antimalarial drugs

1. Anti-malarial drugs
Dr. Lokendra Sharma,
Professor, Pharmacology
S.M.S. Medical college, Jaipur

2. Introduction
Malaria
• Caused by Plasmodium protozoa – 4 different species
• P. falciparum
• P. vivax
• P. malariae
• P. ovale
• Cause: the bite of an infected adult female anopheline mosquito
• Also transmitted by infected individuals via blood transfusion,
congenitally, or infected needles by drug abusers

3. Malarial Parasite (Plasmodium)
Two interdependent life cycles
• Sexual cycle: occurs in the mosquito
• Asexual cycle: occurs in the human
• Knowledge of the life cycles is essential in understanding antimalarial
drug treatment
• Drugs are effective only during the asexual cycle

4. Types of Malaria
Plasmodium falciparum
-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
Plasmodium vivax
Causes a milder form
of the disease
Plasmodium malariae
Common to many
tropical regions
Plasmodium ovale
Rarely encountered

6. Plasmodium Life Cycle
Asexual cycle: two phases
• Exoerythrocytic phase
• Occurs “outside” the erythrocyte
• Also known as the tissue phase
• Erythrocytic phase
• Occurs “inside” the erythrocyte
• Also known as the blood phase
Erythrocytes = RBCs

8. Antimalarial Drugs
• Attack the parasite during the asexual phase, when it is vulnerable
• Erythrocytic phase drugs: chloroquine, hydroxychloroquine,
quinine, mefloquine
• Primaquine: kills parasite in both phases
• May be used together for synergistic or additive killing power

9. Antimalarial Drugs
Classes Drugs
4-Aminoquinolines Chloroquine (CQ) ,Amodiaquine (AQ), Piperaquine
Quinoline-methanol Mefloquine
Cinchona alkaloid Quinine, Quinidine
Biguanide Proguanil (Chloroguanide)
Diaminopyrimidine Pyrimethamine
8-Aminoquinoline Primaquine ,Tafenoquine
Sulfonamides and sulfone Sulfadoxine , Sulfamethopyrazine, Dapsone
Antibiotics Tetracycline, Doxycycline, Clindamycin
Sesquiterpine lactones Artesunate, Artemether, Arteether, Arterolane
Amino alcohols Halofantrine ,Lumefantrine
Naphthyridine Pyronaridine
Naphthoquinone Atovaquone

10. Antimalarial drugs

13. 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

14. Antimalarial Therapy
Antimalarial therapy is given in following ways:
1. Causal prophylaxis: Destroy parasite in liver cells and prevent invasion
of erythrocytes
Drug : Primaquine, proguanil
2. Suppressive Prophylaxis: Suppress the erythrocytic phase and thus
attack of malarial fever can be used as prophylactics
Drug : Chloroquine, proguanil, mefloquine, doxycycline

15. Antimalarial Therapy
3.Clinical cure: erythrocytic schizonticides used to terminate an episode of
malarial fever
Fast acting high efficacy Chloroquine, quinine, mefloquine, atovaquone,
artemisinin
Slow acting low efficacy drugs Proguanil, pyrimethamine, sulfonamides,
tetracyclines
4.Radical curatives: Eradicate all forms of P.vivax & P.ovale from the body
Supressive drugs + hypnozoitocidal drugs For vivax: primaquine 15 mg
daily for 14 days

16. Antimalarial Therapy
5. Gametocidal: Destroy gametocytes and prevent transmission
Drugs :Primaquine, artemisinin – against all plasmodia Chloroquine,
quinine – P Vivax
Proguanil ,pyrimethamine – prevent development of sporozoites

17. Chloroquine
 Synthesized by Germans in 1934 ( resochin)
 d & l isomers, d isomer is less toxic
 Cl at position 7 confers maximal antimalarial efficacy
 Rapidly acting erythrocytic schizontocide against all species of
plasmodia

