Antimalarial drugs

1. Antimalarial Drugs

2. Malaria
• Malaria is an acute infectious disease
• Causative agent : Plasmodium species
o Protozoan parasite
o 4 species infecting humans
i. P. falciparum
ii. P. vivax
iii. P. malariae
iv. P. ovale
• Transmitted by female Anopheles mosquito
• Is characterized by high fever with rigor, anaemia, profuse
sweating

3. Types of malaria
Plasmodium
falciparum
Plasmodium vivax Plasmodium
malariae
Plasmodium ovale
•most dangerous
species
•causes an acute,
rapidly fulminating
disease i.e.
characterized by
persistent high fever,
orthostatic
hypotension, and
massive
erythrocytosis
•capillary obstruction
and death if
treatment is delayed
•Causes a milder
form of the disease
•Common to many
tropical regions
•rarely encountered

4. Life cycle of Malaria
1. Hepatic (Pre erythrocytic) stages
-parasites localize in liver
-patient is asymptomatic
2. Erythrocytic stages
-parasite invade RBCs
-patient develops fever cycle
3. Development of sexual forms
-occurs in Anopheles mosquitos

5. Life cycle of Malaria

6. Antimalarial Drugs
CLASSES DRUGS
1. 4-Aminoquinolines Chloroquine (CQ)
Amodiaquine (AQ)
Piperaquine
2. Quinoline-methanol Mefloquine
3. Cinchona alkaloid Quinine, Quinidine
4. Biguanide Proguanil (Chloroguanide)
5. Diaminopyrimidine Pyrimethamine
6. 8-Aminoquinoline Primaquine
Tafenoquine

7. Antimalarial Drugs
CLASSES DRUGS
7. Sulfonamides and sulfone Sulfadoxine
Sulfamethopyrazine
Dapsone
8. Antibiotics Tetracycline
Doxycycline
Clindamycin
9. Sesquiterpine lactones Artesunate
Artemether
Arteether
Arterolane
10. Amino alcholos Halofantrine
Lumefantrine
11. Naphthyridine Pyronaridine
12. Naphthoquinone Atovaquone

8. Drugs used in malaria
• Tissue schizontocides- drugs eliminating developing or
dormant liver forms
• Blood schizontocides- drugs acting on erythrocytic parasites
• Gametocides- drugs that kill sexual stages and prevent
transmission to mosquitoes

9. Forms of Antimalarial Drugs
• Clinically malarial infections can be controlled by the drugs
used in following ways:
1. Causal prophylaxis
2. Suppressive prophylaxis
3. Clinical cure
4. Radical cure
5. Gametocidal

10. 1. Causal prophylaxis
• Drugs prevent the maturation of or destroy the sporozoites
within the infected hepatic cell- thus prevent erythrocytic
invasion
• Primaquine – for all species of malaria but not used due to its
toxic potential
• Proguanil- primarily for P. falciparum and not effective against
P. vivax (weak activity), rapid development of resistance

11. 2. Suppressive prophylaxis
• Schizontocides inhibit erythrocyte phase and prevent the
rupture of the infected erythrocytes, lead to freedom from
rigors and pyrexia
• Includes quinine, chloroquine, proguanil, pyrimethamine,
artemicinin and tetracycline

12. 3. Clinical cure
• Erythrocytic schizontocides are used to terminate episodes of
malarial fever
• Fast acting high efficacy drugs:
o Chloroquine, quinine, mefloquine, halofantrine, artemicinin
o Used singly to treat malaria fever
o Faster acting, preferably used in falciparum malaria where
delayed treatment may lead to death even if parasites are
clear from blood
• Slow acting low efficacy drugs:
o Proguanil, pyrimethamine, sulfonamides, tetracyclines
o Used only in combination

13. 4. Radical cure
• Drug attack exoerythrocytic stage (hypnozoites) given with
clinical curative for the total eradication of the parasite from
the patient’s body
• Radical cure of the P. falciparum malaria can be achieved by
suppressives only
• For radical cure of P.vivax infection, primaquine and
proguanil are effective

14. 5. Gametocial
• Removal of male and female gametes of Plasmodia formed in
the patient’s blood
• It has no benefit for treated patient
• Primaquine and artemisinins are highly effective against
gametocytes of all species

15. Antimalarial drugs
CHLOROQUINE (CQ)
• Rapidly acting erythrocytic schizontocide against all species of
Plasmodia
• Drug of choice for treating acute attacks caused by sensitive
strains of P. vivax or P. falciparum
• Controls most clinical attack in 1-2days with disappearance of
parasite from peripheral blood in 1-3days
• No effect on exo- erythrocytic phase
• Neither prevent primary infection nor relapse in P. vivax and
P.ovale
• Drug of choice for use in pregnancy, prophylaxis

