
Artemisinin
Conventional
Treatment

36. Methyl ether ofdihydroartemisinin
Converted to DHA-dihydroartemisinin,not given IV, t1/2-3-10hrs
Dose: Oral & IM-80 mg BD on day 1 (3.2 mg/kg)
80 mg OD (1.6 mg/kg) for 7 days
ARTEETHER–
Ethylether of dihydroartemisinin
Therapeutically equivalent to quinine in cerebral malaria
A longer t
1/2& more lipophilic than artemether favoring
accumulation inbrain
Given IM only T1/2-23hrs
Dose:3.2 mg/kg on day1 followed by 1.6 mg/kg daily for next 4
days
ARTEROLANE-available for oral use only in combination

37. Leucopenia
Hypersensitivity: Drug fever, itching
GIT: nausea, vomiting, abdominal pain (common)
ECG changes: ST-T changes, QT prolongation
Abnormal bleeding, dark urine
Reticulocytopenia
D/I-concurrent administration withastemizole,
antiarrhythmics, tricyclic antidepressants and
phenothiazinesincrease the risk of cardiac conduction
defects

38. Artemisinin compounds 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
Artemisinin compounds with one long acting drug like
mefloquine 15 mg/kg single dose
Indicated by WHO in acute uncomplicated resistant
falciparum malaria
Rapid clinical & parasitological cure
High cure rates and low relapse rates

39. There are now more trials involvingArtemisininand its derivatives than
other antimalarial drugs, so although there are still gaps in our
knowledge, there is a reasonable evidence base on safety and efficacy
from which to base recommendations.
Combinationswhich have been evaluated:
piperaquine
Artemisinin+
mefloquine
Artesunate+
piperaquinedihydroartemisinin +
mefloquine
lumefantrine
artemether +
mefloquine
naphthoquine
chloroquine
amodiaquine
sulfadoxine-
pyrimaethaminine
mefloquine
proguanil-dapsone
chlorproguanil-dapsone
atovaquone-proguanil
clindamycin
tetracycline
doxycycline

40. 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

41. Quinine ,
Artemisinincompounds
Pyrimethamine sulfadoxine
Amodiaquine
Drugsused in chloroquine resistant malaria
Mefloquine
Quinine
Sulfadoxine pyrimethamine
Artemisinin compounds

42. Lumefantrine is highlyeffective,long acting oral
erythrocytic schizonticide related to mefloquine
MOA-similar to chloroquine
-also affects nucleic acid and protein synthesis of parasite
Fatty food increases absorption
Highlylipophilic onset delayed ,
peak6 hrs
Available as fixed dose combination
80 mg artemetherbdwith 480 mg lumefantrinebdfor 3
days

43. Tetracyclines and doxycycline
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
CLINDAMYCIN
Bacteriostatic antibiotic, erythrocyticschizontocide
Potentiates the action of quinine and artemisinin

44. 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
Primaquine 45 mg single dose for falciparum after
chloroquine (gametocidal)

45. 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

46. 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
Chloroquine resistant malaria

47. 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

48. 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

49. 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
Chloroquine in usual doses
Mefloquine C/I in first trimester
Primaquine/ tetracycline avoided
Anemia: folic acid & iron
Malaria inchildren

50. THANK YOU
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