18. Chloroquine Mechanism of action

19. Chloroquine Pharmacological Actions
1. Antimalarial activity:
High against erythrocytic forms of P. vivax, P. ovale, P. malariae & sensitive strains of P.
falciparum
 Gametocytes of P. vivax, P. malariae, P. ovale
No activity against tissue schizonts
2. Other parasitic infections:
Giardiasis, taeniasis, hepatic amoebiasis
3.Other actions:
Anti-inflammatory, local irritant, , local anaesthetic , weak smooth muscle relaxant ,
antihistaminic, antiarrhythmatic

20. Chloroquine Pharmacokinetics
 Well absorbed, peak plasma concentration in 2-5 hrs , 60 % protein
bound
Concentrated in liver , spleen, kidney, lungs , leucocytes
 Selective accumulation in retina: occular toxicity
T1/2 = 3-10 days increases from few days to weeks 13

22. Contraindications of Chloroquine
 Psoriasis ,porphyria
Retinal and visual field abnormalities or myopathy
 Calcium , magnesium containing antacids

23. Chloroquine Adverse effect

24. Adverse Effects
*Q*Chloroquine is concentrated in melanin containing
tissues like retina and skin.
Short –term use “ as in malaria”
1) Mild headache and visual disturbances
2) Gastro-intestinal upsets; Nausea, Vomiting
3) Pruritis, urticaria “allergy”

25. Prolonged therapy “as in Rheumatoid arthritis”
1. Retinopathy, characterized by loss of central acuity,
macular pigmentation and retinal artery
constriction
2. Lichenoid skin eruption, bleaching of hair.
3. Weight loss
4. Hemolytic anemia in patients with G6PD
deficiency
Bolus injection ------ hypotension and dysrrhythmias

26. Bull eye
maculopathy ?

27. Chloroquine Uses
Malaria
 Extra intestinal amoebiasis
Rheumatoid arthritis
Discoid lupus erythematousus
Lepra reaction
Photogenic reaction

28. CQ Resistance:
• The mechanism of resistance involves a reduced accumulation of the
drug.
• Possible explanations include an energy-dependent efflux of
preaccumulated drug via parasite protein named PfCRT,
• the mutated form of which is able to reduce chloroquine
accumulation in the digestive vacuole of the pathogen
• or an increase in vacuolar pH such that the proton gradient
responsible for drug concentration is reduced.

29. Quinine
• l-isomer of alkaloid obtained from cinchona bark
• Quinidine (antiarrhythmic) - 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)

30. Mechanism of action ??
**Weak base, and acts by inhibiting
polymerization of heme to hemozoin.
•Free heme or heme-quinine complex damages
parasite’s membrane and kills it.

31. Adverse effects ??
Cinchonism:
• Higher dose symptoms include nausea,
vomiting, tinnitus, vertigo, headache,
mental confusion, difficulty in hearing and
visual defects, diarrhea, flushing
Rapid i.v. injection:
• Hypotension and cardiac arrhythmias
• Hypoglycemia

33. Uses
Malarial attacks
•Uncomplicated resistant falciparum
•Complicated and severe malaria
including cerebral malaria
•Adjunctive therapy with
doxycycline, tetracycline and
clindamycin needed.

34. 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

35. Mechanism of action
• Like CQ, it accumulates in infected RBCs, binds to heme and this
complex damages the parasite’s membrane.
• Recently it was suggested that the site of action of MQ is in the
parasitic cytosol rather than in the acidic vacuole.