16. Chloroquine
Mechanism of action

17. Chloroquine
Mechanism of action
i. The parasite digests the host cell’s hemoglobin to obtain
essential amino acids
ii. The process releases large amounts of heme, which is toxic
to the parasite
iii. To protect itself the parasite ordinarily polymerizes the
heme to nontoxic hemozoin, which is sequestered in the
parasite’s food vacuole
iv. Cholroquine prevents the polymerization to hemozoin
v. The accumulation of heme results in lysis of both the
parasite and the red blood cell

18. Chloroquine
Pharmacokinetics
• Rapidly and completely absorbed from GI tract
• Substantial amount is deposited in erythrocytes, liver, spleen,
kidney, lung, melanin containing tissues and leukocytes
• Slow release from these sites helps in maintaining the
therapeutic plasma levels – when used for prophylaxis, it is
administered just once a week
• Also crosses the blood- brain barrier and traverses the
placenta
• Excreted predominantly in the urine

19. Chloroquine
Adverse effects
• CNS- mild headache, confusion, psychosis,
convulsion, impaired hearing
• Eye (with high dose)- loss of vision due to retinal
damage, reversible corneal damage
• GIT- Nausea, vomiting, anorexia, epigastric pain,
diarrhea( can be minimized by taking with meal)
• Skin- uncontrolled itching, urticaria, exfoliative
dermatitis
• Parenteral administration- Hypotension, cardiac
arrhythmias, cardiac depression

20. Chloroquine
Uses
• Extraintestinal amoebiasis
• Rheumatoid arthritis
• Discoid lupus erythematosus
• Lepra reaction
• Photogenic reactions
• Infectious mononucleosis

21. Chloroquine
Contraindications
• Patient with psoriasis, porphyria
• In dermatitis, liver damage, alcoholism, neurological, retinal
and hematological diseases

22. MEFLOQUINE (MQ)
• Fast acting erythrocytic(blood) schizontocide but slower than
CQ or quinine
• Effective against CQ-sensitive as well as resistant Plasmodia
• Efficacious suppressive prophylactic for multi-resistant P.
falciparum

23. Mefloquine
Mechanism of action
• Like CQ, it accumulates in infected RBCs, binds to heme and
this complex damages the parasite’s membrane
• However recent evidence suggests that the site of action of
MQ is in the parasitic cytosol rather than in the acidic vacuole

24. Mefloquine
Pharmacokinetics
• Prolonged absorption after oral ingestion
• It is highly plasma protein bound and concentrated in the
liver, lung and intestines
• Extensive metabolism occurs in liver and is primarily secreted
in bile
• It has a long half life (17days) due to its concentration in
various tissues and its continuous circulation through the
enterohepatic and enterogastric systems
• Its major excretory route is feces

25. Mefloquine
Adverse effects
• MQ is bitter in taste
• At high doses:
o Nausea, vomiting, diarrhea, abdominal pain, bradycardia
o Ataxia, hallucinations, depression
• MQ is safe in pregnancy
• Rare events of toxicity are seen
Contraindications
• In patients with anxiety, depression, psychosis, and in cardiac
conduction defects

26. Mefloquine
Drug interactions
• Cardiac arrests are possible if MQ is taken concurrently with
quinine or quinidine
Uses
• Effective for multidrug resistant P. falciparum
• However its use is restricted due to its toxicity, cost and long
half life

27. QUININE
• Quinine is a l-isomer of alkaloid obtained from cinchona bark
and quinidine (antiarrhythmic) is its d-isomer
• An effective erythrocytic schizontocide as suppressive and
used to prevent or terminate attacks of vivax, ovale, malariae,
sensitive falciparum
• Moderately effective against hepatic form (pre-
exoerythrocyte and gametocytes)

28. Quinine
Mechanism of action
• Like CQ it is a weak base, and acts by inhibiting polymerization
of heme to hemozoin
• Free heme or heme-quinine complex damages parasite’s
membrane and kills it
Pharmacokinetics
• Well absorbed from GI tract, even in patients with diarrhea
• Metabolized in liver and excreted in urine

29. Quinine
Adverse effects
• Cinchonism:
o Higher dose symptoms include nausea, vomiting, tinnitus,
vertigo, headache, mental confusion, difficulty in hearing and
visual defects, diarrhea, flushing
• Rapid i.v. injection:
o Hypotension and cardiac arrhythmias
• Can cause profused hypoglycemia

