Antimalarial Drugs Pharmacology

A PowerPoint presentation on Fluoroquinolones suitable for reading by UG level Medical and Nursing students

1. Antimalarial drugs
Dr. D. K. Brahma
Associate Professor
Dept. of Pharmacology
NEIGRIHMS

2. Introduction
•Malaria is major health problem in India & tropics
•Malaria caused by 4 species of plasmodium parasite:-
>Plasmodium vivax(tertian)
>Plasmodium ovale(tertian)
>Plasmodium falciparum (tertian)(severemalaria)
>Plasmodium malariae(quartan)

3. Life cycle(brief)
•Causativeorganism -Plasmodiumvivax
•Vector/definitive host -female anopheles mosquito,
intermediate host -man.
•Life cycle occurs partly inside the mosquito (sexual sporogony)&man
(asexualschizogony)
•Mosquito bites man-transmitssporozoitesto hisblood.
•Sporozoites -liver and reproduces asexually (tissue schizogony) producing
merozoites.
•Merozoites infect new RBCs and initiate asexual multiplication in RBC (blood
schizogony) -production of more merozoites.
•The RBC bursts and starts the infective cycle. Some merozoites develop into
male and female gametes.
•Some merozoites remain dormant in the liver (hypnozoites) which can cause a
relapse of infection later (p. vivax &ovale)

4. •Whenmosquitobitesinfectedperson,gametesaretaken
upwiththeblood.
•Thegametocytesmatureinthemosquitogutandfuseto
formanookinatewhichdevelopsintosporozoites.(Sexual
sporogony)
•Sporozoitesmigratetosalivaryglandsandinfectanew
hostwhenmosquitobitestheperson.
Recurrent malaria : Can be relapse(hypnozoites) or
recrudescence (parasites surviving in blood due to
incompletetreatment)

5. Antimalarialdrugs
Drugs for treatment/prophylaxis /prevention of
relapses ofmalaria

6. Antimalarialdrugs-History
•17
th
Century –Cinchona Tree in Peru
•1820 till 1942 –Cinchona Bark
•WW I and WW II –Java blocked
•1926 –Mepacrine
•1945 –Proguanil
•Proguanil, Pyrimethamine
Sir Ronald Ross

7. Objectives of use of antimalarial drugs
•To prevent clinical attack of Malaria (prophylactic)
•To treat clinical attack of malaria (curative)
•To completely eradicate the parasite from patients
body (radical cure)
•To cut down human-to-mosquito transmission
(Gametocidal)

8. THERAPEUTICCLASSIFICATION
To prevent clinical attack of malaria(prophylactic)
-Causal prophylactics attack the pre-erythrocytic phase in liver which is
the cause of malarial infection.(TISSUE SCHIZONTOCIDE) E.g.
Primaquine,proguanil(100) and atovaquone(250)
-Suppressive prophylactics suppress the erythrocytic phase &
prevents attack of malarial fever.E.g.
Chloroquine,mefloquine,proguanil,Doxycycline
Prophylaxis advicedin(short term)
-Non immune travellers to endemicareas
-Non immune persons living in endemic areas for fixed time
(e.g.armyunits)
-Infants, children, pregnant women in endemicareas
-Intermittent preventive treatment in pregnancy –Pyri75 mg +
Sulfadoxine(1500 mg) –1 month –2
nd
and 3
rd
trimester (Pf endemic)

9. To treat clinical attack of malaria (clinicalcuratives)
-Attack the erythrocyte schizonts & terminates episode
of malarial fever(ERYTHROCYTICSCHIZONTOCIDE)
Fast acting high efficacy ones (E.g.Chloroquine,quinine,
artemisinin, mefloquine, halofantrinelumifantrine,
atovaquone))
Slowacting low efficacy drugs (E.g.Proguanil,
pyrimethamine, sulfonamides, tetracycline and
clindamycin)

10. To completely eradicate the parasite from the body
(radicalcure) –erythrocyticschizontocides–
faster acting drugs in falciparum
-Indicated only in P.vivax& P. ovalebecause they
produce relapsing malaria due to persistence of
hypnozoites
-Recrudescnces-falciparum
Gametocidaldrugs
-Helps in decreasing the transmission of malaria from infected
person toanother.
-No use to the infectedperson
Eg. Primaquine, proguanil,pyrimethamine.