36. Adverse effects
• Bitter taste
• At high doses:
• Nausea, vomiting, diarrhea, abdominal pain, bradycardia
• Ataxia, hallucinations, depression
• Safe in pregnancy
Contraindications
• In patients with anxiety, depression, psychosis, and in
cardiac conduction defects

37. Primaquine
• Poor erythrocytic schizontocide
• Marked effect on primary and secondary hepatic
phases of malarial parasite
• Highly active against gametocytes and hypnozoites

38. Primaquine

39. Primaquine Pharmacokintics

40. Adverse effects ??
• Abdominal pain, gastrointestinal upset, weakness or
uneasiness chest
• Leucopenia (high dose)
• *Q*Hemolysis
• *Q*Methaemoglobinaemia
• Tachypnoea
• Cyanosis

41. Contraindications
• Pregnancy -- fetus - glucose-6-phosphate
dehydrogenase (G-6-PD) deficient
Clinical uses
• *Q*Radical cure of relapsing malaria (P.ovale and
P.vivax)
• *Q*Single 45 mg dose given with curative dose of
chloroquine to kill gametes (P. falciparum)

42. Proguanil (Chloroguanide)
• Slow acting erythrocytic schizontocide
• Cyclized in body to a triazine derivative
(cycloguanil)
*Q*Inhibits plasmodial dihydrofolate reductase
(DHFRase)
• Resistance developed due to mutational changes in
the plasmodial DHFRase enzyme

43. Adverse effects
•Mild abdominal upset, vomiting
•Stomatitis
•*Q* Haematuria, rashes and transient loss
of hair
•Safe during pregnancy

44. Pyrimethamine
• Slow acting erythrocytic schizontocide.
*Q*Direct inhibitor of plasmodial dihydrofolate
reductase (DHFRase)
• High doses inhibits Toxoplasma gondii
• Resistance develops by mutation in DHFRase enzyme

45. Adverse effects
• Nausea and rashes
• Folate deficiency - rare
*Q*Megaloblastic anaemia and granulocytopenia with
higher dose
• Combined with a sulfonamide (S/P) or dapsone for
treatment of falciparum malaria

46. Sulfonamide-pyrimethamine (S/P)
• Sulphadoxine competes with para–amino benzoic
acid – inhibits the formation of dihydrofolic acid.
• Pyrimethamine inhibits DHFRase enzyme as a result
of which conversion of dihydrofolic acid to
tetrahydrofolic acid is blocked.
• Treatment and prophylaxis of falciparum malaria
resistant to chloroquine

47. Adverse effects??
• Mild GIT upset
• Megaloblastic anemia, bone marrow depletion
• Rashes, urticaria, serum sickness, drug fever
*Q*Exfoliative dermatitis, Stevens Johnson syndrome
• Nephrotoxicity

49. Artemisinin and Its Derivatives:
Active principle of plant Artemisia annua
It includes:
1. Artesunate
2. Artemether
3. Arteether
4. Arterolane
Artemisia annua

50. Mechanism of action

51. 1. Artesunate
• Sodium salt - water soluble and is administered by oral, i.m. or i.v.
route
• Rapidly converted to active metabolite dihydroartemisinin (DHA)
• Q*After repeated dosing, causes autoinduction of its own metabolism
by CYP2B6 and CYP3A4

52. 2. Artemether
• Lipid soluble and is administered orally or i.m.
• Absorption - slower taking 2-6 hrs
• Substantial first pass metabolism and is converted to
DHA

53. 3. α/β Arteether
•Available for i.m. administration only to adults
for complicated malaria
•Q*Longer elimination (t1/2=23hrs), so
recommended in a three day schedule

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

55. Artemisinin Based Combination Therapy
(ACT)
•*One of artemisinin compound in
combination with another effective
erythrocytic schizontocide.
•Kills >95% of the plasmodia

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

57. 1. Artesunate-sulfadoxine + pyrimethamine(AS-S/P)
• First line drug for uncomplicated falciparum malaria
• Fewer side effects than AS/MQ
2. Artesunate/mefloquine(AS/MQ)
• Highly effective and well tolerated in uncomplicated falciparum
malaria

58. 3.Artemether-lumefantrine(AS/LF)
• Clinical efficacy: 95-99%
• Q*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

59. 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
First trimester of pregnancy , lactation

60. 4. Dihydroartemisinin(DHA)-piperaquine
• Q* 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