30. Adverse effects
• Pregnancy:
o Causes abortion in early pregnancy by stimulating
myometrium and premature labor by stimulating uterus
o Hypoglycaemia
Clinical uses
• Malarial attacks
o Uncomplicated resistant falciparum
o Complicated and severe malaria including cerebral malaria
• Is not highly active, adjunctive therapy with doxycycline,
tetracycline and clindamycin is needed

31. PROGUANIL (CHLOROGUANIDE)
• Slow acting erythrocytic schizontocide
• Cyclized in body to a triazine derivative(cycloguanil)
• Cycloguanil inhibits plasmodial dihydrofolate reductase
(DHFRase)
• Resistance developed due to mutational changes in the
plasmodial DHFRase enzyme

32. Proguanil
• Slow but adequate absorption from the gut
• Partly metabolized and excreted in urine
• Half life 16-20 hour ; noncumulative
Adverse effects
• Mild abdominal upset, vomiting
• Occasional stomatitis
• Haematuria, rashes and transient loss of hair
• Note : Safe during pregnancy

33. PYRIMETHAMINE
• Slow acting erythrocytic schizontocide
• Direct inhibitor of plasmodial dihydrofolate reductase
(DHFRase)
• Conversion of dihydrofolic acid to tetrafolic acid is inhibited
• High doses inhibits Toxoplasma gondii
• Resistance develops by mutation in DHFRase enzyme

34. Pyrimethamine
Adverse effects
• Occasional nausea and rashes
• Folate deficiency rare
• Megaloblastic anaemia and granulocytopenia with higher
dose
• Can be treated with folinic acid
• Combined with a sulfonamide (S/P) or dapsone for treatment
of falciparum malaria

35. SULFONAMIDE-PYRIMETHAMINE(S/P)
• Sulphadoxine is a sulfonamide thus competes with para–
amino benzoic acid – inhibits the formation of dihydropteric
acid
• Pyrimethamine inhibits DHFRase enzyme as a result of which
conversion of dihydrofolic acid to tetrahydrofolic acid is
blocked – thus inhibits DNA synthesis
• Effective blood schizontocide against Plasmodium
falciparum
• Treatment and prophylaxis of falciparum malaria
resistant to chloroquine

36. Sulfonamide-Pyrimethamine(S/P)
Adverse effects
• Mild GIT upset
• Megaloblastic anemia, bone marrow depletion
• Rashes, urticaria, serum sickness, drug fever
• Exfoliative dermatitis, Stevens Johnson syndrome
• Nephrotoxicity

37. PRIMAQUINE
• Poor erythrocytic schizontocide
• Has marked effect on primary and secondary hepatic phases
of malarial parasite
• Highly active against gametocytes and hypnozoites
Mechanism of action
• Intermediate act as oxidant that are responsible for the
schizontocial action

38. Primaquine
Pharmacokinetics
• Readily absorbed after oral absorption
• Oxidized in liver with a plasma half life of 3-6 hours
• Excreted in urine within 24 hour
• Not a cumulative drug

39. Primaquine
Adverse effects
• Abdominal pain, gastrointestinal upset, weakness or
uneasiness chest
• Leucopenia (high dose)
• Hemolysis
• Methaemoglobinaemia
• Tachypnoea
• Cyanosis

40. Primaquine
Contraindications
• Should not be given during pregnancy because fetus is
glucose-6-phosphate dehydrogenase ( G-6-PD) deficient
Clinical uses
• radical cure of relapsing malaria (P.ovale and P.vivax)
• single 45mg dose given with curative dose of chloroquine
to kill gametes (P. falciparum)

41. TETRACYCLINE AND DOXYCYCLINE
( Antibiotics)
• Used against chloroquine resistant malaria
• Kills erythrocytic stage of the malarial parasite
• Tetracycline is used for acute attack only
• Doxycycline is used for prophylaxis and acute attack
• For treating acute attack they are used in combination with
quinine
• Should not be given to children and pregnant women

42. CLINDAMYCIN
( Antibiotics)
• Active against the erythrocytic stage of the malaria parasite
• Liver stage and gametocytes are not affected
• Drug used adjunct to quinine to treat malaria caused by
chloroquine resistant Plasmodium falciparum
• Can be used in children and pregnant women

43. ARTEMISININ AND ITS DERIVATIVES:
• Active principle of plant Artemisia annua
• Sesquiterpene lactone endoperoxide
• It includes:
1. Artesunate
2. Artemether
3. Arteether
4. Arterolane

44. Mechanism of action

45. 1. ARTESUNATE
• Its sodium salt is water soluble and is administered by oral,
i.m. or i.v. route
• Rapidly converted to active metabolite dihydroartemisinin
(DHA)
• After repeated dosing, artesunate causes autoinduction of its
own metabolism by CYP2B6 and CYP3A4