11. Source: Textbook of K. D. Tripathi, JaypeeBrothers Medical Publishers, 8
th
Edition , 2019

12. Chemicalclassification
Source: Textbook of K. D. Tripathi, JaypeeBrothers Medical Publishers, 8
th
Edition , 2019

13. Chloroquine(CQ)
-Rapid action Erythrocytic schizontocide of all species
of Plasmodium
-CQ-resistant falciparum
-No effect on primary and secondary hepatic stages
and gametes
-Controls clinical attacksin 1-2days.

14. Hemoglobin Globin utilizedby
malarialparasite
Heme (highly toxicformalariaparasite)
Chloroquine
Quinine,
mefloquine(-)
(+)HemePolymerase
Hemozoin (Not toxic toplasmodium)
Mechanism ofaction

15. Mechanism ofaction
•Plasmodia digest hemoglobin to heme & globin in their acidic
vacuole. Globin is used by plasmodia for nutrition
•Heme being toxic to plasmodium is converted to non toxic
pigment hemazoinby heme polymerase enzyme of theparasite
•Chloroquine concentrates inside the acidic vacuole of parasite
& raises the pH of vacuole
•Interferes with conversion of toxic heme to non toxic
hemazoin by inhibitinghemepolymerase
•CQ-Heme complex formed damages plasmodial membranes

16. Chloroquineresistance
•Chloroquine resistance is fast developing in
P.falciparum & is a major problem because severe
cases of malaria are caused by thisspecies.
•Slow in vivax
•Multidrug resistance –Sulfa-
pyrimethamine, proguanil, quinine
•Resistance develops due to effluxmechanism

17. Pharmacologicalactions
1.Antimalarialactivity
2.Other parasiticinfections:
–Giardiasis,extrainstestinalamoebiasis
3.Other actions:
–Antiinflammatory, antihistaminic, local
anaesthetic, weak smooth muscle relaxant,
Antiarrhythmicactivity.

18. Pharmacokinetics
•Good oralabsorption
•Concentratedin liver, spleen, kidney, lungs,skin,
leucocytes
•Selective accumulation in retina: ocular toxicity
on prolongeduse
•Metabolized in liver, excreted inurine
•T1/2 = 3-10 days. Due to tissue binding, small
amounts persist in body with terminal t1/2 of 1-2
months

19. Adverse drugreactions
Occuring at low dose/ short durationuse
–Nausea, vomiting, anorexia, epigastricpain
–uneasiness
–Uncontrollableitching
–Headache, difficulty inaccommodation
–abortion
Occuring at high doses/prolongeduse
-Loss of vision(retinal damage)/, corneal deposits
leading to diminishedvision
-Loss ofhearing
-Mentaldisturbances
-Graying ofhair
-Rashes,photoallergy

20. Contraindication
•Liverdamage
•Severe GIT, neurological, retinal , hematological
diseases.
•Should not be co-administered with mefloquine,
amiodarone,antiarrhythmics.
•Can be given inpregnancy
•250 mg oral tablet ofchloroquinephosphateconsists of150
mgbase

21. Therapeuticuses
1.Malaria : Used for clinical cure against P. ovale,
P.malariae, P.ovale& some P. falciparum that are
stillsensitive.
2.Giardiasis
3.Extraintestinalamoebiasis
4.Rheumatoidarthritis
5.Discoid LupusErythematosus
6.Leprareaction
7.Infectiousmononucleosis
8.Photogenicreactions

22. Amodiaquine
•Identical properties tochloroquine
•Even Chloroquine resistant strains may be
effective.
•Less bitter
Piperaquine
•Effective in resistantcases