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

63. Tetracycline and Doxycycline
• *Q*Used against chloroquine resistant malaria
• Kills erythrocytic stage of the malarial parasite
• For acute attack only
• Doxycycline - for prophylaxis and acute attack
• Q *Should not be given to children and pregnant
women

64. Clindamycin
• Q*Active against the erythrocytic stage of the malaria parasite
• Liver stage and gametocytes are not affected
Q*Drug used adjunct to quinine to treat malaria caused by chloroquine
resistant Plasmodium falciparum
• Q*Can be used in children and pregnant women

65. Treatment of Malaria

72. Future therapies

76. Self- Assessment

77. Why Chloroquine concentration is 1000 times more in food vacuole
of parasite?
1. Its protonation and ion trapping occures in the vacuole (because it
is acidophilic and food vacuoles have low PH)
2. Its active uptake by a parasite transporter.
3. Its binding to a specific receptor in the food vacuole.

78. What is the mechanism of Chloroquine
Resistance?
• Resistance occure due to increased expression of the human multidrug
resistance transporter(PfCRT) and
• it leads to efflux of preaccumulated drug and second mechanism is
that there is increase in vacuolar pH such that the proton gradient
responsible for drug concentration is reduced.

79. What is the mechanism of Antimalarial drug
induced hemolytic anaemia?
Primaquine produces hemolytic anaemia in G6PD deficiency
It oxidizes the glutathione=>no enough NADPH=> therefore thee is
reduced form of glutathion and RBCs lysis by oxidants.

80. Mechanism of bull eye ?
The possible mechanism is that the drugs bind to melanin in the retinal
pigment epithelium (RPE)
and affect photoreceptor metabolism.

81. Antimalarial Drug having slight neuromuscular blocking property
and Oxytoxic property?
Quinine is the drug having neuromuscular blocking property.
Therefore useful in some muscular disorders, especially nocturnal leg
cramps and myotonia congenita,
and also stimulates uterus contraction to deliver the fetus .

82. Mechanisms of non malarial uses of choloroquine?
Due to its anti inflammatory action, it can be used in rheumatoid
arthritis and SLE.
It also decreases the formation of peptide-MHC protein complexes
required
To stimulate CD4+ T cells and result in down-regulation of the immune
response against autoantigenic peptides.
In Amebiasis act by directely on the trophozoites of E. histolytica.

83. What happens when choloroquine gets accumulated in melanin
containing tissues like skin & retina?
It is accumulated in pigment epithelium and choroid in much higher
concn than in other eye tissues.
It leads to Retinopathy, characterized by loss of central visual
acuity,Lichenoid
Accumulation in skin leads to Pruritus,urticaria, eruption,bleaching of
hair.

84. Chloroquine is safe in pregnancy, but yet not given.Why?
Because its resistance is very common if the pregnant lady has
P.falciparum infection,
she will die from the infection due to resistance parasite not from the
drug.
So we must give another drug that is both safe and can attack all
parasites whether sensitive or resistance.

85. Why relapse do not occure in case of P.
falciparum &P.malariae?
In both the species Exo-erythrocytic stage is absent
and
therefore do not form hypnozooites.Therefore no
relapse

86. Why does only female anopheles mosquito
cause malaria?
Because female need blood from vertebral host to nourish eggs.

87. Role of Leucovorin in folate-deficient megaloblastic anemia
produced by pyrimethamine?
It is a DHFRase inhibitors which inhibit formation of folic acid in the
body.
Hence Leucovorin(folinic acid ) , reduced form of folic acid is gven in
a dose of 5-10 mg daily
prophylactically to all patients receiving pyrimethamine.

88. Urinary excretion of quinine (or
chloroquine) can be enhanced by?
Quinine, chloroquine, Quinidine are basic drugs and there excertion can
be enhanced by acidifying the urine by Ammonium chloride

89. Urinary excretion of quinine (or chloroquine) can be
enhanced by?
Quinine, chloroquine, Quinidine are basic drugs and theri
excertion can be enhanced by acidifying the urine by
Ammonium chloride

90. Thanks