46. 2. ARTEMETHER
• Lipid soluble and is administered orally or i.m.
• Absorption after oral or i.m. dosing is slower taking 2-6 hrs
• Undergoes substantial first pass metabolism and is converted
to DHA
• Extensive metabolism by CYP3A4 yields a variable half life of
3-4 hrs

47. 3. α/β ARTEETHER
• Available for i.m. administration only to adults for complicated
malaria
• Due to its longer elimination (t1/2=23hrs), it is recommended
in a three day schedule

48. ARTEMISININ
Adverse effects
• First degree A-V block
• Q-T prolongation
• Transient reticulopenia and leucopenia (rare)
• Bleeding, dark urine
• Headache, tinnitus, dizziness
• Abdominal pain, itching, nausea, vomiting

49. Artemisinin
Drug interaction
• Concurrent administration of artemisinins with drugs
prolonging Q-T like astemizole, antiarrhythmics, tricyclic
antidepressants and phenothiazines may increase the risk of
cardiac conduction

50. ARTEMISININ BASED COMBINATION
THERAPY (ACT)
• One of artemisinin compound in combination with another
effective erythrocytic schizontocide is used.
• Consideration must be made about t1/2 of companion drug to
maintain its effective concentration in the blood for at least
3-4 asexual cycles of the parasite.
• Kills >95% of the plasmodia

51. Advantages of ACT
• Rapid clinical and parasitological cure
• High cure rates(>95%) and low recrudescence rate
• Absence of parasite resistance
• Good tolerability profile
• Dosing schedule is simpler

52. 1. Artesunate-sulfadoxine +
pyrimethamine(AS-S/P)
• First line drug for uncomplicated falciparum malaria
• Not effective against multidrug-resitant strains which are non
responsive to S/P
• Fewer side effects than AS/MQ
2. Artesunate/mefloquine(AS/MQ)
• Highly effective and well tolerated in uncomplicated
falciparum malaria

53. 3.Artemether-lumefantrine(AS/LF)
• Clinical efficacy: 95-99%
• Must be administered with fatty food or milk to allow
absorption and ensure adequate blood level of AS/LF
• Quickly reduces parasite biomass, resolve symptoms, prevent
recrudescence, check gametocyte population

54. AS/LF
Adverse drug reaction
• Headache, dizziness, abdominal pain, arthralgia, myalgia,
pruritus and rashes
Drug interaction
• Not to be given with drugs metabolized by CYP2D6( e.g.
metoprolol) as lumefantrine inhibits isoenzyme CYP2D6
Contraindication
• during first trimester of pregnancy and lactation period

55. 4. Dihydroartemisinin(DHA)-
piperaquine
• Used in dose ratio of 8:1 for multidrug resistant Plasmodium
falciparum
• Good safety profile and even tolerated by children (>98%
response rate)
Adverse drug reaction
• Dizziness, rashes
• Vomiting and GI symptoms

56. 5. Artesunate-amodiaquine(AS/AQ)
• First line therapy of uncomplicated falciparum malaria
• To be taken twice daily for three day treatment
• Other recently developed ACT are:
6. Arterolane-piperaquine
• Acts rapidly at all stages of asexual schizogony of malarial
parasite including multidrug resistant P. falciparum
7. Artesunate-pyronaridine
• Under clinical trial

57. CEREBRAL MALARIA
• Most severe neurological complication of infection
with Plasmodium falciparum
• Aggregation of infected and non infected red cells and
plugging in capillary endothelium of brain due to secreted
proteins on red cell surface by late stage schizonts
• Enhanced by the pro-inflammatory status of the host and
virulence characteristics of the infecting parasite variant
• Manifested by confusion, coma and death due to anoxia,
ischaemia and haemorrhage

58. Drugs used in Cerebral malaria
• Quinine by slow intravenous infusion
• Artemisinin derivatives that produce a very rapid therapeutic
response and are effective against multi-drug resistant P.
falciparum are preferred
• Some of the drugs used as a combination therapy for cerebral
malaria are:
o Arteether with quinine
o Artemether with quinine

59. REFERENCES
1. Tripathi KD, Essentials of MEDICAL PHARMACOLOGY, Jaypee
Brothers Medical Publishers (P) Ltd, 7th edition, 2013.
2. Finkel Richard et all, Pharmacology, Lippincott’s Illustrated
Reviews, 4th edition.
3. The treatment of complicated and severe malaria, BRITISH
MEDICAL BULLETIN.