23. Mefloquine (Quinolinemethanol)
•Developed to deal with chloroquine resistantP.falciparum
•Rapidly acting Erythrocytic schizonticideof chloroquine sensitive
& resistant plasmodia (clinicalcurative)–single dose.
•Also effective suppressive prophylactic for multidrug resistant
P.falciparum.
•But not gameticidalor kills hypnozoites
•Mechanism of action similar toChloroquine –Relapse
•Kinetics: Well absorbed orally –peak conc. In 5 –15 hours
•Highly bound to plasma protein
•Conc. In liver, lung and intestine
•Enterhepaticcirculation –2-3 weeks

24. Mefloquine (Quinolinemethanol)
•Adverse effects : Bitter taste, Nausea, vomiting, diarrhoea, QT
prolongation, neuropsychiatric reactions (ataxia, anxiety,
hallucinations)
•Contraindicated in psychiatric disorders, cardiac conduction defects,
1
st
trimester ofpregnancy.
•Uses: in multidrug resistant malaria in combination with ACT –
uncomplicated falciparum, CQ resistant and CQ-pyrimethamine
resistant
•Prophylactic use

25. Quinine
•L-isomer alkaloid isolatedfromcinchonabark. (Quinidine is d-
isomer used asantiarrhythmic(mainly) & asantimalarial)
•Erythrocyte schizontocide against all plasmodium (including
CQ &MDRP.falciparum)butmore toxic than CQand also less
effective
Also kills gametes ofP.vivax
Resistance developed and cross resistance with Mefloquine
Effective in terminating acute attack of falciparum–recrudescence
–Doxy and clinda
•Mechanism of action: Similar tochloroquine
•Other actions: Local irritant and anaesthetic, analgesic,
antipyrreticand skeletal muscle relaxant

26. Adverse drugreactions
Cinchonism(large single dose/higher therapeutic doses
for longerperiod)
•Tinnitus,nausea& vomiting
•Headache, mental confusion, vertigo, difficulty in hearing &
visualdisturbances
•Diarrhoea, flushing & markedperspiration
•Still higherdoses :exaggerated symptoms with delirium,
fever, tachypnoea, respiratory depression , pulmonary
edema,hypoglycemia.
-Idiosyncrasyin some individuals: cinchonism developsat
therapeutic dosesitself
-Occasional hemolysisin pregnant women & patients with P.
falciparum→hemoglobinuria (black water fever)&kidney
damage

27. Uses
•Malaria:
–uncomplicated resistant falciparum malaria –oral
quininegiven–when ACT not available
–Complicated & severe malaria including cerebral
malarial –IV quinineDOC
–Artesunate(IV/IM, artemether(IM), Artether
(IM)
•Nocturnal musclecramps

28. Proguanil
–Not a popular drug for acute attack (slowaction)
Pyrimethamine
Directly acting DHFRaseinhibitor –high affinity
Used only in combination with sulfonamidesor dapsone
for falciparummalaria treatment.

29. Sulfadoxine-pyrimethamine
•Long acting sulfonamides (Sulfadoxine)/dapsoneare not effective
antimalarial but combination with Pyrimethamine causes
sequentialblockade of folic acid synthesis in
plasmodia.
•Slow acting –but combination faster
•Effective against erythrocytic stage ofP.falciparum.
•Combination acts faster &prevents development of
resistance.
•Uses: P. falciparumas curative but not vivax
•Risk of hypersensitivity reactions due to sulfonamide
component–SJS, Exfoliative–prophylactic dose lesser
(pregnancy)

30. Primaquine
•Most active against Liver hypnozoites (pre-erythrocytic
phase).
•Weak action against erythrocytic stage of vivax. No
action against erythrocytic stage offalciparum
•Has gametocidal action against allspecies.
•MOA: Not known –electron transport

31. Adverseeffects
•Gastrointestinal
–epigastric distress, abdominal cramps,
•Hemopoetic:
–mild anemia, methaemoglobinemia, cyanosis,
hemolytic anemia in G6PDdeficiency.
•Avoidedduringpregnancy,G6PDpatients

32. Uses
•Primary use is radical cure of relapsing malaria in P.
vivax.( 15 mg daily for 14 days with dose of
chloroquine)
•Gametocidal in Falciparum malaria(45 mg of single
dose with chloroquine ) & cut down transmission of
malaria.

33. Tafenoquine
•Single dose antirelapse therapy for vivax
malaria.

34. Antibiotics
•Slow but potent action on erythrocytic stage of all
malarial parasites including multidrug resistantones.
•Always used in combination with quinine or S-P for
treatment of chloroquine resistantmalaria.

35. Halofantrine &Lumefantrine
•Aminoalcohols
•Used in chloroquine resistant malaria since1980
•Erratic bioavailabilty, lethal cardiotoxicity & cross
resistance to mefloquine limited its use
•Now a days used only when no other alternative
available

36. Atovaquone
•Not used inIndia

37. Artemisinin
•Artemisinin is the active principle of the plant
Quinghaosu(Artimisiaannua)
•Sesquiterpine lactonederivative.
•Most potent and rapid acting against blood schizonticides
of P.falciparum resistant to all other drugs.
•Potent and rapid scizontocidalaction –rapid parasite
clearance
•Lethal to early gametes
•Do not kill primary liver forms of hypnozoites
•Due to short duration of action→high
recrudescence rate

38. Artemisininderivatives
•Artemisinin: Poorly soluble in water and oil
•Derivatives:
•Artesunate: In water (oral, IV and IM)
•Artemether: In oil (oral and IM)
•Dihydroartemisin” Oral
•Arteether: India (In oil and IM)
•Arterolane: Oral synthetic

39. Mechanism ofaction
•These compounds have endoperoxidebridge.
•Hemeiron cleaves thisendoperoxidebridgeto form
highly reactive free radicals(FE-Iron mediated cleavage)
which damage parasite membrane by covalently
binding to membraneproteins

40. Adverseeffects
•Mild adverse effects like nausea, vomiting, abdominal
pain, drug fever, itching(common)
•Tinnitus, dizziness, bleeding, dark urine, ECG changes ,
QT prolongation, leucopenia arerare.

41. Uses
•Uncomplicated P.falciparum(CQ sensitive &
resistant)
•Severe & complicated malaria : givenparenterally.

42. Artemisinin based combination therapy
(ACT)
•Artemisinin compunds are shorter actingdrugs.
•Monotherapy needs to be extended beyond
disappearance of parasite to preventrecrudescence.
This can be prevented by combining artemisin
compounds with one long acting drug like mefloquine
etc.

43. Why combination therapy?
•Rapid clinical & parasitologicalcure
•High cure rates and low relapserates
•Absence of resistance
•Good tolerabilityprofile

44. ACT Regimens inuse
•Artesunate –Sulfadoxine-pyrimethamine
•Artesunate -Mefloquine
•Aretemether-lumefantrine
•Artesunate-amodiaquine
•Arterolane-piperaquine

45. Management ofMalaria

46. •Chloroquine phosphate 250mg
–Contains 150 mg ofbase
–Give 4 tablets stat, 2 tablets after 8 hours and, 1
tablet BD for 2days
•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 sensitivemalaria

47. Occasional chloroquine resistantmalaria
–Quinine8hry + Doxycyclinedaily + Clindamycin12
hrly… Primaquine
–ACT

48. •Pts who cannot takeorally
–Inj Quinine Hcl 20 mg/kg in 500 ml dextrose saline
over 4 hrsthen
–10 mg/kg in dextrose saline over 2 hrs every 8 hrly
till patient is able toswallow
–Then quinine 600 mg TDS for 7 days &
tetracycline/doxycycline
Or,
–artemether / arteetherinjection

49. Source: Textbook of K. D. Tripathi, JaypeeBrothers Medical Publishers, 8
th
Edition , 2019

50. Source: Textbook of K. D. Tripathi, JaypeeBrothers Medical Publishers, 8
th
Edition , 2019

51. For Examination
•Classification of antimalarial drugs
(chemical/therapeutic)
•Chloroquine
•Primaquine
•Quinine
•Artemisinin/sesquiterpinederivatives

52. THANKYOU